PaCCSC Standard Operating Procedures FINAL_PaCCSC... · The PaCCSC Standard Operating Procedures (SOPs) have been adopted by the Cancer ... 5.1.1 SOP Development 2.2 2/18 ... 4 Short

February 2018

PaCCSC

Standard Operating Procedures

February 2018

The PaCCSC Standard Operating Procedures (SOPs) have been adopted by the Cancer Supportive Care Clinical Studies Collaborative (CSCCSC) and are applicable to all clinical research conducted by both entities.

February 2018

PaCCSC Standard Operating Procedures

Contents

ICH GCP reference

code Standard Operating Procedures (SOPs)

Current version

Revision date

Glossary 2.2 2/18

4.0 Investigator Roles and Responsibilities 2.2 2/18

4.1 Conflict of Interest 1.1 2/18

4.2 Confidentiality 1.3 2/18

4.2.4 Delegation of Duties 1.0 2/18

4.5 Protocol Deviations and Violations 1.2 2/18

4.5.3 File Notes 1.3 2/18

4.7.1 Randomisation and Allocation 2.2 2/18

4.7.2 Unblinding 2.3 2/18

4.8 Informed Consent 1.3 2/18

4.9.2 Source Data and Documentation 1.1 2/18

5.1.1 SOP Development 2.2 2/18

5.5.1 Electronic Data Handling 2.2 2/18

5.5.2 Electronic Data Transfer 2.2 2/18

5.5.5 Allocation of Participant ID Numbers 2.3 2/18

5.5.10 Data Ownership and Utilisation 1.3 2/18

5.61 Site Selection 1.3 2/18

5.7 Site initiation 1.0 2/18

5.14.1 Investigational Product Handling 2.2 2/18

February 2018

ICH GCP reference


Current version

Revision date

5.17 Adverse Event Reporting 2.2 2/18

5.17.1 Medical Monitor 1.1 2/18

5.18 Monitoring 2.2 2/18

5.18.1 Site Closure 1.1 2/18

5.18.2 Study Closure 1.2 2/18

5.19 Audit (deleted, as Audit are externally arranged and constituted, therefore PaCCSC SOP is over ridden)

2.1 2/18

5.23.1 KPI Compliance (deleted, as much information is now contained within other SOPs)

2.1 2/18

5.23.2 CRF Completion 2.2 2/18

6.0 Protocol Development 2.3 2/18

6.0.1 New Study Ideas/Proposals 1.3 2/18

6.0.2 Pilot Studies 1.1 2/18

6.5.1 Study Recruitment 2.2 2/18

6.5.2 Re-Screening 2.2 2/18

6.10 Version Tracking 2.2 2/18

6.12 Ethics Approval and Reporting 2.3 2/18

6.15 Authorship 3.3 2/18

6.15.1 Dissemination of Study Results 1.2 2/18

8.0 Essential Documents 2.2 2/18

8.1 Concurrent Medications (deleted, as concurrent medication is now protocol specific)

1.1 2/18

8.4.1 Archiving of Research/Project Materials 2.2 2/18

February 2018

ICH GCP reference


Current version

Revision date

8.4.2 Record Destruction 2.2 2/18

Guidance

1 File Note Completion

2 Documentation of Consent

4 Monitoring Guidelines for Site

5 Monitoring Guidelines for Monitors

6 Prescription of Study Drug

7 Unblind Contact Numbers

8 PID Number Sequencing

11 Data Usage Rules

12 Publication Planning

13 Pilot Feasibility Studies

14 Symptom Nodes and Studies Matrix

15 Recruitment Matrix

Templates

1 Staff Signatures and Delegation Log

2 Staff Meeting Log

3 Staff Training Log

4 Short CV

5 Site Feasibility Checklist

6 Site Risk Assessment Toolkit

7 Protocol Deviation and Violation Report Form

8 Protocol Violation Form

9 File Notes

10 Data Management Plan

11 Source Document Log

12 Patient Master Index

13 Data Closure Form

14 Adverse Event Form

February 2018

15 Corrective Action Sheet

16 Monitoring Log

17 Randomisation Registration Notification

18 Unblind Request Form

19 Unblind Report Notification

20 Trial Master File Index

21 Study Feasibility Checklist

24 Dissemination Plan

25 Data Requests Log

27 Pilot Study Progress Plan

28 Protocol template including pilot

29 Study Closure Checklist

29a Study Closure Checklist (each site)

29b Study Closure Checklist (all sites)

30 SOP Development Template

31 New Study Proposal

32 New Study Proposal Evaluation

33 Site Initiation One Day Program

34 Site Initiation Two Day Program

35 Study Monitoring Plan

36 Study Recruitment Plan

37 Recruitment Review

38 Recruitment Phone Calls

39 ISF Contents Page

* Not updated # Not completed Last Updated: 28/02/2018


Glossary V2.2 Page 1 of 20

Glossary

Version V2.2

Author/s B Fazekas, S Kochovska

Approved D Currow

Effective date 30/09/2017

Review date 30/09/2019

DO NOT USE THIS GLOSSARY IN PRINTED FORM WITHOUT FIRST CHECKING IT IS THE LATEST VERSION AS AVAILABLE FROM www.uts.edu.au/paccsc

PaCCSC SOP Feb 2018


Adverse Event (AE)

Any untoward or unexpected occurrence in a clinical investigation participant where the occurrence does not necessarily have a causal relationship with the study intervention.

An adverse event can be any unfavourable, unusual or unintended sign, response, symptom, or disease where the outcome was not expected and has potentially negative consequences for the participant or the caregiver. This can include events such as: An abnormal laboratory finding An abnormal or unusual emotional or cognitive response Distress caused by the burden of the intervention or by participation and can occur:

o During participation in a study, if absent at baselineo During participation in a study, if present at baseline, can appear to worseno After completion and exiting from a study but as a direct result of participation

Distress that occurs outside of clinical investigations in settings such as focus groups orquestionnaire responses

A response or reaction that was not anticipated

Adverse Drug Reaction (ADR) Drugs, or medicines, are routinely trialled prior to general release to establish therapeutic dose, safety and efficacy; or to test the drug outside of the registered use. During such a trial, any noxious and unintended response to the medication related to any dose is considered to be an ADR.

The phrase ‘responses to a medicinal product’ means that a causal relationship between that medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.

Any unintended response during a trial of a medication is regarded as an ADR or adverse event.

The reaction is considered unexpected where the nature or the severity is inconsistent with the product information or the investigators brochure.

AllocationThe assignment of an intervention to the participant enrolled in a PaCCSC study according to the randomisation table.

Allocation codeThe code that is assigned to an intervention to which a participant is allocated. The Allocation Code is the output from the randomisation process. This code (for e.g., A=intervention 1, B=intervention 2, and C=intervention 3) does not change throughout the study or from one site to another.

AmendmentA change to a document which results in a new version and submission to a Human Research Ethics Committee (HREC) for approval or to other regulatory documents such as TGA Clinical Trial Notifications or clinical trial registries. Examples of amendments include: changes to the intervention or intervention period major changes to study design (for e.g., introduction of a further intervention arm) changes to inclusion or exclusion criteria addition of tests or procedure

PaCCSC SOP Feb 2018


Amendment Types

Minor change (to document)The document is updated for typing, formatting, or noting of changes in non-essential siteinformation. The change(s) do not impact on the conduct of the study, HREC approval isnot required.

Significant change (to document)The document is updated to clarify specific sections, or where the changes are definedas significant modifications (for example, protocol amendments).

Major change (to document)The document is updated and the changes have an impact on the content.

Annual Research Forum (PaCCSC) An annual scientific meeting convened by PaCCSC and open to anybody with an interest in palliative care clinical trials. The aim of the forum is to share knowledge and build capacity within the palliative care research community. The forum also provides an opportunity for the presentation of current, planned or recently undertaken research studies in palliative care in Australia.

Assessment Codes – Levels of Deficiency As part of the monitoring process, an overall assessment is made of the site visit based on the levels of deficiencies recorded in the PaCCSC Corrective Actions Sheet subsequent to the review. These are: None

o Completeo Error free, or corrected appropriatelyo Filed and accessibleo Clear documentation of procedures

Minoro Source data does not support CRF entryo Late approvalso Poor filing and documentationo Difficult to follow errors

Majoro Approvals absento Protocol violationo Critical documents not availableo Errors not accounted for

Assessment Codes – Overall As part of the monitoring process, the overall assessment recorded in the PaCCSC Monitoring Report will be one of the following: Acceptable

o No deficiencieso Few minor deficiencieso Major deficiencies were identified and/or corrected prior to the monitoring visit, and

no further action is required

PaCCSC SOP Feb 2018


Acceptable needs follow-upo Any major deficiency identified during the monitoring visit, not identified or corrected

prior to the visito Multiple minor deficiencies identified

Unacceptableo Multiple major deficiencies identifiedo A single major blatant deficiency (total disregard for protocol)o Excessive number of minor deficiencies

Audit A systematic and independent examination of study related activities, documents and performance to determine whether the evaluated study related activities were: Conducted The data recorded, analysed and accurately reported according to:

o Protocolo Standard Operating Procedures (SOPs)o Good Clinical Practice (GCP)o Regulatory requirement(s)

Audit is the process of evaluating the study by individuals independent of the study, at the request of the Palliative Care Clinical Studies Collaborative (PaCCSC) Trials Management Committee (TMC).

This ensures compliance by the investigating sites.

Auditor An individual trained in research who has also undergone specific training on study audit related activities. The auditor uses their research experience and training in the auditing process to ensure that the work being conducted is of the highest quality and meets established guidelines. The auditors are independent of PaCCSC who, in conjunction with the PaCCSC National Manager, audit all PaCCSC investigating sites, including the PaCCSC Coordinating Centre. Their qualifications are verified and documented by the PaCCSC Coordinating Centre.

Auditee The study site(s) or individual(s) whose practices, processes and outcomes are being audited. All PaCCSC study sites are eligible for auditing, including the clinical teams and pharmacies where records regarding the study drugs are held. The PaCCSC Coordinating Centre, the organisation contracted to undertake the development of the randomisation schedules, and individual investigators may also be auditees.

Audit Report A written evaluation by the auditor of the results of the audit.

Australian New Zealand Clinical Trials Registry The Australian New Zealand Clinical Trials Registry (ANZCTR) is an online register of clinical trials being undertaken in Australia and New Zealand. The ANZCTR includes trials from the full spectrum of therapeutic areas of pharmaceuticals, surgical procedures, preventive measures, lifestyle, devices, treatment and rehabilitation strategies and complementary therapies. It has nationwide coverage of all clinical trials involving Australian researchers or Australian participants.

PaCCSC SOP Feb 2018


Australian Code for the Responsible Conduct of Research The Code developed jointly by the National Health and Medical Research Council, the Australian Research Council and Universities Australia to guide institutions and researchers in responsible research practices and to promote research integrity.

BlindingThe procedure in which one or more parties in the study are kept unaware of the treatment assignment (i.e., medicine 1 vs medicine 2, study medicine vs placebo) or the allocation code (i.e., A or B). All PaCCSC studies are double-blind, meaning that the participant, investigators, and other study staff are unaware of the treatment assignment. This process is also called “masking”. The allocation code and participant’s treatment assignment are known to the following: The Site Pharmacy at each site involved in administration of blinded medicine as the

study intervention. The site pharmacy holds the record of randomisation for that site. The Study Statistician who is responsible for reporting unblinded analyses to the PaCCSC

Data Safety Monitoring Committee (DSMC). The Central Randomisation Centre where the schedules for each site are developed.

Case Report Form (CRF) A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the PaCCSC Coordinating Centre for each participant. All events described within the study protocol are captured in the CRF.

Central Randomisation ServiceThe service where the allocation codes for the whole study, across all sites, are generated. The schedule for each site is prepared and sent to the PaCCSC Coordinating Centre for distribution to the individual site pharmacies.

Central RegistryThe location that holds the allocation codes for each participant in a study in the form of unblinding envelopes. This will vary from one study to the next, and is specified within the study protocol. This location varies between studies, and is specified within the study protocol. This location may include; the site pharmacy, a central pharmacy (a pharmacy nominated to hold the unblinding envelopes), the Lead Investigator, or delegate, or the Central Randomisation Service.

Clinical Trial Research Agreement (CTRA) A document between clinical trial research sponsors and institutions, formalising the roles, responsibilities and procedures in a research study. The CTRA outlines standard contractual obligations for all parties for the conduct of the study at that site. In addition, the CTRA contains detailed information about the budget, protocol and HREC submission documentation and any other site specific clauses that are agreed to by both parties.

The Clinical Trials Research Agreement templates used by PaCCSC were jointly developed by the Governments of New South Wales, Queensland, Victoria and South Australia; and Medicines Australia to promote fairness to all parties.

PaCCSC SOP Feb 2018


Clinical Trial Notification (CTN) Form The Clinical Trial Notification (CTN) form is a document signed by the trial site, the Human Research Ethics Committee (HREC), the hospital and the study sponsor prior to submitting to the Therapeutic Goods Administration (TGA). This submission results in the approval by the TGA to conduct the study at named site (on the CTN form). Recruitment does not commence at the site before this approval is obtained.

Clinical Trial/Study A research investigation in which people (participants) volunteer to test new treatments, interventions or tests as a means to prevent, detect, treat or manage various diseases or medical conditions. Participants are assigned to receive one or more interventions (or no interventions) so that researchers can evaluate the effects of the interventions on biomedical or health related outcomes (including clinical, pharmacological and pharmacodynamic outcomes). This helps determine if a new intervention works, if it is safe, and if it is better than interventions that are already available. The terms clinical trial and clinical study are synonymous.

Clinical Trial/Study Report A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in participants, in which clinical and statistical description, presentations, and analyses are fully integrated into a single report.

Concurrent Medication Any compound taken by a participant for medicinal purposes during the course of their participation in a clinical trial. Concurrent medications include (but are not limited to): Prescription medications Herbal / homeopathic medications Over-the-counter medications

Confidentiality Prevention of disclosure, to other than authorised individuals, of a sponsor’s proprietary information or a participant’s identity.

Conflict of interest A conflict of interest can arise when a person is faced with a decision that may be influenced by two or more competing interests. These may include: A financial conflict of interest, involving money, shares, stock or other matters A non-financial conflict of interest, related to personal matters A real conflict of interest actually exists A perceived conflict of interest may be thought to exist and may require confirmation by

others

Coordinating Centre (PaCCSC)The Coordinating Centre for PaCCSC is IMPACCT (Improving Palliative, Aged and Chronic Care through Clinical Research and Translation) at University of Technology Sydney. The PaCCSC National Manager and Project Officer at this site work closely with the Lead Investigator, all Principal Investigators, the local site staff, the Study Statistician, and the Central Randomisation Service to manage the operational study procedures.

PaCCSC SOP Feb 2018


Data Custodian Person or entity responsible for holding a dataset. Data custodians collect and hold research data on behalf of the Lead Investigator.

Data Management Plan A document that describes what data will be collected during a project and how it will be managed. A Data Management Plan addresses: Data ownership and responsibilities Legal rights Data securing and sustainability Access and reuse of data

Data Owner Data resulting from any activity of the Palliative Care Clinical Studies Collaborative is owned by University of Technology Sydney. Accountabilities for working with the data are assigned as follows: PaCCSC Chief Investigator – holds overall authority regarding the collection, storage,

access, security and primary and secondary use of all data created or held by PaCCSCfrom any activities.

PaCCSC National Manager/National Project Officer – act as delegates of the PaCCSCChief Investigator to ensure that the collection, storage, access, security and primary andsecondary use of all data created or held by PaCCSC from any activities is managedaccording to the relevant Standard Operating Procedures and risk managementstrategies engaged by PaCCSC.

Day 1 The day the intervention commences. Days are numbered according to the study schema (detailed in the study protocol).

Delivery Where the Investigational Product is given to the participant after dispensing by the pharmacy. For example, where the Investigational Product is delivered by a study team member to the participant for either self-administration or for administration via an infusion or other route.

Destruction A means by which records are destroyed, which renders them unable to be read, accessed or used at any time in the future.

Dispensing Where the Investigational Product is provided to the study participant by the pharmacist who prepared the drug. In most cases this will be a secondary process, as the Investigational Product may be dispensed to the study team member for delivery to the participant.

Essential documentsDocuments that: permit evaluation of the conduct of a trial and the quality of the data produced are usually audited and inspected by the regulatory authorities to demonstrate

compliance with GCP and all other regulatory requirements assist with trial management are those usually audited and monitored confirm the validity of the trial conduct and the integrity of the data collected

PaCCSC SOP Feb 2018


Exclusion Criteria A list of conditions that exclude a potential study participant from participating in the study. These conditions may include (but are not limited to): Age groups Disease groups or types Clinical events Family circumstances Previous medical history Concurrent medications Clinical investigation results (for e.g., blood tests)

File Notes Short documents that are used to explain discrepancies in data, deviations from protocol, and where sites have specific procedures that vary from the study protocol. Examples include (but are not limited to): Discrepancy between source documents and CRF entries Source data cannot be located A deviation between randomisation request and allocation is found

File notes serve to provide verification that data was collected and recorded according to established procedure.

Good Clinical Practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical studies that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of participants are protected. The GCP guideline was developed by International Conference on Harmonisation (ICH) in 1996.

Grading Where possible, the grade or severity of the event is established. The Common Terminology Criteria for Adverse Events (https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf) are recommended and the relevant sections are included in study protocols and CRFs.

Human Research Ethics Committees (HREC) An independent body (a review board or committee, institutional, regional, national or supranational), duly constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of participants involved in a trial and to provide public assurance of that protection by, among other things, reviewing and approving/providing acceptance opinion on the study protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the participants.

Impartial WitnessA person, who is independent of the study, who cannot be unfairly influenced by people involved with the study, who attends the informed consent process if the potential participant or their legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the potential participant. The witness signs the consent form to indicate that the consent process was followed, not to witness the signature

PaCCSC SOP Feb 2018


alone. Some PICFs contain a witness signature block, if no witness was required as part of the consent process, this block can be left blank.

Inclusion Criteria A list of requirements that potential study participants must meet in order to be eligible to participate in the study.

Informed Consent A process by which a participant voluntarily confirms his or her willingness to participate in a particular study, after having been informed of all aspects of the study that are relevant to their decision to participate. Informed consent is documented by means of a written, signed and dated consent form, unless otherwise dealt with in an institutional ethics approved protocol.

Where a potential participant lacks the capacity to give consent (as with PaCCSC studies using a proxy consent process), the person or appropriate statutory body exercising lawful authority for the potential participant should be provided with relevant information and decide whether he or she will participate.

Intellectual Property Intellectual property (IP) means any proprietary right which arises under, or is capable of being obtained under, legislation relating to copyright, patents, designs, circuit layouts or plant varieties, or which otherwise exists at law, including trade secrets, know-how and other confidential information and unregistered trademarks and tradenames.

Interim Analysis An analysis of the data before a trial has been completed, to obtain any evidence that the treatment might be harmful.

Interim Clinical Trial/Study Report A report of intermediate results and their evaluation based on analyses performed during the course of a trial.

InterventionThe investigational product, equipment or procedure being tested by the study protocol. The interventions vary according to each study protocol. Interventions in the PaCCSC studies may include investigational products prepared so that the active and inactive (or active and comparator) are identical in look, smell and taste.

Investigational Product (IP) A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical study, including: A product with a marketing authorisation when used or assembled (formulated or

packaged) in a way different from the approved form. A product with a marketing authorisation when used for an unapproved indication. A product with a marketing authorisation when used to gain further information about an

already approved use.

PaCCSC SOP Feb 2018


Journal Notes Journal notes provide rich additional data to explain data held within the Case Report Form (CRF). For example, when quality of life (QOL) is being measured and the participant has had a recent bereavement, a journal note can record the bereavement to explain why the QOL may record unexpected data. Journal notes do not replace study data recorded within the CRF.

Key Performance Indicators (KPIs) Key performance indicators are data elements that are monitored routinely and identify how effectively study sites and the study are meeting the mutually defined endpoints and timelines. Examples of KPIs include: Recruitment numbers

o Referral to screeningo Screening to eligibilityo Eligibility to consento Consent to completiono Screening to completiono Loss to follow-up

Actual versus projected recruitment estimateso Timeliness of data collections pointso Withdrawal rates and reasons for withdrawalo Data input error rateso Adverse event occurrences

Specific KPIs vary from study to study. Each study has particular issues related to recruitment, retention or follow-up which require specific focus. KPIs in the PaCCSC studies are similar between studies, mainly due to the target population of the studies (people receiving palliative care).

Lead Investigator The investigator who leads the study protocol development. The Lead Investigator in a multi-centre study also takes responsibility for the coordination of investigators at different sites.

Lead Site The PaCCSC study site which also assumes (under the direction of the Lead Site Principal Investigator) responsibility for the submission of the study to Human Research Ethics Committee (HREC), reporting, communications and filing regarding the overall ethical approval of the study. This may be studies occurring in a single state, or across multiple states. The Lead Site ensures that communications with HRECs are disseminated to the other study sites, and ensure that the appropriate documents, versions and files are kept.

Lead Site Principal Investigator The Principal Investigator who assumes the lead role at the site which takes on the lead site responsibilities with respect to HREC approval, reporting and communications.

Legally Acceptable RepresentativeAn individual or juridical or other body authorised under applicable law to consent, on behalf of a potential participant, to their participation in the study. This is also referred to ‘Third party consent’ or ‘Proxy consent’.

PaCCSC SOP Feb 2018


Monitoring The act of overseeing the progress of a clinical study, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP, and any applicable regulatory and legislative requirements.

Monitoring is a process internal to the clinical study, where the study management, investigators or other groups within the study can monitor their own progress, and ensure that the study complies with internal and external requirements.

This process differs from Audit which is a process conducted by personnel external to the study. Monitoring enables problems and deficiencies to be detected and corrected at an early point, to be dealt with prior to auditing and to assist sites’ ability to meet study requirements. Monitoring enables the study team to be confident about undergoing an external audit process.

Monitor An individual trained in research who has also undergone specific training on audit related activities. Within PaCCSC, the monitors include the site coordinators who, in conjunction with the PaCCSC National Project Officer, monitor other PaCCSC investigating sites.

The study monitor is thoroughly familiar with the study protocol, investigational product, consent processes and related study requirements.

The study monitor has completed training at the PaCCSC Coordinating Centre and is responsible for: Answering study related questions. Providing additional support to the site in order to successfully complete their recruitment

and regulatory obligations. On site data verification. Resolution of outstanding data queries. Documenting and reporting visits. Completing a monitoring log for filing at the study site

Monitoring Log A record of all monitoring visits for a specific study at a specific site. The monitoring log is held at each site for each study. It is signed by the monitor at the end of each monitoring visit.

Monitoring Report A written evaluation by the monitor of the outcomes from the monitoring visit.

Multi-centre Trial A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.

National Ethics Application Form (NEAF) This on-line form contains specific information regarding the conduct of the study other than outlined within the study protocol and is based on requirements by HREC on a national level.

PaCCSC SOP Feb 2018


Non-serious or Expected Adverse Event Expected adverse events are recorded and reported within the Palliative Care Clinical Studies Collaborative (PaCCSC) participating sites in accordance with the ICH GCP guidelines. These events are reported to the local HREC as part of the annual reporting requirements, and also aggregated by the Coordinating Centre.

In PaCCSC studies, non-serious or expected adverse events include expected death in the palliative care setting, where there is no indication that the intervention contributed to a hastened death, especially if the study requires participation or follow-up to death, or where death is expected as part of the disease trajectory, and where death is attributed to the underlying disease or sequelae.

Each HREC associated with PaCCSC sites have provided direction on the reporting of expected deaths of participants. These reporting timeframes are negotiated locally, and the outcomes are summarised in the table “Reporting Expected Deaths”.

ParticipantAn individual who participates in a study, either as a recipient of the investigational product(s) or as a control or who provides study data in some other capacity.

Participant Identification Number (PID number) A unique identifier assigned by the investigator to each participant in the study to protect their identity and used in lieu of the participant’s name. The PID number is usually a combination of the study code, site code and participant number. For example, 01/02/001.

Patient Master Index A list of all people who proceed to the screening stage (following pre-screening and obtaining consent) of recruitment, regardless of whether the participant goes on to be randomised. A Patient Master Index is maintained for each study at each site and is used for reporting on Key Performance Indicators for the site.

Permanent Record A record which has archival value and may be required to be permanently retained after the administrative value or 15 years has elapsed (whichever is sooner). Research record that are kept as a permanent record relate to: Legitimate and sustained allegations of misconduct that resulted in a formal inquiry and

appeals The preparation and submission of applications to conduct research The establishment of committees/boards/task force, and the records of the meetings Meeting the requirements of the National Health and Medical Research Council (NHMRC)

such as annual reports Evaluation of significant programmes Obtaining resources to undertake significant projects, which may include project plans,

grant proposals, funding applications Development of agency wide policies relating to research and ethical research conduct Master copies of final reports, published and unpublished produced by the researcher

which document the findings and outcomes

PaCCSC SOP Feb 2018


Pilot Study (also known as a Feasibility Study) A small scale, preliminary study conducted to test the feasibility of a large scale study. Elements tested in a pilot study include (but are not limited to): Practical application of the protocol Ability to recruit Effect size (statistical variability) Prediction of appropriate sample size for a larger study

Phase III (3) Study Clinical trials are conducted in a series of steps (phases). Each phase is designed to answer a separate research question. Phase III (3) clinical trials is when the intervention (Investigational Product) is given to a large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will enable the intervention to be used safely.

Pre-screening The evaluation of a set of characteristics assessed and recorded prior to screening that determine eligibility to participate in the study. Examples of pre-screening include chart review and discussion with clinical team. The pre-screening information assists the study team member to determine if the potential participant should proceed to screening.

Prescribing The written prescription (where applicable) detailing the Investigational Product for a specific participant.

Privacy Act The Privacy Act 1988 (Privacy Act) regulates how personal information is handled. The Privacy Act defines personal information as:

“[…] information or an opinion, whether true or not, and whether recorded in a material form or not, about an identified individual, or an individual who is reasonably identifiable.”

Common examples are an individual’s name, signature, address, telephone number, date of birth, medical records, bank account details and commentary or opinion about a person.

The Privacy Act includes thirteen Australian Privacy Principles (APPs), which apply to some private sector organisations, as well as most Australian and Norfolk Island Government agencies. These are collectively referred to as ‘APP entities’. The Privacy Act also regulates the privacy component of the consumer credit reporting system, tax file numbers, and health and medical research.

Privacy Act - Health and Medical Research In certain circumstance, the Privacy Act permits the handling of health information and personal information for health and medical research purposes, where it is impracticable for researchers to obtain individuals' consent. This recognises: The need to protect health information from unexpected uses beyond individual

healthcare The important role of health and medical research in advancing public health

PaCCSC SOP Feb 2018


To promote these ends, the Privacy Commissioner has approved two sets of legally binding guidelines, issued by the National Health and Medical Research Council (NHMRC). Researchers must follow these guidelines when handling health information for research purposes without individuals' consent. The guidelines also assist Human Research Ethics Committees (HRECs) in deciding whether to approve research applications. The guidelines are produced under sections 95 and 95A of the Privacy Act. The guidelines are: Guidelines under Section 95 of the Privacy Act 1988, which set out procedures that

HRECs and researchers must follow when personal information is disclosed from aCommonwealth agency for medical research purposes.

Guidelines under Section 95A of the Privacy Act 1988, which provide a framework forHRECs to assess proposals to handle health information held by organisations for healthresearch (without individuals' consent). They ensure that the public interest in theresearch activities substantially outweighs the public interest in the protection of privacy.

Principal Investigator The person responsible for the conduct of a clinical study at a study site. If a study is conducted by a team of individuals at a study site, the Principal Investigator is the responsible leader of the team. The Principal Investigator is qualified by education, training and experience to assume responsibility for the proper conduct of the study, is thoroughly familiar with the use of the investigational product and is aware of (and complies with) the applicable regulatory requirements. The qualifications of the Principal Investigator are appropriate to their role in the study.

Protocol A document that describes the objective(s), design, methodology, statistical considerations, and organisation of a study. The protocol also includes the background and rationale for the study (these can be provided in other protocol referenced documents). Consistent with the ICH GCP Guidelines, the term protocol refers to protocol and protocol amendments.

Protocol Amendment A written description of a change(s) to, or a formal clarification of a protocol. An amendment results in a new version. Changes to an approved protocol are required to be approved by the Human Research Ethics Committee before the changes can be implemented. Examples of changes include (but are not limited to): Changes to the intervention or intervention period Significant changes to study design (for e.g., introduction of a further intervention arm) Changes to inclusion or exclusion criteria Addition of tests or procedure

RandomisationThe process of allocating participants to one treatment group or the other using an element of chance to determine the assignment. Randomisation is intended to reduce the chance of systematic bias that can be encountered when investigators, study staff, or study participants make decisions regarding which intervention is received by which participant. In most cases, blocks and standard random number tables are used to generate the allocation codes. An independent research group not associated with PaCCSC have been contracted to undertake the randomisation for PaCCSC studies.

PaCCSC SOP Feb 2018


Receipt Where the prescribed Investigational Product has been handed over to another person. In most cases this will be to the study team member for transport and delivery to the participant.

Record holder The person (nominated by the Lead Investigator) responsible for supervising the archiving, storage and destruction record of the study materials.

Recruitment The process where people are identified, screened and contacted for the study, or identified, screened and determined not to be eligible.

Reporting Expected DeathsEach study protocol states the conditions and events that are excluded from the definition of an Adverse Event (AE) or Serious Adverse Event (SAE) and those which constitute a non-serious or Expected Adverse Event.

Relatedness of Adverse Event to an InterventionThe site investigator includes the best estimate of the relationship between an intervention and an adverse event (AE) in the report. A guide to grading the degree of certainty about such a relationship is available at https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. A summary of this grading:

Unrelated Where the AE is clearly not related. Unlikely Where the AE does not have a clear relationship to the intervention. Possible Where the AE follows a known pattern of response. Probable Where the AE reduces or ceases with withdrawal of the intervention or has

a close temporal relationship to the intervention’s introduction and is clinically plausible.

Definite Where the AE ceased with withdrawal of the intervention or is an incontrovertible temporal relationship to the introduction of the intervention.

Research Data The information, records, files or other elements that form the basis of the main inferences, observations, findings, conclusions, outcomes or elements of a research project or publication, irrespective of the form in which it exists (for e.g., in print, electronic, physical, multi-media or other forms).

Data are pieces of information, for example: What people say in interviews, focus groups, questionnaires, personal histories and

biographies Study protocols, or part thereof; study instruments; any type of data collection form such

as study diaries Analysis of existing information (clinical, social, observational or other) Information derived from human tissue such as blood, bone, muscle and urine

Data may be collected, stored or disclosed in three mutually exclusive forms: Individually identifiable data Re-identifiable data Non-identifiable data

PaCCSC SOP Feb 2018


Research data management system Research Data Management Systems have been developed to support research work conducted through IMPACCT by providing access to a tool that: Enables the online design of data collection forms and questionnaires Allows for web-based and email-based form completion Enables data entry from multiple sites with a single coordinating site Provides for basic reporting of results with features such as percentages, graphs, and

tables Allows export of data to other programs such as Excel, Access or SPSS

The password protected system is used by PaCCSC for entry of all participant data collected during the course of each study.

Return Where all used and unused Investigational Product and the associated records are returned to the pharmacy of origin after each participant has ceased their participation in the study.

Scientific Committee (PaCCSC) The Scientific Committee is a group of individuals experienced in multi-site research, policy development or evidence based practice, with at least three members with expertise in the conduct of clinical studies, preferably within palliative care or multi-site in nature.

The role of the Scientific Committee is to: Advise the PaCCSC Executive Group, PaCCSC Management Advisory Board, PaCCSC

Trial Management Committee, Lead Investigator and study sites on scientific matters thatmay arise

Assist the Management Advisory Board with the recommendations on the developmentof new study proposals

Review KPIs before prior to recruitment commencement Indicate, as required, an internal audit of any site or study and if necessary, act upon the

findings of audit

Screening Screening is the collection of information that is additional to the clinical care from (or about) a potential participant. The information informs the potential participant’s eligibility for the study. Screening data may include assessments for cognition, functional ability, taking blood samples, requesting medication history, etc.. Screening information is collected following obtained consent.

Screen Failure Where the person has provided consent after being fully informed of the study, and has been found ineligible, either because the inclusion criteria have not been met or an exclusion criteria was met.

Serious Adverse Event (SAE) Any untoward medical occurrence that: Results in death (requiring rapid reporting on the day of discovery)

o Results in attempted suicide (requiring rapid reporting on the day of discovery)o Is life-threatening (requiring rapid reporting on the day of discovery)o Requires a change in planned clinical management

PaCCSC SOP Feb 2018


o Requires inpatient hospitalisation or prolongation of existing hospitalisationo Results in persistent or significant disability/incapacityo requires ongoing medical or professional attentiono Are judged to represent significant hazard

In certain circumstances, serious adverse events do not require reporting: Planned surgery or medical intervention that was known at the start of the study

(screening) for a pre-existing condition. By contrast, if this elective admission is extendeddue to some unexpected occurrence, this admission becomes a serious adverse eventand should be reported.

Overdose with no associated adverse reaction.

Site PharmacyThe pharmacy that is contracted to undertake the randomisation at the study site, maintains the allocation logs, and supplies the study medicines. The Site Pharmacy collates and records the allocation codes for each study site and may provide out-of-hours access to the allocation codes (if acting as the Central Registry). The Site Pharmacy maintains a register of people in the study, and the allocation code for that site for the duration of the study.

Site Specific Assessment (SSA) The Site Specific Assessment is a final component of the National Ethics Application Form (NEAF) where each site is required to address specific questions regarding the local approval, resources and implementation factors that may impact on the conduct of the study at that site. Each Australian state has different requirements; the SSA may be an ‘add-on’ to the NEAF, a separate ‘module’ to be submitted with the NEAF or a series of other locally developed documents. The SSA is assessed by the local research governance office prior to approval for local recruitment.

Source Documents Original documents, data and records such as hospital records, clinical file charts, laboratory notes, diaries, checklists, dispensing records etc. These documents allow for reconstruction and evaluation of the study. Data held within source documents are the first record of clinical observations. Examples include: Pathology reports to confirm blood results used at eligibility screening and throughout the

study Clinical records charting patient clinical assessment, used to monitor patient eligibility or

progress Dangerous Drug Accountability signature sheets to show correct checking and

dispensing procedures Case Report Forms (CRF) where participant vital signs are recorded during a consultation

(this is particularly relevant if this forms the only record of the vital signs and is not atranscription of vital signs recorded elsewhere)

Quality of life (QOL) forms completed as part of the study measures, and where thisrecording is the original or only recording of the QOL at that time

Other notations or records that form the data for the study

PaCCSC SOP Feb 2018


Source documents may also include the data recorded within CRFs (or contained on audiotapes) if these data form clinical data from which analysis is conducted, are not contained within other source documents and are specified within the study protocol. For example, if clinical observations are recorded within the CRF and used as study data, this is then source data.

Standard Operating Procedure (SOP) Detailed, written instructions to achieve uniformity of the performance of a specific function.

State Records Individual Australian states and territories have hospital, file archive and destruction procedures and facilities. ‘State Records’ refers to such a facility.

Stopping Rule The criteria, defined in the trial protocol, for stopping a trial prior to completion due to evidence that continuing the trial may put the participants at risk or that there is already sufficient evidence of the efficacy of treatment.

Storage Where the Investigational Product is stored on a temporary basis due to a delay (either planned or unplanned) in the transport from the receipt to delivery.

Stratum and StrataA “stratum” designates the study group within which an individual participant is categorised (the pleural term for stratum is “strata”). This may be determined by demographic grouping (age group, gender, diagnosis), disease stage or other parameter where the investigators decide that stratification is required. Not all studies require stratification at the point of randomisation.

Study SiteThe local site for participant enrolment and study conduct. Each site has a Principal Investigator, local site study staff, and an associated site pharmacy.

Study StatisticianThe lead statistician for the study. The Study Statistician is responsible for all study analyses, and final study reporting. The Study Statistician is also responsible for reporting unblinded data to the PaCCSC Data Safety Management Board (DSMB). The Study Statistician may vary between studies.

Sub-Investigator Any individual member of the clinical study team designated and supervised by the Principal Investigator at a study site to perform critical study-related procedures and/or to make specific study-related decisions.

Temporary Record A record that does not have archival value, and can be destroyed when the retention period has elapsed. In most cases this is 15 years.

PaCCSC SOP Feb 2018


Toxicity The degree to which a substance can harm humans or animals. Toxicity can be acute, sub-chronic, or chronic: Acute toxicity involves harmful effects in an organism through a single or short-term

exposure Sub-chronic toxicity is the ability of a toxic substance to cause effects for more than one

year but less than the lifetime of the exposed organism Chronic toxicity is the ability of a substance or mixture of substances to cause harmful

effects over an extended period, usually upon repeated or continuous exposure,sometimes lasting for the entire life of the exposed organism

Transporting Where specific Investigational Product is moved from one location to another. For example, from the pharmacy to the participant in their own home.

Trial Management Committee (PaCCSC) The Trial Management Committee has overall responsibility for the development, review and oversight issues specific to each of the studies including applications for external funding for individual studies, recruitment, outcomes and study milestones. Each study has a Trial Management Committee and members include the Lead Investigator, Principal Investigators (from each site) and site coordinators (if available).

UnblindingThe process by which the allocation code is broken, revealing the intervention allocated to the participant. The usual reason for unblinding in a study context is that a participant has encountered an urgent medical problem necessitating the need for the clinician to know his/her intervention allocation. People are not unblinded at the end of their participation in the study.

Unblinding EnvelopesA series of envelopes, each labelled with the randomisation number containing the Allocation Code for each individual participant. These envelopes are sealed and provided by the Central Randomisation Service. They are only opened if emergency unblinding is required.

Version The tracking system whereby different versions of the same document are used and identified. PaCCSC uses a specific and standardised version control. Versions are referred to with Vx.x.x with these being defined as:

Vx.x.x – a minor modification or amendment Example: V3.2.1 becomes V3.2.2 when a minor amendment is made Vx.x.x – a significant modification or amendment Example: V3.2.1 becomes V3.3.1 when a significant amendment is made Vx.x.x – a major modification or amendment Example: V3.2.1 becomes V4.1.1 when a major amendment is made

Wellbeing (of study participants) The physical and mental integrity of the participants participating in a clinical research study. The study protocol should specify that participants have had the benefit and burden of participation in the study clearly identified and dealt with in a way that complies with the National Statement on Ethical Conduct in Human Research (2007) (Updated May 2015).

PaCCSC SOP Feb 2018


History

Version Date Author Reason

1.1 5/03/2008 B Fazekas Initial development

1.2 12/09/2010 B Fazekas Periodic review

2.0 3/02/2011 B Fazekas Update resulting from MAB feedback on SOPs

2.1 9/06/2015 C Hope Periodic review (update following periodic review of all PaCCSC SOPs)

2.2 28/02/2018 B Fazekas, S Kochovska

Periodic review Publication of the ICH GCP E6 (R2)

Approval

Version Approval Name Approval Signature

2.2 David Currow


4.0 V2.2 Page 1 of 6

4.0 Investigator Responsibilities

Version V2.2


Approved D Currow



DO NOT USE THIS SOP IN PRINTED FORM WITHOUT FIRST CHECKING IT IS THE LATEST VERSION AS AVAILABLE FROM www.uts.edu.au/paccsc

http://www.uts.edu.au/paccsc

PaCCSC SOP Feb 2018

4.0 V2.2 Page 2 of 6

Introduction / Background

Good Clinical Practice defines the requirements to ensure that all patients on clinical trials are safe and that their rights are protected. The care and safety of the patient is the responsibility of the Principal Investigator and any clinical sub- or co-investigator as delegated. The Principal Investigator (and duly delegated sub- or co-investigator) also has responsibility for the overall management of the clinical trial.

While trial-related tasks and duties can be delegated to other appropriately qualified and trained staff, the responsibility for the clinical trial cannot be delegated and remains with the Principal Investigator. The Principal Investigator is responsible for supervising any individual or party to whom they have delegated study tasks/duties.

Objective

This SOP defines the Principal Investigator’ responsibilities and provides instruction when performing clinical study(ies) under applicable regulatory requirements. It is applicable to all phases of clinical investigation of medicinal products.

Scope

This SOP applies to all staff involved in clinical studies conducted by PaCCSC irrespective of individual organisational employment, role or position.

Ownership and Responsibility

The Principal Investigator and/or other designee(s) as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties).

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4.0 V2.2 Page 3 of 6

Procedure The Principal Investigator:

Should ensure that clinical studies are carried out according to International Conference on Harmonisation of Good Clinical Practice (ICH GCP) guidelines, regulatory authorities requirements and any other local requirements.

Should have an understanding that when a trial is sponsored by an agency/pharmaceutical company, they may be requested to follow their procedures in order to comply with company obligations. Agreement between all parties should be discussed before initiating the trial (refer Clinical Trial Research Agreement (CTRA)).

Should inform the participant's primary physician about the participant's participation in the trial if the participant has a primary physician and if the participant agrees to the primary physician being informed.

Must declare any conflicts of interest, payments etc. from other parties.

Must ensure that the financial aspects of a trial are documented in an agreement between the Sponsor and the investigator/institution.

Must maintain a list of any delegated duties with respect to the trial, and the persons and qualifications of those persons to whom the duties are assigned.

Must ensure that they provide appropriate supervision, oversight and management to all staff to whom specific trial related duties have been delegated (refer SOP 4.2.4 Delegation of Duties).

Must ensure they provide regular, appropriate and timely training to all staff. All training should be clearly documented and filed in the Investigator Site File (refer SOP 8.0 Essential Documents).

Should be able to demonstrate that adequate participant recruitment is likely to be possible, with necessary time available to conduct the study to Good Clinical Practice (GCP) requirements, and with adequate facilities and trial staff.

Must provide medical care to trial participants that is necessary as a result of any adverse events experienced during or following the trial that are related to the trial, and must be responsible for all trial-related medical decisions.

Must possess, prior to trial commencement, a favourable HREC endorsement of trial protocol, patient information and consent documents, recruitment procedures, consent form updates and any other information given to participants (refer SOP 6.12 Ethical Approval, Review and Reporting).

Must present all trial related documents to the HREC for review including the Investigator’s Brochure as well as updates.

Must ensure that the trial is conducted according to the approved protocol.

Must document any deviation from the protocol for later review (refer SOP 4.5 Protocol Violation; SOP 4.5.3 File Notes).

Must ensure that no deviation from the protocol occurs without HREC endorsement, unless it is required to prevent imminent harm to participants.

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4.0 V2.2 Page 4 of 6

Must maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site’s trial participants. Source data should be attributable, legible, contemporaneous, original, accurate and complete (refer SOP 4.9.2 Source Data and Documentation).

Must maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (refer SOP 8.0 Essential Documents).

Must ensure accountability of the investigational product at the trial site(s) (refer SOP 5.14.1 Investigational Product Handling).

Must ensure that participants have made fully informed, written consent, with all trial procedures and risks adequately explained and that the principles and essential elements of Informed consent are up held and included in the information document (refer SOP 4.8 Informed Consent).

Note: Although a participant is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the participant's rights.

Should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator's Brochure, in the product information and in other information sources provided by the sponsor.

Should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions.

Should submit written summaries of the trial status to the HREC annually, or more frequently, if requested by the HREC.

Should provide written reports to the sponsor, the HREC and, where applicable, the institution promptly on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

Should comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the HREC.

Should promptly inform the trial participants if the trial is prematurely terminated or suspended for any reason as well as the institution and should assure appropriate therapy and follow-up for the participants, and where required by the applicable regulatory requirement(s), inform the regulatory authority(ies).

Note: If the investigator terminates or suspends a trial without prior agreement of the sponsor, they should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the HREC, and provide the sponsor and the HREC a detailed written explanation of the termination or suspension. Should, upon completion of the trial, where applicable, inform the institution; the

investigator/institution should provide the HREC with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.

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4.0 V2.2 Page 5 of 6

Other related SOPs 4.2.4 Delegation of Duties 4.5 Protocol Violation 4.5.3 File Notes 4.8 Informed Consent 4.9.2 Source Data and Documentation 5.14.1 Investigational Product Handling 6.12 Ethical Approval, Review and Reporting 8.0 Essential Documents Other related documents Clinical Trial Research Agreement (CTRA) References International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). November 2016 (accessed 23/10/2017) https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf Praxis Australia

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf

PaCCSC SOP Feb 2018

4.0 V2.2 Page 6 of 6

History


1.1 10/01/2006 Contributing authors

New procedure

1.2 25/02/2007 S Whicker Administrative update

1.3 11/07/2007 B Fazekas Update prior to MAB review

1.4 13/08/2007 B Fazekas Changes ratified by MAB

1.5 16/10/2007 B Fazekas Update after David Currow review

1.6 7/06/2010 B Fazekas, T Shelby-James

Periodic review

2.0 20/01/2011 B Fazekas,

T Shelby-James Changes ratified by MAB

2.1 13/05/2015 C Hope Periodic review

2.2 28/02/2018 B Fazekas,

S Kochovska

Periodic review

Publication of the ICH GCP E6 (R2)

Approval


2.2 David Currow


4.1 V1.1 Page 1 of 6

4.1 Conflict of Interest

Version V1.1


Approved D Currow




PaCCSC SOP Feb 2018

4.1 V1.1 Page 2 of 6


A conflict of interest exists where there is a divergence between the individual interests of a person and their professional responsibilities such that an independent observer might reasonably conclude that the professional actions of that person are unduly influenced by their own interests (Australian Code for the Responsible Conduct of Research 2007).

A conflict of interest in the context of research exists where a person’s individual interests or responsibilities have the potential to influence the carrying out of his or her institutional role or professional obligations in research; or an institution’s interests or responsibilities have the potential to influence the carrying out of its research obligations (National Health and Medical Research Council 2007).

The perception that a conflict of interest exists in a research project can be as serious as an actual conflict of interest.

The Australian Code for the Responsible Conduct of Research (2007) requires research institutions to have policies that manage any conflicts of interest that may be apparent or that may emerge during the research project.

Objective

This SOP describes the process for managing actual, potential and perceived conflicts of interest that occur in PaCCSC studies.

Scope



All: recruiting site-based staff staff at the Coordinating Centre, and individual members of the various governance committees of PaCCSC

are responsible for disclosing any actual, potential or perceived conflicts of interest prior to the commencement of a committee meeting, being provided with new study information, the commencement of a study at the recruiting site and/or immediately as they emerge during the course of the usual business of the Collaborative.

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4.1 V1.1 Page 3 of 6

Procedure

1. Disclosure

Committee members will be asked to disclose any actual, potential or perceived conflicts of interest to the meeting Chair at the beginning of the meeting. All meetings of committees include a standard agenda item pertaining to conflict of interest and this is captured in the minutes.

Study site team members disclose any actual, potential or perceived conflicts of interest to the Principal Investigator at their site.

PaCCSC Coordinating Centre staff and non-site base staff (e.g. statisticians) disclose any actual, potential or perceived conflicts of interest to the Lead Investigator (or delegate, for e.g., the PaCCSC National Manager).

Full public disclosure of all details regarding the conflict of interest is strongly encouraged. If the individual is not willing to disclose full details publicly, an opportunity to provide details to the Lead Investigator (or delegate) is offered. If the individual is not willing to disclose full details to the Lead Investigator (or delegate), the individual is withdrawn from any involvement in the meeting/study.

Study team members must also comply with individual institutional (e.g. local hospital) policies and procedures regarding disclosure of actual, potential or perceived conflicts of interest.

2. Management of Conflict of Interest

Conflicts of interest are managed by an appropriate governance committee. The Lead Investigator (or delegate) refers the conflict of interest to the governance committee best placed to address it, such as the PaCCSC Trial Management Committee, the Study Sub-committee, the Scientific Committee or the Management Advisory Board, depending on the nature of the conflict of interest and the individual with the conflict of interest.

The committee assigned to address the conflict of interest (herein referred to as ‘the Committee’) develops an action plan. Actions will vary according to the nature of the conflict of interest and the potential impact on the research.

Conflicts of interest are tabled at a Committee meeting. If it is an emergent issue, a meeting is convened as soon as it is practical.

The conflict of interest is presented by the Lead Investigator of PaCCSC or the Principal Investigator of the site, whichever is appropriate, regarding where the conflict of interest has been identified.

The individual with the conflict of interest may contribute to the discussions of the Committee but the individual is not involved in the decision making process around the management of the conflict of interest.

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4.1 V1.1 Page 4 of 6

The Committee: o May decide that the declared conflict of interest does not exist. In such

circumstances, the decision is clearly documented in the meeting minutes that are distributed to all stakeholders.

o Evaluates the risk of potential impact on the integrity of the research, based on the following: • the nature of the interest • how closely the interest is related to the research • the degree to which the interest may affect the research and/or participants

o May seek additional information or advice from other parties (for e.g., the PaCCSC Data Monitoring and Safety Committee or legal counsel provided by University of Technology Sydney).

A management plan, consistent with the evaluated risk (as above), for the conflict of interest is agreed by the Committee. The management plan may include (but is not limited to): o Withdrawal of the individual from all research related activities o Withdrawal of the individual from recruitment of participants o Withdrawal of the individual from all financial decisions and decisions that may

impact the research project budget o Withdrawal of the individual from the analysis of data and study results o Education of research staff o Disclosure of the conflict of interest to study participants.

In exceptional circumstances (where the risk to the integrity of the research or risk of harm to participants is high), the management plan may include (but is not limited to): o Ceasing the research at the study site where the conflict of interest exists o Modification of the research protocol.

The conflict of interest and management plan is documented and kept at the study site where the conflict of interest exists. A copy is also held by the Coordinating Centre.

If appropriate, the relevant Human Research Ethics Committees (HRECs) are informed of the conflict of interest and management plan. If an HREC requires additional actions in relation to the conflict of interest, the management plan is updated by the PaCCSC Coordinating Centre and redistributed to the relevant site.

The decision regarding the management of the conflict of interest by the Committee (subject to HREC review) is final.

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4.1 V1.1 Page 5 of 6

Other related SOPs

N/A

Other related documents

N/A

References

Australian Code for the Responsible Conduct of Research 2007 (accessed 20/10/2017) https://www.nhmrc.gov.au/guidelines-publications/r39

National Statement on Ethical Conduct in Human Research (2007) - Updated March 2014 - (accessed 19/10/2017) http://www.nhmrc.gov.au/guidelines-publications/e72

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4.1 V1.1 Page 6 of 6

History


1.0 17/08/2015 C Hope New procedure



Approval


1.1 David Currow


4.2 V1.3 Page 1 of 6

4.2 Confidentiality

Version V1.3


Approved D Currow




PaCCSC SOP Feb 2018

4.2 V1.3 Page 2 of 6


PaCCSC is committed to maintaining confidentiality of all its research data and related materials that is consistent with confidentiality requirements, legislation, privacy rules and other guidelines.

Objective

This SOP describes the process for managing confidentiality of all study materials held or created by the PaCCSC project or its members.

Scope

This SOP applies to all PaCCSC members and all staff involved in clinical studies conducted by PaCCSC irrespective of individual organisational employment, role or position.


Disclosure of ‘Confidential Information’

1. University of Technology Sydney (henceforth UTS) has confidentiality obligations which flow from the PaCCSC Agreements, Confidentiality Deeds or other applicable contracts*. This means that UTS must maintain the confidentiality of all information which can be considered ‘Confidential Information’ under these agreements. It must be ascertained from the relevant agreement what the Confidential Information is.

2. UTS must, prior to disclosing any information which may be considered ‘Confidential Information’ under the relevant Agreements, form a view about whether the disclosure is in fact permitted under the confidential obligations set out in the relevant contract. This can only be determined by reference to the terms of the relevant contract. This is UTS responsibility.

3. If disclosure is not permitted under the terms of the relevant contract, UTS will need to obtain the other party/parties’ approval, prior to any disclosure (i.e. the Commonwealth or parties to Confidentially Deeds or other applicable contracts).

4. If disclosure is permitted under the terms of the relevant contract, UTS can disclose the information provided a number of steps are taken.

* Contracts and agreements include (but not limited to): Commonwealth Department of Health, National Health and Medical Research Council, Cancer Council, Cancer Australia, philanthropic organisations, a variety of Universities, and commercial agreements.

PaCCSC SOP Feb 2018

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Procedure

1. Making confidential information available to another party

A Confidentiality Deed is required to be executed with the receiving party prior to disclosure of any PaCCSC study protocols or other information considered confidential.

UTS have two standard Confidentiality Deed templates (one mutual and one unilateral) which can be used for this purpose.

The PaCCSC National Manager must authorise the disclosure of the confidential information and the use of the template.

2. Confidentiality statements

A simple non-disclosure statement on the study protocol or other document does not in itself create a legally binding obligation on the receiver of the confidential information. However a generic statement is more practical, and the UTS recommended statement is as follows:

The information in this document is strictly confidential. By accepting or reviewing this document, you agree to hold the information in confidence and not to disclose it to others (except with the prior written authorisation of the University of Technology Sydney or where required by applicable law). The information is provided for the exclusive use of investigators involved in the study and, subject to the foregoing, may only be disclosed to other persons involved in the study who have a need to know with the obligation not to further disseminate the information. In the event of any actual or suspected breach of these obligations the University of Technology Sydney should be promptly notified.

This statement is to be inserted on all new study protocols at the development stage.

In summary:

You must ascertain from the relevant agreement what the confidential information is; You must ascertain from the agreement what may be disclosed and what you need

permission to disclose; You must seek permission where necessary; You should have the receiver of the information sign a standard Confidentiality Deed; Just putting a ‘confidentiality statement’ on the front of a document does not bind the

receiver of the information.

2.1 Examples of when Confidentiality Deeds should be used

The standard UTS Confidentiality Deed template is used in all instances where UTS wish to bind a party to confidentiality obligations. In relation to PaCCSC, this includes a range of reasons/events such as:

Prior to attending the PaCCSC Annual Research Forum Prior to attending the IMPACCT Incubator Sessions and IMPACCT Concept

Development Workshops

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Prior to engaging a service provider where confidential information will be shared as part of the service provision

Prior to the release of PaCCSC owned data for any reason Prior to new members joining PaCCSC By all members of the PaCCSC governance committees

3. Breach of Confidentiality

Any breach of confidentiality will be investigated and managed appropriately.

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4.2 V1.3 Page 5 of 6

Other related SOPs

N/A


N/A

References



University of Technology Sydney Code of Conduct (accessed 21/12/2017) http://www.gsu.uts.edu.au/policies/code-conduct.html

University of Technology Sydney Research Ethics and Integrity Policy (accessed 21/12/2017) http://www.gsu.uts.edu.au/policies/research-ethics-integrity-policy.html

University of Technology Sydney Intellectual Property Policy (accessed 21/12/2017) http://www.gsu.uts.edu.au/policies/intellectual-property-policy.html

PaCCSC SOP Feb 2018

4.2 V1.3 Page 6 of 6

History


1.0 18/08/2015 L Devilee New procedure

1.1 25/01/2016 L Devilee Update to procedure following August Scientific Committee

1.2 5/07/2016 L Devilee Update to procedure following March Scientific Committee



Approval


1.3 David Currow


4.2.4 V1.0 Page 1 of 7

4.2.4 Delegation of Duties

Version V1.0


Approved D Currow




PaCCSC SOP Feb 2018

4.2.4 V1.0 Page 2 of 7


It is a requirement of Good Clinical Practice that personnel employed to work on clinical research studies are qualified to do so by education, training and experience.

While maintaining responsibility for the conduct of the clinical trial, the Principal Investigator may delegate significant clinical study related tasks and duties to appropriately qualified and trained staff.

It is the responsibility of the Principal Investigator to ensure that all study staff at the site understand and undertake their delegated tasks/duties in accordance with study protocol and regulatory requirements to ensure the protection of the rights, safety and well-being of participants.

The Principal Investigator is responsible for supervising any individual or party to whom they have delegated tasks/duties at the trial site.

For a clinical study to be conducted appropriately, it is essential that all involved personnel are aware of the anticipated extent of their involvement, their responsibilities relating to the International Conference on Harmonisation of Good Clinical Practice (ICH GCP) and the limits to their authority.

Objective

This SOP describes the process of delegating tasks and duties related to the clinical trial.

Scope

This SOP applies to all staff directly involved in the conduct of the study including (but not limited to): Sub-Investigators/Co-Investigators Research Nurses Study Co-ordinators Clinical Trial Assistants Clinical Trial Pharmacists

This SOP also applies to staff associated with, but not directly involved in the research including (but not limited to): Clinicians Specialist nurses Laboratory staff Radiologists Support staff

Some research will involve participants who are inpatients at the time, and where the nursing staff on the ward are required to collect data for the safety or primary outcome of the study. It is not feasible to require each rostered nurse to be delegated tasks on the Staff Signature and Delegation Log (Template 1), taking into account roster and rotation. It is acceptable to consider ward nursing staff in the description above, and to require the unit nurse manager (or

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equivalent) to sign the Staff Signature and Delegation Log. It is appropriate to complete a Staff Training Log (Template 3) for all staff within the inpatient unit.


The Principal Investigator is responsible for delegating significant trial-related tasks/duties and for supervising any individual or party to whom they have delegated activities. Delegation of tasks/duties will be dependent on the qualifications and experience of team members.

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Procedure

Individual study related tasks and duties are defined, established and allocated prior to the initiation of a study as per the Staff Signature and Delegation Log.

The Principal Investigator may delegate key tasks and duties to other individuals based on their skill level, qualifications and the tasks required. These delegations are recorded on the Staff Signature and Delegation Log.

It is important for the Principal Investigator to note that although tasks/duties may be delegated, responsibility for the clinical trial cannot be delegated (refer SOP 4.0 Investigator responsibilities). Therefore, it is important that the Principal Investigator ensures all tasks/duties are delegated to appropriately trained personnel.

The Staff Signature and Delegation Log must be completed at each site and held in the Investigator Site File for that site (refer SOP 8.0 Essential Documents). New personnel or new delegation of tasks/duties must be updated on this Log as appropriate and at the time of delegation.

The Principal Investigator must assess each person for their qualification and experience to determine if each task/duty is appropriate for that person. This may include a review of the person’s CV and other relevant documentation/qualifications.

The Principal Investigator must undertake a detailed discussion of each task/duty being delegated to that person in the context of the study and must ensure that the person fully understands the tasks/duties being delegated to them.

The person who accepts those tasks/duties must fully understand the study, their role and the specific scope and limitations of the tasks/duties delegated to them.

Joint signatures on the Staff Signature and Delegation Log are a confirmation that this discussion takes place and that both parties fully understand the tasks/duties to be undertaken by each party.

Only one Staff Signature and Delegation Log will be maintained for each study and this must be filed in the study specific Investigator Site File at all times. All personnel delegated tasks/duties will be listed on the one log i.e. there will be no second log or copy of the log maintained elsewhere.

The Staff Signature and Delegation Log will:

State names and roles of staff members delegated to complete specific trial related tasks/duties. Only staff members who are appropriately qualified, and who have received the relevant protocol training (documented), should be listed on the log.

Have one member of staff from each department involved in the study, including pharmacy, radiology and pathology (where appropriate) and including both internal departments and external provider staff (where appropriate), sign the log as the person responsible for that department and the staff within it.

Be signed and dated by the Principal Investigator (PI), as staff are added. PI’s signature must never be added retrospectively i.e. the date of the PI’s signature must be the

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same or prior to the start date listed for the staff member. Be made available to the Sponsor, where applicable. Be updated when new members join or leave the study team, and as otherwise required. Be filed in the appropriate section of the Investigator Site File. Be retained with the archiving, including a copy of each version, for audit purposes.

The Principal Investigator must ensure regular supervision and oversight of all staff on the Staff Signature and Delegation Log. Ongoing training and communication is a core activity of supervision. All supervision and communication by the Principal Investigator to site staff should be documented and retained. A number of different approaches can be used appropriate to the site and to the study.

In order to demonstrate ongoing supervision, training and communication, the Principal Investigator can make use of:

group email with return acknowledgements Staff Meeting Log (Template 2) Staff Training Log (Template 3)

These documents must be retained in the Investigator Site File.

If a third party provider is required for any aspect of trial management (such as radiology or pathology providers), a policy must be developed that is specific to the site and the third party, to ensure that the Principal Investigator is able to comply with their responsibilities and the study requirements are met. The policy must be followed at all times.

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Other related SOPs

4.0 Investigator Responsibilities 8.0 Essential Documents


Template 1: Staff Signature and Delegation Log Template 2: Staff Meeting Log Template 3: Staff Training Log (study or individual) Template 4: Short CV

References

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). November 2016 (accessed 23/10/2017) https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf

Praxis Australia

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History



New procedure

Approval


1.0 David Currow


4.5 V1.2 Page 1 of 8

4.5 Protocol Deviations and Violations

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Where there is poor compliance with the study protocol regulatory authorities can reject the data, patient safety can be compromised and indemnity may not apply.

It is the responsibility of the study Sponsor to ensure compliance with the study protocol. It is essential to record deviations and violations that occur throughout a study so that they can be identified easily and reviewed by the appropriate trial sub-committee. Unavoidable violations may indicate previously unanticipated problems with the study design and if identified early, steps can be put in place to change the protocol.

Objective

This SOP describes the process for the recording and reporting of protocol deviations and violations. I t describes what considerations must be taken into account to assess whether the deviations/violations also meet the requirements for reporting. This SOP also describes how violations are assessed and what remedial or corrective actions are to be applied.

Scope



The Principal Investigator and study Sponsor are responsible for recording and reporting of any protocol deviations and/or violations. The task may be delegated to another suitably trained individual but the responsibility remains with the Principal Investigator and study Sponsor.

Delegation of duties by the Principal Investigator must be recorded in the Staff Signature and Delegation Log (refer SOP 4.2.4 Delegation of Duties) prior to the task being undertaken, and only after the designee has completed the relevant study related training.

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Procedure

1. Protocol deviation

A protocol deviation is usually an unintended departure from the expected conduct of the trial (with regards to the protocol and/or SOPs). These events may be identified by the trial team during trial conduct and must be continually monitored by the Principal Investigator for repeated occurrences.

The majority of these events are technical deviations that do not result in harm to the trial participants or significantly affect the scientific value of the reported results of the trial.

All such cases must be documented in the appropriate Case Report Form (CRF) or study File Note and appropriate corrective and preventative action must be taken to ensure they do not recur. In addition, a notation within the database may be required.

Examples of deviations may include, but are not limited to:

A case where a potential participant does not meet, or only partially meets, one of the eligibility criteria, and the issue has been discussed with the Lead Investigator or PaCCSC Coordinating Centre and it has been agreed that the participant can proceed;

A protocol visit date deviation outside the study visit window, or not conducted; Isolated incident of a missed or incomplete study procedure (e.g. laboratory test or

completion of a questionnaire); Isolated incident of a missed or incomplete study evaluation (e.g. exam).

2. Protocol violation

A protocol violation is any departure from the approved protocol, trial documents, or any other information relating to the conduct of the study which may affect the safety of trial participants or the study outcomes.

Any violations that may impact on the participants’ safety or affect the integrity of the study data must be reported to the Sponsor and the approving HREC.

Examples of violations may include, but are not limited to:

Failure to obtain informed consent (i.e. there is no documentation of this in source data or a signed Informed Consent form);

Enrolment of participants that do not meet the inclusion/exclusion criteria; Undertaking a trial procedure not approved by the HREC (unless for immediate safety

reasons), or HREC approval not obtained or incomplete (refer SOP 6.12 Ethical approval);

Failure to report adverse events, serious adverse events or suspected unexpected serious adverse reactions (SUSARs) in accordance with the legislation and sponsor and protocol requirements;

Investigational product dispensing/dosing error.

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3. Persons responsible

The Principal Investigator is responsible for: Recording and reporting any deviations/violations to the PaCCSC Coordinating Centre

as soon as the deviation/violation is identified using the Protocol Deviation/ViolationReport Form.o In addition, if these are deemed a potential serious breach or an urgent safety

measure, the Principal Investigator is to report the deviations/violations to theapproving HREC.

The PaCCSC National Project Officer is responsible for:

Logging all violations on a Protocol Deviation/Violation Log, assigning a de-identifying IDnumber, and completing a Protocol Violation Form with a code for the violation.

Ensuring that the violations are reviewed by an appropriate committee and the decisionsrecorded. Updates to the study database may also be required.

The Lead Investigator, along with the appropriate committee, is responsible for:

Reviewing and assessing each protocol violation and to ensure that a decision about theviolation with respect to the integrity of the study data is made.

4. Identification of deviations and violations

The judgment on whether a deviation is likely to have a significant impact on the scientific value of the trial depends on a variety of factors (e.g. the design of the trial, the type and extent of the data affected by the breach, the overall contribution of the data to key analysis parameters, the impact of excluding the data from the analysis, etc.).

Once a deviation/violation has been identified, it is important that the site notifies the PaCCSC Coordinating Centre of what corrective and preventative actions they have taken so that a formal plan of corrective and preventative actions can be devised. The site uses the Protocol Deviation/Violation Report Form to report self-identified issues (Template 7).

Other deviations or violation can be identified during on-site monitoring visits, or through central monitoring (refer SOP 5.18 Monitoring, or protocol specific Monitoring Plan). These are recorded using the monitor Protocol Violation Form (Template 8).

4.1 Deviations

Recording: Deviations are recorded in the Case Report Form (CRF) (refer SOP 5.23.2 CRF Completion), study File Notes (refer SOP 4.9.2 File Notes), as a notation in the database, and/or an email discussion.

Appropriate record should be kept in the essential documents (if staff training, a change to internal procedures, etc., are required) (refer SOP 8.0 Essential Documents), or in the patient study records (CRF folder). Any corrective and preventative action should also be documented and retained in the site file.

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4.2 Violations

Recording: Violations are recorded in the Case Report Form (CRF), protocol Deviations/Violations Log and study File Notes, if necessary.

Reporting: Violations of Good Clinical Practice (GCP), protocol and regulations must be reported to the Sponsor within 3 calendar days of staff becoming aware of that violation. Violations, if identified by the site, are to be reported to PaCCSC using the protocol Deviations/Violations Report Form for further assessment and onward reporting if required.

Escalation: Corrective and preventative actions should be implemented for violations.

If the violation is determined to be a potential safety concern this must be reported to the competent authority and HREC within regulatory timelines.

If the violation is identified by PaCCSC Coordinating Centre during remote or on-site monitoring, the violation is to be recorded within the corrective action sheet (if appropriate) and a completion of a Protocol Violation Form and then logged into the Protocol Deviation/Violation Log. The Lead investigator is notified of the violation via email of the Protocol Deviation/Violation Form. The Lead Investigator may then form a sub-committee based on the seriousness of the violation.

A violation may constitute a triggered monitoring visit. All major violations must be resolved to conclusion. Depending on its nature, the violation may constitute a Serious Breach of Good Clinical Practice (GCP) and further follow up and reporting maybe required by PaCCSC Coordinating Centre in line with current regulations.

Reoccurring violations must be discussed at any meetings with the site team and/or at the Trials Management Committee, and detailed in the clinical study report (if required).

4.3 Assessment by PaCCSC

PaCCSC will form a Trial Sub-Committee to consider study specific protocol violations. If there is more than one violation, these will usually be discussed in a batched manner, unless the Principal Investigator considers any individual violation serious enough to form a specific meeting urgently.

The Trial Sub-Committee will generally consist of the following members:

Chair of the PaCCSC Trials Management Committee; The study Lead Investigator, unless the Lead Investigator is also the Principal Investigator

where the urgent protocol violation occurred; The study statistician; At least one other clinician/protocol investigator with expertise who can assess the clinical

implications of the violation; PaCCSC National Manager and/or National Project Officer.

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4.3.1 Corrective and Preventative Actions (CAPA)

The Trial Sub-Committee must agree on the appropriate corrective and preventative action to be taken and this should be documented and detailed within the body of the initial notification report.Follow-up reports

Follow-up reports should be made in writing (the Protocol Deviation/Violation Form can also be used for this) and should:

Be clearly identified as a follow-up report; Identify the unique ID allocated when the initial report was generated; Document the outcome of the decision; Detail any follow-up to the discussion (e.g. further site or Principal Investigator training,

removal of the participant data, protocol amendment); Be placed in the central record of the participant file.

4.3.2 Escalation and dissemination process

Internally: The protocol violations or the summarised outcomes are reported to the following PaCCSC committees:

Trial Management Committee; Scientific Committee; Management Advisory Board; Data Safety Monitoring Committee (if the protocol violation is considered to be a breach

of participant safety and/or will impact on the overall quality of the study data).

The issues resulting from the considerations of violations will also form an agenda item for Site Coordinator Teleconferences or meetings.

Externally: External reporting will be dependent on the nature of the violation and may include reporting to other sites and pharmacies affected, Ethics Committees, etc.

The breach should be circulated to relevant staff so that it is included as relevant information in the study report or publications. Serious violations relating to investigator sites, laboratories, etc., should also be made available relevant staff during the process of site selection for future studies (.i.e. careful assessment should be made before using a non-compliant site in future studies).

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Other related SOPs

4.2.4 Delegation of Duties 4.9.2 File Notes 5.18 Monitoring 5.23.2 CRF Completion 6.12 Ethical Approval 8.0 Essential Documents


Template 7: Protocol Deviation/Violation Report Form Template 8: Protocol Violation Form

References


NHS Lothian and The University of Nottingham, Academic and Clinical Central Office for Research and Development Standard Operating Procedures. Management of Protocol Deviations and Violations. 24 Feb 2011.

Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95). Annotated with TGA comments 2000 (accessed 17/10/2017) https://www.tga.gov.au/sites/default/files/ich13595an.pdf

Praxis Australia

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History


1.1 23/02/2016 B Fazekas New procedure



Approval


1.2 David Currow


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4.5.3 File Notes

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File notes, or notes to file, are sometimes used within the practice of clinical trials. File notes are additional to all essential documents (Case Report Forms, etc.) and source documents (investigation results, etc.). File notes can be used to explain an issue which is not (and cannot) be explained elsewhere in the documentation.

The International Conference for Harmonisation of Good Clinical Practice (ICH GCP) guidelines do not specifically or directly address the use of file notes in clinical trials. It is important to understand the purpose of file notes and to use them appropriately.

Objective

There are some circumstances where a well written file note may be appropriate. This SOP describes the use of file notes for PaCCSC studies to achieve consistency in the use, writing and application of appropriate file notes within PaCCSC studies.

Scope



Responsibilities of the Principal Investigator and/or other designee(s) as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties)

To oversee the overall conduct of the study at their site, including those activities that may vary from the study protocol, or where documents or source documents indicate a discrepancy with the study data via the Case Report Forms (CRFs) and other study documents

To identify discrepancies in the research processes and correct them appropriately To initiate a file note if an identified discrepancy cannot be corrected

Responsibilities of the PaCCSC Coordinating Centre

To review file notes for appropriateness and content. This can be done during central monitoring, site visit monitoring or when file notes are generated spontaneously (or on request)

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Procedure

1. Determining if a File Note is appropriate

First, identify if other study documentation exists where the issue can be addressed.Acceptable documentation includes:o Within the CRF, using an accepted method of correction, or within a comment

section at the appropriate data point;o As part of a response to monitoring through the Corrective Action Sheet (refer SOP

5.18 Monitoring) and confirmation that the action has been completed;o Within the participants clinical record;o Within the notes and discrepancy items within the study database;o Within other forms of correspondence where the issue was discussed and a solution

reached, such as Human Research Ethics Committee (HREC) correspondence toclarify or amend erroneous approvals, or email correspondence of decisionsreached between the investigator and sponsor regarding recruitment.

If a File Note is determined to be the appropriate form of documentation and correctionof the identified issue, the File Note Template is used (Template 9).

2. Generating a File Note

The following general principles of generating a file note for PaCCSC studies apply: File notes are generated on a case-by-case basis; File notes include the participant and study protocol referred to; File notes are signed and dated by the individual who writes them and who can confirm

the accuracy of the events detailed in the file note; File notes are legible, if handwritten; File notes clearly and specifically explain the reason for the error/omission/discrepancy

or process/policy it aims to address; File notes include any corrective action or follow-up when applicable; File notes are filed with the document, participant file or study folder tab to which it

applies; A file note is not a solution to an issue; it is a vehicle to explain the problem and the

solution; All file notes include a plan to correct the problem and a plan to prevent future problems.

It is not appropriate to generate file notes for the sole purpose of documenting the following:

Incorrect (or incorrectly signed) consent form; Incorrectly administered (or omitted) study drug; Missed scheduled visit; Routine trial conduct; A statement that a file note has been written (as a request of monitoring for example).

3. Completing a File Note

A file note is to be completed by following the File Note Guidance (Guidance 1).

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Other related SOPs

4.2.4 Delegation of Duties 5.18 Monitoring 5.23.3 CRF Completion


Template 9: File Notes Guidance 1: File Note Completion

References

Aditi Hazra. Use and misuse of notes to file. Perspectives in Clinical Research. 2(1): 38-40. 2011

Carl Anderson – Note to self – no more file notes. Applied Clinical Trials. March 2008

Tatjana Markovic. Writing notes to file at the study site. Journal of Clinical Research Best Practices. 7(1): Jan 2011


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History






Approval


1.3 David Currow


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4.7.1 Randomisation and Allocation

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Rigorous methodology for randomisation and for the allocation of people to study interventions is a critical element of randomised studies.

Correct documentation of the randomisation and allocation process ensures that the study results can be verified and are able to withstand external examination. Errors in the randomisation procedure itself, or shortcomings in documentation of the randomisation and allocation procedures, expose the study results to criticism, which could render the results dubious. This situation is avoided at all costs.

PaCCSC aims to conduct rigorous and quality clinical studies. All stages (design, execution and reporting) are conducted to the highest possible standard. An established mechanism for assessing the quality of a study via its report is the Jadad score, which allows a score to be allocated to the study by external review. A maximum score of 5 indicates high quality randomisation and masking of allocation (Jadad 1996).

Objective

This SOP details the procedures by which participants are allocated to an intervention, and the roles and responsibilities of each party involved in these procedures.

This SOP does not describe the randomisation process by which the allocation codes are generated prior to distribution to each site. This process is described in the study protocol and is recorded by the Central Randomisation Service.

Scope



Responsibilities of the Study Site

To recruit participants for clinical studies To ensure informed consent and confirmation of eligibility are provided for each

participant prior to randomisation To ensure randomisation and all study procedures are according to the study protocol To liaise with the Site Pharmacy regarding prescriptions

Responsibilities of the Site Pharmacist

To undertake the randomisation at the Study Site in accordance with the study protocol To maintain the allocation logs To supply the study medicines as per the study protocol

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To manage the operationalisation of the study

Responsibilities of the Central Randomisation Service

To develop the schedules for each site for each study To design and implement a methodology for providing the allocation To provide a mechanism by which the code can be broken

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Procedure

This SOP is organised in sections corresponding to each of the parties actively involved in the study’s randomisation and allocation procedures.

1. Study Site

Following provision of informed consent and confirmation of eligibility, the participant is randomised.

A member of the study team determines the day the participant will commence the study (Day 1) to ensure that all study procedures, such as supply of investigational product, pathology results and medical review, are undertaken at the times specified within the study protocol.

A formal request for randomisation is recorded and sent to the Site Pharmacy. The formal request is a prescription (signed by the Principal Investigator). Most PaCCSC studies involve investigational product that require a medical order (refer SOP 5.14.1 Investigational Product Handling).

After confirmation of the randomisation from the Site Pharmacy, a member of the study team is provided with the randomisation number (refer SOP 5.5.5 Allocation of Identification Number). This number is referred to as the PID number and is recorded in the Patient Master Index (Template 12), and on all subsequent CRFs for that participant.

A participant cannot be randomised to the same study more than once, regardless of the circumstances of the first enrolment or outcome. In the unlikely event that re-randomisation of a participant occurs, the first data set is maintained, and the second data set is deleted from the data base.

2. Study Pharmacy

Procedures for randomisation and allocation are kept in the pharmacy Randomisation/Study folder at each Site Pharmacy; all documents related to the procedure are filed within that folder.

The Site Pharmacy receives the Randomisation/Study Folder (provided by the PaCCSC Coordinating Centre) containing allocation code schedules (sealed), instructions, study protocols, medicine accountability logs, and documents relating to the recording and reporting of study randomisation for each study. This folder is maintained by the clinical studies pharmacist in keeping with Good Clinical Practice.

At the time a participant is randomised and allocated to an intervention, the Site Pharmacy receives a prescription (which also confirms the stratum assignment, if applicable) (refer to Guidance 6: Prescription of Study Drug). This serves as confirmation of the person’s eligibility for the study, and specifies Day 1 of the intervention (the day the participant commences the study).

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The site pharmacist checks the prescription for completeness and legibility. The study site is notified if the prescription does not meet requirements.

The site pharmacist follows the study specific procedures described within the pharmacy instructions. In most cases, this procedure involves a telephone call or email to the Central Randomisation Service to be provided with the allocation and the randomization number, to be followed with email confirmation.

Site pharmacy staff locate the appropriate study drug and dispenses in accordance with the protocol and instructions.

Should the site pharmacist receive more than one request in one day, the pharmacist: o Undertakes the randomisation procedure in the order that the prescriptions are

received;o Records each randomisation according to the prescription, and completes the dispensing

of investigational product before undertaking the next randomisation.

If the pharmacist makes an error in recording data within any documents related to allocation and logging, the pharmacist takes the following actions: o Strike out the error with a single line, then sign and date the randomisation log next

to the error. Use pen and ink, but not liquid paper. Do not obliterate the original error; the original writing must remain intact and

visible.

If the process involves site generated randomisation tables, the study specific instructions and other guidance documents are to be followed.

The site pharmacist completes a Randomisation Registration Notification (Template 17) and emails this to the PaCCSC Coordinating Centre on the day of the randomisation.

The site pharmacist prepares the study medicine according to the allocation code for each individual person.

The site pharmacist delivers the study medicine to the person participating in the study (or the ward if inpatient, or the study team member if the study drug is to be delivered to the participant at home) on the day specified within the study protocol (this might be the previous day in the case of people at home for the morning intervention doses) and as per the arrangements already confirmed with the study team member.

The site pharmacist performs internal checks and maintains records that make it possible to verify that the participant actually received the intervention as determined by the allocation code.

At the end of the study and after the close out monitoring visit, the Randomisation/Study folder containing all of the randomisation records, instructions, logs and related correspondence are sealed and provided to the Site Principal Investigator for inclusion in the Investigator Site File.

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3. PaCCSC Coordinating Centre

The role of the PaCCSC Coordinating Centre is operational management of the study. The Coordinating Centre:

Receives automatic notification when the Study Site has entered eligibility and baseline data (including any stratum data) into the RDMS.

Upon automated email notification of data entry from the RDMS, checks: o the randomisation data against the expected stratum assignment based upon the

predetermined characteristics o all eligibility have been met prior to the randomisation process

Maintains a log of those enrolled in the study as per the data entry and compares the participant registration faxes received from the Site Pharmacies.

If discrepancies are identified, the Coordinating Centre contacts the Study Site.

4. Central Randomisation Service

The primary responsibility of the Central Randomisation Service is to develop the schedules for each site for each study, and to provide a mechanism by which the code can be broken (unblinding envelopes).

5. Contact details

Any problems during the study are to be directed to the company or service as per the contact listing provided within the Randomisation/Study Folder.

Any problems with materials, procedures, timeframes or other questions are directed to:

Ms Belinda Fazekas National Project Officer Palliative Care Clinical Studies Collaborative University of Technology Sydney PO Box 123 Broadway, NSW 2007 Telephone: +61 (0)8 7421 9796 [email protected]

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Other related SOPs

5.14.1 Investigational Product Handling 4.7.2 Unblinding 5.5.1 Electronic Data Handling 5.5.5 Allocation of Identification Numbers


Template 9: File Notes Template 12: Patient Master Index Template 17: Randomisation Registration Notification Guidance 6: Prescription for Study Drug (example)

References

Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996; 17:1-12.


Acknowledgments

Trans-Tasman Radiation Oncology Group (TROG), for generous access to the Policy and Procedure Manual – the Red Book.

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History


1.1 21/08/2007 B Fazekas New procedure adapted from Oxygen study SOP V4.2.6

1.2 14/12/2007 B Fazekas Update after MAB review







Approval


2.2 David Currow


4.7.2 V2.3 Page 1 of 7

4.7.2 Unblinding

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Unblinding is the process by which the allocation code is broken revealing the intervention allocated to the participant. Unblinding is undertaken by a pre-determined process to ensure that participants are not unblinded unnecessarily and study results are not compromised.

Emergency unblinding occurs when clinically indicated, in the following circumstances:

When clinical treatment decisions require the intervention to be known; When an unexpected Serious Adverse Event occurs and the intervention must be made

known.

Other circumstances when unblinding occurs are: When an (unblinded) interim analysis is required, in accordance with the study analysis

plan; When requested by the PaCCSC Data Safety Monitoring Committee; At the conclusion of the study, to determine the effect of the intervention.

Objective

This SOP describes the timing and process for unblinding to ensure correct unblinding procedures are followed.

Scope



Responsibilities of the Lead Investigator

To approve unblinding for safety reasons (emergency unblinding), for unblinded analysis and on study completion

To inform the PaCCSC Coordinating Centre that unblinding has been approved


To assess the need for unblinding To request approval for unblinding from the Lead Investigator To record participant withdrawal in case of unblinding


To coordinate between the Lead Investigator, Lead Statistician, Site Pharmacies To contact the Central Registry to request unbinding of individual participants To obtain randomisation schedules from study sites and site pharmacies

Responsibilities of the Lead Statistician

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To merge the randomisation schedules and allocation schedules To merge main study data with the allocations in preparation for analysis To complete the unblinded analysis as determined by the PaCCSC Data Safety

Monitoring Committee

Responsibilities of the PaCCSC Data Safety Monitoring Committee (DSMC)

To determine when an unblinded analysis is required

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Procedure

1. Individual participant – emergency binding

If a Serious Adverse Event occurs (where the participant’s wellbeing may be compromised), the Principal Investigator, in consultation with the clinical team, assesses the need for unblinding.

If unblinding is indicated, the Principal Investigator contacts the Lead Investigator to discuss the clinical situation and request approval for unblinding

If approval to unblind is confirmed, the Lead Investigator contacts the PaCCSC Central Randomisation Service, or the National Project Officer at the PaCCSC Coordinating Centre (as described in each study protocol) and provides the following information: o Caller details (own name and position) o Study site o Principal Investigator o Name of participant o Study protocol number or identifier o Study Identification Number if known o The reason for unblinding

Upon receipt of an unblinding request, the Central Randomisation Service o Completes an Unblind Request Form (Template 18) and obtains the unblinding

contact details (Guidance 7) (this is filed for future auditing) o Discusses the unblinding authorisation with the Lead Investigator if appropriate o Identifies the unblinding information (envelope, schedule or similar) associated with

the specific randomisation number (Guidance 8) provided by the Lead Investigator and determines the intervention allocation.

The Central Randomisation Service contacts the site and informs the Principal Investigator and the Site Pharmacy of the intervention allocation.

The Central Randomisation Service completes an Unblind Report Notification (Template 19) and emails this to the Coordinating Centre.

When a participant is unblinded, the Principal Investigator (or delegate) records the participant withdrawal and allocation in their clinical and study notes along with the appropriate clinical notations.

The Coordinating Centre logs the Unblind Reports and periodically reports unblinding rates to the Study Sub-committee and PaCCSC Trials Management Committee (TMC). o Aggregated assessment of unblinding for each study will be provided by the

PaCCSC Medical Monitor to the PaCCSC TMC every six months (refer SOP 5.17.1 Medical Monitor V1.1).

2. Unblinded analysis

The PaCCSC Data Safety Monitoring Committee (DSMC) or Medical Monitor (MM) determines when an unblinded analysis is required. This decision is documented within the DSMC meeting minutes or email correspondence.

PaCCSC SOP Feb 2018

4.7.2 V2.3 Page 5 of 7

A written request for unblinding analysis is made by the DSMC/MM to the Lead Investigator.

Upon receipt of the request, the Lead Investigator requests the PaCCSC Coordinating Centre to provide the randomisation schedules to the Lead Statistician or the DSMC.

The Coordinating Centre makes requests to all Site Pharmacies to copy the table of allocation schedules and email to the Lead Statistician or DSMC, or requests that the Central Randomisation Service provide the list of allocations to date.

If via pharmacies, each Site Pharmacy checks their allocation logs for completions to date, signs and dates the last entry in to the allocation log with a note to indicate the request and faxes the table of allocation schedules to the Lead Statistician or DSMC).

Upon receipt of all the allocation schedules from the study sites, the Lead Statistician merges the study data with the table of allocation codes as per the data transfer instructions (refer SOP 5.5.2 Electronic Data Transfer).

The Lead Statistician completes the unblinded analysis as determined by the DSMC.

3. Unblinding on study completion

The Lead Investigator determines that study recruitment is complete and unblinding is required for analysis.

The Lead Investigator (or Lead Statistician) makes a written request to the PaCCSC Coordinating Centre to proceed for study unblinding.

Upon receiving the written request to unblind the study, the PaCCSC Coordinating Centre either: o Contacts each Site Pharmacy and requests a copy of the randomisation schedule

for the study by registered mail, or scanned and emailed. Upon receipt of a request from the PaCCSC Coordinating Centre, each Site Pharmacy: Checks the randomisation schedule for completeness; Signs and dates the last entry; Provides the Coordinating Centre with the randomisation schedule; Ensures all invoicing is completed; or

o Collates the Randomisation Record held by the Central Randomisation Service and; o Requests the return of all unblinding envelopes (if used) for the study by registered

mail; o Enters all Identification Numbers and allocations into an Excel file; o Sends the Excel file via email to the Lead Statistician (refer SOP 5.5.2 Electronic

Data Transfer).

Upon receipt of the Excel file from the Coordinating Centre, the Lead Statistician: o Confirms receipt of the Excel file containing the ID numbers and allocations (to the

Coordinating Centre); o Merges the main study data with the new Excel file in preparation for analysis.

PaCCSC SOP Feb 2018

4.7.2 V2.3 Page 6 of 7

Other related SOPs

4.2.4 Delegation of Duties 4.7.1 Randomisation and Allocation 5.5.1 Electronic Data Handling 5.5.2 Electronic Data Transfer 5.5.5 Allocation of Participant ID Numbers


Template 18: Unblind Request Form Template 19: Unblind Report Notification Guidance 7: Unblind Contact Numbers Guidance 8: PID Number Sequencing

References


Acknowledgments


PaCCSC SOP Feb 2018

4.7.2 V2.3 Page 7 of 7

History





1.4 7/06/2010 B Fazekas T Shelby-James

Periodic review


2.1 28/10/2013 B Fazekas L Devilee

Review of procedure following unbinding




Approval


2.3 David Currow


4.8 V1.3 Page 1 of 8

4.8 Informed Consent

Version V1.3


Approved D Currow




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The International Conference on Harmonisation of Good Clinical Practice (ICH GCP) guidelines and the National Health and Medical Research Council (NHMRC) National Statement on Ethical Conduct in Human Research describe in detail the process of obtaining consent from potential participants, including the use and detail of the participant information sheets and consent forms. These principles and requirements apply to all studies conducted by PaCCSC and are underpinned by the suite of PaCCSC Standard Operating Procedures (SOP).

Objective

This SOP operationalises the national and international requirements by describing: the manner by which informed consent is obtained; and the manner by which the process is documented in all studies undertaken or auspiced by

PaCCSC, where the suite of PaCCSC SOPs form the guiding procedural framework.

While this level of detail is not covered by other applicable clinical trial documents, the special considerations for the study population of PaCCSC studies necessitate this level of detail.

This SOP does not replace other requirements from the ICH GCP, NHMRC and Human Resource Ethics Committee (HREC) documents.

Scope



The Principal Investigator and/or other designee(s) as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties).

Responsibilities of the Principal Investigator

To ensure that the correct Participant Information Sheet and Consent Form (PICF) has been approved (as a master version) by the HREC and subsequently approved for local use by the site RGO (Research Governance Office) and is the only version used at the site

To oversee the process of obtaining informed consent from potential participants at the site

To obtain informed consent from potential participants for PaCCSC studies in accordance with applicable regulatory and ethical requirements

To authorise other individuals (such as study nurses, site coordinators, sub-investigators) to assist in the process of obtaining consent, ensuring the delegates have undertaken suitable training in the process

To ensure that all requirements for participant consent are met, in keeping with the NHMRC National Statement on Ethical Conduct in Human Research and ICH GCP guidelines

PaCCSC SOP Feb 2018

4.8 V1.3 Page 3 of 8

To ensure that those who obtain consent also document the process of consent within the clinical record. Where the study participant may reside at home whilst enrolled in the study, written consent documentation is held in the site study file

The Principal Investigator may delegate the duties for the informed consent process to another suitably trained individual (e.g. Sub-Investigator, Site Study Coordinator, study nurse etc.) as documented on the Staff Signature and Delegation Log (refer SOP 4.2.4 Delegation of Duties) but the Principal Investigator is responsible for supervising any staff to whom they have delegated such duties:

To ensure that consent is explained to potential participants in a manner consistent with the study protocol and the approved PICF

To obtain consent, where approved to do so and in keeping with HREC approval and delegation on the Staff Signature and Delegation Log

To document the process of consent in the clinical record To file appropriately signed consent forms

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4.8 V1.3 Page 4 of 8

Procedure

1. Training about consent procedures

The Principal Investigator is responsible for ensuring all site team members who are delegated the task of obtaining informed consent (as documented on the Staff Signature and Delegation Log; refer SOP 4.2.4 Delegation of Duties) complete training in consent processes.

The training in the process of obtaining consent is consistent with international and national standards and includes:

Role playing, using the study PICF as a template, ‘key messages’, and plain language; Practice explaining to a ‘lay’ person such as a family member or non-clinical work

colleague, and answer their questions; Practice explaining the study to another clinician, such as medical officer or clinical

nurses, based in the potential referral area; Familiarisation with frequently asked questions to ensure the team member can answer

questions to the participant’s satisfaction.

Each session provides an opportunity to critically analyse and amend the terminology used and the understanding of the study in plain language.

2. The Consent Form

The Consent Form meets the requirements of the approving HREC, the NHMRC National Statement on Ethical Conduct in Human Research and ICH GCP guidelines.

When the Consent Form and Participant Information Sheet are approved by the HREC as one document, they remain together in the study file and clinical notes (i.e. when the signature page is page 14 of 14, then the previous 13 pages remain attached).

3. Person obtaining consent

The study team member obtaining consent from the potential participant is trained in the process of obtaining informed consent and is included on the Staff Signature and Delegation Log, with the specific delegation role of obtaining consent.

Each site complies with any local restrictions and/or obligations imposed by the HREC.

The study team member obtaining consent does not have any conflict of interest with the process. For example, if a potential participant is also a relative of the team member explaining the study, it is not appropriate for that person to obtain consent as there is a conflict of interest.

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4. Documentation of consent

The completed Consent Form, by itself, is not regarded as adequate documentation that consent was obtained in accordance with the relevant regulatory requirements. PaCCSC studies require additional documentation of the actual process in the clinical record (refer SOP 4.0 Investigator Responsibilities), as confirmation that consent has been obtained. This may occur during several clinical encounters and all require to be documented. The reasons for this additional documentation are:

To inform all other clinicians involved in the clinical management of the participant that the correct procedures for consent are followed, including appreciation of the vulnerable position of the participant; and that consent was provided with full disclosure and full understanding.

To provide evidence of the time line for participation in the study (i.e. consent is obtained prior to study registration and initiation of study related procedures).

To provide substantiation of the process being a dialogue and sharing of information. To confirm the process in the event that the Consent Form cannot be located at a future

time.

Any documentation in the clinical record regarding the consent process is completed by the study team member who obtains the consent. A stamp can be used if approved by the HREC (refer SOP 6.12 Ethical Approval). See Guidance 2 for sample documentation considered to be appropriate.

5. Filing of the Consent Form

The original signed Consent Form is filed in the study file or investigator folder and is considered the source document. One copy of the signed Consent Form is provided to the person who provided consent, and a second copy is filed in the medical record, clinic record, outreach records, or other file as appropriate so that other clinicians involved in the care of the participant are aware of their participation in the study.

6. Changes to the Consent Form

Changes to the approved Participant Information Sheet and/or Consent Form are approved by the HREC (refer SOP 6.12 Ethical Approval) and the local Research Governance Office (RGO), and contain the appropriate track changes and version changes. Changes to a Consent Form may occur under the following circumstances:

A protocol amendment; Changes of study personnel, requiring changes to contact details on the Consent Form; An error is discovered on the Consent Form.

When changes are made to the Consent Form while a participant is still enrolled in the study, either during intervention or during follow-up, consent is re-obtained; except where a new protocol amendment has been approved but not yet applied (to the current participants).

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7. Obtaining consent when the potential participant is unable to read or write English

If a potential participant is unable to read or write and if the legally acceptable representative is unable to read or write, an Impartial Witness should be present during the entire informed consent discussion. The Impartial Witness signs the Consent Form after:

The Participant Information Sheet and Consent Form (and any other written material supplied) is read to the potential participant and/or their legally acceptable representative;

The potential participant (or their legally acceptable representative) consents verbally to participation in the study;

If able to do so, the potential participant (or their legally acceptable representative) signs and dates the Consent Form.

By signing the Consent Form, the Impartial Witness attests that the information in the Consent Form and any other written information was accurately explained to, and apparently understood by, the participant or the participant's legally acceptable representative, and that informed consent was freely given by the participant or the participant’s legally acceptable representative.

Where a witness is not required, but there is space on the consent form for ‘Witness Signature’, this section is struck through by the study staff with their initials and date, to indicate this section is not required as part of the informed consent process.

8. Obtaining proxy (third party) consent

In certain circumstances the medical condition of the intended participant precludes their capacity to consent to the study in their own right (e.g. when studying conditions such as delirium). Such studies require informed consent to be provided by a ‘responsible person’, ‘proxy’ or ‘third party’.

Obtaining consent for these studies is still a process of information exchange between the study staff, the potential third party and any other person the potential third party believes should be included in the discussion, including the participant (a health care interpreter can be used to assist if English is not the primary language). In such cases, the HREC approved third party information sheet is used as a basis for the discussion, which covers all procedures, benefits, burdens and side effects that may be possible during the study. The study team ensures the third party has been given sufficient time and opportunity to consider the study and discuss with other family members.

It is critical that the third party is made aware that consent for the study must be in keeping with what the potential participant would want if they had capacity to consent in their own right, and that the consent is not based on the personal views of the third party.

Written informed proxy consent is to be obtained from a responsible person. No information collected for this study is to be released to the proxy consent person.

The definition of third party for consent to participate in clinical trials varies across Australia, with state specific directions on the identification of an appropriate third party. These state definitions and any associated approvals are strictly adhered to and the identification of the third party is documented within the Medical Record.

PaCCSC SOP Feb 2018

4.8 V1.3 Page 7 of 8

Other related SOPs

4.0 Investigator Responsibilities 4.2.4 Delegation of Duties 6.10 Version Tracking 6.12 Ethical Approval 8.0 Essential Documents


Guidance 2: Documentation of Consent (example)

References

COSA Standard Operating Procedures for Investigational Sites, Centre for Clinical Research Practice, Clinical Oncology Society of Australia, March 2006




Praxis Australia

Acknowledgments


PaCCSC SOP Feb 2018

4.8 V1.3 Page 8 of 8

History






Approval


1.3 David Currow


4.9.2 V1.1 Page 1 of 7

4.9.2 Source Data and Documentation

Version V1.1


Approved D Currow




PaCCSC SOP Feb 2018

4.9.2 V1.1 Page 2 of 7


Source data and documentation is identifiable data that verifies the information contained within the study Case Report Forms (CRFs). Copies of source data and documentation are not held by the study site or PaCCSC Coordinating Centre; they are accessed at the site during monitoring and auditing visits.

A statement of permission to access source data for regulatory and audit purposes is included within the Participant Information and Consent Form for the study, with explicit explanation of this given as part of the consent process.

Source data are usually found in the participant’s medical record file. Source data include (but are not limited to): Medical assessment notes Progress notes/records Medication chart Medical letters/correspondence Investigational reports (for example, pathology, x-ray, spirometry, echocardiogram etc.)

The International Conference on Harmonisation of Good Clinical Practice (ICH GCP) guidelines specify that source documents may also include the data recorded within CRFs (or contained on audiotapes) if these data form clinical data from which analysis is conducted, are not contained within other source documents and are specified within the study protocol. For example, if clinical observations are recorded within the CRF and used as study data, this is then source data.

The purpose of source data and documentation are:

Confirmation of unidentified data to protect the integrity of the study results. For example, a diagnosis given in a medical assessment notation in the clinical record can verify the diagnosis information in a CRF.

Substantiation that proper and due process was followed. For example, description of the consent process in the clinical record can confirm that proper consent process was followed and that the consent form was verified.

Safety of the participant. For example, documentation of study activity in the clinical record provides information about the study to other clinicians involved in the care of the participant, and that problems reported in the clinical record are accurately reflected in the CRF.

Objective

This SOP describes the requirements for source data and the processes for accessing source data and documentation when required.

Scope

This SOP applies to all staff involved in clinical studies conducted by PaCCSC irrespective of individual organisational employment, role or position. All staff responsible for caring for a patient on a clinical trial may contribute to clinical trial source data.

PaCCSC SOP Feb 2018

4.9.2 V1.1 Page 3 of 7



To articulate the source data and documentation requirements in the study protocol To review source data and documentation as and if required

Responsibilities of the Principal Investigator (or delegate) as documented on the Staff Signature and Delegation Log (refer SOP 4.2.2 Delegation of Duties)

To ensure source data and documentation is collected / completed as per the protocol To ensure all source documents contain the participants name or Participant Identification

Number (PID) and date of document generated To record all study related activity with the participant in their clinical or progress notes To ensure source data and documentation are available for review during monitoring and

auditing visits, in accordance with local hospital/service policy To provide source data and documentation to the Human Research Ethics Committee

(HREC) and the Data Monitoring and Safety Committee (DMSC) as and if required


To provide sufficient notice of monitoring and auditing visits to study sites To provide direction and advice on source data and documentation to sites To monitor source documentation as part of routine study monitoring process

PaCCSC SOP Feb 2018

4.9.2 V1.1 Page 4 of 7

Procedure

1. Source data

Participants for PaCCSC studies are often assessed within environments where other traditional source documentation may not be present. These environments may include: Participant own home; Residential aged care facility; Hospice or palliative care unit where some study requirements are not collected.

PaCCSC therefore considers that much of the data within the CRFs is the first, and often the only record, of observations or assessments. In these circumstances, the data within the CRF is source data, and there is no requirement to subsequently duplicate the data into another record for the purpose of generating source data.

The Principal Investigator should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site’s trial subjects. Source data should be:

Attributable – it should be clear who made the entry Legible – the entry must be readable Contemporaneous – the entry must indicate both when the event occurred as well as

when it was entered Original – the entry must be the first place the information was recorded Accurate – the entry must reflect what occurred Complete – the entry must be complete, with no missing data In addition, any changes to source data must be traceable, should not obscure the original

entry and should be explained if necessary. At PaCCSC, Guidance 2 (Documentation of Consent) is used for all patients who

participate in a clinical trial to record specific visits, and for both electronic and paper medical records.

Source data location and access is to be recorded in a log and filed in a prominent position in the Investigator Site File (refer to SOP 8.0 Essential Documents).

The following describes the procedures for accessing source documents when required.

1.1. Clinical notes vs progress notes

PaCCSC recognises that some home based (community) participants may not have clinical notes in which to record study activity. In such circumstances, the Principal Investigator (or delegate) is to document all study activity relating to the participant in progress note format. The progress notes must include the record number of the participant, date of activity and

name (and signature, if in written form) of study team member writing the notation. (referGuidance 2: Documentation of Consent)

Written (hard copy) notes must be stored separately from the study files (due to potential re-identification of participants).

A copy of the notes must be submitted to the organisation’s Medical Record Department for inclusion in the participant’s medical record.

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4.9.2 V1.1 Page 5 of 7

2. Monitoring / Auditing Visits

The PaCCSC Coordinating Centre Monitor arranges to visit the site as per SOP 5.18Monitoring.

A minimum of 2 weeks’ notice of visit (and Participant Identification Numbers beingmonitored) is given to ensure sufficient time to obtain access to source documents.

2.1. Accessing paper (hard copy) clinical documentation

The Principal Investigator (or delegate) arranges for the clinical files containing all sourcedocuments (related to the participants being monitored) to be available during themonitoring visit.

2.2. Accessing electronic (soft copy) clinical documentation

Ideally, the monitor/auditor views the electronic documents on screen during the visit. Access to the electronic documents is determined according to local hospital/service

policy. Options for access are:o The Principal Investigator (or delegate) arranges an individual ‘log on’ to the system,

for the monitor prior to the visit. The monitor should only be able to access theclinical files of the participants being monitored.

o In the event that the above contravenes local hospital/service policy, the PrincipalInvestigator (or delegate) may sit with the monitor during the visit and access theclinical files using their own access ‘log on’.

o If neither of the above options is possible, the Principal Investigator (or delegate)may print off the electronic source documents and provide them to the monitor forreview. Printed electronic source documents are only accepted when they includethe participants name or PID and the date the document was generated. ThePrincipal Investigator (or delegate) must be available to provide further (missing)source documents required by the monitor during the visit. Failure to do so mayresult in corrective actions and/or incomplete monitoring.

3. Request from the PaCCSC Data Monitoring and Safety Committee (DMSC)

The PaCCSC Coordinating Centre informs the Principal Investigator what specific sourcedocuments are required for review by the DSMC.

When possible, the Principal Investigator (or delegate) send copies of the required sourcedocuments to the Coordinating Centre via secure email.

If necessary, a delegate of the DSMC may visit the site and review the source documentsin person, following the procedures set out above.

PaCCSC SOP Feb 2018

4.9.2 V1.1 Page 6 of 7

Other related SOPs

4.2.4 Delegation of Duties 5.18 Monitoring 8.0 Essential Documents


Guidance 2: Documentation of Consent (example)

References


Praxis Australia

PaCCSC SOP Feb 2018

4.9.2 V1.1 Page 7 of 7

History





Approval


1.1 David Currow


5.1.1 V2.2 Page 1 of 6

5.1.1 Standard Operating Procedure Development

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

5.1.1 V2.2 Page 2 of 6


Standard Operating Procedures are a mechanism by which important trial activities can be standardised, and measured against in order to assess the conduct of the study and compliance with ICH GCP and other applicable regulations.

Objective

This SOP describes the process of SOP development, approval, and maintenance of written procedures to ensure compliance with regulations, guidelines and policies at study sites. This SOP also describes the procedures for training and updating study staff in existing and new SOPs.

Scope

This SOP applies to all members of the PaCCSC clinical research team and all staff involved in clinical studies conducted by PaCCSC irrespective of individual organisational employment, role or position.


Responsibilities of the PaCCSC National Project Officer / National Manager

To develop all new SOPs or revise existing SOPs To maintain a table of contents by number and title of SOP To maintain a historical record of all previous versions of SOPs To ensure appropriate copyright is maintained for all SOPs To monitor site compliance with SOPs

Responsibilities of the PaCCSC Scientific Committee

To review all new and revised SOPs To approve all new and revised SOPs


To sign and date SOPs on behalf of the approving committee To assume accountability for compliance with SOPs

Responsibilities of all members of the clinical research team involved in supervising, managing, or conducting PaCCSC study-related activities

To familiarise themselves with and comply with the PaCCSC SOPs


To assume accountability for compliance with the PaCCSC SOPs

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5.1.1 V2.2 Page 3 of 6

Procedure

1. Preparing new SOPs or revising previous SOPs

PaCCSC National Project Officer / National Manager:

Develop a new SOP or revise as existing SOP following any of these circumstances: o Requests from the PaCCSC Trials Management Committee (TMC), the PaCCSC

Management Advisory Board (MAB), PaCCSC Scientific Committee (SC), or PaCCSC Data Safety Monitoring Committee (DSMC)

o Changes in practice, policy or regulations o Periodic review of SOP o Expiry of existing SOP

Include in each SOP the following template information (see Template 30): o SOP title o SOP number (generally related to the appropriate section of ICH GCP E6) o SOP version o Date of current version o SOP history o SOP approval o Number of pages

Develop the SOP content with: o Introduction / Background o Objective o Scope o Ownership and Responsibility o Procedure o Other related SOPs o Other related documents o References o Acknowledgments

Maintain a table of contents by number and title of SOP Maintain a historical record of all previous versions of SOPs Maintain copyright by inserting the copyright symbol in the page header of each SOP

PaCCSC Scientific Committee:

Review the draft SOP to ensure accuracy and completeness Submit to other committees as appropriate (TMC, MAB, DSMC) Approve the SOP following finalisation

2. Reviewing SOPs

PaCCSC National Project Officer:

SOPs are periodically reviewed every two years (or more often if required). The review includes accuracy, currency and compliance with regulations and guidelines using the procedure above.

When no changes are required to the content of the SOP, a new version number and review date are generated.

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5.1.1 V2.2 Page 4 of 6

3. Approval of SOPs

New and revised SOPs are distributed to the relevant committee for discussion and approval.

SOPs are signed and dated by the Lead Investigator of PaCCSC on behalf of the approving committee.

The PaCCSC Scientific Committee is responsible for approval of new and/or revised SOPs.

PaCCSC SOPs are covered by the UTS Intellectual Property Policy and as such are subject to copyright.

PaCCSC National Manager:

Following sign-off, the finalised SOP is converted to PDF format An electronic copy is saved on the PaCCSC Coordinating Centre shared network drive New and revised SOPs are disseminated to all team members and study sites via:

o The provision of paper copy o Email distribution notice to all study sites and team members o Direct teleconference o Upload onto www.uts.edu.au/paccsc after email notification

4. Training on new or revised SOPs

The PaCCSC Coordinating Centre is responsible for disseminating information about and training on all SOPs within one month of approval of the SOP. Training is via one or more of the following:

Site coordinators teleconferences Individual telephone calls to sites Workshops and training sessions

Following receipt and training of new SOP, it is the responsibility of all study sites to:

Insert the updated table of contents into the site SOP folder Insert the new/revised SOP into the site SOP folder Train and instruct the relevant site staff including study nurses and administrative

assistants. This must be recorded in the Staff Training Log (refer SOP 4.2.4 Delegation of Duties)

PaCCSC SOP Feb 2018

5.1.1 V2.2 Page 5 of 6

Other related SOPs

4.2.4 Delegation of Duties


Template 30: SOP Development Template SOP Contents Page SOP Glossary

References

COSA Standard Operating Procedures for Investigational Sites. March 2006. A publication of the Centre for Clinical Research Practice, Inc.



PaCCSC SOP Feb 2018

5.1.1 V2.2 Page 6 of 6

History



New procedure

2.0 1/02/2010 B Fazekas Ratified by MAB




Approval


2.2 David Currow


5.5.1 V2.2 Page 1 of 8

5.5.1 Electronic Data Handling

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

5.5.1 V2.2 Page 2 of 8


The correct management of research data and files is crucial to the integrity of the final results. Correct management enables researchers to accurately substantiate publication results, and also meet reporting and auditing requirements.

Objective

This SOP describes the procedure for electronic data management, data entry and error resolution. A comprehensive manual for CRF completion and data entry will be available for each site to refer to for specific routine site data management.

Scope

This SOP applies to all sites involved in clinical studies conducted by PaCCSC. It also applies to all staff involved in clinical studies conducted by PaCCSC irrespective of individual organisational employment, role or position.


It is the responsibility of the Principal Investigator to ensure that all data and files are accurately managed. The task may be delegated to another suitably trained individual as documented on the Staff Signature and Delegation Log (refer SOP 4.2.4 Delegation of Duties) but the responsibility remains with the Principal Investigator.

PaCCSC SOP Feb 2018

5.5.1 V2.2 Page 3 of 8

Procedure

1. Source documents

These include: original documents, data and records (hospital records, clinical file charts, laboratory notes, diaries, checklists, dispensing records, etc.). These documents allow for reconstruction and evaluation of the study. Data held within source documents are the first record of clinical observations. Examples include (but are not limited to):

Original signed consent form; Pathology reports to confirm blood results used as eligibility screening; Clinical records charting patient clinical assessment, used to monitor patient eligibility or

progress; Dangerous Drug Accountability signature sheets to show correct checking and

dispensing procedures; CRFs where patient information, (such as, vital signs, patient responses to specific

questions, assessments made while with the patient, among others), are recorded during a patient visit (especially if this forms the only record of the information and is not a transcription recorded elsewhere);

Quality of life or other participant completed questionnaires and forms completed as part of the study measures, and where this recording is the original or only recording of the scores and responses at that time.

Source data also include the data recorded within case report forms (CRFs) or contained on audiotapes if these data forms clinical data from which analysis is conducted and not contained within other source documents. For example, if clinical observations are recorded within the CRF and used as study data, this is then source data (refer SOP 4.9.2 Source Data and Documentation).

2. Research data management systems (RDMS)

PaCCSC uses the following research data management systems:

CareSearch OpenClinica REDCap

These systems have been developed to support research work within palliative care by providing access to tools that:

Enable the online design of data collection forms and questionnaires; Allow for web-based and email-based form completion; Enable data entry from multiple sites with a single coordinating site; Provide for basic reporting of results with features such as percentages, graphs, and

tables; Allow export of data to other programs such as Excel, Access or SPSS.

These password protected systems are used by PaCCSC for entry of all participant data collected during the course of each study procedure.

PaCCSC SOP Feb 2018

5.5.1 V2.2 Page 4 of 8

These systems contain the data for the CRFs and a range of data collection forms specific for each study. Access is allowed via the PaCCSC National Project Officer. There are a number of levels of access to the data management systems:

Administrator access – very limited number of people have password access to enable website design and maintenance.

Manager access – users can check and query data entered by others, with access to the forms provided by the administrators. This level of access enables data correction and query generation, reporting and download functions.

Project officer access – users can access a restricted number of forms (allocated by the manager) and are able to view the CRFs for printing and direct data entry only.

Nominated study staff will have access to enter data only. This will require password access. This access must not be given to anyone else through the sharing of passwords.

The PaCCSC National Project Officer will maintain a register of those provided with access to the data entry system, along with the date of access and the date access ceased.

Separate instructions are provided during site initiation for each study and in the PaCCSC work instructions.

3. Data collection

The points at which specific data are collected are specified within the study protocols (e.g. the table of study measures). All investigations, forms, questionnaires and all other data are to be included.

4. Electronic recording

Study data will be recorded in a number of files for both the administration of the study and collection of subject data.

At each site, a Patient Master Index (Template 12) will contain the confidential subject contact information and will be the only link between individual subjects and the ID number. Each site will generate a site specific Patient Master Index for subjects recruited at that site.

The PaCCSC Coordinating Centre will maintain a register of data entry and checking, the date of return to the study site for correction, the date of return or correction, and the date of resolution. This log will enable paper or electronic data to be tracked for query resolution, completeness, and invoice generation.

The data files will be held and administered in the PaCCSC Coordinating Centre, and will contain the subject data as downloaded from the Electronic Data Capture System (CareSearch; OpenClinica; REDCap). These data will then be transferred to the data set for analysis on request and on completion of the study enrolment.

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5.5.1 V2.2 Page 5 of 8

5. Data entry

Data will be entered from each site into a web-based interface specifically developed for each study. This password protected interface is protected to reduce the risk of unauthorised access.

No personally identifying information will be entered on this interface at any time. Specific care is to be taken when recording clinical information such as notes within Serious Adverse Events.

The PaCCSC Coordinating Centre will download and store the data on a regular basis as an excel file. The data can then be transferred to the study statistician using SOP 5.5.2 Data Transfer for conversion into other file types for analysis.

5.1 CRF data entry

The paper CRFs will be designed to capture the required data and to enable smooth data entry through similar question and response structures so as to reducing data entry errors.

Data entered on the paper CRFs will be transferred to the web-based data entry form. On completion of data entry for each form, the study site will ‘submit’ the data. Any further changes to the data will initiate a log of changes in the form of an audit trail. A copy of the original CRF will be forwarded to the coordinating site to enable verification

of data entry and filing.

6. Data verification

The PaCCSC Coordinating Centre will systematically conduct a manual check of the data recorded on the CRFs against the data recorded online to ensure completeness and accuracy of data entry.

The extent of the data checking will be decided by the study investigator group and in accordance with the study Data Management Plan (Template 10).

7. Data safety

The online data entry systems are held within off-site servers. The servers have specific back-up and safety in accordance with the practice of the system.

8. Data archiving

Electronic archiving (refer SOP 8.4.1 Archiving) can take place once:

Study recruitment is complete; All data have been entered; All data have been checked and errors resolved; The database has been closed to any further changes; The data have been downloaded as the final data set and sent to the study statistician; The main results publication has been accepted for publication in a peer reviewed journal;

or The decision has otherwise been made by the Lead Investigator to archive the data.

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5.5.1 V2.2 Page 6 of 8

At this point the RDMS database administrator is informed of data closure using the form of notification in accordance with the requirement of the RDMS (Template 13).

The data base owner will confirm destruction to the CareSearch / OpenClinica / REDCap Administrator to enable removal of the data from the research data management platform. The data will then be permanently deleted from the research data management system in accordance with their Standard Operating Procedures.

8.1 Data retention

The retention of closed or locked data will be in accordance with the study protocol, ethics

approval, and the NHMRC Australian Code for the Responsible Conduct of Research.

The database will be electronically archived or deleted, after the study team confirms that data can be deleted and a secure archive back-up has been generated (refer SOP 8.4.2 Record Destruction). The process will be minuted for auditing purposes.

PaCCSC SOP Feb 2018

5.5.1 V2.2 Page 7 of 8

Other related SOPs

4.9.2 Source Data and Documentation 5.23.1 CRF Completion 5.5.2 Electronic Data Transfer 5.18 Monitoring 8.0 Essential Documents 8.4.1 Archiving 8.4.2 Record Destruction


Template 10: Data Management Plan Template 12: Patient Master Index Template 13: Data Closure Form

References



King DW, Lashley R. A quantifiable alternative to double data entry. Controlled Clinical Trials 2000; 21(2):94-102.


PaCCSC Work Instructions

Praxis Australia

PaCCSC SOP Feb 2018

5.5.1 V2.2 Page 8 of 8

History







2.0 1/02/2011 B Fazekas New version with all updates




Approval


2.2 David Currow


5.5.2 V2.2 Page 1 of 5

5.5.2 Electronic Data Transfer

Version V2.2


Approved D Currow




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5.5.2 V2.2 Page 2 of 5


Data for clinical studies may need to be stored, checked and managed in a separate location from where the data will be monitored or analysed. PaCCSC need to ensure that study data are transferred from one person and location to another in a timely, safe and secure manner that will maintain data integrity and participant anonymity.

Objective

This SOP describes the procedure for data transfer for data generated within PaCCSC. In most cases this data transfer occurs when the study statistician needs to check allocation codes against study data (for data safety monitoring) or for study analysis (interim or final). Subject to approval by the Lead Investigator, others may request access to the study data at various times throughout the study.

Scope

This SOP applies to all sites involved in clinical studies conducted by PaCCSC. It also applies to all staff involved in clinical studies conducted by PaCCSC irrespective of individual organisational employment, role or position.


It is the responsibility of the Principal Investigator to ensure that all data and files are accurately managed. The task may be delegated to another suitably trained individual as documented on the Staff Signature and Delegation Log (refer SOP 4.2.4 Delegation of Duties) but the responsibility remains with the Principal Investigator.

Responsibilities of the PaCCSC National Project Officer

To download data from the Coordinating site and save on a secure drive as a back up To save the data with clear version control to enable changes and updates to be tracked

over time

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5.5.2 V2.2 Page 3 of 5

Procedure

1. Data download

This procedure is undertaken by the PaCCSC National Project Officer at the Coordinating site, and downloaded onto a password protected network drive, with clear and secure backup and retrieval procedures.

On each occurrence, the following procedure is followed:

Data download is saved to password protected computer as an excel workbook or CSV text file with file name indicating Case Report Form (or other data file) name and date.

The downloaded file is viewed for completeness and gross validation. This is not data checking (refer SOP 5.5.1 Electronic Data Handling) but a check to see that all data fields have been downloaded in a complete and consistent manner.

2. Database checking

The date base for each study is checked by the Coordinating site at the time of download for the following elements:

To identify and remove any duplicate or blank entries Correct any participant ID numbers that have been incorrectly entered, and where the ID

number can be verified from another source (for e.g., email confirmation or Randomisation Registration Notification)

File notes and data report forms are used in order to document changes to the data base.

3. Data safety

This procedure is undertaken when there has been an authorised specific request for data from an external source (refer SOP 5.5.10 Data Ownership and Utilisation):

Each data file is protected within Excel using encryption and password through the Protect Worksheet function.

All files are then “zipped” into a Winzip file. The data file is sent via email to the responsible party (this may be the PaCCSC Coordinating Centre, Lead Investigator, PaCCSC Data Safety Monitoring Committee member or Lead Statistician depending on the data and the request).

The password to open the zipped data file is forwarded to the responsible party separately via telephone or by email where the subject line does not link the two emails.

The responsible party opens the encrypted data file using the password and imports the data into an appropriate statistics programme using the import function.

Field and data codes are entered as per the study data dictionary in order to facilitate analysis.

The main study data are merged with the table of allocation codes by the responsible party. This will only take place in the following situations: o For unmasked data analysis as requested by the PaCCSC Data Safety Monitoring

Committee o At the completion of study accrual to facilitate all study analyses

PaCCSC SOP Feb 2018

5.5.2 V2.2 Page 4 of 5

Other related SOPs

4.2.4 Delegation of Duties 5.5.1 Electronic Data Handling 5.5.10 Data Ownership and Utilisation 8.0 Essential Documents


N/A

References


PaCCSC SOP Feb 2018

5.5.2 V2.2 Page 5 of 5

History










Approval


2.2 David Currow


5.5.5 V2.3 Page 1 of 6

5.5.5 Allocation of Participant Identification Numbers

Version V2.3


Approved D Currow




PaCCSC SOP Feb 2018

5.5.5 V2.3 Page 2 of 6


Participants in clinical studies have the right to have their identity protected. Data collected about the participant is recorded in such a way that it is not possible to link individual study data (held by the Coordinating Centre) with the participant. This is done through the use of unique identification numbers to replace the use of participant initials or name.

Objective

This SOP describes the process of assigning identification numbers to participants of Palliative Care Clinical Studies Collaborative (PaCCSC) studies.

Scope




To develop a unique and unambiguous identification code schema that allows identification of all the data reported for each participant in the study

To disseminate the code schema to study sites so they can use it to assign Participant Identification (PID) numbers to participants

Responsibilities of the Principal Investigator or delegate as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties)

To assign a unique code to each participant as they are consented to the study, in accordance with the schema devised by the coordinating site

To maintain the Patient Master Index which provides the site specific link between the details of the participant and the unique PID number assigned to them

To ensure that the unique PID number assigned to each person is correctly used on all data forms and reporting records

PaCCSC SOP Feb 2018

5.5.5 V2.3 Page 3 of 6

Procedure

Following referral of a potential participant to a study, a pre-screening form is completed containing the 7 digit ID number allocated as described below.

The 7 digit number contains:

A two (2) digit study code A two (2) digit site code A three (3) digit participant number

o This number is a sequential number starting at 001. o This number is entered along with the participant’s details into the site maintained

Patient Master Index (Template 12) as the site record of screening.

1. Study code

This code identifies each participant within a specific study. The study code is a two digit number generated from the protocol code and listed in Guidance 8 PID Number Sequencing. Protocol codes for PaCCSC are usually a 3 digit sequential number associated with the 2 digit year of development (013/15). The study code takes the last 2 numbers, for example 13 for a protocol code of 013/15.

2. Site Code

This code identifies each site within each study. Each site is assigned a unique code number by PaCCSC. This number forms part of the ID number. This enables recruitment numbers by site to be easily tracked at any point for reporting and monitoring of Key Performance Indicators. The site codes are listed in Guidance 8 PID Number Sequencing.

3. Pre-screening

Upon completion of the pre-screen process a combination of numbers are assigned to the participant.

For example: The construction of the ID number structure is: Study code/Site code/ID number

In practice, the actual ID number is: 01/02/001

In this example, this number indicates the following participant details: Ketamine study/Braeside/individual number 001

4. On screening

The number sequence described above continues through the screening process.

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5.5.5 V2.3 Page 4 of 6

5. On randomisation

When a participant becomes eligible for the study and is randomised to receive a study intervention, a further number sequence is added to the existing ID number.

The randomisation number provided by the clinical study pharmacist is also added on to the ID number sequence. This is a 3 digit number.

For example: The explanation of the ID number structure at randomisation is: Study code/Site code/ID number/ randomisation number

In practice, the actual ID number is: (03/02/001/ 001)

This number indicates the following participant details Octreotide study/Braeside/individual 001/randomisation number 001

The full sequence of numbers enables the investigators to determine how many participants have been referred to any study at any site, how many of them have been randomised and to which strata.

Further examples:

02/07/030/003 Risperidone study at Calvary Mater Newcastle, 30 people have been referred to the study, and 3 are randomised.

05/04/006/006 Megestrol acetate study at Southern Adelaide Palliative Services, 6 people referred to the study, all are randomised.

For earlier studies where the randomisation was stratified, a letter code (indicating the strata) was also provided and added to the ID number.

PaCCSC SOP Feb 2018

5.5.5 V2.3 Page 5 of 6

Other related SOPs

4.2.4 Delegation of Duties 5.5.1 Electronic Data Handling


Template 9: File Notes Template 12: Patient Master Index Guidance 8: PID Number Sequencing

References


Acknowledgments


PaCCSC SOP Feb 2018

5.5.5 V2.3 Page 6 of 6

History








2.2 6/05/2016 L Devilee Update to site and study numbers



Approval


2.3 David Currow


5.5.10 V1.4 Page 1 of 7

5.5.10 Data Ownership and Utilisation

Version V1.4


Approved D Currow




PaCCSC SOP Feb 2018

5.5.10 V1.4 Page 2 of 7


The Australian Code for the Responsible Conduct of Research (2007) requires research institutions to have policies that address the ownership of data, including their retention beyond the end of the project and appropriate access to them by the research community.

Furthermore, The Australian Code of the Responsible Conduct of Research (2007) requires research collaboratives to have agreed arrangements in place for data ownership prior to the commencement of the project.

Data ownership is different from data storage and data management. The data owner is the person(s) (or entity) identified as having overall responsibility for the research data. Research data may be stored at multiple research sites during and following the research project.

Objective

This SOP defines and describes how data ownership is determined within PaCCSC to ensure its integrity, safety and use, now and in the future.

Scope



Responsibilities of the PaCCSC National Manager

To negotiate data ownership agreements between commercial sponsor and PaCCSC on behalf of University of Technology Sydney

To manage requests for access to or utilisation of PaCCSC data To liaise with the study Chief Investigator and the Chairs of the PaCCSC Scientific

Committee, the Publications Sub-Committee, and any other relevant study sub-committee, regarding requests for data access or utilisation

To maintain a log of requests for data access or utilisation To provide the log for review at each meeting of the PaCCSC Scientific Committee

PaCCSC SOP Feb 2018

5.5.10 V1.4 Page 3 of 7

Procedure

1. PaCCSC-sponsored studies

Data created in any PaCCSC-sponsored study are owned by PaCCSC (legal entity is University of Technology Sydney) and are managed by the PaCCSC Scientific Committee with advice from the Lead Investigator of the particular study.

The data relating to any PaCCSC-sponsored study will be owned by PaCCSC (University of Technology Sydney) unless the study is conducted as per items 2 or 3 below.

PaCCSC is the data custodian for all PaCCSC-sponsored studies.

The data owner is documented in the Clinical Trial Research Agreement (as per the Medicines Australia Standard Agreement), held between PaCCSC and each participating site for each PaCCSC-sponsored study.

Data ownership is reviewed and updated whenever appropriate, including (but not limited to): o If the agreed, documented data owner leaves the collaboration. o If the agreed, documented data owner moves from one institution / organisation to

another. o Following completion of the project.

Requests for access to data from any party (recruiting site, other research centre or collaboration, etc.) are referred to the Scientific Committee or under the direction of the Chair referred for consideration by the PaCCSC Publications Subcommittee.

Data collected by individual trial sites in relation to a specific trial/study is referred to in the Clinical Trial Research Agreement (CTRA) in place for each individual study and referred to as Study Materials. For information regarding ownership, rights and use of such materials the CTRA for the site/study should be referred to.

2. Joint ownership

As well as sponsoring studies, PaCCSC also conducts and coordinates clinical research trials in collaboration with other Universities and research collaboratives. These are referred to herein as joint ownership research.

Prior to agreement to conduct external collaborative research, data ownership is negotiated between the parties by UTS Legal Services on behalf of University of Technology Sydney. Specific data ownership issues negotiated include (but are not limited to): o Arrangements if the research is terminated early; o Arrangements if one party withdraws from the study; o Arrangements for data ownership at the completion of the study; o Process for addressing requests to access data from external parties.

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The agreed data ownership arrangements are documented in the head Research Collaboration or Multi-institutional Agreement (or equivalent) between the external party and University of Technology Sydney. This Agreement is produced by one party, usually the Grant Holder, and negotiated between the parties.

The Research Collaboration or Multi-institutional Agreement is reviewed by UTS Legal Services (legal body of University of Technology Sydney) and once agreement is reached the agreement is signed by an approved person of both legal entities.

3. Commercial studies

As well as sponsoring studies, PaCCSC also conducts and coordinates clinical research trials on behalf of commercial organisations (for e.g., the pharmaceutical industry). These are referred to herein as commercially sponsored trials.

Prior to agreement to conduct a commercially sponsored trial, data ownership is negotiated between the commercial sponsor and the PaCCSC Lead Investigator and National Manager on behalf of University of Technology Sydney. Specific data ownership issues negotiated include (but are not limited to): o Arrangements if the commercially sponsored trial is ceased; o Arrangements if the data owner withdraws from the study; o Arrangements for data ownership at the completion of the study; o Process for addressing requests to access data from external parties.

In most commercially sponsored trials, data ownership sits with the commercial entity and University of Technology Sydney (PaCCSC) is given rights to use the data for the purposes of publishing study results. However, these arrangements are individually negotiated for each study and each commercial sponsor.

The agreed data ownership arrangements are documented in the head Clinical Trials Research Agreement (or equivalent) between the commercial sponsor and University of Technology Sydney. This Agreement is produced by the commercial sponsor and negotiated between the parties.

The head Clinical Trials Research Agreement is reviewed by UTS Legal Services (legal body of University of Technology Sydney) and once agreement is reached the agreement is signed by an approved person of both legal entities.

PaCCSC initiates Clinical Trials Research Agreements for all the participating recruiting sites in the commercially sponsored trial. The data ownership arrangements are included in these Agreements. The participating sites retain no ownership over the data in commercially sponsored trials.

Data ownership arrangements are regularly reviewed in accordance with the requirements of the Australian Code for the Responsible Conduct of Research (2007).

Disputes regarding data ownership are referred to the PaCCSC Scientific Committee for consideration and engagement of legal representation from UTS Legal Services if deemed necessary.

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4. Procedure for handling of requests for access to or utilisation of PaCCSC data

Requests for the use, viewing, manipulation or otherwise of PaCCSC data are to be made to the PaCCSC National Manager (NM).

The NM will keep a log of requests (Template 25), including dates, names, outcome of Chair approval, date data provided to requester, date for 12 month follow up of requester where required.

The NM will provide a descriptive outline of the request to the following: o Chair of the Scientific Committee o Chair of the Publications Sub-Committee o Study Chief Investigator o Chair of any study sub-committee (if in place).

The Chairs and study Chief Investigator will liaise accordingly to discuss the request and provide a response to the NM. This will be on a case by case basis.

If access is allowed by the Chairs and study Chief Investigator, the NM will: o Ask the requester to sign the PaCCSC (University of Technology Sydney)

Confidentiality Agreement (unless one is already in place). o Provide the requester with the ‘Rules’ as listed in Guidance 11 and seek their

agreement to these in writing (email is sufficient). o Once the confidentiality agreement is signed and the ‘Rules’ for use of data agreed

upon, provide the requester with the data requested, or part thereof, as approved o Add the information as an entry to the Planned Publications Master List (refer SOP

6.15.1 Dissemination of Study Results) as a means of maintaining a log of the data use.

o Ensure that the requester is prompted to destroy or return the data to PaCCSC 12 months from provision of the data.

o Complete the log.

If the Chairs determine access cannot be given to the requester, the NM will: o Advise the requester of the decision o Complete the log.

The NM will provide the ‘log’ file for review at each meeting of the Scientific Committee.

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5.5.10 V1.4 Page 6 of 7

Other related SOPs

6.15 Authorship 6.15.1 Dissemination of Study Results 5.5.1 Electronic Data Handling 5.5.2 Electronic Data Transfer 8.4.1 Archiving of Research/Project Materials 8.4.2 Record Destruction


Template 25: Data Requests Log Guidance 11: Data Usage Rules

References




Practical Data Management: A Legal and Policy Guide Version 1. Queensland University of Technology 2008

University of Technology Sydney Code of Conduct (accessed 21/12/2017) http://www.gsu.uts.edu.au/policies/code-conduct.html

University of Technology Sydney Research Ethics and Integrity Policy (accessed 21/12/2017) http://www.gsu.uts.edu.au/policies/research-ethics-integrity-policy.html


PaCCSC SOP Feb 2018

5.5.10 V1.4 Page 7 of 7

History


1.1 1/06/2015 L Devilee New procedure

1.2 28/01/2016 L Devilee Updated draft to include comments from Scientific Committee August 2015

1.3 9/06/2016 L Devilee Updated draft to include comments from Scientific Committee June 2016



Approval


1.4 David Currow


5.6.1 V1.3 Page 1 of 5

5.6.1 Site Selection

Version V1.3


Approved D Currow




PaCCSC SOP Feb 2018

5.6.1 V1.3 Page 2 of 5


There are several factors that influence the capacity of a site to undertake research, successfully recruit participants and meet the state, national and international regulations of clinical trials conduct.

Sites participating in or wishing to participate in clinical studies conducted by PaCCSC must undergo site feasibility/risk assessment prior to the start of a clinical trial to establish their capacity and resource capabilities to undertake research (including, but not limited to, their clinical expertise, access to specialities, patient population, and capacity of Principal Investigators).

Objective

This SOP provides guidance on the selection of new sites to participate in a given PaCCSC clinical trial, and details the site feasibility/risk assessment of the site prior to the start of the clinical trial.

Scope

This SOP applies to all sites that have either expressed interest or been approached to take part in clinical studies conducted by PaCCSC.


Responsibilities of the Principal Investigator (of the new study site)

To notify the PaCCSC National Manager of their intention to become a new site


To provide the Principal Investigator of the potential new site with: o A summary of the specific study under enquiry o A confidentiality agreement form o General information about PaCCSC and the contractual and agreement

documents required


To follow up with the new site To provide contact information about the new site To provide the site feasibility checklist To provide any further information to the site To commence study initiation procedures as appropriate

PaCCSC SOP Feb 2018

5.6.1 V1.3 Page 3 of 5

Procedure

When a new site approaches PaCCSC or PaCCSC approaches a potential new site:

The National Manager contacts the potential Principal Investigator at the new site via email and provides the Site Feasibility Checklist.

The new site Principal Investigator determines if the site would like to progress and informs PaCCSC National Manager.

PaCCSC conducts a site feasibility and study feasibility evaluation of all potential pilot sites, using the Site Feasibility Checklist (Template 5), Study Feasibility Checklist (Template 21) and Site Risk Assessment Toolkit (Template 6). o The Site and Study Feasibility Checklists are sent by the PaCCSC Coordinating

Centre to the Principal Investigator.

The Principal Investigator completes the Site Feasibility Checklist (Template 5) and Study Feasibility Checklist (Template 21) based on the current clinical and administrative context at the site (not prospective context). The PaCCSC Coordinating Centre can assist with any specific queries regarding the checklists.

The Principal Investigator sends the completed Site Feasibility Checklist and Study Feasibility Checklist to the PaCCSC Coordinating Centre (a copy of the checklists is kept by PaCCSC for future reference).

The PaCCSC Coordinating Centre uses the Site Feasibility Checklist to complete the Site Risk Assessment Toolkit (Template 6), and works with the site to address any issues identified in the Site and Study Feasibility Checklists and Site Risk Assessment Toolkit.

The study Lead Investigator determines (in consultation with the PaCCSC National Manager) when a new site is ready to be initiated in to the study.

The decision to initiate a new site is emailed to the Principal Investigator of the new site.

The initiation of a new site is communicated (by email, meeting minutes or by telephone) to all other sites participating in the study, the PaCCSC Trials Management Committee and the PaCCSC Scientific Committee.

For each trial, a structured risk assessment is undertaken by the Sponsor to identify potential patient, study or organisational hazards.

PaCCSC SOP Feb 2018

5.6.1 V1.3 Page 4 of 5

Other related SOPs

N/A


Template 5: Site Feasibility Checklist Template 6: Site Risk Assessment Toolkit Template 21: Study Feasibility Checklist

References






Praxis Australia

PaCCSC SOP Feb 2018

5.6.1 V1.3 Page 5 of 5

History






Approval


1.3 David Currow


5.7 V1.0 Page 1 of 6

5.7 Site Initiation

Version V1.0


Approved D Currow




PaCCSC SOP Feb 2018

5.7 V1.0 Page 2 of 6


All studies conducted at PaCCSC must undergo a set process for study start-up, following Human Research Ethics Committee (HREC) and Governance approval, and before subject recruitment.

Objective

This SOP describes the procedure for setting up a study sponsored or hosted by PaCCSC at a recruitment site.

Scope

This SOP applies to Principal Investigators running a research study (both Investigational drug studies and non-drug studies, conducted in Australia) sponsored or hosted by PaCCSC. It applies to all members of staff who manage, coordinate or advise on clinical research.


Responsibilities of PaCCSC/Sponsor

The responsibility for setting up sites lies with the external sponsor, on behalf of the lead investigator team

Responsibilities of the site Principal Investigator and/or other designee(s) as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties)

To provide adequate training and preparation at the site for which they are responsible

PaCCSC SOP Feb 2018

5.7 V1.0 Page 3 of 6

Procedure

After successful completion of the Site Feasibility Checklist (Template 5), Study Feasibility Checklist (Template 21) and the Site Risk Assessment Toolkit (Template 6) (refer SOP 5.6.1 Site Selection):

The study Lead Investigator determines (in consultation with the PaCCSC National Manager) when a new site is ready to be initiated in to the study.

The decision to initiate a new site is emailed to the Principal Investigator of the new site.

The initiation of a new site is communicated (by email, meeting minutes or by telephone) to all other sites participating in the study, the PaCCSC Trials Management Committee and the PaCCSC Scientific Committee.

The Principal Investigator is invited to attend the appropriate committees, usually the Trial Management Committee.

1. Site initiation Meetings

All sites undergo site initiation prior to the trial starting. The agenda is determined by their previous exposure to conducting studies and their prior involvement with PaCCSC.

1.1 Existing sites

Existing sites (i.e. sites that have participated in a PaCCSC study prior to the study in question) undergo a one day meeting with members of the PaCCSC Coordinating Centre, following the appropriate Agenda (Template 33).

1.2 New sites

New sites (i.e. sites that participate for the first time in a PaCCSC study) undergo a two day meeting with members of the PaCCSC Coordinating Centre, following the appropriate Agenda (Templates 34).

Site initiation meetings will take the following format:

The site initiation meeting is arranged for all research staff involved, including Pharmacy and supporting services as appropriate, once all the agreements and approvals are in place.

The meeting covers a review of the study protocol highlighting procedures and drawing attention to any study specific Standard Operating Procedures (SOPs). It also covers Patient Information and Consent Forms (PICFs). Research staff are also reminded of the importance of Research Governance and attention drawn to the principles of Good Clinical Practice (GCP), relevant legislation and subsequent amendments (if applicable).

o The agenda, attachments and attendance is to be filed in the Trial Master File Index (Template 20).

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Study specific procedures and training also take place at this meeting, in addition to a general discussion about recruitment barriers, local issues, and other times identified during the risk assessment and other contact.

The site initiation meeting is also a good opportunity for the study staff to complete the delegation log and ensure their Curriculum Vitae (CV) is signed and on file.

2. Approvals

It is the responsibility of the Principal Investigator to ensure that appropriate regulatory and ethics approvals are in place before the Site Initiation Visit / Study Start-up Meeting and recruitment starts. This includes a Therapeutic Good Administration (TGA) Clinical Trials Notification (CTN) acknowledgement or a Clinical Trial Exemption (CTX) approval), and HREC approval.

It is the responsibility of the Principal Investigator at each site to ensure that local Governance approval is in place before recruitment begins.

The Principal Investigator is also responsible for ensuring that the sponsor and the site agreements (for multi-centre studies) are in place before recruitment begins.

For Investigational Drug studies, Governance approval will not be issued until appropriate regulatory approvals and sponsorship agreements are in place.

3. Establishing a Trial Master File (TMF) and Investigator Site File (ISF)

The PaCCSC Coordinating Centre is responsible for establishing a Trial Master File Index.

The Trial Master File Index is to be distributed to each Principal Investigator at start up to enable comprehensive document management at each site.

An Investigator Site File (ISF) must also be established for all research sites before recruitment begins. It is the responsibility of the Principal Investigator at each site (if multi-centre) to ensure that all required documents are collected and filed in the ISF. o This task may be delegated to another member of the research team but this

delegation should be formally documented in the study Staff Signature and Delegation Log.

o Once established, the ISF should be kept in a secure location and be updated as the study progresses.

PaCCSC SOP Feb 2018

5.7 V1.0 Page 5 of 6

Other related SOPs

4.1 Investigator Responsibilities 4.2.4 Delegation of Duties


Template 5: Site Feasibility Checklist Template 6: Site Risk Assessment Toolkit Template 21: Study Feasibility Checklist Template 33: Site Initiation One Day Program Template 34: Site Initiation Two Day Program

References

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). November 2016. (accessed 23/10/2017) https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf

Praxis Australia

PaCCSC SOP Feb 2018

5.7 V1.0 Page 6 of 6

History



New procedure

Approval


1.0 David Currow


5.14.1 V2.2 Page 1 of 6

5.14.1 Investigational Product Handling

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

5.14.1 V2.2 Page 2 of 6


Good Clinical Practice requites investigational product accountability at the trial site. It also requires that the investigational product(s) are used only in accordance with the approved study protocol.

Objective

This SOP describes the processes for investigator and study personnel when prescribing, receiving, transporting and accounting of investigational products involved in clinical studies.

This SOP does not cover the following:

Preparation of investigational products by the sponsor or Site Pharmacy; Transport of investigational product between manufacturer and pharmacy; Transfer of investigational product between sites and pharmacies.

These procedures are described within the pharmacy manuals supplied to Site Pharmacies for each study.

Scope



Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.


To receive prescriptions, transport, deliver and return Investigational Products

Responsibilities of the Site Pharmacy

To account for and destroy or return all product containers (including the unused product) on exit from the study

PaCCSC SOP Feb 2018

5.14.1 V2.2 Page 3 of 6

Procedure

1. Prescribing

All prescriptions for the use of Investigational Products for clinical studies are:

Completed in accordance with standard hospital prescription procedures and the study protocol (refer Guidance 6).

2. Receipt

Prescriptions for Investigational Products can be received by:

The participant and/or family member Clinical study team member (as designated in the study staff signature sheet)

The person receiving the Investigational Product signs the receipt of the Investigational Product as specified by the appropriate legislation (for e.g., where Schedule 4 or 8 drugs are being dispensed).

The Investigational Product being received is checked against the prescription. In the event of an unanticipated delay in transporting the Investigational Product (for e.g., if the Investigational Product has been collected from pharmacy for delivery to the participant, and the participant is not available to receive the Investigational Product as planned), the Investigational Product is returned to the pharmacy for storage, if possible.

In the event that returning the Investigational Product to pharmacy is not possible, the Investigational Product is stored within a storage safe, consistent with regulatory and legislative requirements. For example, Schedule 4 and Schedule 8 products are stored within a securely fixed and locked safe which meets the local State or Territory requirements. The short term storage must also meet the specified storage requirements for the investigational product, such as refrigeration, protection from light etc.

Investigational Products must not be stored within unsecured premises at any time.

3. Transporting

The Investigational Product is contained within a zip lock pack (or other suitable packaging) for one participant only with the associated prescribing and checking documents. This pack is transported intact and within any other necessary packaging to further ensure safety and maintenance of temperature (if required) during transport. This may include storage within the car boot, within a bag or case, within a cooler or ice pack as determined by the protocol and/or instruction from the pharmacist.

PaCCSC SOP Feb 2018

5.14.1 V2.2 Page 4 of 6

Security of the Investigational Product is paramount during transportation. Security measures include (but are not limited to):

Planning ahead to ensure receipt and dispensing times coincide with as little delay as possible.

When transporting the Investigational Product by car, the model of car optimises security. For example, a car boot that is fully enclosed and has a well-fitting door. A station wagon/hatch model car may not suit this requirement.

Locking the transport vehicle at all times, with the key carried by the driver. The vehicle must not be left unattended with the engine running.

The transport vehicle must not be left unattended for extended periods of time while carrying Schedule 4 or 8 drugs.

4. Delivery

The Investigational Product is delivered to the participant. The following measures are considered when planning and executing delivery of an Investigational Product:

Ensuring the participant is available to receive the Investigational Product. The product is explained by an appropriate person as delegated by the Principal

Investigator as per the Study Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties).

The Investigational Product container is checked for contents. Shortages or discrepancies are reported immediately to the pharmacy of origin. In the case of Drugs of Dependence, any unresolved discrepancies are reported to police within 24 hours in accordance with the local State or Territory regulatory and legislative requirements.

Where required, the study team member delivering the Investigational Product signs the prescription copy to indicate delivery to the participant. When able, the participant signs the appropriate section to indicate receipt of the product.

Participants are requested to retain all packages and containers when empty. Participants are advised not to share the product with any other person under any

circumstances.

5. Return

All containers, packs and other packaging for the Investigational Product are retained by the participants and returned to the study team on exit from study.

The study team member collects all study documents, packages, containers and records. All product containers, including the unused product, are collected and returned to the

Site Pharmacy for accounting and destruction. The return of the Investigational Product (used and unused packets) are recorded within

the Case Report Form. The appropriate signatures are made on return to pharmacy if required (in the case of

Schedule 4 and 8 drugs, for example) Any unused product is never passed on to others for further use.

PaCCSC SOP Feb 2018

5.14.1 V2.2 Page 5 of 6

Other related SOPs

4.0 Investigator Roles 4.2.4 Delegation of Duties


Guidance 6: Prescription of Study Drug Other: Any state or national regulations that cover the transport or storage if medicines

that exceed the requirements described in this SOP.

References

Code of Practice for the storage and transport of drugs of dependence, Department of Human Services, 31 July 2000 (South Australia).

Controlled Substances Act (SA) 1996.


PaCCSC SOP Feb 2018

5.14.1 V2.2 Page 6 of 6

History







2.1 19/05/2015 C Hope Review of procedure



Approval


2.2 David Currow


5.17 V2.2 Page 1 of 6

5.17 Adverse Event Reporting

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

5.17 V2.2 Page 2 of 6


Good Clinical Practice clarifies the responsibilities of research sponsors and investigators with regards to research related adverse events in an attempt to forestall adverse events and to ensure when they occur that systems are in place to accurately report, record, and investigate them.

It is important to record adverse events for both Investigational drug and non-drug studies (such as trials that involve surgery, radiotherapy or are observational).

Objective

This SOP describes the procedure by which adverse and serious adverse events are recorded, reported and evaluated as required by Hospital Research Ethics Committees (HRECs) and the International Conference on Harmonisation of Good Clinical Practice (ICH GCP) guidelines.

Scope

This SOP is to be used for any study where adverse and serious adverse events are to be reported. It applies to all staff involved in clinical studies conducted by PaCCSC irrespective of individual organisational employment, role or position.


All staff in contact with participants are responsible for noting adverse and serious adverse events that are reported by the participant or observed, and making them known to the study team caring for the participant in a particular study.

It is the responsibility of the Principal Investigator to ensure that all adverse and serious adverse events are accurately assessed and recorded. While this task can be delegated to other suitably trained study member and should be recorded in the Staff Signature and Delegation Log (refer SOP 4.2.4 Delegation of Duties), overall supervision and responsibility remains with the Principal Investigator.

PaCCSC SOP Feb 2018

5.17 V2.2 Page 3 of 6

Procedure

1. Identification of possible adverse events

At each assessment and/or visit the participant should be assessed for the following: 1) Have there been any problems since the last assessment? 2) Have there been any new medications, or changes to other medications?

If the answer is “yes” to either of those two questions, further assessment is needed to determine if the change constitutes an adverse event.

In addition, each protocol may specify specific symptoms that need to be assessed.

2. Assessing the severity of adverse events

All problems/symptoms that meet the criteria of an adverse event are to be assessed using the NCI CTCAE criteria.

The severity is to be a grade between 1 and 5. All adverse events are to be discussed with the Principal Investigator.

3. Recording adverse events

All adverse events are to be fully recorded in the patient clinical record and within the study specific Adverse Event Form or Case Report Form.

All adverse events are to be followed to resolution. All adverse events are to be clearly recorded within the participant’s medical record.

4. Assessing the seriousness of adverse events

All adverse events must be assessed to determine if the event also meets the criteria of a serious adverse event.

This will be a “yes” or “no” response on the Adverse Event Form or Case Report Form.

5. Recording serious adverse events

If an adverse event is determined to be a Serious Adverse Event (SAE), the details are to be recorded on a Serious Adverse Event Form.

The SAE is also to be entered into the database within 24 hours of becoming aware of the event. o Once entered, the PaCCSC Coordinating Centre will check the SAE report and

seek clarification when required. The SAE will be reported to HREC if indicated by the initial assessment (as outlined above), and in accordance with the approving HREC requirements, and will also be reported to: • The Trials Management Committee and the Management Advisory Board • The Data Safety Monitoring Committee/Medical Monitor • The regulatory authorities when the adverse events are both serious and

unexpected drug reactions OR serious and expected drug reactions or when the SAE may affect the conduct of the trial, the safety of the participants or their willingness to continue participation in the trial using the standard form for Adverse Drug Reactions Advisory Committee (ADRAC) by the PaCCSC National Manager only.

PaCCSC SOP Feb 2018

5.17 V2.2 Page 4 of 6

The requirements of the approving HREC and local research governance office are to be followed at all times.

6. Follow-up of serious adverse events

The serious adverse event is to be followed up to resolution, death, or where further information is no longer possible to obtain.

PaCCSC SOP Feb 2018

5.17 V2.2 Page 5 of 6

Other related SOPs

4.2.4 Delegation of Duties 5.5.5 Allocation of Participant ID Number 5.5.1 Electronic Data Handling 5.17.1 Medical Monitor 6.0 Protocol Development 8.0 Essential Documents


Template 14: Adverse Event Form

References

Australian guideline for pharmacovigilence responsibilities of sponsors of registered medicines regulated by drug safety and evaluation branch. 2003, Department of Health and Ageing, Therapeutic Goods Administration. Amended 31 Mar 2005.

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, V4.0, DCTD, NCI, NIH, DHHS, May 28, 2009.



Note for Guidance on Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 2000 (accessed 12/11/2017) https://www.tga.gov.au/sites/default/files/ich37795.pdf


Acknowledgments

Praxis Australia

PaCCSC SOP Feb 2018

5.17 V2.2 Page 6 of 6

History



New procedure



1.4 18/08/2007 B Fazekas Changes ratified by MAB and external review


1.6 21/01/2008 B Fazekas Administrative update following new reference material


Periodic review





Approval


2.2 David Currow


5.17.1 V1.1 Page 1 of 8

5.17.1 Medical Monitors

Version V1.1


Approved D Currow




PaCCSC SOP Feb 2018

5.17.1 V1.1 Page 2 of 8


The International Conference on Harmonisation of Good Clinical Practice (ICH GCP) guidelines require organisations that conduct clinical research studies to have a system for the appropriate oversight of the conduct of clinical trials to ensure the safety of study participants.

PaCCSC is responsible for monitoring study participant safety. For most trials this monitoring will be through the establishment of an independent Data and Safety Monitoring Committee, but in some instances the trial can be judged to be adequately monitored through the oversight of a Medical Monitor (MM).

An MM will be appointed by the PaCCSC Scientific Committee under the following criteria.

Where the trial:

Is judged to be low risk; Is recruiting for pilot data; Includes fewer than 5 sites, and/or two states; Is approved by the Scientific Committee for monitoring by a Medical Monitor.

PaCCSC Coordinating Centre collaborates with the MM on safety oversight. This collaboration helps to meet human participants’ safety standards as defined by applicable regulations, ICH GCP, and PaCCSC Standard Operating Procedures.

Objective

This SOP describes the PaCCSC procedure for the role of a Medical Monitor (MM) in providing safety oversight to clinical research studies.

This procedure applies to PaCCSC studies where risk/resource assessment indicates the need for medically qualified individuals to be involved in safety oversight of the clinical research study.

Scope

The role of Medical Monitors can be very broad to include safety and other considerations in the development of the protocol, and to advise on inclusion and exclusion criteria through the conduct of the study. The role of the MM within this SOP is restricted to oversight and review of safety reports for clinical trials where a risk assessment has determined that a Data Safety Monitoring Committee is not required.


Responsibilities of the PaCCSC Trials Management Committee and Scientific Committee

To determine if a Medical Monitor is appropriate for any specific trial To recommend an appropriate Medical monitor To assist MM with pharmacovigilance activities To interact with the MM on safety oversight

PaCCSC SOP Feb 2018

5.17.1 V1.1 Page 3 of 8

Responsibilities of the PaCCSC National Manager / National Project Officer

To contact the medical monitor as determined by the TMC and SC To provide the study protocol and appropriate training in the protocol and safety reporting

requirements To ensure that MM receives the adverse event reports from sites during the recruitment

period To provide any follow-up information requested by the MM To review findings from MM activities as applicable

Responsibilities of the Medical Monitor

To review protocol halting rules To advise protocol team on safety oversight To evaluate adverse events/Serious Adverse Events (SAEs) and review safety reports To provide findings or recommendations from the review of adverse events To participate on PaCCSC Trial Management Committee To advise sponsor of patterns or trends in safety reports To review a sample of the reported deaths for safety implications To prepare a summary of events for reporting every six months or otherwise agreed

period

PaCCSC SOP Feb 2018

5.17.1 V1.1 Page 4 of 8

Procedure

1. Medical Monitor procedures

The PaCCSC Scientific Committee will approve the appointment of an MM to review and evaluate information relevant to the safety of all PaCCSC-supported clinical trials and selected studies approved by the Committee.

The Medical Monitor will:

Be appropriately qualified to provide medical oversight of the trial; Be independent of the trial, not listed as an investigator and not involved as a Principal

Investigator in the recruitment of the trial; Have a good understanding of safety monitoring in clinical trials and of GCP; Agree to undertake the role of MM; Ensure, where required, that reporting to the TGA is undertaken.

The MM will be responsible for providing safety oversight and reviewing the protocol (e.g. study halting rules) and information about the study as it becomes available, such as the Investigational Brochure (IB) and reported safety events.

The PaCCSC MM, in consultation with the investigator team and safety oversight committees, will provide safety review during the execution of the clinical trial. This oversight includes reviewing safety information and providing applicable recommendations.

The PaCCSC MM provides recommendations, as appropriate, to members of the investigator team, which may include, but is not limited to: PaCCSC, the funding body, manufacturer, and participating recruiting sites via the PaCCSC Trials Management Committee (TMC). This data and safety review facilitates early detection of safety signals and maximises the chances for continued appropriateness of the research and protection of human subjects.

Based on a synthesis of this information, the PaCCSC MM will provide appropriate recommendations to the study TMC and PaCCSC Scientific Committee (where necessary). When PaCCSC is the study sponsor, the MM is the person who is responsible for reviewing and evaluating safety information.

2. Before the trial

The trial investigators will determine the level of risk of the study and decide the overall safety oversight requirements of the study.

If the role of MM is considered sufficient to provide the required level of safety oversight for the study, the protocol investigator team then discuss an appropriate MM and subsequently appoint the MM.

The MM accepts the role in writing. The MM for the study is provided with the study protocol. The MM discusses, either in meeting or via email, the potential safety implications of

the study and reviews the safety reporting procedures.

PaCCSC SOP Feb 2018

5.17.1 V1.1 Page 5 of 8

3. During the trial

Safety reports are provided by sites in the usual manner, using the Adverse Event or Serious Adverse Event Report Form. All reports are forwarded to the PaCCSC National Manager and National Project Officer, who review the event for completeness of data and assess if the event is to be reported to HREC and/or MM (refer SOP 5.17 Adverse Event Reporting).

If the event is a grade of 3 or more, or is a Serious Adverse Event and is assessed as not being exempt from reporting (as defined within the study protocol), the email report is then forwarded to the MM for review.

The MM will review the report to determine if the event report is complete and if there is agreement with the assessment of causality, relationship and reporting assessment.

If the report is incomplete, or if further information is required in order to make a full assessment of the adverse event report, the MM emails a request for further information via the PaCCSC Coordinating Centre. Further information will be provided back to the MM when available from the reporting site.

The MM will make an assessment of the adverse event report, based on the information within the initial report and any subsequent follow-up information. This assessment will be: o Relationship to study drug; o Confirmation that the event was a Serious Adverse Event; o If trial discontinuation is recommended.

The assessment can be as individual assessment, or aggregated into a table, if numerous reports are received.

The MM will be asked to provide aggregated assessments to the study Trials Management Committee six monthly. This report will contain an overall assessment such as: o No action needed, trial continues as planned; o Early stopping due to, amongst other things, safety concerns, futility, slow

recruitment, or external evidence (refer SOP 4.7.2 Unbinding); o Stopping recruitment within a subgroup; o Extension of recruitment or follow-up; or o Advising on or proposing protocol changes.

Figure 1 details the MM procedure during the trial.

PaCCSC SOP Feb 2018

5.17.1 V1.1 Page 6 of 8

Figure 1 Medical Monitor procedure during the trial

4. After the trial

The MM may be asked to review the summary tables and reports or recommendations developed for the clinical study report or safety reporting table in the results manuscript.

Adverse event report entered into the RDMS

Email of report received by PaCCSC

Reviewed and requires assessment by MM & Lead Investigator(s)

AE grade 3 or more SAE

Exempt from reporting

Event requires no further action

Report to PaCCSC, PaCCSC SC, HREC,

and/or TGA

Further information required

PaCCSC obtains and provides to MM

Event requires further action

Assessed by MM

Action and follow-up via PaCCSC

PaCCSC SOP Feb 2018

5.17.1 V1.1 Page 7 of 8

Other related SOPs

4.7.2 Unbinding 5.17 Adverse Event Reporting


N/A

References


PaCCSC SOP Feb 2018

5.17.1 V1.1 Page 8 of 8

History


1.0 10/12/2015 B Fazekas, L Devilee

New SOP



Approval


1.1 David Currow


5.18 V2.2 Page 1 of 7

5.18 Monitoring

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

5.18 V2.2 Page 2 of 7


The purpose of monitoring is to undertake a detailed review of the study documentation, protocol implementation and procedures, to correct outstanding data queries, and to assess and provide support for site specific problems.

PaCCSC undertakes monitoring to ensure the investigating sites comply with Good Clinical Practice (GCP), the protocol, and the Standard Operating Procedures relevant to the study.

The monitor from the PaCCSC Coordinating Centre examines all study documents, Case Report Forms (CRFs), reports, correspondence, etc. Issues identified during monitoring visits and correction plans are discussed with the site team along with a written report following the visit.

Pharmacy monitoring is undertaken by an independent sub-contractor with expertise in the area. Pharmacy monitoring is unblinded and includes a review of the pharmacy folder, compliance with randomisation schedules, study medication accountability, storage and destruction of study medications.

The study monitor is given access to all study related material, and adequate space and privacy in order to review the materials, including access to source documents as required.

Objective

This SOP:

Defines the role and responsibility of PaCCSC monitoring; Describes the monitoring process; Describes the process of reporting results and action that arises from those results; Ensures there is capacity building across the network through ongoing training during

monitoring.

Scope



Monitoring of PaCCSC clinical studies is the responsibility of the PaCCSC Coordinating Centre.

All monitoring visits are conducted in the presence of the Principal Investigator and/or other designee(s) as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties).

PaCCSC SOP Feb 2018

5.18 V2.2 Page 3 of 7

Procedure

1. Timeframe

Monitoring is undertaken as per the Study Monitoring Plan (Template 35) or as specifiedwithin the study protocol.

Monitoring is then conducted during the entire recruitment period and prior to studyconclusion for Phase III studies. Additional monitoring is conducted at the request of otherPaCCSC Committees.

2. Monitoring sites

Each individual study site for a specific study is monitored. The study sites are theparticipating sites for Phase III studies for PaCCSC.

3. Personnel involved

Ideally, all monitoring visits are completed by an appropriately trained and experienced staff member of the PaCCSC Coordinating Centre. The Coordinating Centre monitor may work with a support monitor. On occasions, when no other monitor is available, the Coordinating Centre monitor works

alone. There may be circumstances where a site coordinator may be asked to assist withmonitoring. This is after discussion with the site PI and appropriate training in the supportrole has taken place.

All monitoring visits are conducted in the presence of the Principal Investigator (ordelegate) of the site being monitored.

4. Extent

Each monitoring visit is designed to ensure that:

The study is conducted in accordance with the protocol and appropriate regulatoryrequirements;

Consent is obtained for every randomised participant; Deviations from the protocol are documented and reported (Template 8); Data on Case Report Forms can be verified; Patients enrolled meet the eligibility criteria; All safety assessments are reported appropriately and any serious adverse events are

followed up until resolution; Personnel at each site are meeting GCP obligations; Randomisation, allocation and study medication accountability procedures are being

followed.

The monitor is able to discuss recruitment and retention issues, clarify protocol issues, and provide training and support, such as worksheets and tracking documents.

PaCCSC SOP Feb 2018

5.18 V2.2 Page 4 of 7

5. Preparation for a visit

The PaCCSC Coordinating Centre formally notifies the site of the upcoming visit date, after negotiating the most suitable date.

The Principal Investigator (or delegate) ensures the site is adequately prepared for a visit (referGuidance 4) providing the following:

A quiet space; An up to date Investigator Folder; Provides all completed CRFs for the participants to be monitored; Organises access to the source data (especially electronic medical records, etc.); Schedules time to be available to discuss study progress with the monitor.

6. Visit procedure

All critical data elements undergo 100% validation checking at each monitoring visit. Critical data elements are:

Subject existence Eligibility Informed consent Primary end points Safety Administration of study medication Study termination (treatment cessation or withdrawal)

Each of the components are coded according to the level of deficiency:

None Minor Major

During the monitoring process (Guidance 5), the monitor documents issues and deficiencies on a Corrective Action Sheet (Template 15). The Corrective Action Sheet is used to summarise all findings identified during the monitoring visit. The monitor is responsible for entering possible solutions for all findings.

At the conclusion of a monitoring visit an exit meeting is held with the Principal Investigator (if available) and study team members to discuss the main summary findings of the visit and the likely content of the report. The required outcome for all findings documented on the Corrective Actions Sheet is completed with the site staff during the exit meeting.

When possible, a copy of the Corrective Actions Sheet is made following the exit meeting. The original is left with the site and the copy is taken by the monitor and sent to the PaCCSC Coordinating Centre for filing.

At the conclusion of each site monitoring visit, the monitor(s) signs the Monitoring Log (Template 16) as a record of the visit.

PaCCSC SOP Feb 2018

5.18 V2.2 Page 5 of 7

7. Monitoring report

Within 14 days following the monitoring visit, the site is emailed a copy of the Corrective Actions Sheet and a summary of the following information:

Date(s) of monitoring visit Name of site and site personnel Name of monitor A summary of the review process A summary of the findings, for the site and the organisation (contains a description of all

major deficiencies in the 2 locations and 7 components under review)

The site being monitored is assigned an assessment of:

Acceptable Acceptable needs follow-up Unacceptable Conclusions and recommendations (a general assessment of the review) Follow-up required

8. Monitoring visit follow-up

The Monitoring Report/email may require a response by the study site to specific issues raised during the monitoring visit. This response is provided, in writing, within 30 days of receipt.

1. Monitor discusses deficiency with the Principal Investigator (or delegate) and agrees onappropriate action.

2. If the monitor is not satisfied with the response from the Principal Investigator, the matteris discussed with the Lead Investigator of the relevant study to determine what furtheraction is required.

3. Any ongoing concerns are referred to the PaCCSC Trial Management Committee fordiscussion and resolution.

The site is responsible for ensuring the Corrective Action Sheet is completed and returned to the monitor for checking, along with any evidence to support compliance with the findings of the visit (refer Guidance 4).

9. Study monitoring report

The study monitor provides a study wide report on conclusion of the study in accordance with the study specific monitoring plan.

PaCCSC SOP Feb 2018

5.18 V2.2 Page 6 of 7

Other related SOPs

4.2.4 Delegation of Duties 5.19 Auditing


Template 8: Protocol Violation Form Template 15: Corrective Actions Sheet Template 16: Monitoring Log Template 35: Study Monitoring Plan Guidance 4: Monitoring Guidelines for Sites Guidance 5: Monitoring Guidelines for Monitors

References


Guidelines for monitoring of clinical study for cooperative groups, CCOP research bases, and clinical study support unit (CTSU). National Cancer Institute. October 2006.




Liu MB, Davis K. Lessons from a horse named Jim. Duke Clinical Research Institute. 2001.

PaCCSC SOP Feb 2018

5.18 V2.2 Page 7 of 7

History



1.2 13/08/2007 B Fazekas Ratified by MAB

1.3 16/10/2007 B Fazekas Update following review by David Currow

1.4 30/12/2009 B Fazekas Update following monitor training

1.5 2/09/2010 B Fazekas, Tania Shelby-James

Periodic review





Approval


2.2 David Currow


5.18.1 V1.1 Page 1 of 7

5.18.1 Site Closure

Version V1.1


Approved D Currow




PaCCSC SOP Feb 2018

5.18.1 V1.1 Page 2 of 7


While participation in PaCCSC may bring benefits to individual sites, there may be circumstances where ongoing participation in PaCCSC may not be in the sites or the Collaborative’s best interests, and therefore the site closes. Reasons for site closure include (but are not limited to):

Voluntary withdrawal from PaCCSC due to:o Lack of interest or support from the clinical teams/institution/trials teams in

research at siteo Lack of clinical support to undertake PaCCSC studieso Competing research demands from non-PaCCSC funded/sponsored studieso Financial hardship due to enforcement of PaCCSC non-performance penaltieso Completion of all PaCCSC studies at site

Enforced withdrawal from PaCCSC due to:o Persistent non-compliance with PaCCSC polices and Standard Operating

Procedureso Breech of Agreement with PaCCSC

Hospital / service shutdown

Objective

This SOP describes the process for managing site closure.

Scope



Responsibility for Site Closure rests with the Lead Investigator, who is supported by the PaCCSC Coordinating Centre. The Lead Investigator responsibilities are delegated to the PaCCSC National Manager. The Principal Investigator at the site is responsible for all processes and procedures at the site.

Responsibilities of the PaCCSC National Manager (or delegate)

To liaise with the Principal Investigator (or delegate(s)) at the closing site To liaise with the Lead Investigator, PaCCSC Management Advisory Board and PaCCSC

Executive Committee To liaise and communicate with other relevant PaCCSC investigators To liaise with regulatory bodies and the Department of Health (Federal Government) To prepare a paper regarding the impact of the site closure on PaCCSC To prepare a Site Closure Plan (including timeline); this will be via email and is site and

study specific To organise any outstanding monitoring of the closing site To ensure all finances are acquitted prior to final sign off that site is closed

PaCCSC SOP Feb 2018

5.18.1 V1.1 Page 3 of 7


To communicate with the PaCCSC National Manager in a timely way To fulfil the required activities at the site to achieve site closure To fulfil the requirements of the local Human Research Ethics Committee To provide financial information as requested

PaCCSC SOP Feb 2018

5.18.1 V1.1 Page 4 of 7

Procedure

1. Decision to shut down

Voluntary withdrawal of site:o The Principal Investigator at the site notifies the PaCCSC National Manager of their

intention to withdraw from PaCCSC. Notification is given in writing with at least 30days of notice.

o If further information is required, the PaCCSC National Manager contacts thePrincipal Investigator.

o The PaCCSC National Manager prepares a report regarding the implications of thesite shut down for PaCCSC and submits this paper to the PaCCSC ManagementAdvisory Board.

o The PaCCSC National Manager informs other PaCCSC Investigators of thewithdrawal of the site.

o The Principal Investigator at the site informs the Human Research Ethics Committeeof the closure as a PaCCSC site.

o In consultation with the Principal Investigator at the site, the PaCCSC NationalManager prepares a Closure Plan for the site, detailing specific tasks andresponsibilities.

Enforced closure of site:o The decision to enforce closure of a site from PaCCSC is taken by the PaCCSC

Management Advisory Board.o The PaCCSC National Manager informs the Principal Investigator at the site in

writing, giving a minimum of 30 days of notice.o The PaCCSC National Manager informs other PaCCSC Investigators and other

interested parties such as external sponsors or funding agencies of the withdrawalof the site.

o The Principal Investigator at the site informs the Human Research Ethics Committeeof the closure as a PaCCSC site.

o In consultation with the Principal Investigator at the site, the PaCCSC NationalManager prepares a Closure Plan for the site, detailing specific tasks andresponsibilities.

2. Ceasing Studies

Recruitment for all studies currently undertaken at the site is ceased on the date ofnotification to withdraw / close study site.

Under the direction of the PaCCSC Coordinating Centre (and following site audit), thefollowing activities are completed at the site by the Principal Investigator (or delegate):o Any remaining investigational products are destroyed or returned to the manufacturer

as per individual site or state guidelines.o Checking and storage arrangements of the site pharmacy folders and the study files

held on site.o Checking and completion of the Investigator Folders.o Final reports are made to the local and institutional HRECs.

PaCCSC SOP Feb 2018

5.18.1 V1.1 Page 5 of 7

3. Site Audit

The PaCCSC Executive Committee determines if the site requires an internal (monitoring)or external audit prior to closure (refer SOP 5.18 Monitoring).

The PaCCSC National Manager arranges an audit visit to the site to ensure all workconducted prior to the notification to withdraw has complied with the PaCCSC StandardOperating Procedures, policies and study protocols.

4. Financials

All study specific funding ceases on the date of notification to withdraw from PaCCSC /date of notification to close the study site.

The site provides PaCCSC with a financial audit detailing the PaCCSC related incomeand expenditure.

All unspent funds are returned as set out in the funding agreement between PaCCSCand the site.

5. Archiving of Research Materials

All research materials for all PaCCSC studies are archived according to SOP 8.4.1Archiving of Research/Project Materials.

6. Additional notes

Ongoing employment of the research staff at the closing site is the responsibility of thesite.

Ongoing representation of the Principal Investigator of the closing site on PaCCSCcommittees (for e.g., PaCCSC Trial Management Committee) will be at the discretion ofthe PaCCSC Management Advisory Board.

It is the responsibility of the Principal Investigator at the closing site to ensure all HRECreporting requirements are met and the HREC are fully informed of the closure.

PaCCSC SOP Feb 2018

5.18.1 V1.1 Page 6 of 7

Other related SOPs

4.2.4 Delegation of Duties 5.18.2 Study Closure 5.18 Monitoring 8.4.1 Archiving 8.0 Essential Documents


N/A

References


PaCCSC SOP Feb 2018

5.18.1 V1.1 Page 7 of 7

History





Approval


1.1 David Currow


5.18.2 V1.2 Page 1 of 6

5.18.2 Study Closure

Version V1.2


Approved D Currow




PaCCSC SOP Feb 2018

5.18.2 V1.2 Page 2 of 6


The purpose of study closure is to finalise all follow-up activities to enable final reporting of the study and archiving of study materials.

Objective

This SOP describes: The activities that are undertaken The closure process and follow-up

Scope




To finalise the Investigator Folder To reconcile and finalise all accounts and payments To prepare and submit final report to the approving HREC To inform participants (or proxies) of the study results To complete and sign the Study Closure Checklist (Template 29), and return to

the PaCCSC Coordinating Centre


To prepare and execute site pharmacy monitoring recommendations regarding remainingInvestigational Product

To guide and facilitate in the preparation and execution of study closure activities To check the Study Closure Checklist (Template 29) completed and returned by each site To complete for each site the Study Closure Checklist (each site) (Template 29a) To complete for the entire study the Study Closure Checklist (all sites) (Template 29b),

once the Study Closure Checklists have been returned by all sites, and checked. Oncecompleted, the entire study checklist is filed in the Trial Master Files to indicate that eachsite has now completed all closure activities and the entire study is now ready for archive.

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Procedure

1. Timeframe

Study closure occurs when:

Recruitment for the study is completed All site monitoring visits at all study sites are completed and The main study results are accepted for publication in an appropriate journal

Study closure may also occur if the study is ceased before the above criteria are met or if a site is to be closed for any reason (refer SOP 5.18.1 Site Closure).

2. Personnel involved

PaCCSC National Manager, PaCCSC National Project Officer, Lead Investigators

3. Preparation

The following activities are completed in preparation for study closure:

All outstanding monitoring activities are completed Data entry of all data is completed Data base is locked Notification (update) is provided to the ANZCTR All follow-up (ongoing AEs) database resolutions are completed Safety database is reconciled with CRF database so that all AEs and SAEs are entered

and reported appropriately All study documents are retrieved Diagnostics is completed and all data is cleaned Unblinding occurs (refer SOP 4.7.2 Unblinding) Analysis is completed by the Study Statistician Draft results manuscript is written

4. Site activities

Each site undergoes a series of activities in order to close the study at that site. These activities are completed by the site under the direction of the PaCCSC Coordinating Centre via email and teleconference:

Final site pharmacy monitoring o Clearance is given by the monitor to destroy any remaining Investigational Product

as per state regulations. Supply of the site pharmacy folder and the study files to the Principal Investigator for

incorporation into the Investigator Folder/Essential Documents (refer SOP 8.0 Essential Documents)

Finalisation of the Investigator Folder Accounts and payments are reconciled, including final payment Submission of final report to the approving HREC, using the reporting template required

by the HREC

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Participants (or proxies) are informed of the study results via letter if appropriate and under the direction of the Lead Investigator, using the following procedure: o Each site is provided with a list of the participant ID numbers for that site along with

the allocation of each participant by the PaCCSC Coordinating Centre. o The site writes a letter, based on the template letter provided, completing the specific

details such as names, dates and allocation. The study summary is attached to each letter.

o The completed personalised letters are checked by the associated clinical team in order that names and addresses are confirmed as correct.

o The letter is sent to the most appropriate person (next of kin, carer, etc.) as known to the clinical service and entirely at the discretion of the clinical team according to their knowledge of the family and circumstances.

Study Closure Checklist is completed o The checklist can be completed by any of the study staff o The checklist is signed by the Principal Investigator

Archiving of files is completed (refer SOP 8.4.1 Archiving)

5. PaCCSC activities

The PaCCSC Coordinating Centre undertakes a series of activities in order to close the study at each site and centrally. These activities involve a number of communications with each site to ensure site responsibilities are upheld. When all site closure responsibilities are completed, the PaCCSC Coordinating Centre undertakes the following activities:

Final payment is sent to every site Accounts and payments are reconciled Archiving of coordinating files Study Closure Checklist (each site) (Template 29a) – is completed by the PaCCSC

National Project Officer to confirm completion of closure activities at each site Study Closure Checklist (all sites) (Template 29b) – is completed when all sites have

indicated completion of the closure activities and these have been checked by PaCCSC Coordinating Centre

Lead Investigator is informed in writing of study closure Written confirmation of study closure from the Lead Investigator is attached to the

checklist and archived

A number of activities may continue after the study is closed at all sites and at the PaCCSC Coordinating Centre including:

Continued analysis of secondary data Further development and completion of the Clinical Study Report Dissemination of findings Reporting to funding agency Study report submission to the TGA

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Other related SOPs

4.2.4 Delegation of Duties 4.7.2 Unblinding 5.18.1 Site Closure 8.0 Essential Documents 8.4.1 Archiving


Template 29: Study Closure Checklist Template 29a: Study Closure Checklist (each site) Template 29b: Study Closure Checklist (all sites)

References





PaCCSC SOP Feb 2018

5.18.2 V1.2 Page 6 of 6

History


1.0 30/08/2012 B Fazekas, L Devilee

New procedure




Approval


1.2 David Currow


5.23.2 V2.2 Page 1 of 7

5.23.2 CRF Completion

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

5.23.2 V2.2 Page 2 of 7


Case Report Forms (CRFs) are the main source of data collection and recording for clinical studies, and are often regarded as study source data. A series of CRFs (electronic and/or paper-based) are used for each study to enable data collection at specific time points.

The data contained within the CRF is entered into a database and is used for data analysis and data reporting.

The accuracy of the data entered into the database is crucial, and is checked against the paper CRF. It is vital that the paper CRF is an accurate, complete and contemporaneous (completed at the time of collection) reflection of the data.

Objective

This SOP details the process by which CRFs are completed.

Scope



Authorisation to complete CRFs is a responsibility delegated by the Principal Investigator and must be recorded in the Staff Signature and Delegation Log (refer SOP 4.2.4 Delegation of Duties), prior to the task being undertaken, and only after the designee has completed the relevant study related training. The responsibility remains with the Principal Investigator.

Responsibilities of the Principal Investigator (or delegate)

To review the CRF prior to data entry To enter the data into the electronic data base To respond to data queries raised during subsequent checking procedures To ensure the CRF is filed in accordance with GCP, both short and long term

Responsibilities of the study site team members

To organise the CRF in preparation for participant use in accordance with the study packcontents prepared for each study

To complete the CRF at the protocol specified time points To ensure that the CRF accurately reflect the data collected at each time point To ensures that the CRF has the associated source documents as described within the

study protocol To prepare the CRF for data entry


To develop the CRF according to the study protocol, and the investigator team instructionsand requirements

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To ensure that the CRF is developed in such a way as to be: o Logical o Clear o Sequential o Complete

To develop and follow the Data Management Plan for the study (Template 10) To develop and follow the Monitoring Plan for the study (Template 35) To monitor data collection, entry and completion via the data management plan and

monitoring plan for the individual studies To receive a copy of the completed CRF from the Principal Investigator (or delegate)

following entry into the electronic database, along with any other documents where the recording is entered into the database (such as questionnaires, assessment tools, etc., but not medical record notations, and all by PID only)


To oversee the maintenance of the data collection and provide routine and ad hoc reports to the PaCCSC Management Advisory Board and Trial Management Committee when requested

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Procedure

1. Case Report Forms (CRFs)

The Principle Investigator should ensure the accuracy, completeness, legibility and timeliness of the data reported to the Sponsor in the CRFs and in all required reports.

Where specified in the study protocol, CRFs may be considered source documentation, where the CRF is the first recording of study data, such as during study visits where other traditional source documents are not available.

The data within the CRF is to be supported by other co-operating information, such as admission, recording of adverse events, clinical visits.

CRFs should be completed according to the specifications of each study, prospectively and where possible as close to the study visit as possible. Data from participants’ visits should be entered into the CRF within 5 business days from the visit if the CRF is NOT the source document.

Data entries must be accurate and legible. All data entries must be verifiable with source data from the participant’s medical records. Any discrepancies with the source data should be documented.

The participant’s identity should remain confidential. The participant should only be identified on the CRF by means of the allocated study number and/or initials, this includes Serious Adverse Event CRFs and other forms of reports.

CRFs should be kept in a secure location during the course of the study. On completion of the study CRFs should be archived as per study protocol (refer SOP 8.4.1 Archiving).

2. CRF completion

2.1. General rules for CRF completion

Use black or blue ball point pen, do not use pencil. The CRF is signed where required by the Principal Investigator (or delegate) to verify its

accuracy, completion, and that the data was collected in accordance with the study protocol. o This is required for eligibility screening to ensure that the participant meets all the

criteria and is approved to participate, at cessation of treatment and at participant withdrawal.

o This may also be required because of a specific medical review, such as review of response prior to changing the study drug dose.

Complete ALL questions; blank fields indicate that data was not collected, or missed. Most questions have an appropriate response available, but in the case where this is not possible: o If a question does not apply, write N.A. o If a test is not done, write N.D. o If a result is zero, write 0.

If an error is made, draw a SINGLE line through the error, write the correct entry in an adjacent space and INITIAL and DATE the correction.

Do not use correction fluid, texta or other means of obliterating the original entry. Do not write over the initial entry in such a way that the initial entry is unclear. Pages must NOT be removed from the CRF (blank or otherwise), unless otherwise

instructed by the study investigators.

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Dates must not be backdated. Late entries are acceptable. Notations within the CRF and the database can be used to explain this.

Do not copy information onto a new clean page even if the CRF looks ‘messy’. Follow any specific instructions that may have been provided within the study CRF. Store the CRF in a secure location.

2.2. Specific rules to enable seamless data entry

All dates are recorded in the format specific to the RDMS for that study (refer SOP 5.1.1 Electronic Data Handling): o Use the ’date picker option’ if provided

Checkboxes – these allow multiple choices to be recorded. Radio buttons – these allow only one choice, and data entry is only possible for a single

choice. If more than one response is made on the CRF, it is not possible for other responses to be recorded. Attempts at multiple responses result in missing data for the data point. Participants are clearly instructed to choose ONLY one option for these questions.

Text fields – there are cases when free text is required. The instructions for these questions should be followed carefully as there may be rules applied regarding data text. This may include the number of characters accepted by the database on entry. In text fields, do not use paragraph breaks to separate pieces of text; use full stops, hyphens, or colons to separate text.

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Other related SOPs

4.2.4 Delegation of Duties 4.5.3 File Notes 4.9.2 Source Data and Documentation 5.5.1 Electronic Data Handling 8.3.11 Communications 8.4.1 Archiving


Study Protocol Template 10: Data Management Plan (study specific) Template 35: Study Monitoring Plan (study specific)

References




Praxis

PaCCSC SOP Feb 2018

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History





2.0 3/02/2011 B Fazekas Changes ratified by the MAB




Approval


2.2 David Currow


6.0 V2.3 Page 1 of 7

6.0 Protocol Development

Version V2.3


Approved D Currow




PaCCSC SOP Feb 2018

6.0 V2.3 Page 2 of 7


All clinical studies must demonstrate that documentation meets the International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines. These guidelines require documentation to show that the study is conducted in an ethical and appropriate manner and all legal and auditing requirements are met. This documentation comprises the study or study protocol and supporting documents. Clinical studies are conducted, monitored, and audited against the protocol.

Objective

This SOP describes what the protocol is, how it is developed, and how and under what circumstances it can be changed. All protocols are developed according to a standard procedure to ensure that the final protocol complies with all regulatory requirements and underpins a sound clinical study.

Scope



Responsibilities of PaCCSC Scientific Committee

To advise on protocol development To approve the final version of the protocol (pilot/feasibility/Phase III) To approve any major amendments to protocols

Responsibilities of the Lead Investigator and the PaCCSC Trial Management Committee

To provide intellectual input and oversee the development of the protocol for: o funding o study design o inclusion/exclusion criteria o analysis o reporting

To meet agreed deadlines for review and comment of the protocol To approve minor and major protocol amendments


To provide the most recent draft protocol and protocol changes to the PaCCSC Scientific Committee for review and comments

To coordinate the review and revision of the protocol within designated timeframes To ensure that all investigators have the latest version for comment, review and input To ensure that the latest version of the approved protocol is distributed for ethical

approval and subsequent study initiation To provide input and comment about the operationalisation of the protocol To ensure historical documentation of versions is maintained

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6.0 V2.3 Page 3 of 7

Responsibilities of the Principal Investigator and/or other designee(s) at site, as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties)

To discuss implementation of the protocol at that site with the study team and during protocol training workshops

To ensure that any site specific plans required to implement the protocol are developed, recorded and discussed with the PaCCSC Coordinating Centre

PaCCSC SOP Feb 2018

6.0 V2.3 Page 4 of 7

Procedure

1. Approval of new studies

The PaCCSC National Manager calls for new study proposals annually. All PaCCSC members and associate members are eligible to submit new study proposals.

A meeting of all PaCCSC members and associate members is held one month after the proposal submission date closure at the PaCCSC Annual Research Forum. Submitted proposals are presented at the Forum. Formal evaluation is undertaken by all members of the PaCCSC Trials Management Committee present.

The evaluations are collated and provided to the PaCCSC Scientific Committee.

The PaCCSC Scientific Committee deliberate the ideas and provide recommendations on whether to proceed to protocol development (refer SOP 6.0.1 New Study Ideas/Proposals).

The PaCCSC Scientific Committee also decides whether the proposed study will be undertaken as: o Pilot work as part of a program of study development that will inform but not translate

into a definitive Phase III study o Pilot work that will both inform and translate into a full Phase lll study o A full Phase III study

Pilot (or feasibility) studies are developed using Template 28 (Section 2) and Guidance 13. Pilot studies are not designed to become full studies in their own right, but the results may lead to a future Phase III study.

Full Phase III studies are developed using Template 28. Full Phase III include pilot (or feasibility) work to be part of the design of the Phase III protocol Template 28 (Section 2). The initial pilot work of a full Phase III study may inform future funding applications, reviews of process, etc., that may enable recruitment to progress to the full study.

Template 28 contains suggested text in italics, and investigators should carefully consider the suggested text and then modify, remove or replace as appropriate to their study.

2. Sub-Committee

A sub-committee of contributing experts is formed for protocols approved by the PaCCSC Scientific Committee. The sub-committee includes (but is not limited to): o The Lead Investigator o Biostatistician o Health economist o PaCCSC National Manager or National Project Officer o Other individuals with the requisite skills to benefit the protocol development process

(people who have attended the ACORD concept development workshop are considered favourably).

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A full pilot study protocol is completed and submitted for approval to relevant Human Research Ethics Committees (HRECs).

PaCCSC assists the development of the full protocol by providing teleconference facilities and practical implementation advice as required.

Note: New study ideas/proposals that fail at any stage of the above process are able to be re-submitted again in the future for one further attempt at gaining the support needed to take the idea/proposal forward.

Figure 1 details the new protocol development flow for PaCCSC studies.

Figure 1 PaCCSC new protocol development flow

Protocol ready for presentation at PaCCSC Scientific Committee within

12 months of development

Protocol is completed and submitted for approval to relevant HREC

New protocol developed as per SOP 6.0 Protocol Development

Using Template 28 & Guidance 13

Pilot studies – Template 28 (section 2)

Phase III studies – Template 28 (including pilot study

proposal; section 2)

No Yes

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6.0 V2.3 Page 6 of 7

Other related SOPs

4.2.4 Delegation of Duties 6.0.1 New Study Ideas/Proposals 6.12 Ethics Approval and Reporting 6.10 Version Tracking 8.0 Essential Documents


Template 28: Protocol Guidance 13: Pilot/Feasibility Studies

References

DeAngelis CD, Drazen JM, Frizelle FA, et al. Clinical Trial Registration: a statement for the International Committee of Medical Journal Editors. JAMA 2004, 292: 1363-1364.


ISRCTN International Standard Randomised Controlled Trial Number Register (accessed 21/12/2017) https://www.isrctn.com/

Liu MB, Davis K. Lessons from a horse named Jim. Duke Clinical Research Institute. 2001.

Medicines Australia (accessed 22/12/2017) https://medicinesaustralia.com.au/



Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, Robson R, Thabane M, Giangregorio L, Goldsmith CH. A tutorial on pilot studies: the what, why and how. BMC Medical Research Methodology 2010; 10: 1-10.

Acknowledgments


PaCCSC SOP Feb 2018

6.0 V2.3 Page 7 of 7

History



New procedure





1.6 21/07/2008 B Fazekas Inclusion of updated proposal template


Periodic review


2.1 7/03/2014 B Fazekas Changed to include pilot/feasibility study conduct following meeting of the Scientific Committee




Approval


2.3 David Currow


6.0.1 V1.3 Page 1 of 9

6.0.1 New Study Ideas/Proposals

Version V1.3


Approved D Currow




PaCCSC SOP Feb 2018

6.0.1 V1.3 Page 2 of 9


Initial studies for the Palliative Care Clinical Studies Collaborative (PaCCSC), funded by the Australian Government Department of Health, were defined by the Palliative Care Medicines Working Group as priority medications for the generation of evidence into their net effect.

Additional new studies have come under the umbrella of PaCCSC where competitive grant funds have been secured to support the conduct of the studies.

PaCCSC now has a well-defined program of work across study phases and covering 6 symptom nodes (Guidance 14) to enable ongoing work to be planned and to build expertise. PaCCSC actively seeks ideas for new clinical medication studies from the palliative care clinical research community and commercial interests that are in line with the existing program of work, and the Collaborative needs a mechanism to provide direction in relation to:

The assessment of new study ideas/proposals brought to PaCCSC; and The support structures available to researchers that (following acceptance of the new

study idea/proposal) can be provided using PaCCSC’ established clinical research infrastructure

Objective

This SOP describes the process all new study concepts/ideas will go through in order to proceed towards pilot or full study recruitment.

Scope

This SOP applies to all individuals and/or organisations who have expressed interest in developing or undertaking new clinical studies with PaCCSC.


Responsibilities of the Lead Investigator (of the new proposed study)

To develop the study concept and submit for evaluation to the PaCCSC Annual Forum or the PaCCSC Trial Management Committee

To develop the draft protocol for the new proposed study and present for review to the PaCCSC Scientific Committee

To develop the full protocol for the proposed study and submit for approval to relevant Human Research Ethics Committees (HRECs).

To apply for competitive research funding


To assist with the development of the draft protocol and full protocol of new proposed studies by providing teleconference facilities and practical implementation advice as required

To provide governance and operationalisation support for new proposed studies

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6.0.1 V1.3 Page 3 of 9

Responsibilities of the PaCCSC Trial Management Committee

To evaluate new study ideas/proposals To assist with the protocol refinement and development To provide guidance regarding investigator team members, and other issues where

appropriate


To review draft protocols for new proposed studies To approve protocols for progression to HREC

PaCCSC SOP Feb 2018

6.0.1 V1.3 Page 4 of 9

Procedure

All new study applications are made to the PaCCSC National Manager, using the New Study Proposal template (Template 31). PaCCSC undertakes to formally review applications for new studies twice per annum.

In line with the purpose and aims of PaCCSC, new study support will be considered for:

Randomised controlled trials (RCTs) Small pilot studies for proof of concept (feasibility, safety, efficacy) Sub-studies embedded within a current study, that adds value to the suite of currently

running RCTs

New studies that do not fit within the criteria listed and within the existing program of work are unable to be considered for support unless there are specific advantages to the larger PaCCSC community to move forward with a proposal.

Applications for new clinical research study ideas/proposals undertake the following staged process in order to be taken into pilot and/or subsequent Phase III clinical study development under the governance and management of PaCCSC.

1. Proposal

Informal discussions of new ideas/proposals can be tabled at any PaCCSC Trial Management Committee meeting to inform the development of a concept or to formulate a trial development group which can progress a concept in preparation for formal presentation.

The study concept is formally presented (15 minute presentation) at the PaCCSC Annual Research Forum or the mid-year Trial Management Committee meeting.

Presentations are given by the Lead Investigator for the new idea/proposal.

The new study idea is evaluated by the Trial Management Committee members using the New Study Evaluation template (Template 32).

All new study ideas must achieve an average score of ~70 or above to progress to stage 2 of the selection process.

The Lead Investigator is informed of the outcome of the evaluation by the Trial Management Committee by the PaCCSC National Manager.

Figure 1 below details the proposal and development process for PaCCSC new study ideas.

PaCCSC SOP Feb 2018

6.0.1 V1.3 Page 5 of 9

Figure 1 PaCCSC new idea proposal and development process

New study proposal

15 min presentation

TMC evaluate the new study proposal

Protocol is developed

No

Refer SOP 6.0 Protocol development

Yes

Protocol ready for presentation at PaCCSC

Scientific Committee within 12 months

PaCCSC Annual Forum Mid-year TMC meeting

New idea

PaCCSC SOP Feb 2018

6.0.1 V1.3 Page 6 of 9

2. Development

The Lead Investigator for the proposed study develops a draft protocol (refer SOP 6.0: Protocol Development) for the study on the appropriate PaCCSC Protocol Template (pilot or full Phase III study template).

If the protocol is not developed and ready for presentation to the PaCCSC Scientific Committee within one year of the initial presentation to the PaCCSC Trial Management Committee, the idea goes back to stage 1 for re-presentation to the PaCCSC Annual Research Forum.

Prior to presentation of the draft protocol to the Scientific Committee, a spokesperson, who is member of the Scientific Committee, is nominated to provide carriage of the study at the meetings of the Scientific Committee and if needed provide feedback to the study investigators. The member will continue as the spokesperson throughout the life of the study and/or their term on the Scientific Committee.

The protocol is presented at the next Scientific Committee meeting (held twice annually), or if required can be reviewed out of session at the discretion of the Chair.

Figure 1 above details the proposal and development process for PaCCSC new study ideas.

3. Ongoing support from PaCCSC

All new studies supported by PaCCSC are conducted under the direction of the PaCCSC governance framework.

All new studies supported by PaCCSC are undertaken within the PaCCSC Standard Operating Procedures and other policy documents for the duration of the study.

All new studies supported by PaCCSC are operationally supported by the PaCCSC Coordinating Centre.

3.1 PaCCSC Support Role (Collaborative Research Group / Sponsor)

PaCCSC is the Collaborative Research Group (CRG) / sponsor for all new studies (whether pilot or phase III) receiving approval from the PaCCSC Scientific Committee.

PaCCSC acts as sponsor of the study for the purposes of the Therapeutic Goods Administration’s (TGA) Clinical Trial Notification (CTN) Scheme or CTX Scheme (or any successor scheme) and is responsible for preparing and submitting all documents required by the TGA to file an application for initiating and conducting the study.

The provision to each Principal Investigator, and (through the Principal Investigator) all institutions participating in the clinical study and the reviewing HREC, of all current and relevant information regarding the investigational product/study medication as reasonably required to justify the nature, scope and duration of the study.

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PaCCSC implements and maintains quality assurance and quality control systems with written SOPs to ensure that the study can be conducted and data generated, documented, recorded and reported. PaCCSC’ assistance include data management, Case Report Form (CRF) development and review, data checking and study monitoring.

PaCCSC designates appropriately qualified personnel to advise on study-related medical questions or problems.

PaCCSC monitors the study and the application of the investigational product/study medication in PaCCSC sites throughout Australia and advises, via the Principal Investigator, all participating sites and TGA of the cessation elsewhere of any relevant trial, or the withdrawal of the investigational product/study medication from any other market for safety reasons.

PaCCSC notifies all participating sites of any adverse events (including serious adverse events) that occur during the course of the study (either at the study site or other study sites, including overseas sites) which may require alteration of the conduct of the study, or which may affect the rights, interests, safety or well-being of study participants.

PaCCSC facilitates cooperation between participating institutions and/or the reviewing HREC in investigating any adverse event (including serious adverse event) arising out of or in connection with the study.

PaCCSC maintains insurance, or ensures that there is a named insurer for each participating site, with respect to its activities and indemnity obligations under any agreement.

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6.0.1 V1.3 Page 8 of 9

Other related SOPs

6.0 Protocol Development

All PaCCSC supported studies are required to operate in accordance with the PaCCSC suite of SOPs and other work instructions and policy documents as developed by PaCCSC.


Template 31: New Study Proposal Template 32: New Study Proposal Evaluation Guidance 14: Symptom Nodes and Study Matrix

References

Nil

PaCCSC SOP Feb 2018

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History


1.0 27/08/2013 L Devilee To document the process and support provided by PaCCSC for new study ideas/proposals


1.2 13/08/2015 L Devilee To clarify some minor discrepancies since development of the pilot protocol within the phase III protocol template



Approval


1.3 David Currow


6.0.2 V1.1 Page 1 of 8

6.0.2 Pilot Studies

Version V1.1


Approved D Currow




PaCCSC SOP Feb 2018

6.0.2 V1.1 Page 2 of 8


The pilot study process underpins the future of the Palliative Care Clinical Studies Collaborative (PaCCSC). Evaluation and data from pilot studies inform the developments of PaCCSC Phase III studies and contribute significantly to the success of PaCCSC.

A pilot study is a small scale investigation that aims to inform the development of a large scale, multi-centre Phase III study. Pilot studies are designed to test the methodology to be used in a subsequent Phase III study, particularly processes around recruitment and retention of participants.

The reasons for conducting a pilot study may differ with individual studies. In general, the purposes of pilot studies are a combination of (Thabane et al. 2010):

Process – Assessment of ‘the steps that need to take place as part of the main study’, such as recruitment rates, retention rates, completion rates, etc.

Resources/Logistics – Assessment of ‘time and budget problems that can occur during the main study’, including the feasibility and time components of each aspect of the research protocol.

Management – Assessment of personnel issues and data collection/management at each participating centre.

Scientific – Assessment of ‘treatment safety, determination of doses and responses, and estimation of treatment effect and its variance’.

PaCCSC pilot study ideas can be developed as part of a Phase III study protocol or as a ‘stand-alone’ pilot study. If successful, all pilot studies will progress to multi-centre Phase III studies (subject to funding and regulatory approval).

It is highly desirable that data from the pilot study is subsequently pooled with the Phase III study data in order to increase the efficiency of the Phase III study (Thabane et al. 2010). Therefore, the sampling frame and methodologies of both pilot and subsequent Phase III studies should be the same.

Objective

This SOP describes the process of developing, conducting and evaluating a pilot study. PaCCSC recognises the iterative nature of pilot studies; therefore this SOP provides an operating framework only. Specific issues that arise in pilot studies will be approached on a case by case basis.

Scope

This SOP applies to all individuals and/or organisations who have expressed interest in developing or undertaking new clinical studies with PaCCSC.

PaCCSC SOP Feb 2018

6.0.2 V1.1 Page 3 of 8



To develop the New Study Idea/Proposal using PaCCSC New Study Proposal Template (refer SOP 6.0.1 New Study Ideas/Proposals)

To present new study idea at the PaCCSC Annual Research Forum or mid-year Trials Management Committee meeting

To develop the pilot study protocol (possibly as part of the multi-centre Phase III study protocol)

To develop a Pilot Study Progress Plan (Template 33), with specific consideration given to potential future funding sources and publication plan

To create a list of potential sites for the pilot studies and send to the PaCCSC Coordinating Centre

To review and select sites for pilot study, in collaboration with the PaCCSC Coordinating Centre, and in accordance with SOP 5.6.1 Site Selection

To regularly liaise with the pilot site Principal Investigators To chair the pilot study management meetings (held a minimum of monthly) To attend and actively contribute to the Pilot Studies Sub-Committee of the PaCCSC

Trials Management Committee

Responsibilities of the site Principal Investigator and/or other designee(s) (for e.g. sub-investigator, site coordinator, study nurse, etc.) as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties)

To complete the Site Feasibility Checklist (Template 5) and return to the PaCCSC Coordinating Centre within the timeframe requested

To conduct pilot study at the site, in line with the protocol and PaCCSC SOPs To actively participate in the pilot study management meetings To provide feedback and data regarding the pilot study to the Lead Investigator and the

PaCCSC Coordinating Centre, within the timeframe requested


To facilitate the approval process for the pilot study, through the PaCCSC Annual Research Forum, the PaCCSC Trial Management Committee and the PaCCSC Scientific Committee

To manage the site selection process for the pilot study To supports the conduct of the pilot study in accordance with SOP 6.0.1 New Study

Ideas/Proposals


To rigorously review the pilot study protocol To monitor the scientific conduct of the pilot study To nominate a member of the Committee as the specific liaison for the pilot study, to

regularly liaise with the Lead Investigator of the pilot study and report back to the Scientific Committee

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6.0.2 V1.1 Page 4 of 8

Procedure

1. Developing a pilot study

PaCCSC pilot study ideas can be developed as a ‘stand-alone’ pilot study or as part of a Phase III study protocol. The latter is PaCCSC’ preferred approach to pilot study development.

New pilot study ideas are pitched and managed in line with SOP 6.0.1 New Study Ideas/Proposals.

New pilot study ideas/proposals that are approved to progress to stage 2 of the selection process require the development of a draft protocol: o Pilot study protocols (developed either as ‘stand-alone’ or as part of a Phase III

study protocol) use the Protocol Template (refer SOP 6.0 Protocol Development). Section 2 of the template addresses the pilot phase of a Phase III study.

The pilot study protocol is developed in line with SOP 6.0 Protocol Development and includes clear feasibility objectives with regards to: o Process (for e.g., recruitment and retention rates) o Resources/logistics (for e.g., time and budget considerations) o Management (for e.g., personnel issues) o Scientific (for e.g., treatment safety, determination of dose, etc.)

The focus of the pilot study protocol is on the assessment of feasibility (not focussed on statistical significance) (Guidance 13).

A Pilot Study Progress Plan (Template 33) is developed and submitted to the PaCCSC Scientific Committee with the pilot study protocol.

2. Selecting appropriate sites for the Pilot Study

PaCCSC recommends that a minimum of two sites are included in the pilot study. This tests the methodology across different sites, thus providing a more rigorous evaluation of the study feasibility and logistics for a future multi-centre Phase III study.

PaCCSC conducts a site feasibility and study feasibility evaluation of all potential pilot sites, using the Site Feasibility Checklist (Template 5), Study Feasibility Checklist (Template 21) and Site Risk Assessment Toolkit (Template 6): o The Site and Study Feasibility Checklists are sent by the PaCCSC Coordinating

Centre to the Principal Investigator at all potential pilot sites. o The Site and Study Feasibility Checklists are completed by the Principal

Investigators and returned to the PaCCSC Coordinating Centre prior to the PaCCSC Scientific Committee review of the template.

o In collaboration with the Lead Investigator for the pilot study, the PaCCSC Coordinating Centre reviews the completed Site Feasibility Checklist, completes the Site Risk Assessment Toolkit (refer SOP 5.6.1 Site Selection) and selects appropriate sites.

o The pilot study Lead Investigator incorporates the selected pilot study sites into the study protocol prior to submission to the PaCCSC Scientific Committee.

PaCCSC SOP Feb 2018

6.0.2 V1.1 Page 5 of 8

3. Conducting a pilot study

A management committee for the pilot study is established following approval to proceed from the PaCCSC Scientific Committee. This committee includes the Lead Investigator, PaCCSC National Manager (or delegate) and Principal Investigators from each pilot site.

Meetings occur a minimum of monthly (via teleconference) and include review of the following: o Recruitment o Logistics o Safety o Study design

The data collection (recruitment) phase of the pilot study is 12 months (see Figure 1). Recruitment beyond 12 months is negotiated with the PaCCSC Scientific Committee.

The Lead Investigator reports the progress of the pilot study to the nominated member of the PaCCSC Scientific Committee and the Pilot Studies Sub-Committee.

At the end of the pilot study: o A final report is submitted to the PaCCSC Scientific Committee o The Scientific determines if the study proceeds to multi-centre Phase III trial o If approved, the Lead Investigator progresses applications for funding to sources

identified in the Pilot Study Progress Plan o The pilot study results are published in an appropriate peer reviewed journal.

PaCCSC SOP Feb 2018

6.0.2 V1.1 Page 6 of 8

Figure 1 Typical Timelines for PaCCSC Pilot Studies

Scientific Committee review and feedback

Submission to Human Research Ethics Committee for

approval

Initial concept presented at the PaCCSC Annual Research

Forum

Protocol development &

Site selection process

Commence recruitment

Cease recruitment Data analysis

Applications for funding of multi-centre Phase III clinical

trial

March

March - August

September

October

January

December

January - March

Year

Year

Year

PaCCSC SOP Feb 2018

6.0.2 V1.1 Page 7 of 8

Other related SOPs

5.6.1 Site Selection 6.0 Protocol Development 6.0.1 New Study Ideas/Proposals


Template 5: Site Feasibility Checklist Template 6: Site Risk Assessment Toolkit Template 21: Study Feasibility Checklist Template 27: Pilot Study Progress Plan Guidance 13: Pilot/Feasibility Studies

References




Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, Robson R, Thabane M, Giangregorio L, Goldsmith CH. A tutorial on pilot studies: the what, why and how. BMC Medical Research Methodology 2010; 10: 1-10.

Acknowledgements


PaCCSC SOP Feb 2018

6.0.2 V1.1 Page 8 of 8

History





Approval


1.1 David Currow


6.5.1 V2.2 Page 1 of 8

6.5.1 Study Recruitment

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

6.5.1 V2.2 Page 2 of 8


The recruitment of participants is crucial to the success of a clinical study. Planning for recruitment and the development of strategies to maximise recruitment is an important activity prior to study commencement.

Poor planning for recruitment can result in poor referral rates to the study and potentially the referral of people who are unlikely to meet the inclusion criteria or not complete the study protocol. Optimising referrals and recruitment to clinical studies, particularly in palliative care, requires intensive effort to overcome barriers such as clinician and family gate keeping, competing clinician responsibilities, and the potential vulnerability of the population, all of which make recruitment problematic.

Objective

This SOP describes the basic principles of recruitment to clinical studies conducted by PaCCSC. In addition, each site is expected to develop individual recruitment strategies (in discussion with the PaCCSC National Manager/National Project Officer) to maximise recruitment potential at that site.

Scope




To develop appropriate recruitment strategies specific for each study To pre-screen potential participants following referral To complete Pre-Screen Forms where appropriate To maintain the Master Patient Index To undertake screening for eligibility To ensure Participant Information and Consent Forms are signed by each participant (or

proxy)


To assist sites in the development of their recruitment strategies To distribute recruitment tools to sites so as to facilitate recruitment of potential

participants

PaCCSC SOP Feb 2018

6.5.1 V2.2 Page 3 of 8

Procedure

1. Prior to Recruitment

Recruitment of participants only commences when the following have been completed:

The study, including the protocol, study documents, advertising materials and PatientInformation and Consent Form have received final approval from the Human ResearchEthics Committee (HREC)

The study has been registered on a publicly accessible clinical study registry The site has been added as a study site with the Therapeutic Goods Administration (TGA)

under the Clinical Trials Notification (CTN) scheme (if applicable) A site initiation visit Clearance has been given to commence the study by the PaCCSC Coordinating Centre

2. Tools to aid recruitment

The PaCCSC Coordinating Centre, in conjunction with the Lead Investigator and study team, has developed a number of tools to assist with recruitment. These tools are regularly revised and updated. Tools can include:

Frequently asked questions Work instructions Workshop materials Prompt sheets and study lanyards Advertising materials

3. Referral

All potential participants are referred by the local clinical service to the PaCCSC studies (rather than through advertising or general invites for participants). Referrals are made via a number of site specific strategies aimed at:

Increasing clinical knowledge and understanding of the study Ensuring that all people with specific characteristics are referred to the study team for

further assessment Making individuals fully aware that they have been referred to a research study team, and

may be contacted as a result

Referrals can be made via several media (described within the study protocol):

Telephone Written referral letter Fax of study referral Email request

PaCCSC SOP Feb 2018

6.5.1 V2.2 Page 4 of 8

All people referred to each study:

Are entered onto the study Patient Master Index maintained at each site (refer SOP 5.5.1Electronic Data Handling) to enable tracking of Key Performance Indicators (KPIs)

Have a notation made within the clinical file concerning referral Have a Pre-Screen Form completed and entered onto the study on-line database

4. Pre-screening

Following receipt of referral, a Pre-Screen Form is completed. Eligibility characteristics required for entry into the study are recorded on the form. If the characteristics are not met, and the person does not proceed to screening, a Pre-Screen Form is still completed.

A Pre-Screen Form is not completed under the following circumstances: The person dies or their condition deteriorates between the time of referral and the time

of contact Other circumstances where the referral was not acted upon (an identification number has

not been allocated, and no data has been entered into the study database)

The Pre-Screen Form can be completed from information obtained from a number of sources, including:

Referral letter Discussion with clinical staff During the initial telephone contact with the person referred to the study Case note review (after seeking permission from the potential participant)

Pre-screening information does not involve collection of information outside of usual clinical care and can be obtained from sources without intervention of any description.

Pre-screening serves a number of purposes to assist with recruitment:

Referrals and prompt follow-up of referrals is encouraged and facilitated The use of broad eligibility characteristics encourages appropriate referrals Pre-screen data can be used to identify potential recruitment strategies Data can be used to review the study inclusion and exclusion criteria if recruitment is

slower than expected

5. Screening and consent

Screening for eligibility takes place after the broad entry characteristics are met as part of Pre-screening. The study is fully explained to the potential participant, using the approved Participant Information and Consent Form. Consent is obtained according to the protocol, and the eligibility assessments (screening) are undertaken.

Screening involves collection of information that is in addition to clinical care in order to assess eligibility for the study.

PaCCSC SOP Feb 2018

6.5.1 V2.2 Page 5 of 8

Following screening, participants either proceed to randomisation or are removed from the study if they do not meet the criteria. This is known as a Screening Failure. All screened participants are recorded in the Patient Master Index at each site. Screening numbers (including participants who proceed to randomisation and those who do not proceed) are reported as part of the KPIs for each site.

The consent and screening procedures vary between studies, and are described within the study protocols. These procedures are followed in order to comply with Good Clinical Practice (GCP) requirements.

Figure 1 details the Participant Recruitment Algorithm for PaCCSC clinical studies.

PaCCSC SOP Feb 2018

6.5.1 V2.2 Page 6 of 8

Figure 1 Participant Recruitment Algorithm

REFERRAL (Received by research team

from clinical team)

PRE-SCREENING (Pre-screen / eligibility CRF

completed)

PROCEED TO RANDOMISATION (Not suitable for Re-screening if participant does not proceed)

INCLUDE ON PATIENT MASTER INDEX

(Could be eligible for Re-screening at a later date)

OBTAIN CONSENT (Participant Information and

Consent Form)

SCREENING (Screening CRF completed)

NO FURTHER INVOLVEMENT

Meets inclusion criteria

Not suitable for study

Could be suitable for study

Excluded from study

Consent given

No consent

PaCCSC SOP Feb 2018

6.5.1 V2.2 Page 7 of 8

Other related SOPs

4.2.4 Delegation of Duties 5.5.1 Electronic Data Handling 5.5.5 Allocation of Participant ID Numbers 5.23.2 CRF Completion 6.5.2 Re-Screening


Template 36: Study Recruitment Plan Template 37: Recruitment Review Template 38: Recruitment Phone Calls Topics/Questions Guidance 15: Recruitment Matrix

References

IUPUI Standard Operating Procedures, Recruitment of Human Participants. V08/2017. http://researchcompliance.iu.edu/hso/hsdocs/IU%20SOPs%20for%20Research%20Involving%20Human%20Subjects%2008.2017.pdf


Work Instructions for PaCCSC studies

Acknowledgements


PaCCSC SOP Feb 2018

6.5.1 V2.2 Page 8 of 8

History



1.2 21/01/2008 B Fazekas Update following MAB review



Periodic review, ratified by MAB

2.0 1/02/2011 B Fazekas New version will all updates




Approval


2.2 David Currow


6.5.2 V2.2 Page 1 of 7

6.5.2 Re-Screening

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

6.5.2 V2.2 Page 2 of 7


People potentially eligible for the PaCCSC clinical studies are screened in accordance with protocol specific procedures. This process ensures that participants (and potential participants) are fully screened, and enter studies after having met all of the inclusion criteria. The screening procedure detailed in SOP 6.5.1 Study Recruitment is followed. However, there are some circumstances where people can be re-screened at a later date for a study, after having already been screened initially.

Objective

This SOP describes the circumstances when re-screening is appropriate and how this is to be recorded.

Scope




To identify potential participants eligible for re-screening To screen participants who have been identified as eligible for re-screening To ensure Case Report Forms are completed for each participant following re-screening To ensure Participant Information and Consent Forms are signed by each participant (or

proxy) following re-screening, if necessary

PaCCSC SOP Feb 2018

6.5.2 V2.2 Page 3 of 7

Procedure

1. Screening

Screening for eligibility to participate in a clinical trial takes place after the broad entry characteristics have been met as part of the Pre-screening process (refer SOP 6.5.1 Study Recruitment).

The study is fully explained to the potential participant, using the approved Participant Information and Consent Form. Consent is obtained according to the protocol, and the eligibility assessments (screening) are undertaken.

Following screening, participants either proceed to randomisation, or are removed from the study if they do not meet the criteria. This is known as a Screening Failure. All screened participants are recorded in the Patient Master Index at each site (refer SOP 5.5.5 Allocation of Participant ID Numbers). Screening numbers (including participants who proceed to randomisation and those who do not proceed) are reported as part of the Key Performance Indicators (KPIs) for each site.

The consent and screening procedures vary between studies, and are described within the protocols. These procedures are followed in order to comply with Good Clinical Practice (GCP) requirements.

2. Re-Screening

Re-screening of participants can occur in certain circumstances and provided the participant has not been randomised in the study already.

Examples of circumstances when a participant can be re-screened:

If a person consents to participate and meets the eligibility criteria but there is a delay in starting due to a change in situation (for e.g., family issues, individual request for attending private matter, etc.)

If the person previously failed screening due to an acute event that has now resolved/reversed

Prescribed medications have stabilised Reversible causes of screen failure have been adequately treated (for e.g., someone who

had anaemia at the original screening that precluded involvement, and this has since been corrected/resolved by a blood transfusion)

Re-screening always occurs if the screening data has been entered into the RDMS but the participant has not been randomised for that study. This is true even if nothing has seemingly changed between the initial screening and re-screening time points.

It is not appropriate to re-screen a person if they have previously failed to meet the eligibility criteria and there have been no further changes or treatments that would now indicate that the person may be suitable.

It is not appropriate to re-screen a person if they have previously been randomised to the study and did not proceed to study intervention. Such course of action may potentially delay the commencement of the study. In this situation, the eligibility data is to be reviewed for currency and the CRF amended accordingly, the timeframe is determined by the Principal Investigator and a file note is completed. Re-screening is not undertaken at this point.

PaCCSC SOP Feb 2018

6.5.2 V2.2 Page 4 of 7

3. Re-Screening Procedure

Screening data has been entered into RDMS o A new Case Report Form – Eligibility form is used (refer SOP 5.23.2 CRF

Completion) o A new Identification number is assigned to the person (the 3 digit patient number).

See SOP 5.5.5 Allocation of Participant ID Numbers. o The person is identified as having been re-screened on both the Case Report Form

and the Patient Master Index. o The Case Report Form is completed. Data is not copied from the previous eligibility

CRF to the next, but completed using the current clinical situation as documented within the patient clinical notes and any other source documents.

o The person may need to sign a new Participant Information and Consent Form as part of the screening procedure (as per the individual study protocol and requirements of Human Research Ethics Committees).

Screening data has not been entered into RDMS o The previous Case Report Form can be reviewed and updated (refer SOP 5.23.2

CRF Completion) o The Case Report Form is completed. Data is not copied from the previous eligibility

CRF to the next, but completed using the current clinical situation as documented within the patient clinical notes and any other source documents.

Figure 1 details the Participant Recruitment Algorithm for PaCCSC clinical studies.

PaCCSC SOP Feb 2018

6.5.2 V2.2 Page 5 of 7

Figure 1 Participant Recruitment Algorithm

REFERRAL (Received by research team

from clinical team)

PRE-SCREENING (Pre-screen / eligibility CRF

completed)

PROCEED TO RANDOMISATION (Not suitable for Re-screening if participant does not proceed)

INCLUDE ON PATIENT MASTER INDEX

(Could be eligible for Re-screening at a later date)

OBTAIN CONSENT (Participant Information and

Consent Form)

SCREENING (Screening CRF completed)

NO FURTHER INVOLVEMENT

Meets inclusion criteria

Not suitable for study

Could be suitable for study

Excluded from study

Consent given

No consent

Condition has changed and now may be

suitable for the study

RE-SCREENING

PaCCSC SOP Feb 2018

6.5.2 V2.2 Page 6 of 7

Other related SOPs

4.2.4 Delegation of Duties 5.5.5 Allocation of Participant ID Numbers 5.23.2 CRF Completion 6.5.1 Study Recruitment


N/A

References


Acknowledgements


PaCCSC SOP Feb 2018

6.5.2 V2.2 Page 7 of 7

History



1.2 8/01/2008 B Fazekas Update following MAB review



Periodic review





Approval


2.2 David Currow


6.10 V2.2 Page 1 of 5

6.10 Version Tracking

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

6.10 V2.2 Page 2 of 5


Maintaining a historical record of changes to documents over the course of a study ensures compliance with the International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines. Furthermore, such a system also ensures that same version of a study document is used across all research sites.

Objective

This SOP describes the procedure for keeping track of multiple document versions, how the version is determined, reasons for updating documents, and the control mechanisms for distribution of document versions.

Scope




To determine if an amendment is minor, significant or major To approve all changes to essential documents To distribute new versions to appropriate study staff and committee members To ensure that the most recent version is in use To ensure that ethics approval has been sought if applicable To maintain a file of old and new versions according to Trial Master File Index

Responsibilities of the Principal Investigator and/or other designee(s) (such as Study Site Coordinator) as documented in the Staff Signatures and Delegation Log (refer SOP 4.2.4 Delegation of Duties)

To maintain a file of old and new versions according to Trial Master File Index To ensure that the most recent version of any document is in use

PaCCSC SOP Feb 2018

6.10 V2.2 Page 3 of 5

Procedure

1. Type of amendments

Minor – changes are of correction or editorial nature, or part of a routine update of ongoingdocuments.

Significant – changes have an impact on the implementation of the document, mayrequire submission for HREC approval (protocol, PICF, etc.), and may require sometraining.o Examples include: changes to some of the data collection or assessments,

clarification or changes to pharmacy procedures, changes to the contact details ina site specific PICF.

Major – changes are significant change from the previous version; the changes have animpact in the implementation across much or all of the document concerned, and mostlikely require HREC approval, and may also require updates in other regulatorydocuments study such as CTN, Trial registry, or as a result of ICH GCP.o Examples include: changes to the inclusion or exclusion criteria of a protocol,

changes to the randomisation or intervention, such as adding or dropping a studyarm.

2. Recording

All documents have the version number printed as part of a footnote.

All electronic documents have the version number as part of the document file name.

Versions are referred to with Vx.x.x with these being defined as:o Vx.x.x – a minor modification or amendment Example: V3.2.1 becomes V3.2.2 when a minor amendment is made.o Vx.x.x – a significant modification or amendment Example: V3.2.1 becomes V3.3.1 when a significant amendment is made.o Vx.x.x – a major modification or amendment.

Example: V3.2.1 becomes V4.1.1 when a major amendment is made.

The latest version is the working document. All previous versions of study documents arekept on file for possible reference and to provide historical information regarding theextent of changes.

All correspondence to and from Human Research Ethics Committees (HRECs) clearlystate the version number currently under review and approved.

3. Reporting

All changes to versions at individual sites are reported to all other sites through thePaCCSC Coordinating Centre.

PaCCSC SOP Feb 2018

6.10 V2.2 Page 4 of 5

Other related SOPs

5.5.1 Electronic Data Handling 6.0 Protocol Development 8.0 Essential Documents


N/A

References





Praxis Australia Ltd. SOP-05 Document and version control. V1.0 (Template for general use).

PaCCSC SOP Feb 2018

6.10 V2.2 Page 5 of 5

History



New procedure





Periodic review





Approval


2.2 David Currow


6.12 V2.3 Page 1 of 10

6.12 Ethical Approval, Review and Reporting

Version V2.3


Approved D Currow




PaCCSC SOP Feb 2018

6.12 V2.3 Page 2 of 10


Good Clinical Practice requires that clinical study investigators are aware of their responsibilities with regard to communication and compliance with Human Research Ethics Committees (HREC) through all stages of the study, and that the clinical study is properly conducted and human participants are adequately protected.

Objective

This SOP describes how sites communicate with the HREC in order to comply with regulations and to protect the safety of participants.

Scope



The PaCCSC Coordinating Centre, the Lead Site Principal Investigator

PaCCSC SOP Feb 2018

6.12 V2.3 Page 3 of 10

Procedure

1. General

Each study protocol is developed in line with SOP 6.0 Protocol Development and SOP 4.0 Investigator Responsibilities.

Each PaCCSC study protocol is registered with the agreed study registry and has an allocated Randomised Controlled Trial Register Number.

Australia has a single ethical review process where one HREC provides approval for all state health hospitals in participating states. During the protocol finalisation process the appropriate HREC and a PaCCSC Lead Site are selected. The HREC is constituted and operates in accordance with the NHMRC National Statement on Ethical Conduct in Human Research (2007) (updated March 2014).

2. Human Research Ethics Committees (HREC)

The Lead Site obtains and files documentation that lists the constitution of the HREC that has provided ethical oversight of the study, the HREC membership, the HREC NHMRC Number, and confirms the committee’s compliance with the national requirements.

3. Initial submission

Documentation submitted to HRECs for approval includes (but is not limited to): o Institutional application form, and payment for industry sponsored studies o Protocol and any protocol amendments including version numbers o Investigator’s brochure if required or Product Information o Master Participant Information and Consent Forms o Other documents being provided to potential participants as master versions such

as questionnaires o Any other supporting documentation to be considered (for e.g., Scientific

Assessment Reviews and Declaration of Prior Review form) o Indemnity certification from the appropriate authority for that site o Completed Clinical Trial Notification forms where applicable o Recruitment materials o Other documents as requested by the HREC

One copy of the submission documents is to be kept in the Lead Site files, with an additional copy provided to the PaCCSC Coordinating Centre.

4. During the approval process

All questions and requests for change arising from the HREC deliberations are copied to the: o Principal Investigator o Lead Investigator (of the protocol) o PaCCSC Coordinating Centre

All correspondence between the Lead Site and the HREC is copied to the PaCCSC Coordinating Centre.

PaCCSC SOP Feb 2018

6.12 V2.3 Page 4 of 10

5. Communications

Following approval of the protocol, any protocol amendment which requires a change inresearch activity is submitted to the approving HREC. Administrative amendments areaddressed in the submission of a revised protocol at the completion of the study.Identification of the protocol and amendments is in line with SOP 6.10 Version Tracking.

The Principal Investigator in consultation with the Lead Investigator provides interimand/or annual reports and a final written report to the HREC. Copies are maintained inthe investigator files in accordance with the SOP 8.0 Essential Documents, SOP 8.4.1Archiving of Research/Project Materials, and SOP 5.5.1 Electronic Data Handling.

In addition, each HREC requires periodic renewal of ethical approval (usually annually).Notification for this is copied to the PaCCSC Coordinating Centre.

Written approval from the relevant HREC on the application to implement the protocolmust be received prior to the commencement of the study. Any documentation modifiedduring the course of the study is submitted to the HREC.

The reporting of all adverse and serious adverse events of studies is in line with SOP5.17 Adverse Event Reporting.

In the event that a study is terminated or suspended prematurely, the HREC isimmediately informed and followed up with a written explanation of the termination orsuspension.

6. Procedures for single ethical review

New South Wales, Victoria, Queensland, Western Australia and South Australia have all agreed on a process of single ethical review by a nominated Lead Site HREC. This lead approval covers all subsequent sites across states and requires submission to local Research Governance Offices for assessment of local implementation issues such as budget, staff, resources etc.

The PaCCSC Coordinating Centre:o Discusses and appoints a Lead Site for the study and determines the Lead HRECo Supplies the:

i. Current protocolii. Master Participant Information and Consent Form (PICF)iii. Draft National Ethics Application Form (NEAF) or Human Research Ethics

Application (HREA)

The Lead Site:o Completes the NEAF/ HREAo Transfers the NEAF/HREA to the PaCCSC National Project Officer where

appropriateo Locks the NEAF/HREA when completed and ready for submission

PaCCSC SOP Feb 2018

6.12 V2.3 Page 5 of 10

The Lead Site Principal Investigator submits the protocol to the Lead HREC for scientific review. Submission includes: o Current protocol o Completed and locked NEAF/HREA o Master PICF based on the master PICF supplied by the PaCCSC Coordinating

Centre o Other required documents o Works with the PaCCSC Coordinating Centre to address any concerns/questions

the Lead HREC raise

The Lead HREC approves the submission as above: o Approval letter is sent to Lead Site Principal Investigator

Lead Site Principal Investigator: o Generates Site Specific Assessment (SSA) forms for each site o Sends copies of the:

i. Lead HREC approval letter ii. Master PICF iii. SSA form iv. HREC approval documents to the PaCCSC Coordinating Centre

Principal Investigators at each study site submit the local application to the local Research Governance Officer. Application includes: o Locked SSA o Master PICF template inserted into local format (use version tracking) o Lead HREC approval letter o Other documents as specified by the Research Governance Officer

The Research Governance Officer approves SSA and provides: o Local approval letter

Principal Investigators at each site send a copy of their specific SSA approval letter to the PaCCSC Coordinating Centre.

The PaCCSC Coordinating Centre arranges: o Sponsor approval and submission of the online Clinical Trial Notification (CTN) o Payment to the TGA

The PaCCSC Coordinating Centre sends confirmation of listing to individual sites with recruitment start date confirmation.

The Lead Site maintains the HREC correspondence for the submission and approval process including (see Figure 2): o Correspondence to and from the Lead HREC o Correspondence to and from each participating state site, including notification of

new sites, change in investigators, protocol amendments, and any subsequent approvals by the site

o And supplies copies of all correspondence to the PaCCSC Coordinating Centre

PaCCSC SOP Feb 2018

6.12 V2.3 Page 6 of 10

Each study site maintains a file of correspondence including: o Correspondence between the site and the Lead Site o Correspondence between the site and the local governance office

All subsequent correspondence is filed as above including: o Amendments o New sites, changes to investigators o Annual reports o Adverse and serious adverse reports o Any other correspondence

Figure 1 details the tasks undertaken by each site (assuming PaCCSC Coordinating Centre as sponsor).

PaCCSC SOP Feb 2018

6.12 V2.3 Page 7 of 10

Figure 1 Flow of tasks for each site (assuming PaCCSC Coordinating Centre as sponsor)

Protocol finalised

Recruitment Site (Site PI)

Lead PI (PaCCSC Coordinating

Centre)

Lead Site and Principal

Investigator decided

Prepares draft Application

Finalises Master PICF, and other

documents

Complete and submit locked SSA and local

forms to RGO

Completes and locks the

Application

Generate local version of Master

forms

Submits to HREC

Template Master PICF and other

documents

Obtains RGO approval including signed CTRA

Answers queries from HREC (jointly with lead PI)

CTN generated by PaCCSC

Lead Site PI

Lead HREC decided

Obtains HREC approval

Generate SSA for each site, send copy of approval, and all approved master documents to

each site.

Ensures sponsor submission of CTN with TGA

PaCCSC SOP Feb 2018

6.12 V2.3 Page 8 of 10

Figure 2 Outline of filing HREC documentation for each site (assuming PaCCSC Coordinating Centre as sponsor)

PaCCSC Coordinating

Centre

files

Copy of HREC submission

Copy of RGO submission

Copy of all subsequent correspondence between:

• PI and HREC• PI and sites• Sites with RGO

Lead Site

files

HREC submission and all master

versions

All subsequent correspondence to HREC and to sites including:

• Approval letter• Amendments• Annual reports• Adverse events• Any other

correspondence

Recruitment Site

files

RGO submission and local versions

based on approved master versions

All subsequent RGO correspondence and

correspondence between site and PI

PaCCSC SOP Feb 2018

6.12 V2.3 Page 9 of 10

Other related SOPs

4.0 Investigator Roles and Responsibilities 5.17 Adverse Event Reporting 5.5.1 Electronic Data Handling 6.0 Protocol Development 6.10 Version Tracking 8.0 Essential documents 8.4.1 Archiving of Research/Project Materials


N/A

References



ISRCTN International Standard Randomised Controlled Trial Number Register (accessed 21/12/2017) https://www.isrctn.com/



PaCCSC SOP Feb 2018

6.12 V2.3 Page 10 of 10

History



New procedure










Approval


2.3 David Currow


6.15 V3.3 Page 1 of 11

6.15 Authorship

Version V3.3


Approved D Currow




PaCCSC SOP Feb 2018

6.15 V3.3 Page 2 of 11


In accordance with the Australian Code of the Responsible Conduct of Research1, all PaCCSC research teams shall have a written policy on the criteria for authorship of the research output. Minimum criteria for authorship are to be in accord with the International Committee of Medical Journal Editors (ICMJE)2, and the Australian Code of the Responsible Conduct of Research1.

Objective

This SOP defines and describes how authorship will be determined within PaCCSC to ensure that publications adhere to international authorship guidelines.

Scope



Responsibilities of the Executive Author

To ensure that the authorship team maintains the highest standards of research integrity To define the types of presentation of the research output To negotiate with the authorship team responsibilities for each conference presentation To negotiate with the authorship team the authorship order and inclusion within all

manuscripts and presentations To oversee the preparation of manuscripts, abstracts and presentations including

accountability for content To oversee the record keeping regarding the research output including circulating drafts,

integrating changes, production of the final version and making the ultimate decisionregarding submission to the publishing company

To prepare and maintain record-keeping regarding the authorship statement To develop timeline and ensure adherence to same


To disseminate authorship information to the authorship team on a quarterly basis To facilitate in conflict resolution regarding authorship To oversee publication timelines as drawn by the Executive Author To send reminders to the Executive Author regarding pending planned publication To send reminders to the Chair of the PaCCSC Publications Sub-Committee regarding

pending planned publication

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Procedure

1. Authorship

An ‘author’ is considered by PaCCSC as someone who has made a substantive intellectual contribution to the published study2.

Authorship is substantial participation, where all of the following conditions are met: o Substantial contributions to conception and design, acquisition of data, or analysis

and interpretation of data2,3,4; o Drafting of the article or critical revision for important intellectual content1,2,4; o Final approval of the version to be published3,4; and o Each author should have participated sufficiently in the work to take public

responsibility for appropriate portions of the content2.

There may be instances where a contributor does not meet the above criteria; however, the individual(s) is clearly accepted by all the other authors as an appropriate member of the authorship team. In this case, the selective contribution needs to be clearly identified and accepted by all members of the authorship team.

Where authorship of multicentre trials is attributed to a group, all members of the group who are named as authors should fully meet the above criteria2.

One co-author will be nominated as Executive Author for the whole research output, and will take responsibility for record-keeping regarding the research output3,4-8.

A signed authorship statement must be generated for each manuscript that acknowledges each author’s contribution in writing. Such contributions may also be requested by the journal3,4-9.

A person who meets the criteria for authorship must not be included or excluded as an author without their written permission. This permission should include a brief description of their contribution to the work.

2. Authorship teams

Since some projects are likely to have a large volume of research output leading to multiple manuscripts, a plan is required for negotiating responsibility for various components of the research output for each individual project. Collaborating researchers agree on authorship at the protocol design stage and review their decisions periodically. The authorship team members and resulting published output from each study is recorded in a specific publications plan for each individual study in conjunction with the study’s dissemination plan, and replicated in brief in the PaCCSC publications/presentations list which is circulated quarterly to members.

A component of research output is defined as the intellectual product of a defined methodology, data collection and analysis subset of the overall study. Occasionally, similar research output may be considered by several authorship teams who approach the content with a different intellectual focus resulting in different manuscripts for publication.

Individual authorship is, where possible, supported within a team framework. As such, authors are encouraged to work in authorship teams focused on various types of research output.

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An Executive Author leads each team. The Executive Author functions as the Guarantor as advocated by editors of BMJ, Lancet and JAMA; and members of the authorship team function as Contributors5-8. Different authorship teams may be comprised of exactly the same members, or membership can shift and teams reframed to accommodate the type of research output, interest of the team members, contributions, etc.. Individuals who are not the Lead Investigator but who contribute significantly to a component of research output may be members of the respective authorship team (e.g. principal investigators, sub-investigators, study site coordinators, or data managers).

Responsibilities of the Executive Author (Guarantor) include (but are not limited to):

Ensuring that the authorship team maintains the highest standards of research integrity5-

8; and Defining the types of presentation of the research output (e.g. conference presentations,

manuscripts); and Negotiating with the authorship team to determine responsibility for each conference

presentation; and Negotiating with the authorship team regarding authorship order and inclusion within all

manuscripts and presentations; and Oversight of the preparation of manuscripts, abstracts and presentations including

accountability for content5-8; and Oversight of the record keeping regarding the research output including circulating drafts,

integrating changes, production of the final version and making the ultimate decision regarding submission to the publishing company, including3,4: o Responsibility for submission of manuscripts in line with the PaCCSC Planned

Publications Master List (Template 26); or the Publication Planning (Guidance 12) for the specific study; and

o Corresponding with all named authors regarding submissions and responses from the publishing company as named in the list/plan and ensuring they are aware of the process to be followed as per this SOP; and

o Responding immediately to reviewers comments that only require minor amendments (i.e. small changes, formatting etc.); or circulating reviewers comments to the authorship team where substantial amendments are required (i.e. rewrites of text) for response within 10 days. For substantial amendments and where discussion is required amongst the authorship team in order to reach a consensus, the Executive Author must conduct a teleconference with the authorship team to address and resolve comments in a timely manner prior to submission. All members of the authorship team are expected to contribute at this stage as there will be no further opportunity provided; and

o Collating authorship team responses to substantial amendments and simultaneously resubmitting the next version to the publishing company and to the authorship team; and

o Communicating with the authorship team regarding the receipt of acceptance or rejection of a manuscript; and

o Provision of ‘authors copy’ of manuscript for uploading to ‘Open Access’ repository where paper is not available ‘Free On Line’.

Preparation and record-keeping regarding the authorship statement9; and Timeline development and adherence.

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Members of the authorship team indicate their contribution to the project in preparation for the authorship statement. PaCCSC, via the National Manager, disseminates authorship information on a quarterly basis in line with the work instruction accompanying this SOP.

To qualify for authorship, contributors have to meet the criteria outlined in Section 1 above. If expertise is contributed for one specific reason but the person is not part of the study team, he/she is acknowledged but is not included as an author.

The following contributions do not justify including a person as an author1:

Recruiting study subjects to a study Departmental head or other positions of authority Personal friendship with the author(s) Providing technical contributions only Providing routine assistance to the work being published Acquiring funding for the work being published General supervision of the research team undertaking the work Providing already published data or materials gained from a third party, but with no other

intellectual input

Publication of studies strive to include all researchers who have made a substantial contribution to the research output and meet the criteria listed in section 1 above, and to avoid disseminating any research findings that do not appropriately indicate participants or acknowledge their work. PaCCSC members can expect that all authors work to ensure the integrity of the published work and avoid any aspects of fraud1-9.

Those who contribute and participate in the study, but do not meet the criteria as outlined, are credited in the Acknowledgements section of the publication manuscript. Indications for Acknowledgement include meeting only one of the authorship criteria5. Written consent is obtained from all individuals who are named in the Acknowledgements section of the manuscript.

3. Authorship order

The rules for authorship order continue to change. Hence, the question of authorship order is considered with flexibility and pragmatism in academic medicine. Generally, the Executive Author is first author. The order of the remaining members of the authorship team is negotiated from within the team5-8.

The Journal of the American Medical Association (JAMA) and British Medical Journal (BMJ) propose that each author indicate his/her percent contribution to each part of the research output, and that the authorship order reflects the relative contribution. This is one suggested method that the authorship team can consider5,7,8.

Critical considerations include first author, corresponding author, last author, and group authorship:

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First Author

Generally the highest impact authorship position10. The Executive Author is usually the first author, however this is still clearly negotiated and articulated within the team. If there is a dispute as to the appropriate first author, the relative percent contribution to the research output, analysis and manuscript is considered. The first author is the person who contributed most to the work, including writing the first draft of the manuscript. Also, when negotiating first authorship key options such as corresponding author and last author are also considered.

Last Author

The position of last author is also negotiated with the team and specifically with the Executive Author and the person selected as the first author. If there is a dispute as to the appropriate last author, the relative percent contribution is considered as well as the authorship tradition of placing more senior authors last who provided the team with expert experience, conceptual advice and guidance10. In general, the person who is the second highest contributor to the research output and manuscript has the opportunity to decide if he/she would like the second author or last author position.

Corresponding Author

This is the person listed to receive all correspondence from the journal on behalf of the authorship team (reviewers’ comments, publication proofs, etc.) and all correspondence from readers after publication. Some researchers consider this position like the last author position; however, journal editors view it as similar in status to an administrative role10. In general, the corresponding author is either the first or last author as negotiated by the team.

4. Contributors listed in acknowledgements

All contributors who do not meet the criteria for authorship in section 1 are listed in the acknowledgements section. Those listed are asked to declare whether they provided assistance with study design, data collection, data analysis, or manuscript preparation. Financial and material support are also acknowledged.

Groups of persons who have contributed materially to papers but whose contributions do not justify authorship may be listed under such headings as ‘clinical investigators’ or ‘participating investigators’, and their function or contribution is described. Written permission from these people is required to be acknowledged in the manuscript.

5. Presentations

Any presentations of results (final, interim or sub-studies) require approval from the authorship team, are listed in the PaCCSC Planned Publications Master List and are subject to the same procedures and authorship rules as publications.

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6. Ownership and Use of Data

The data is ultimately owned by PaCCSC and the sites, and is managed by the Scientific Committee (refer SOP 5.5.10 Data Ownership and Utilisation). Individual study sites maintain ownership of their own data to use as they wish provided that they do not pre-empt the major study findings by publication or presentation. Publications and presentations of site specific data are acceptable provided they seek approval from the authorship team for the study in question and are required to:

Comply with this SOP for Authorship; Be approved by the Publications Sub-committee; Accept that whole-of-study presentations and publications take precedence and site-

specific outputs must not inhibit any planned whole-of-study output. Where there is any overlap approval by the Publications Sub-committee would form part of the overall approval relating to the output of a particular study.

Where access and use of PaCCSC data is requested by an external person, the request is considered by the Publications Sub-committee, after having been reviewed in light of the publication schedule. This enables consideration of conflict with other planned analyses and publication. Requests for and the use of PaCCSC data by external individuals/organisations are managed as per SOP 5.5.10 Data Ownership and Utilisation.

7. Data Analysis and Interpretation

On completion of a study, data is compiled by the PaCCSC National Project Officer and provided to the biostatistician for analysis. Initial results are discussed by the authorship team and presented by a member or members of the authorship team to all contributing sites. The presentation of the results at this stage is strictly confidential. These presentations may use electronic means of presenting the information and they may take place during regular scheduled meetings of the PaCCSC Trial Management Committee.

8. Reporting of Data

PaCCSC recommends that all reporting of randomised controlled trials is in accordance with the CONSORT Statement (http://www.consort-statement.org/) and the Jadad randomisation scoring instrument13. Both these documents aim to improve the quality of reporting of randomised controlled trials. They offer a standard way for researchers to report studies. The CONSORT checklist includes items, based on evidence, that need to be addressed in the report; the flow diagram provides readers with a clear picture of the progress of all participants in the study, from the time they are randomised until the end of their involvement. The intent is to make the experimental process clearer, flawed or not, so that users of the data can more appropriately evaluate its validity for their purposes. The Jadad instrument has three questions assessing randomisation, blinding and drop outs/withdrawal rates from the study.

The first draft of the study report is written by the Executive Author and then shared initially with the authorship team. The introduction and methods sections are drafted from the study protocol. The format of the report follows the ICH GCP guidelines for reporting13.The source of funding, acknowledgements listing and reference section can be included at this point.

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9. Conflict Resolution

The Australian Code for the Responsible Conduct of Research suggests that all groups of researchers establish procedures to resolve conflicts arising through disputes about authorship1.

In the event that there is a dispute or concern about authorship or the journal order to be considered for publication, the conflict is resolved with the help of the Publications Sub-committee (a sub-committee of the PaCCSC Scientific Committee).

If it becomes evident that an Executive Author or contributor needs or wants to be removed from an authorship team (e.g. inability to meet deadlines or participate in team discussions, membership in multiple other teams), the person can write to the Executive Author or PaCCSC National Manager to indicate that they wish to withdraw from the team. Otherwise, the person can only be removed from the authorship team through a recommendation of the publications subcommittee for decision by the Scientific Committee.

An important component of authorship is the preparation of abstracts, presentations and manuscripts, and getting the product out in a timely manner. The PaCCSC Planned Publications Master List includes a goal date for submission of the proposed research output. The Executive Author is responsible for time management. Provided that the analysed results have been provided by the data analysis team: If the research output is not prepared by four months after the goal date, then the

Executive Author will receive an initial reminder from the PaCCSC National Manager that the product is pending.

If the product is still not ready one month later, a second reminder is issued. If the product is still not ready one month after the second reminder, the National

Manager submits a notice to the Chair of the Publications Sub-committee who makes a decision regarding possible replacement of the Executive Author and re-organisation of the authorship team.

10. Reference Collection

Any articles or references collected for individual clinical studies are: Obtained in hard copy. Numbered according to an agreed electronic library file. Copied and placed in the project file in the coordinating site. These references then

remain permanently attached to the other documents used in preparation of any manuscripts.

Inserted into the electronic bibliography. The format is determined at the commencement of the study protocol.

The electronic reference file accompanies the electronic circulation of the manuscript.

Where the reference is cited within the project submission documents or draft manuscripts, the relevant section of the reference is highlighted. These papers are placed in a folder accompanying the manuscript.

Where the reference is not cited but may be used in the future or provides some useful background, the article is kept in another folder.

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Other related SOPs

6.0 Protocol Development 5.5.1 Electronic Data Handling 5.5.10 Data Ownership and Utilisation 6.15.1 Dissemination of Study Results


CONSORT Checklist Template 24: Dissemination Plan Template 26: Planned Publications Master List Guidance 12: Publication Planning

References

1. NHMRC Australian Code for the Responsible Conduct of Research 2007 (accessed 20/10/2017) https://www.nhmrc.gov.au/guidelines-publications/r39

2. International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Annals of Internal Medicine. 126; 36-47, 1997.

3. Joint NHMRC/AVCC Statement and Guidelines on research practice 1997 (accessed 250207) http://www.nhmrc.gov.au/funding/policy/researchprac.htm

4. Huth EJ. Writing and Publishing in Medicine. 3rd Ed. Williams and Wilkins, Baltimore, 1999, pp 42-44.

5. Rennie D, Yank V, Emanuel L. When authorship fails. A proposal to make contributors accountable. JAMA. 278:579-85, 1997.

6. Horton R. The signature of responsibility. Lancet. 350:5-6, 1997.

7. Smith R. Authorship is dying: long live contributorship. BMJ. 315; 696, 2001.

8. Smith R. Maintaining the integrity of the scientific record. BMJ. 323; 588, 2001.

9. JAMA Authorship Statement. JAMA 288; 114, 2002.

10. Albert T, Wager E. How to handle authorship disputes: a guide for new researchers. Committee on Publication Ethics (accessed 250207) http://www.publicationethics.org.uk/reports/2003/2003pdf12.pdf/view?searchterm=handle%20authorship%20disputes2003

11. Dickersin K, Scherer R, Sri Tyas Suci E, Gil-Montero Michelle. Problems with indexing and citation of articles with group authorship. JAMA. 287; 2772-4, 2003.

12. Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled ClinTrials 1996; 17:1-12.

13. Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95). Annotated with TGA comments 2000 (accessed 17/10/2017)

https://www.tga.gov.au/sites/default/files/ich13595an.pdf

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Additional references

DeAngelis C et al. Is this clinical trial fully registered? JAMA; 293: 2927-2729, 2005.

Ehringhaus S, Korn D. Principles for protecting integrity in the conduct and reporting of clinical trials. Association of American Medical Colleges. January 6, 2006.

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History


1.1 10/01/2006 A Abernethy New procedure




Revision following MAB review


Periodic update


2.1 27/09/2012 L Devilee

Revisions following discussions at TMC, Scientific Committee and Management Advisory Committee 2012 and development of work instruction and publications sub-committee Terms of Reference

3.0 6/08/2013 L Devilee

Revisions following first meeting of the publications sub-committee. Presentation of changes to the Scientific Committee and final approval by MAB 26th August 2013.

3.1 6/01/2014 L Devillee

Revisions following meeting of the publications sub-committee on 8th

November 2013 and 4th March 2014, and approval by MAB 21st March 2014.




Approval


3.3 David Currow


6.15.1 V1.2 Page 1 of 8

6.15.1 Dissemination of Study Results

Version V1.2


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PaCCSC recognises the importance and responsibility to disseminate the results of its clinical studies in accordance with the Australian Code for Responsible Conduct of Research.

PaCCSC also recognises the importance of maintaining clinician engagement with contributing sites and shares information in line with contractual requirements and processes described in this Standard Operating Procedure (SOP).

Centralised management of the dissemination of study results is required in order to:

Protect the integrity of the study results and their interpretation Prevent duplication of publication of study results Reduce the risk of individual site data appearing to conflict with aggregated study results Prevent re-identification of participants in local study populations Reduce the potential for clinician recall bias in results dissemination

Objective

This SOP describes the processes for managing the dissemination of study results following study closure.

Scope



Responsibility for dissemination rests with the Lead Investigator, who is supported by the PaCCSC Coordinating Centre. The Lead Investigator responsibilities regarding dissemination can be delegated to the PaCCSC National Manager. The Principal Investigator at the site is responsible for all processes and procedures at the site.


To assist with the development of the study Dissemination Plan To monitor the execution of the Dissemination Plan once it is mobilised To liaise with the Executive Author to ensure timely execution of the study Dissemination

Plan To liaise with the PaCCSC Trials Management Committee, PaCCSC Scientific

Committee and PaCCSC Publications Sub-Committee during the review and ratification of the study Dissemination Plan


To participate in the development of the study Dissemination Plan

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The review and ratify the Dissemination Plan for each study To determine the timing and form of presentations, publications, press releases and other

information for dissemination

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Procedure

1. Timing

The Lead Investigator and the PaCCSC Scientific Committee determine the timing and form of presentations, publications, press releases and other information for dissemination.

The full disclosure of study results will only be made, other than verbally through presentation of the results by the Lead Investigator or their delegate at leading scientific meetings, after the main study manuscript is accepted for publication in an appropriate peer-reviewed scientific journal.

An embargo is placed on individual site data being released back to the site until the main study manuscript is published in an appropriate peer reviewed scientific journal.

Dissemination of results proceeds in accordance with the study’s Dissemination Plan.

2. Study Dissemination Plan

A Dissemination Plan for each PaCCSC study is developed by the PaCCSC National Manager, in collaboration with the Lead Investigator. Ideally the Dissemination Plan is developed concurrently with the study protocol.

The Dissemination Plan is developed using the Dissemination Plan Template (Template 24).

The Dissemination Plan is shared with Principal Investigators and the PaCCSC Publications Sub-Committee who are invited to comment.

The Dissemination Plan is reviewed and ratified by the PaCCSC Scientific Committee.

The Dissemination Plan is mobilised immediately upon initial publication of the main study results: o 60% of actions are completed by 3 months from mobilisation o 90% of actions are completed by 12 months from mobilisation o 100% of actions are completed by 18 months of mobilisation

Publications and presentations identified in the Dissemination Plan are transcribed in the PaCCSC Planned Publications Master List (refer SOP 6.15 Authorship).

3. Journal Publications

Manuscripts for publication are developed in line with SOP 6.15 Authorship.

The PaCCSC National Manager is notified of an intention to develop a manuscript for publication via email from the executive author.

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Upon email notification, the PaCCSC National Manager updates the PaCCSC Planned Publications Master List.

The executive author submits the full manuscript to the agreed authorship team (consistent with SOP 6.15 Authorship) for comment (and amendment) prior to submission for publication.

Any conflicts are resolved using the Conflict Resolution process detailed in SOP 6.15 Authorship.

4. Scientific Meeting Presentations

National and international scientific meetings are targeted for the dissemination of PaCCSC study results.

Submissions of abstracts for scientific meetings are consistent with the Dissemination Plan and SOP 6.15 Authorship.

Prior to submission of an abstract for presentation at a scientific meeting: o The PaCCSC National Manager is notified of an intention to develop a manuscript

for publication via email from the executive author. o The executive author is required to circulate the draft abstract/publication with the

authorship team as per SOP 6.15 Authorship.

Following acceptance of an abstract for presentation at a scientific meeting: o The abstract author shares the abstract with the PaCCSC National Manager. o The PaCCSC National Manager distributes the abstract to the PaCCSC Trials

Management Committee and Principal Investigators. o The abstract is discussed at the next scheduled PaCCSC Trials Management

Committee meeting (the abstract author must be present) and content of the presentation is agreed.

o Full disclosure of the results must wait until the main paper has been accepted for publication in a peer-reviewed journal.

Following presentation of the study results at the scientific meeting: o The abstract author (presenter) sends an email of the presentation details to the

PaCCSC National Manager. o Upon acceptance for publication the main paper is disseminated to members of the

PaCCSC Scientific Committee and PaCCSC Trials Management Committee.

Restrictions on results dissemination and the role of individual site contributions: o Individual site data must remain aggregated until after publication. It cannot be

subject to a separate or secondary analysis or published as a stand-alone item without the written permission of PaCCSC and the Lead Study Investigator. Why? Because: • Most journals do not permit release of a manuscript’s content in advance of

publication. Simultaneous release of the publication in line with the dissemination plan is preferred.

• There is an inherent risk that an individual site’s data may appear differently to the aggregated study results and/or the individuals site findings may not

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support the overall study findings; • The local population could potentially be re-identified; • Rules regarding unblinding during the trial should remain in place until

publication of the study results; • Recall bias becomes a risk – a clinician’s (local site investigator’s) desire to

see whether their clinical suspicion about which arm a patient was randomised is difficult and drawing conclusions is not possible without prospective documentation of clinical opinion during the participant’s time on study, exploration an individual case with any accuracy about individual decision making is problematic.

o PaCCSC recognises the importance of maintaining clinician engagement with contributing sites and will wherever possible continue to share information in line with the above process.

o Participant and consumer feedback will be conducted as per the Dissemination Plan for each study.

o An embargo on individual site data remains in place until publication of the full study results.

5. Impact measurement

The impact of the Dissemination Plan and dissemination activities is measured using any of the following strategies: o Impact

• Peer reviewed journal star rating • Positive evaluation of outsourced critical appraisal workshops • External audit

o Number of citations • Measured at 6 months post publication • Measured at 12 months post publication

o Responses received from organisations / groups contacted for any means • No response • Response without action from responder • Response indicates action will be taken • Response actioned (i.e. published article/letter, reference on website, link

to study report etc.) o Monitoring of timelines set out in this SOP o Change to health professional practice

• Survey sites after one year post publication of study results

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Other related SOPs

4.2.4 Delegation of Duties 5.18.2 Study Closure 6.15 Authorship 5.5.10 Data Ownership and Utilisation


Template 24: Dissemination Plan

References



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History


1.0 18/08/2015 C Hope, L Devilee

New procedure

1.1 9/06/2016 L Devilee Update following March 2016 governance meetings



Approval


1.2 David Currow


8.0 V2.2 Page 1 of 6

8.0 Essential Documents

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All clinical studies need to demonstrate that documentation meets the International Conference on Harmonisation of Good Clinical Practice (ICH GCP) guidelines, and that documentation shows that the study is conducted in an ethical and appropriate manner and all legal and auditing requirements are met.

The correct establishment, maintenance and storage of files enable assessment that the study was conducted in accordance with ICH GCP guidelines. A standardized file system also enables all of the site team, and any external parties, such as monitors and auditors, to locate and review the files.

Objective

This SOP describes the process of establishing and maintaining trial-related files to ensure all required files are kept and can be maintained and located.

Scope

This SOP applies to all sites involved in clinical studies conducted by PaCCSC. Each study site establishes and maintains a filing system that ensures appropriate filing of study documents as specified in ICH GCP.


The Lead Investigator, PaCCSC Coordinating Centre, Principal Investigator and Sponsor. The task may be delegated to another suitably trained individual (e.g. Sub-Investigator, Site Study Coordinator, study nurse etc.) as documented on the Staff Signature and Delegation Log (referSOP 4.2.4 Delegation of Duties) but the responsibility remains with the Principal Investigator.


To oversee the study To ensure the PaCCSC Coordinating Centre has developed and maintains the system

for the files


To develop the Trial Master File Index (consistent with the requirements of ICH GCP Essential Documents)

To develop and distribute standardised templates to all sites To provide advice to sites regarding filing To ensure all study sites are provided with a full set of essential documents within the

ISF required to conduct the study

Responsibilities of the Principal Investigator (or delegate)

To ensure that all documents for that site are produced and filed appropriately To provide file notes where files cannot be located

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To retain original and revised documents to enable a document history to be reviewed To ensure that participant files are kept confidential and are stored appropriately To ensure that participant files are complete in preparation for monitoring and audit, and

to follow-up on the documentation issues that arise from these visits

Responsibilities of the Sponsor

To provide necessary information and documents when requested

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Procedure

1. Establish a Trial Master File

The Trial Master File Index (Template 20) is created by the PaCCSC Coordinating Centre at the initiation of study design and protocol development. The files are subsequently maintained and expanded as required. The Trial Master File enables all study related documents at the Coordinating Centre to be appropriately filed and stored. The ISF contains the site storage and filing requirements from the TMF.

2. Establish and Maintain an Investigator Site File

All files related to each study are stored according to the Investigator Site File (ISF) at all sites. The contents page of the ISF (Template 39) provides the structure for the filing of all essential documents for the conduct of the study at the site.

The ISF is created by the PaCCSC Coordinating Centre at the time of study initiation at the sites. The files are subsequently maintained and expanded as required.

Depending on the activities being carried out, individual trials may require additional documents not specifically mentioned in the Trial Master File Index/ISF. The Sponsor and/or Principal Investigator should amend the Trial Master File Index/ISF to include these.

The Principal Investigator ensures that all documents are filed in the appropriate section of the ISF, and that the file is available and in good order throughout the study.

3. Maintain Participant files

Participant data is held within one section of the ISF and contains the data collected from participants during recruitment. Each participant has an individual study file prepared which contains all de-identified data including:

All case report forms; All quality of life and other participant completed documents, with names removed and

ID number inserted; All concurrent medication forms; Any other documents that relate to participant data that cannot be filed with the clinical

file and have had all identifiable information replaced with the participant ID number.

In addition, the identifiable data, such as consent forms, pathology reports, medication records and clinical notes or medical assessments, are kept in a separate file or folder which assists monitoring where required, and also protects the confidentiality of the participant.

If any documents are filed separately from the ISF (e.g. source documents etc.), then a log should be created and placed in the ISF detailing where the documents are stored (refer SOP 4.9.2 Source Data and Documents for further guidance).

As per ICH GCP 8.1, it is a requirement that a record is maintained of the location(s) of all essential documents. The ISF should contain a summary log of all the source documents and exactly where they can be located. The Source Document Log (Template 11) provides an example of how such a log may look.

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4. Changes to an Investigator Site File

The ISF contents are regularly reviewed by the PaCCSC Coordinating Centre to ensure its currency and applicability.

Any changes to the ISF made by the Coordinating Centre (as a result of changes to regulations or similar) must be acknowledged and implemented by the Principal Investigator within one week of the changes taking place. The Principal Investigator must also notify the Coordinating Centre that this has occurred.

Other related SOPs

4.9.2 Source Data and Documentation 5.5.1 Electronic Data Handling 5.18 Monitoring 8.4.1 Archiving of Research/Project Materials 8.4.2 Record Destruction


Template 11: Source Document Log Template 20: Trial Master File Index Template 39: ISF Contents Page

References





Praxis Australia

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History



New procedure









Approval


2.2 David Currow


8.4.1 V2.2 Page 1 of 6

8.4.1 Archiving of Research/Project Materials

Version V2.2


Approved D Currow




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Projects and clinical studies generate numerous files and other material during the course of the project. State and federal laws require research files to be archived for a specific period of time following the completion of the study.

This Standard Operating Procedure (SOP) aims to introduce uniformity in the archiving and storage of research and project materials whilst ensuring that clinical study files meet the International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines.

Objective

This SOP describes the archiving process to ensure that materials are stored to: Enable access at a later date for follow-up Comply with National Health and Medical Research Council (NHMRC) and jurisdictional

regulatory requirements Allow timely destruction of materials once the required storage period has elapsed.

Scope



Responsibilities of the Lead Investigator/Sponsor (PaCCSC)

To arrange archiving of the central study materials To negotiate the long term storage responsibility with local or intra collaboration research

infrastructure


To ensure all identifiable participant data is de-identified prior to archiving To ensure that the archiving procedure is followed as per this SOP To ensure safe and appropriate transport of study materials to the storage site

PaCCSC SOP Feb 2018

8.4.1 V2.2 Page 3 of 6

Procedure

1. At the commencement of the study

Clarification and communication are sought regarding what materials are to be stored to meet research archiving requirements.

The site for archive storage is identified. The Principal Investigator (or delegate) prepares a Master File Index (refer SOP 8.0

Essential Documents) to ensure that all study materials are filed in an appropriate manner that enables retrieval during the course of the study.

2. At the conclusion of the study

The Principal Investigator (or delegate):

Ensures that all identifiable participant data is de-identified prior to archiving. This is done by physically storing the identified materials in a different location to the materials identified by PID. o Often, the identified materials can be filed along with the Participant Information

Sheet and Consent Forms (PICFs) Ensures all electronic files are copied onto a storage disc in a transportable format, and

labelled. The electronic format must be accessible over time. Ensures all files are clearly labelled and ordered (for e.g., subject data, study

administration files, manuscript files, etc.). Removes all reference materials from the study files (for e.g., articles, etc.). Places the files into the boxes, without the hanging files, clips, folders, or other binding

materials. File groups can be held together with a band. Checks the labelling requirements of the storage site. If appropriate, complete an Archive

Label and attach firmly to the outside of the box. Ensure all parts of the label are completed.

Completes any documentation in accordance with the local requirements Arranges for safe and appropriate transport to the storage site. All storage facilities ensure

the long term safe storage including fire and theft security and provide a system for retrieval and re-storage if required.

3. Retention of research data and research materials

The Australian Code for the Responsible Conduct of Research (2007) states that for most clinical trials, retaining research data for 15 years or more may be necessary.

State and territory schedules for the retention and disposal of records specify retention periods for research material. The longer period specified is always applied.

There may be individual state requirements that apply to the retention of research materials (for e.g., some states require permanent retention of certain research materials). Each site is responsible for complying with any state requirements for the retention of records relating to:

The preparation and submission of applications to conduct research The establishment of committees/boards/task force, and the records of the meetings

PaCCSC SOP Feb 2018

8.4.1 V2.2 Page 4 of 6

Legitimate and sustained allegations of misconduct that resulted in a formal inquiry and appeals

Meeting the requirements of the NHMRC such as annual reports Evaluation of significant programs Obtaining resources to undertake significant projects, which may include project plans,

grant proposals, or funding applications Development of agency wide policies relating to research and ethical research conduct Master copies of final reports (published and unpublished) produced by the researcher

which document the findings and outcomes

4. Archived documents

The documents to be archived on completion of a study include (but are not limited to):

The study protocol and all approved amendments The final study report All source data, including biologic specimens. If the source data are patient clinical files,

they will be archived as part of the institutional archiving arrangements. Case Report Forms (CRFs) are held in the study files. Pathology services and laboratories archive specimens where possible.

Copies of electronic versions of the analytic data sets and programs. Manually developed calculations are documented on worksheets and retained.

All essential documents (refer SOP 8.0 Essential Documents) Documentation relating to the collection and processing of data, including notebooks,

training and reference documents, coding manuals, etc. Updated Source Document Log (Template 11) to reflect the contents of the archived

materials, and the location of other study related materials such as clinical records, pathology samples and/or results, computer programmes and files

Participant files containing the original CRFs are stored at the participating site for long term archiving. The PaCCSC Coordinating Centre maintains copies forwarded to it for the purpose of data checking; these copies are archived centrally. Sites should prepare their participant files in the following manner:

File for site archive: o All CRFs including pre-screen CRFs o All file notes o Copies of the medication record or concurrent medications o Consent forms o Medical assessment o Original patient measures such as Mini Mental Status Examination, Quality of Life

forms, laboratory and test results, NuDesc score sheets, any other score forms given to the participant and then comprise source data

PaCCSC SOP Feb 2018

8.4.1 V2.2 Page 5 of 6

Other related SOPs

4.2.4 Delegation of Duties 5.5.1 Electronic Data Handling 8.0 Essential Documents 8.4.2 Record Destruction


Template 11: Source Document Log

References





Praxis Australia

Acknowledgments


PaCCSC SOP Feb 2018

8.4.1 V2.2 Page 6 of 6

History



New procedure




1.5 21/01/2008 B Fazekas Administrative update, new reference

1.6 7/06/2010 B Fazekas Periodic review, ratified by MAB





Approval


2.2 David Currow


8.4.2 V2.2 Page 1 of 5

8.4.2 Record Destruction

Version V2.2


Approved D Currow




PaCCSC SOP Feb 2018

8.4.2 V2.2 Page 2 of 5


Projects and clinical trials generate numerous files and other material during the course of the project. There are state and national requirements to ensure that the files are destroyed in an appropriate manner after the specified period of time.

The purpose of this SOP is to ensure that materials are methodically destroyed to:

Comply with state, national and international regulations and guidelines Ensure that materials are not stored once the required storage period has elapsed

Objective

This SOP describes the destruction procedure for research and project materials, both temporary and permanent.

Scope



The responsibility for all records retention and disposal rests with the Principal Investigators at each site. Master copies of records retained and destroyed are not the responsibility of the institutional ethics committee, office of research, publisher etc. The Principal Investigator generates their own Trial Master Index or Investigator Site File.


To ensure long term storage of PaCCSC central research files To select the Record Holder


To ensure long term storage and destruction of the locally generated files To maintain and complete the Trial Master Index or Investigator Site File

Responsibilities of the nominated Record Holder

To ensure destruction of all research files

PaCCSC SOP Feb 2018

8.4.2 V2.2 Page 3 of 5

Procedure

1. Persons responsible

The PaCCSC Lead Investigator is responsible for the long term storage of PaCCSC central research files and to select the Record Holder. This may be the research unit of the Lead Investigator’s institution, a ‘State Record’ facility or some other safe and appropriate storage site.

Each Principal Investigator is responsible for the long term storage and destruction of the locally generated files in accordance with the requirements of the local institution, nominated record holder, and other national and international requirements.

Destruction responsibility rests with the nominated Record Holder.

2. Destruction

At the end of the required storage period (usually 15 years):

The Record Holder notifies the Lead Investigator (nominated on the box label or other identifying label for the material) of the end of the retention period.

The box(es) containing the study materials are opened and the following files are separated: o Records that have temporary archival status o Records with permanent archival value

Permanent records: o Are removed from the general material, and stored within a separate box o The box is labelled in line with the requirements of the state facilities o The new box of permanent records is sent to a suitable storage facility for permanent

storage

Temporary records: o Complete any required documentation from the Record Holder facility in the

Australian State to enable destruction o The form is completed according to the destruction schedule that applies in the state

of storage o Paper records are shredded, pulped or burnt, within the storage facility. If an external

means of destruction is used, a confirmation note is obtained. o Electronic records are reformatted, overwritten or shredded, then disposed of

through normal channels o Complete a destruction register as determined within the storage facility, or other

similar record that logs the documents destroyed in order to comply with state requirements

The destruction register is filed within the permanent records if required.

PaCCSC SOP Feb 2018

8.4.2 V2.2 Page 4 of 5

Other related SOPs

5.5.1 Electronic Data Handling 8.0 Essential Documents 8.4.1 Archiving of Research/Project Materials


Template 11: Source Document Log Template 20: Trial Master File Index

References




PaCCSC SOP Feb 2018

8.4.2 V2.2 Page 5 of 5

History



New procedure








Approval


2.2 David Currow

February 2018


Guidance Documents

February 2018


Guidance 1

PaCCSC File Note Completion

This document is part of the suite of PaCCSC SOPs Page 1 of 2


Section 1

Date / Time Date of identification of issue (date of commencing the file note)

Forum Meeting Telephone Other :

Staff Member Who is writing this file note?

Other staff Who else is involved in the discussion about the issue and resolution?

Study ID Study ID, or name of study PID of patient if applicable

Subject What does the file note refer to?

Section 2

Item no. Details of File Note

This section should contain a detailed description of the issue

An explanation of how the event occurred in the first place is appropriate

Some options for resolution of the issue should be detailed

Action

Specify what has been specifically undertaken in order to correct the discrepancy

Describe how will this be prevented from occurring in the future

Signature The file note should be signed by the person who can verify the discrepancy or who can verify the action taken as a result

Date of completion

This should be the date all actions have been completed

Guidance 1



Section 1

Date /Time o Complete the actual date (and time if appropriate) of the writing of the file note

Forum o Tick if the file note is a result of any discussion via

− Meeting − Telephone − Or other forum

o State who is writing the file note o Describe or name any other person involved in the process

− Investigator − Other study staff − PaCCSC monitor − Name of other person

Complete study ID o E.g.: 05/007 (megestrol study) o The PID of the participant, if appropriate

Provide a subject line o E.g.: consent form, pathology results

Section 2

Item number o This will usually be only one item, but there may be a series of separate activities of

events that need to be described o It is helpful to separate the activities involved in the resolution of the issue (the

subject of the file note) by providing separate item numbers o Detail of the file note

− This section contains a detailed description of the issue − An explanation of how the event occurred in the first place is appropriate − Some options for resolution of the issue are detailed

o Action − Specify action(s) to correct the discrepancy − Describe how the issue will be prevented from occurring in the future

o Signature − The file note is signed by the person who can verify the discrepancy or who

can verify the action taken as a result − This person must be appropriate to the issue

• Pharmacy discrepancies will be signed by the pharmacist • Issues related to visits, data, approvals or filing may be signed by the

site/study coordinator or study nurses • Issues related to consent, eligibility, protocol, etc. are signed by the

Principal Investigator o Date of completion

− The date all actions are completed • This may be the same date as appears at the top of the file note • Some actions may occur over a period of days or weeks, the actual date

of no further action should be entered at this point

Guidance 2

PaCCSC Documentation of Consent


PaCCSC Documentation of Consent (example)

Consent

To be completed in the clinical record at any time during the process of consent and when informed consent is provided.

Date, Palliative care research [Study name] was presented to [patient] and [other family members present] after being referred by [Dr ]. The study participant information sheet was used as a basis for discussing the study. The discussion included: purpose, duration, intervention, assessments, risks and side effects, confidentiality and voluntary nature of the study. The [participant or family] asked about ……….. and the following questions were answered to their satisfaction with further information [provide detail of the question and responses]. Following this discussion, the consent forms have been signed and the study eligibility will now be completed.

Progress notations

To be completed in the clinical record at any time of contact with the participant, either as face-to-face visit or telephone contact.

Date, Palliative care research [Patient] is participating in the [study name] and is currently on day x of x. The intervention has been administered without problem. [Patient] has been assessed for response and is currently scoring [outcome measure]. There have been no new adverse events/ new adverse events include….. Vital signs (if not recorded in nursing charts) are T… P… R… BP …/… [patient] will be reviewed again [next visit scheduled], instructions [until next visit] are…..

Exit notation

To be completed in the clinical record when the participant completes the study intervention for any reason, including cessation (if prior to primary endpoint) and exit (at primary endpoint).

Date, Palliative care research [Patient] is completing the [study name] today. The intervention will cease at [time]. [Patient] has been assessed for response and is currently scoring [outcome measure]. There have been no new adverse events/ new adverse events include….. Vital signs (if not recorded in nursing charts) are T… P… R… BP …/… [Patient] will now be commenced on [clinical intervention] and will be reviewed weekly for the next 4 weeks for safety and economic data.

Guidance 4

PaCCSC Monitoring Guidelines for Sites



1. Background

The monitoring process in as on-going and intensive programme initiated by PaCCSC and involves all sites. Monitoring is an important internal mechanism for ensuring compliance with Good Clinical Practice and PaCCSC own internal procedures, maintaining the quality of participant data for each of the studies undertaken by PaCCSC, and provides an excellent way ensuring quality across the Collaborative.

While there is a Standard Operating Procedure for monitoring (refer SOP 5.18 Monitoring), these guidelines have been collated to assist all sites in a more practical sense.

2. Preparation

Adequate preparation enables the monitoring visit to proceed in a smooth manner with fewer disruptions to the daily work of the site team.

The PaCCSC monitoring team attempt to give sites at least 2 weeks’ notice of a visit, and in many cases the negotiation of a suitable visit date means that there is often 4 weeks or more notice of the date listing the ID numbers of the participants to be monitored.

Sites are asked to set some time aside in the days prior to the scheduled visit to undertake the following activities.

Prepare the investigator folder or fileso Ensure the folder or files are up to date, contain all necessary supporting

documentation and are in order. The monitors will check the entire folder or filecontents on an initial visit. On subsequent visits there are selected sections that willbe reviewed. The following sections should have particular attention given prior toeach visit:− Ethics or RGO correspondence, in order and complete, including approvals,

amendments, reports and adverse event reports.− Staff Signatures and Delegation Log. Up to date and tagged for easy

reference.− The CV, either full or abridged for each person on the Staff Signatures and

Delegation Log.− Patient Master Index printed off and containing the ID numbers to be monitored

so that the PID and the medical record number can be matched.− Signed consent forms for participants (if not stored in the study files).− Monitoring Log should be up to date showing previous visits and tagged for

easy reference. This log will be signed by the monitors at the completion of thevisit and will need to be signed by the members of the site team who assistedwith the visit.

Prepare the participant fileso Ensure all the relevant CRFs are within the participant file and filed in order of their

use.o Ensure that all the required source documents are also within the file such as:

− Patient completed scores

Guidance 4



− Questionnaires and assessment tools − Concomitant medications − Pathology reports, − Print off online conversions

o Adverse event reports.

Locate the clinical recordso Paper files.

− These must be requested from the Medical Record Department with the appropriate approvals well in advance. They should be requested to be provided to the team office if possible rather than held within the medical record department. Care should be taken to ensure that the volume provided by MR includes the appropriate clinical record for the time the participant was in the study and follow-up.

− Check the file for the consent, and tag its location. − Tag the pages that refer to the consent discussion(s). − Tag the pages that indicate study commencement.

o Electronic medical records. − Ensure that the appropriate login for monitors has been obtained. If login has

not been obtained, the site team need to be prepared to login to the system and remain with the monitors during the clinical file reviews. An alternative to this is to print off electronic records that relate to the study, however access to the other parts of the record should be available on request.

− The e-record needs to enable the monitors to review all of the content in order to ascertain eligibility, such as prior medical history, pathology and prescription records.

− Ensure familiarity with the content and structure of the e-record. If necessary, make notes of where the study documentation can be located, specifically: • Consent form and documentation of the process. • The progress notes relevant to the patient participation, either inpatient,

outpatient or community outreach notes. • Medication charts, infusion records relevant to the study.

Ensure the monitors have adequate facilitieso Monitoring requires the review of a number of records and reports simultaneously,

as well as making notes and completing checklists. This takes up a reasonable area of desk space. The monitors also discuss each participant as the records are being reviewed.

o If possible, the monitors should be provided with − A separate room in order to discuss the findings for each participant and to

spread the records in order to adequately review them − A desk or table large enough to accommodate two people sitting side by side

with room to open records and files at the same time − Room space to accommodate the suitcases and other files that are part of the

review.

Guidance 4



3. During the visit

The monitors attempt to disrupt the working day of the study staff as little as possible but some situations arise during the course of the review that require assistance from the team in order to progress the review. For example:

Documents cannot be located, without which the review of that participant cannot progress.

Documentation is not consistent with other documents and requires clarification in order to continue the review without unnecessary file notes or corrective actions.

In addition, the monitors require a short period of time towards the end of the visit to summarise the findings, with both the site coordinator/study nurse and the site investigator, so that the report that follows is as expected. It gives the opportunity to discuss any study wide issues of problems and well as specific participant problems.

The monitors will attempt to complete the data corrections and file notes during the visit if time permits, in addition to any photocopying. A copy of the corrective action sheet will be left at the end of the visit to enable actions to be taken quickly.

The Monitoring Log will be signed at the end of the visit and will be left out so that site staff can also sign it.

4. Follow-up to the visit

The monitors will send an email of the visit in the week or two following the visit. This email will be accompanied by:

A summary report An electronic copy of the corrective action sheet (PDF or excel) Other documents as required

o Outstanding documents from the central office such as: − HREC letters − TGA listing − Logs or charts that may have been missing from the site files and can be

replaced from Central files.

The letter and report should be shown and discussed with the investigator and then filed within the monitoring section of the study files.

The corrective action sheet should have the following activities performed:

The column headed ‘Agreed outcomes’ will specify the outcome required in order to rectify the ‘Findings’. Look at this column and relate this to the relevant participant file or issue.

Complete the ‘Agreed outcomes’ as specified. Complete the column ‘Actual outcomes’ detailing the action taken, this might be:

o A file note o Confirmation of training or a discussion/meeting

Guidance 4



o A correction to the specific data item within a CRF o Location and confirmation of a document

Complete the ‘Date completed’ column. Send the completed corrective action sheet back to the PaCCSC Coordinating Centre

with any relevant file notes, pages of corrected CRFs, medication pages, etc., to confirm that the action was completed. Do not send documents that contain identifiable information. Examples of corrective actions are provided below.

5. Second and subsequent visits

After initial monitoring, subsequent reviews will review only those sections of the investigator folder that required updating since the previous visit, such as:

Ongoing HREC communications Protocol amendments Staff Signatures and Delegation Log Monitoring logs The next list of participants Any corrective actions that are outstanding from the previous visit

Examples: Corrective actions

Findings Lists the problem or issue. Can be related to site documents, organisation, or participant review. Anything related to the visit that is not as it could or should be.

Agreed outcomes Suggestion for how the finding can be rectified. Can be a single suggestion or a number of suggestions in order to rectify, correct or resolve the issue listed as a finding.

Actual outcomes The action taken by the site to rectify the finding. Maybe one or all of the suggestions made by the monitor/s, or maybe another outcome as a result of the site reviewing the circumstances.

Date The date recorded by the site when the outcome was completed, and the finding has now been resolved.

Additional examples: Corrective actions

Finding Agreed outcome Actual outcomeGeneral documentsMissing documents Regulatory documents,

Consent forms, CRFs, Source documents, Eligibility documents

Locate document and confirm

Reconstruct document from other sources and file note that source was usedCan’t locate and file note to confirm document did exist and can be verified by person

Guidance 4



Can’t locate and cannot be confirmed, file note. This may be a protocol violation

HREC documents missing, approval for amendment 1.3 cannot be located

Locate approval and confirm File note lost document, obtain copy form HREC

Approval found in other folder, attached

Doctor is not listed on the SSS, but has performed medical assessments

File note by PI: explained protocol, qualifications have been checked, appropriate delegated activities were assigned, delegated tasks were performed as per delegation

File note attached to the relevant CRF and copy attached to the SSS

Consent formsConsent form has not been dated by patient

File note that patient missed placing the date and was incorrectly inserted by study staff

File note attached (written by staff member who obtained or witnessed consent)

Staff training that patient must sign and date the consent form

Discussed at team meeting on (date)

Written procedures provided to nurses

Consent form not signed by patient

File note by person who obtained consent

Person no longer employed at site, file note attached. (if the file note cannot be written by person who obtained consent, this is a protocol violation)

Refer to comprehensive clinical progress notes

Incorrect consent form in use

File note to explain difference in version of consent form

File note attached

HREC informed that incorrect version has been approved, or not listed on approval letter, attached

Case report formsCRF missing Locate and confirm to

PaCCSC, provide copy and enter data

CRF found, data entered, and copy attached OR Not completed, CRF constructed from clinical record, withdrawal CRF, file note written, CRF and file note attached, data entered

Guidance 4



Document is incorrect or conflicts with other documents

CRF against source, Eligibility against clinical record, Prescription not followed or incorrect, consent form problem

Correct the document if it can be confirmed by other documents, initial and date the correction

File note the correction such as medical assessment, dosing can be confirmed as correct, file note that date on consent form was correct (signed by person who took consent)File note to explain discrepancy, may be a protocol violation

Medical assessment indicated no previous adverse reaction to opioids, medical record records allergy to morphine

Review clinical record, amend medical assessment, file note eligibility, amend CRF (initial and date correction)

Medical record records allergy, but actually reaction was dose related, assessed by investigator as no problem, medical assessment form has note added

Documents are incomplete Consent form not fully filled in, signatures missing, missing data points, PID missing from pages, dates of review for confirmation for study

Complete if possible, initial and date

File note to confirm that incomplete was correct at the time and can be confirmedFile note that data is missing and cannot be traced as person has left, may be a protocol violation

[PID] 24 hours. NuDesc for 8am blank

Complete CRF (initial and date correction) File note that score not done Protocol violation

8am score located on source document in clinical record (archived in different place). CRF amended, copy attached

Response assessment (or primary outcome) is inconsistent with other data or is incorrect (according to monitor calculations)

Reassess, correct CRF, file note. Protocol violation

File note attached. CRF corrected and copy attached

PID, date , study nurse intials missing from the top of each page

The information is required on each page for identification purposes

All of the header information should be completed but does not need to be sent to PaCCSC. Note: This is the only exception whereby

Guidance 4



PaCCSC do not need to be provided with evidence the action has been completed

PI has not signed the eligibility (or cessation/withdrawal) CRF

PI to sign and date CRF, with appropriate notation of actual date of signature

CRF signed and dated by PI, dated xx/xx/xx

PI has not circled appropriateness to continue study

PI to circle CRF with initial and date of change

CRF amended, copy attached

Guidance 5

PaCCSC Monitoring Guidelines for Monitors



The monitoring process in as on-going and intensive programme initiated by PaCCSC and involves all sites. Monitoring is an important internal mechanism for ensuring compliance with Good Clinical Practice and PaCCSC own internal procedures, maintaining the quality of participant data for each of the studies undertaken by PaCCSC, and provides an excellent way ensuring quality across the Collaborative.

While there is a Standard Operating Procedure for monitoring (refer SOP 5.18 Monitoring), a few tips and guidelines have been collated to assist all sites in a more practical sense. These guidelines have been developed out of learnings so far, and during a period of the Collaborative being partway through an intensive period of monitoring.

1. Preparation

Adequate preparation by both the PaCCSC Coordinating centre and the site being monitored enables the monitoring visit to proceed in a smooth manner with fewer disruptions to the daily work of the site team.

The PaCCSC monitoring team should give sites at least 2 weeks’ notice of a visit, and in many cases the negotiation of a suitable visit date means that there is often 4 weeks or more notice of the date along with the ID numbers of the participants to be monitored.

Email site coordinator and site investigator to discuss the need to monitor and somesuggested dates and study. Finalise the dates via email and send the participant PIDnumbers.o Select 6-8 participants for monitoring if a full day is to cover one study.o Select participants based on early through to late recruitment, or if specific

participants are known to have been a problem; or for a single study if recruitmenthas closed.

Email the site coordinator and site investigator to request a date for a visit, and the PIDsfor review. Include a summary of the local requirements such as study files, medicalrecords and Investigator Site File.o Save the email in the central study Master File.

Start local preparation for the visit. Print the ‘Site Periodic Review’ tab, amended for the site. Print the corrective action sheet, amended for the site. Print the review documents for each PID being monitored:

o Insert the PID onto the ‘Timeline check’ and printo Print any other study specific checklist developedo Compile for each participant

− Timeline check− Any specific check sheet− Randomisation fax− Other notices as required

Guidance 5



Check the following documents: o HREC approvals and/or the approval letters for the site/study o CTN copy and TGA listing if first periodic review visit o Any other central files as part of the Investigator Site File

2. During the visit

The monitors attempt to disrupt the working day of the study staff as little as possible but some situations arise during the course of the review that require assistance from the team in order to progress the review. For example:

Documents cannot be located, without which the review of that participant cannot progress.

Documentation is not consistent with other documents and requires clarification in order to continue the review without unnecessary file notes or corrective actions.

In addition, the monitors require a short period of time towards the end of the visit to summarise the findings, with both the site coordinator/study nurse and the site investigator, so that the report that follows is as expected. This gives the opportunity to discuss any study wide issues of problems and well as specific participant problems.

Using the check lists, review the investigator files and participant files and complete the Corrective Action Sheet (Template 15) to record any errors or issues found during the review. o Refer to the attachment for completing the ‘corrective action sheet’. o The first few columns should be completed in order to identify which document is

referred to. In addition, the ‘Findings’ should clearly identify what the problem or deficiency is, and the ‘Agreed Outcomes’ should detail what is required in order to correct the deficiency (or give guidance to the site team about correction).

The Monitoring Log will be signed at the end of the visit and will be left out so that site staff can also sign it.

1. Site periodic review a. Review all HREC documents, or those since the last monitoring visit.

i. Check the site file to ensure that all protocol amendments have been submitted and approved

ii. All SAEs have been reported as required and acknowledged iii. All other correspondence appears to be complete

1. Compare the site file against the PaCCSC Coordinating Centre listing to ensure that both lists reflect the full correspondence

2. Obtain or leave copies of documents to ensure the file is complete b. Review TGA listing is on file (if early monitoring visit to that site). c. Check the remaining investigator folder for completeness and organisation. d. Check and hold aside the monitoring log:

i. Check that is was signed after the previous visit ii. Ensure the log is signed by the monitors during this visit and left out for signing

by staff

Guidance 5



e. Locate and hold aside the Staff Signatures and Delegation Log: i. Check that all people listed on the log have been signed on completely ii. Check that the delegation seems appropriate iii. Check against each participant during the patient file review, particularly if the

appropriate signature is on the SSS for: 1. Consent signature 2. Medical assessment 3. Order of study medication 4. Collection of CRF data

2. Patient review

a. Timeline check i. This provides a summary of how the patient proceeded through the study and

can provide useful information when the report is written. ii. The dates of each visit should be filled in along with other pertinent information

which may vary between studies, for example: 1. Risperidone study: it is important to track delirium resolution, which can

be easier to track on this page rather than flicking through numerous pages.

2. Sertraline study: where there are numerous visits and phone calls, it is important to tract the actual date against the expected date.

ii. The timeline check can also give room for comments specific to this patient, such as protocol violation or other information that may become important when the data is being examined later

b. Other study specific check list (if used) i. This form guides through each CRF for each participant. ii. Each check point should be checked, the trigger column can give guidance on

where or how to locate specific information in order to verify CRF data. iii. All lines for each CRF for that participant should be completed.

3. Visit assessment

An overall assessment is made of the site visit based on the levels of deficiencies recorded in the Corrective Actions Sheet (Template 15) subsequent to the review. These are:

None o Complete o Error free, or corrected appropriately o Filed and accessible o Clear documentation of procedures

Minor o Source data does not support CRF entry o Late approvals o Poor filing and documentation o Difficult to follow errors

Major o Approvals absent

Guidance 5



o Protocol violation o Critical documents not available o Errors not accounted for

The overall assessment recorded in the Monitoring Report will be one of the following:

Acceptable o No deficiencies o Few minor deficiencies o Major deficiencies were identified and/or corrected prior to the monitoring visit, and

no further action is required

Acceptable needs follow-up o Any major deficiency identified during the monitoring visit, not identified or corrected

prior to the visit o Multiple minor deficiencies identified

Unacceptable o Multiple major deficiencies identified o A single major blatant deficiency (total disregard for protocol) o Excessive number of minor deficiencies

4. Follow-up to the visit

Complete a report of the visit findings:

Use the site review and Corrective Actions Sheet to formulate specific and general comments for the Monitoring Report

The site will be sent the report in the week or two following the visit. This letter will be accompanied by:

The original copy, or electronic version of the corrective action sheet o Other documents as required from the central office such as:

− HREC letters − TGA listing − Logs or charts that may have been missing from the site files and can be

replaced from Central files.

The completed sheet should be returned to the monitors within 4 weeks of receipt and should document the activities that have taken place in order to correct the findings of the visit.

The column ‘Actual outcomes’ detailing the action taken should be completed for each issue; these might be: o A file note o Confirmation of training or a discussion/meeting o A correction to the a specific data item within a CRF o Location and confirmation of a document

Guidance 5



Examples of this might be: o File note confirming consent form written, attached o CRF amended as requested, page attached o No CRF change required, rescue medications checked and are correct in the CRF o Or other statements that address the finding by the monitors

The ‘Date completed’ column should be completed. The completed corrective action sheet is sent back to the PaCCSC Coordinating Centre

with any relevant file notes, pages of corrected CRFs, medication pages etc. to confirm that action was completed.

The PaCCSC Coordinating Centre checks each completed outcome against any other supporting documents (such as CRFs, file notes, or comments of training or other outcomes), the line on the corrective action sheet is then initialled and dated by the monitor.

The completed corrective action sheet is logged.

5. Follow-up

The PaCCSC National Project Officer should review each finding and outcome to ensure that the outcome has now resolved the issue; the National Project Officer should initial and date the line as closure of that finding.

File notes should be checked to ensure that the problem has been adequately explained, outcome should indicate that the finding is now resolved, any changes to CRFs should be attached so that the data base can be amended following established procedures (the amended page is to be handed to the data checking team in order that the data base be updated).

6. Second and subsequent visits

After initial monitoring subsequent reviews will review only those sections of the investigator folder that required updating since the previous visit, such as”

Ongoing HREC communications Protocol amendments Staff Signatures and Delegation Logs Monitoring logs The next list of participants Any corrective actions that are outstanding from the previous visit

7. Support monitors

Support monitors assist the main (PaCCSC Coordinating Centre) monitor while undertaking file review. They are not familiar with the study protocols or with the structure or content of the CRFs. They are employed in a support capacity because of their clinical skills. The main monitor is expected to lead the monitoring process and utilise the support monitor appropriately. The support monitor can:

Examine the medical record for each participant as the main monitor reviews the CRFs. Locate the consent form and confirm the documentation of the consent process.

Guidance 5



Locate and confirm the medications that form the inclusion or exclusion criteria for the study.

Confirm diagnostic and medical conditions that are used to assess eligibility to the study. Locate and confirm laboratory, pathology or radiology results. Confirm that certain timepoints were followed by notation of study progress within the

medical record. Locate any other information within the medical record such as nursing plans, falls risk

assessments, vital sign measures, infusion charts. Read and interpret medical, nursing and allied health notes for general progress and for

any change in condition that may constitute adverse events.

The main monitor should instruct the support monitor throughout the review for the information to be located and the two monitors should have a continuing discussion about findings from both the medical record and CRFs to compare notes and confirm the accuracy of the data.

8. Corrective actions

Findings Lists the problem or issue. Can be related to site documents, organisation, and

participant review. Anything related to the visit that is not as it could or should be.

Required outcomes Suggestion for how the finding can be rectified. Can be a single suggestion or a number of suggestions in order to rectify, correct or resolve the issue listed as a finding.

Actual outcome The action taken by the site to rectify the finding. Maybe one or all of the suggestions made by the monitor/s, or maybe another outcome as a result of the site reviewing the circumstances.

Date The date recorded by the site when the outcome was completed, and the finding has now been resolved

8.1. Examples of corrective actions

Findings Required outcome Actual outcome

General documentsMissing documents Regulatory documents,

Consent forms, CRF’s, Source documents, Eligibility documents

Locate document and confirm

Reconstruct document from other sources and file note that source was usedCan’t locate and file note to confirm document did exist and can be verified by person

Guidance 5




Can’t locate and cannot be confirmed, file note. This may be a protocol violation.

HREC documents missing, approval for amendment 1.3 cannot be located

Locate approval and confirm File note lost document, obtain copy form HREC

Approval found in other folder, attached

Doctor is not listed on the SSS, but has performed medical assessments

File note by PI: explained protocol, qualifications have been checked, appropriate delegated activities were assigned, delegated tasks were performed as per delegation

File note attached to the relevant CRF and copy attached to the SSS

Consent formsConsent form has not been dated by patient

File note that patient missed placing the date and was incorrectly inserted by study staff

File note attached (written by staff member who obtained or witnessed consent)

Staff training that patient must sign and date the consent form

Discussed at team meeting on (date)

Written procedures provided to nurses

Consent form not signed by patient

File note by person who obtained consent

Person no longer employed at site, file note attached. (if the file note cannot be written by person who obtained consent, this is a protocol violation)

Refer to comprehensive clinical progress notes

Incorrect consent form in use

File note to explain difference in version of consent form

File note attached

HREC informed that incorrect version has been approved, or not listed on approval letter, attached

Case report formsCRF missing Locate and confirm to

PaCCSC, provide copy and enter data

CRF found, data entered, and copy attached OR Not completed, CRF constructed from clinical record, withdrawal

Guidance 5




CRF, file note written, CRF and file note attached, data entered

Document is incorrect or conflicts with other documents

CRF against source, Eligibility against clinical record, Prescription not followed or incorrect, consent form problem

Correct the document if it can be confirmed by other documents, initial and date the correction

File note the correction such as medical assessment, dosing can be confirmed as correct, file note that date on consent form was correct (signed by person who took consent)File note to explain discrepancy, may be a protocol violation

Medical assessment indicated no previous adverse reaction to opioids, medical record records allergy to morphine

Review clinical record, amend medical assessment, file note eligibility, amend CRF (initial and date correction)

Medical record records allergy, but actually reaction was dose related, assessed by investigator as no problem, medical assessment form has note added

Documents are incomplete Consent form not fully filled in, signatures missing, missing data points, PID missing from pages, dates of review for confirmation for study

Complete if possible, initial and date

File note to confirm that incomplete was correct at the time and can be confirmedFile note that data is missing and cannot be traced as person has left, may be a protocol violation

[PID] 24 hours. NuDesc for 8am blank

Complete CRF (initial and date correction); File note that score not done; Protocol violation

8am score located on source document in clinical record (archived in different place) CRF amended, copy attached

Response assessment (or primary outcome) is inconsistent with other data or is incorrect (according to monitor calculations)

Reassess, correct CRF, file note; Protocol violation

File note attached CRF corrected and copy attached

PID, date , study nurse initials missing from the top of each page

The information is required on each page for identification purposes

All of the header information should be completed but does not need to send to PaCCSC

Guidance 5




(this is the only exception whereby PaCCSC do not need to be provided with evidence the action has been completed)

PI has not signed the eligibility (or cessation / withdrawal) CRF

PI to sign and date CRF, with appropriate notation of actual date of signature

CRF signed and dated by PI, dated dd/mm/yyyy

PI has not circled appropriateness to continue study

PI to circle CRF with initial and date of change

CRF amended, copy attached

Guidance 6

PaCCSC Prescription of Study Drug


PaCCSC Prescription of Study Drug (example)

Prescription sample – [ study ]

Study ID number: [Protocol Number]

Study name: [Short Title]

The prescription for requesting study medicine must be:

Written by an appropriately qualified person

Written on the hospital prescription forms either

o the inpatient medication forms or o a negotiated prescription form

Written in the doctors own handwriting

o Signed o Dated o In black ink pen o Written in full as shown below.

Protocol number Strata ___________

STUDY DRUG OR PLACEBO DOSE, DOSE, OR DOSE

PLEASE SUPPLY # (number) TABLETS/CAPSULES/SYRINGES

Number of dose 1 or placebo



Prescription must meet hospital, state and national regulations, and must comply with any applicable schedules. The prescription can be designed within the hospital electronic system if applicable.

Guidance 7

PaCCSC Unblind Contact Numbers


PaCCSC Unblind Contact Numbers

In the event of unblinding being requested by a study site to the Central Registry, the following contact numbers can be used:

Lead Investigator David Currow 0401 710 240

Alternate Investigator Meera Agar 0430 212 912

PaCCSC National Manager Linda Brown 0437 816 884

PaCCSC National Project Officer Belinda Fazekas 0414 190 084

Central Randomisation Service Linda Brown 0437 816 884

Order of calls for unbinding:

1. Study site to call Lead Investigator

2. Lead Investigator (or site) calls Central Randomisation Service

3. Central Randomisation Service calls the study site

Guidance 8

PaCCSC Determining PID Number Sequencing


Determining PID Number Sequencing for PaCCSC Studies

Each PID (Participant Identification) Number is 10 digits and consists of the following:

A two (2) digit study code (derived from the protocol number or otherwise allocated by PaCCSC)

A two (2) digit site code (allocated by PaCCSC and is maintained across studies) A three (3) digit participant number

o This number is a sequential number starting at 001and is determined by the study staff at the site.

Randomisation number o This number is determined after reference to the randomisation schedule at the time

of randomisation.

Study code

This code identifies each participant within a specific study. The codes are:

Study Code Protocol number

Ketamine 01 001/07Risperidone 02 002/07Octreotide 03 003/07Megestrol 05 005/07Phase IV 07 007/08Opioids in dyspnoea 08 008/08Phase IV prospective 09 009/09Nausea Part 1 10 010/09Nausea Part 2 11 011/09Consumer impact 12 012/09Sertraline 13 013/09Clonazepam 15 015/09Medications Management 17 017/10Can Less be Better 18 018/10Methoxyflurane 19 019/10Rapid reporting 20 020/11Melatonin Pilot 21 021/12Opioids plus 1 22 022/13Pyridostigmine 23 023/14Nausea Part 3 24 024/14Pulmonary Rehabilitation 25 025/14Cadet Study 26 026/15Cannabis for anorexia Pilot 27 027/15PERT study pt1 28 028/15Natraguard 29 029/15BEAMS 30 030/15Cannabis extension 31LICpain 32 032Pert 2 33

Guidance 8



Study Code Protocol number

Pert 3 34Melatonin PIII 35Preserve 36Nurse Led Triage 37

Site code

This code identifies each site within each study. Each site is assigned a unique code number by PaCCSC. This number forms part of the ID number. This enables recruitment numbers by site to be easily tracked at any point for reporting and monitoring of Key Performance Indicators. The site codes are:

Phase 3 sites Code

Mater Health Services 01Braeside Hospital (HammondCare) 02Peter MacCallum Cancer Centre 03Southern Adelaide Palliative Service 04Hollywood Private Hospital (closed) 05Sydney Cancer Centre (closed) 06Calvary Mater Newcastle 07Sacred Heart Hospice/St Vincents Hospital 08Camden Hospital 09Calvary Health Care Kogarah 10Ballarat Palliative Care 11St Vincent’s Hospital Melbourne 12The Alfred Hospital 13Austin Hospital 14Barwon Health, Geelong 15Royal Melbourne Hospital 16Modbury Hospital 17Flinders Medical Centre 18The Prince Charles Hospital 19St Vincent’s Hospital Brisbane 20Greenwich Hospital (HammondCare) 21Nepean Hospital (NBMLHD) 22Westmead Hospital (WSLDF) 23Liverpool Hospital (SWSLHD) 24Lyell McEwin Hospital 25Sunshine Coast (Nambour) 26Gold Coast Hospital 27Cabrini 28Concord Hospital (SLHD) 29John Hunter Hospital 30Sir Charles Gairdner 31

Guidance 8



Participant ID number

When a person completes the eligibility process, a combination of numbers are assigned.

For example: The construction of the ID number structure is: Study code/Site code/ID number In practice, the actual ID number is: 01/02/001 In this example, this number indicates the following participant details: Ketamine study/Braeside/individual number 001

Randomisation code

When a participant becomes eligible and is randomised to receive a study intervention, a further number sequence is added to the existing ID number.

The randomisation number provided by the Site Pharmacy is also added to the ID number sequence. This is a 3 digit number.

For example: The construction of the ID number is: Study code/Site code/ID number/randomisation number In practice, the actual ID number is: 01/02/001/001 In this example, this number indicates the following participant details: Ketamine study/Braeside/individual 001/randomisation number 001

The full sequence of numbers enables the investigators to determine how many people have been referred to any study at any site, and how many of them are randomised.

Further examples:

02/07/030/003 Risperidone study at Calvary Mater Newcastle, 30 people have been referred to the study, and 3 are randomised.

05/04/006/006 Megestrol acetate study at Southern Adelaide Palliative Services, 6 people referred to the study, all are randomised.

Exceptions to envelopes

Periodically, sequences of randomisation schedules developed for one site may be re-allocated to a different site. This occurs if the original site ceases to recruit to a study. In these circumstances: The PaCCSC Coordinating Centre changes site code and details in the schedule and on

the randomisation envelopes. The PaCCSC Coordinating Centre provides a File Note to this effect (including the date

of the change) to the Site Pharmacy. The contents of the randomisation envelopes do not change – just the details on the

outside of the sealed envelopes (with date of change).

Guidance 11

PaCCSC Data Usage Rules


PaCCSC Data Usage Rules

Where there is a request for access to and/or use of PaCCSC data the following rules apply:

1. The use of the data will be for the purposes requested and cannot be used for any other purpose unless separately approved by the Chairs.

2. The use of the data must comply with the NHMRC Responsible Conduct of Research and other legally enforceable guidelines and Australian Privacy legislation.

3. All data provided to a third party under SOP 5.5.10 Data Ownership and Utilisation is provided for a period of 12 months after which time the data must be returned to PaCCSC or an extension period applied for by the requester.

4. Where the data is used to create new data (derivatives, secondary etc.): a. The newly created data remains the sole property of PaCCSC unless otherwise

agreed by the Chairs. b. The newly created data must be provided to PaCCSC at the expiration of the 12

month access period granted. The use or re-use of any PaCCSC data should clearly acknowledge the source and is subject to acknowledgement of the development of the data under the auspices of PaCCSC.

5. Data returned or destroyed to PaCCSC must be confirmed via email to the PaCCSC National Manager and describe the destruction or return procedure used.

6. The use or re-use of any PaCCSC data should clearly acknowledge that the permission for its use has been approved by PaCCSC.

An example citation:

Source: This [insert name] was developed under the auspices of the Palliative Care Clinical Studies Collaborative (PaCCSC). Permission has been provided by University of Technology Sydney for its use.

Guidance 12

PaCCSC Publication Planning


PaCCSC Publication Planning

Project task Writing task

Project planning

Investigator team Identify potential papers and record in the Planned

Publications Master List for the study, including agreed order of journals to be targeted

Commence the Dissemination Plan (refer SOP 6.15.1 Dissemination of Study Results)

Project ethics and funding submission

Literature search Literature review Reference collection

Project start

Establish authorship teams Ratify authorship protocol Include draft manuscript title, Executive Author and authorship

team in the Planned Publication Master List

Start of data collection

Database development Draft Background/Introduction section

Within 8 weeks of commencing data collection

Redraft Background/Introduction section

Midway through data collection

Draft Methods section

Start of data analysis Review literature search Update Background/Introduction section Finalise Methods section

Preliminary reporting to teams

Presentation of the results and their interpretation to the participating sites in confidence. (Note: The authorship team should determine if confidentiality agreements are necessary prior to presentation; refer SOP 4.2 Confidentiality.)

Draft and circulate Results section to authorship team Decide Journal

4 weeks post results

Draft Discussion section Draft paper circulated to authorship team The draft paper may also be circulated to the PaCCSC

Scientific Committee, the Publications Sub-committee, the PBAC or other key stakeholder body if determined necessary by the authorship team

8 weeks post results Final paper signed and submitted

Dissemination

Formal dissemination processes as recorded in the Dissemination Plan commence immediately following announcement of publication. (Note: Some presentation of the results may have already occurred following study closure.)

Guidance 13

PaCCSC Pilot/Feasibility Studies



To date, completed and current PaCCSC studies have not included pilot/feasibility work. PaCCSC has experienced significant issues (major protocol changes and study cessation) which may have been avoided if pilot / feasibility work had been conducted prior to the full Phase III study.

The reasons for conducting a pilot/feasibility study may differ with individual studies. In general, the purposes of such studies will be a combination of1:

Process – Assessment of ‘the steps that need to take place as part of the main study’, such as recruitment rates, retention rates, completion rates, etc.

Resources/Logistics – Assessment of ‘time and budget problems that can occur during the main study’, including the feasibility and time components of each aspect of the research protocol.

Management – Assessment of personnel issues and data collection/management at each participating centre.

Scientific – Assessment of ‘treatment safety, determination of doses and responses, and estimation of treatment effect and its variance’.

Stand-alone pilot/feasibility studies and those completed as part of a Phase III protocol ensure that the Phase III study protocol is feasible, practicable and that the outcomes are measurable. The PaCCSC Scientific Committee requires that each new Phase III study proposal exploring a new paradigm includes a pilot/feasibility study protocol. This document outlines the purpose and outcome measures for the associated pilot/feasibility part of the Phase III study.

The PaCCSC Scientific Committee recommends that the pilot/feasibility study protocols are adaptive so as to allow design modifications for the future Phase III study1.

If an investigating team considers that there is a strong argument not to conduct a pilot/feasibility study for a particular planned Phase III study, the investigators are required to submit to the PaCCSC Scientific Committee, a separate covering document explaining their argument. For example, the planned Phase III study is an extension of a previous study in the same centres, using the same patient groups with similar treatments and outcome measures.

Pilot/Feasibility studies (whether stand-alone or as part of a Phase III study) are submitted using the PaCCSC Pilot/Feasibility template (Template 27).

Following approval by the PaCCSC Scientific Committee, the protocol is submitted (with all appropriate accompanying documentation) to the institutional human research ethics committees (refer SOP 6.12 Ethics Approval and Reporting).

Following completion of a pilot/feasibility study, a concise report is submitted to the PaCCSC Scientific Committee concerning the performance of the pilot/feasibility phase against its planned outcome measures. The PaCCSC Scientific Committee expedites the review of this

Guidance 13



report using electronic communication between members. A recommendation is made by the Scientific Committee following review of this report:

Continue without modifications – feasible as is; Continue without modifications, but monitor closely – feasible with close monitoring; Continue, but modify protocol – feasible with modifications; Stop – main study not feasible.

If the PaCCSC Scientific Committee recommends progressing to full Phase III study, a decision will be made regarding the inclusion of the pilot/feasibility study data in the full Phase III study.

The report of the pilot/feasibility phase and the report from the PaCCSC Scientific Committee following consideration of the pilot/feasibility study’s results is sent to all institutional human research ethics committees which have given approval for the study to proceed.

Where possible, a paper is prepared for publication of the results of the pilot/feasibility study, notwithstanding the PaCCSC Scientific Committee’s decision about the study’s continuation, or otherwise. A paper for publication can be prepared and submitted while the main study is still in progress.

The final Phase III study protocol is developed, circulated to and approved by the PaCCSC Scientific Committee prior to the study commencing and the study is registered with the Australian New Zealand Clinical Trials Registry.

References

1. Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, Robson R, Thabane M, Giangregorio L, Goldsmith CH. A tutorial on pilot studies: the what, why and how. BMC Medical Research Methodology 2010; 10: 1-10.

Guidance 14

PaCCSC Symptom Nodes and Studies Matrix


PaCCSC Symptom Nodes and Studies Matrix

Current program as of November 2017

Guidance 16

PaCCSC Recruitment Matrix



1. Background

Recruitment is at the core of successful research in any setting. Without participants, research is not possible. The number and timeliness of patients entering a study is a measure of PaCCSC overall performance as a successful research network. The frailty of the population in palliative care means that PaCCSC faces unique difficulties in securing study participants and maintaining recruitment targets for all studies it undertakes.

Achieving the requisite number of referrals and converting them to randomised participants with fully informed consent is therefore pivotal to success and yet, maintaining motivation at both the sponsor organisation’s central infrastructure and the participating recruiting sites is not always easy.

The matrix is part of a suite of documents that brings together a raft of measures for PaCCSC as the sponsor organisation to provide encouragement and support to sites with recruitment to its studies. The measures include a range of strategies to be implemented by PaCCSC to maintain momentum and provide support at all levels and to all participating recruiting sites. The PaCCSC Recruitment Plan (Template 26) also addresses individual site performance and measures that will be taken by the central coordinating office to assist sites at the individual level to attract patient referrals and optimise study recruitment.

2. What does the Literature say?

What makes a difference to site performance according to the literature?

1. Past performance: Sites that have performed well in past studies have a 70% higher chance of

performing better than those that haven’t performed well. Conversely poor performing sites in one study have a high likelihood of under-performing in subsequent studies.

Sites quick to randomise their first patient tend to perform better overall. Early recruiters know what they are doing, they move through the contracts process

faster, start screening patients sooner, and they leave more time to screen patients throughout the study.

2. Experience: The experience of the site investigator and their historical site performance serves

to explain continuing site performance with some consistency. Once a site has conducted 6-10 clinical trials, that site has a higher likelihood of

meeting randomisation targets in the required time frame. There is a ‘site learning curve’ whereby a site moves up the curve in terms of their

speed and effectiveness with each new trial conducted. Site focus and commitment to conducting clinical trials is associated with higher

performance. Sites which demonstrate the site learning curve and are committed to clinical research are 41% better randomisers than sites which devote their time to clinical practice with limited attention to clinical research – where it’s considered an add-on.

Guidance 16



3. Investigative site focus: It remains a cottage industry, with the majority of stand-alone sites conducting trials

within a clinical practice. Majority of sites are novices; new entrants. Turnover remains very high. Difficulties with onerous compliance burdens; recruiting participants; slow payment

cycles and diminishing attractiveness of study grants all contribute to high dropout rates.

Sponsors diversify risks by engaging a large number of sites to recruit a smaller average number of participants.

4. Sponsors can also positively affect site performance through: Improvements in protocol design. More complex protocols are associated with poor

recruitment and retention rates, longer cycle times, and larger numbers of protocol amendments. Each protocol amendment requires on average two months of time. Streamlined and simplified protocols, designed with feasibility input from study coordinators and investigators, dramatically and positively impacts the performance of sites.

Site-sponsor relationship building to maximise each site’s performance; increased attention and support of site recruitment initiatives and operations management; need to make calls to action specific, with no ambiguity and with deadlines attached (e.g., We need to recruit 30 patients by Christmas).

Provide the site with evidenced based data about their recruitment; indicate how far above or below the study – wide average each particular site falls.

Providing support for education and outreach initiatives. Such initiatives routinely show positive impacts on recruitment and retention rates.

Advertising campaigns, etc..

5. Metrics for generating evidence based recruitment data: Site activation date (site informed they could commence recruitment). Screened dates; how many screened; when last screen occurred to provide:

o The number of days that have passed since last screening o The number of days that have passed since last randomisation o The screen failure rate o The average number of screenings per month o The average number of randomisations per month o The percent difference between individual site screening rates and the trial

wide screening rates o The percent difference between individual site randomisation rates and the trial

wide randomisation rates o The number of participants who reach primary endpoint o The number of participants who reach end stage 2 o The number of participants who reach end stage 3 o The number of participants who reach end stage 4 o The number of participants who consent to sub-studies (those with stand-alone

consent forms only)

Guidance 16



Why might sites be underperforming: o Need to support sites on a path towards improved performance o Share best practices between sites o Clinical Trials Participation Equation (CTPQ) methodology/equation which

states that participation is a function of AE + CRC/PI (see Table 1) 1. A = Awareness of the trial + the Availability of the patient population +

the extent to which they feel their contributions and efforts are Appreciated

2. E = How well Educated the site is about the trial and their Experience in conducting prior trials

3. C = The Credibility of the Sponsor/CRO staff in interacting with the site, how Collaborative the interactions are + their level of Commitment to the trial (particularly by the PI)

4. R = The strength of the Relationship they have with the sponsor and the Responsiveness of the Sponsor/CRO to the site’s needs + the Resources available to support the study (human and financial).

5. C = The nature and frequency of Communication between the sponsor/CRO and the key site staff.

Divided by: 6. The Peril or Risk of participating in the trial in terms of lost revenue,

disruption to the staff schedule and workload (e.g., Will the study require weekend, on-call appointments for site staff).

7. The level of Inconvenience (e.g. administrative burden, complexity) and amount of Protocol Intimidation involved (difficulty interpreting the protocol, complex visit requirements, equipment and preparation involved)

o Pay particular attention to and try to decrease PI o Which of the above factors are at play for any given site? Are any of these

holding the site back from recruiting? o What type of interventions might get the site back on track? How are they to

be prioritised?

Guidance 16



Table 1 Clinical Trials Participation Equation (STPQ)

Clinical Trials Participation Equation (CTPQ)

Item Description

Awareness Where do site personal place the trial in terms of their working day?

Appreciation Do sites feel acknowledged and appreciated for their contributions to the overall research effort?

Credibility of Sponsor / CRO

Does the Sponsor have sufficient data to provide the sites to assist with their efforts locally and to enhance their credibility?

Collaboration Is the spirit of collaboration conveyed adequately?

Relationship Are there techniques aimed at furthering a productive and positive relationship between the parties?

Communication Are the techniques robust enough for both general all site communication and site specific communication? Does the level of communication and recognition need to be ramped up?

Availability of patients Does the site have access to the patient population needed for the study?

Education & experience Are all staff sufficiently educated and have experience, or a willingness to gain experience. Is the site in need of additional education?

Commitment Is the PI willing and committed to conducting the trial within the timeframes, protocol and budget?

Responsiveness Does the Sponsor/CRO respond to enquiry from sites in a timely manner?

Resources Is the trial resourcing reflective of the work effort. Is there a particular resource issue at the site?

Risk or Peril What is the sites perception of the trial and how can the site be assisted to be successful in recruiting to the trial?

Inconvenience and Protocol Intimidation

Solicit the sites perspectives of the trial design and protocol early on

February 2018


Templates

February 2018


Template 1


PaCCSC Staff Signatures and Delegation Log

Protocol / Study Number: Sponsor Name:

Site Name: Site Number:

THIS FORM IS TO BE COMPLETED BY ALL PERSONNEL INVOLVED IN THE STUDY

AFTER RECEIVING PROPER STUDY TRAINING AND PRIOR TO TAKING PART IN ANY STUDY ACTIVITIES

Name of Principal Investigator (PI) PI Signature1 PI Initials Start End

1 My signature confirms/acknowledges that:

• The tasks listed below will only be delegated to appropriately trained, skilled and qualified staff.• I will conduct the study in accordance with the protocol and remain responsible for the overall study conduct and reported data.• I will ensure study oversight.• I authorise the delegation of study tasks to personnel as listed below.• I will ensure that all personnel assisting in the conduct of this study are informed about their obligations and have not performed any study tasks prior to

appropriate delegation and completion of appropriate training.• I will ensure that mechanisms are in place to ensure that site staff receive the appropriate information and training throughout the study and that a 2-way

communication channel exists between staff and self.• I will declare any actual or potential conflicts of interest to the relevant ethical review body.• I will ensure that any and all changes in staff or delegated study tasks will be recorded in timely manner.

Template 1





Site Staff * This form is to be signed contemporaneously by PI and Staff *

Name & Title Initials Study RoleKey Study Task(s)

(choose from index below)

Duration Signature2 & Date

PI Initials & Date

CV3

(Y/N) Start End

2 My signature confirms/acknowledges that I accept the assigned study task(s) 3 CV has been received by PI (new version is required annually)

Comments: ___________________________________________________________________________________________________________________

_____________________________________________________________________________________________________________________________

Template 1





Site Staff * This form is to be signed contemporaneously by PI and Staff *

Name & Title Initials Study RoleKey Study Task(s)

List all appropriate from the index below

Duration Staff Signature2

& Date PI Signature &

Date CV3

(Y/N) Start End

2 My signature confirms/acknowledges that I accept the assigned study task(s) 3 CV has been received by PI (new version is required annually)

Comments: ___________________________________________________________________________________________________________________

_____________________________________________________________________________________________________________________________

Template 1





Study Roles and Key Tasks Index

• Identification of study roles includes but is not limited to sub-investigators, study nurses, pharmacist (when appropriate) and data recorders. • Identify key study tasks delegated by the Principal Investigator from the list below:

1 Informed Consent collection 7 Review of blood samples. 13 CRF Completion 19 Study conclusion signature

2 Medical History review 8 Review of incl./exclusion criteria 14 CRF Signature 20 Archive functions

3 Con. Meds review 9 Safety assessments 15 Data query initiation 21 Monitoring

4 Measure of vital signs 10 Authorisation to randomise 16 Data Query Completion 22 Randomisation

5 Collection of blood samples 11 Product dispensing 17 Product delivery 23 Handling, manufacture, storage of investigational product

6 Handling of blood samples 12 Product Accountability 18 Communications 24 Other [please specify]

Template 1





Electronic Signature Declaration for Principal Investigator and Site Staff

• My electronic signature as it applies to entering electronic data or signing records in sponsor-owned or sponsor-outsourced computer systems is the legally binding equivalent of my handwritten signature.

• I will not share password(s) assigned to me for this study with any other person.

Principal Investigator’s End of Study Declaration

I hereby confirm that the above information is accurate and complete, and that I authorised the delegation of study-related tasks to each individual as listed above.

Principal Investigator’s Signature _______________________________________________

Date _______________________________________

Template 2

Principal Investigator Meetings with Study Teams


Principal Investigator Meetings with Study Teams

PI Name: __________________________________ Trial Name: __________________________________

Date of meeting

Staff in attendance

Comments PI signature

PaCCSC [Study]

Site Person trained Position Training Forum Date Trained by

This document is part of the suite of PaCCSC SOPs Template 3 - Staff Training Log Page 1

PaCCSC Name: _____________________________ [Study]

Site Position Training Forum Date Trained by

This document is part of the suite of PaCCSC SOPs Template 3 - Staff Training Log Page 1

Template 4

[Letterhead of Organisation]


CV Registration with PaCCSC Studies

This can be used as a short CV for junior staff delegated restricted duties as per the Staff Signature and Delegation Log. It is to be updated annually.

Name

Qualifications

Current Position

Length of time in current position

Positions in previous 5 years

Experience, training in previous 5 years

Date:

Signature:

Noted: [Site Investigator, Date]

Template 5

PaCCSC Site Feasibility Checklist



Ethics, Legal and Regulatory Capabilities

• Does the organisation participate in the singleethical review process and accept HREC approvalfrom others?

• Is there a Research Governance Office (RGO)to process a submission for local approval anddo they have capacity to work through therequired steps (legal, contractual)?

• Is there staff who can work on theapplication to submission and undertakeongoing reporting requirements?

• What are the overall approval timelines and havethere been any previous difficulties meeting thosetimelines?

• Are there specific regulatory requirements for theorganisation?

Template 5



PaCCSC Site Feasibility Checklist (cont.)

Medical

• Who are likely PIs and what is their specialty?

• Palliative care service, comment on inpatient,consultative and outreach service, number ofpatients per year, disease profile.

• Relationships with other clinicians such asoncology, respiratory, general medicine, agedcare.

• Can suitable participants be approached fromthese other clinics, and will there be support?

• General interest in research from others,openness to introducing other treatment patterns,readiness and acceptance of background andcomparative therapy.

• Information on the study specific population (interms of stage of disease, protocol baseddefinition of study disease and population).

• Can estimate of the likely recruitment numbers ona per annum basis be provided?

Template 5




Operational

• Is the patient population likely to havecharacteristics that compete with any otherstudies?

• Are there any cultural imperatives in relation tothe study design or the tools used?

• How might such issues be dealt with?

Site demographics

• Does the organisation have prior experience inclinical trials, and prior experience in conductingsimilar studies?

• Are study coordinators, pharmacists andnurses available to participate?

• Does the site have staff with sufficient training andcapacity to perform the role of site investor andstudy nurse?

• Are there any pre-existing competing studies thatmay impact on recruitment, such as similar patientpopulation or competing with investigator or studystaff time?

Template 5




Site infrastructure

• Specific availability of offices space, storage andsecure filing, computing and photocopyingequipment.

• Availability to study staff via telephone and mobilephone

• Is there IT infrastructure with internet capacityand user support

• Is there the capacity to visit patients athome for follow-up?

Quality

• Whether sites have undergone sponsor/independent site audits in the past.

• Previous experience with clinical trial audits, ifso, were any concerns raised.

• Are there any training requirements identified forany of the team?

Briefing Notes

[Insert name of site/sponsoring organisation] - PaCCSC Site Risk Assessment Toolkit

Toolkit Release: September 2017

Action required: This planning tool is to be completed by PaCCSC Coordinating Centre after each study completes the

Site Feasibility Checklist and in the context of a completed Study Feasibilty Checklist.

It will help PaCCSC to assess any operational concerns about the site which may impact on their ability

to participate in the study or cause issues with study delivery. In certain circumstances it may indicate

that the site should not be considered further and the investigator informed accordingly.

The assessment is proportionate to the risks associated with undertaking this study.

All questions should be answered based on the site's experience of the sponsoring process and this

study. Select the most appropriate option for each question.

As a planning aid, please add a short note on concerns and management actions (proportionate to the

risks associated with undertaking the study) needed to address these concerns during the process and

study delivery.

Where the response to any question is unclear (e.g. because it is not possible to discuss quickly with

the relevant person) then this would indicate a risk that may need to be managed later in the process,

and so this may indicate option 3 or 4 is appropriate.

Additional 'help' information is provided for each question when the cursor hovers over a 'cell'.

This help text is also provided in the Help Text sheet.

Background: This planning tool will quickly highlight any weaknesses or risks and the site's capabilities in

relation to a particular PaCCSC study.

The assessment is based on the organisation's capabilities to support a specific study at a specific time

(i.e. organisation capabilities may vary over time for operational reasons).

It is to be completed by PaCCSC Coordinating Centre.

Some areas may require early a short early discussion with the investigator(s) or other contacts in the

organisation (e.g. finance managers) to share opinions on the study.

Understanding any concerns quickly means that they can be addressed early with the funder /

investigator or that appropriate plans can be put in place early in the process.

Notes: The planning tool can also be used when there is a significant change to any of the areas described to

support changes to management actions.

This assessment should be undertaken for each PaCCSC study.

This tool is not intended to duplicate activities within the decision-making process.

It assesses the likelihood of the organisation successfully completing the process within an

appropriate timescale and completing the study effectively and safely.

Assumptions: That each site has an overall understanding of its clinical trial capabilities supported by relevant policies

and governance.

That the site has been provided with sufficient and relevant information about the study by PaCCSC so

as to assess its readiness (and risks) appropriately when completing their Site Feasibility Checklist.

Accountability: PaCCSC Coordinating Centre.

Template 6: This document is part of the suite of PaCCSC SOPs

Page 1 of 6

[insert name of site / sponsoring organisation] - PaCCSC Site Risk Assessment Toolkit

name of department where study will be conducted

name/ref of study

PaCCSC Coordinating Centre

The feasibility/risk assessment of the site to participate in a PaCCSC clinical trial 1. using existing/proven processes and arrangements in the organisation.

will be determined as follows: 2. with only minor changes to processes and arrangements in the organisation.

3. using new/changed processes and arrangements in the organisation.

4. may not be practical to achieve within a reasonable timetable.

Unknown. Insufficient information available.

1 2 3 4 U

Add notes on any management actions requiredduring site selection decision, study set-up and delivery

A Ethics, Legal and Regulatory Capabilities 1 2 3 4 U

5

B Local Alignment 1 2 3 4 U

4

C Investigator Team 1 2 3 4 U

3

D Research Team 1 2 3 4 U

4

E Science Design 1 2 3 4 U

5

F Patient Safety Design 1 2 3 4 U

1

G Patient Group Design 1 2 3 4 U

1

H Medical 1 2 3 4 U

2

I Management and Monitoring/Site Demographics 1 2 3 4 U

3

J Site Infrastructure 1 2 3 4 U

2

K Quality 1 2 3 4 U

2

L External Agreements 1 2 3 4 U

1

17 May 2017

Is it likely that the organisation will be able to understand and manage contractual risks

relating to this study? (including access to any additional and specialist contract

knowledge)

on:

Is it likely that the organisation will be able to address aspects of study design relating to

any additional patient safety requirements?

Is it likely that the organisation will have the appropriate patient population, and experience

/ guidance needed for working with any vulnerable groups as part of the study?

Is it likely that the organisation will be able to support study feasibility from a medical

perspective?

Is it likely that the organisation will be able to manage the study at a site level?

(taking into account single / multiple centres, study risk etc)

Is it likely that he organisation will have appropriate quality capabilities and staff resources

to assess and manage risks relating to this study?

Is it likely that the organisation will have appropriate quality capabilities and staff resources

to assess and manage risks relating to this study (e.g. auditing and training

requirements)?

Select the most appropriate option

Is it likely that the organisation will be able to address aspects of study design relating to

the science of the study?

Is it likely that the organisation will be able to address ethics, legal and regulatory

requirements relating to the study? (e.g. approvals including ethics opinion and regulatory,

appropriate SOPs, indemnity cover, licences, etc.)

Is the organisation already aware of any constraining factors in the PaCCSC SOPs that

may impact on sponsoring or delivery of the study (and which may require escalation

within the organisation to be resolved)?

Is it likely that the organisation will be able to provide additional support (if required) to the

senior investigator in delivering the study?

Department

Study

Completed by:

Is it likely that the organisation will be able to provide appropriately experienced research

staff that may be needed in delivering the study as planned by the senior investigator?

A> Ethics, Legal andRegulatory Capabilities

B> Local Alignment

C> Investigator Team

D> Research Team

E> Science Design

F> Patient Safety Design

G> Patient Group Design

H> Medical

I> Management andMonitoring/SiteDemographics

J> Site Infrastructure

K> Quality

L> External Agreements

Sponsoring Organisation: Summary of Key Management Action Areas

Unknowns

Additional actions

Standard arrangements

This charts provides ahigh-level summary of thekey management actionareas anticipated duringsponsor decision-makingand delivery for this study.

[insert name of site / sponsoring organisation] - PaCCSC Site Risk Assessment Worksheet

Toolkit Release: September 2017 Summary Sheet

Organisation: name of department where study will be conducted

Study: name/ref of study

Completed by: PaCCSC Coordinating Centre

On:

Summary of management actions from planning sheet

A> Ethics, Legal and Regulatory Capabilities 0 Insufficient information. Refer back to investigator

0

B> Local Alignment 4 High level of management required

4

C> Investigator Team 3 Significant additional management required

3

D> Research Team 4 High level of management required

4

E> Science Design 0 Insufficient information. Refer back to investigator

0

F> Patient Safety Design 1 Follow standard management process

1

G> Patient Group Design 1 Follow standard management process

1

H> Medical 2 Some additional management required

2

I> Management and Monitoring/Site Demographics 3 Significant additional management required

3

J> Site Infrastructure 2 Some additional management required

2

K> Quality 2 Some additional management required

2

L> External Agreements 1 Follow standard management process

1

KEY 1 Follow standard management process

2 Some additional management required

3 Significant additional management required

4 High level of management required

0 Insufficient information. Refer back to investigator

17 May 2017

PaCCSC Site Risk Assessment ToolkitToolkit Release: September 2017 Help Text (comments from Planning Toolkit sheet)

A Sponsoring Planning Tool: Notes for A> ETHICS, LEGAL AND REGULATORY

Sponsoring Planning Tool: Notes for A> ETHICS, LEGAL AND REGULATORY

Does the organisation expect to be able to assess and address the legal and regulatory requirements (including

determining the appropriate regulatory framework) in a way appropriate to the complexity and size of the study

within a reasonable timescale agreed with the senior investigator?

Consider the following:

1. Does the organisation participate in the single ethical review process and accept HREC approval from others?

2. Is there a Research Governance Office (RGO) to process a submission for local approval and do theyy have

capacity to work through the required steps (legal, contractual)?

3. Is there staff who can work on the application to submission and undertake ongoing reporting requirements?

4. What are the overall approval timelines and have there been any previous difficulties meeting those timelines?

5. Are there specific regulatory requirements for the organisation?

B Sponsoring Planning Tool: Notes for B> LOCAL ALIGNMENT

Sponsoring Planning Tool: Notes for B> LOCAL ALIGNMENT

Is it expected that the study is likely to be compatible with the organisation's R&D Operational Capability Statement

(or similar policy statements) and associated R&D policies? (e.g. are there other reasons to delay or withhold a

sponsoring decision appropriate to the complexity and size of the study?)

OR

Does the organisation expect that the study decision can be escalated for senior level acceptance within the

organisation within a reasonable timescale agreed with the senior investigator?

C Sponsoring Planning Tool: Notes for C> INVESTIGATOR TEAM

Sponsoring Planning Tool: Notes for C> INVESTIGATOR TEAM

Does the organisation expect to be able to provide any appropriate support that may be required for the duration of

the study (in a way proportionate to the complexity and size of the study) for the investigator / investigator team

during the study (e.g. to complete honorary contracts, to supplement necessary experience, to manage any conflicts

of interest) within a reasonable timescale agreed with the senior investigator?

D Sponsoring Planning Tool: Notes for D> RESEARCH TEAM

Sponsoring Planning Tool: Notes for D> RESEARCH TEAM

Does the organisation expect to be able to provide sufficient and appropriately experienced and trained research

staff (internally or contracted in) that may be required for the duration of the study in a way proportionate to the

complexity and size of the study within a reasonable timescale agreed with the senior investigator?

E Sponsoring Planning Tool: Notes for E> SCIENCE DESIGN

Sponsoring Planning Tool: Notes for E> SCIENCE DESIGN

Does the organisation expect to be able to (in a way proportionate to the complexity and size of the study) undertake

an appropriate independent (peer) review of the scientific design, quality and value aspects of the study,

and assess that it can manage appropriately any changes to the study,

and assess that it can manage the processing and dissemination of the final study findings and conclusions all

within a reasonable timescale agreed with the senior investigator?


1. Is the patient population likely to have characteristics that compete with any other studies?

2. Are there any cultural imperatives in relation to the study design or the tools used?

3. How might such issues be dealt with?

F Sponsoring Planning Tool: Notes for F> PATIENT SAFETY DESIGN

Sponsoring Planning Tool: Notes for F> PATIENT SAFETY DESIGN

Does the organisation expect to be able to (in a way proportionate to the complexity and size of the study) assess

and confirm the patient safety aspects of the study, and assess that it can manage appropriately any changes to the

study all within a reasonable timescale agreed with the senior investigator?

G Sponsoring Planning Tool: Notes for G> PATIENT GROUP DESIGN

Sponsoring Planning Tool: Notes for G> PATIENT GROUP DESIGN

Does the organisation expect to be able to (in a way proportionate to the complexity and size of the study) assess

and confirm that the consent and other processes related to vulnerable groups (such children, prisoners, the

mentally impaired and those with heightened emotional states), and assess that it can manage appropriately any

changes to the study all within a reasonable timescale agreed with the senior investigator?

This is partly assessed through the completion of a Study Feasibility Checklist

H Medical Sponsoring Planning Tool: Notes for H> Medical

Sponsoring Planning Tool: Notes for H> MEDICAL

Does the organisation expect to be able to support study feasibility with candidate participating organisations and/or

Networks using appropriate processes and staff in a way proportionate to the complexity and size of the study within

a reasonable timescale agreed with the senior investigator?


1. Who are likely PIs and what is their specialty?

2. Palliative care service, comment on inpatient, consultative and outreach service, number of patients per year,

disease profile.

3. Relationships with other clinicians such as oncology, respiratory, general medicine, aged care.

4. Can suitable participants be approached from these other clinics, and will there be support?

5. General interest in research from others, openness to introducing other treatment patterns, readiness and

acceptance of background and comparative therapy.

6. Information on the study specific population (in terms of stage of disease, protocol based definition of study

disease and population).

7. Can an estimate of the likely recruitment numbers on a per annum basis be provided?

This is partly assessed through the completion of a Study Feasibility Checklist

I Management and Monitoring/Site Demographics Sponsoring Planning Tool: Notes for I> Site Demographics

Is it likely that the organisation will be able to manage the

study at a site level? (taking into account single / multiple

centres, study risk etc)

Sponsoring Planning Tool: Notes for I> MANAGEMENT AND MONITORING/SITE DEMOGRAPHICS

Does the organisation expect to be able to support the management and monitoring of the study using appropriate

processes and staff which are proportionate to the complexity and size of the study (e.g. single or multiple centres,

study risks, delegated responsibilities, etc) within a reasonable timescale agreed with the senior investigator?


1. Does the organisation have prior experience in clinical trials, and prior experience in conducting similar studies?

2. Are study coordinators, pharmacists and nurses available to participate?

3. Does the site have staff with sufficient training and capacity to perform the role of site investor and study nurse?

4. Are there any pre-existing competing studies that may impact on recruitment, such as similar patient population

or competing with investigator or study staff time?

J Site Infrastructure Sponsoring Planning Tool: Notes for J> Site Infrastructure

Is it likely that the organisation will be able to support study

feasibility from a medical perspective?

Is the organisation already aware of any constraining factors

in the PaCCSC SOPs that may impact on sponsoring or

delivery of the study (and which may require escalation within

the organisation to be resolved)?

Investigator Team

Is it likely that the organisation will be able to provide

additional support (if required) to the senior investigator in

delivering the study?

Science Design

Is it likely that the organisation will be able to address aspects

of study design relating to the science of the study?

Research Team

Is it likely that the organisation will be able to provide

appropriately experienced research staff that may be needed

in delivering the study as planned by the CI?

Is it likely that the organisation will be able to address aspects

of study design relating to any additional patient safety

requirements?

Is it likely that the organisation will be able to address legal

and regulatory requirements relating to the study? (e.g.

approvals including ethics opinion and regulatory, appropriate

SOPs, indemnity cover, licences, etc)

Is it likely that the organisation will have the appropriate

patient population, and experience / guidance needed for

working with any vulnerable groups as part of the study?

HREC/RGO Requirements

Local Alignment

Patient Safety Design

Patient Group Design

Page 5 of 6

Is it likely that he organisation will have appropriate quality

capabilities and staff resources to assess and manage risks

relating to this study?

Sponsoring Planning Tool: Notes for J> SITE INFRASTRUCTURE

Does the organisation expect to be able to confirm in a way proportionate to the complexity and size of the study,

that all sponsor and, where appropriate, funder responsibilities are clearly defined across all relevant parties within a

reasonable timescale agreed with the senior investigator?


1. Is there specific availability of office space, storage and secure filing, computing and photocopying equipment?

2. Can study staff be contacted via telephone and mobile phone?

3. Is there IT infrastructure with internet capacity and user support?

4. Is there the capacity to visit patients at home for follow-up?

K Quality Sponsoring Planning Tool: Notes for K> Quality

Is it likely that the organisation will have appropriate quality

capabilities and staff resources to assess and manage risks

relating to this study (e.g. auditing and training requirements)?

Sponsoring Planning Tool: Notes for K> QUALITY


1. Has the site undergone sponsor/independent site audit in the past?

2. Does the site have previous experience with clinical trial audits, if so, were any concerns raised?

3. Are there any training requirements identified for any of the team?

L External Agreements Sponsoring Planning Tool: Notes for L> External Agreements

Is it likely that the organisation will be able to understand and

manage contractual risks relating to this study? (including

access to any additional and specialist contract knowledge)

Sponsoring Planning Tool: Notes for L> EXTERNAL AGREEMENTS

Does the organisation expect to be able to use a standard template or other appropriate study contract / agreement

with participating organisations which is proportionate to the complexity and size of the study within a reasonable

timescale agreed with the senior investigator?

Page 6 of 6

Template 7

PaCCSC Protocol Deviation/Violation Report Form


PaCCSC PROTOCOL DEVIATION/VIOLATION REPORT FORM

** DO NOT SEND IDENTIFIABLE DATA WITH THIS FORM **

REPORT DETAILS

Study title

Site number

Participant number

Date occurred

Could this occurrence have an impact on:

Safety of participant

Yes Details:

No

Study Outcomes

Yes Details:

No

If the answer is “Yes” to both of these questions – this event is a serious violation and must be reported to the approving HREC

Now complete the following sections where applicable:

ASSESSMENT TO CONFIRM DEVIATION

A potential participant does not meet, or only partially meets, one of the eligibility criteria

Yes Details:

No

A protocol visit date deviation outside the study visit window, or not conducted

Yes Details:

No

Isolated incident of a missed or incomplete study procedure (e.g. laboratory test, study evaluation or questionnaire)

Yes Details:

No

Other deviation

Yes Details:

No

Template 7

PaCCSC Protocol Deviation/Violation Report Form


PaCCSC PROTOCOL DEVIATION/VIOLATION REPORT FORM (cont.)

**DO NOT SEND IDENTIFIABLE DATA WITH THIS FORM**

ASSESSMENT TO CONFIRM VIOLATION

Description of violation

ACTIONS TAKEN

Date

Corrective action

Preventative action

Action required

Participant(s) to remain on trial

Participant(s) to be withdrawn from trial

INFORMATION SOURCE

Name, address and telephone number of Principal Investigator or designee

Signature of Principal Investigator or designee

Dated

This form must be sent to PaCCSC Coordinating Centre within 3 days of any trial site member becoming aware of Deviation/Violation of Protocol

Email: [email protected]

Template 8

PaCCSC Protocol Violation Form


PaCCSC PROTOCOL VIOLATION FORM

** To be completed by PaCCSC Coordinating Centre staff **

Principal Investigator

Participant ID

Date of event

Date event became known

Date form completed

Type of violation

Incorrect consent procedure

Incorrect randomisation

Randomisation of ineligible patient

Enrolled outside prescribed time periods

Incomplete data for enrolled patient

Treatment cannot be verified

Serious Adverse Event (SAE) not reported

Other

Description

Action taken

Patient withdrawn

Data inclusion to be modified

Data Safety Monitoring Committee notified

Ethics committee notified

No action – include in analysis

Signatures

Monitor

Site investigator

____________________________

____________________________

Date _________________

Date _________________

Template 9

File Notes


PaCCSC File Notes

Section 1

Date / Time

Forum Meeting Telephone Other :

Staff Member

Other staff

Study ID PID of patient if applicable

Subject

Section 2

Item no. Details of File Note

Action

Signature

Date of completion

Template 10

PaCCSC Data Management Plan

Vx.x Month/Year Page 1 of 12

[Study name] Data Management Plan

Purpose

This data management plan has been developed to tailor the data management activitiesof the generic PaCCSC SOP 5.5.1 Electronic Data Handling as they apply to the [insertname] study.

This is to ensure the management of data for the [insert name] study meets all therequirements for a pre-registration study, and that the data management is adaptive,comprehensive and focusses on review, training and mentorship.

FULL TITLE Specify full title for the study

ABBREVIATED TITLE Specify abbreviated title for the study

ACTRN REGISTRATION Specify trial registration on ACTRN

LEAD STUDY INVESTIGATOR Name Position Organisation Address Phone Fax Email

STUDY SPONSOR Palliative Care Clinical Studies Collaborative IMPACCT, University of Technology Sydney 235 Jones Street Ultimo NSW 2007 Australia Phone: (08) 7421 9796 Email: [email protected]

Template 10



NOTE TO INVESTIGATORS

• This data management plan template contains instructions and sample text in italics.Investigators should carefully consider the suggested text under each section, and thenmodify, remove or replace as appropriate to their study.

• This instruction page should be removed once the data management plan is completed.

Template 10



Definitions

eCRF Case Report Form (electronic, captured within the RDMS)

Source (s)CRF The paper form completed during the visit and constitutes source data, not captured elsewhere

Source Any other material constitutes source data as defined in PaCCSC SOPs

PID Patient Identification Number

SDV Source Data Verification

RDMS Research Data Management System

1. Introduction

Data is collected by study nurses at recruiting sites when a patient is screened and then continues into the study. The information collected from the patient (or other participant, which may be a caregiver, nurse or someone else) is entered into a paper Source Case Report Form (sCRF) for the specific time or contact that the participant is reviewed, or the data is collected on a questionnaire or other ‘tool’ as required by the study protocol. Where data is completed directly by the patient the paper form is attached to the sCRF.

The data is then entered into UTS licenced REDCap database (or other study specific RDMS) (eCRF) and this forms the study data from which the study results are drawn. It is very important that the data held within the database accurately reflects the data collected by study nurses when they review study participants.

The responsibility of the PaCCSC Coordinating Centre is to ensure that the data entered onto the eCRF is as per the data collected (in the sCRF), and that it is clear what has been collected, entered, checked, and what is missing.

In order to ensure this process is complete, the PaCCSC office follows a number of steps. These are described here. These steps sit alongside the Standard Operating Procedures for Data Management.

2. Receipt of Participant Registration Notification

The receipt of a Participant Registration Notification (Template 17) indicates that a patient has been randomised or allocated to the study and the Site Pharmacy has been provided with the allocation.

The following information is entered:o The PIDo The details of the registration notification

An electronic folder is created in the Data Management folder for the PID where:o The e-copy of the notification is filed, ando Any subsequent e-copies of data for that PID are stored (as per below).

Template 10



3. Electronic data capture and electronic CRF design

The Electronic Case Report Form (eCRF) is designed and implemented using a validated web based system, OpenClinica, by MCG Study Clinical Programmer and Study Data Manager. The eCRF should only capture data specified in the Protocol which will be used for statistical analysis.

Below is the listed data to be collected during the study according to the study Protocol. Data will be stored and handled directly by the sites/Sponsor and will not be entered in the clinical database:

All blood sampling results (except specific sample level as required at Eligibility visit) Telephone call data Pre-Screen data

Before releasing, the eCRF will be reviewed and approved by the Sponsor representative, Study Data Manager, Study Statistician (or other appropriate person suitable for the study).

Once final, a PDF image will be made of the eCRF and this will be archived along with the eCRF specifications document or data dictionary. If any modifications are made during the course of the study, these must also be approved and archived using the process outlined above.

4. Data base set up

The data base, using an approved RDMS, should be tested and released for use.

5. Data Entry

Each person will be provided with a password and access code for the RDMS, which is to be changed at first login. This password is not to be shared, and should meet the security requirements of the RDMS used for the study. The names and dates of access to the RDMS are to be recorded.

Site personnel are required to complete CRF within 5 days after each patient contact.

CRF data entry will be performed by site personnel into the RDMS. Training on data entry will be provided by the Study Coordinator. The RDMS User Guide can be used for general information on managing and entering patient data. CRF completion guidelines are incorporated into the eCRF and sCRF forms to provide study specific instructions (where required).

Template 10



6. Receipt of Source CRFs

The sCRFs will generally be received via email as a PDF.

Each sCRF is to be saved into the PID folder in the following format:

[Study code]-[site code]-[screening number]-timepointo 30-12-001-baseline

If a second (amended) version is received it is to be saved in the same way with anadditional identifier such as ‘amended’, date, or similar.o 30-12-001-baseline-v2

The time points (and therefore the total possible individual sCRF files for each PID) for a study may include (as examples):

Randomisation (registration notification) Eligibility Medical assessment Baseline Caregiver Intervention forms Cessation/withdrawal SAE (can have numerous events for each PID) Adverse Events Concurrent medications Follow-up weeks 1 Extension forms File note (add date), can also have numerous notes for each PID. Monitoring record

Any attachments related to any individual sCRF (such as questionnaires) are to be merged into the sCRF PDF for that visit.

The Data Log is to be updated by entering the receipt of the sCRFs.

7. Data Checking

Open the file Study ‘Data Log’ for the specific study. Open the PDF copy of the sCRF for checking. Log on to the RDMS and open the specific PID from the home page (subject matrix).

Follow the training and instructions for data checking as monitor. Copies of sCRFs are visually checked against the eCRF to assess whether there are any

inconsistencies or errors between the information entered into the database and thesCRF copy.o This is a page by page comparison of both the paper and the electronic CRFs. The

underlying assumption is that in most cases the data recorded by the studynurse on the original sCRF is assumed to be correct as the sCRF wascompleted at the time the data was collected.

The Data Management Plan is to be followed with reference to Table 1 (Appendix 1) for the specific items to be checked.

Template 10



8. Maintaining and Audit Trail

8.1. Modifications

The sCRF and eCRF will be reviewed and approved by the Lead Investigator and/or the study statistician prior to release. Any further changes require a clear email or written trail of the request and required changes. All changes will be recorded via version control (sCRF) and internal mechanisms within the RDMS. If internal mechanisms are not available, a clear description for the changes are to be recorded within a centrally located record.

9. Data Errors

When data errors are identified, the person checking the data will:

Visually compare each sCRF data point against the eCRF entered onto the RDMS Identify any errors Raises a query within the RDMS for:

o Proposal of a resolution by the site if− The visit dates do not line-up with other data− the RDMS has raised a query for a ‘Out of Range’ measure which requires

further review and response by the site teamo Resolution and Closure by the Central Office if;

− The eCRF is different to the sCRF (and assuming that the sCRF is correct)− The site has proposed a resolution (through notes and annotations) which

confirms the error− The site has returned amended sCRFs

10. Form Errors

A form error is when data has been entered into the eCRF that is not on the sCRF or where it seems obvious that information has been missed or incorrect in the sCRF. Occasionally it is obvious that data has been correctly entered but does not match information written on the sCRF. Examples may include:

Date incorrect on sCRF (e.g., respiratory rate of 120) but correct in REDCap (e.g.,respiratory rate of 20) (obvious transposition of closely spaced data fields).

Additional typing or expansion of typing in the RDMS that is not in the sCRF. Entries for ‘not collected’ entered but completely blank in the sCRF. Where data from different fields have been ‘swapped’ around when writing into the sCRF.

In these cases the eCRF may not need correcting, but the site needs to confirm the data against the sCRF and then make the changes to the sCRF in line with the data entered in the RDMS eCRF.

A query is to be raised within the RDMS to enable the site to confirm that the sCRF has been corrected, an amended copy of the sCRF is to be sent to the PaCCSC Coordinating Centre for checking, ‘Closure of the query’ and filing.

Template 10



11. File Closure

The PID file is considered closed when any of the following occurs:

The RDMS being corrected either by the site, with the completion of the system raisedquery; or

By the site sCRF having been corrected and sent to the PaCCSC Coordinating Centre PaCCSC Coordinating Centre resolution in accordance with the process specified above The query in the RDMS is marked as ‘complete’

The entire data for each patient will be complete when all the required sCRFs have been:

Received Checked Logged All errors resolved

The PID file will be renamed with the addition of - Complete

12. Definition of clean data

Date is considered clean when the following has occurred:

All expected data approved by nominated site personnel All expected eCRF forms have been completed No outstanding discrepancies All data review activities completed and reviewers have no further queries regarding the

data All eCRF have been signed and approved by site investigators within the RDMS or as

specified by the protocol

13. Central and on-site monitoring

Data checking sits alongside monitoring which takes two forms, on-site and central.

Monitoring activities have a different function to data checking. Whereas data checking ensures that the database (eCRF) accurately reflects the data recorded within the sCRF, monitoring ensures that the data collected within the sCRF accurately reflects the clinical situation as per the medical records and other records held within the clinical setting (this is referred to as Source Data Verification – SDV). Monitoring also ensures that the data within the sCRF is clinically consistent, demonstrates compliance with the protocol, allows correct assessment of safety and patient compliance as well as enabling other site specific issues to be addressed. Past the primary endpoint, these activities will be completed centrally where review of the sCRF can highlight clinical issues and protocol questions.

Onsite monitoring will focus on the following items:

Consent Eligibility Data to Primary endpoint/cessation Safety

Template 10



Investigational product

This will be detailed further in the Study Monitoring Plan (Template 35).

Queries are raised within the RDMS by the monitors in the same way the queries are raised during data checking to ensure that the eCRF accurately reflects the source documentation.

The checked eCRFs are marked as SDV during monitoring (if the RDMS has this feature) while on-site or on return to the central office. Any follow-up to monitoring, such as ‘Propose resolution’ in the RDMS, provision of amended sCRFs, or other communication to indicate follow-up of the issue, and SDV checked again.

14. Summary of data entry and monitoring

Table 1 (Appendix 1) details the specific item of interest for; data entry, data checking and monitoring as an example from one PaCCSC study.

The ‘Data Log’ is to contain each of the CRFs and documents listed in Column 1, while not all of the CRFs or data points are to be checked, the existence of the form is to be recorded in the ‘Data Log’.

Key dates and formulas will be used to ensure that other required documents and visits are also displayed. Checking of the entered data is to be consistent with the ‘Data Checking’ column in the summary table, the instructions through this document are to be followed.

15. Data base security

User accounts and access permission to the RDMS and to the study data will be managed by the RDMS administrator upon evidence of completion of training. All the roles and responsibilities are pre-defined within the RDMS and only authorised staff will have access to the database.

16. Data base closure

Database closure occurs when:

Study recruitment has been stopped All data has been entered and checked The data meets the definition of Clean Data

At this time, all access to the data base for users will be ceased, except for the coordinating office team who will have ongoing activities for download. An email will be sent to all users 4 weeks prior to data base closure to enable any outstanding data queries to be resolved, this date will be recorded within the study files.

After the date of database closure, all the data will be downloaded and filed in a secure network protected file using naming conventions for date and version (refer SOP 5.5.1 Electronic Data Handling).

Template 10



Once all data has been handed to the study statistician and any resultant queries have been resolved, the data base is locked, all continuing access is ceased, except for the data manager or coordinator, and using the mechanism required by the RDMS.

Template 10



Appendix 1

Table 1: Items to be checked

CRF (line in the Data Log)

Data point Data entry REDCap

Data checking Monitoring

Pre-screen

Eligibility Visit dates Consent dates Inclusion criteria Exclusion criteria Scheduled day 1 date Other critical inclusion elements

Visit plans File note Approval

Medical assessment Cancer diagnosis Physical examination Tumor stages Charlson Comorbidity Index Specific review points Specified questionnaires and assessments Final checklist Approval

Baseline Dates Demographics

Template 10







Vital signs Medications checklist Specified questionnaires and assessments Adverse Event form Carer Experience Scale File note

Daily Assessment Visit dates Study day Adverse Event form Vital signs Administration of intervention Specified questionnaires and assessments Response Assessment File note

Other visit time points Visit dates Study day Adverse Event form Vital signs Specified questionnaires and assessments DSM V diagnosis Economic evaluation Medication assessment Response Assessment File note

Template 10







Cessation/withdrawal Visit dates Study day Cessation form Discharge/Death Dates Specified questionnaires and assessments File note Approval

Weekly Follow-up Visit dates Safety Assessment Medication Assessment Economic evaluation Specified questionnaires and assessments File noteDelirium Exp Questionnaire

Adverse event

Concurrent medications

Template 11

Source Document Log


Notes

As per ICH GCP 8.1, it is a requirement that a record is maintained of the location(s) of all essential documents (refer SOP 8.0 EssentialDocuments).

The table below can be adapted to use in order to log the location of source documents related to a trial. This log is to be located in a prominent position within the Investigator Site File (ISF).

Source Document Log

Protocol Code: [insert] Site: [insert details] Hospital/Organisation: [insert details]

Source Document Location within the Organisation Source document location Contact person

Patient Medical Records Medical Records, level 5, building 10

All clinical notes Head of Medical Records

Patient Medical Records Electronic system – EPAS Login to EPAS required Head of Medical RecordsPharmacy Records Level 2 Clinical Trials Pharmacy Clinical Trials PharmacistRadiology Records Building 3 Electronic Records Head of Radiology

[Study] Version number

Study

code

Site

codePT I.D. First Name Last Name URN D.O.B Address Phone Carer name Carer contact GP GP Phone GP Fax GP Email GP Address

Referring

PhysicianDiscipline Diagnosis Location on referral

Total 0

ID coding Demographic details

Patient Details

Template 12

This document is part of the suite of PaCCSC SOPs 1 of 3 Belinda Fazekas PaCCSC National Project Officer


Study

codeSite code PT I.D Referral date

Date of First

ContactContact delay

Consent

1=yes

Consent

dateScreen date Screen delay Sceening comment Re-screen date

Eligible

1=yes

Randomisa

tion

request

Randomisa

tion date

Total 0 0 0

ID coding Referral details

Screening Details

Template 12

This document is part of the suite of PaCCSC SOPs 2 of 3 Belinda Fazekas National Project Officer


Study

codeSite code PT I.D

Commence

Baseline

Commence

Study DrugVisit 1 Visit 2 Visit 3

Reached primary

endpoint (0=no,

1=yes)

Date of cessation

of study drugWithdrawal

Reason (1=AE,

2=unwell,

3=changed

mind,

4=medication

AE, SAE 1=yes Follow-up CommentContinuation of study

drug post follow-up

Total 0 0 0 0 0 0

Participation detailsID coding

Participation details

Template 12

This document is part of the suite of PaCCSC SOPs 3 of 3 Belinda Fazekas PaCCSC National Project Officer

Template 13

PaCCSC Data Closure Form


PaCCSC Data Closure Form

CareSearch / OpenClinica / REDCap Survey Title

Name of Sponsor [if a clinical trial]

Date of final data download by PaCCSC

Download performed by [individual name]

Download stored by [entity name]

Name of Lead Investigator / delegate / external collaborator

Approval of Lead Investigator / delegate / external collaborator for deletion

[signature]

Date of approval for deletion by Lead Investigator / delegate / external collaborator

Name of Research Data Management System Administrator

Date of deletion from CareSearch / OpenClinica / REDCap

PID: __ __ / __ __ / __ __ __ / __ __ __ [STUDY] Adverse Event CRF

Line

#

Study

StageSystem # Adverse Event

Start

Date of

Event

Grade

#Serious

AE of

special

interest?

Relationship

to study drug

Action

TakenOutcome

Date of

Outcome

1

2

3

4

PaCCSC Adverse Events Form - Exel Version

Template 14This document is part of the suite of PaCCSC SOPs Version number

System Code System

1 Blood and Lymphatic

2 Cardiac disorders

3 Congenital, familial and genetic disorders

4 Ear and labyrinth disorders

5 Endocrine disorders

6 Eye disorders

7 Gastrointestinal disorders

8 General disorders and administration site conditions

9 Hepatobiliary disorders

10 Immune system disorders

11 Injury, poisoning and procedural complications

12 Investigations

13 Metabolism and nutrition disorders

14 Musculoskeletal disorders

15 Neoplasms benign, malignant and unspecified (incl cysts and polyps)

16 Nervous system disorders

17 Pregnancy, puerperium and perinatal conditions

18 Psychiatric disorders

19 Renal and urinary disorders

20 Reproductive systam and breast disorders

21 Respiratory, thoracic and mediastinal disorders

22 Skin and subcutaneous tissue disorders

23 Social disturbances

24 Surgical and medical procedures

25 Vascular disorders

General Grade Coding Description1 Grade 1: Mild; asymptomatic or mild, intervention not indicated

2 Grade 2: Moderate; minimal local or non-invasive intervention indicated

3 Grade 3: Severe of medically significant but not immedicately life threatening

4 Grade 4: Life threatening consequences; urgent intervention indicated

5 Grade 5: Death related to AE.

99 Unable to be graded

Symptom of interest NCI Terms Definition Grade Coding

Grade 1: -

Grade 2: -

Grade 3: -

Grade 4: Life-threatening consequences; urgent intervention, intubation, or ventilatory support indicated;

Grade 5: Death

Grade 1: Asymptomatic, intervention not indicated.

Grade 2: Symptomatic, medical intervention indicated.

Grade 3: Severe, medically significant, medical intervention indicated.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Grade 5: Death.

Grade 1: Brief partial seizure; no loss of consciousness.

Grade 2: Brief generalized seizure.

Grade 3: Multiple seizures despite medical intervention.

Grade 4: Life-threatening; prolonged repetitive seizures.

Grade 5: Death.

Grade 1: Mild disorientation.

Grade 2: Moderate disorientation; limiting instrumental ADL.

Grade 3: Severe disorientation; limiting self care ADL.


Grade 5: Death.

Grade 1: Mild unsteadiness or sensation of movement.

Grade 2: Moderate unsteadiness or sensation of movement; limiting instrumental ADL.

Grade 3: Severe unsteadiness or sensation of movement; limiting self care ADL.

Grade 4: -

Grade 5: -

Grade 1: Fatigue relieved by rest.

Grade 2: Fatigue not relieved by rest; limiting instrumental ADL.

Grade 3: Fatigue not relieved by rest, limiting self care ADL.

Grade 4: -

Grade 5: -

Grade 1: -

Grade 2: Present (e.g., near fainting).

Grade 3: Fainting; orthostatic collapse.

Grade 4: -

Grade 5: -

Grade 1: Occasional or intermittent symptoms; occasional use of stool softeners, laxatives, dietary modification, or enema.

Grade 2: Persistent symptoms with regular use of laxatives or enemas; limiting instrumental ADL.

Grade 3: Obstipation with manual evacuation indicated; limiting self care ADL.


Grade 5: Death.

Grade 1: Transient flushing or rash, drug fever <38 degrees C (<100.4 degrees F);

intervention not indicated.

Grade 2: Intervention or infusion interruption indicated; responds promptly to

symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics); prophylactic

medications indicated for <=24 hrs.

Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief

interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g.,

renal impairment, pulmonary infiltrates)


Grade 5: Death.

Grade 1: Loss of appetite without alteration in eating habits.

Grade 2: Oral intake decreased without significant weight loss, dehydration or malnutrition.

Grade 3: Inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated.

Grade 4: -

Grade 5: -

Grade 1: 1 - 2 episodes (separated by 5 minutes) in 24 hrs.

Grade 2: 3 - 5 episodes (separated by 5 minutes) in 24 hrs.

Grade 3: >=6 episodes (separated by 5 minutes) in 24 hrs; tube feeding, TPN or hospitalization indicated.


Grade 5: Death.

Grade 1: Mild pain.

Grade 2: Moderate pain; limiting instrumental ADL.

Grade 3: Severe pain; limiting self care ADL.

Grade 4: -

Grade 5: -

Grade 1: Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline.

Grade 2: Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output

compared to baseline.

Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated;

severe increase in ostomy output compared to baseline; limiting self care ADL.


Grade 5: Death.

Grade 1: Mild pain.

Grade 2: Moderate pain; limiting instrumental ADL.

Grade 3: Severe pain; limiting self care ADL.

Grade 4: -

Grade 5: -

Grade 1: Mild symptoms; intervention not indicated.

Grade 2: Moderate symptoms; limiting instrumental ADL.

Grade 3: Severe symptoms; limiting self care ADL; hospitalization not indicated.

Grade 4: Life-threatening; hospitalization indicated.

Grade 5: Death.

Grade 1: Mild memory impairment.

Grade 2: Moderate memory impairment; limiting instrumental ADL.

Grade 3: Severe memory impairment; limiting self care ADL.

Grade 4: -

Grade 5: -

Grade 1: Mild difficulty falling asleep, staying asleep or waking up early.

Grade 2: Moderate difficulty falling asleep, staying asleep or waking up early.

Grade 3: Severe difficulty in falling asleep, staying asleep or waking up early.

Grade 4: -

Grade 5: -

Grade 1: Loss of appetite without alteration in eating habits.

Grade 2: Oral intake altered without significant weight loss or malnutrition; oral nutritional

supplements indicated.

Grade 3: Associated with significant weight loss or malnutrition (e.g., inadequate oral caloric and/or fluid intake); tube feeding or

TPN indicated.


Grade 5: Death.

Grade 1: Increased oral fluids indicated; dry mucous membranes; diminished skin turgor.

Grade 2: IV fluids indicated <24 hrs.

Grade 3: IV fluids or hospitalization indicated.


Grade 5: Death.

Grade 1: -

Grade 2: Symptomatic; altered GI function; bowel rest indicated.

Grade 3: Severely altered GI function; TPN indicated.


Grade 5: Death.

Dehydration Dehydration

A disorder characterized by excessive loss of water from the

body. It is usually caused by severe diarrhea, vomiting or

diaphoresis.

Atonic colon IleusA disorder characterized by failure of the ileum to transport

intestinal contents.

Sleep problems, insomnia InsomniaA disorder characterized by difficulty in falling asleep and/or

remaining asleep.

Loss of appetite Anorexia A disorder characterized by a loss of appetite.

Anxiety Anxiety

A disorder characterized by apprehension of danger and dread

accompanied by restlessness, tension, tachycardia, and dyspnea

unattached to a clearly identifiable stimulus.

Memory problems Memory impairment A disorder characterized by a deterioration in memory function.

Diarrhoea DiarrhoeaA disorder characterized by frequent and watery bowel

movements.

Headache Headache

A disorder characterized by a sensation of marked discomfort in

various parts of the head, not confined to the area of distribution

of any nerve.

Vomiting VomitingA disorder characterized by the reflexive act of ejecting the

contents of the stomach through the mouth.

Stomach pain Abdominal PainA disorder characterized by a sensation of marked discomfort in

the abdominal region.

Flushing of the skin Allergic reactionA disorder characterized by an adverse local or general response

from exposure to an allergen.

Nausea NauseaA disorder characterized by a queasy sensation and/or the urge

to vomit.

Constipation ConstipationA disorder characterized by irregular and infrequent or difficult

evacuation of the bowels.

Dizziness DizzinessA disorder characterized by a disturbing sensation of

lightheadedness, unsteadiness, giddiness, spinning or rocking.

Weakness Fatigue

A disorder characterized by a state of generalized weakness with

a pronounced inability to summon sufficient energy to

accomplish daily activities.

Light headed or fainting

PresyncopeA disorder characterized by an episode of lightheadedness and

dizziness which may precede an episode of syncope.

SyncopeA disorder characterized by spontaneous loss of consciousness

caused by insufficient blood supply to the brain.

Seizure SeizureA disorder characterized by a sudden, involuntary skeletal

muscular contractions of cerebral or brain stem origin.

Confusion ConfusionA disorder characterized by a lack of clear and orderly thought

and behavior.

Adverse Events of Special Interest

Respiratory depression Respiratory Failure

A disorder characterized by impaired gas exchange by the

respiratory system resulting in hypoxemia and a decrease in

oxygenation of the tissues that may be associated with an

increase in arterial levels of carbon dioxide

Slow heartbeat Sinus bradycardiaA disorder characterized by a dysrhythmia with a heart rate less

than 60 beats per minute that originates in the sinus node.

[Study] Corrective Action Sheet

PaCCSC Corrective Action Sheet

Date:

PID CRF/form Findings Required outcomes Error code

Actual

outcomes

Date

completed

None Minor Major

None Minor Major

None Minor Major

None Minor Major

None Minor Major

None Minor Major

None Minor Major

None Minor Major

Monitor

signatures Date

Study:

This corrective actions sheet is to be used to summarise all findings identified during the visit. The monitor is responsible for entering possible solutions for all findings, the agreed outcome for all

findings must be cmpleted by the monitored site during the exit meeting.

Site:

Site staff present:

Template 15This document is part of the suite of PaCCSC SOPs Belinda Fazekas PaCCSC National Project Officer

Template 16

PaCCSC Monitoring Log


PaCCSC Monitoring Log

Study:

PI Name: Site Name:

Date of visit Type of visit Monitor name Monitor signature Site personnel signature

Visit type

Initiation Periodic Closure Other

Monitor signature ___________________________ Date _________________________

Template 17

PaCCSC Randomisation Registration Notification


Randomisation Registration Notification

To: [Study Coordinator] From:

Phone:[Telephone number] Phone:

Pages:1 Date:


Dear PaCCSC Coordinating Centre

The following patient has been randomised for a PaCCSC clinical study.

Study ID Number:

Participant ID number:

Strata: [remove if not required]

Site Name:

Randomisation date:

Date of treatment commencement:

Yours sincerely

[Signature]

Site Pharmacy:

Template 18

PaCCSC Unblind Request Form


PaCCSC UNBLIND REQUEST FORM

** To be completed by the Central Registry **

Request details

Study code or name

Site code or name

Requesting person

Position of requesting person

Call back number STD:

Date/Time of request dd/mm/yyyy <specify time>

Unblinding authorized by <Full Name> <Position>

Details of participant

Date of Birth

Study ID Number

Randomisation Number

Result of request

Code

Intervention

Signature

Date

This form is

• To be filed in the unblinding folder along with the unblinding envelope.

• To be filed by the Central Randomisation Service or other facility with authorisedaccess to the allocation codes.

• To be made available to the PaCCSC Coordinating Centre only post study closure.

Template 19

PaCCSC Unblind Report Notification

This document if part of the suite of PaCCSC SOPs Page 1 of 1

Unblind Report Notification

** To be completed by the Central Registry to confirm a participant unblinding **

To: National Project Officer From:

Phone:+61 8 7421 9796 Phone:

Pages:1 Date:


Dear PaCCSC Coordinating Centre

The following patient has been unblinded for the clinical study - [name of study].

Study ID Number:

Site Name:

Reason for unbinding:

Date of unbinding:

Method of confirmation of notification to site:

NO ALLOCATION OR CODE IS TO BE REVEALED ON THIS NOTICE.

Yours sincerely

[Signature]

Central Registry:

Template 20

PaCCSC Trial Master File Index


PaCCSC Trial Master File IndexIs docrequired?

OriginalFiled

Responsible Location

Y/N Y/N

1.0 Funding applicationsSubmitted version

Old versions

Correspondence

2.0 ProtocolsFinal approved protocol

Old Versions

Protocol amendments

Insurance/ indemnity

Related correspondence/ telephone conversations

3.0 Ethics/ RegulatoryContact details

Ethics approval letter/s

Ethics application

Progress and final reports


4.0 ContractsFunding body

Laboratory

Institution/investigator

Collaborative group

Confidentiality agreements

Conflict of interest statements

Memorandums of understanding


5.0 FinanceStudy budget

Study cost reports/tracking

Study meeting budget/costs

Site payments

Contracts

Ordering and shipping

Supplies accountability

Related correspondence/quotes

Purchase order details forms

Drug destruction records

6.0 CommitteesChief investigator

Executive/steering

Team

Stakeholder

Reference group

Other (Named)

Template 20



Trial Master File Index (cont.)Is docrequired?

OriginalFiled


Y/N Y/N

7.0 Investigator/study staffParticipating investigatorsInvestigators

Study staff details list

Positions

Correspondence

8.0 Study sitesParticipating study site list, contact details

Site feasibility assessments

Pharmacy site list

Related documents/correspondence

9.0 Funding body correspondenceContact details

Agenda and minutes of sponsor meetings

General correspondence

10.0 General correspondencexxx correspondence

yyy correspondence

zzz correspondence

11.0 Study progress reportsEnrolment/randomisation

Status reports

Distribution lists

Data extractions

12.0 Study recruitment/follow-upStrategies: advertising, workshops, mailout etc

Resources: posters, brochures

Newsletters

13.0 Study managementStudy plan

Internal correspondence

Gantt charts

Directories

Trial master file directory - project specific

Electronic trial directory - project specific

Superseded directories

Template 20




OriginalFiled


Y/N Y/N

14.0 LaboratoryCertification/accreditation and CV's

Normal ranges and methods

Related correspondence/telephone conversations

15.0 Investigator's brochureCurrent approved version

All approved versions and dates

17.0 Case report forms CRF Final version

CRF drafts

CRF tracking instructions

Data query rules

Resolved queries

Final file document sign off forms


18.0 Monitoring - general Current monitoring guidelines

Current monitoring forms

Consent form check list

Source data verification forms

Drug allocation forms

Serious adverse event checklist

CRF correction form

Monitoring follow-up actions form

Monitoring report form

Schedule/s of monitoring visits

Superseded monitoring guidelines and forms


Declaration of facilities

19.0 Adverse events/outcomes Serious adverse event reporting plan

Reports SAEs


Outcomes

20.0 Procedure manuals Current

Old/previous versions

In-service manual

Correspondence

Template 20




OriginalFiled


Y/N Y/N

21.0 Randomisation/unblinding Master randomisation list

Unblinding - codes

List of subjects unblinded

Other

22.0 Participant data Patient master list

Participant study files

Consent forms

Correspondence

23.0 Statistical analysis and outputProject statistician information

Randomisation design, stratification, unblinding

Statistical design and considerations, including sample size

Statistical analysis plan, including interim analysis, stopping rules

Interim analysis

Tables, figures and listings

Statistical analysis

Reports

Other relevant documents

Final analysis

Tables, figures and listings

Statistical analysis

Reports

Other relevant documents

Correspondence

24.0 PublicationsAuthorship protocol

Study newsletters

Patient newsletters

Conference abstracts/presentations

Papers

Authorship groups

Drafts

Final version

References

Correspondence

Template 20




OriginalFiled


Y/N Y/N

25.0 SubstudiesSubstudy 1

Protocol

Ethics

Funding applications

Correspondence

Data analysis

Final report

Publications

Substudy 2

Protocol

Ethics

Funding applications

Correspondence

Data analysis

Final report

Publications

Template 21

PaCCSC Study Feasibility Checklist


[STUDY] – FEASIBILITY/SCREENING CHECKLIST

(Record details of patients with SYMPTOM)

Principal Investigator:

Site:

STUDY POPULATION Statement of target population described in protocol.

Item Inclusion criteria Item Exclusion criteria1. Main criteria 1 7. Main criteria 72. Main criteria 2 8. Main criteria 83. Main criteria 3 9. Main criteria 94. Main criteria 4 10. Main criteria 105. Main criteria 5 11. Main criteria 116. Main criteria 6 12. Main criteria 12

13. Main criteria 1314. Main criteria 14

Item Referring clinics1. Palliative care2. Oncology3. Respiratory4. Cardiac5. Respiratory rehabilitation6. Community care7. Other

Template 21



Referring clinic

Date Screened

Patient Eligible?

(Y/N)Reason for Non Eligibility * Comments

1. __/__/__

2. __/__/__

3. __/__/__

4. __/__/__

5. __/__/__

6. __/__/__

7. __/__/__

8. __/__/__

9. __/__/__

10. __/__/__

11. __/__/__

12. __/__/__

13. __/__/__

14. __/__/__

15. __/__/__

16. __/__/__

17. __/__/__

18.

Template 21



Referring clinic

Date Screened

Patient Eligible?


19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

Template 21



Referring clinic

Date Screened

Patient Eligible?


37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

*Indicate the item number from the list on cover page, the item that means the person is not suitable for the study.

Template 24

PaCCSC Dissemination Plan



1. Who are we targeting? Who are our audience?

External/funding requirements Professional groups/organisations Examples

EXAMPLE ONLY DoH; Clinical sector - Pharmacy

EXAMPLE ONLY Council of Australian Therapeutic Advisory Groups (CATAG); Pharmacy Networks and Hospital Pharmacists; Society Hospital Pharmacists of Australia

EXAMPLE ONLY - Pharmacies/pharmacists co-located in large

inpatient settings with dedicated palliative carebeds (>5)

- Pharmacies in women’s hospitals- Hospital drug committees

Template 24



PaCCSC Dissemination Plan (cont.)

2. What information/results/findings are available for dissemination?

Critical sources of information for dissemination

Information medium Detailed information item Responsibility Comments/follow-up

1 Publications (refer Guidance 12 to develop this part of the dissemination plan)

2 Conference presentations

3 Provisional results dissemination

4 Meeting with manufacturer

5 Marketing/promotional materials

6 Other face-to-face meetings

Template 24



PaCCSC Dissemination Plan (cont.)

3. Organisations to be targeted and suggested targeting action(s)

Group/Organisation Action(s)/Information Target audience Comments/follow-up Responsible person(s)

Pharmaceutical companies

Public – Consumers/Policy Makers

Clinical Sector – Pharmacy Networks and Hospital Pharmacists

Clinical Sector – Palliative Care Professionals

Clinical Sector – Oncology Professionals

Clinical Sector – Health care/Clinical Research Professionals

Other – Non-Clinical

Template 25

PaCCSC Data Requests Log


PaCCSC Data Requests Log

** see also Planned Publications Master List for more information (refer SOP 6.15.1 Dissemination of Study Results) **

Date request received

Name(s) of Requester

Confidentiality Agreement

Data requested Chair

response Yes/No

Response to Requester

12 month follow up (if

required)

Template 27

PaCCSC Pilot Study Progress Plan



Title of Pilot Study

Lead Investigator Name

Date

A. Potential Funding Sources for Multicentre Phase III study (following this pilot)

1. Primary source for future funding

Name of funding source

Category (if applicable)

Key dates

Further information

2. Secondary source for future funding

Name of funding source

Category (if applicable)

Key dates

Further information


Template 27


B. Potential Publications

Publication of Pilot Study Data

1

Title of Journal

Impact Factor

Reason for selection

2

Title of Journal

Impact Factor


Publication of Future Multicentre Phase III Clinical Trial Study

1

Title of Journal

Impact Factor


2

Title of Journal

Impact Factor


VX.x Page 1 of 53

Protocol (with inbuilt pilot phase)

TITLE: Full title

PROTOCOL NUMBER XXX/XX V.x.x

STUDY MEDICINE Medicine 1 dose, route Medicine 2 dose, route

LEAD STUDY INVESTIGATOR

Name Position Organisation Address Phone Fax Email

DATE OF PROTOCOL Date of this version


Confidentiality Statement

The information in this document is strictly confidential. By accepting or reviewing this document, you agree to hold the information in confidence and not to disclose it to others (except with the prior written authorisation of the University of Technology Sydney or where required by applicable law). The information is provided for the exclusive use of investigators involved in the study and, subject to the foregoing, may only be disclosed to other persons involved in the study who have a need to know with the obligation not to further disseminate the information. In the event of any actual or suspected breach of these obligations the University of Technology Sydney should be promptly notified.

Regulatory Statement

All study procedures will be conducted within ICH GCP guidelines (TGA annotated version) and all other regulatory requirements.

Protocol Preparation

This protocol has been prepared in conformance of the CONSORT Guidelines1 and Jadad scores.2 It complies with Guidelines for Good Clinical Practice in clinical research.3

VX.x Page 2 of 53

Investigator Team

Name Faculty/Department Telephone Qualifications

VX.x Page 3 of 53

Protocol History


1.1 New protocol from draft

Protocol Approval

Version Date Approval Name Approval Signature

VX.x Page 4 of 53

TRIAL SUMMARY Background: Study design: Objectives: Treatment schedule: Assessments: Definition of response: Primary endpoint Analysis: Economic analysis:

VX.x Page 5 of 53

Study Diagram

VX.x Page 6 of 53

Table of study measures

VX.x Page 7 of 53

Dose schedule timeline

VX.x Page 8 of 53

CONTENTS TRIAL SUMMARY ..................................................................................................................... 4

CONTENTS ................................................................................................................................ 8

LIST OF ABBREVIATIONS ..................................................................................................... 11

1.0 BACKGROUND AND RATIONALE ............................................................................... 14

1.1 REVIEW OF THE LITERATURE .......................................................................................... 141.2 EXISTING EVIDENCE ....................................................................................................... 141.3 RATIONALE FOR INTERVENTION ...................................................................................... 141.4 CONCLUSIONS AND AIMS ................................................................................................ 141.5 RATIONALE AND SIGNIFICANCE ....................................................................................... 14

2.0 FEASIBILITY AND PILOT PHASE ................................................................................. 15

2.1 AIM ............................................................................................................................... 172.1.1 Process: .............................................................................................................. 172.1.2 Resources/Logistics: .......................................................................................... 172.1.3 Management: ...................................................................................................... 172.1.4 Scientific: ............................................................................................................ 17

2.2 REVIEW OF FEASIBILITY OR PILOT PHASE ......................................................................... 172.3 REPORTING ................................................................................................................... 17

3.0 STUDY OBJECTIVES ..................................................................................................... 19

3.1 AIM ............................................................................................................................... 193.2 OBJECTIVES .................................................................................................................. 19

3.2.1 Primary objective ................................................................................................ 193.2.2 Secondary objectives ......................................................................................... 19

3.3 NULL HYPOTHESIS ......................................................................................................... 19

4.0 STUDY POPULATION .................................................................................................... 20

4.1 TARGET POPULATION ..................................................................................................... 204.2 INCLUSION CRITERIA ...................................................................................................... 204.3 EXCLUSION CRITERIA ..................................................................................................... 20

5.0 INVESTIGATIONAL PLAN ............................................................................................. 21

5.1 STUDY DESIGN .............................................................................................................. 215.2 STUDY DIAGRAM ............................................................................................................ 21

6.0 INTERVENTIONS ....................................................................................................... 22

6.1 STUDY MEDICATION ....................................................................................................... 226.2 DOSING SCHEDULE ........................................................................................................ 226.3 DOSE SCHEDULE DIAGRAM ............................................................................................. 226.4 DOSE SCHEDULE TIMELINE ............................................................................................. 226.5 METHOD OF ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ....................................... 226.6 BLINDING ...................................................................................................................... 236.7 METHOD OF ADMINISTRATION ......................................................................................... 236.8 DRUG ACCOUNTABILITY.................................................................................................. 236.9 DRUG SUPPLY ............................................................................................................... 236.10 DRUG DESTRUCTION ................................................................................................. 236.11 CONCURRENT TREATMENTS ....................................................................................... 246.12 RESCUE MEDICATIONS ............................................................................................... 24

6.12.1 Symptom cluster 1 ......................................................................................... 246.12.2 Symptom cluster 2 ......................................................................................... 24

6.13 DOSE MODIFICATION.................................................................................................. 246.14 CESSATION OF STUDY DRUG ...................................................................................... 24

6.14.1 Treatment failure ............................................................................................ 246.14.2 Cessation for reasons other than treatment failure ........................................ 24

6.15 POST STUDY TREATMENTS ......................................................................................... 25

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6.16 EXTENSION PHASE CRITERIA ...................................................................................... 256.17 ECONOMIC EVALUATION ............................................................................................. 25

7.0 OUTCOMES AND MEASURES ...................................................................................... 26

7.1 PRIMARY OUTCOME AND MEASURE ................................................................................. 267.2 SECONDARY OUTCOMES ................................................................................................ 26

7.2.1 Efficacy ............................................................................................................... 267.2.2 Toxicity ................................................................................................................ 267.2.3 Health service utilisation and long term outcomes ............................................. 26

8.0 STUDY ASSESSMENTS ................................................................................................ 27

8.1 LABORATORY MEASURES ............................................................................................... 278.1.1 Measure 1 ........................................................................................................... 278.1.2 Measure 2 ........................................................................................................... 27

8.2 MEDICAL AND PHYSICAL MEASUREMENTS ........................................................................ 278.3 DEMOGRAPHICS ............................................................................................................ 278.4 MAIN CLINICAL DIAGNOSIS .............................................................................................. 278.5 PERFORMANCE STATUS ................................................................................................. 27

8.5.1 Australia - modified Karnofsky Performance Status ........................................... 278.6 PAIN ............................................................................................................................. 28

8.6.1 Global Impression of Change ............................................................................. 288.6.2 Brief Pain Inventory ............................................................................................ 28

8.7 COGNITION .................................................................................................................... 288.7.1 Mini mental status examination .......................................................................... 28

8.8 QUALITY OF LIFE ........................................................................................................... 288.8.1 EORTC QLQ 30/15 ............................................................................................ 288.8.2 Caregiver quality of life ....................................................................................... 28

8.9 SAFETY ASSESSMENT .................................................................................................... 298.10 EFFICACY ASSESSMENTS ........................................................................................... 298.11 ASSESSMENTS FOR ECONOMIC ANALYSIS ................................................................... 29

9.0 STUDY PROCEDURES .............................................................................................. 30

9.1 TABLE OF STUDY MEASURES .......................................................................................... 309.2 REFERRALS ................................................................................................................... 319.3 CONSENT PROCESS ....................................................................................................... 31

9.3.1 Carer consent ..................................................................................................... 319.4 SCREENING FOR ELIGIBILITY ........................................................................................... 329.5 RE-SCREENING ............................................................................................................. 329.6 PROCEDURE TO REQUEST RANDOMISATION ..................................................................... 339.7 PRESCRIPTION OF STUDY DRUGS .................................................................................... 339.8 TREATMENT COMMENCEMENT ........................................................................................ 339.9 DAILY ASSESSMENTS ..................................................................................................... 349.10 EXIT ASSESSMENTS ................................................................................................... 349.11 WITHDRAWAL ASSESSMENTS ..................................................................................... 349.12 FOLLOW-UP PHASE ASSESSMENTS ............................................................................. 349.13 EXTENSION PHASE FOR ECONOMIC EVALUATION ......................................................... 34

10.0 ADVERSE EVENTS.................................................................................................... 35

10.1 REPORTING OF ADVERSE EVENTS............................................................................... 3510.2 CRITERIA FOR ASSESSING SEVERITY .......................................................................... 35

10.2.1 Adverse events............................................................................................... 3510.2.2 Serious adverse events .................................................................................. 35

10.3 CRITERIA FOR ASSESSING CAUSALITY ......................................................................... 3610.3.1 Time period for assessing AE’s and SAE’s .................................................... 3610.3.2 National Cancer Institute, Common Terminology Criteria for Adverse Events.V4.0 37

10.4 ADVERSE EVENT ASSESSMENT DIAGRAM ................................................................... 3710.5 FOLLOW-UP OF AE’S AND SAE’S ............................................................................... 38

10.5.1 Post study AE’s and SAE’s ............................................................................ 3910.6 UNBLINDING .............................................................................................................. 39

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10.7 STOPPING RULES ...................................................................................................... 39

11.0 TRIAL MONITORING ................................................................................................. 40

11.1 ADVERSE EVENTS AND EFFICACY ............................................................................... 4011.1.1 Adverse events............................................................................................... 4011.1.2 Efficacy ........................................................................................................... 40

11.2 DATA SAFETY MONITORING COMMITTEE .................................................................... 40

12.0 STATISTICS ............................................................................................................... 41

12.1 NULL HYPOTHESES TO BE TESTED .............................................................................. 4112.2 STATISTICAL ANALYSIS OF EFFICACY PRIMARY OUTCOME ............................................. 4112.3 STATISTICAL ANALYSIS OF SECONDARY END POINTS .................................................... 4112.4 STATISTICAL ANALYSIS OF TOXICITY OUTCOMES .......................................................... 4112.5 STATISTICAL ANALYSIS OF OTHER EFFICACY OUTCOMES .............................................. 4112.6 OTHER ANALYSES ..................................................................................................... 4112.7 POWER AND SAMPLE SIZE .......................................................................................... 4112.8 END POINTS .............................................................................................................. 41

13.0 ETHICS ....................................................................................................................... 42

13.1 BENEFIT ANTICIPATED FROM THE STUDY ..................................................................... 4213.2 THE POSSIBILITY OF PHYSICAL STRESS OR DISCOMFORT .............................................. 4213.3 THE POSSIBILITY OF PSYCHOLOGICAL STRESS OR DISCOMFORT ................................... 4213.4 RESEARCH ON PEOPLE IN DEPENDENT RELATIONSHIPS ................................................ 4313.5 SEPARATION OF RESEARCH AND CLINICAL RESPONSIBILITIES ....................................... 4313.6 METHOD AND NATURE OF RECRUITMENT AND ADVERTISING ......................................... 4313.7 PROTECTION OF PRIVACY AND PRESERVATION OF CONFIDENTIALITY ............................ 4313.8 RESTRICTION OF USE OF DATA ................................................................................... 4313.9 USE OF PERSONAL INFORMATION ............................................................................... 4413.10 ESTIMATED TIME OF RETENTION OF PERSONAL INFORMATION AND PLANNED DISPOSAL .. 44

14.0 STUDY ADMINISTRATION ........................................................................................ 45

14.1 DATA HANDLING AND RECORD KEEPING ...................................................................... 4514.1.1 Direct access to source data: ......................................................................... 4514.1.2 Data collection ................................................................................................ 4514.1.3 Electronic recording ....................................................................................... 4614.1.4 Data entry ....................................................................................................... 4614.1.5 Data querying ................................................................................................. 4614.1.6 Data storage ................................................................................................... 46

14.2 QUALITY CONTROL .................................................................................................... 4714.2.1 Training procedures: ...................................................................................... 4714.2.2 Blood collection .............................................................................................. 4714.2.3 Peer review and site visits .............................................................................. 4714.2.4 Pharmacy training .......................................................................................... 4814.2.5 Monitoring visits.............................................................................................. 48

15.0 REFERENCES ............................................................................................................ 49

16.0 APPENDICES ............................................................................................................. 51

16.1 PROTOCOL AMENDMENTS .......................................................................................... 5116.2 AMENDMENT NUMBER - 1 .......................................................................................... 5116.3 INFORMATION SHEETS AND CONSENT FORMS .............................................................. 5116.4 CRFS (SEE ATTACHED) ............................................. ERROR! BOOKMARK NOT DEFINED.16.5 OTHER RELATED FORMS ............................................................................................ 5216.6 SOP’S RELATED TO THIS STUDY. ................................ ERROR! BOOKMARK NOT DEFINED.16.7 PRODUCT INFORMATION ............................................................................................ 53

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LIST OF ABBREVIATIONS µg microgram

AE Adverse Event

AIN Assistants in Nursing.

AKPS Australia – modified Karnofsky Performance Status

AMH Australian Medicines Handbook

BD Twice daily

BPI Brief Pain Inventory

BT Breakthrough

CADSS Clinician Assessed Dissociative States Scale

CAM Confusion Assessment Method

CIRS Cumulative Illness Rating Scale

CRF Case Report Forms

DRG Diagnosis Related Group

DRS Delirium Rating Scale

DSM III R Diagnostic and Statistical Manual of Mental Disorders. Third edition – revised

DSM IV R Diagnostic and Statistical Manual of Mental Disorders. Fourth edition - revised

ECOG Eastern Co-operative Oncology Group

EORTC-QLQ- C

European organization for Research and Treatment of Cancer- Quality of Life Questionnaire- core

EPS extrapyramidal side effects

ESRS Extrapyramidal Symptom Rating Scale

FACIT-PAL Palliative care quality of life instrument used in this protocol

FDA Food and Drug Administration

HIC Health insurance commission

HREC Human Research Ethics Committee

ICH GCP International Conference on Harmonisation, Good Clinical Practice

ID Identification number

IQCODE Short informant Questionnaire on Cognitive Decline in the Elderly

IVI Intra Venous Injection

kg Kilogram

LANSS Leeds Assessment of Neuropathic Symptoms and Signs

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MA Medicare Australia

MDAS Memorial Delirium Assessment Scale

mg milligram

ml millilitre

N/saline Normal saline

NCI National Cancer Institute

NMDA N-methyl-D-aspartate

NRS Numeric Rating Scale

NSAID Non steroidal anti-inflammatory drug

NuDesc Nursing Delirium Screening Scale

O2 Oxygen

PaCCSC Palliative Care Clinical Studies Collaborative

PBS Pharmaceutical Benefits Scheme

PS Performance status

QALY Quality adjusted life years

QOL Quality of life

QT Interval The relationship between two conduction points on an electrocardiograph (ECG)

RASS Richmond Agitation Sedation Scale

SAE Serious Adverse Event

SC Subcutaneous

SOP Standard Operating Procedure

TGA Therapeutic Goods Administration

VAS Visual Analogue Scale

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• This protocol template contains instructions and sample text in italics. Investigators should carefully consider the suggested text under each section, and then modify, remove or replace as appropriate to their study.

• This instruction page should be removed prior to submission to HREC.

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1.0 BACKGROUND AND RATIONALE

1.1 Review of the literature

1.2 Existing evidence

1.3 Rationale for intervention

1.4 Conclusions and aims

1.5 Rationale and significance

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2.0 FEASIBILITY AND PILOT PHASE [NOTE: This section in italics is for the benefit of the investigator team and can be removed from the protocol prior to submission to HREC]

Introduction There are strong reasons to consider having a pilot/feasibility component for each of the planned PaCCSC studies which are testing a new paradigm (e.g. different patient groups, new treatment regimen, new outcome measures, new centres, etc.) to give greater assurance that recruitment will be feasible, that the protocol and measurements of outcomes will be practicable, and that the planned treatment regimens are likely be adequately tolerated to ensure that those patients randomised into each study have a high chance of completion.

The reasons for conducting a pilot/feasibility study may differ with individual studies. In general, the purposes of such studies will be a combination of [Thabane et al, 2010]:

• Process – Assessment of ‘the steps that need to take place as part of the main study’,

such as recruitment rates, retention rates, completion rates, etc.

• Resources/Logistics – Assessment of ‘time and budget problems that can occur during

the main study’, including the feasibility and time components of each aspect of the

research protocol.

• Management – Assessment of personnel issues and data collection/management at

each participating centre.

• Scientific – Assessment of ‘treatment safety, determination of doses and responses,

and estimation of treatment effect and its variance’.

Requirement The expectation from the PaCCSC Scientific Committee is now that each new Phase III study proposal exploring a new paradigm submitted for consideration by the Committee should provide not only the full protocol document for the particular Phase III study but also an additional protocol document which outlines the purposes and outcome measures of the associated pilot/feasibility phase for the main Phase III study. It is strongly recommended that, for those studies which do have such a planned pilot/feasibility phase, the design of the main Phase III study should be ‘adaptive’ so as to allow modifications to the trial’s design or statistical procedures during its conduct’ [Thabane et al, 2010]. If an investigating team considers that there is a strong argument not to conduct such a pilot/feasibility study for a particular planned Phase III study, the investigators should submit a separate covering document to the Committee justifying why such a pilot/feasibility study will not take place. This latter may be, for example, because the planned study is an extension of a previous study in the same centres and using the same patient groups with similar treatments and outcome measures.

For each study which will include a pilot/feasibility phase, Section 2 of this document should be completed as part of the main study protocol document. The completed document should then be submitted to the PaCCSC Scientific Committee for approval as well as to each participating institutional ethics committee. Once the study has been approved by both the

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Scientific Committee and all relevant institutional ethics committees, the pilot/feasibility phase of the study can commence using the main study protocol.

Reporting Once the pilot/feasibility phase is complete, a concise report should then be submitted to the Scientific Committee concerning the performance of the pilot/feasibility phase against its planned outcome measures. This report will be dealt with expeditiously by the Committee using electronic communication between members. One of a number of decisions could be taken by the Committee on receiving this report [Thabane et al, 2010]:

• Continue without modifications – feasible as is;

• Continue without modifications, but monitor closely – feasible with close monitoring;

• Continue, but modify protocol – feasible with modifications;

• Stop – main study not feasible.

The Committee will also make a decision as to whether the patients who have been included during the pilot/feasibility phase of the study can continue to be included for analysis purposes in the main Phase III study. It is highly desirable wherever possible that this should be the case.

Transitioning from pilot to phase III If the Committee agrees that the main Phase III study has been shown to be feasible and has approved any modifications to the protocol as a result of the pilot/feasibility phase, the study can continue. The report of the pilot/feasibility phase and the report from the Scientific Committee following consideration of the pilot/feasibility study’s results should be sent to all institutional ethics committees which have given approval for the study to proceed. It is also strongly recommended that a paper be prepared for publication of the results of the pilot/feasibility phase of the study, notwithstanding the Committee’s decision about the study’s continuation or otherwise. Such a report can be prepared and submitted while the main study is still in progress.

• Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, Robson R, Thabane M,

Giangregorio L, Goldsmith CH. A tutorial on pilot studies: the what, why and how. BMC

Medical Research Methodology 2010; 10: 1-10.

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2.1 Aim

2.1.1 Process:

Assessment of ‘the steps that need to take place as part of the main study’, such as

recruitment rates, retention rates, completion rates, etc.

2.1.2 Resources/Logistics:

Assessment of ‘time and budget problems that can occur during the main study’, including

the feasibility and time components of each aspect of the research protocol.

2.1.3 Management:

Assessment of personnel issues and data collection/management at each participating

centre.

2.1.4 Scientific:

Assessment of ‘treatment safety, determination of doses and responses, and estimation of

treatment effect and its variance’.

2.2 Review of feasibility or pilot phase The timeframe, or anticipated recruitment milestones should be described in full in order to set parameters for the pilot phase of the study. This will vary according to the type of study and the intention of the pilot phase, but might include;

Absolute participant numbers (X recruited) Numbers completing (X completed) How many can be recruited within a time frame (recruit for X months across X sites)

2.3 Reporting Once the pilot/feasibility phase is complete, a concise report should then be submitted to the Scientific Committee concerning the performance of the pilot/feasibility phase against its planned outcome measures. This report will be dealt with expeditiously by the Committee using electronic communication between members. One of a number of decisions could be taken by the Committee on receiving this report [Thabane et al, 2010]:

• Continue without modifications – feasible as is;

• Continue without modifications, but monitor closely – feasible with close monitoring;

• Continue, but modify protocol – feasible with modifications;

• Stop – main study not feasible.

The Committee will also make a decision as to whether the patients who have been included during the pilot/feasibility phase of the study can continue to be included for analysis purposes in the main Phase III study. It is highly desirable wherever possible that this should be the case.

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If the Committee agrees that the main Phase III study has been shown to be feasible and has approved any modifications to the protocol as a result of the pilot/feasibility phase, the study can continue. The report of the pilot/feasibility phase and the report from the Scientific Committee following consideration of the pilot/feasibility study’s results should be sent to all institutional ethics committees which have given approval for the study to proceed. It is also strongly recommended that a paper be prepared for publication of the results of the pilot/feasibility phase of the study, notwithstanding the Committee’s decision about the study’s continuation or otherwise. Such a report can be prepared and submitted while the main study is still in progress.

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3.0 STUDY OBJECTIVES

3.1 Aim

3.2 Objectives

3.2.1 Primary objective

3.2.2 Secondary objectives

A: Efficacy

B: Toxicity

C: Pathophysiology

D: Health outcomes and health services utilisation

3.3 Null Hypothesis

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4.0 STUDY POPULATION

4.1 Target population

4.2 Inclusion criteria

• age 18 years or more • English speaking and able to read study questionnaires (5th grade level) • proxy written informed consent • cancer or non-cancer life limiting illness • participant is capable of completing assessments and complying with the study

procedures • participant is able to give fully informed written consent • Mini Mental State of >23 at consent

4.3 Exclusion criteria

• previous adverse reaction to any of the study medications • clinician predicted survival less than seven days • pregnant or breastfeeding • chronic alcoholism or drug abuse • Australian-modified Karnofsky performance score less than 30 at the beginning of the

study • participants who have participated in a clinical study of a new chemical entity within the

month prior to study entry

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5.0 INVESTIGATIONAL PLAN

5.1 Study design

5.2 Study diagram

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6.0 INTERVENTIONS [NOTE: While this section focusses on medication, this section should contain a full description of the intervention (if not medication) and how many arm, cross over etc., will be designed]

6.1 Study medication [Description of treatment arms] 1. 2. 3. 4. Rescue

Product information has been attached in the appendices.

6.2 Dosing/intervention schedule All study drug will be prescribed as a daily dose to be taken in the X of each day of the intervention period. There will be X changes or modifications during the treatment period, and X rescue medications will be administered. Describe any contingencies if time of dosing needs to be changed.

6.3 Dose/intervention schedule diagram

6.4 Dose/intervention schedule timeline

6.5 Method of assigning participants to treatment groups At each centre, people referred to the study will be sequentially allocated an ID number. This ID number will be used for all subsequent study documentation for that participant. The procedures outlined in the Allocation of ID Number Standard Operating Procedure (5.5.5 Allocation of ID number) are to be followed.

Randomisation schedules will be developed for each site using random number tables, generated at an independent central registry. Treatment for each participant will be allocated according to a block randomisation schedule in a 1:1 ratio. Block randomisation will ensure even allocation to each code. The central registry will supply site randomisation schedules to each site pharmacy. There will be no stratification at the randomisation level for this study.

On notification of a participant, the pharmacist at each site contact the Central Randomisation Service (or other methodology appropriate to the study) and prepare the active or inactive medicine delivered in a labeled syringe. The participant ID, allocation code, dates of request, preparation, and dispensing will be recorded in a log maintained by the pharmacist and supplied to the central registry on each randomisation.

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At all times, from eligibility screening to completion of the study, all study staff are unaware of the treatment allocation. Allocation is concealed from the investigator at the time of the participant inclusion in the trial; the allocation is determined by contacting the site pharmacy.

6.6 Blinding All medicine bottles will be prepared by the site clinical trial pharmacist according to the randomisation schedule.

Each [bottle, pack, syringe, ampoule] will be numbered according to the pre-determined allocation code and labeled as;

Study [code][ study acronym]. Drug 1 (dose), Drug 2 (dose), placebo. Take X [tablets, capsules, infuse…] every morning until finished.

Treatment allocation will not be disclosed to study staff, treating clinicians or investigators. The code will only be broken in cases of extreme emergency. Such situations only include where knowledge of the code will have consequences for clinical decision making in consultation with the Lead Chief Investigator.

6.7 Method of administration [or description of intervention and how it will be implemented and accounted]

The pharmacists at the study sites will dispense the study medication. All medications must be dispensed in accordance with the delivery system used within the study site.

The intervention will be delivered as XXXX. [Details of dosage: route of administration, time]

6.8 Drug accountability All active medicine must be stored undiluted in a locked medicine cabinet at or below X°C within the site pharmacy. The pharmacy will maintain accountability records, in addition to the study allocation records. On dispensing to the inpatient unit, the medicine will be stored within a locked medicine cabinet appropriate to state regulations. The medicine will be checked and recorded by an appropriately qualified nurse on administration to the patient.

6.9 Drug supply The medicine will be supplied in the following manner; 1. medicine 1. 2. medicine 2. 3. medicine 3.

6.10 Drug destruction All unused study drug will be destroyed on completion of the study. Unused and empty [bottles, pack, syringes, ampoules] in the inpatient unit will be delivered back to the pharmacy, using the established practice within the hospital.

All unused [bottles, pack, syringes, ampoules] returned to pharmacy will be destroyed in a manner consistent with the applicable regulations governing destruction in each state. The pharmacy Standard Operating Procedures and state regulations are to be referred to and adhered to at all times.

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6.11 Concurrent treatments Trial patients are to continue their current medicine regimen. Any changes in concomitant medications must be documented in the Case Report Form.

6.12 Rescue medications Rescue medications are available for administration throughout the X hour intervention period. The medicine can be initiated at the time of first treatment if the indications below are met. [Details of rescue medicines, dosage, circumstances for administration]

6.12.1 Symptom cluster 1

[Symptom requiring rescue, description of symptom, how to recognise. Action and symptom management (immediate cessation of study medicine, administration of X medicine)]

6.12.2 Symptom cluster 2

Example Symptom cluster: Dyspnoea, laryngeal stridor, patient may grab throat or chest, respiratory distress. Dystonic reactions may be present in other parts of the body e.g head, neck, pharynx. Differential diagnosis is acute anaphylaxis or airway obstruction from other causes.

Immediate cessation of study drugs/intervention. Urgent medical attention is required and attention to airway, breathing and circulation. IVI benzotropine 1 – 2 mg.

6.13 Dose/intervention modification The study medicine dose can be increased or decreased according to participant response [give details]

6.14 Cessation of study drug/intervention

• Participant request • Unacceptable side effects from study medications (defined by National Cancer Institute

Common Criteria for Adverse Events; CTCAE version 4.0). • Participants who in the opinion of the investigator are not well enough to continue the

study (Specific reasons for withdrawal need to be documented in the Case Report Form)

6.14.1 Treatment failure

• Adverse events related to the study medicine unacceptable to participant/carer or clinician in charge

• Treatment deemed ineffective by treating clinician, who wishes to use alternative therapy.

• Other situations that may require cessation of study medicine o X administration of rescue medicines o Extended non-response

6.14.2 Cessation for reasons other than treatment failure

• Participants who in the opinion of the investigator are not well enough to continue the study medicine

• It is inappropriate to continue the study medicine for whatever reason

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• The participant or proxy withdraws their consent, with or without consent to use already collected data.

6.15 Post study treatments All participants will be followed by their clinician for continuing care, irrespective of the point at which they exit the study.

Treatment continuation: participants who continue to respond after X weeks should be treated at the clinicians’ discretion.

In all study participants, regardless of above choices, secondary outcomes and collection of data for economic evaluation will occur until the end of X after randomisation, unless consent is withdrawn.

6.16 Extension phase criteria During the extension phase frequency of [symptom], adverse events, quality of life, medication usage and compliance will be measured up to death or 28 days after ceasing study medication (whichever is the shorter period). These data will be collected via a weekly telephone call to the participant if they have been discharged home.

6.17 Economic evaluation Economic evaluation will be undertaken based on data collected from randomisation to 28 days post treatment or death (whichever is the shorter period) for each patient including: • number of inpatient admissions by DRG and days spent in hospital by level of

dependency (low, medium, high); • home care palliative care team visit; • general practitioner visits; • concomitant medications; • days of survival without vomiting; • caregiver impact; and • medication compliance

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7.0 OUTCOMES AND MEASURES

7.1 Primary outcome and measure

7.2 Secondary outcomes

7.2.1 Efficacy

7.2.2 Toxicity

7.2.3 Health service utilisation and long term outcomes

• Number of inpatient admissions and days spent in hospital by level of dependency (low, medium, high) level;

• Home care palliative care team visit; • General practitioner visits; • Concomitant medications; • Caregiver impact; • Patient preferences for where prefer to be receiving care given current health state; • Medication compliance; • Number of days in high dependency or intensive care beds (costs will be derived from

hospital data)

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8.0 STUDY ASSESSMENTS

8.1 Laboratory measures

8.1.1 Measure 1

8.1.2 Measure 2

8.2 Medical and physical measurements The study assessments are tabulated in 8.1 Study Procedures. The study period will be for 28 days post treatment or until death whichever is the shorter time.

8.3 Demographics 1. Age 2. Gender 3. Availability of primary caregiver:

a. lives with carer; b. lives alone but carer available; c. lives with non-carer; d. lives alone, no carer

4. Postcode 5. Language spoken at home 6. Aboriginal or Torres Strait Islander status

8.4 Main clinical diagnosis The following clinical data will be collected: 1. Main life limiting illness: 2. For cancer life limiting illness:

i. Tumour stage ii. Sites of metastases (especially if known cerebral metastases).

3. Reason for admission to palliative care unit: symptom control/respite/terminal care. 4. Other central nervous system pathology.

8.5 Performance status This section should contain a full description of each and every measure to be collected, any relevant references and justification for inclusion, and when and how the measure will be collected.

8.5.1 Australia - modified Karnofsky Performance Status

The Australia - modified Karnofsky Performance Status is a validated variant of the Karnofsky Performance Status.4 The Australian version has criteria that can be applied in either the inpatient or outpatient setting, which is more appropriate to the population seen in palliative care. This objective measure has high inter-rater reliability and is sensitive to changes in

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function over time. A score of 0 to 100 (in increments of 10) is assigned to participants based on their ability to undertake a range of daily tasks. The score gives an indication of the participant condition (in terms of physical ability) and can assist in prognostication. The tool will be used in this study to assist investigators to determine participant condition and possible prognosis, together with any measurable improvements in functional status as a result of the intervention.

8.6 Pain

8.6.1 Global Impression of Change

This participant rated 7 point scale (1-7) provides information about the participant perception of their change in pain, specifically their improvement since the commencement of the study. This will allow the investigators to compare the pain rating using the NRS with participant perception of improvement. The results of this scale over the study period will assist to determine the clinical significance of any improvement seen.5

8.6.2 Brief Pain Inventory

The Brief Pain Inventory has been used as it is a brief and easy tool for the assessment of pain within both the clinical and research settings. It has been validated in both the chronic pain and cancer settings. The scale of 0 to 10 is simple for participants to use, and reflects common clinical assessment of pain.6 This study will use 5 measures from this tool, those of the average, best, worst and current pain, and pain relief scores from the preceding 24 hours Visual Analogue Scales and Numeric Rating Scales (NRS) have been commonly used in clinical pain management, and both scales are well validated. This study has chosen to use the Numeric Rating Scale (as part of the Brief Pain Inventory) based on the participant population. The Numeric Rating Scales is more easily understood, based on previous experience, can be more accurately measured, and is used in widespread clinical practice, so participants are very familiar in rating their pain using this method. Only those measures from the inventory appropriate to the inpatient setting will be used.

8.7 Cognition

8.7.1 Mini mental status examination

The Mini Mental Status Examination is used in this study to assist the screening eligibility for the study. This tool is in widespread use to determine higher cognitive function.7

8.8 Quality of Life

8.8.1 EORTC QLQ 30/15

Quality of life of participants will be measured using the EORTC QLQ-C30.8 There is currently no single agreed measure of health related quality of life in palliative care populations. However, the EORTC QLQ-C30 is the most widely used cancer-specific quality of life measure. It has been found valid for use in a wide variety of cancer populations, including participants undergoing palliative care.9-11 This study will use a palliative care subset of the 15 questions (EORTC QLQ C15) to minimise participant burden.

8.8.2 Caregiver quality of life

The quality of life of caregivers for people undergoing palliative care has been identified as a central aim in the National Palliative Care Strategy.12 Quality of life for those caregivers who

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provide consent will be measured using the Caregiver Quality of Life Index – Cancer (CQOLC).13 A recent review14 rated the CQOLC as the questionnaire with the best established psychometric properties for measuring health related quality of life in caregivers of people with cancer. The CQOLC has been validated in caregivers of both of in- and out-patients and hospice patients with a range of cancer types.15 Informed consent will be obtained from caregivers in order to measure the caregiver QOL. Participants who do not have a caregiver, or where the caregiver declines to participate are still eligible to participate in the study.

8.9 Safety assessment Safety assessments are made at all participant contacts as described earlier. All safety assessments are made before efficacy assessments. If burden, side effects or safety issues are identified, continuation in the study will be stopped.

In the event of an adverse event clinicians will manage the event according to best medical practice.

Further, the research nurse who visits the participants and their carers will also ask about any other unexpected adverse outcomes. The study investigators will oversee this research nurse. All serious adverse events will be reported to the Research and Ethics Committee within 24 hours (see section 9.0 Adverse Events). Other adverse events will be described in the Annual Report to the Committee.

Serious adverse events will be followed until documentation of resolution or the successful initiation of relevant management strategies.

8.10 Efficacy assessments Assessment of participants at X time points for [the main outcome measure]. In addition, functional status, other symptom control measures, use of rescue medicines … will be collected for secondary assessments.

Response and non-response definition.

8.11 Assessments for economic analysis This needs to be a full description of the economic analysis plan.

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9.0 STUDY PROCEDURES

9.1 Table of study measures Eligibility Baseline Day x Exit

assessmentResolution Discharge Follow up

InvestigationsLiver function * *Electrolytes * *Full blood count

* *

Serum markers

* *

MeasuresMedical file reviewDemographics *Diagnosis *AKPS *Barthel index * * * * *Con meds * * * * *Rescue medications

*

Anticholinergic scale

* * * *

Admission data

*

Patient measuresVision *Hearing *AKPS * * * * *MMSE * * *Pulse oximetry * * *Patient rated distress

* Week 4

EORTC QLQ – C30

*

Medical assessment

* * *

Clinician assessedToxicity * * * *Cumulative illness rating scale

* * * * *

Charlson * * * * *

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comorbidity indexSedation * *ESRS * * *MDAS * * * *NuDESC * * * shiftIQCODE *Nursing rated distress

* * *

Caregiver distress

* * * Week 4

9.2 Referrals All people with [symptom] should be referred to the study. The study nurse will ask the consultant in charge for permission to approach potentially eligible participants. This referral will be recorded within both the Case Report Form and the participant’s clinical file.

9.3 Consent process Obtaining consent for this study will be a process of information exchange between the study staff, the potential participant and any other person the potential participant believes should be included in the discussion.3 The participant information sheet will be used as a basis for the discussion, which will cover all procedures, benefits, burdens and side effects expected of possible during the study. The participant will be given opportunity (in time and physical capacity) to consider the study and formulate questions. Any questions will be addressed and answered fully. An actual time period is not specified as this will be determined in part by the participant condition and pain at the time. The study nurses will be trained to determine suitable time for discussion of the study against the need to participants to be provided with pain relief.

Prior to study commencement, during the site initiation visit, the study nurse, site coordinator and the investigator will be trained in consent procedures for this study, with the opportunity to role play scenarios and develop a consent script to ensure all information is fully covered. The consent form is completed by the study nurse in accordance with the requirements of the institutional ethics committee. The form is signed and dated by the participant in front of the witness. The witness can be anyone who observes the participant signing the consent form, and is able to say that the participant was signing of their own free will, but cannot be the researcher.

The completed consent form is copied (at the time of signing or on return to the study office) • one copy is to be given to the patient • one copy is to be inserted into the medical file (with research sticker on file if required) • one copy is to be filed in study file.

9.3.1 Carer consent

Any participant who has consented to join the study and who has been shown to be eligible will be asked to nominate their primary carer and for permission to approach them regarding the study. The carer will then be approached and asked if they would be prepared to

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complete the carer QOL assessments as per the study schedule. If in agreement, they will be given the carer information sheet and asked to give informed consent for their participation. A primary carer is defined as a spouse/relative or partner of the patient and not someone who has been employed to care for the person.

Consent by the carer, or otherwise, will not have any effect on the continued participation of the eligible participant.

9.4 Screening for eligibility A Participant Master Index (an excel file to track participant names, ID numbers, and progress through the study, developed and maintained at each site) will be kept of all potentially eligible participants including the reasons for non-entry. Participants suitable for entry who are approached about the study and who have given consent for the study nurse to obtain information about them, will undergo a review of eligibility criteria and complete the eligibility screening as per the Eligibility Case Report Form

• Some items will be obtained while in discussion with the potential participant • Specific items will require intervention or assessments that are specific for the purposes

of research and can only be completed after specific consent to participate in the study has been obtained o those items are to be left until it appears that the person is likely to be eligible o obtain consent prior to conducting the interventional assessments

• Other items will be completed by referring to the person’s clinical file or medical record • The plan of management will be checked with treating team (i.e. ensure no planned or

likely change in management during the study period)

The completed Case Report Form -A will be discussed with the Site Investigator. The CRF A will be entered into the online data base to enable the Project Officer at the coordinating centre to monitor eligibility of those enrolled in the study and cross reference with the randomisation process. This data entry will occur within 24 hours of CRF completion. If eligibility is confirmed proceed to baseline investigations and randomisation. The study will commence the following day (start Day 1).

9.5 Re-screening In some cases it is possible that potential participants will need to be re-screened, for example: • If a person consents to participate, meets the eligibility criteria but there is a delay in

starting due to a change in situation (family issues, individual request for attending private matter, etc.);

• If the person previously failed eligibility due to an acute event that has now resolved; or • Medications have now stabilised In these situations, if randomisation has not occurred; • A new Eligibility Case Report Form is used • A new ID number is assigned to the participant • The participant is flagged as having been re-screened on both the Case Report Form

-A and the site master list • The Eligibility Case Report Form is completed as if being fully screened, data is not

copied form one form to the next, but completed using the current clinical situation as documented within the patient clinical notes.

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It is not appropriate to re-screen a person if they have previously failed to meet the eligibility criteria and there have been no further changes or treatments that would now indicate that the patient may be suitable.

More detail is provided within the Standard Operating Procedure for re-screening (6.5.2, Re-Screening).

9.6 Procedure to request randomisation Pharmacy will be contacted whenever a person is under-going the screening process to warn them of a potential trial candidate. This will be followed up by a confirmatory call as soon as the person’s eligibility has been confirmed. The randomisation request will take the form of the prescription of the study drugs.

The site clinical trials pharmacist will prepare the study drugs for the participant according to the allocation determined in the supplied schedule, and label the syringes providing the details as described above.

The allocation will be recorded on the schedule along with the date of allocation, the signature of the pharmacist preparing the syringe and the patient ID number.

Participant randomisation will be registered with the coordinating site. PaCCSC has a Standard Operating Procedure for Randomisation (4.7.1, Randomisation), this procedure is to be followed. In summary, the procedure outlines that on randomisation of a participant, the site pharmacy is to fax a notification to the coordinating site. This notice will be monitored alongside the participant eligibility as entered onto the on-line data base from Eligibility CRF.

9.7 Prescription of study drugs All prescriptions for the use of investigational products for clinical trials must be: • Completed by a person authorised to do so

o the Principal site investigator o sub/co investigators o those medically authorised to prescribe the specific product under investigation

• Completed on a hospital prescription form and detail full description of the o participant details o study protocol number o medicine (this will be [study drug/intervention]/placebo) o dose (this will specify the dose level/s) o frequency o route

In this study the prescription will therefore read – [detail of template prescription words].

9.8 Treatment commencement All baseline assessments will be undertaken as soon as eligibility is confirmed, and treatment initiated as soon as practicable.

All baseline assessments will be undertaken immediately before the first study dose on Day 1, treatment will be then initiated on the first X dosing. Local hospital procedures are to be followed regarding checking of study medicine.

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The regular dosing will be commenced in the morning of day one if prior to midday, at which time the morning dose will be given, or the evening of day 1 if after midday at which time the evening dose will be given. Rescue medicine can be used prior to the first study dose if immediate control of symptoms required (as per criteria on rescue protocol).

9.9 Daily assessments Participants will be visited daily by the study nurse in the inpatient unit, at the same time in the morning of each day. Prior to reviewing the participant, the study nurse will check with the unit nursing staff regarding the participant’s condition, and any recent events.

During the visit, the study nurse will take the measures and assessments as outlined in the table of study measures and record the visit in the Case Report Form for that time point. This visit will also be recorded within the participant clinical file, along with any instructions or changes regarding the infusion.

9.10 Exit assessments Participants will be visited X hours following the last dose of the study intervention (last day of data collection, or when treatment is ceased, if earlier cessation occurs) for collection of exit data. During the visit, the study nurse will take the measures and assessments as outlined in 8.1 Table of study measures and record the visit in the CRF. This visit will also be recorded within the participant clinical file, along with any instructions or changes regarding ongoing management.

9.11 Withdrawal assessments If participants are to be withdrawn, a ‘Withdrawal Case Report Form’ will be completed by the study nurse on instruction from the investigator. The assessments and reason for withdrawal will be recorded. Withdrawal will be initiated if the participant meets any of the withdrawal criteria as described in section 5.13 Cessation of study medicine. All associated documents will be completed (Serious Adverse Event report, adverse event assessment score etc.).

9.12 Follow-up phase assessments Participants will enter a follow-up phase irrespective of their place of care until death or withdrawal of consent. Follow-up data will be collected by the study nurse weekly for 4 weeks by telephone. A medication list will be updated at each contact to record actual prescribed and taken medications since the preceding visit.

9.13 Extension phase for economic evaluation Participants will be telephoned by the study nurse on a weekly basis if discharged from inpatient care, or visited in the inpatient unit as appropriate. The contact data will be recorded within the follow-up Case Report Form, and will provide data on compliance, and long term clinical and economic outcomes.

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10.0 ADVERSE EVENTS

10.1 Reporting of adverse events All adverse events will be reported via an online reporting system to enable study wide reporting. The Palliative Care Clinical Studies Collaborative (PaCCSC) has a Standard Operating Procedure for Adverse Event reporting (5.17, Adverse Event Reporting) that will operate at all study sites. In addition there will be specific events and reporting mechanisms required due to the nature of the study medicine. This is described below.

10.2 Criteria for assessing severity Severity of adverse events will be assessed according to Good Clinical Practice guidelines and National Institutes of Health Common Terminology Criteria for Adverse Events.Error!

Reference source not found.

10.2.1 Adverse events

Adverse events are defined as any untoward or unexpected occurrence in a patient or clinical investigation participant where the occurrence does not necessarily have a causal relationship with the study intervention.

There are circumstances where adverse events will not be reported. Examples are; • An expected side effect from a study intervention, such as constipation unless the side

effect required additional treatment or assessment • Signs or symptoms associated with the disease or disorder under study, unless they are

more severe than expected. • Social admission to hospital

10.2.2 Serious adverse events

Serious Adverse Events are any untoward medical occurrence that meets one or more of the following criteria/outcomes; • death • life-threatening (i.e. at immediate risk of death) • in-patient hospitalisation or prolongation of existing hospitalisation • persistent or significant disability/incapacity • congenital anomaly or birth defect • other medically relevant condition judged as serious

“Life threatening” means that the participant was at immediate risk of death from the event as it occurred. It does not include an event that, had it occurred in a more serious form, might have caused death.

“Requires inpatient hospitalisation” is defined as hospital admission for treatment of the adverse event. Hospital admission for scheduled elective surgery would not be a serious adverse event.

“Other medically relevant condition judged as serious” is where medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or

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result in death or hospitalisation but may jeopardise the participant or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development of drug dependency or drug abuse. A diagnosis of a new cancer during the course of the treatment should be considered as medically important.

Progression of a participant’s underlying condition leading to one of the above should always be reported as a serious (but expected) adverse event, which is unrelated to protocol treatment, or caused by failure of the anticipated therapeutic effect of the study drugs/intervention.

The expected study population have an underlying disease that is expected to significantly shorten life expectancy, they are already termed palliative and are expected to die within a short period of time.

The conditions recognised as being excluded from SAE reporting are as follows: • Where participants are admitted as a planned admission due to respite, family or social

issues, or for pre-planned treatment • Where participants are admitted (or admission is prolonged) due to a documented

expected deterioration in their condition due to the underlying disease process, or where the admission is prolonged for this reason

• Where participants die due to a well-documented decline in their condition due to the underlying disease process

In all other cases, serious adverse events will be reported according to the requirements of the local Hospital Ethics Committee and also reported within 24 hours to the Data Safety Monitoring Committee. A subset of all deaths that occur during the study including during follow-up will be randomly selected for evaluation by the Data Safety Monitoring Committee.

10.3 Criteria for assessing causality The site investigator will assess each event for relatedness or causality of the intervention and the event. A guide to grading the degree of certainty about such a relationship is available at http://apps.who.int/medicinedocs/en/d/Jh2934e/15.html. A summary of the grading is as follows:

Unrelated Where the adverse event is clearly not related Unlikely Where the adverse event does not have a clear relationship to the

intervention Possible Where the adverse event follows a known pattern of response Probable Where the adverse event reduces or ceases with withdrawal of the

intervention Definite Where the adverse event ceased with withdrawal of the intervention

and recurs with re-exposure.

10.3.1 Time period for assessing AEs and SAEs

At each visit, the participants are encouraged to mention any problems since the last visit. In addition, the following standard questions should be asked;

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1. Have you had any medical problems since the last visit or study assessment? 2. Have you started any new medications, other than given to you in this study, since the

last visit or assessment?

For all randomised participants all AEs, irrespective of causality, will be assessed and recorded as per the standard operating procedures. The time period includes the time from randomisation, the 5 day treatment period and the 4 week extension phase (by telephone).

For patients who meet the eligibility criteria and then do not proceed to randomisation, any AEs detected during that window of time, should be reported. If an AE is the reason that a person does not proceed to randomisation, this should be recorded within the CRF, adverse event report and in the clinical record, irrespective of causality or seriousness.

10.3.2 National Cancer Institute, Common Terminology Criteria for Adverse Events.V4.0

These criteria have been used to determine adverse events likely to occur during the study period and will be used to determine adverse event reporting and study progress. Criteria specific to the expected events know to be associated with [intervention] have been listed. This is administered by study staff.17

Symptoms will be identified during each visit using criteria established by the National Cancer Institute, and will be graded accordingly. Specifically, for this study, the symptoms of interest will be;

• List the symptoms of interest • List the symptoms that will be of specific risk and may constitute SAE to be reported (for

example; falls)

A grade of 3 (that has not responded to symptomatic treatment instituted by the treating physician according to local protocols) or 4 will activate cessation of study intervention and an adverse event report.

All adverse events will be collated by the project officer, and reported to the executive committee on a monthly basis. Adverse event rates will form part of the Key Performance Indicators for the study and will be reported on a regular basis to the Trial Steering Committee and the ethical review boards of the participating sites.

10.4 Adverse Event Assessment Diagram

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Serious Adverse Events will be reported by the study site, to the local Hospital Research Ethics Committee and to the study coordinating site for study wide reporting. This will occur within 24 hours of first knowledge of the event unless death or life threatening which must be immediate. In addition, events deemed to be both serious and unexpected, and related to the study intervention, will be reported by the coordinating site to the Therapeutic Goods Administration using a ‘Blue Form’.

In addition, PaCCSC has a Standard Operating Procedure that describes the reporting of adverse events in detail (5.17, Adverse Event Reporting). The on-line reporting is to be used to enable reporting between sites, local forms of reporting are also to be used for reporting to local sites.

10.5 Follow-up of AEs and SAEs After the initial report, investigators are required to follow-up each adverse event and provide further information both to the coordinating centre and the local HREC. All events reported as

Adverse event score

of 3 or more

No Score of 3

Score of ≥= 4

Continue study

Responds to appropriate definitive or symptomatic

treatment

Yes No

Adverse event report

Serious

Yes No Each study site notified

Serious and unexpected adverse drug reaction –

report to TGA

Cease intervention

Treat as clinically appropriate

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ongoing are to be reviewed at subsequent visits or appointments in order to report progress and resolution.

All events are to be followed until:

• resolution;

• the condition of the participant stabilises;

• the event can be explained;

• the participant is lost to follow-up;

• death.

Reports are to contain details of follow-up investigations, result reports or reports from other consultations, and are to be updated in a report to the coordinating centre and the local HREC.

10.5.1 Post study AEs and SAEs

A post study event is defined as any event that occurs outside of the time period described in section 9.3 of the protocol. Investigators are required to report any events they become aware of if;

• the event occurs at any time after study participation has ceased, and

• the event is assessed as being reasonably related to the study intervention.

Investigators are not obliged to actively seek events that occur after the study period defined in 9.3.

10.6 Unblinding In cases of medical need, where urgent medical decisions will be influenced by knowledge of the treatment assignment, the Lead Investigator will have access to the sealed unblinding envelopes and must be contacted in the first place. Clinical staff will be able to discuss the clinical situation with the Lead Investigator to determine the urgency and need for unblinding, and will be informed by the Lead Investigator of the assignment based on these discussions.

In the case of not being able to contact the Lead Study Investigator, the Finance Administrator for PaCCSC should be contacted (Ms Christine Wiltshire, listed after the study investigators).

PaCCSC has a Standard Operating Procedure for unblinding (4.7.2, Unblinding), and is to be referred to in the occurrence of unblinding. The PaCCSC coordinating centre will monitor real time unblinding frequency by collecting CRF withdrawal data and unblinding reporting from the Lead Study Investigator.

10.7 Stopping rules The study will be stopped if new literature indicates findings that can be applied to this question in terms of benefit or side effects, or if reporting of adverse events indicate that review of the study protocol is required, for either or both of the study drugs, or rescue medicine.

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11.0 TRIAL MONITORING

11.1 Adverse events and efficacy Adverse events and efficacy for the entire study will be reviewed via a number of mechanisms.

11.1.1 Adverse events

In line with the PaCCSC Standard Operating Procedure for Adverse Events (5.17 Adverse Event Reporting), reports of serious adverse events will be sent to the Trial Management Committee, all participating site Hospital Ethics Review Committees (see Table below) and the Data Safety Monitoring Committee within 24 hours of knowledge of the event, while adverse events will be reported as summary reports as stipulated in the table below.

10.1.1.1 The Trial Management Committee Each meeting of the Trial Management Committee will receive from the coordinating centre a summary report of the adverse events reported by the investigators. Each summary report will be generated from the on-line entry of adverse event reports by PaCCSC sites. This summary report will be reviewed for reporting compliance, trends in events, and outstanding events that require specific attention. All Trial Management Committee discussions will be minuted, with actions detailed, and reviewed at the subsequent meeting. The chairperson’s report to the Scientific Committee will contain a summary of the discussions of the adverse event report and the agreed outcomes. The Trial Management Committee will not have access to unblinded reports of adverse events.

10.1.1.2 Hospital Ethics Review Committees Adverse events and serious adverse events are to be reported to site HRECs and where appropriate the DSMC in the format and timeframe stipulated by each individual committee.

11.1.2 Efficacy

This study has been adequately powered using available data to ensure a primary efficacy end point that will address the null hypothesis. Interim unblinded analysis is not planned for this study given the impact that this will have on the sample size calculation. An unblinded analysis is likely to increase the need for recruitment and potentially delay the availability of results without addressing the secondary outcomes particularly if the study were to be prematurely closed.

11.2 Data Safety Monitoring Committee/Medical Monitor This section should contain a description of the safety oversight proposed for the study. It may be a DSMC or medical monitor, it needs to be described here with reference to any SOPs that may apply. Refer to SOP 5.18 Monitoring for implementation

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12.0 STATISTICS

12.1 Null hypotheses to be tested

12.2 Statistical analysis of efficacy primary outcome

12.3 Statistical analysis of secondary end points

12.4 Statistical analysis of toxicity outcomes

12.5 Statistical analysis of other efficacy outcomes

12.6 Other analyses

12.7 Power and sample size

12.8 End points

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13.0 ETHICS

13.1 Benefit anticipated from the study At present, there is no medicine specifically approved for the treatment of [symptom], despite this symptom being relatively common in the palliative care setting, and the cause of considerable distress to patients, care givers and clinical staff.

This study therefore proposes to validate the use of a treatment that could provide significant improvement in symptom control where current treatments are not efficacious. The results of this study will provide evidence for the use of [intervention] in this population, and if positive, may provide information to enable this medication to be submitted for approval by the Therapeutic Goods Administration and for listing on the Pharmaceutical Benefits Scheme for use in the community. If negative, given this is an adequately powered study that will help to inform clinical practice.

13.2 The possibility of physical stress or discomfort Each of the study measures have been carefully selected to ensure they provide the best possible data with the least impact on the participant, and have been validated. As much as possible, the study measures are non-invasive in order to minimise physical stress.

Participants will be asked to provide a blood sample for baseline physiological measures. The taking of blood is uncomfortable, but short term. This is the only invasive procedure during the study period.

The study protocol is carefully planned to ensure that each participant’s symptoms can be responded to by either increasing the study medication, and/or providing rescue medication that is currently used in clinical practice.

Side effects will be carefully monitored to ensure any anticipated discomfort is detected and treated in a timely manner.

13.3 The possibility of psychological stress or discomfort Some participants may experience stress associated with completing some of the study measures. This is a vulnerable population, where sensitive issues about ability to continue to function, quality of life and other questions may raise broader issues of psychological distress.

Emotional distress caused by any of the questions in the quality of life measures will be dealt with by members of the palliative care team who would be involved either directly or in consultation with the care of the people under those circumstances. Although there may be acute distress, the weight of evidence is that such ‘prompt’ questions are in fact an avenue to open up discussions which are well regarded by people despite their initial potential distress on occasion.

There will be no deception of participants at any stage of the project. Each participant interaction will be undertaken by carefully selected and trained study staff. This training will initially be undertaken in conjunction with investigators and senior research personnel, who have been trained in Good Clinical Practice, to ensure that staff are able to detect and

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monitor participant distress. Ongoing site monitoring will provide ongoing training opportunities.

13.4 Research on people in dependent relationships The nature of doctor-participant relationships dictates that participants may feel that they are in the dependent position. The investigators and their designees will work to minimise any concern of inappropriate influence—the presentation of the study will be as unbiased as possible, the information sheet and consent forms will be clear, and participants will be able to withdraw from the study at any time. A person not directly involved in the clinical care of the participant will obtain consent. Each site will employ a recruitment nurse who will approach participants for permission to present the study. Each recruitment nurse will be trained in presenting the study in such a way that clinical care is separated.

13.5 Separation of research and clinical responsibilities There are many distressing symptoms faced by participants with a life limiting illness and there is very little research to support many of the interventions that palliative medicine doctors provide daily around the world. Although research in this area poses its own unique dilemmas, the ethics of not conducting research into the best management of the dying participants is untenable. Importantly, participants will be cared for as individuals with specific needs; the needs of research will come second. Research staff, (medical or nursing), will clearly identify themselves and the purpose of their visit at their contact with the participant as being part of the research process. Training at the site initiation visit will provide an opportunity for study staff to determine appropriate ways of dealing with clinical situations that might arise during their research visits.

13.6 Method and nature of recruitment and advertising Participants will be recruited on admission to the palliative care service and during initial screening in the participating clinics at each site. Advertising brochures will not be provided, only the information sheet and a verbal explanation. Any participant who is approached to take part in this study has the right of refusal. Refusal to take part in this study will not adversely affect the provision or quality of care provided to any participant in any way.

13.7 Protection of privacy and preservation of confidentiality The participants will be allocated a unique ID number. The master list linking identifying participant information and ID number will be maintained in a locked cabinet, separate from the participant database. Form tracking will be via participant ID number only. There will be master lists held at each participating site and at the coordinating site at Flinders University in South Australia. The participant database will be stored on a password-protected hard drive maintained by the study investigators. Data will be analysed by ID number only.

13.8 Restriction of use of data Investigators will have access to data by ID number only for the purposes of data monitoring and analysis. The Project Officer will have access to all study data for the purposes of data checking, monitoring and preparation for analysis. Study project officers and site coordinators will have access to the local site Case Report Forms and the data contained within for the purposes of data collection, data entry and data query resolution. The Data Safety Monitoring Board will have access to de-identified data for safety and efficacy assessments. Study auditors will have access to Case Report Forms (by ID number only) and study files in order

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to audit the study. Site research ethics committees will have access to local data for audit purposes.

13.9 Use of personal information Only enough personal information to give a general demographic and disease profile of the participant will be collected. The participant responses collected are limited to those that will address the study’s primary and secondary aims.

13.10 Estimated time of retention of personal information and planned disposal

Records from the study will be maintained for 15 years after study completion in secure archiving facilities. Once the 15 year waiting period is complete, the files will be erased from the database hard-drive and any paper copies shredded, including the master list linking participant name and treatment number.

The data will be retained in accordance with good clinical practice recommended by the NHMRC National Statement and the CGP guidelines, and in a form that is at least as secure as the sources from which it was obtained.

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14.0 STUDY ADMINISTRATION

14.1 Data handling and record keeping A separate data management plan can be developed (see PaCCSC templates) which can be referred to here, or fully describe in this section the data management methods to be employed.

A description of the data handling and data management proposed for the study, such as: The Palliative Care Clinical Studies Collaborative (PaCCSC) has a number of Standard Operating Procedure that will apply to all sites for the management of study data. Specifically, the following Standard Operating Procedures apply: • 5.5.1 Electronic Data Handling • 5.23.2 CRF completion • 8.0 Essential documents • 8.4.1 Archiving of research/project materials • 8.42 Record destruction

14.1.1 Direct access to source data:

A statement of permission to access source data for regulatory and audit purposes is included within the participant consent form with explicit explanation about this given as part of the consent process. Specifically, access will be required by study staff (including investigators, site coordinators and study nurses), Hospital Research Ethics Committees (HRECs), Data Safety Monitoring Committee (DSMC) and the PaCCSC data management team (National Project Officer and Administrative Officer) In addition de-identified data will be made available for meta-analysis and where requested by journals for publication purposes.

Case Report Forms will include: • CRF – Eligibility • CRF – Baseline • CRF – Intervention • CRF – Treatment Cessation • CRF - Withdrawal

• CRF – Follow-up

• Medical Assessment and Screening Form

14.1.2 Data collection

Data will be sourced from the following:

Measure Source Completed by:General demographic details Clinical file Study nurseGeneral Medical information Clinical file Medical officerConcurrent medications Clinical file Medical officerPathology results Pathology report Pathology serviceVital signs Clinical file Study nurseMini Mental Status Examination CRF Study nurseQuality of Life CRF Study nurse

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Medical assessments CRF Medical officerEfficacy CRF Study nurseSide effects, safety CRF Study nurse

14.1.3 Electronic recording

Study data will be recorded in a number of files for both the administration of the study and collection of participant data.

1. A master index will contain confidential participant contact information and will be the only link between individual participants and the ID number. This will be an Excel spreadsheet (Master patient index.xls).

2. The Data file will be held and administered in the coordinating site, and will contain all the participant data as downloaded from the web site data forms. This data will then be transferred to the data set for analysis.

14.1.4 Data entry

Describe the data entry system to be used, such as: Data will be entered from each site into a web-based interface specifically developed for this study. This password protected interface is protected behind a ‘Ciskopix’ firewall which helps prevent unauthorised access. No personally identifying information will be entered on this interface. The coordinating site will download the data on a regular basis as a comma delimited file.

On completion of data entry for each form, the study site will ‘submit’ the data, generating an automatic email sent to the project manager as part of the auditing process. The original form will be sent to the coordinating site for verification and then filed.

14.1.5 Data querying

Data will be checked according to the Data Management Standard Operating Procedure (5.5.1, Electronic Data Handling). Data errors detected during the data checking procedures will be queried to the study site when a data report form will be raised. The data report form will be sent to the site, recording the details of the query, and the correction and resolution instructions. The data base will be updated according to the instructions, again generating an automatic email providing an audit trail of data changes.

The coordinating site will maintain a register of data checks for monitoring purposes. The register will record the date of data entry and checking, the date of return to the study site for correction, the date of return of correction, and the date of resolution. A log will be maintained detailing the corrections required for each data form.

14.1.6 Data storage

All data collected at each site for each participant will be kept in a participant file (identified by ID number only) which will contain the Case Report Forms, any corrected and amended data, copies of adverse event reports, file notes etc. All data will be stored at each study site in a locked filing cabinet with all identifying information removed, away from the administrative files for the study. All study files will be stored in accordance with Good Clinical Practice guidelines

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All identifiable data (consent forms, pathology reports, etc.) will be de-identified and filed with the study documents during the recruitment period. At completion of the study, all Case Report Forms will be sent to the coordinating site by registered mail, for collation and archiving. All participant files will be reconciled and stored along with all study materials – both hard copy and electronic – consistent with the applicable regulations regarding the retention and disposal of participant records.

14.2 Quality control

14.2.1 Training procedures:

The following training procedures will be conducted to ensure quality control.

Person trained Description Assessed byAll site staff ICH Good Clinical

Practice trainingNational manager (PaCCSC)

Study nurse Blood sampling Pathology departmentStudy nurse Eligibility assessment Site investigatorStudy nurse Consent procedure Study coordinatorInvestigator, sub investigators

ICH Good Clinical Practice training Protocol

National manager (PaCCSC) Chief investigator

Study nurse, investigators Data management National manager (PaCCSC)Medical staff Prescription Site investigatorClinical trials pharmacist Randomisation,

medication preparation procedures

National manager (PaCCSC) Chief investigator

Competency will be recorded at the study coordinating site with a copy filed in each study site.

14.2.2 Blood collection

Venous blood samples will be drawn for eligibility screening. In some instances blood samples, checked in the preceding 3 days, will be used for eligibility if the clinical situation is otherwise unchanged. The results will be held in the participant study file as source data.

Each study site will keep a copy of the pathology service guidelines for obtaining, transporting and storing blood samples.

14.2.3 Peer review and site visits

There may be a separate monitoring plan developed, or describe the monitoring methods here.

Each study site will be visited by the PaCCSC Project Officer prior to recruitment commencement, when the site coordinator and study nurse will be assessed as appropriate, and trained in the data collection, data entry, and filing and other trial procedures in order to comply with Good Clinical Practice. Peer review will be undertaken via regular study nurse telephone links and ongoing assessment by the study investigator. The assessment will be recorded and a copy sent to the study site.

VX.x Page 48 of 53

14.2.4 Pharmacy training

At the site initiation visit the pharmacy will be visited by the coordinating site Project Officer. At this time the pharmacy procedures will be clarified, the protocol reviewed in detail and a pharmacy manual provided.

14.2.5 Monitoring visits

Internal monitoring of the study is described in detail in the Monitoring Standard Operating Procedure (5.18, Monitoring).

Briefly, each study site will be visited by staff from the coordinating site at initiation, mid recruitment and study closure where all study procedures, recording, reporting and maintenance will be checked, including the pharmacy records. This will include data quality, protocol violations, adverse event reporting, participant existence and eligibility, and other aspects to determine Good Clinical Practice compliance.

VX.x Page 49 of 53

15.0 REFERENCES

1. International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Annals of Internal Medicine. 1997. 126; 36-47.

2. Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled ClinTrials 1996; 17:1-12.

3. Guideline for Good Clinical Practice ICH Harmonised Tripartite 1996. 4. Abernethy AP, Shelby-James T, Fazekas B, Woods D, Currow DC. The Australian-

modified Karnofsky Performance Status (AKPS) scale: a revised scale for contemporary palliative care clinical practice. BMC Palliative Care 2005;4:7.

5. Farrar J, Young J, LaMoreaux L, Werth J, Poole M. Clinical importance of changes in chronic pain intersity measured on an 11 - point numerical pain rating scale. Pain 2001;94:149-58.

6. Cleeland CS. Measurement of pain by subjective report. In: Chapman CR, Loeser JD, editors. Advances in Pain Research and Therapy, Volume 12: Issues in Pain Measurement. New York: Raven Press; 1989. p. 391-403.

7. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 1975;12:189-98.

8. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. Journal of the National Cancer Institute. 1993;85:365-376.

9. Blazeby JM, Williams MH, Brookes ST, Alderson D, Farndon JR. Quality of life measurement in patients with oesophageal cancer. Gut. Oct 1995;37(4):505-508.

10. Kaasa S, Bjordal K, Aaronson N, et al. The EORTC core quality of life questionnaire (QLQ-C30): validity and reliability when analysed with patients treated with palliative radiotherapy. European Journal of Cancer. Dec 1995;31A(13-14):2260-2263.

11. Kyriaki M, Eleni T, Efi P, Ourania K, Vassilios S, Lambros V. The EORTC core quality of life questionnaire (QLQ-C30, version 3.0) in terminally ill cancer patients under palliative care: validity and reliability in a Hellenic sample. International Journal of Cancer. Oct 1 2001;94(1):135-139.

12. Aust Government Department of Health and Ageing. National Palliative Care Strategy 2000

13. Weitzner MA, Jacobsen PB, Wagner HJ, Friedland J, Cox C. (1999a) The Caregiver Quality of Life Index-Cancer (CQOLC) scale: development and validation of an instrument to measure quality of life of the family caregiver of patients with cancer. Quality of Life Research. 1999;8:55-63.

14. Edwards B, Ung L. Quality of life instruments for caregivers of patients with cancer: a review of their psychometric properties. Cancer Nursing. Oct 2002;25(5):342-349.

15. Weitzner MA, McMillan SC. The Caregiver Quality of Life Index-Cancer (CQOLC) Scale: revalidation in a home hospice setting. (1999b) Journal of Palliative Care. 1999;15(2):13-20.

VX.x Page 50 of 53

16. Briggs A., O’Brien B., and Blackhouse G. (2002). Thinking outside the box: recent advances in the analysis and presentation of Uncertainty in cost effectiveness studies. Annual Review of Public Health 23: 377-401.

17. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, V4.0, DCTD, NCI, NIH, DHHS, March 31 2003, published May 28, 2009.

VX.x Page 51 of 53

16.0 APPENDICES

16.1 Protocol amendments

16.2 Amendment Number - 1

Date of amendment –

Statement of intent –

List of specific changes

Change #1 Section number and name

o Reason for change − Original text

• xxx − New text

• xxx

Change #2

Change #3

Change #4

16.3 Information sheets and consent forms

Patient Information and Consent Form Carer Information and Consent Form

VX.x Page 52 of 53

16.4 Other related forms Submit separately with individual version and date control, with appropriate licence acknowledgement

VX.x Page 53 of 53

16.5 Product information

Template 29

PaCCSC Study Closure Checklist


Study: ________________________________

Site: ________________________________


Activity Detail Yes No N/A

Final pharmacy monitoring

Has the monitoring been undertaken by the contracted company?

Has the report been provided to pharmacy?

Has the Investigational Product been destroyed in accordance with the applicable regulations?

Has the completed Pharmacy folder been provided to site coordinator?

Comments

All invoices and payments have been raised and finalised

Has an Invoice been raised for the last patients and related activities?

Has payment been received from PaCCSC?

Comments

Final report sent to HREC

Has the report been submitted using the approving HREC standard format?

Has the closure letter been attached, with results publication and any appropriate participant correspondence?

Has an acknowledgement letter been received and filed, with a copy to PaCCSC?

Has a copy of the report and acknowledgement letter been submitted to the RGO?

Comments

Letter sent to participants

Have the allocation codes been received from coordinating site?

Has a letter been written addressed to each participant or their remaining family, with the appropriate allocation inserted?

Have the letters for all participants been forwarded to clinical team to send to patients or remaining family? Note: Instruct the clinical team to post out.

Comments

Template 29



PaCCSC Study Closure Checklist (cont.)


Essential documents finalised

Has all correspondence been included in the investigator folder/file?

Are all HREC and RGO letters included?

Are all reports for monitoring and follow-up included in the folder/file?

Check that the Staff Signatures and Delegation Log has completed including a cease date for each delegated person on the sheet?

Insert a copy of results publication

Comments

Copy of this checklist to PaCCSC

Send a copy of this final checklist to PaCCSC

Comments

Name

Signature

Data completed

Template 29a

PaCCSC Study Closure Checklist (each site)



Study:

Site:


Completion of previous monitoring

Are there any outstanding data queries?

Are there any outstanding amendments and file notes?

Comments

Draft HREC letter written

Has the draft letter been sent to this site?

Has a copy of the letter been sent to HREC and to the relevant RGO?

Has a copy of the acknowledgement letter been received at PaCCSC?

Comments

Draft Participant letter written

Has this letter been sent to sites for finalisation?

Has the table of allocation codes been sent to each site with only their allocations?

Comments

Confirmation of final pharmacy monitoring

Has there been receipt of the monitoring letter from monitors for that pharmacy (if received by PaCCSC, has that letter been forwarded to the site?

Comments

Final payment has been sent to every site

Are there any outstanding invoices or payments?

Comments

Template 29a





Email and telephone discussions of site closure activities

Has these discussions been conducted after the draft letters were sent to each site and as site procedures are underway?

Update the study KPI database to track progress for that site Has the final HREC and RGO correspondence been received from this site?

Comments

Archiving underway at each site

Pharmacy manual

Investigator manual

Email and telephone discussions

Comments

Confirm final site closure

Has the completed Study Closure Checklist been received from the site?

Comments

Name

Signature

Date completed

Template 29b

PaCCSC Study Closure Checklist (all sites)



Study:

Site:


Completion of monitoring

Are there any outstanding data queries?

Are there any outstanding amendments and file notes?

Comments

Draft HREC letter written

Has the draft letter been sent to this site?

Has a copy of the letter been sent to HREC and to the relevant RGO?

Has a copy of the acknowledgement letter been received at PaCCSC?

Comments

Draft Participant letter written

Has this letter been sent to sites for finalisation?

Has the table of allocation codes been sent to each site with only their allocations?

Comments

Confirmation of final pharmacy monitoring

Has there been receipt of the monitoring letter from monitors for that pharmacy (if received by PaCCSC, has that letter been forwarded to the site?

Comments

Final payment has been sent to every site

Are there any outstanding invoices or payments?

Comments

Template 29b





Email and telephone discussions of site closure activities

Have these discussions been conducted after the draft letters were sent to each site and as site procedures are underway?

Update the study KPI database to track progress for that site Has the final HREC and RGO correspondence been received from this site?

Comments

Archiving underway at each site

Pharmacy manual

Investigator manual

Email and telephone discussions

Comments

Confirm final site closure

Has the completed Study Closure Checklist been received from the site?

Comments

Name

Signature

Date completed


X.X.X V1.1 Page 1 of 5

X.X.X Standard Operating Procedure Template

Version V1.1


Approved D Currow




PaCCSC SOP Feb 2018


Introduction/background

Provide a context for the SOP and relate it to Good Clinical Practice (GCP). Provide a rationale why the SOP is needed.

Objective

State the objective of the SOP.

Scope

Scope refers to who the SOP might apply to or the extent of coverage of the SOP. What is included in the SOP and also maybe what might not be covered by the SOP.


Specify the person(s) or role(s) that are responsible for implementing the SOP.

PaCCSC SOP Feb 2018


Procedure

Provide a clear and unambiguous description of the procedure that is to be followed.

PaCCSC SOP Feb 2018


Other related SOPs

List all other SOPs related to this SOP


List all PaCCSC Templates and PaCCSC Guidance documents related to this SOP List all other relevant documents related to this SOP

References


Praxis Australia

List any/all other relevant references

Acknowledgements

List any/all acknowledgements

PaCCSC SOP Feb 2018


History


1.0 25/05/2016 D Currow New procedure



Approval


1.1 David Currow

Template 31

PaCCSC New Study Idea/Proposal


PaCCSC New Study Idea/Proposal

** For presentation at the PaCCSC Annual Research Forum or June meeting of the PaCCSC Trial Management Committee **

Investigator(s)

Study title

Collaborating partners PaCCSC only

Other trial groups, specify:

Pharmaceutical companies, specify:

Background and rationale (including key papers)

Study objectives

Aim

Null hypothesis

Primary outcome measure

Secondary outcome measure(s)

Template 31 PaCCSC New Study Idea/Proposal


Study population

a. Inclusion criteria

b. Exclusion criteria

c. Any recruitment issues of note

Investigational plan

Overall study design

Treatment arms

Intervention(s)

Sample size estimate

Statistical analysis plan

Health economic analysis

Ethics, including any perceived/real issues with ethics approval

Other trials or initiatives with which this proposed study links

Equipment or other resources required to conduct the study

Template 32

PaCCSC New Study Idea/Proposal Evaluation



** For use at the PaCCSC Annual Research Forum or June meeting of the PaCCSC Trial Management Committee **

New study evaluation

Members of the PaCCSC Trials Management Committee are requested to evaluate allnew study proposals presented at the Annual Research Forum or June meeting of theTrial Management Committee to determine the feasibility of taking the two highest rankedRCTs or pilots in order to underpin an RCT forward with the support of the PaCCSC sitesand the PaCCSC Coordinating Office.

PaCCSC support

PaCCSC will act as CRG/sponsor for all new studies (whether pilot or Phase III) receivingapproval from the PaCCSC Scientific Committee as provided in the SOP 6.0.1 New StudyIdeas/Proposals.

New study ideas/proposals criteria

Studies that complement the portfolio of trials already run by PaCCSC will be givenprecedence. No study that directly competes with a current PaCCSC open study will besupported until such time as the recruitment targets for the current open study arereached. In line with the purpose and aims of PaCCSC, new study support will beprovided to studies that:o Randomised controlled trials (RCTs)o Small pilot studies for proof of concept (feasibility, safety, efficacy)o Additionally, studies that value add to the suite of currently running RCTs, i.e. sub-

studies that are genuinely embedded within a current study, may be considered. Any new studies that do not fit within these criteria are unable to be supported.

Evaluation conduct and announcement of results

All TMC members are requested to complete the evaluation (next page) following the newstudy presentation at the Annual Research Forum or June meeting of the TMC.

New study presenters will be notified by the PaCCSC national manager of the outcomeof the evaluation process.

Template 32




Trials Management Committee (TMC) members are asked to complete the below evaluation and return to the PaCCSC Coordinating Centre before the end of the Annual

Research Forum or within one week of the June TMC meeting date.

Study title:

Investigators:

(Score: 10 = excellent - 1 = poor)

Evaluation items Score out of

Scored as

Is the study in an area where current evidence is limited or low level?

Will the study build on other work being undertaken by PaCCSC?

Is the study design sufficient to achieve the primary and secondary aims?

Is the study likely to receive ethics approval?

Is recruitment of participants to the study likely to be relatively easy?

Will the outcomes have a health economic benefit?

Would you support the undertaking of this study at your site?

Does the study design include input from health disciplines other than palliative care?

Have all efforts to reduce burden on either patients or staff been considered?

Total 100

Is there funding from other sources available? Yes/No

If a pilot study, will the evidence gained be scientifically robust to enable a submission for competitive funding?

Yes/No

Other comments:

Signed:

Name:

Template 33

Site Initiation – One Day Program


Site Initiation [study] – One Day Program

** Use this template if a site is already recruiting to other PaCCSC studies and their overall research capacity and training needs have been assessed and addressed on a previous occasion. **

Day Month Year

Attendees

Please specify name & position

of attendees

PaCCSC Coordinating Centre members: • National Manager• National Project Officer• OtherSite members:• Principal Investigator• Study Coordinator• Study Nurse(s)

Apologies

Times

0830 Regulatory review summary

GCP, Roles and responsibilities; Consent process; Adverse event reporting

1000

Protocol Review Background, Study design;

Inclusion / exclusion criteria; Discussion/questions

1030 Morning tea

1045 Investigator Site File

Trial Master Files; Patient Master Index

1100 Safety assessment and reporting

NCI CTCAE; PaCCSC reporting; HREC reporting

1200 Lunch

1230 Case Report Forms

Completion timepoints; CRFs; Associated documents; Source documents

1400 Sub-Studies

1500 Site Implementation and Recruitment Plan

Referrals and networks; Recruitment planning and resources

1530 Monitoring and trial management

1600 Questions; review; close

Template 34

PaCCSC Site Initiation – Two Day Program


Site Initiation [study] – Two Day Program

** Use this template if a site has not previously been involved in another PaCCSC study and overall research training needs have been assessed and addressed in addition to study specific training. **

Day 1

Day Month Year

Attendees


of attendees

PaCCSC Coordinating Centre members: • National Manager• National Project Officer• OtherSite members:• Principal Investigator• Study Coordinator• Study Nurse(s)

Apologies

Times

0830 Arrival & Introductions

0900 Trials and Regulations ICH GCP; HREC; TGA

0930 Standard Operating Procedures

Understanding; Implementation

1000 Roles, Responsibilities, Communication (SOP)

Sponsor; Site Investigator; Research staff Absence process – contingency plans

1045 Morning tea

1100 Adverse Event Assessment and reporting (SOP)

CTCAE NCI criteria; HREC reporting

1200 Monitoring and record keeping Documentation and study filing

Master files; Essential documents; Investigator Site Files

1300 Lunch

1400

Consent process HREC / RGO / local site requirements

Documentation of consent Consent procedure(s)

1530 Contracts and invoicing

1630 End day 1

Template 34

PaCCSC Site Initiation – Two Day Program


Site Initiation [study]

Day 2

Day Month Year

Attendees


of attendees

PaCCSC Coordinating Centre members: • National Manager • National Project Officer • Other Site members: • Principal Investigator • Study Coordinator • Study Nurse(s)

Apologies

Times

0900 Pharmacy meeting

1030

Protocol review Background; Study design Inclusion/exclusion criteria

Learnings from [other study], early results

Schedule and questionnaires Visit schedule; Tests and questionnaires

Randomisation and prescription Procedures, unblinding

Site implementation and recruitment plan Referrals and barriers

Recruitment base/prescreening

Substudies Consent; Management and decision making

1230 Lunch – Protocol overview with teams

1400

CRFs (SOP) Completion timepoints and requirements CRFs and other associated documents

1530 Study equipment

1600 General discussion and commencement plans

1630 End day 2

Template 35

PaCCSC Study Monitoring Plan


[Study name] Monitoring Plan

Purpose

This monitoring plan has been developed to tailor the monitoring activities of thegeneric PaCCSC SOP 5.18 Monitoring as they apply to the [insert name] study.

This is to ensure the monitoring for the [insert name] study meets all the requirementsfor a pre-registration study, and that the monitoring program is adaptive,comprehensive and focusses on review, training and mentorship.

FULL TITLE: Specify full title for the study

ABBREVIATED TITLE: Specify abbreviated title for the study




Template 35




• This study monitoring plan template contains instructions and sample text in italics. Investigators should carefully consider the suggested text under each section, and then modify, remove or replace as appropriate to their study.

• This instruction page should be removed once the study monitoring plan is completed.

Template 35



Procedure

1. Trial Summary

Primary objectives The primary objective is to determine …..Study timelines Commence recruitment ….

Complete recruitment …. Closure and analysis ….

Planned number of participants …. completed to primary endpoint Planned number of Centres ….Participant numbering system Study code-site code- screening number

(xx-xx-xxx)External partners [Company]

Case Report Form (CRF) Paper completion, entry into eCRF [RDMS]Data entry and query responsibilities Site staff data entry.

Checking, validation and query management with PaCCSC

Randomisation Developed by [Company/process], central randomisation by a telephone call, follow-up using email by PaCCSC National Manager

Data and Safety Monitoring Committee (DSMC)

[Details]

2. Trial start up

PaCCSC will approach and select all trial sites to participate in the trial. The PaCCSC Coordinating Centre will facilitate the application for the relevant HREC and local approvals by the individual sites and will provide guidance as necessary. The Coordinating Centre will facilitate the set up and approval of all site agreements and co-sponsorship agreements (if appropriate).

The trial will not be allowed to commence at participating sites until all necessary approvals have been granted and all essential documentation listed in Table 1 is present in the Investigator Site File (ISF) and has been verified by PaCCSC.

Table 1: Investigator Site Folder documentation

Document Original kept Frequency of update Funding agreement PaCCSC Trial registration Lead PI Annual HREC approval Lead site; copies in ISF Annual Local approval (Site Specific Assessments)

Investigator Site File Annual

CTRA PaCCSC and ISF On protocol amendmentCTN Online;

acknowledgement in site ISF

Each new site

Principal Investigator CV Investigator Site File Annual

Template 35



Staff Signature and Delegation Log Investigator Site File Ongoing Site Initiation Report Investigator Site File Single

The PaCCSC Coordinating Centre will work with the site staff to ensure that all required trial materials are present at site in sufficient quantities prior to initiation as detailed in Table 2.

Table 2: Quantities of trial material per site

Material Quantity required Re-supply procedure Investigator Site File Pharmacy Folder CRFs folder Patient Questionnaires Study drug

3. Types of monitoring

3.1. Central monitoring

Trial activities will be monitored centrally throughout the trial and will form part of the trial reporting. Central monitoring will include the following:

A. Investigator Site File

A pre-populated Investigator Site File (ISF) is provided to each PI during study initiation, containing: o Contents page o Contact details o Protocol and Product information o Regulatory documents to date including HREC approval letters, Trial Registry listing

and approved documents o Template documents for training, delegations, logs, reporting forms o Draft Case Report Forms (CRFs) o CTRA where possible o Questionnaire licences

Updates of files in the ISF will be ongoing throughout the study. Correspondence related to regulatory approvals and reporting will be copied to PaCCSC

Coordinating Centre for review. Any irregularities, lack of reporting or errors will be addressed by direct communication

between the PaCCSC Coordinating Centre and the site concerned. A log of the required approvals will be kept by the PaCCSC Coordinating Centre to ensure

each site has ongoing ethical and local approval with the correct study documents.

Template 35



B. Recruitment

Recruitment across the entire study and by site will be monitored for unexpected highrecruitment, general recruitment rates and deviations, and apparent problems (refer alsoto Guidance 10, Site Management Plan).

C. Randomisation

Notification of randomisation will be by email to PaCCSC Coordinating Centre. This notification will be reviewed against eligibility data for consistency and accuracy. The randomisation numbering will be checked by the Central Randomisation Service to

ensure compliance with the schedule.

D. Safety reporting

Serious adverse events will be circulated to the PaCCSC Coordinating Centre as part ofdata entry within the pre-determined timeframes for reporting of such events.

The onward reporting and follow-up will be tracked and monitored by the PaCCSCCoordinating Centre.

Individual safety reports will be circulated to the PaCCSC Data and Safety MonitoringCommittee (DSMC)/Medical Monitor for review subsequent to each event, and as asummary at the committee teleconferences to be conducted twice per annum.

E. Data quality

The PaCCSC Data Checking Procedure will be followed as per the study specific DataManagement Plan (Template 10)

3.2. Internal PaCCSC monitoring

In addition to the central monitoring of recruitment site activities, the PaCCSC Coordinating Centre will also monitor internal activities within the [insert name] study. These activities will include:

Compliance with SOP 5.18 Monitoring timeframes Time taken to complete processing of agreements, contracts and invoices Actioning of outlying information from the tracking of KPIs and recruitment Compliance with requests from the PaCCSC Data and Safety Monitoring Committee

(DSMC) and Trial Management Committee (TMC) Updating of monitoring training skills Verification of Source Data upon receipt of Source Documents in the form of paper CRFs.

3.3. On-site monitoring

The frequency of monitoring visits is partly determined by a risk assessment of each site and the application of monitoring triggers (completion of a study specific risk assessment using Template 6: Risk Assessment Toolkit, Completion of the Recruitment Matrix (Guidance 15), or as described within the study protocol is required).

Template 35



A telephone call between the PaCCSC Coordinating Centre and the site team will be conducted after the completion or withdrawal of the first participant. This telephone call will enable discussion of the protocol and any residual questions, review of the paperwork, and overall discussion of problems and progress.

3.3.1 Planned first on-site monitoring visit

The first on-site monitoring visit following initiation of the site and trial commencement will take place within approximately 3 weeks after the inclusion of the second participant at the site, or as deemed appropriate following the initial telephone call and the completed Risk Assessment.

The first visit will involve review of the Investigator Site File (ISF) in full to determine appropriate compliance with filing of essential documents, a review of the participants, and a discussion with the study team regarding:

The protocol, specifically to include any updates or amendments to the study design Compliance and implementation issues Recruitment Compliance and understanding of data management procedures Additional training as appropriate such as GCP, assessments, equipment, etc.

3.3.2 Planned second and subsequent monitoring visits

Subsequent monitoring visits will take place in response to predetermined triggers, requests by the PaCCSC DSMC or TMC, or as close as possible to participants reaching primary endpoint or cessation if earlier).

On-site monitoring will focus on the following items: Consent Eligibility Data to primary endpoint/cessation Safety Investigational product accountability

The interval for monitoring visits may be longer or shorter than stated above, and will depend on participant enrolment rate, quality issues, trial site compliance or other trial site issues. Any significant deviation from the planned monitoring timelines will be explained and documented in the monitoring visit report and the monitoring plan will be amended if appropriate.

Each participant monitored will have a single page summary completed, to be filed in the electronic central files, the completed and returned Corrective Sheet will be scanned and filed electronically after having been checked for resolution of the errors found.

3.3.3 Unplanned on-site monitoring

In addition to planned on-site monitoring, additional visits may be triggered by events during the recruitment period. The triggers for on-site monitoring outside of the pre-planned initiation or within recruitment monitoring may include any combination of:

Protocol violation at the first on-site visit

Template 35



Inexperience of the site with the conduct of clinical trials, and where performance at thefirst visit (after 2 participants) indicates that more support is required

Change in Principal Investigator and/or significant site staff Where recruitment does not occur within 6 months of local approval Continued lower than expected recruitment Unusual serious adverse event incidence Increased incidence of protocol violations Continued or sustained deviations such as missed visits, missing CRFs or data entry,

numerous data outliers Where the central documents of the ISF fail to document compliance with regulations,

protocol or study administration and review of the on-site file is indicated Repeated issues related to consent procedures, incorrect Patient Information and

Consent Form (PICF) use, failure to report Serious Adverse Events, missing primaryoutcome data

On-site visits made as a result of any single trigger or a combination of triggers will be preceded by an email and teleconference to discuss the issues, to seek clarification, and to plan ways to redress and avoid future problems.

On-site monitoring visits and documentation will be in accordance with SOP 5.18 Monitoring.

3.4. Pharmacy monitoring

Each pharmacy will be monitored by a trained monitor, who will monitor in accordance with established SOPs. This may be through the use of an outsourced provider contracted by PaCCSC for the purpose of supply of the investigational product, and pharmacy monitoring. An agreement is to be established for the delivery of these services.

The frequency of monitoring will be determined by recruitment rate and the capacity of the pharmacy to hold the returned study drug, to coincide with monitoring of another nearby pharmacy, and the study completion.

The pharmacy monitor will provide PaCCSC with a copy of the monitoring report. This report will be checked to determine if there are any actions required by PaCCSC to assist the site pharmacy to address the findings. A copy of the report will be filed in the Trial Master File, and a copy will be sent to the pharmacy for their filing within the site study folder.

Template 35



References


International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). November 2016. (accessed 23/10/2017) https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf


US Department of Health and Human Services, Food and Drug Administration. Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring. August 2013.

Smith CT, Williamson P, Jones A, Smyth A, Langton Hewer S and Gamble C. Risk-proportionate clinical trial monitoring: an example approach from a non-commercial trials unit. Trials 2014, 15:127

Template 36

PaCCSC Study Recruitment Plan


[Study name] Recruitment Plan

Purpose

This study recruitment plan has been developed to tailor the recruitment activities ofthe generic PaCCSC SOP 6.5.1 Study Recruitment as they apply to the [insert name]study.

This is to ensure the recruitment for the [insert name] study meets all the requirementsfor a pre-registration study, and that the recruitment is adaptive, comprehensive andfocusses on review, training and mentorship.

FULL TITLE: Specify full title for the study

ABBREVIATED TITLE: Specify abbreviated title for the study




Template 36




• This study recruitment plan template contains instructions and sample text initalics. Investigators should carefully consider the suggested text under eachsection, and then modify, remove or replace as appropriate to their study.

• This instruction page should be removed once the study recruitment plan iscompleted.

Template 36



1. Measures

Each study should consider the recruitment measures appropriate to the study, and to each site, and can include the following:

A. Direct site support

1. To support all site investigators locally and through monthly PaCCSC TrialsManagement Committee (TMC) to maximise recruitment at their site;

2. To support all site coordinators through monthly teleconferences (opposite fortnight tothe TMC in 1. above) and individually through one on one support provided by thePaCCSC Coordinating Centre.

3. Through direct one on one contact with sites at strategic time points, and can includeconsideration of the any of the following:

a. By phone 2 weeks from study commencement where there has been no pre-screenactivity

b. By phone 4 weeks from study commencement where no recruitment has occurredc. By phone 8 weeks from study commencement where no recruitment has occurred;

or at 8 weeks from the most recent recruitmentd. By phone 12 weeks from study commencement where no recruitment has occurred;

or at 12 weeks from the most recent recruitmente. In person 16 weeks from study commencement where no recruitment has occurred;

or at 16 weeks from the most recent recruitment; for a formal site performance visitf. By phone 20 weeks from study commencement where no recruitment has occurred;

or at 20 weeks from the most recent recruitment;g. By phone 24 weeks from study commencement where no recruitment has occurred;

or at 24 weeks from the most recent recruitment; to determine if the site remains aviable and continuing proposition.

h. By phone on reaching primary endpoint of the first participanti. By on site visit on completion of the first 2 study participants for monitoring and for

review of procedures and protocol review

B. Centralised support

4. Activities conducted by the PaCCSC Coordinating Centre to the benefit of allparticipating sites:

a. Direct access to the PaCCSC Coordinating Centre to discuss the studyb. Standard Operating Procedure for Study Recruitment (refer SOP 5.6.1 Site

Selection; SOP 6.5.1 Study Recruitment)c. Near Miss procedure and availability of study CId. Recruitment resources for all sites:

i. Recruiting in palliative care: Guidelines for research teamsii. Consent script as a living document, update as sites provide feedback on

questions asked by potential participants, their families or cliniciansiii. Advertising posters (for waiting rooms and staffing areas)

Template 36



iv. Clinic recruitment cards (for waiting rooms)v. Letter to GP’svi. Referral template (for other departments)vii. PaCCSC generic brochureviii. PaCCSC study PowerPointix. PaCCSC Coordinating Centre team presentations

e. Weekly emailed recruitment updates/League tablef. Literature searchesg. Recorded interviews with top performing sitesh. External advertising and promotion activities

Table 1 below forms the basis of the study recruitment plan. Table 1 is to be completed for each study, where all risks have been considered and addressed.

Template 36



Table 1: Measures to support recruitment

Measures Information Dates/Time periods

Direct Site SupportSite Investigators as a Group

At a senior level, the Trials Management Committee (TMC) meet on a monthly basis to bring together each site investigator to discuss a set agenda which includes recruitment items of best and poorest performing studies and recruitment strategies employed. Sharing of local practices to engage with and promote study recruitment is encouraged.

Site Coordinators as a Group

Site coordinator teleconferences are conducted monthly with all site coordinators and all members of the sites research team encouraged to attend. The agenda is similar in format to the TMC regarding recruitment specific items.

One on One meetings – Individual sites through one on one contact with the PaCCSC team

These calls will be implemented at strategic time points for each participating site and dependent on recruitment performance. No recruitment at a site for 4 weeks will trigger a phone call and will be ongoing for up to 16 weeks at which point a site visit will occur. Phone calls will be made by the National Manager and National Project Officer to review the sites recruitment efforts and pre-screening information at weeks 4, 8 and 12. Should a site reach 16 weeks without recruitment then a site visit will be conducted for a formal site performance visit. If there remains no recruitment at the site for a following 8 weeks a further phone contact will be made where the discussion will centre on the sites ability to remain viable and a decision made as to whether the site should exit from the study. This item is expanded on later in the document.

Centralised SupportDirect access to PaCCSC team

Any PaCCSC collaborating site staff can, and are encouraged to, make contact directly with the NM or NPO as and when required for any study related matter including recruitment.

SOP for Study Recruitment

The PaCCSC Coordinating Centre as the Sponsor organisation has a SOP for study recruitment (refer SOP 6.5.1 Study Recruitment).

Near Miss procedure

The study CI is available at all times for calls from sites regarding patient eligibility.

PaCCSC Coordinating Centre

The recruitment folder developed by PaCCSC will undergo an update and be relaunched in PDF format as a ready reckoner and contain a range of information related to study

Template 36



Measures Information Dates/Time periods

recruitment resources

recruitment. Sites are encouraged to use and tailor the resources to meet their internal needs in promoting the clinical research of the Collaborative and the [name] study in particular. Included resources that may be tailored for use by sites includes:

- Consent script- Posters x 2 (for waiting rooms and staff rooms)- Clinic recruitment cards (for waiting rooms)- Template letter to GPs- Referral template (for other departments within a health care service to refer)- PaCCSC generic brochure- [name] study PowerPoint- Other relevant PaCCSC team presentations

Weekly emailed recruitment updates/ Leader board

Each week the PaCCSC Coordinating Centre collates the previous week’s results into a tabulated form and circulates to all sites. Graphical representation of this information may also be provided from time to time.

Literature searches Literature searches are undertaken on an ad hoc basis on recruitment in clinical trials related to strategies and motivating factors. This information will be shared across the participating recruiting sites.

Advertising Advertising of the study through national bodies, health network newsletters, media requests, other specific campaigns.

Template 36



2. Assessment of Measures

Recruitment phone calls (week 2 if there has been no pre-screening activity, weeks 4, 8, 12, 20 & 24 where no recruitment has taken place). Topics to be covered (Template 38):

1. Recruitment activities conducted locally; discussion of what local activities have beenconducted to influence recruitment; review of past study performance and comparison.

2. Pre-screens reviewed: how many; where are referrals coming from; what are the majorreasons for screen failure.

3. Networking: what avenues are open to the site that haven’t yet been explored?

4. Site difficulties: are there events at the site that have reduced their capacity to recruit?

Recruitment visit (week 16 where no recruitment has taken place). Aims of the meeting:

1. Provide data from metrics discussed in the Recruitment Matrix (Guidance 15).

2. Work through Section 5c of the Recruitment Matrix (Guidance 15) regarding why sitesmight be underperforming and document discussion to enable agreement of outcomesfor site/Sponsor to implement.

3. Provide copy of written outcomes back to site within 7 days.

Template 37

PaCCSC Recruitment Review


PaCCSC Recruitment Review

Study

Site

Date

Date of last pre-screen

Discussion around pre-screens or referral patterns

New referral activity Strategies being used – success or

otherwise Strategies tried and failed Other plans to be considered

Prospect of likely recruitment

Problems with referrals, clinical teams

Staffing or other issues

Any support from PaCCSC to be considered.

Template 38

PaCCSC Recruitment Phone Call


PaCCSC Recruitment Phone Call Topics / Questions

** The questions below are to be reviewed during phone calls between recruiting study sites and the PaCCSC Coordinating Centre, to facilitate assessment of measures as outlined in

the Study Recruitment Plan **

1. What recruitment activities have been conducted locally in the past two/four weeks?

a. Are these activities you had in place with previous [specify type (e.g.breathlessness)] studies?

b. Are they new activities?c. How do your activities compare now to those that you did with past studies?d. What worked last time?

2. Let’s review your pre-screens information:

a. How many pre-screens have been entered?b. Where are your pre-screens coming from? Are there other areas that you have

approached, from which you have not received a referral?c. What at the major reasons for screen failure at your site?d. Are you familiar with the near miss policy?

3. Networking: what avenues are open to the site that haven’t yet been explored?

a. Presentations, journal clubs, etc.b. Other clinical areasc. External consultants/[specify type (e.g. respiratory)] physiciansd. Are there any private providers that might be interested in referring?e. Community service interactionsf. [specify type (e.g.pulmonary)] rehabilitation servicesg. Other clinical trials runningh. Has the PI undertaken any promotional/networking activities?i. Other resources: clinic cards, posters, rewards for referrals, etc.

4. Site difficulties: are there events at the site that have reduced their capacity to recruit?

5. Sponsor support:

a. Is the level of support from the PaCCSC Coordinating Centre helpful?b. Are there other areas of support from the PaCCSC Coordinating Centre you would

appreciate?c. Are there logistical issues with the conduct of the trial that you are grappling with?

Template 39

IFS Contents Page


Current protocolCurrent approved, superseded, correspondence

Investigator BrochureProduct information, Investigator brochure, superseded

HREC administration- LEAD siteHREC correspondence, submissions, approval letter, annual reports

HREC local siteHREC correspondence, submissions, approval letter, annual reports

RegulatorySite listing, ANZCTR, CTRA, Insurance, TGA

Site staffContacts, SSS, CVs, training, GCP certificates

LaboratoryAccreditation certificate, reference ranges

Governance approvalsApproved PICF, advertising, assessment forms, questionnaires

Case report formsMaster copies, licences, completion guideline

Participant informationMaster index, file notes

Consent formsSigned originals, file notes, other identifying documents

Serious adverse eventsTemplate, completed SAE report forms, DSMC reports

MonitoringSite visit log, visit reports, corrective action sheets, reports

Finance and contractsContracts, budgets, invoices and payments

PharmacyPharmacy file kept in pharmacy until study closure

CorrespondenceGeneral correspondence not located elsewhere

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