Sponsor Responsibilities ICH E6 Good Clinical Practice Guidance

2012-12-16

NIDCR National Institute of Dental and Craniofacial ResearchNational Institutes of Health

CROMS Clinical Research Operations and Management SupportRho, Inc., Federal Division

Sponsor Responsibilities ICH E6 Good Clinical Practice Guidance

An individual, company, institution, or organization which takes responsibility for the initiation, management and/or financing of a clinical trial

Sponsor

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Implement and maintain QA and QC systems with written SOPs to ensure GCP compliance

Secure agreements from all sites for monitoring, auditing, and inspections

QC of data handling◦ Reliable

◦ Processed correctly All agreements should be in writing

Quality Assurance /Quality Control (ICH 5.1)

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A person or an organization contracted by the sponsor to perform one of more of a sponsor’s trial related duties and functions◦ Commercial◦ Academic◦ Other

Contract Research Organization (CRO)

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Sponsor may transfer all or some trial duties/functions to a CRO

Ultimate responsibility lies with the sponsor Transferred duties should be specified in writing

◦ Not specified = retained by sponsor References to sponsor apply to CRO for duties that

are transferred

Contract Research Organization (CRO) (ICH 5.2)

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Designate qualified medical personnel to advise on trial questions or problems

Outside consultants may be appointed if needed

Medical Expertise (ICH 5.3)

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Utilize qualified individuals: Biostatisticians, Clinical pharmacologists, Physicians

Use as appropriate through all trial stages◦ Protocol design◦ CRF development◦ Analysis (planning/preparing study reports)

For further guidance:◦ Clinical Trial Protocol and Protocol Amendments (Sec. 6)

Trial Design (ICH 5.4)

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Utilize qualified individuals to supervise conduct of trial, handle and verify data, conduct statistical analysis, and prepare trial reports

Can create independent data monitoring committee (IDMC) to assess progress◦ Safety data and critical efficacy endpoints◦ Recommendations to sponsor: continue, modify or stop trial◦ IDMC should have SOPs and maintain written records of

meetings

Trial Management, Data Handling, and Recordkeeping (ICH 5.5)

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When handling electronic trial data:◦Data processing system should conform to sponsor

requirements◦Maintain SOPs◦Permit changes that are documented(audit trail)◦Maintain a security system to prevent unauthorized

access◦Maintain list of individuals authorized to make changes◦Maintain data backup◦Safeguard blinding (if applicable) during data

entry/processing


Possible to compare original data to processed data Use an unambiguous subject identification code Retain all essential documents pertaining to trial and regulatory

requirements If clinical development of an investigational product is

discontinued:◦ Retain essential documents for up to 2 years◦ Notify site investigators and appropriate regulatory authorities

Transfer of ownership of data should be reported to appropriate authorities, as per applicable regulatory requirements


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Retain sponsor-specific essential documents until:◦ At least 2 years after the last approval of a marketing application in

an ICH region , and until there are no pending or contemplated marketing applications in an ICH region, OR

◦ At least 2 years after formal discontinuation of clinical development of the investigational product

◦ Retain longer if required by applicable regulatory requirements or needed by the sponsor

Sponsor should communicate in writing to investigator/institutions:◦ Inform of the need for record retention◦ Notify when the trial-related records are no longer needed


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Sponsor selects investigators and/or institutions Provide protocol and up-to-date Investigator’s

Brochure◦ Ensure time to review before agreement

Obtain agreement to:◦ Conduct trial in compliance with GCP◦ Comply with data recording procedures◦ Permit monitoring, auditing and inspection◦ Retain essential documents

Investigator Selection (ICH 5.6)

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Before the trial begins, ensure that all duties and functions are:◦ Defined◦ Established◦ Allocated

Allocation of Duties and Functions (ICH 5.7)

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Provide insurance or indemnify the investigator/institution (if required)

Policies and procedures should address costs of treatment for trial-related injuries

Method and manner of compensation should comply with regulatory requirements

Compensation of Subjects and Investigators (ICH 5.8)

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Documented in agreement between sponsor and investigator/institution

Financing (ICH 5.9)

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Before initiating trial, the sponsor (or sponsor & investigator) should submit required applications to appropriate authorities for:

Review Acceptance Permission

Any submission should be dated and include protocol identifiers

Notification/Submission to Regulatory Authority(ies) (ICH 5.10)

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Obtain IRB/IEC documentation from investigator◦ IRB/IEC name and address

◦ Statement that IRB/IEC is organized and compliant with GCP and applicable regulations

◦ Documented approval to begin study

◦ If requested by the sponsor: Copy of protocol, written informed consent and other written

information to be provided to subjects Subject recruiting procedures Documents related to subject payment

Confirmation of Review by IRB/IEC (ICH 5.11)

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Obtain copy of modifications made and date of IRB/IEC approval :◦ Modification to protocol

◦ Written informed consent

◦ Other written information to subjects Obtain documentation and dates of re-approvals/re-

evaluations or withdrawals/suspensions

Confirmation of Review by IRB/IEC continued (ICH 5.11)

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During planning, ensure that safety and efficacy data are available to support human exposure◦ By the route

◦ At the dosages

◦ For the duration

◦ In the trial population Update Investigator’s Brochure as new information

becomes available

Information on Investigational Products (IP) (ICH 5.12)

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Manufactured in accordance with applicable GMP Coded and labeled to protect blinding, if applicable Labeling complies with regulatory requirements Determine acceptable storage temperatures and

conditions and inform involved parties

Manufacturing, Packaging, Labeling, and Coding IP (ICH 5.13)

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Product packaged to prevent contamination and unacceptable deterioration

Blinded trials should include a mechanism for rapid product identification (in case of medical emergency)◦ Should not permit undetectable breaks

Results of studies on significant formulation changes should be assessed before new clinical trials

Manufacturing, Packaging, Labeling, and Coding IP (ICH 5.13)

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Obtain all required documentation Supply investigator/institution with the products Ensure that written procedures include instructions for

handling and storage of IP Ensure timely delivery Maintain records of IP shipment receipt, disposition,

return, and destruction Maintain system for disposition of unused product Ensure that product is stable over period of use

Supplying and Handling Investigational Products (IP) (ICH 5.14)

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Protocol or other written agreement should state that investigator will provide direct access to source data for monitoring, audits, IRB review and regulatory inspection

Verify that each subject consented to direct access to medical records◦ Must be in writing

Record Access (ICH 5.15)

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Responsible for ongoing safety evaluation of the IP Should promptly notify all investigators/institutions

and regulatory authorities of findings that could:◦ adversely affect safety of subjects

◦ impact conduct of trial

◦ alter IRB approval

Safety Information (ICH 5.16)

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Expedite reporting of adverse drug reactions to:◦ Concerned investigators/institutions,

◦ IRBs/IECs

◦ Regulatory authorities Expedited reports should comply with applicable

regulatory requirements and ICH Guidance Submit to regulatory authorities required safety

updates and reports

Adverse Drug Reaction Reporting (ICH 5.17)

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Verify that:◦ The rights and well-being of human subjects are protected

◦ The reported trial data are accurate, complete, and verifiable from source documents

◦ Conduct of trial is in compliance with: Approved protocol/amendments GCP Applicable regulatory requirements

Monitoring: Purpose (ICH 5.18)

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Monitors should be appointed by sponsor Appropriately trained; have the needed scientific and/or

clinical knowledge◦ Qualifications should be documented

Familiar with:◦ Investigational product◦ Protocol, written informed consent form, and other written

information for subjects◦ SOPs ◦ GCP and applicable regulatory requirements

Monitoring: Selection and Qualification of Monitors (ICH 5.18)

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Ensure trials are adequately monitored Determine extent and nature of monitoring based

on:◦ Objective , Purpose and Endpoints

◦ Size, Design and Complexity

◦ Blinding On-site monitoring before, during, and after the trial

◦ Central monitoring in exceptional circumstances

Monitoring: Extent and Nature of Monitoring (ICH 5.18)

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Main line of communication between sponsor and investigator Verify investigator qualifications & resources Verify staff and facilities are adequate to safely and properly

conduct the trial Verify investigational products

◦ Acceptable storage times and conditions and sufficient supplies ◦ Supplied only to eligible subjects and at protocol-specified dose◦ Subjects provided with instruction before use◦ IP receipt, use and return is controlled and documented◦ Disposition of unused product complies with requirements

Monitoring: Monitor’s Responsibilities (ICH 5.18)

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Verify that investigator follows approved protocol and amendments

Verify that written informed consent is obtained before participation

Ensure that investigator receives current Investigator’s Brochure and all documents/supplies needed

Ensure that investigator and trial staff are informed about the trial

Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18)

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Verify that trial staff are performing specified trial functions in accordance with protocol

Verify that only eligible subjects are being enrolled

Report the subject recruitment rate Verify documents and records are complete and up-to-

date Verify that investigator provides all reports,

notifications, applications and submissions


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Check accuracy and completeness of CRF entries◦ Data required by protocol are reported accurately

◦ Dose/therapy modifications are well-documented

◦ Adverse events, concomitant medications, and intercurrent are reported

◦ Missed visits, tests, and examinations are reported

◦ Withdrawals and dropouts are reported


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Inform investigator of CRF entry error, omission, or illegibility◦ Ensure that corrections, additions, or deletions are made,

dated, explained, and initialed

Determine if adverse events are reported appropriately

Determine if the investigator is maintaining essential documents


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Communicate deviations from the protocol, SOPs, GCP, and regulatory requirements to the investigator

Take appropriate action designed to prevent recurrence of the detected deviations.


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Follow the sponsor’s written SOPs and procedures set by the sponsor for a specific trial

Monitoring: Monitoring Procedures (ICH 5.18)

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Submit written report to sponsor after each trial-related visit/communication◦ Date, site, name of monitor, name of investigator

◦ Summary of review, monitor statements on findings, facts, deviations, deficiencies, conclusions, actions taken, and actions recommended

Review and follow up of the report should be documented by sponsor’s designated representative

Monitoring: Monitoring Report (ICH 5.18)

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An audit is independent of and separate from routine monitoring or quality control functions

Evaluate trial conduct and compliance with the protocol, SOPs, GCP, and regulatory requirements

Audit: Purpose (ICH 5.19)

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Sponsor appoints individuals, independent of the clinical trial

Ensure auditors are qualified by training and experience◦ Qualifications should be documented

Audit: Selection and Qualification of Auditors (ICH 5.19)

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Conducted in accordance with sponsor’s written procedures ◦ What to audit◦ How to audit◦ Frequency, form, and content

Audit: Auditing Procedures (ICH 5.19)

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Audit plan and procedures should be guided by:◦ Importance of trial to submission to regulatory authorities◦ Number of subjects◦ Type and complexity ◦ Levels of risks◦ Any identified problems

Observations and findings should be documented When required, provide and audit certificate

Audit: Auditing Procedures (continued )(ICH 5.19)

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Defined as noncompliance with protocol, SOPs, GCP, and/or regulatory requirements

Should lead to prompt action by the sponsor to secure compliance

If monitoring or auditing identifies serious or persistent noncompliance, sponsor should terminate participate in the trial and notify regulatory authorities

Noncompliance (ICH 5.20)

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Inform and provide reasons◦ Investigators/institutions, and regulatory authorities◦ IRB/IEC

Premature Termination or Suspension of a Trial (ICH 5.21)

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Ensure clinical trial/study reports are prepared and provided to regulatory agencies as required

Reports in marketing applications should meet the standards of the ICH Guidance for Structure and Content of Clinical Study Reports

Clinical Trial/Study Reports (ICH 5.22)

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All investigators conduct the trial in strict compliance with protocol

CRFs are designed to capture data at all multicenter sites

Supplemental CRFs should be provided for investigators who are collecting additional information

Responsibilities of coordinating investigators are documented prior to start of trial

Multicenter Trials (ICH 5.23)

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All investigators are given instructions on following:◦ The protocol ◦ Compliance with uniform standards for the assessment of

clinical and laboratory findings◦ Completing the CRFs

Facilitate communication between investigators

Multicenter Trials (continued)(ICH 5.23)

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Questions?

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