SOPTemplate Safety Reporting v4.2

7/30/2019 SOPTemplate Safety Reporting v4.2

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STANDARD OPERATING PROCEDURE Insert Department

SOP No: Insert number

SOP Title: Safety Reporting

SOP Number Insert Number

SOP Title Safety Reporting

NAME TITLE SIGNATURE DATE

Author

Reviewer

Authoriser

Effective Date:

Review Date:

READ BY

NAME TITLE SIGNATURE DATE

Adapted from CTRG Template SOP v4.2 Page 1 of 13 Copyright: The University of Oxford 2009


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This SOP has been written as an example which can be adapted for use in any departmentconducting clinical research where there are no SOPs in place. The contents of the SOPshould be reviewed in conjunction with the procedures which take place within the

department and the text should be altered accordingly.

Delete all text highlighted in yellow before finalising the document.

1. PURPOSE

The purpose of this Standard Operating Procedure (SOP) is to describe theresponsibilities and processes related to the collection and reporting of adverseevents (AEs) originating from clinical trials in accordance with regulatoryrequirements.

2. INTRODUCTIONThe Medicines for Human Use (Clinical Trials) Regulations 2004 and amendmentsrequire that organisations which take on the role of Sponsor of clinical trials musthave systems in place to record adverse events relating to those trials. To complywith the Regulations, those taking on pharmacovigilance responsibilities must ensurethat the necessary quality standards are observed in documentation of cases, datacollection, validation, evaluation, archiving and reporting of adverse events in theclinical trial. This includes devising Standard Operating Procedures (SOPs) orequivalent written policies/guidelines.

The Department of Health Research Governance Framework for Health and SocialCare 2005 requires that organisations providing health and social care that host,

fund, manage or sponsor research, retain a responsibility for the participants to whomthey have a duty of care. The safety of research participants should be given priorityat all times. Learning from adverse events will promote good practice, enhance theethical and scientific quality of research, and safeguard the public.

3. SCOPE

This SOP applies to Adverse Events (AEs) originating from clinical trials sponsoredby the University of Oxford, in INSERT NAME department/ for the INSERTNAME/NUMBER trial (delete as appropriate) where responsibility for safety reportinghas been delegated to the Chief Investigator (CI) and where a trial-specific Safety

Monitoring Committee is not in place for that study.

This SOP does not apply to commercially funded research or research sponsored byan external non-commercial organization or if a trial or department specific SafetyMonitoring Committee is in place.

4. DEFINITIONS

4.1 Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject

administered a pharmaceutical product and which does not necessarily have a causalrelationship with this treatment. An AE can therefore be any unfavourable and



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unintended sign (including an abnormal laboratory finding), symptom, or diseasetemporally associated with the use of a medicinal (investigational) product, whether ornot related to the medicinal (investigational) product] (see the ICH Guideline for

Clinical Safety Data Management: Definitions and Standard for Expedited Reporting).

4.2 Adverse Reaction (AR)

All untoward and unintended responses to a medicinal product related to any dose.

The phrase "response to medicinal products" means that a causal relationshipbetween a study medication and an AE is at least a reasonable possibility, i.e. therelationship cannot be ruled out.

4.3 Unexpected Adverse Reaction

An adverse reaction, the nature or severity of which is not consistent with theapplicable product information (e.g. Investigators brochure or summary of product

characteristics).

4.4 Serious or Severe Adverse Events

To ensure no confusion or misunderstanding of the difference between the terms"serious" and "severe", which are not synonymous, the following note of clarificationis provided:

The term "severe" is often used to describe the intensity (severity) of a specific event(as in mild, moderate, or severe myocardial infarction); the event itself, however, maybe of relatively minor medical significance (such as severe headache). This is not thesame as "serious," which is based on patient/event outcome or action criteria usuallyassociated with events that pose a threat to a patient's life or functioning.

Seriousness (not severity) serves as a guide for defining regulatory reportingobligations.

4.5 Serious Adverse Event (SAE)

Any untoward medical occurrence that at any dose:

Results in death

Is life-threatening*

Requires inpatient hospitalisation or prolongation of existing hospitalisation**

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Other important medical event(s)***

*The term life-threatening in the definition of serious refers to an event in which thepatient was at risk of death at the time of the event. It does not refer to an event thathypothetically might have caused death if it were more severe.

**Hospitalisation for a pre-existing condition, including elective procedures, which hasnot worsened, does not constitute a serious adverse event.

*** Other events that may not result in death, are not life threatening, or do not requirehospitalisation, may be considered a serious adverse event when, based upon

appropriate medical judgement, the event may jeopardise the patient and may requiremedical or surgical intervention to prevent one of the outcomes listed above.



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(see the ICH Guideline for Clinical Safety Data Management: Definitions andStandard for Expedited Reporting).

4.6 Serious Adverse Reaction (SAR) / Suspected Serious Adverse Reaction (SSAR)An adverse event (expected or unexpected) that is both serious and, in the opinion ofthe reporting investigator, believed with reasonable probability to be due to one of thestudy treatments, based on the information provided.

4.7 Expected Serious Adverse Event / Reaction

A serious adverse event /reaction that could be reasonably expected when taking intoaccount the likely course of the disease or condition during the course of the study orexpected from the study medication(s).

4.8 Suspected Unexpected Serious Adverse Reaction (SUSAR)

A serious adverse drug reaction, the nature or severity of which is not consistent withthe applicable product information (e.g. Investigators Brochure for an unapprovedinvestigational product or package insert/Summary of Medicinal ProductCharacteristics for an approved product). (See the ICH Guideline for Clinical SafetyData Management: Definitions and Standard for Expedited Reporting).

When determining the expectedness of an AE consideration should be given to:

the underlying condition of the subject

o co-morbidity

o concomitant medications

patient population

severity and frequency of the occurrence

An unexpected adverse event meets one or more of the following criteria:

not attributed to the underlying condition of the subject being studied

not attributed to the patient population being studied

not anticipated on the basis of prior experience with the drug under

investigation or with related drugs

not identified in the product information (e.g., Investigators Brochure for an

unapproved investigational product or package insert/summary of productcharacteristics for an approved product)

not defined in the study protocol

4.9 Chief Investigator (CI)

The investigator who signs the ethics application for the study.

4.10 Principal Investigator (PI)

For multi-centre studies the principal investigator will be the lead investigator for asite.



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5. RESPONSIBILITIES

Sponsor responsibilities for safety reporting will be delegated to the CI or the

company supplying the drug / substance as appropriate and according to riskassessment. In such cases, all detailed responsibilities will fall to the delegatedperson/body. This SOP gives procedures for cases where these responsibilities aredelegated to the CI.

For studies where the safety reporting responsibilities are delegated to a companythe wording of this section must be amended accordingly.

5.1 Chief Investigator (CI)

Undertake responsibility for safety reporting on behalf of the Sponsor, wheredelegated by the sponsor.

Be responsible for receipt, review, reporting and coordination of all SAE forms (from

all centres in multi-centre studies) in accordance with the protocol, including followingup all SAEs to resolution.

Be responsible for the ongoing safety evaluation and reporting of SUSARS to theMHRA, Main REC, relevant host NHS Trust, and Clinical Trials and ResearchGovernance (CTRG) as sponsor, within the timelines required by those bodies.

Provide investigator updates for suspected unexpected serious adverse reactions(SUSARs) to all centres (for multi-centre studies).

Be responsible for instigating any urgent safety measures required to protect trialsubjects and reporting these to the MHRA within 3 days.

Ensure any SAEs which are detailed in the protocol as not requiring immediate

reporting are recorded on the CRFs and that any SARs are included in the AnnualSafety Report.

Prepare and submit Annual Safety Reports to the Medicines and Healthcare productsRegulatory Agency (MHRA), Main Research Ethics Committee (REC), NHS Trust(s)and CTRG.

5.2 Principal Investigator (PI)

(For multi-centre studies; For single centre studies safety reporting and recordingresponsibilities will fall to the CI so these sections need to be amended accordingly)

Ultimate responsibility for safety reporting at a site remains with the PI, however,initial form completion and submission may be undertaken by other designated studypersonnel who are appropriately trained and experienced.

Be responsible for reporting all SAEs to CTRG, CI, NHS Trust R&D as soon as theybecome aware of the event, except for those identified in the protocol as not requiringimmediate reporting. Provide further information and updates as required.

Record and report non-serious AEs in accordance with the protocol.

5.3 Research Study Staff

Report all suspected SAEs to the CI or PI (or in their absence a delegated seniormember of the research team) as soon as they become aware of the event.



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5.4 Clinical Trials and Research Governance

Undertake to log all reported SAEs and monitor progress of any required regulatorynotification, ensuring all SUSARs are submitted to the MHRA and main REC within

the required timelines.

Ensure all SAE reports, including SUSARs are reviewed by the Medical Monitor andby the Oxford Radcliffe Hospital Trust / University of Oxford Trials Safety Group.Where other local arrangements for review apply they should be described here.

Keep track of submission of Annual Safety Reports to the MHRA and Main REC andif necessary, remind investigators when these are due.

5.5 Medical Monitor

The Medical Monitor on behalf of the TSG will review SAEs that require immediatereporting. Where other local arrangements for review apply (e.g. review by

commercial company) they should be described here.Document the review using the CTRG SAE Review Form.

Follow up, requesting further information if appropriate, all reported SAEs to closure.

Review all identified fatal or life threatening SUSARs within three days and all otherSUSARs within seven days.

Provide review of the safety section of protocols of new studies undertaken by theTSG.

5.6 Oxford Radcliffe Hospital Trust / University of Oxford Trials Safety Group (TSG)

Each quarter the TSG will review all SAEs occurring in the trial to date. Any issues

arising will be communicated to the CI by CTRG and appropriate actions agreed.

6. SERIOUS ADVERSE EVENT PROCESSING AND REPORTINGPROCEDURE

6.1 Collection, Review and Reporting of Serious Adverse Event Data

When the investigator or their delegate becomes aware of an SAE they will completean SAE Report Form (unless it is an SAE identified in the protocol as not requiringimmediate reporting). The SAE Report form shall include, as a minimum, thefollowing essential elements:

Identifiable patient

Identifiable drug

Identifiable event

Identifiable reporter

Identifiable source

Study number and / or title

Assessment of relatedness and expectedness**



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The investigator or delegate faxes the report to CTRG, the appropriate R&D Trustoffice, and other relevant parties in accordance with the protocol. The report must besent within one working day of the investigator becoming aware of the event.

**If relatedness and expectedness have not yet been assessed by a medicallyqualified practitioner the initial report should be sent within one working day anyway.A follow up signed copy with the assessment outcomes should be sent as soon aspossible.

CTRG will acknowledge receipt of the SAE form by fax or email including notifying theinvestigator of an assigned unique CTRG tracking number. If acknowledgement is notreceived within one working day the investigator should contact CTRG as a matter ofurgency. CTRG will send any queries arising to the reporter by phone, fax or emaildepending on urgency.

The investigator shall provide updated information as it becomes available or as

requested by CTRG until closure of the event by the Medical Monitor.

6.2 Expedited Reporting of Suspected Unexpected Serious Adverse Reactions

If it is established that the event is a Suspected Unexpected Serious AdverseReactions (SUSAR), the investigator or delegate informs CTRG immediately. CTRGthen forwards the SUSAR information to the Medical Monitor acting on behalf of theTSG.

In accordance with Article 2 of the European Clinical Trials Directive 2001/20/EC, alladverse events judged by either the investigator or the Medical Monitor as having areasonable suspected causal relationship to an IMP will be treated as adversereactions. The causality assessment given by the investigator will not be downgraded

by the Medical Monitor. If there is disagreement both opinions must be reported.For a fatal or life threatening event, the Medical Monitor provides a review within 3calendar days, and for other events, within 7 calendar days. Upon receipt of thereview, the chief investigator or delegate submits the report to the MHRA and sendscopies to the main REC, CTRG and relevant Trust R&D departments. The SUSARreport must reach the MHRA within 7 calendar days of awareness for a fatal or lifethreatening event and fifteen calendar days for other events.

The clock start date and progress of the reporting is tracked by CTRG in an SAE log.

6.3 Other Adverse Events

Other SAEs that have been identified in the protocol as not requiring immediate

reporting and non serious adverse events should be reported in accordance with theprotocol.

6.4 Urgent Safety Measures

The CI must take appropriate urgent safety measures as necessary to protect trialsubjects. The measures should be taken immediately. The CI phones the ClinicalTrial Unit at the MHRA and discusses the issue with a medical assessor as soon aspossible. The CI notifies the MHRA, in writing within 3 days of instigating the urgentsafety measure. The notification is submitted as a substantial amendment form plus acovering letter detailing the measures taken, the reason(s) for them, medicalassessor details and any supporting documentation. Copies are sent to the mainREC, CTRG and Trust R&D.



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Current details on where to submit notifications are available on the MHRA website.

7. ANNUAL SAFETY REPORTS

7.1 Reporting requirements

Annual Safety Reports must be submitted by the CI to the MHRA, REC and copies toCTRG and the Trust R&D on the anniversary of the Clinical Trials Authorisation(CTA).

The CI, on behalf of University of Oxford shall submit the Annual Safety Report oncea year throughout the clinical trial or on request to the MHRA and the main REC,taking into account all newly available safety information received during the reportingperiod.

If the trial is short term (i.e. less than 6 months), the Annual Safety Report is duewithin 90 days of the end of the trial, together with the notification of end of trial.

If the trial is terminated early for any reason, (not limited to safety reasons) a safetyreport must be submitted to the MHRA within 15 days of the date of termination.

The Annual Safety Report must be submitted for all trials where regulatoryauthorisation has been granted, whether or not the trial has started or there havebeen any SSARs or SUSARs.

7.2 Contents

The Annual Safety Report should have three parts: CTRG have an Annual SafetyReport Template available from their website which can be adapted for use.

Analysis of the subjects safety in the clinical trial

A line listing of all SSARs (including all SUSARs) occurred in the trial, including alsoSSARs from third countries

An aggregate summary tabulation of SSARs that occurred in the trial.

The Annual Safety Report shall include all SUSARs occurring in the reporting periodin other trials using the same product which are conducted by the University of Oxfordoutside the UK. This paragraph applies to University of Oxford sponsored trials of EUlicensed products. For trials using an EU unlicenced product all SUSARs, includingany worldwide which the sponsor becomes aware of, require expedited reporting;they must not be restricted to the Annual Safety Report.

If in any year there are no SARs to report the report can take the form of a letterstating this.

The Annual Safety Report sent to the REC should be accompanied by a standardcover sheet available from the NRES website.http://www.nres.npsa.nhs.uk/applicants/after-ethical-review/safetyreports/safety-reports-for-ctimps/

8. FORMS/TEMPLATES TO BE USED

Where Forms/Templates are referenced in the text, the numbers and titles are to belisted under this section.

http://www.nres.npsa.nhs.uk/applicants/after-ethical-review/safetyreports/safety-reports-for-ctimps/http://www.nres.npsa.nhs.uk/applicants/after-ethical-review/safetyreports/safety-reports-for-ctimps/http://www.nres.npsa.nhs.uk/applicants/after-ethical-review/safetyreports/safety-reports-for-ctimps/http://www.nres.npsa.nhs.uk/applicants/after-ethical-review/safetyreports/safety-reports-for-ctimps/


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Serious Adverse Event Reporting Form

Annual Safety Report Template



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9. FLOW CHART

Multi-centre and single centre versions provided, to be adapted as required by theuser

a) for use in a single centre trial


CTRG sendsacknowledgment by e-mail

Is the event considered to berelated to the study drug?

CI reports to MHRA, main ethicscommittee, CTRG and Trust R&D

within 15 days

SAE identified in the protocol as notrequiring immediate reporting

YesSAE recorded in

CRF only

No

CTRG checks form foressential information

SAE form completed, faxed to CTRG, & TrustR&D within one working day (even if clinician

not available to assign causalityandexpectedness and sign form)

CTRG requests missing information andupdated SAE form

If e-mail not received within 1 working dayCI requests acknowledgement from CTRG

No

Yes

Is the event expected? Yes

NoYes

CTRG refersSAE to TSG /

MedicalMonitor for

independentreview

CI reports to MHRA, main ethicscommittee, CTRG and Trust R&D

within 7 days

SAE followed to resolution

Report filed appropriately

SARs annual safety report

No = SUSAR

Is the SUSAR fatal or life-threatening?

SAE identified, CI or delegate made aware


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b) for use in a multi centre trial


CTRG sendsacknowledgment by e-mail

SAE identified in the protocol as notrequiring immediate reporting

YesSAE recorded in

CRF only

No

CTRG checks form foressential information

SAE form completed, faxed to CI, CTRG, &Trust R&D within one working day (even if

clinician not available to assign causalityandexpectedness and sign form)

CTRG requests missing information andupdated SAE form

If e-mail not received within 1 working dayCI requests acknowledgement from CTRG

Is the event considered to berelated to the study drug? No

Yes

Is the event expected? Yes

NoYes

CTRG refersSAE to TSG /

MedicalMonitor for

independentreview

CI reports to MHRA & main ethicscommittee within 7 days: CI Informsother sites, CTRG and Trust R&D

CI reports to MHRA & main ethicscommittee within 15 days: CI informs

other sites, CTRG and Trust R&D

SAE followed to resolution

Report filed appropriately

SARs annual safety report

No = SUSAR

Is the SUSAR fatal or life-threatening?

SAE identified, PI or delegate made aware


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10. REFERENCES

This section is used to list all controlled internal references (e.g. SOPs) and externalreferences referred to within the text of the SOP only.

10.1 Internal References

Insert

10.2 External References

Clinical Safety Data Management: Data Elements for Transmission of Individual CaseSafety Reports [E2B] (CPMP/ICH/287/95 modification).

Clinical Safety Data Management: Periodic Safety Update Reports for Marketed

Drugs [E2C] (CPMP/ICH/288/95).Clinical trial authorisations: Safety reporting - SUSARS and ASRs, annual safetyreports, urgent safety measures and end of trial notifications. MHRA website:http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safetyreporting-SUSARSandASRs/index.htm

Detailed guidance on the collection, verification and presentation of adverse reactionreports arising from clinical trials on medicinal products for human use (ENTR/CT3revision 2, April 2006).

Good Clinical Safety Data Management: Definitions and Standards for ExpeditedReporting [E2A] (CPMP/ICH/377/95).

The Medicines for Human Use (Clinical Trials) Regulations 2004 and AmendmentsMay 2006, Nov 2006 and May 2008.

The Department of Health Research Governance Framework for Health and SocialCare 2005.

European Commission (2001) Directive 2001/20/EC of the European Parliament andof the Council. Official Journal of the European Communities 1.5.2001 L124-44.http://europa.eu/eur-lex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf

11. CHANGE HISTORY

Where the SOP is the initial version:

SOP No: Record the SOP and version number

Effective Date: Record effective date of the SOP or see page 1

Significant Changes: State, Initial version or new SOP

Previous SOP no.: State NA.

Where replacing a previous SOP:

SOP No: Record the SOP and new version number

Effective Date: Record effective date of the SOP or see page 1

http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safetyreporting-SUSARSandASRs/index.htmhttp://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safetyreporting-SUSARSandASRs/index.htmhttp://europa.eu/eur-lex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdfhttp://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safetyreporting-SUSARSandASRs/index.htmhttp://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/Clinicaltrials/Safetyreporting-SUSARSandASRs/index.htmhttp://europa.eu/eur-lex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf


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Significant Changes: Record the main changes from previous SOP

Previous SOP no.: Record SOP and previous version number

SOP no.EffectiveDate

Significant ChangesPreviousSOP no.


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SOPTemplate Safety Reporting v4.2