STANDARD OPERATING PROCEDURE

Insert Department SOP No: Insert number SOP Title: Safety Reporting

SOP Number SOP Title

Insert Number 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 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 department conducting clinical research where there are no SOPs in place. The contents of the SOP should 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 the responsibilities and processes related to the collection and reporting of adverse events (AEs) originating from clinical trials in accordance with regulatory requirements.

2.

INTRODUCTION
The Medicines for Human Use (Clinical Trials) Regulations 2004 and amendments require that organisations which take on the role of Sponsor of clinical trials must have systems in place to record adverse events relating to those trials. To comply with the Regulations, those taking on pharmacovigilance responsibilities must ensure that the necessary quality standards are observed in documentation of cases, data collection, validation, evaluation, archiving and reporting of adverse events in the clinical trial. This includes devising Standard Operating Procedures (SOPs) or equivalent written policies/guidelines. The Department of Health Research Governance Framework for Health and Social Care 2005 requires that organisations providing health and social care that host, fund, manage or sponsor research, retain a responsibility for the participants to whom they have a duty of care. The safety of research participants should be given priority at all times. Learning from adverse events will promote good practice, enhance the ethical and scientific quality of research, and safeguard the public.

3.

SCOPE
This SOP applies to Adverse Events (AEs) originating from clinical trials sponsored by the University of Oxford, in INSERT NAME department/ for the INSERT NAME/NUMBER trial (delete as appropriate) where responsibility for safety reporting has 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 by an external non-commercial organization or if a trial or department specific Safety Monitoring Committee is in place.

4.
4.1

DEFINITIONS
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 causal relationship with this treatment. An AE can therefore be any unfavourable and

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

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unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not 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 relationship between a study medication and an AE is at least a reasonable possibility, i.e. the relationship cannot be ruled out. 4.3 Unexpected Adverse Reaction An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. Investigators brochure or summary of product characteristics). 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 clarification is 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, may be of relatively minor medical significance (such as severe headache). This is not the same as "serious," which is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 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

4.4

Other important medical event(s)*** *The term life-threatening in the definition of serious refers to an event in which the patient was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death if it were more severe. **Hospitalisation for a pre-existing condition, including elective procedures, which has not worsened, does not constitute a serious adverse event. *** Other events that may not result in death, are not life threatening, or do not require hospitalisation, may be considered a serious adverse event when, based upon appropriate medical judgement, the event may jeopardise the patient and may require medical or surgical intervention to prevent one of the outcomes listed above.

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

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(see the ICH Guideline for Clinical Safety Data Management: Definitions and Standard 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 of the reporting investigator, believed with reasonable probability to be due to one of the study treatments, based on the information provided. Expected Serious Adverse Event / Reaction A serious adverse event /reaction that could be reasonably expected when taking into account the likely course of the disease or condition during the course of the study or expected from the study medication(s). Suspected Unexpected Serious Adverse Reaction (SUSAR) A serious adverse drug reaction, the nature or severity of which is not consistent with the applicable product information (e.g. Investigators Brochure for an unapproved investigational product or package insert/Summary of Medicinal Product Characteristics for an approved product). (See the ICH Guideline for Clinical Safety Data Management: Definitions and Standard for Expedited Reporting). When determining the expectedness of an AE consideration should be given to: o o the underlying condition of the subject co-morbidity concomitant medications patient population severity and frequency of the occurrence 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 product characteristics for an approved product) not defined in the study protocol

4.7

4.8

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

4.9

Chief Investigator (CI) The investigator who signs the ethics application for the study. Principal Investigator (PI) For multi-centre studies the principal investigator will be the lead investigator for a site.

4.10

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

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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 risk assessment. In such cases, all detailed responsibilities will fall to the delegated person/body. This SOP gives procedures for cases where these responsibilities are delegated to the CI. For studies where the safety reporting responsibilities are delegated to a company the wording of this section must be amended accordingly.

5.1

Chief Investigator (CI) Undertake responsibility for safety reporting on behalf of the Sponsor, where delegated 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 following up all SAEs to resolution. Be responsible for the ongoing safety evaluation and reporting of SUSARS to the MHRA, Main REC, relevant host NHS Trust, and Clinical Trials and Research Governance (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 trial subjects 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 Annual Safety Report. Prepare and submit Annual Safety Reports to the Medicines and Healthcare products Regulatory 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 recording responsibilities 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 study personnel who are appropriately trained and experienced. Be responsible for reporting all SAEs to CTRG, CI, NHS Trust R&D as soon as they become aware of the event, except for those identified in the protocol as not requiring immediate 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 senior member of the research team) as soon as they become aware of the event.

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

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5.4

Clinical Trials and Research Governance Undertake to log all reported SAEs and monitor progress of any required regulatory notification, 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 and by 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 and if necessary, remind investigators when these are due.

5.5

Medical Monitor The Medical Monitor on behalf of the TSG will review SAEs that require immediate reporting. 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 other SUSARs within seven days. Provide review of the safety section of protocols of new studies undertaken by the TSG.

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.
6.1

SERIOUS ADVERSE EVENT PROCESSING AND REPORTING PROCEDURE

Collection, Review and Reporting of Serious Adverse Event Data When the investigator or their delegate becomes aware of an SAE they will complete an SAE Report Form (unless it is an SAE identified in the protocol as not requiring immediate reporting). The SAE Report form shall include, as a minimum, the following essential elements: Identifiable patient Identifiable drug Identifiable event Identifiable reporter Identifiable source Study number and / or title Assessment of relatedness and expectedness**

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

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The investigator or delegate faxes the report to CTRG, the appropriate R&D Trust office, and other relevant parties in accordance with the protocol. The report must be sent within one working day of the investigator becoming aware of the event. **If relatedness and expectedness have not yet been assessed by a medically qualified 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 as possible. CTRG will acknowledge receipt of the SAE form by fax or email including notifying the investigator of an assigned unique CTRG tracking number. If acknowledgement is not received within one working day the investigator should contact CTRG as a matter of urgency. CTRG will send any queries arising to the reporter by phone, fax or email depending 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 Adverse Reactions (SUSAR), the investigator or delegate informs CTRG immediately. CTRG then forwards the SUSAR information to the Medical Monitor acting on behalf of the TSG. In accordance with Article 2 of the European Clinical Trials Directive 2001/20/EC, all adverse events judged by either the investigator or the Medical Monitor as having a reasonable suspected causal relationship to an IMP will be treated as adverse reactions. 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 3 calendar days, and for other events, within 7 calendar days. Upon receipt of the review, the chief investigator or delegate submits the report to the MHRA and sends copies to the main REC, CTRG and relevant Trust R&D departments. The SUSAR report must reach the MHRA within 7 calendar days of awareness for a fatal or life threatening 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 the protocol. Urgent Safety Measures The CI must take appropriate urgent safety measures as necessary to protect trial subjects. The measures should be taken immediately. The CI phones the Clinical Trial Unit at the MHRA and discusses the issue with a medical assessor as soon as possible. The CI notifies the MHRA, in writing within 3 days of instigating the urgent safety measure. The notification is submitted as a substantial amendment form plus a covering letter detailing the measures taken, the reason(s) for them, medical assessor details and any supporting documentation. Copies are sent to the main REC, CTRG and Trust R&D.

6.4

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

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

7.
7.1

ANNUAL SAFETY REPORTS

Reporting requirements Annual Safety Reports must be submitted by the CI to the MHRA, REC and copies to CTRG 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 once a 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 reporting period. If the trial is short term (i.e. less than 6 months), the Annual Safety Report is due within 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 safety report 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 regulatory authorisation has been granted, whether or not the trial has started or there have been any SSARs or SUSARs.

7.2

Contents The Annual Safety Report should have three parts: CTRG have an Annual Safety Report 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 also SSARs 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 period in other trials using the same product which are conducted by the University of Oxford outside the UK. This paragraph applies to University of Oxford sponsored trials of EU licensed products. For trials using an EU unlicenced product all SUSARs, including any 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 letter stating this. The Annual Safety Report sent to the REC should be accompanied by a standard cover sheet available from the NRES website. http://www.nres.npsa.nhs.uk/applicants/after-ethical-review/safetyreports/safetyreports-for-ctimps/

8.

FORMS/TEMPLATES TO BE USED
Where Forms/Templates are referenced in the text, the numbers and titles are to be listed under this section.

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

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Insert Department SOP No: Insert number SOP Title: Safety Reporting

Serious Adverse Event Reporting Form Annual Safety Report Template

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

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9.

FLOW CHART
Multi-centre and single centre versions provided, to be adapted as required by the user a) for use in a single centre trial
SAE identified, CI or delegate made aware

SAE identified in the protocol as not requiring immediate reporting

Yes

SAE recorded in CRF only

No

SAE form completed, faxed to CTRG, & Trust R&D within one working day (even if clinician not available to assign causality and expectedness and sign form) CTRG requests missing information and updated SAE form

CTRG refers SAE to TSG / Medical Monitor for independent review

CTRG checks form for essential information CTRG sends acknowledgment by e-mail

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

Is the event considered to be related to the study drug?

No SAE followed to resolution

Yes

Report filed appropriately SARs annual safety report

Is the event expected?

Yes

No = SUSAR

Is the SUSAR fatal or life-threatening?

Yes

No

CI reports to MHRA, main ethics committee, CTRG and Trust R&D within 7 days

CI reports to MHRA, main ethics committee, CTRG and Trust R&D within 15 days

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

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b) for use in a multi centre trial

SAE identified, PI or delegate made aware

SAE identified in the protocol as not requiring immediate reporting

Yes

SAE recorded in CRF only

No

SAE form completed, faxed to CI, CTRG, & Trust R&D within one working day (even if clinician not available to assign causality and expectedness and sign form) CTRG requests missing information and updated SAE form

CTRG refers SAE to TSG / Medical Monitor for independent review

CTRG checks form for essential information CTRG sends acknowledgment by e-mail

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

Is the event considered to be related to the study drug?

No SAE followed to resolution

Yes

Report filed appropriately SARs annual safety report

Is the event expected?

Yes

No = SUSAR

Is the SUSAR fatal or life-threatening?

Yes

No

CI reports to MHRA & main ethics committee within 7 days: CI Informs other sites, CTRG and Trust R&D

CI reports to MHRA & main ethics committee within 15 days: CI informs other sites, CTRG and Trust R&D

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

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10.

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

10.1

Internal References Insert External References Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety 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 safety reports, 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 reaction reports arising from clinical trials on medicinal products for human use (ENTR/CT3 revision 2, April 2006). Good Clinical Safety Data Management: Definitions and Standards for Expedited Reporting [E2A] (CPMP/ICH/377/95). The Medicines for Human Use (Clinical Trials) Regulations 2004 and Amendments May 2006, Nov 2006 and May 2008. The Department of Health Research Governance Framework for Health and Social Care 2005. European Commission (2001) Directive 2001/20/EC of the European Parliament and of 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

10.2

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. SOP No: Record the SOP and new version number Effective Date: Record effective date of the SOP or see page 1

Where replacing a previous SOP:

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

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Insert Department SOP No: Insert number SOP Title: Safety Reporting

Significant Changes: Record the main changes from previous SOP Previous SOP no.: Record SOP and previous version number

SOP no.

Effective Date

Significant Changes

Previous SOP no.

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

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