Regulations amending the Food and Drug Regulations (1024- clinical trials)

Guidance for Clinical Trial Sponsors: Clinical Applications (Section 12.3)

ICH Topic E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

ADR Expedited Reporting Summary for ADRs Occurring During Clinical Trials

Medical Device Regulations (sections 59-62)

Guidance document: Mandatory and Voluntary Problem Reporting for Medical Devices

Adverse Event (AE)

Any adverse occurrence in the health of a clinical trial participant who is administered a drug, device or research intervention that may or may not be caused by the administration of the drug, device or research intervention.

Any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.

An adverse drug reaction or adverse event that:

· Results in death or

· Is life threatening or

· Requires in-patient hospitalization or prolongation of existing hospitalization or

· Results in persistent or significant disability or incapacity, or

· Causes congenital malformation.

A serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out in the investigator's brochure or on the label of the drug.

An adverse reaction identified in regulatory documents such as the Investigators Brochure or Product Monograph occurring within the expected frequency estimate; or identified in the Research Ethics Board (REB) submission and letter of information to participants; or is related to study intervention and was the result of the natural progression of the person's disease/illness and/or state of health.

Related to the Drug or Research Intervention:There is a reasonable possibility that the reaction or event may have been caused by the drug or research intervention (i.e. a causal relationship between the reaction and the drug or research intervention cannot be ruled out by the investigator).

The relationship of an AE to the study drug is graded as follows:

(a) None: The AE is definitely not associated with the study drug administered.

(b) Remote: The temporal association is such that the study drug is not likely to have had an association with the observed event.

(c) Possible: This causal relationship is assigned when the AE: (i) follows a reasonable temporal sequence from study drug administration; (ii) could have been produced by the participant's clinical state or other modes of therapy administered to the participant.

(d) Probable: This causal relationship is assigned when the AE: (i) follows a reasonable temporal sequence from study drug administration; (ii) abates upon discontinuation of the study drug; (iii) cannot be reasonably explained by known characteristics of the participant's clinical state.

(e) Definitely related: This causal relationship is assigned when the AE: (i) follows a reasonable temporal sequence from study drug administration; (ii) abates upon discontinuation of the study drug; and (iii) is confirmed by reappearance of the adverse event on repeat exposure (rechallenge).

3.1  Protocol Requirements for Reporting and Monitoring Adverse Events

The protocol must outline how adverse events will be defined, documented, monitored and reported to the sponsor, Health Canada, regulatory authorities and the Research Ethics Board (REB).

Clinical trials, particularly multi-centre trials, should have an Independent Data Safety Monitoring Board or similar committee that reviews all adverse events. If the study does not have an independent monitoring committee the BREB/HREB may request justification or reserve the right to suspend initial approval until such a committee is formed.

3.2  Requirements for Initial Local Serious and Unexpected Adverse Drug Reactions

• Report an adverse event ONLY if the adverse drug reaction is BOTH serious and unexpected in relation to study treatment within 7 days of discovery of the event. Note: include local SAEs regardless of whether they are related to the drug or research intervention.
• The Bannatyne Campus Local SAE report must be used to report these events. All other documentation will be returned to the Investigator. Do not attach related medical records, lab reports or autopsy reports. The REB office will request these reports if considered necessary in assessing the causality of the event.
• With the request for Annual Approval list all unexpected SAEs on the Annual Study Status Report or append a list that indicates the date of initial notification to the REB.
• The Final Study Status Report must also list all local unexpected SAEs that occurred during the trial.
• Do not report adverse drug reactions to the Bannatyne Campus REB if they are: Serious but expected

3.3  Requirements for Initial Non-Local Serious and Unexpected Adverse Drug Reactions

• Report an adverse event ONLY if the adverse drug reaction is BOTH serious and unexpected AND related/possibly related to the study treatment within 30 days of being notified of the event.
• The Bannatyne Campus Non-Local SAE report form must be used to list the SAE. All other documentation will be returned to the Principal Investigator. When the SAEs applies to several studies submit only one copy of Non-Local SAE for each related study. When the form is being submitted for more than one site with different Principal Investigators, please ensure the Principal Investigator from each site (or delegated Co-investigator) signs the form.
• Do not submit International Safety Reports (i.e. CIOMS reports, MedWatch Letters, Dear Investigator letters) or sponsor generated SAE reports. These reports must be retained in the Investigator file and will be requested by the REB office if considered necessary in assessing the causality of the event. There is no regulatory requirement that states these full reports must be submitted to the REB.
• Do not report adverse drug reactions to the Bannatyne Campus REB if they are:

• Serious but expected
• Serious but unrelated to study treatment

3.4  Exceptions

• Other adverse events may be submitted ONLY if the sponsor's protocol has specific stipulations for the submission of these events to the REB.
• The ICH Topic E2A Guidance (Section III A (2)) includes a provision for submitting a serious and expected adverse event report if there is an increase in the rate of occurrence, which is judged to be clinically important.
• These types of events must also be recorded on the appropriate Bannatyne Campus Adverse Event Form.

3.5  Requirements for Follow-Up Reports

• Submit follow up notification of a serious and unexpected adverse drug reaction using the appropriate Bannatyne Campus REB SAE forms only if the participant's condition worsened and/or relationship of the adverse event to the study drug changed.

3.6  Requirements for Serious and Unexpected Medical Device Incidents

• Report an adverse event only if the event is related to a failure of the device or a deterioration in its effectiveness and has led to the death or a serious deterioration in the state of health of the participant (patient), user or other person, or could do so if it were to recur.
• Local events should be reported on the Bannatyne Campus SAE form.
• Non-local events may be reported on the sponsor reporting form.

3.7  Requirements for Serious and Unexpected SAE’s for Studies Involving Other Research Interventions (e.g. protocols not testing a drug but a new surgical procedure)

• Report an adverse event only if it is an unexpected event or occurrence (based on past experience or literature) which led to the death or a serious deterioration in the state of health of the participant or is required by study protocol.
• Local events must be reported on the appropriate Bannatyne Campus SAE forms.

• Report a pregnancy only if there is suspicion that the investigational product under study may have interfered with the effectiveness of a contraceptive treatment; there was a serious complication in the pregnancy (including spontaneous miscarriage) or an elective termination was performed for medical reasons. Elective abortions do not need to be reported as an adverse event.

• Submit all Data Safety Monitoring reports to the REB office with an accompanying cover letter addressing any recommendations that apply to local participants (i.e. Informed consent changes, protocol amendments, study termination etc).

• Updated Investigators Brochures (IB) and any addendums to the IB must be submitted using the Bannatyne Campus Form. If this form does not accompany the IB, the IB will be returned to the Investigator's site.
• Additional information and any changes that have been incorporated in the updated Investigator's Brochure should be highlighted for ease of review and evaluation (Health Canada Guidance for Clinical Trial Sponsors - Section 12.4).
• When the IB applies to several studies submit only one copy of the IB accompanied by the IB form for each related study. When the form is being submitted for more than one site with different Principal Investigators, please ensure the Principal Investigator (or delegated Co-investigator) from each site signs the form.

7.1  SAE Review Process

• The REB coordinator initially reviews all local and non-local SAEs and reports trends and/or any specific recommendations made by safety committees to the REB Chair. All SAEs reported for local participants are reviewed by the REB Chair. Board members receive appendices to the previous month's minutes indicating sites that have submitted SAEs reviewed by the REB coordinator and Chair.
• A verification of the completion of the review will not be sent to the investigator, as this is not a regulatory requirement. However, the REB coordinator will contact the Investigator with concerns or recommendations suggested by the Chair or committee.
• All Bannatyne Campus SAE report forms will be retained in the REB study file.

7.2  Updated IB Review Process

• The REB coordinator initially reviews updated IB forms and reports to the Chair any changes that may be required to the protocol or informed consent. Board members receive appendices to the minutes each month indicating sites that have submitted revised IBs reviewed by the REB coordinator and Chair.
• A verification of the completion of the review will not be sent to the investigator, as this is not a regulatory requirement. However, the REB coordinator will contact the Investigator with concerns or recommendations suggested by the Chair or committee.
• All IBs submitted after January 1, 2004, are listed in a REB IB database, which references applicable studies. Any duplicate IBs submitted by other research sites will be referenced in the database. The REB office will keep only one copy of the IB.
• Outdated IB’s will be destroyed in a confidential manner. The IB cover page and IB form will be retained in each REB study file.

• The Bannatyne Campus REB will now acknowledge receipt of Bannatyne Campus SAEs and IB report forms to provide evidence to the investigator of their submission. This does not imply however that the submission and accompanying documents have been assessed or checked for content, completeness or accuracy. It should be noted, there is no regulatory requirement for acknowledgement of the SAEs or IBs by REBs.
• The Investigator must provide 2 copies (photocopy acceptable) of the Bannatyne Campus SAE form and/or IB form, which will be initialled by REB staff and dated (stamped). The duplicate form will be mailed back to the contact person within 7 working days.

9.1  University of Manitoba Bannatyne Campus Local SAE form

9.2  University of Manitoba Bannatyne Campus Non-Local SAE form

9.3  Updated Investigator Brochure Form

Revised: June 11, 2006