THREB SOP 4.5

1. Purpose

This section describes the policy for the reporting of Adverse Events and other Unanticipated Problems to the Tri-Hospital Research Ethics Board.

This policy supersedes previous policies regarding reporting of Serious Adverse Events (SAEs) and is based on the CAREB to which Health Canada had no objections.

2. Policy

Continuing review includes review of adverse events. The principal investigator is required to report to the REB only those local adverse events that are deemed to be unanticipated problems (unexpected, related and involving greater than expected risk (see definitions below).

3. Definitions

  • Unanticipated problem: any incident, experience, or outcome that meets all of the following criteria:
  • Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document, or the Investigator Brochure; and (b) the characteristics of the research participant population being studied;
  • Related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the (investigational product(s)) or procedures involved in the research); and suggests that the research places research participants or others at a greater risk of harm(including physical, psychological, economic, or social harm) than was previously known or recognized.
  • Periodic safety update report: a summary report, created by the sponsor, listing all of the suspected unexpected serious adverse events that have occurred in that reporting period and that also includes a concise summary highlighting the main points of concern and the evolving safety profile of the investigational product.

Specific policies

4. What events must be reported to the RED?

4.1 Local (internal) adverse events

The principal investigator is required to report to the REB only those local adverse events that are deemed to be unanticipated problems (unexpected, related and involving greater risk – see definition). Upon becoming aware of a local adverse event, the investigator should assess whether the adverse event represents an unanticipated problem. If the investigator determines that the adverse event represents an unanticipated problem, the investigator must report it to the REB. If the investigator determines that an adverse event is not an unanticipated problem, but the sponsor subsequently determines that it is, the sponsor should report this determination to the principal investigator, and such reports must then be submitted to the REB. The principal investigator must clearly explain how the event represents an “unanticipated problem”. A description of any proposed protocol changes or other corrective actions to be taken by the principal investigator or sponsor in response to the event must also be described in the report.

The following local adverse events ordinarily should be reported to the REB:

  • Serious adverse events that are considered expected
  • Serious adverse events that are considered not related to the investigational product or research procedures, whether the event is expected or not.
  • Non-serious adverse events, whether expected or not

Reference: ICH Harmonised Tripartite Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A). 27 October 1994

4.2 External (non-local) adverse events

THREB does not review and will not acknowledge receipt of non-local Serious Adverse Events. Although it may be a requirement for some studies to submit non-local SAEs, THREB acknowledgement of receipt is not required by TCPS, GCP or Health Canada or OHRP. Evaluable information regarding the safety implications of non-local events is provided to THREB by DSMB or Sponsor-generated summary safety reports.

If the Local Investigator absolutely requires some acknowledgement of receipt of submission of non-local SAEs, it will be provided only if the request is submitted with 1) a cover letter or form for REB stamp or signature AND 2) a self-addressed envelope.

The FDA and OHRP note that it is neither useful nor necessary for reports of individual adverse events occurring in research participants enrolled in multi-centre studies to be distributed routinely to investigators at all centres conducting the research or to the REB overseeing those centres. There is no Health Canada regulation for reporting external adverse events to the REB. ICH requirements will be met if unanticipated problems are reported to the REB as described in this guidance. (see ICH reference at side)

In general, the investigators and REBs are not appropriately situated to assess the significance of individual external adverse events. For multi-centre studies, the sponsor and/or data and safety monitoring committee is in a better position to process and analyse adverse event information for the entire study, and to assess whether an event is an “unanticipated problem". Accordingly, investigators may rely on the sponsor's assessment and provide to the REB a
periodic summary safety update report prepared by the sponsor. The format used for annual summary safety reports is acceptable. (see European Commission reference at side.)

In general, the sponsor should amend the Investigator's Brochure as needed so as to keep the description of safety information updated. Single isolated external adverse events rarely meet the requirements for reporting to REBs. (See HHS and OHRP references at side.)

Reference: ICH E2A, II.A.1 indicates that expedited reporting is required for serious unexpected ADRs from clinical trials as well as spontaneous or other sources. ICH E6, 5.17 notes that the sponsor should expedite the reporting of these reports to IRBs [in accordance with ICH E2A] where required. There is no Health Canada requirement for this; therefore these reports do not need to be sent to the REB unless they meet the definition of unanticipated problem as described in this guidance.

European Commission. . April 2006, or the ICH E2F draft consensus guideline “” 5 June 2008

US Department of Health and Human Services. , January, 2009

Office for Human Research Protections (OHRP) and Department of Health and Human Services (HHS) –

Individual isolated external adverse events should only be reported to the REB if they are unanticipated problems and the report includes all of the following information:

  • the event described is both serious, unexpected and related or possibly related to participation in the study,
  • the report identifies all previous safety reports concerning similar adverse experiences,
  • the report analyzes the significance of the current adverse experience in light of the previous reports, and
  • the report outlines any proposed protocol changes, informed consent form changes or other corrective actions to be taken by the sponsor in response to the unanticipated problem.

Reports not meeting these requirements will be returned to the submitter with a description of the REB reporting requirements (e.g., a copy of this REB policy)

In summary, only adverse events that are unanticipated problems should be reported to the REB with the required accompanying documentation:

Reference: Other Entities – see Section 602
Review Procedures for Ongoing Research – see TCPS, Article 1.13, p. 1.10

4.3 Other unanticipated problems

There may be other incidents, experiences, or outcomes not considered adverse events but that meet the definition of unanticipated problems; such events, in the opinion of the investigator or sponsor, place research participants or others at a greater risk of physical or psychological harm than was previously anticipated, or have implications for the conduct of the study or the integrity of research data.

Upon becoming aware of any other incident, experience, or outcome that may represent an unanticipated problem, the investigator should assess whether it does constitute an unanticipated problem. If the investigator determines that it is an unanticipated problem, the investigator must report the problem to the REB. In general, only those incidents, experiences, or outcomes that require a change to the study procedures, study documents and/or require notifying the research participants of a change in the risk/benefit ratio should be reported to the REB. This may include:

  • For an "expected," serious adverse reaction, an increase in the rate of occurrence which is judged to be clinically important,
  • A significant hazard to the research participant population, such as lack of efficacy with a investigational product used in treating life-threatening disease,
  • A major safety finding from a newly completed animal study that suggests a significant risk for human participants (such as carcinogenicity),
  • Breaches of privacy and confidentiality,
  • Acts of nature that impact the study conduct or data integrity (e.g. – floods, hurricanes, earthquakes, pandemics, etc.)

5. When to report unanticipated problems to the REC

  • Reportable local adverse events (i.e., those that represent unanticipated problems) should be reported to the REB within 15 calendar days of the principal investigator becoming aware of them.
  • Fatal or life-threatening reportable local adverse events should be reported to the REB with 7 calendar days.
  • Periodic safety update reports, individual reportable external adverse events (i.e., those that represent unanticipated problems), and other unanticipated problems should be reported to the REB within 15 calendar days of the sponsor (i.e., Health Canada Clinical Trial Application holder) becoming aware of or receiving the event/the report.
  • Principal investigators should continue to report unanticipated problems to the REB for the duration of the study (i.e., until the study is closed at the principal investigator’s institution).

6. Corrective actions/substantive changes

An incident, experience, or outcome that meets the three criteria listed in the definition of unanticipated problem generally will warrant consideration of substantive changes in the research protocol or informed consent documents or other corrective actions in order to protect the safety, welfare, or rights of research participants or others. Corrective actions or substantive changes might include:

  • Changes to the research protocol initiated by the principal investigator prior to obtaining REB approval to eliminate apparent immediate hazards to research participants;
  • Modification of inclusion or exclusion criteria to mitigate the newly identified risks;
  • Implementation of additional procedures for monitoring research participants;
  • Suspension of enrollment of new research participants;
  • Suspension of research procedures on currently enrolled research participants;
  • Modification of informed consent documents to include a description of newly recognized risks; and
  • Provision of additional information about newly recognized risks to previously enrolled research participants.

7. Protocol deviations

A protocol deviation is an unanticipated or unintentional divergence or departure from the expected conduct of an approved study that is not consistent with the current research protocol, consent document or study addenda.

Examples of protocol deviations include:

  • changes in procedures initiated to eliminate immediate hazards to study subjects;
  • enrolment of subjects outside protocol inclusion/ exclusion criteria, whether agreed to or not by the sponsor;
  • medication/intervention errors (i.e. incorrect drug/intervention, incorrect dosage of the drug);
  • unintentional deviation in specific research intervention procedures or timing of the research intervention which could impact upon the safety or efficacy of the study-related intervention or upon the experimental design;
  • breach of confidentiality or privacy without a need to know, or by data exposure (computer security breach, documents left unsecured), and;
  • significant deviation from the consenting process.

For protocol deviations as described above the Investigator must submit a letter to THREB

  1. describing the deviation,
  2. assessing its impact on the research participant and the study integrity, and
  3. describing what is being done to correct the deviation or prevent a re-occurrence.

Upon receipt of the protocol deviation report the THREB Chair, or designate, will review the report and submit it to the full THREB if appropriate.

As noted in 3.4 above, the Investigator should not implement any deviation from, or changes of the protocol without prior THREB approval, except where necessary to eliminate an immediate hazard(s) to subjects, or when the change(s) involves only logistical or administrative aspects of the trials (e.g. change in monitor(s), change of telephone number(s)).

The Investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to subjects without prior THREB approval. However, as soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) must be submitted to the THREB for review.