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1.0 PURPOSE

This standard operating procedure (SOP) describes the procedures for the ongoing review activities that occur after the initial Research Ethics Board (REB) approval of a research project and before the formally scheduled continuing review of the research project.

2.0 SCOPE

This SOP pertains to REBs that review human participant research in compliance with applicable regulations and guidelines.

3.0 RESPONSIBILITIES

All REB members, REB Office Personnel and Researchers are responsible for ensuring that the requirements of this SOP are met.

The Researcher is responsible for reporting to the REB any new information generated throughout the research that might affect the rights, safety, and well- being of research participants, including reportable events that meet the reporting criteria as per this SOP. Once the REB has been informed of this new information, the participants may also need to be informed. Any documents altered or produced to communicate this new information to participants must be reviewed and approved for use by the REB before the implementation and exchange with participants. In a situation where an urgent safety issue arises that could put the participants in significant harm. In that case, the PI/study team should cease the study procedures, communicate with the participants immediately, and report to the REB after the communication and action taken within five days.
The Researcher is responsible for reporting to the REB any information about the conduct of the research that could affect the rights, safety, and well-being of research participants, including information about any serious or continuing non- compliance.

When action is taken to ensure the protection of participants' rights, safety, and well-being (e.g., for an unanticipated problem involving risks to participants or others), the REB is responsible for reporting to the Researcher and the Organizational Official(s). It has the authority to notify the Sponsor and/or the appropriate regulatory authorities of any events that meet the reporting criteria. The REB may delegate regulatory authority reporting (as applicable) to the organization.

The REB Chair or designee is responsible for reviewing all reportable events submitted to the REB and any proposed amendments to the research and determining the type of review (i.e., delegated or Full Board) or action required.

The REB members are responsible for reviewing any new information, reportable events or proposed amendments assigned to them or assigned to a Full Board meeting and for recommending the appropriate course of action.

4.0 DEFINITIONS

See Glossary of Terms.

5.0 PROCEDURE

It may be that the real risk/benefit ratio can be evaluated only after the research has begun. Therefore, in addition to the formally scheduled continuing review, the REB must receive and review any new information generated throughout the research that might affect the rights, safety and well-being of research participants. Such information may include:

• Modifications or changes to the previously approved research,
• Reports of unanticipated problems involving risks to participants or others,
• Reports of any serious or continuing non-compliance,
• Reports of any changes significantly affecting the conduct of the research or increasing the risk to research participants,
• Results of any interim analysis or Data and Safety Monitoring Board (DSMB) assessments,
• Deviations from the previously approved research,
• Adverse events that meet the reporting criteria,
• Reports of any privacy breaches,
• Summary reports of any audits and inspections,
• Any other new information that may adversely affect the safety of the research participants or the conduct of the research,
• Modifications to the approved research may only be initiated with prior REB review and approval except where necessary to eliminate apparent immediate hazards to human participants. If changes are made to eliminate immediate risks, the Researcher must notify the REB immediately.

5.1    Amendments to the Approved Research

5.1.1    The Researcher is responsible for submitting any changes to the approved research to the REB as an amendment. In CTO, changes will be submitted as Provincial Amendment (PAM). In TRAQ, this will be submitted as an Amendment. Any centre that operates under the provincial amendment will also have to submit the change that is applicable. NOTE: centre consent forms are to reflect 1 version date (that of the provincial document). Changes to the approved research include modifications to the research, to the consent form, to the Investigator Brochure (IB) or product monograph (PM), changes in participant materials (e.g., wallet cards, diary cards, recruitment materials), a change in the Researcher etc.

A Centre Amendment (CAM) is required if the centre applicant has changed.

5.1.2    When the amendment includes a change to the consent form, the Researcher must indicate his/her recommendation for the provision of the new information to current and/or past research participants.

5.1.3    The Researcher must indicate the requested review type (i.e., Full Board, delegated review or acknowledgement for a minor correction). Supporting correspondence documentation and/or background information may be appended to the amendment submission.

5.1.4    The REB Chair or designee reviews the amendment to determine the appropriate level of REB review required (i.e., Full Board or delegated review).

5.1.5    The REB Chair or designee may also use delegated review procedures to review amendments when the conditions are met.

5.1.6    If the proposed change represents more than minimal risk, it must be reviewed by the REB at a Full Board meeting. Amendments that may be classified as more than minimal risk may include:

• Addition of genetic testing, new genetic tests, or tissue banking where genetic testing may or will be performed,
• Addition of an open-label extension phase following a randomized trial,
• Emergency amendments that arise because of participant safety and may include, but are not limited to:
  1. A change in drug dosing/duration of exposure,
  2. A change in recruitment that may affect confidentiality or the perception of coercion,
  3. A change in experimental procedure or research population.

5.1.7    For amendments requiring Full Board review, the responsible REB Office Personnel assigns the amendment to the next available Full Board meeting. For amendments that meet the criteria for delegated review, the responsible REB Office Personnel will forward the amendment to the designated reviewer.

5.1.8    When an amendment involves a revised consent, the REB will consider the recommendations of the Researcher in determining if, how and when the new information should be provided to the research participants and whether re-consent is required.

5.1.9    The REB must find that the criteria for approval are still met to approve the amendment.

5.1.10    The amended research may not be implemented before the REB review and approval except when necessary to eliminate immediate hazards to participants.

5.2    Reportable Events

5.2.1    The Researcher is responsible for submitting reportable events that meet
the REB’s reporting criteria according to the local procedures.

5.2.2    Local Adverse Events (AEs): The Researcher must report the following to the REB in a timely manner. There are 2 types of Local AEs: Adverse Event (AE) or Serious Adverse Event (SAE):

• Any local adverse event that, in the opinion of the Researcher, meets the definition of an unanticipated problem, this means an AE meets all the following criteria:
   
  • Unexpected/unanticipated in terms of nature, severity and frequency
    
    AND
     
  • May be related to the study intervention/procedure
    
    AND
     
  • Participants could be placed a higher risk than what was originally consented to or originally known
     
• Any SAE that, in the opinion of the Researcher, meets the definition of a serious unanticipated problem – this means the SAE meets all the following criteria:
   
  • Event was serious- serious means noxious and unintended response to a drug or intervention that occurs and requires in-patient hospitalization, prolonged existing hospitalization, sever traumatic experience, congenital malformations, results in a significant or chronic disability or incapacity and is life threating or results in death.
    
    AND
     
  • Unexpected/unanticipated in terms of nature, severity and frequency
    
    AND
     
  • MAY be related to the study intervention/procedure
    
    AND
     
  • Participants could be placed at higher risk than what was originally consented to or originally known
     
• All reports submitted to the REB must have all research participant identifiers removed (i.e., participant research number only),
   
• Once the REB acknowledges a local AE, subsequent important follow-up reports related to the AE should be submitted when relevant information is available as an AE update(s). All initial and subsequent follow-up reports will be retained with the reportable event.

5.2.3    Non-Local (External) Adverse Events: Upon receipt of an external adverse event (EAE) or a periodic safety update or safety summary report, the Researcher must determine if it meets the REB reporting criteria:

• Non-local adverse event reports are reportable to the REB if in the opinion of the Researcher, it meets the definition of an unanticipated problem AND require a change to the research and/or informed consent form and/or require immediate notification to participants for safety reasons,
• The report submitted to the REB must include all the following information:
  • The description of the serious and unexpected event(s),
  • All previous safety reports concerning similar adverse events,
  • An analysis of the significance of the current adverse event(s) considering the previous reports, and
  • The proposed research changes, informed consent form changes or other corrective actions to be taken by the sponsor in response to the event(s),
• The individual AE reports or periodic safety updates or safety summary reports that meet the reporting criteria must be submitted to the REB in a timely manner.

5.2.4    Other Reportable Events: The Researcher is responsible for reporting to the REB other events or findings, such as:

• Any new information (e.g., sponsor’s safety notice or action letter) that would cause the sponsor to modify the Investigator’s Brochure, the research or the consent form, or would prompt other action by the REB to ensure protection of research participants,
• Any changes to the risks or potential benefits of the research, such as:
  • An interim analysis indicates that participants have a lower rate of response to treatment than initially expected,
  • Safety monitoring indicates that a particular side effect is more severe, or more frequent than initially expected,
  • Information is published from another research project that shows that an arm of the research is of no therapeutic value,
• A change in Health Canada or FDA safety labeling or withdrawal from marketing of a drug, device, health product, genetic therapy or biologic used in research,
• The Researcher is also responsible for submitting to the REB other types of reportable events, such as:
  • DSMB reports,
  • Interim analysis results,
  • Any unanticipated problems or other events that could significantly impact the overall conduct of the  research or alter the REB’s approval or favorable opinion to continue the research,
• A change to the research that was initiated without prior REB review to eliminate an apparent immediate hazard to a research participant,
• Any unanticipated problems or other events that could significantly impact the conduct of the research at the site (e.g., concerns of non- compliance),
• Other reportable events must be submitted to the REB within a timely manner.

5.2.5    Deviations to Previously Approved Research: The Researcher must report to the REB any deviations that meet the following reporting criteria:

• Deviations that in the opinion of the Researcher jeopardize the safety of research participants, or that jeopardize the research efficacy or data integrity,
• Any sponsor-approved waivers to the participant eligibility criteria,
• Any change in the approved process for obtaining consent (e.g., improper translation, current ICF not implemented),
• Any deviations that lead to an SAE,
• Deviations must be reported within a time frame specified by the REB; deviations that lead to an SAE should be reported with a timely manner.

5.2.6    Privacy Breaches: The Researcher must report to the REB any unauthorized collection, use, or disclosure of personal information (PI) including, but not limited to:

• The collection, use and disclosure of PI that is not in compliance with the jurisdictional legislation or its regulation,
• Circumstances where PI is stolen, lost or subject to unauthorized use or disclosure or where records of PI are subjected to unauthorized copying, modifications or disposal,
• In the Researcher context, any unauthorized collection, use or disclosure of PI that was not authorized under the research and approved in the plan that was submitted to the REB,

The breach must be reported to the REB and to the appropriate Organizational Official as soon as the Researcher becomes aware of the breach.

5.2.7    Audit or Inspection Findings: The Researcher must report to the REB a summary of any relevant audit or inspection findings following a Health Canada inspection, an FDA or other regulatory audit, an internal QA audit, or other on-site audits.

5.2.8    Research Participant Complaint: The Researcher must report to the REB and the organization, if required by local procedures, a complaint from a participant when the participant reports concerns about their rights as a research participant or about ethical issues related to the research.

5.3    Review of Reportable Events by the REB

5.3.1.    The responsible REB Office Personnel will screen the reportable event submission for completeness.

5.3.2.    The REB Chair or designee reviews privacy breaches, and any recommendations, including remedial action, are determined in consultation with the organization’s privacy office. The privacy breach report is forwarded to the REB Chair or designee for review and final acknowledgement.

5.3.3.    The REB Office Personnel may route the submission back to the Researcher to request clarifications, missing documents, or additional information.

5.3.4.    The REB Office Personnel will forward the submission to the designated REB reviewer(s).

5.3.5.    The assigned REB reviewer(s) will conduct a review of the report and determine if any action or follow-up is required.

5.3.6.    The assigned reviewer(s) may request further information from the Researcher.

5.3.7.    When reviewing a reportable event, the REB should:

• Assess the appropriateness of any proposed corrective or preventative measures by the sponsor and/or Researcher,
• Consider any additional appropriate measures that may or may not have been identified or proposed by the sponsor and/or Researcher,
• Consider whether the affected research still satisfies the requirements for REB approval; in particular, whether risks to research participants are still minimized and reasonable in relation to the anticipated benefits, if any, to the research participants and the importance of the knowledge that may reasonably be expected to result,
• Consider whether some or all the research participants should be
• notified of the events (i.e., if it may affect the participant’s willingness to
• continue participation in the research) and
• Consider whether suspension or termination of the ethics approval of the research is warranted.

5.3.8.    If the event does not raise concerns and does not appear to involve risks to research participants or others, the REB Chair or designee acknowledges the report, and no further action is required.

5.3.9.    If the REB Chair or designee determines that the event meets the criteria for an unanticipated problem, and if immediate action is required to protect the safety of research participants, they may suspend ethics approval of the research pending review by the Full Board, providing the justification for such action is documented.

5.3.10.    If the event raises concerns or involves risk to research participants such that REB action may be required, the item is added to the agenda of the next Full Board meeting.

5.3.11.    For reportable events reviewed at a Full Board meeting, the REB determines whether further action is required. Possible actions that could be taken by the REB include, but are not limited to:

• Placing a hold on the research pending receipt of further information from the Researcher,
• Requesting modifications to the research,
• Requesting modifications to the consent form,
• Providing additional information to past participants,
• Notifying current participants when such information might affect the participants willingness to continue to take part in the research, and requiring that current participants re-consent for ongoing participation,
• Altering the frequency of continuing review,
• Observing the research or the consent process,
• Requiring additional training of the Researcher and research staff,
• Termination or suspension of the research,
• If the REB determines that the event does not raise concerns about risks to research participants, the REB may decide that no further action needs to be taken.

5.3.12.    When action is taken to ensure the protection of the rights, safety, and well- being of participants (e.g., for an unanticipated problem involving risks to participants or others) the REB chair or designee is responsible for reporting to the Researcher and the Organizational Official(s) and has the authority to notify the sponsor and the appropriate regulatory authorities (as applicable). The REB may delegate regulatory authority reporting (as applicable) to the organization.

5.4    Administrative Amendments

Administrative amendments may include:

• Spelling corrections
• Changes in study personnel (except for the PA and Centre PI)
• Replacement of an incorrect document (providing the correct document has been reviewed and approved)
• Inconsistent page numbers or version dates
• Administrative amendments may be processed and acknowledged by the REB Office Personnel.

In the CTO system, if a document has been submitted and qualifies for an administrative acknowledgment, the document may be categorized as approved, to ensure the correct categorization of the study documents.
However, the document will be acknowledged on the approval letter with a statement acknowledging the administrative change.

6.0 REFERENCES

See References.