Post-Approval Guidance Notes

A Certificate of Research Ethics Approval will be valid for no longer than a one-year term (UBC Clinical Research Ethics General Guidance Notes, Article 7.3 ). This means that at a minimum, approved studies must be re-reviewed on or before the one-year anniversary date of the previous REB review. Subsequent renewals of approval will expire on the one-year anniversary date of the previous REB review.

The determination of what constitutes a one-year term varies slightly, depending upon whether or not the study was reviewed by the full board process, by a delegated review process or whether or not it is a renewal of a previously approved study. Full Board Approvals are effective one year from the meeting date at which the application was reviewed and approved. Delegated review approvals are effective one year from the date that the approval certificate of the study was issued. Annual renewal approvals will be effective one year from the date of issuing of the certificate of approval, unless the annual renewal was required to be reviewed by the Full Board. If the annual renewal is required to be reviewed and approved in a full board meeting, the one-year period will be effective from the date of the meeting in which the renewal application was reviewed and approved. (Article 7.3).  

In certain circumstances, renewal will be less than a year if:
a) the board, chair or designate would like to have more frequent updates/progress reports for a particular study.  
b) application has been flagged for re-review and new application is requested.

Amendments approvals do not change study expiry date. 

Please note that the RISe system sends out automated reminders 60 days, 45 days and 14 days ahead of the current approval's expiry date, as well as on the actual date of expiry.  It is expected that the Principal Investigator will respond to this notice in a timely fashion and well ahead of the approval expiry date either by submitting an application for renewal or by submitting a closure of the study.  

Annual Renewal must be submitted by the Principal Investigator until the study can be considered closed by the REB, and until a Completion of Clinical Study Form is received and acknowledged by the REB.  See Section V  for the Guidance Note for Notification of Study Closure to determine when a study may be submitted for closure and annual progress/ renewal requests may be discontinued.

Annual renewal of studies may always continue at the request of the investigator.  This may occur if, for example, the investigator believes that there may be a future need to obtain more data for a research project.  

While the RISe system sends out automated reminders 60 days, 45 days and 14 days ahead of the current approval's expiry date, as well as on the actual date of expiry, it is the Principal Investigator's responsibility to submit the application for annual renewal to the REB office in a timely manner.  Ideally, the REB office should receive the submission at least six weeks before the expiry date of the most recent Certificate of Approval.  This will ensure that the Principal Investigator has time to respond to any concerns raised by the REB before the approval certificate expires.  If an annual renewal requires full board approval the Investigator is responsible for ensuring that the application is submitted by the appropriate REB meeting deadline.

 An "annual renewal" form and a separate "amendment form" may be submitted simultaneously and each may be individually marked for either full board or expedited review.  The Certificate of Approval for each submission will be issued separately.

Please note if a study is in an expired state, an amendment cannot be created until the study has been renewed.

TCPS2 Article 6.12 and 6.14 reiterate the principle of proportionate research ethics review (see also TCPS2 Article 2.9) and stipulate that for both initial and ongoing research ethics review, the level of REB review (either Full Board or Delegated review) shall be determined in accordance with the level of risk to participants.  In practice, where there have been no significant changes to the research, and no increase in risk (or other ethical implications) for research participants, AND provided that the study Sponsor, Funding Agency or Regulatory Agency (see 2.2. below) does not require that annual review be conducted by the Full board, then the Chair (or designate) will review the request for approval under the category of 'Delegated Review'.

The Chair (or designate) can at any time put a request for annual renewal forward to the Full Board.  Where the delegated reviewer would refuse ethics approval, the decision shall be referred to the full REB for review before such decision is communicated to the researcher. 

2pt2 If the Annual Renewal does not qualify for delegated review (for example, if there has been a change in the risk to research participants) or if the granting agency, study sponsor or regulatory agency requires it, the application for annual renewal will be reviewed by the convened (full) REB. These requirements are described below.  If any of these apply, please ensure that 'No' is selected in Question #2 (Level of Review) of the Annual Renewal Coversheet/ Form.

The approval date on the Certificate(s) of Annual Renewal will be the one-year anniversary of the original approval/subsequent renewal date.  The determination of what constitutes a one-year term varies slightly, depending upon whether or not the study was reviewed by the full board process, by a delegated review process or whether or not it is a renewal of a previously approved study. Please see 1.1 above for more details.

Industry sponsors/institutions that require renewal at a particular time before the expiry date must submit their application for renewal before this required date.

The Certificate of Annual Renewal will not be backdated for any reason. 

If the request for renewal is approved after the expiry date, the Certificate of Approval will be dated with the date on which the request for renewal was actually approved by the REB. 

The Principal Investigator for a study is responsible for ensuring that amendments are submitted to the REB prior to implementation and for understanding and adhering to the TCPS2) and other relevant guidelines, including ICH GCP when applicable.  In particular, ICH GCP Article 4.5.2 specifies that: "The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment…". 

Amendments may only be submitted for review AFTER the study has received initial approval from the REB. 

The term of the approval for the amendment expires at the same time as the initial approval or annual renewal for the study.  

Changes to any of the investigator's/contact person's contact information (i.e. address, telephone number, email) must be updated by that person in RISe by updating the person's Profile. 

Please see Article #3 below for additional requirements for a change of principal investigator.

Pursuant to TCPS2 Article 6.12, the REB can delegate to the Chair or other REB members authority for the review and approval of "research that is confidently expected to involve minimal risk.".  In relation to ongoing review, this would include for example:

• minimal-risk changes to approved research;
• annual renewals of approved minimal risk research;
• annual renewals of more than minimal risk research in which there has been:
  • no significant changes to the research,
  • no increase in risk to (or other ethical implications for) the participants since the most recent review by the full REB, and
  • the REB Chair has determined that the delegated review process is appropriate.

*Note that other applicable guidelines or policies (such as ICH-GCP) may require a full REB review of the annual renewal for specific types of research.

For further discussion of what constitutes minimal risk in relation to clinical studies, as well as examples of types of minimal risk studies that may qualify for delegated review and those that may not, please see the CREB Guidance Notes at Articles 5.2, 5.3 and 5.4 respectively.

Amendments that MUST be reviewed by full board are detailed in Article 2.2 below.

As outlined in UBC SOP 402, studies that are funded or supported by the U.S. federal government or regulated by the US Food and Drug Administration, are eligible for expedited/delegated review if listed in the OHRP and FDA guidances and are no more than minimal risk or include only, minor changes in previously approved research as defined by the applicable regulations and in UBC's SOPs.

The REB Chair (or designate) may at any time put forward a request for approval of an amendment to the Full Board.

IV2pt2 The following types of amendments for previously approved studies that are clinical trials (drug, device, natural health product) must be referred to the Full Board for review as required by Health Canada.

1. Addition of an open label extension phase following a randomized trial;
2. Emergency amendments that arise because of subject safety concerns and that are submitted after implementation as a result, and;
3. Significant changes to a protocol that may affect subject safety and may include a (but are not limited to):
   1. change in drug dosing/duration of exposure,
   2. decrease in monitoring,
   3. change in recruitment technique that may affect confidentiality or the perception of coercion,
   4. change in experimental procedure or study population.
4. Any amendment that requires approval from Health Canada

All necessary documents must be submitted. Incomplete submissions will not be reviewed and will have to be resubmitted.  Amended documents must be submitted in such a way that any changes are clearly identified.  All amended documents must be attached on Page 9 of the revised application form.  Revised documents must be marked in a way that the changed text can be identified (via tracked changes or highlight function), and should include updated version dates in the footer. 

Protocol amendments should include a separate document that lists both the original section(s) and the subsequent revision(s) so changes to the original text are easily seen.  

Submit the amended consent form with the changes underlined, in bold text or highlighted so that it is easy to see how the original consent form has been altered.  Please ensure previous tracked changes are accepted prior to making new changes to study documents.  The amended consent form should include a footer with an updated version date.  It is not necessary to submit both a tracked and "clean" version of study documents.  Please only submit documents which clearly outline changes.

A Certificate of Approval is issued only if the updated Investigator Brochure (IB) is accompanied by documentation that summarizes the changes to the IB.  Otherwise, the submission of IBs and Safety Data Reports as amendments will be acknowledged by memo only.  IBs are necessary to be submitted via an Amendment so they can be attached to Box 9.4 of the RISe application form.

Documents attached to Page 9 of the revised initial Application Form must be recorded accurately with the document name and version numbers because this information is included in the Certificate of Approval. 

Refer to the links on your homepage in RISe for the REB schedules of meetings and submission deadlines for amendments that require full board approval.  Amendments that meet the criteria for delegated review may be submitted at any time.

All decisions arising from the review are emailed to the Principal Investigator and the Primary Contact person identified in Question #1.2 of the Application Form.  An Approval Certificate is displayed on the application homepage in RISe, as well as on the Amendment submission, and is the REB's official notification of the decision.

A study may be closed only when ALL data collection procedures as per the approved protocol have been completed.  Studies that have completed subject recruitment [i.e. closed to accrual] are not considered closed if data related to the subject is still being collected.  This type of data collection activity can include the following: 

• post-treatment contact with research subjects; for example, when data is collected via imaging reports, blood analysis reports, etc. and incorporated into the research study database. 
• indirect collection of data for follow up purposes after treatment with the study intervention is completed; for example, quality of life/late side effects/survival data.  As an example, this type of data might be collected by telephone contact with the research subject or via a third party such as a family physician.  

If the study is funded or supported by the US Federal Government (NIH, etc.) it cannot be considered closed until all follow up of subjects is final AND there is no further data analysis involving individually identifiable information.

Grant Funded Studies:  If a study is grant funded a completion notice should not be submitted to the REB until there is no active grant that requires ethics approval. 

Subject to the requirements for US studies, studies that do not involve direct subject participation, for example, secondary use of data, are considered closed when data acquisition is completed.

Subject to the requirements for US studies, studies that involve the analysis of tissue only are considered closed when no more tissue samples or data are being acquired.

Confirm that "data/specimen collection is complete":  The principal investigator/designate for any study involving human subjects must affirm that data collection has been completed so that there is no direct or indirect contact with the subject for purposes of collecting data or biological materials related to that individual, or for US funded studies, no further data or specimen analysis involving personally identifiable information.  For a study monitored by the NCIC CTG to be considered complete, the Principal Investigator must have been notified by the NCIC CTG.

The principal investigator/designate must submit the closure information to the REB using RISe.  The information that must be included in the submission varies for different types of studies and is detailed below.  

As of 2022, Health Canada has reduced the period for keeping clinical trial records for drugs and natural health products from 25 years to 15 years. This change reflects amendments to the Food and Drug Regulations and Natural Health Products Regulations.  

Health Canada Guidance provides researchers with guidance pertaining to retention and storage requirements of clinical trial documents. 

In accordance with the guideline: The period for keeping records starts on the date the record is created. To simplify the process, sponsors may choose to "start the clock" for keeping all study records when the trial is completed or terminated.

According to UBC Policy SC6 Scholarly Integrity Article 2.1.4, Investigators are responsible for:

"Keeping complete and accurate records of data, methodologies and findings, including graphs and images, in a manner that will allow verification or replication of the work by others. This includes recording all primary data in clear, adequate, original and chronological form, and retaining it in a repository from which it cannot be removed. The principal investigator is responsible for the collection, maintenance and retention of research data. Records of data should normally be retained in the unit in which they are produced for at least five years after the work is published or otherwise presented (if the form of the record or data permits this, and subject to any assurances that data would be destroyed to assure anonymity). Records should be retained in their original medium, or transferred to a secondary medium provided that the transfer process is fully validated, and the person who transfers the data from the original to the secondary medium attests that the secondary documents are true copies of the respective original record including any and all notations, corrections, or other changes made to the original record prior to the creation of the secondary documents. In the case of collaborative research all those involved in the conduct of the research will have accessto the data (subject to any assurancesthat accessto the data would be restricted to assure anonymity), and will normally be allowed to make copies of the record.  Such access may be restricted only when a request to do so is made in writing and approved by the Vice‐President"

New Information:  Any new information that might adversely affect the safety or well-being of the study participants, the conduct of the trial, or the subject's willingness to continue in a study. Please note any information that must be relayed to subjects should be submitted via a PAA – Amendment, along with a description of how the information will be relayed.

New information includes but is not limited to any relevant recent literature, interim findings, preliminary results of the study or of any other study (e.g. using the same drug).

Protocol Deviation: Protocol deviations are identified as any unplanned or unforeseen change to a Research Ethics Board (REB) approved protocol or protocol procedures.  Deviations are different from amendments in that they general apply to a single occurrence or participant and are not intended at the time to modify the entire protocol.  If a protocol deviation is expected to occur beyond a single occurrence then it is recommended to submit an amendment to update the protocol/procedures. 

Unanticipated Issues: Unanticipated issues are issues that occur during the conduct of research that may increase the level of risk to participants or have other ethical implications that may affect participant's welfare and were not anticipated by the researcher in the research proposal submitted for research ethics review. 

Unanticipated issues include, but are not limited to:

• A breach of confidentiality or privacy
• Problems with the investigator or study personnel
• Fire, flood or other natural disaster
• Incidents of continuing and serious noncompliance with the ICH-GCPs, REBs requirements or applicable laws and regulations
• Termination or suspension of the study by a regulatory authority.
• Any complaint by a subject that includes a report of an unanticipated risk or which cannot be resolved by the research staff
• Protocol deviations that in the opinion of the investigator places one or more participants at increased risk, or affects the rights, safety, or welfare of research participants.

Unanticipated problems are any incident, experience or outcome (including an adverse event) 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 Research Ethics Board (REB) approved research protocol and informed consent document, or the Investigator Brochures; and (b) the characteristics of the research participant population being studied; and

**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.

*Unexpected: an event is "unexpected" when its specificity and severity are not accurately reflected in the protocol-related documents such as the Research Ethics Board (REB) approved research protocol, the Investigator Brochure, or the current REB approved informed consent document, or other relevant sources of information such as product labelling and package inserts; or when the event is not associated with the expected natural progression of any underlying disease, disorder, predisposing risk factor, or condition of the participant(s) experiencing the adverse event.

** Related to the research procedures: an event is "related to the research procedures" if in the opinion of the Researcher or sponsor, the event was more likely than not caused by the research procedures.

As soon as reasonably possible:  The term "as soon as reasonably possible" means that the timing of reporting will vary in accordance with the severity/seriousness of the information being reported, including the nature of the research associated with the problem.  Unless, however, the event is a routine safety letter, DSMB report, periodic safety update report, summary of changes to the Investigator's brochure that are minor and/or routine in nature, all new information, unanticipated issues and unanticipated problems must be reported within seven days of the incident, occurrence, outcome event, or the Investigator's receipt of the notice of the event or the new information.

Adverse Event (AE): Any untoward medical occurrence in a research participant administered an investigational product including an occurrence which does not have a causal relationship with this product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of an investigational product, whether or not related to the investigational product.

Local (Internal) Adverse Event:  Those adverse events experienced by research participants enrolled by the investigator(s) at one or more centres under the jurisdiction of the REB of Record. In the context of a single-centre clinical trial, all adverse events would be considered local adverse events. 

Non-Local (External) Adverse Event (EAE): From the perspective of the REB overseeing one of more centres engaged in a multi-centre clinical trial, external adverse events are those adverse events experienced by research participants enrolled by investigator(s) at other centres/institutions outside the REB's jurisdiction.

Adverse Drug Reaction (ADR):  Any response to a drug, biologic, or natural health product which is noxious and unintended, which occurs at doses normally used or tested for the diagnosis, treatment or prevention of a disease or the modification of an organic function. A reaction, as opposed to an adverse event, is characterized by the fact that a causal relationship between the product and the occurrence is suspected (i.e. judged to be at least a reasonably possibility).

Serious Adverse Event (SAE): Any untoward medical occurrence at any dose that:

• Results in death
• Is life-threatening
• Requires inpatient hospitalization or prolongation of existing hospitalization
• Results in persistent or significant disability/incapacity
• Results in a congenital anomaly/birth defect
• Based upon appropriate medical judgement, is an important medical event that may jeopardize the patient or may require medical intervention to prevent one of the outcomes listed above.

Unexpected Adverse Drug Reaction (UADR): An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. the Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product).

Medical Device Serious Adverse Event (MDSAE):  An adverse event associated with a medical device complaint meets the criteria of a medical device SAE when both of the following are fulfilled:

• The event involves contact with the medical device and
• The event results in death or serious deterioration in state of health.  This includes:
  • Life-threatening illness or injury
  • Permanent impairment of a body function
  • Permanent damage to a body structure

A condition that requires medical or surgical intervention to prevent permanent impairment of a body function or permanent damage to a body structure

Unanticipated Problem: Any incident, experience, or outcome (including an AE, SAE, MDSAE, or UADR) 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 REB-approved research protocol and informed consent document, or the Investigator Brochure; and (b) the characteristics of the research participant population being studied; and
• **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.

*Unexpected: an event is "unexpected" when its specificity and severity are not accurately reflected in the protocol related documents such as the REB approved research protocol, the Investigator Brochure or the current REB approved informed consent document, or other relevant sources of information such as product labelling and package inserts; or when the event is not associated with the expected natural progression of any underlying disease, disorder, predisposing risk factor or condition of the participant(s) experiencing the adverse event.

**related to the research procedures: an event is "related to the research procedures" if in the opinion of the Researcher or sponsor, the event was more likely than not, caused by the research procedures.

New Information:   Any new information that might adversely affect the safety or well-being of the study participants, the conduct of the trial, or the participant's willingness to continue in a study.  New information includes, but is not limited to any relevant recent literature, interim findings, preliminary results of the study or of any other study (e.g. using the same drug).  Please note any information that must be relayed to subjects should be submitted via a PAA – Amendment, along with a description of how the information will be relayed.

Only those local (internal) serious adverse events that meet the definition of an unanticipated problem (i.e. unexpected, related and involving greater risk – see definition above) are required to be reported to the REB. Local serious adverse events that meet the definition of an unanticipated problem should be reported to the REB promptly, but in any case no later than seven (7) days subsequent to the occurrence of the local event. Such events should be reported using the REQUEST FOR ACKNOWLEDGEMENT FORM, and should include:

• The status of the study and summary of participants enrolled
• A detailed description of the local event including an assessment as to whether the event reaction was mild, moderate or severe
• An opinion expressed by the local investigator that the event is both serious and unexpected and a justification of that opinion
• An opinion expressed by the local investigator that the event is related or potentially related to the study drug/procedure/device and an explanation of that opinion.
• An opinion expressed by the local investigator respecting the implications of the SAE on the continuation of the study and any further actions that may be required such as changes to the study procedure, informed consent or protocol.
• A statement of the study team response to the event and the patient outcome of the SAE

The following local adverse events ordinarily should NOT 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

UBC's REBs have adopted the CAREB Guidance dated July, 2010

In accordance with the CAREB Guidance non-local (external) serious adverse events should be reported to the REB in the form of periodic safety update reports, accompanied by information that is meaningful and of use to the REB.  The contents of the safety report(s) should ordinarily at a minimum, include a sponsor analysis of the significance of the adverse event or perhaps such an analysis from an independent Data Safety Monitoring Board (DSMB), with (where appropriate) a discussion of previous similar events and a position statement as to whether any changes are required.  Investigators may rely on the sponsor's assessment and provide to the REB a periodic safety update report prepared by the sponsor.  The format used for annual safety reports is acceptable.   UBC's REBs expect that sponsors will be amending their reporting processes to provide for periodic safety update reports at least semi-annually.  Periodic Safety Update Reports, should be reported to the REB as soon as reasonably possible, but in any case no later than fifteen (15) calendar days, after the Principal Investigator has received the report from the Sponsor.

Such reports should be submitted using the Request for Acknowledgement Form. UBC's REBs will ONLY accept individual case reports of non-local (external) SAE's if they are unanticipated problems (see definition above).  In the limited circumstances where an Individual Non-Local (external) SAE constitutes an unanticipated problem the report should be submitted to the REB as soon as reasonably possible, but in any event, no later than within seven (7) days after the Investigator has received the report from the sponsor.  Such reports should be submitted using the Request for Acknowledgement Form.  The report must include all of the following information:

• Justification of the assessment that the event described is both serious and unexpected
• Identification of all previous safety reports concerning similar adverse experiences
• Analysis of the significance of the current adverse experience in light of the previous reports, and
• Outline of 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 as outlined above. 

Submit International Safety Reports (i.e. CIOMS reports, Medwatch letters, Dear Investigator letters), using the Request for Acknowledgement procedure and form.

Updated Investigator Brochures and any addendums should be submitted as an amendment so that the current version will be readily accessible in the document section of RISe application along with the current approved protocol and consent.

Summary Reports, including periodic line listings submitted in accordance with the provisions of the European Union directive or the FDA Guidance on Adverse Event Reporting to IRB's, should be submitted using the Request for Acknowledgement form and procedure.

Data Safety Monitoring Board reports should be submitted as soon as possible following receipt by the Principal Investigator, using the Request for Acknowledgement form and procedure.

Article 4.5.4 of the ICH-GCP:

"The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion.  As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:

• To the IRB/IEC for review and approval/favourable opinion,
• To the sponsor for agreement and, if required,
• To the regulatory authority(ies)."

"The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g. change in monitor(s), change of telephone number(s))." 

A deviation from of change of, the protocol to eliminate immediate hazards to the study subjects must be reported to the REB as soon as reasonably possible [see Definitions in VI Reporting Unanticipated Problems].  All other deviations must be reported to the UBC REB within 15 days of their discovery.

If appropriate, amendments to the protocol must also be submitted to the applicable REB at the time that the protocol deviation report is submitted.

Notification of protocol deviations will be acknowledged.  Depending on the circumstances of the specific deviation, a request for further information may be to the investigator by the REB Char/designate.  UBC's REBs do not approve deviations from the protocol.

The protocol deviation report is submitted to the REB via RISe using the Request for Acknowledgment form.  The report must include the following information:

• The status of the study (i.e. open or closed to enrolment or on-hold etc.)
• Summary of the status of participants enrolled
• A description of the deviation that occurred with an explanation of the circumstances that led to the deviation and the resulting problem
• An explanation as to whether or not the deviation compromised the scientific integrity of the study
• An explanation of whether or not the deviation increased the risk or the possibility of risk for the research subject(s)
• If applicable, an explanation of whether and how subjects affected by a protocol deviation will be informed
• A description of the steps taken or that will be taken to correct/ address the problem resulting from the deviation; and
• A plan for ensuring that similar deviations do not occur in the future
• Confirmation as to whether any previous protocol deviation(s) have occurred that have been previously reported to the REB.