The following guidance notes relate to ongoing responsibilities to REB after the initial approval of a study.
See also Forms and Templates.
Jump to Sections:
I. Introduction
II. Key Contacts
III. Annual Renewals
IV. Amendments
If you wish to search for a specific term in the page, please first expand all of the content. Open All
I. INTRODUCTION
Following the initial approval of a study, researchers have ongoing reporting responsibilities to the REB.
These responsibilities may take a variety of forms, including: progress reports, study amendments or providing the REB with new information that arises during the course of the study. All progress reports, new information or amendments to an approved study must be submitted using the Post Approval Activity (PAA) online application form. This form can be found on the left hand side of your study homepage – just click the 'New Post Approval Activity' icon.
You will then be presented with a list of six PAA options:
- Annual Renewal
- Annual Renewal with Amendments to Study
- Amendments to Study
- Completion of Clinical Study
- Request for Acknowledgement
- Response to Request for Information
Select the appropriate option and then click "continue".
For detailed step-by-step instructions on how to submit Post Approval Activities on RISe please click here.
II. Key Contacts
Questions regarding the completion of Post-Approval Activities forms preparation of an Annual Renewal submission can be directed to:
BC Cancer Research Ethics Board - (604) 877-6284 or email reb@bccancer.bc.ca
Providence Health Care Research Ethics Board - email alex.trethewey@ubc.ca
Clinical Research Ethics Board - email creb.rise@ors.ubc.ca
Behavioural Research Ethics Board - (604) 827-5114 or email breb.rise@ors.ubc.ca
Children & Women's Health Centre Research Ethics Board – (604) 875-3103 or email cwreb@bcchr.ubc.ca
UBC Okanagan Research Ethics Board – (250) 807-8289 or email researchoffice.ubco@ubc.ca
RISe Support – (technical questions concerning RISe) (604) 878-7473 or email risesupport@ors.ubc.ca
III. Annual Renewals
The UBC REBs conduct continuing review of research taking place within their jurisdiction at intervals appropriate to the degree of risk, but not less than once per year. UBC Policy 89, Article 6.14 of the TCPS2(2014), the ICH-GCP's, as well as the US DHHS 45 CFR 46 and the FDA 21 CFR 56 Federal Regulations all stipulate that the REB must require a progress report from the responsible investigator on at least an annual basis. However, the REB may determine at the time of initial review that additional ongoing review is appropriate for a particular study, making it clear to the researcher what is required (for example, the nature and frequency of reports). The level of research ethics review may also be adjusted over time, based on the level of risk.
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 delegated reviewer issued his or her approval of the study and the certificate 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)
Amendments approved after the initial approval/renewal date also expire at the same time as the initial approval/renewal of the study.
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 notifying the CREB of the closure of the study.
Requests for 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.
TCPS2(2014) Article 6.12 and 6.14 reiterate the principle of proportionate research ethics review (see also TCPS2(2014) 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 convened REB, 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 and endorsement before such decision is communicated to the researcher.
The time from submission of a renewal application to review will vary according to the volume of submitted renewals as well as amendments, which is why Investigators are advised to submit the Request for Annual Renewal at least six weeks prior to the expiry date of the previous approval.
All decisions arising from the review are emailed to the Principal Investigator and the contact person identified in Question #1.2 of the Application for Initial Review. A Certificate of Approval is displayed on the application homepage in RISe, as well as on the Renewal submission, and this constitutes the REB's official notification of the decision.
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.
Please note that if you are submitting an Annual Renewal with Amendments, if the Amendment requires Full Board review, the Renewal will also be reviewed at Full Board. Please keep this in mind when submitting an amendment close to the study expiry date.
Some sponsors, such as the NCIC Clinical Trials Group or the National Cancer Institute (U.S.) may require Full Board Review for renewal. Please review sponsor requirements prior to selecting Delegated or Full Board Review in Question #2 of the Annual Renewal Application Form and refer to Article #3 for details on the required documentation.
Studies sponsored by the United States Department of Health and Human Services (DHHS) (e.g. NIH and its related Institutes, US Center for Disease Control, etc.) may require Full Board Review under 45 CFR 46.109 (e) and 45 CFR 46.110 (Code of Federal Regulations), unless they fall into one of the 9 categories recognized as eligible for expedited review. Refer to Guidance on the Use of Expedited Review Procedures issued by the US Department of Health and Human Services for an interpretation of these categories, and particularly Section E that outlines when expedited review procedures may be used in the context of continuing review.
Generally, if a study subject to these regulations was initially reviewed by Full Board Review, the annual renewal must also be conducted by the Full Board unless the research meets the criteria outlined in category (8) or (9). For example, category (8) allows expedited review for research previously approved by the convened board as follows:
"(a) Where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; OR
(b) Where no subjects have been enrolled and no additional risks have been identified; OR
(c) Where the remaining research activities are limited to data analysis."
Category 9 in turn allows for expedited review of research previously approved by the convened board, where that research is not conducted under an investigational new drug application or investigational device exemption, and where exemptions outlined in categories (2)-(8) do not apply, if the REB has determined and documented at a full board meeting that the research involves no greater than minimal risk and no additional risks have been identified.
Studies that are funded by other American federal agencies (e.g. US Department of Defense) or that are subject to the US Food & Drug Administration Regulations may require Full Board Review under 21 CFR 56.110. Refer to FDA's Guidance entitled IRB Continuing Review after Clinical Investigation Approval for further information on expedited continuing review for clinical investigations.
As with studies sponsored by DHHS, annual renewals of studies that are funded by other American federal agencies or that are subject to US Food & Drug Administration Regulations and that were initially approved by a convened board must generally also be conducted by the Full Board unless the research meets the criteria outlined in category (8) or (9). (See IRB Continuing Review after Clinical Investigation Approval, Section D)
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. Refer to the links on the relevant REB's homepage for the REB meeting schedule and submission deadlines. For example CREB dates.
All decisions arising from the review are emailed to the Principal Investigator and the contact person identified in Question #1.2 of the Application for Initial Review. A Certificate of Approval is displayed on the application homepage in RISe, as well as on the Renewal submission, and this constitutes the REB's official notification of the decision.
Monitoring or Summary Report: UBC REB Policy 406 (Annual Renewals) specifically requires that a summary of the impact of all Unanticipated Problems including Serious and Unexpected Adverse Events be provided in the application for annual renewal, as well as a summary of any monitoring that took place and any reports from Data Safety Monitoring Boards that may be available. More detailed information regarding ongoing review, including Researchers' reporting requirements to the REB for Unanticipated Problems and Serious Adverse Events are provided in UBC REB Policy 405 (Ongoing Review and Reporting). For studies sponsored by the National Cancer Institute of Canada – Clinical Trial Group (NCIC-CTG) a copy of the recent NCIC CTG Data Safety Monitoring Committee Report must be attached or an explanation provided concerning why one is not available.
Protocols and Consent Forms: It is not necessary to resubmit the protocol, most recent versions of Investigator Brochures, advertisements, letters of initial contact, consent forms or questionnaires/tests/interview scripts, if updated since the original approval, provided these have been previously reviewed and are listed in a previously issued Certificate of Approval (i.e. for amendment).
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.
While it may seem obvious, it is not always readily apparent that a study requires an annual renewal, and it may in fact, be possible for the study to be closed. In Question 1, please indicate briefly, why the study requires an annual renewal, and provide an explanation if the study is on hold and/or the research has not started.
TCPS2 (2014) Article 6.14 requires that "annual renewals must have at minimum, an annual report with sufficient details to enable the REB to make an informed judgment about the continued ethical acceptability of the research." Given this, the summary of progress to date (Question 5 in RISe Annual Renewal Application) should include information on whether subjects are still participating in the research study, especially, when in the case of clinical trials, the trial is closed to enrolment. Remarks about the ability to recruit subjects are also appropriate. Any monitoring that has been done since the last review should be detailed, together with a summary of the results and any specific steps that the Investigator will take in the next review period to ensure that there is on-going ethical conduct of the study.
For Clinical trials: Please note that if you are conducting a clinical trial, a sponsor's summary report containing up-to-date information about the safety of participants is required. If a report is not being attached, please explain why and whether or not any monitoring or interim analyses of this study took place. If so, indicate by whom and summarize the results.
The Principal Investigator is responsible for summarizing the impact of all unanticipated problems including serious and unexpected adverse events either observed throughout the study period or submitted to the Principal Investigator by the sponsor for other sites in multi-centre trials.
New Information is anything that might adversely affect the safety or well-being of the study participants or the conduct of the study, or the participant's willingness to continue in a study, including any information that might alter the REB's approval or favourable opinion to continue the study. The Investigator is responsible for describing any new information that may change the scientific / ethical background, relevance or validity of the study since the last review. This includes any relevant recent literature, interim findings, preliminary results or amendments or modifications to the research since the last review.
Any changes in relation to the conflict of interest status of the Principal Investigator and/or other members of the study team must also be reported (Question 8 in RISe Annual Renewal Application).
While the REB will determine in its discretion whether the study should be continued, the opinion of the Investigator concerning this is important information for the REB in making its determination.
If the study has expired, the Principal Investigator must provide a written explanation for the late renewal and confirmation that NO study related actions took place during the time over which there was no valid ethics approval (unless such continued activity was specifically approved beforehand by the REB—see immediately below).
Where there has been a lapse in ethics approval, the Principal Investigator must notify the REB if there is a need to continue research related medical treatment of current participants for their safety and well-being, and provide as much detail as possible about the proposed continued activities. The REB Chair or designate will review the request as quickly as possible using RISe to seek additional information from the Investigator as required.
Failure to apply for annual renewal before the expiry date of the study's current REB certificate of approval or to notify the REB office of any reason for delay may result in the following actions being taken:
- Notification of the investigators' department head regarding the failure to comply;
- Suspension of the financial account such that no further funds will be released until the expired status of the study has been addressed;
- Discontinuation of the study's REB approval and formal closure of the study file.
Please note that reactivation of the study thereafter will require a new Application For Ethical Review, unless the REB advises otherwise.
Fees for annual renewal of ethics approval for privately sponsored (industry funded) studies were introduced by UBCs affiliated Research Ethics Boards effective April 1st, 2012. For studies initially approved prior to April 1, 2011, the annual renewal fee is $250. Studies submitted for initial approval after April 1st, 2011 are subject to a charge of $500 when they are submitted for annual renewal. Certificates of Approval for Annual Renewals may be withheld until the fee has been received by the research ethics board. For more information about these fees, please click here.
IV. Study Amendments
The Tri-Council Policy Statement 2 (TCPS2(2014)), Health Canada Division 5 Regulations, the ICH-Good Clinical Practice Guidelines and the US Federal Regulations all require researchers to submit proposed changes to previously approved research projects to the Research Ethics Board for approval. ALL changes must be submitted prior to the changes being implemented except where necessary to eliminate an immediate hazard to subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in study staff, change of telephone number(s)) (ICH GCP, 4.5.2; TCPS2(2014), 6.16). The REB must be informed of any such changes, as soon as possible after the change has been made, together with information concerning the rationale for such actions. All such changes must be formalized by the subsequent filing of a Post-Approval Activity – Amendment to Study.
An amendment may be defined as a permanent intentional action or process that revises, amends and/or modifies a previously approved research protocol, and/or other study documents reviewed by the REB, including but not limited to the consent documents and other participant-directed materials such as data collection instruments (questionnaires, diaries), or recruitment related material. If researchers are changing any part of a study, regardless of whether it is merely an "administrative" or "minor" change an amendment must be submitted. However, and as discussed in more detail in this guidance, many Amendments (including all Administrative changes) will qualify for delegated or expedited review by the Chair or other REB member.
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(2014) 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.
For studies submitted to the UBC Clinical Research Ethics Board (CREB), Behavioural Research Ethics Board (BREB) or Children's and Women's REB (C&W REB), amendments may be submitted with, and will be reviewed at the same time as, a request for Annual Renewal by selecting the combined 'Annual Renewal with Amendments to Study' form. For detailed instructions on submitting amendments on RISe (including annual renewals with amendments) please click here. Please do not use the 'Annual Renewal' form for amendments.
For studies submitted to the UBC REB's where the "Annual Renewal with Amendments to Study" form is not available (i.e., to REBs other than CREB, BREB or C&W REB), a Request for Amendment form and a separate Request for Annual Renewal form may be submitted simultaneously and may be marked individually for expedited or full board review.
Please note if a study is in an expired state, an amendment cannot be created until the study has been renewed
The term of the approval for the amendment expires at the same time as the initial approval/annual renewal for the study.
Changes to any of the investigator's/contact person's contact information (i.e. address, telephone/fax 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(2014) 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.
Minor changes may be defined as those that do not materially affect an assessment of the risks and benefits of the study and do not substantially change the specific aims/design of the study.
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.
- 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 subject safety concerns and that are submitted after implementation as a result, and;
- Significant changes to a protocol that may affect subject safety and may include a (but are not limited to):
- change in drug dosing/duration of exposure,
- decrease in monitoring,
- change in recruitment technique that may affect confidentiality or the perception of coercion,
- change in experimental procedure or study population.
- Any amendment that requires approval from Health Canada
In order to change the Principal Investigator, the original Principal Investigator must submit a signed "Notification of Temporary or Permanent Change of Principal Investigator" Form requesting the change to the new Principal Investigator. The Form must be signed by the original principal investigator, the new principal investigator and their department head. The Form to be signed is located in RISe in Question #2 of the 'Amendments to Study' Coversheet or in Question #9 of the 'Annual Renewal with Amendments to the Study' Coversheet form. The signed form includes the new PI's attestation to abide by the TCPS2(2014) and a declaration of any potential conflict of interest that could arise from assuming this role.
Updated study documentation (i.e. informed consent form) and an updated Application Form is required so that the appropriate contact information is included for the new PI
A Certificate of Approval of Amendment will be posted on the application homepage, as well as with the Amendment submission in RISe.
Changes to co-investigators, study personnel, site changes (added or removed), changes to funding agencies and changes to study titles are considered administrative amendments. All such changes to the study must be entered in the appropriate sections of the application.
ANY changes to the funding agency, (e.g. when the funding agency's name is changed from Roche Products Ltd. To Hoffmann-LaRoche Limited) REQUIRE the submission of a revised consent form.
When a study is given a new title, the application form and all study documents should be updated to reflect the change. The name of the new title will be reflected on the new Certificate of Approval. The UBC Office of Research Services will only release specific project funds to the Investigator if the Certificate of Approval includes the funding agency that matches the correct study title.
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 initial application form. Revised documents must be marked in a way that the changed text can be identified, 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.
Briefly describe the nature of the proposed change(s), the reason for it, and indicate whether or not the change will result in any increase in risk or discomfort for the study participants. If it will, explain what these are and why they are required.
Describe any changes to the study, involving the study's objectives, research design, sample size, inclusion/exclusion criteria, and/or changes to the treatment/intervention procedures/dosage and explain how any changes will affect the study.
Describe any changes to consent form(s) (and any other documentation, such as advertisements/information sheets, questionnaires) in this section of the Application Form as well.
If the change requires a revision to the informed consent, include information on how the subjects (who are already enrolled) will be contacted and how the new information about their participation in the study will be given to them.
The notification of a new risk(s) must be documented in a revised consent form for new subjects. Depending on the nature of the risk(s), the REB may require that subjects already enrolled in the study be reconsented.
The REB may request that subjects already enrolled are either notified by letter or reconsented when significant changes are made in the sponsorship of the research.
For studies that involve tissue/DNA banking, when the sponsor has changed or a different storage facility is used to store the subjects' specimens, subjects should either be reconsented or informed of the change to the study via a letter, which gives the subjects the opportunity to withdraw their tissue from storage should they have any concerns.
V. Study Completion
The completion of a study is a change in activity and must be reported to the REB. Although participants will no longer be "at risk", a final report / notice to the REB allows it to close its files as well as providing information that may be used by the REB in the evaluation and approval of related studies. It is important to inform the REB how data or biological materials collected during the study will be finally disposed of or stored in order to protect privacy and confidentiality.
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 are being withdrawn from the tissue bank or acquired from another research group for studies which analyze human tissue.
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 may submit the closure information to the REB using RISe. Please note that there are separate forms for the Behavioural Research Ethics Board and for the Clinical Research Ethics Board(s). The information that must be included in the submission varies for different types of studies and is detailed below.
(Reference: ICH Good Clinical Practice Guidelines Article 4.13 "Final Report(s) by Investigator")
Once the study has been completely closed by a sponsor, RISe must be used to notify the REB of the study closure. The submission should include:
- the Principal Investigator's affirmation that subject data/sample collection is complete;
- total number of research subjects enrolled at the (local) site;
- the number of unanticipated problems, including local reportable serious and unexpected Adverse Events;
- the date of the study monitor's final visit;
- the final disposition /storage of all research-related study documents/specimens;
- the final disposition of any electronic data (i.e. locked), and;
- any other information required by the study sponsor or the REB.
- The official "close-out letter" from the sponsor, if applicable.
Using RISe, notify the REB that the study has been completed. The submission should include:
- the Principal Investigator's affirmation that subject data/specimen collection is complete;
- total number of research subjects enrolled at the (local) site;
- the arrangements for final storage and disposal of all research-related study documents/specimens, and;
- the arrangements for final storage and disposal of any electronic data (i.e. locked).
- Note for clinical studies, the REB requires at a minimum, an end-of-study report for all studies at study completion.
Using RISe, notify the REB that the acquisition of data/specimens is complete.
The REB office will issue an acknowledgement of the closure notice generally within five business days. Once the Acknowledgement has been issued the study will show as "Terminated" under the Investigator's Inactive tab in the RISe system. The only activity available to an Investigator subsequent to this is a Request for Acknowledgement, if needed. The study cannot be amended or reactivated.
According to Regulation C.05.012 (4) The sponsor shall maintain all records referred to in this Division for a period of 25 years.
Health Canada's Guide 0068 "Guidance for Records Related to Clinical Trials":
Health Canada Guidance provides researchers with guidance pertaining to retention and storage requirements of clinical trial documents.
In accordance with the guideline: The starting time to calculate the retention time is the date when a record is created. For example, when an informed consent is signed, the date of the signature by the subject is the starting date. In practice, it may be easier to calculate the starting date for record retention, as the date of completion or termination of the trial.
Researchers converting regulatory documents into an electronic format should ensure that the requirements stated in the Guidance for Records Related to Clinical Trials (Guide-0068) are met. These may be summarized as follows:
Essential documents should be kept for the entire retention period and in their original medium. Transfer of essential documents from their original medium to a secondary medium may be acceptable, preferably at the completion of a trial, and only if:
- the corrections to the original data can be clearly captured in the secondary medium,
- the person that performs the task of transferring from the original to the secondary medium attest (sign and date an attestation), that the secondary documents are true copies of their respective primary documents, and
- the transfer process has been fully validated. Evidence of validation should be available for inspection
According to UBC Policy Scholarly Integrity (SC6) 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."
VI. Request for Acknowledgement
The Request for Acknowledgement Form should be submitted in any instance where the Investigator or the Sponsor requires an acknowledgement that the REB has received specific information. These situations include, but are not limited to:
- Protocol Deviations
- Safety letters (provided that they do not meet the criteria for an SAE)
- DSMB reports
- Summary Reports
- Unanticipated Issues
- Unanticipated problems
- New Information
- Studies on hold, off hold
- Studies closed to accrual/enrollment
Please note: Documents such as an updated Investigator Brochure (IB) need to be attached to the application and are required to be submitted via the PAA - Amendment form. Requests for Acknowledgement do not allow access to the Application. An Acknowledgement Letter will be issued for this.
Should the IB require changes to the Protocol or Consent Form, this should be submitted as an Amendment with the completed documents attached. A Certificate of Approval will be issued for this.
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: The term protocol deviation is not well defined by regulations or guidelines, but 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.
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.
All Requests for Acknowledgement should be submitted as soon as reasonably possible after the Principal Investigator receives the relevant documentation or becomes aware of the new information, unanticipated issue or unanticipated problem.
The term as soon as reasonably possible means that timing of reporting will vary in accordance with the severity / seriousness of the information being reported. Unless, however, the event is a routine safety letter, DSMB, summary report or changes to the Investigator's Brochure that are minor and/or routine in nature, all unanticipated problems, unanticipated issues, local serious adverse events and new information must be reported within seven days of the incident, occurrence, outcome, event or the Investigator's receipt of the new information.
All Requests for Acknowledgement should contain:
- appropriate identifying information for the study
- a description of the incident, experience or outcome if applicable
- a summary of the new information if applicable
- a description of any changes to the protocol or other corrective actions that have been taken or are proposed to be taken in response to the new information, unanticipated problem or new documentation.
Investigators conducting studies that are funded or supported by the U.S. Federal Government or that are regulated by the U.S. Food & Drug Administration are required to report all unanticipated problems to the Institution, relevant regulatory authorities and if applicable, the study sponsor.
VII. Submitting Unanticipated Problems
In Canada, under the Food and Drug Act Regulations Division 5, Clinical Trials, a clinical trial sponsor is legally required to report serious unexpected adverse drug reactions to the Minister (Health Canada) either within 15 days (not fatal or life-threatening) or within 7 days (fatal or life threatening) of becoming aware of the information.
The ICH Good Clinical Practice Guidelines stipulate that Research Ethics Boards must establish, document in writing and follow procedures for:
- Determining the frequency of continuing review as appropriate (including adverse drug reactions and adverse events) and
- Requiring that the Investigator should promptly report to the REB
- Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial;
- All adverse drug reactions that are both serious and unexpected
- New information may affect adversely, the safety of the subjects or the conduct of the trial.
In the United States, U.S. Federal Regulations require REBs to have among other things, information concerning unanticipated problems involving risk to human subjects in the study, including adverse events (AE's) that are considered unanticipated problems (21 CFR 56.108(a)(3)(4)(b) https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?f...
Investigators are reminded that in addition to being required to report serious and unexpected adverse events / reactions to the REB, they are required to report such events to the study sponsor and, appropriate Health Canada agencies where applicable. The UBC Office of Research Ethics will report all reportable unanticipated problems to the Office of Human Protections or the U.S. Food & Drug Administration, if the unanticipated problem occurs in a study that is funded by or supported by the U.S. Federal Government or that is subject to the U.S. Food & Drug Regulations. Investigators MUST indicate in the Request for Acknowledgement form that the unanticipated problem relates to a US funded or regulated study, including providing the FDA IND or IDE number where applicable.
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.
There is no Canadian regulatory requirement for REB acknowledgement to investigators of the submission of unanticipated problems including serious and unexpected events, however, an acknowledgment certificate will be issued within the RISe on-line system.
VIII. Protocol Deviations
The term protocol deviation is not well defined by regulations or guidelines. Deviations are identified as any unanticipated or unintentional divergence or departure from the expected conduct of an approved study that is not consistent with the approved Research Ethics Board (REB protocol or protocol procedures). Deviations are different from amendments in that they generally apply to a single occurrence or participant and are not intended at the time to modify the entire protocol. Protocol Deviations are unanticipated issues and they include unauthorized collection, use or disclosure of personal health information that is not in compliance with the approved study protocol, jurisdictional legislation or its regulation.
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))."
It is the responsibility of the Principal Investigator to notify the applicable UBC REB of all protocol deviations that:
- Expose subjects to potential increased risk;
- Compromise the integrity of the entire study;
- Are repetitive in nature
- Alter subject eligibility, or
- Affect the privacy of the subject.
The Principal Investigator, or person designated by the Investigator, must complete and sign a report that documents the protocol deviation that occurred and submit it to the applicable UBC REB using the Request for Acknowledgement form in RISe.
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.