All research projects involving TAHSN Institution physicians, staff (including staff acting as investigators outside the Institution), students (i.e., research within the institution or using institutional resources), or patients, must obtain ethical approval from the Research Ethics Board (REB) before research can begin.The REB is responsible, on behalf of the institution, for ensuring that all research involving human subjects under the auspices of its institution meets current ethical standards. Heads of departments /divisions /programs are responsible for ensuring that all such research is submitted for ethics review. Proposals are reviewed by the full board at a scheduled meeting, or in an expedited manner, depending on level of risk associated with the study, and on prior review. Regardless of the type of review, a full application form must be completed. A complete research proposal/and or protocol must also be submitted.
I. FULL BOARD REVIEW:
This is the default that will apply unless there is sufficient justification for other levels of review. Submissions are reviewed in the order of their arrival at the Research Ethics office. Please contact your REB regarding meeting dates and deadlines for submission.
II. EXPEDITED REVIEW:
Studies that may qualify for expedited review:
- Are considered either minimal risk and non-invasive (e.g. retrospective chart reviews, nonintrusive questionnaires or surveys, non-invasive assessments, use of existing samples), or
- Involve only current standards of care, or
- Have had prior approval from a TAHSN Institution Research Ethics Board. Studies that have been approved by a TAHSN or other REB are not considered for expedited review unless the relevant documentation (REB review letter, reply to any REB concerns and approval letter) is provided.
The investigator must include the justification for requesting expedited review. The decision of whether a study qualifies for expedited review rests with the REB Chair. Where expedited review is not granted, the investigator will be informed that a full board review will be required.
THE APPLICATION FORM - INSTRUCTIONS
Electronic or paper Application Forms are available from the Research Ethics Board Office. If this is a multi-centre study, a complete application must be submitted to each local REB. Ensure that the appropriate signatures are obtained for each site. The entire form must be completed. If a section does not apply, indicate N/A. Do not refer to or attach other documents in response to questions except where indicated. The following are further explanatory notes regarding some items on the application form. The numbering corresponds to the items on the application form.
SECTION I: GENERAL INFORMATION
1. PRINCIPAL INVESTIGATOR
The Principal Investigator is the responsible leader of the research team and must be clearly designated for each site. There should be one PI per site per protocol. Students/trainees cannot be listed as the PI. Where the investigator is a student, the supervisor should usually be designated as the PI and sign this section. Some institutions require the PI to be a staff member at the institution where the research will take place. Check with your institution.
For “clinical studies” as defined by Health Canada (i.e. involving an investigational drug or medical device), the Principal Investigator must be a Qualified Investigator (a physician or, where applicable a dentist, and a member in good standing of a professional medical or dental association).
2. FULL STUDY TITLE
Include the full title as it appears on the protocol.
4. INVESTIGATORS
4C. Contact Person
For studies originating from outside of the institution, a staff member must be involved as the institutional liaison who will accept responsibility for the research activities at the institution, as well as serve as the administrative contact with the REB. The role of institutional liaison applies only at those institutions that do not require the PI to be a staff member, and only for studies where the PI is not a staff member.
Signatures
All applicable signatures must be obtained before the REB reviews the application. All sections of the form must be completed before signatures are obtained.
5. DEPARTMENT/DIVISION/PROGRAM APPROVAL
The application forms for all projects submitted for review will require the signature of the Division/Department Head/Program Director where the research is to be conducted. The signature indicates agreement that the Division/Department/Program supports the project and that the PI is qualified by education, training, and experience to perform his/her role in the study. When the Division/Department Head/Program Director is the investigator, the signature of an individual one level above the investigator is required.
7. OTHER ETHICS/SCIENTIFIC/ SCHOLARLY REVIEW
Indicate in the table where this application is being submitted, including sites where an application has been or will be submitted, and REB review status. If a Research Ethics Board at a University of Toronto Affiliated Teaching Hospital or other institution has approved the study, it may qualify for expedited approval. The relevant documentation (REB review letter, reply to any concerns, approval letter) must be provided.
8. CLINICAL TRIAL REGULATIONS
This section need only be completed if the research study is a clinical trial. Health Canada, under Division 5 defines a clinical trial (requiring Health Canada approval) as “an investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug. Investigational drugs or devices include all drugs (including biologics and natural health products) or medical devices requiring Health Canada approval, as well as all approved drugs being tested for a new indication (e.g., age group, disease entity), dosage or method of administration.
Studies involving investigational drugs or medical devices must apply for authorization for research use from Health Canada. For investigational drug trials a “Clinical Trial Application” form must be submitted to Health Canada. Provide a copy of the authorization or “No objection” letter from Health Canada as soon as it becomes available. Final REB approval of the study will not be granted until the no objection letter has been received. For certain medical device studies (class III and IV devices), however, Health Canada requires REB approval first.
If results are to be submitted for US Food and Drug Administration (FDA) approval, provide the IND number (drug studies) or PMA number (device studies).
SECTION II: STUDY SUMMARY
A size limit has been set for some of the items in this section, as indicated on the form.
10. ABSTRACT
Ensure that the abstract is described using lay language.
11. RATIONALE AND HYPOTHESIS/RESEARCH QUESTION
Ensure that the rationale and hypothesis are described using lay language For studies involving investigational new drugs or devices or use of an approved product for a new indication, provide justification to support the investigational use in this project.
12. STUDY DESIGN
12A. Design/methodology
Describe the basic study design and method. If this is a randomized trial, explain how subjects will be assigned to each group. If this is a pilot study, indicate briefly how the data will be used to develop a full follow up study.
12B. Primary outcome measures
List the primary endpoints, or key data items that are required to answer the study question.
12C. Criteria for Early Withdrawal
Indicate what endpoints or stopping rules will serve as triggers/thresholds for early withdrawal for subject safety (e.g. regarding treatment failure/adverse events), such as blood pressure levels, laboratory values, disease status assessments, etc.
12D. Placebo
The Tri-Council Policy Statement (TCPS) indicates that, with some exceptions, placebo should not be used for conditions where an effective treatment is available. If the research involves placebo, explain the justification for its use and what provisions are in place to reduce any increased risk associated with the use of placebo.
12E. Deception or Lack of Disclosure
The TCPS permits the REB to approve a consent procedure which does not include, or which alters some information about the study only when the deception or lack of disclosure poses no more than minimal risk, the research could not practicably be carried out in another way, the subjects are provided with full disclosure at a later date (where possible) and the deception or lack of disclosure does not involve a therapeutic intervention. Deception or lack of disclosure is used most often in social science or psychology research, where full disclosure would likely affect the responses of the subjects and thus invalidate the research.
12F. Study Restrictions
List in this section any restrictions on medications/treatments or lifestyle, such as diet, exercise, smoking, exposure to sun, driving, etc. Specify the duration of restrictions and the reasons the restrictions are necessary.
13. SUBJECTS/CONTROLS
Selection of subjects must be equitable. Include the rationale for the choice of control group if applicable. If a vulnerable population is used (e.g., children, incompetent adults), include justification for this choice (e.g., has the research question been previously addressed in a less vulnerable populations). Justification is not required at institutions where these vulnerable populations are the primary patient population (e.g., paediatric or geriatric centres). If a group (e.g., women of childbearing potential, the elderly) is excluded from a study involving a general patient population, justify. Where women of childbearing potential are excluded will consideration be taken for inclusion of women who are not at risk of becoming pregnant?13D. Sample Size Justification For quantitative studies, include sample size calculations and source for standard deviation. For qualitative studies indicate approximate sample size and rationale. You may refer to the protocol for this information.
14. STUDY INTERVENTIONS OR PROCEDURES INVOLVING HUMAN SUBJECTS
14A. Usual Standard of Care
This section must specify what is standard care specifically as it relates to the population under study and any study interventions, and how participation in the study will alter standard care if applicable (i.e. what would happen if the study were not being done).
14B. Changes/additions to Standard of Care
Describe any procedures that are being done in the study that are not part of standard of care, including any procedures performed purely for research purposes (e.g. extra blood samples, evaluations, telephone surveys, questionnaires). If subjects are required to meet certain eligibility criteria that necessitate changes to or termination of treatments, describe them too. Include all patient contact and be as specific as you can.
Attach a copy of all instruments (i.e. questionnaires (non-standardized), interview scripts and rating scales) that will be administered during the study.
SECTION III: ETHICAL ISSUES
16. RECRUITMENT AND CONSENT
16A. Identification of potential subjects.
Specify how potential subjects will be identified and by whom. Respect for patient privacy requires that patient records be reviewed by persons within the patient’s circle of care, who have access to patient information as part of their normal professional duties, or their delegates (e.g. study coordinator working on behalf of investigator who has access).
Health Records include but are not limited to: slides (e.g. pathology), radiology films/reports, surgical lists and databases.
The REB must review all study-related materials that will be given to subjects, including advertisements or letters regarding recruitment. Note that no specific dollar amount of payments to subjects should be listed in the advertisement.
Finder’s Fees include money or other reward given to a physician (or group of physicians, or other health care providers) in payment for identifying or recruiting a patient into a study or a trial. Finder’s fees are prohibited. For more information the University of Toronto Policy on finder’s fees can be found at:
http://www.facmed.utoronto.ca/scripts/index_.asp?action=31&U_ID=0&N_ID=13&P_ID=9976
16B,C and D. Initial contact with subjects and consent process.
Issues to consider include whether the contact person is known to the subject/authorized third party, has access to patient information as part of their normal professional duties, or is able to assess capacity to consent.
16E. Checklist of Study Subjects
The purpose of this checklist is to flag for the REB any research scenarios that may raise special concerns. “Subjects unable to communicate” refers to patients who are mentally competent, but who, because of certain conditions (e.g. stroke), are unable to communicate or have difficulty communicating their intentions. “Marginally incompetent” refers to patients who fall in the grey area between competent and incompetent, and whose capacity may fluctuate over time.
16F. Enrollment in Multiple Studies
There may be occasions where a number of different research projects focus on a particular patient population, and individual patients may be eligible for more than one study. Enrollment in multiple studies raises concerns whether the studies are ongoing simultaneously or in succession. In this situation, investigators must explain what procedures are in place to avoid enrollment of patients in multiple studies. If enrollment in multiple studies is anticipated, justify and explain what extra precautions are in place to ensure patient safety and welfare.
17. RISK/BENEFIT ESTIMATES
It is the expectation of the Tri-Council Policy Statement that proposed research will be designed to benefit participants where possible. Studies that involve significant risk without a balance of significant benefit may be inappropriate.
17A. Benefits
The list of benefits may include direct benefits to the subjects or benefits to knowledge or to society.
17B. Potential Harms
Describe all risks associated with the study interventions and the likelihood of these events occurring. If there are no known risks, check the appropriate box.
17B.v)
If participation in the study may affect a patient’s options for future care (e.g., making them ineligible for other standard therapies or the possible development of antibodies which might prevent future treatment with the investigational agent), explain what options will and will not be available.
18. PAYMENTS
Subjects should not be expected to incur expenses as a direct result of participation in a research study; reimbursement for out-of-pocket expenses (e.g. travel) is encouraged. Payment should not be used in such a way that it could be construed as an undue inducement to participate (e.g. unreasonable amount, payment tied to completion of study). Reimbursement should be for expenses, time or inconvenience, but should not be used to encourage subjects to accept increased risk. If reimbursement for time is proposed, explain. It is expected that expenses will be fully covered and any payments for time (including honoraria) will be pro-rated for partial participation.
19. MONITORING
Monitoring refers to oversight activities performed by groups other than the REB, such as the study sponsor (e.g. site visits to check for GCP compliance, interim analysis of results by a data and safety monitoring board or steering committee).
20. POTENTIAL CONFLICTS OF INTEREST
The term "conflict of interest" refers to situations in which financial or other personal considerations may compromise, or have the appearance of compromising, a researcher’s professional judgments. The bias such conflicts could conceivably impart may inappropriately affect the goals of research. “Apparent” or “perceived” conflicts of interest refer to situations which appear to present a conflict to an outside observer, although they may not give rise to an actual conflict. The mere appearance of a conflict may be as serious and potentially damaging as an actual conflict. Immediate family includes an investigator’s spouse and dependent children (including stepchildren). For more information, you may refer to the University of Toronto policy on Conflict of Interest at the following internet location:
http://www.utoronto.ca/govcncl/pap/policies/conacad.html
21. PUBLICATION/DISSEMINATION OF RESULTS
Since the contribution to knowledge is one of the primary purposes of medical research, researchers are encouraged to publish the results of their research. Furthermore, where possible, researchers are strongly encouraged to share the study results of the research with the subjects who made the research possible, and/or with the relevant patient communities.
SECTION IV: PRIVACY AND CONFIDENTIALITY
22. COLLECTION AND USE OF PERSONAL HEALTH INFORMATION
During collection and storage data and samples must be kept secure from theft, interception, unauthorized reading and copying. Investigators must state their means of protecting study data or samples from such violation, for instance by coding systems and/or security systems.
The Personal Health Information Protection Act (Bill 31) which came into force in Ontario on Nov. 1, 2004, requires that for research studies involving the collection, use and disclosure of personal health information the REB must receive a description of what information will be collected, and how it will be collected, used and stored. The act defines personal health information as follows (s. 4):
Personal Health Information means identifying information about an individual in oral or recorded form, if the information,
- Relates to the physical or mental health of the individual including information that consists of the health history of the individual’s family,
- Relates to the providing of health care to the individual, including the identification of a person as a provider of health care to the individual,
- Is a plan of service within the meaning of the Long-Term Care Act, 1994 for the individual,
- dRelates to payments or eligibility for health care in respect of the individual,
- Relates to the donation by the individual of any body part or bodily substance of the individual or is derived from the testing or examination of any such body part or bodily substance,
- Is the individual’s health number, or
- Identifies an individual’s substitute decision-maker.
Identifying Information means information that identifies an individual or for which it is reasonably foreseeable in the circumstances that it could be utilized, either alone or with other information, to identify an individual.
SECTION V: FUNDING and CONTRACTS
23. BUDGET
Include a detailed, itemized budget listing expenses for the study. The REB will consider aspects such as investigator payments, reimbursement for subjects, and whether there are adequate funds to cover study treatments and procedures.
24. AGREEMENTS
Refer to the institution specific instruction page for details regarding submission of contracts or research agreements.
24C. Liability
Please indicate who will cover the costs of treatment not covered by the provincial health plan in case of injury directly resulting from participation in a research study (i.e. sponsor, institution, other).
24D. Publication Agreements
Agreements regarding publishing of medical research should not prevent the publication of results or the communication of information important to subject safety.
25. MATERIAL TRANSFER AGREEMENT
This refers to agreement for transfer of biological materials (e.g., tissues, cell lines) from the institution to another institution or other entity. The agreement usually originates from the institution sending out the materials. If biological material (e.g., tissues, cell lines) is to be transferred from this institution to another institution or entity, indicate what arrangements are in place to ensure that appropriate consent has been obtained for this use and that donor confidentiality will be protected.
26. INFORMATION SHARING AGREEMENT
An information sharing agreement is recommended when a health information custodian shares a patient’s personal health information with a researcher from another hospital or institution. The agreement should specify who are the information custodians, and the outside researcher with whom the information is being shared. The agreement should also describe the use, storage and disposal of the information. Contact your REB or contracts office for more information regarding the use of information sharing agreements at your institution.
These guidelines are in compliance with the requirements for continuing ethical review as set out in the Tri-Council Policy Statement and in the regulations and guidelines governing clinical trials (Health Canada Clinical Trial Regulations for new investigational drugs, radiopharmaceuticals, biological drugs, natural health products, and medical devices), ICH GCP, and where relevant, US Codes of Federal Regulations. All revisions, additions or deletions to approved studies are considered amendments and must be submitted to the UHN Research Ethics Board (REB) for review to ensure that the research remains scientifically and ethically sound. The Principal Investigator (PI) is responsible for ensuring that amendments are submitted to the REB for review and written approval is received prior to implementation.
Definitions
1. Amendment
A written description of a change(s) to, or formal clarification of an ongoing currently approved protocol. Amendments include any change to the study documents that affects the scientific intent, study design, patient safety, or human subject protection.
Some examples of amendments include:
- change of Principal Investigator or change of Co-Investigator(s)
- change in recruitment methods
- change in sample size or study duration
- change to inclusion/exclusion criteria
- change in study procedures
- change to protocol that affects the selection, monitoring or dismissal of a
- study subject(s)
- change to protocol that affects the evaluation of the clinical efficacy and
- safety of the drug
- change to protocol that alters the risk to the study subject(s)
- rephrasing a line or section, or typographical or numeric corrections that may affect safety of subjects (i.e. change in eligibility criteria, change of dose, change in risk regardless if risk is increased or decreased.
2. Administrative Change
A minor change(s) to any study document(s) that does not affect the scientific intent of the study, study design, study subject risk, or human subject protection.
Some examples of administrative changes include:
- Rephrasing a sentence or section to add clarity or correct inconsistencies
- Reformatting the document
- Change of study coordinator or monitor
- Change of address, telephone, or e-mail address of study staff.
Sub-Studies
The REB generally does not consider sub-studies, ancillary studies, rollover studies, continuation studies, and extension studies to be amendments. These are usually considered new studies and the decision of whether they qualify for review as amendments rests with the REB Chair.
Exceptions
Although most amendments must be reviewed and approved prior to implementation, amendments can be implemented prior to REB review and approval under the following circumstances:
- Amendments should be implemented prior to REB review and approval when the amendment is essential to eliminate any immediate hazards to research subjects. These amendments must be submitted to the REB within 7 days of implementation.
- Amendments may be implemented prior to REB review and approval when the amendment involves only logistical or administrative aspects of the study. These administrative changes must be submitted to the REB within 30 days of implementation.
Procedures
1. Submitting an Amendment and Administrative Change
The REB Amendment and Administrative Change Form must accompany all amendments and administrative change submissions. The form directs the PI to identify change(s) to be made to study documents and to provide justification/rationale for the change(s). All study documents affected by the change must be included with the submission (e.g.):
- amendment document
- revised protocol
- informed consent form(s)
- supporting documentation (e.g. new information supporting the amendment)
All revised study documents must have version dates that reflect the most recent amendment/ administrative change submission. Further details regarding version dates can be found below.
The REB will not accept amendment/administrative change submissions without the original signature of the PI. This signature attests that the PI accepts the amendment/administrative change. For amendments, the PI’s signature further attests that the PI has assessed the safety implications of the amendment, its impact on study procedures and is prepared to take all necessary steps to implement the change. Incomplete amendment/administrative change submissions will be returned to the Principal Investigator with a return notification form that indicates the documentation that is outstanding. The REB will process and review the amendment/administrative change submission once all required documentation is received.
2. Version Dates
Version dates identify the latest edition of study documents. Version dates, including the day, written month, and year (e.g. 04-Jan-05) must be presented in this format in the footer of all study documents. If a study document requires further modification based on comments received during the REB review process, the version date must be modified to reflect the most recent edition of the study document. Informed Consent Forms will not be approved without revised version dates in the format outlined above.
3. Review Process
Full board review of amendments is the default requirement for all research involving human subjects. The decision of whether an amendment qualifies for expedited review is based primarily on the risks that are expected to arise from the change to the research protocol. The decision of whether an amendment qualifies for expedited review rests with the REB Chair. Full Board Review The following types of amendments will be considered for full board review and approval:
- changes that increase the risks to the study subject(s) and/or changes that significantly affect the study procedures, study design, or conduct of the study
- changes that have been implemented to eliminate any immediate hazards to study subjects without prior REB approval. (The REB office will review these amendments and provide a preliminary decision; however, the final decision rests with the full board.)
Amendments that qualify for full board review are reviewed at the next meeting of the board that conducted the initial review of the study. REB questions or concerns regarding amendment submissions are communicated to the PI in a written format that is sent to the PI following the review.
Health Canada No Objection letters (NOLs) must be included with amendment submissions for clinical trials when applicable. REB approval will not be granted until the NOL is received.
For full board review attach:
- Ten copies of relevant study documents with changes tracked, (or in bold or highlighted) that accurately reflects the changes to study outlined in the request form.
- One clean copy of relevant study documents (without tracked changes, handwritten notes or highlights)
Expedited Review
Many amendments and all administrative changes qualify for review under the expedited review process. REB questions, concerns and/or recommendations regarding amendment/administrative change submissions are generally communicated to the PI via email.
For expedited review attach:
- one copy of relevant study documents with changes tracked (or in bold or highlighted) that accurately reflects the changes (additions and deletions to study outlined in the amendment form.
- one clean copy of relevant study documents (without tracked changes, handwritten notes or highlights)
In the event that the REB finds one or more of the parts of an amendment/administrative change submission unacceptable, the PI will be informed via written letter or email communication of what was not acceptable and why. The PI will have the opportunity to submit a revised amendment that corrects the issues outlined by the REB or provides additional justification to support the original request.
4. Amendments Submitted During the Initial Review Process
Whether an amendment submitted for a study that has not yet been approved by the REB is reviewed by the full board or qualifies for expedited review depends upon the risk(s) associated with it.
Amendments that have greater than minimal risk(s) associated with them will be reviewed at the next meeting of the same full board that conducted the initial review of the study. Once all of the concerns are addressed, the initial approval and the amendment to study will be approved in separate approval letters that reflect the dates of the full board meetings where the review of each was conducted.
Amendments that have minimal risk(s) associated with them will be expedited and once all of the concerns are addressed, the initial approval and the amendment to study will be approved in separate approval letters that reflect the dates and types of review.
Amendments Not Approved by the REB
In the event that the concerns of the REB cannot be resolved and an acceptable alternative cannot be found, the amendment will not be approved and the reasons will be communicated to the Principal Investigator. In accordance with Division 5 C.05.008 (C) (ii), it is the responsibility of the Sponsor (for clinical trials only) to inform Health Canada that the amendment was not approved by the REB and the reasons for this.
REFERENCES
- Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. August 1998.
- Good Clinical Practice: Consolidated Guideline. ICH Harmonised Tripartite Guideline. 1997.
- Health Canada Consolidated Statutes and Regulations, Food and Drug Act, Division 5 Drugs For Clinical Trials Involving Human Subjects. August 2004.