These guidelines and procedures have been identified as being beneficial in the various REB application and reporting processes.
Applications Guidelines for Protocols reviewed by the Full Board
Clinical drug trials (Phase I, II, and III) must be approved by Health Canada prior to their commencement. A copy of the Health Canada ‘No Objection Letter’ (NOL) must be forwarded to the REB office prior to final approval of the protocol. Refer to the HPFB website for Guidance for Clinical Trial Sponsors for further information. The Board will only accept applications for clinical drug trials after a Clinical Trial Application (CTA) has been filed with Health Canada, and a control number has been issued by Health Canada.
For Clinical drug trials, the REB requires an investigator’s brochure or product monograph (as applicable) for clinical drug trials. The Director of Pharmacy must approve these studies prior to submission to the Board.
Clinical trials of natural health products must also be approved by Health Canada prior to their commencement. The will only accept applications for clinical trials of natural health products after an application has been filed with Health Canada, and a notice of authorization has been issued by the ministry (or control number).
Clinical medical device trials must have been authorized by Health Canada (see relevant Health Canada regulations).
In Canada, medical devices are categorized into four classes based on the level of risk associated with their use. Class I devices present the lowest potential risk (e.g. thermometers) and do not as a result, require investigational testing authorization. Class II, III, and IV devices present higher risks to the individual and must be reviewed by Health Canada prior to undergoing further study.
Following a favourable Health Canada review of the Application for Investigational Testing of a Device, Health Canada issues an authorization to conduct research. Health Canada requires notification of REB approval for a study prior to issuing such authorization. Under these circumstances, the CHEO REB can provide to the investigator certification of conditional approval for the study if such approval is the only impediment to the Health Canada license. The final REB approval would only be issued when the CHEO REB had received documentation regarding the Ministry’s approval.
Placebo Controlled Trials are permissible under specific circumstances. The Tri-Council Guidelines for research with human subjects outlines these requirements.
The use of an active treatment comparator in a clinical trial of a new therapy is an appropriate study design when established effective therapy or therapies exist for the population and indication under study.
- A placebo comparator is only acceptable in the following situations:
- There are no established effective therapies for the population and for the indication under study.
- Existing evidence raises substantial doubt regarding the net therapeutic benefit of available therapies,
- Patients are refractory to the available therapies by virtue of their past treatment history or known medical history,
a. The study involves adding a new investigational therapy to established effective therapies (established effective therapy + new therapy vs. established effective therapy + placebo),
b. Patients have determined that the response to the established effective therapies for their condition is unsatisfactory to them,
c. Patients have previously refused established effective therapies for their condition.
Full Board protocols should include the following information:
Please note that protocols submitted to REB must include the information outlined in the CHEO REB protocol template. If the study is occurring at multiple sites and the main protocol does not contain all the required information, a separate site-specific protocol addendum should be developed.
Objectives: State the objectives of the study as hypotheses.
Study design and methods:
- Describe the involvement of human participants, including study procedures. Give detailed procedures for treatment, dose adjustments, etc.
- Clearly delineate standard vs. experimental aspects of the treatment provided.
- Describe alternatives to experimental therapy, if any.
- Describe the randomization procedure, if applicable.
- Describe the types, frequency and duration of tests, admissions, outpatient visits.
- Consider specifying a Data Safety Monitoring Board (DSMB) if the study involves an investigational agent & blinded design.
- Define criteria for withdrawing participants from the study.
- Specify the number of participants drawn from CHEO and other centres.
Analysis of the study:
- Delineate the outcomes to be measured and analyzed.
Participant selection and recruitment:
Describe the rationale for research participant selection based on age/gender/ethnicity/racial categories.
- Of note, investigators who intend to collect racial information on participants will be asked by the Board to describe the scientific basis for doing so. Health research that includes race as a variable has been criticized for lacking rigour in conceptualization, terminology and analysis. The issues include: the stigma associated with medical research that includes race or ethnicity (e.g., Ashkenazi Jews & Tay-Sachs), the inappropriate aggregation of heterogeneous racial/ethnic groups; ethnocentric bias in defining categories (e.g., non-whites), and the use of race as an explanatory variable when the underlying constructs are variables that should & can be measured directly (e.g., SES, educational status, ethnicity).
- If justified, the Board routinely recommends that the investigators consider using the categories employed by Statistics Canada, that are felt to be more appropriate to Canadian society. The Census categories are also nice because they give respondents the opportunity to describe themselves in their own terms rather than forcing choices among pre-coded categories. These can be accessed from the Statistics Canada website (under groups of people designated as visible minorities).
- Describe the process for recruiting patients into this research study; physicians have a duty to manage existing and potential conflicts of interest. The College of Physicians & Surgeons of Ontario’s (CPSO) has issued relevant guidance.
- Strategies/procedures for recruitment
- PHIPA (Personal Health Information Protection Act, 2004) prohibits the use of patient contact information for the purposes of recruitment into a research study without the express consent of the patient. Accordingly, information about patient eligibility cannot be released to a research team, unless members of that team would normally have access to such information in the provision of clinical care (e.g., an endocrinologist who is both an investigator and clinician studying diabetic children), or the patient has consented to such a release of information.
- When the practitioner is also an investigator on the research team, the Board requires that recruitment occur at arms-length from clinical care. The Board is concerned that eligible families who are under a practitioner’s care may feel beholden to him/her and inclined to agree to the study to please them or express their appreciation for their child’s care. To minimize this possibility, the Board requires that another member of the care team first approach families about the study. If required, the treating practitioner-investigator can then answer any questions raised by families who were interested in participating.
- When this standard cannot be met, the Board may require additional measures to ensure that consent is entirely voluntary and uninfluenced by the patient-practitioner relationship and the potential research interests of the investigator. These decisions are made on a case-by-case basis.
Evaluation of benefits and risks/discomforts:
- Describe any potential risks and benefits (e.g.; physical, psychological, social, legal or other) and assess their likelihood.
- Describe any procedures for offsetting risks.
- Of note, investigators should ensure that the blood collection does not exceed those outlined in the Sick Children’s Hospital guidelines for blood sampling in research, which are also endorsed by the CHEO REB, i.e., ‘For research of infants, children and adolescents, the REB will allow total blood-drawing of up to 5% of the research participant’s total blood volume over a 3 month period, on a single occasion or in divided portions. Example: a newborn weighing 2.5 kg has a blood volume of 85 X 2.5= 212 mL. Up to 5% can be removed for research: .05 X 212=10.5cc. * from Pearson HA, “Blood and Blood-forming Tissues ” in Rudolph’s Pediatrics, CD Rudolph and AM Rudolph (Editors), McGraw-Hill, New York, 21st Edition, 2003, page 1521.
Consent and assent processes and documents:
- Describe the consent procedures to be followed, including the circumstances under which consent will be sought and obtained.
- The CHEO Research Ethics Board requires informed consent forms to be available in both English and French as per the Board’s Bilingualism policy enacted on October 1, 2004.
- The REB reviews study budgets to examine possible conflicts of interest that would appear in the form of ‘overpayment’ for the recruitment and subsequent care of research participants.
- An itemized per patient budget should be submitted to the Board for review. The budget should indicate whether or not a fee for service will be paid to the investigator and/or referring physician and on what basis it is calculated. Review the CPSO policy for more information. Both the REB and the CPSO do not permit physician investigators to receive compensation for recruiting patients into clinical trials. That being said, a recruiting physician can receive appropriate compensation for clinical and/or administrative services, which are beyond his/her normal practice activities and are required to recruit patients into a study. Parameters such as time, expenditure and complexity of the work required may be relevant considerations in determining what an appropriate compensation amount is. The concern with the payment of ‘recruitment fees’ not directly linked to a recognized fee schedule, is that they create a potential conflict of interest in which the physician’s interests appear to diverge from those of his/her patients.
- Financial agreements between the Primary CHEO Site Investigator and the Sponsor of the study must be described.
Data Sharing Agreements:
Data sharing agreements between CHEO and the study sponsor must be vetted by the RI Contracts Officer.
Scientific Peer reviews:
Protocols that expose human research participants to more than minimal risk must show evidence that the study has undergone independent scientific peer review. The peer review process ensures that all research meets the highest scientific standards. In the absence of scientific rigour, there is no justification to exposing humans to research-related risk. Research that is poorly justified or designed cannot advance knowledge and should therefore, not be permitted.
The initial submission must include two independent scientific peer reviews for review by the Board. To qualify as an independent scientific peer review, a review must:
- Appraise the scientific merit and rigour of the study;
- Be conducted by qualified experts within the field;
- Be de-identified such that the name of the reviewer is not revealed to the study team; and be obtained independently (i.e., not through the study team). Studies with scientific peer review as part of their funding (e.g., CIHR):The Researcher should upload copies of the two required independent scientific peer reviews in their application to the Board. Studies that do not have accompanying scientific peer review from funding agencies or are unfunded: The Researcher must obtain a scientific peer review though the CHEO Research Institute peer review program (under special review). The following submissions are excluded from this requirement:
- Research sponsored and initiated by Industry; and
- Research sponsored and initiated by a recognized cooperative research group; e.g., Children’s Oncology Group. The REB reserves the right to request scientific peer reviews regardless of the Sponsor type, should they deem it necessary.
Electronic Consent Forms and Signature Policy
Rationale, Purpose and Scope
The advancement and integration, as well as possibilities, of technology in the everyday life of Canadian citizen and residents calls for the movement of research ethics boards and regulatory agencies in recognizing the use of technology in the informed consent process. Technology may provide opportunities as well as new ideas. However, this also presents new questions and concerns. The term written informed consent is often viewed as synonymous with obtaining handwritten (‘wet ink’) signatures from a study participant or their legal representative on a paper informed consent document. However, the term written is not defined and can be interpreted differently. The Canadian legal system recognizes and qualifies an electronic signature, obtained & documented in compliance with the regulations set out in the Canadian Evidence Act and the Personal Information Protection and electronic documents Act (PIPEDA), as equal to a handwritten (‘wet ink’) signature of an individual.
The following document outlines the policy of the CHEO REB regarding the use of electronic consent forms (eIC) and electronic signatures (eSIG) in the consent process for researchers. The use of eIC & eSIG for consent processes will be limited to non-regulated research studies. Consultation with the regulatory authorities is an on-going venture.
Guidelines for delegated research protocols
Protocols that present only minimal or very low risk to participants are reviewed by the Chair or a delegate of the Board. Minimal or low risk is ordinarily taken to mean those risks normally encountered in everyday life by the research participant.
There is no submission deadline for delegated reviews; they can be submitted at any time. The turn-around time upon receipt of completed submissions that receive delegated review is generally within six (6) weeks. Submissions that are incomplete or require modifications will necessarily delay this process. Please note that protocols submitted to REB must include the information outlined in the CHEO REB protocol template. If the study is occurring at multiple sites and the main protocol does not contain all the required information, a separate site-specific protocol addendum should be developed.
There are three streams of delegated review:
1. Research projects involving minimal risk that proposes a prospective collection of data involving families or staff. The appropriate authorization from the manager responsible for the staff or the clinical population involved in the study is required. Complete the Application Form for Prospective Studies involving Minimal Risk (e.g.; Surveys, Quality of Life Questionnaires, Non-Invasive Procedures).
2. Retrospective chart reviews/secondary analysis of clinical samples. Complete the Application Form for Retrospective Chart Review and Secondary Use of Clinical Data or Biological Samples.
3. Databases. Complete the application for Prospective Studies Involving Minimal risk in Romeo. 4. Record Level Requests from the BORN Datasets – complete the application in Romeo. 5. Prescribed Entity or Prescribed Registry – complete the application in Romeo.
Application Procedures for Databases
Databases refers to the use in research of data contained in a previously created data set, whether it is retrospective or prospective. Database projects often use the same data set to answer several, related research questions. The REB requires that investigators submit a general description of the project including all the elements specified above (study rationale, identifiers to be retained, etc.). The overall database project is reviewed under the ‘delegated’ stream (previously expedited review). In an addendum to the application, investigators must describe each publication or sub-study relating to the database.
Access to the database should be limited to the investigator and his/her delegates as outlined in the application. REB approval should be obtained prior to any release of the data to other investigators.
Authorization from the appropriate division head from which the database information would be obtained.
Definition Of Secondary Analyses Of Clinical Data
The secondary use of data refers to the use in research of clinical data already contained in participant’s health record and collected through the normal provision of routine care.
The Provincial Personal Health Information Protection Act of Ontario (PHIPA) sets forth the following requirements for the secondary use of clinical data in research:
- The scientific question being asked is valuable and justifiable;
- Appropriate measures are being taken to protect the privacy of the individuals, to ensure the confidentiality of the data, and to minimize harm to participantss;
- The patients regarding whom the data refer will not be directly contacted by the researchers without their prior express and informed consent;
- Identifying information will not be released to researchers outside the hospital without the patient’s express and informed consent;
- Individuals to whom the data refers have not previously objected to such secondary use;
- The data being collected would normally be obtained in the provision of care (section 29 (2)). As a consequence, the REB must ensure that the research plan limits its analysis to those data fields that would normally be available in the health record (departmental or centralized chart). If an investigator wishes to look at variables that are supplemental to care (e.g., in many instances, this could include race and SES), the individual’s express and informed consent must first be obtained and the research plan approved by the board.
- It should be noted that PHIPA (health privacy legislation in Ontario) allows researchers to use clinical data to answer questions on the basis of ‘implied consent’. Implied consent can be assumed if the institution has posted public notices to advise patients of the different uses that it makes of personal health information & that an REB has approved the research plan. CHEO has fully implemented the legislation and posted notices are found in high traffic areas around the hospital.
Pediatric Research Blood Volume Draw Guidance
The table below sets out guidance for researchers and REB reviewers for assessing the risk level associated with total research blood volumes (TBV) drawn from children and adolescent research participants. Clinical blood work must always take precedence over research blood work. When research blood volumes are large, the most responsible physician should ensure that the patient’s clinical needs are met first and foremost. In addition, the investigators should make every effort to minimize the discomfort associated with blood draws.
- • Research blood volumes falling within the limits outlined below may be considered minimal risk. Additionally, maximal blood draws (5% of TBV monthly) should not occur more than 3 months in a row.
- • Research blood volumes falling above the volume indicated in the table below will be required to undergo Full Board review. Justification for these research blood volumes should be described in the REB application, and the study protocol.
- • Research blood draws in infants with a body weight of less than 7.3 kg (16 lbs) and/or less than 6 months of age will always be reviewed at the Full Board.