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Applications Guidelines for Protocols reviewed by the Full Board
(i.e., those presenting more than minimal risk to participants)

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. Submit eight (8) copies of with your submission. 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:

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.
Budget:
  • 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 (see http://www.cpso.on.ca/policies/policies/default.aspx?ID=1536). 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.
 
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