Multi-site research conducted among a University of Ottawa affiliated institution

The CHEO REB has agreed to accept (but not require) submissions using the common application form developed by the University of Ottawa- affiliated REB’s (Council of REB’s; COREB).  Investigators are required to submit an application to each COREB member facility in which the research would be conducted.  The investigator should first submit the protocol for ethics review to the REB responsible for the primary site of the research. 

N.B. The University of Ottawa- affiliated REB’s have agreed to share with one another information regarding site reviews of protocols.

 

Introduction:

 

• Describe the background, including the research that is relevant to the design and conduct of the study.  Preliminary human data on the drug or device must be included. 

• Clinical drug and Medical Device trials

        Investigators can refer to the Consort statement (http://www.consort-statement.org/) for information on the necessary components of clinical trials.  The International Conference on Harmonization has also produced two guidance documents that are very useful (i.e., The Good Clinical Practice: consolidated guideline from the International Conference on Harmonization (E6) & The Clinical Investigation of Medicinal Products in the Pediatric Population (E11).  Both documents can be found on the general web site by using the search terms, ‘E11’ or ‘E6’ (http://www.ich.org/).

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.  Please refer to the HPFB website  for further information.  The board will only accept applications for clinical drug trials when a Clinical Trial Application (CTA) has already been filed with Health Canada. 

 For Clinical drug trials, the REB requires an investigator’s brochure or drug monograph (as applicable) for clinical drug trials.  The Director of Pharmacy must approve these studies.

Clinical medical device trials must comply with the regulations set forth by the appropriate Health Canada regulations.  To apply for medical device licensure in Canada, please complete a Medical Devices Establishment Licence Application Form . If the device is licensed, or was licensed at the time of purchase, an authorization from Health Canada for research applications is not required under the Medical Devices Regulations. A listing of medical devices licensed in Canada can be found at www.mdall.ca.

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.  If the investigational testing of a device is in conjunction with a drug in a clinical trial then the sponsor must obtain authorization for the clinical trial and authorization for the use of the investigational medical device.

 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 will only be issued when the CHEO REB receives the No Objection Letter from the Investigator via the sponsor.

        In addition, the Chair of the CHEO Product Evaluation Committee must be notified in writing of any purchase of medical devices or equipment to be used for research purposes.  The committee shares responsibility with Material Management in ensuring that the supplies used are safe and suitable for our patients as well as works to prevent product duplication and promote standardization of supplies used in the hospital.

Placebo Controlled Trials are only permissible under specific circumstances.  The Tri-Council Guidelines for research with human subjects and the Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Canada (July 2004) makes the following statements about placebo versus active treatment controls. 

• 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,

• The study involves adding a new investigational therapy to established effective therapies, (established effective therapy + new therapy vs. established effective therapy + placebo) ,

• Patients have determined that the response to the established effective therapies for their condition is unsatisfactory to them,

• Patients have previously refused established effective therapies for their condition.

Pandemic planning

The Board had endorsed the following principles for planning in a pandemic. 

• Any mobilization and re-allocation of research staff should be based on the needs of human subjects. 

• Every effort should be made to preserve the integrity and viability of those clinical trials meeting the following criteria:

• The trial holds out the prospect of immediate (physiologic) benefit (that relates to improved disease state / morbidity etc) to the research subject, AND

• The trial involves the provision of optimal care to research subjects that would otherwise not be available off – study. 

• Other criteria could be added to these as required.  For example, if a further rationalization of services was required, those clinical trials studying interventions to cure or alleviate illness could be retained whereas those aimed at preventing illness or improving health might be inactivated for the duration of the crisis.

During a pandemic influenza outbreak, the Board’s activities would similarly be reorganized to focus on those having an immediate impact on the welfare and safety of human subjects.  Practically speaking, initial and ongoing review would be restricted to protocols meeting the above criteria.  The Board would partner with any centralized REB that might be implemented by the federal or provincial governments and the federal funding agencies.

Objectives:  State the objectives of the study as hypotheses.

Study design and methods: 

• Describe the involvement of human subjects, 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 subjects 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.

Subject selection:

• Describe the rationale for research subject selection based on age/gender/ethnicity/race categories.

• The Primary CHEO Site Investigator’s name should not be included in any advertisement for research.  The College of Physicians & Surgeons of Ontario prohibits the use of the physician’s name in any communication offering a product or service to the public.

• Strategies/procedures for recruitment (including advertising). 

• 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 then 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.

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 (see page 34).  Please refer to the informed consent template appearing on page 24 of this document. 

Budget:

• The REB reviews study budgets to examine possible conflicts of interest that would appear in the form of ‘overpayment’.

• 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 on what basis it was calculated.

•  Whether the PI fee for service will be used for further research or claimed by the individual?

• Financial agreements between the Primary CHEO Site Investigator and the Sponsor of the study must be described.

References 

 

Back Up

 

Instructions for Applications to the Full Board

1.        Proposals are due (by 12:00 p.m.) on the 3rd Tuesday of every month (See submission schedule on page 4).  The REB meets the first Wednesday of every month to review the submissions (See meeting schedule on page 4).  In most instances, investigators of applications submitted to the full board will be generally invited to attend a board meeting of the REB to discuss their project.

2.        The number of protocols reviewed per month is limited to ensure thorough review of each application. Protocols are generally reviewed on a first–come first–served basis, although priority may be given to a proposal because of mitigating circumstances (e.g., the protocol offers treatment that would not be available otherwise and is considered urgent).

3.        All proposals must be in English.  Materials should be double-sided and pages numbered consecutively; collated in complete packages, and stapled or black-clipped in complete packages (not paper-clipped).

4.        The board requires one original package with original signatures, and 18 copies of the complete package.   The complete package includes:  The application form, the protocol, the synopsis and the consent/assent and recruitment documents as well as the investigator’s brochure and drug monograph for clinical drug trials, as appropriate.

5.        The turn-around time for submissions that require review by the full board is approximately six (6) weeks from the date of submission. Submissions that are incomplete or require modifications will delay this process. 

6.        Under exceptional circumstances, an executive committee of the REB can be convened to review a protocol in which the standard of full review could not be met for compassionate reasons or because of the delays involved in full board review would seriously compromise the research.  Examples of this type might include ‘natural experiments’ that merit immediate study such as the impact of a catastrophic event on the number and nature of mental health patients presenting to the ER.  Urgent submissions of this type can also occur when a clinical trial protocol provides the only modality for eligible patients to access treatment and no other alternative treatment is available. 

The REB Chair or his/her proxy should be consulted to determine whether or not a submission will be considered for this type of urgent review.  The authorizations of the Department Head and the Division Chief as well as that of Director of Pharmacy (for clinical drug trials) are required prior to submission.  Other routine authorizations required of full board submissions can be secured after the initial submission.  The Ethics Coordinator should be notified as soon as possible of an investigator’s intent to submit an urgent review request. 

7.        Proposals are to be submitted to:

Mrs. Sharon Haig, Ethics Coordinator

Research Ethics Board

Children’s Hospital of Eastern Ontario

Room R250F, 401 Smyth Road, Ottawa, Ontario, K1H 8L1

Telephone:  (613) 737-7600, ext. 3272

What is a clinical trial?

A clinical trial is a study that measures the outcomes of human participants who receive an intervention. There are numerous elements involved when a REB is deciding whether a clinical trial is ethical. One of those considerations is whether the clinical trial is likely to result in scientifically valid data. An appropriate sample size is essential to making that determination.

What should a research protocol contain regarding sample size?

The research protocol for a clinical trial must identify the specific outcome(s) that will be used to assess the efficacy of an intervention. If several outcomes will be used, one must be identified as the primary outcome. In order to determine whether the results of a clinical trial are statistically significant and therefore have the potential to improve health care, the study must plan to enroll a sufficient number of participants. The research protocol must indicate the desired study sample size and provide a suitable justification for it.

Why are REB’s interested in sample size calculations?

Sample size calculations are inherently ethical. A clinical trial that plans to recruit too few participants may be unable to accomplish its statistical objectives, thereby jeopardizing its scientific validity. This reduces the study’s potential to benefit society, threatening the risk/benefit ratio presented to participants during the informed consent process. Conversely, a clinical trial should not expose more participants than absolutely necessary to an unproven and potentially harmful intervention.

Should I consult a statistician?

Yes. These guidelines are intended to outline requirements for the simplest of sample size calculations and will not be applicable to all studies. Investigators contemplating clinical trials are strongly encouraged to consult with a statistician regarding sample size calculations prior to submitting a proposal to the REB. When applicants do not provide a suitable justification for the proposed sample size, they will be asked to do so prior to final REB approval.

What about pilot studies?

The REB recognizes that many clinical trials being proposed are innovative and may not be able to provide all parameters needed to justify the sample size. When faced with this situation, it is generally recommended to first conduct a small pilot study. Pilot studies provide investigators with an opportunity to assess the feasibility of their study methods with a small number of participants prior to undertaking a large clinical trial. In addition, one of the objectives of a pilot study is to gather data on the outcome measure that will be used in sample size calculations for future clinical trials. If an investigator is unable to provide the REB with any credible data on which to base a sample size calculation, and they are in fact proposing to conduct a pilot study, a statement to that effect may be provided in lieu of a sample size calculation.

Steps for calculating a sample size for a clinical trial with a continuous outcome measure:

1.     Specify the primary outcome and outcome measure

        It is best to choose a primary outcome that is clinically relevant and for which a validated and responsive outcome measure is available. Although multiple outcomes may be collected, one must be identified as the primary outcome.

2.     Identify the minimal clinical important difference (MCID) in the primary outcome measure

        This is the threshold difference below which clinicians do not feel the improvement noted is important enough to change their practice. This can be established from previous studies or may have been reported when the outcome measure was validated.

3.     Specify the expected variance in the outcome measure

        The clinical presentation of participants will often vary over time and can be established from a pilot study, previous studies for the same intervention/indication/population, or may have been reported when the outcome measure was validated.

4.     Select the desired power level

        The power level varies from 0 to 1 (or 0-100%) and represents the likelihood that a study will report statistically significant results with the parameters entered into the sample size calculation.

5.     Select the type-I error rate

        The type-I error rate also varies from 0 to 1 (or 0-100%) and represents the likelihood that a study will report statistically significant results when no true difference exists between the groups being compared.

6.     Select 1-sided or 2-sided hypothesis testing

        A 1-sided sample size calculation can only report whether the intervention is statistically significantly superior to the control. A 2-sided sample size calculation can report whether the intervention is statistically significantly superior to the control, as well as whether the control is in fact superior to the intervention. Investigators should always select a 2-sided sample size calculation unless there are compelling reasons not to do so.

7.     Estimate study loss to follow-up: The sample size calculation reports the final number of participants required for data analysis, not the starting number of participants enrolled. It must therefore be increased to adjust for projected study dropouts.

8.     Input parameters into sample size statistical software.

 Impact of individual components on sample size

Here is the impact of varying each component of the sample size calculation on the sample size:

Component	Impact
Primary outcome measure	A more responsive outcome measure decreases sample size
MCID	A larger MCID decreases sample size
Variance	A smaller variance decreases sample size
Power	A smaller power decreases sample size
Type-I error rate	A larger type-I error rate decreases sample size
Tails	A 1-tailed analysis decreases sample size
Loss to follow-up	A lower rate of loss to follow-up decreases sample size

 

Other comments

When a clinical trial will measure multiple outcomes that are of equal importance, investigators can provide a sample size calculation for each outcome in the research protocol. The largest sample size among these equally important outcomes can then be used for enrolment purposes.

Rather than providing the result of a sample size calculation as a single number (i.e. n=48 participants), investigators are encouraged to provide a range of numbers based on different assumptions regarding the parameters. A research protocol could provide a table or graph reporting the required sample size for a range of values for each parameter (i.e. MCID, standard deviation, power, type-I error rate, tails, loss to follow-up) if there is uncertainty requiring their estimated values.

Example

A clinical trial is designed to determine the efficacy of an analgesic compared to a placebo for post-surgical pain.

Here are the parameters reported in the research protocol for the sample size calculation:

1.     The primary outcome is pain and the outcome measure is the visual analogue scale (VAS).

2.     The MCID for post-surgical pain using the VAS is 2.0.

3.     The expected standard deviation in VAS in this population is 1.5.

4.     A 2-sided calculation is chosen since both possibilities are of clinical interest.

5.     A power of 90% is chosen.

6.     A type-I error rate of 0.01 is chosen.

7.     A loss to follow-up rate of 25% is expected.

8.     The above parameters are entered into sample size calculation software, with the result that each study group must enroll 24 participants for a total of 48 participants.

Impact of individual components on sample size

Here is the impact of varying each component of the sample size calculation on the sample size:

Component	Impact
Primary outcome measure	A more responsive outcome measure decreases sample size
MCID	A larger MCID decreases sample size
Variance	A smaller variance decreases sample size
Power level	A smaller power level decreases sample size
Significance Type-I error rate	A larger significance type-I error rate decreases sample size
Tails	A 1-tailed analysis decreases sample size
Loss to follow-up	A lower dropout rate of loss to follow-up decreases sample size

 

Other comments

When a clinical trial will measure multiple outcomes that are of equal importance, investigators can provide a sample size calculation for each outcome in the research protocol. The largest sample size among these equally important outcomes can then be used for enrolment purposes.

Rather than providing the result of a sample size calculation as a single number (i.e. n=48 participants), investigators are encouraged to provide a range of numbers based on different assumptions regarding the parameters. A research protocol could provide a table or graph reporting the required sample size for a range of values for each parameter (i.e. MCID, standard deviation, power level, significance Type-I error rate, tails, loss to follow-up) if there is uncertainty requiring their estimated values.

Example

A clinical trial wants is designed to determine the efficacy of an analgesic compared to a placebo for post-surgical pain.

Here are the parameters reported in the research protocol for the sample size calculation:

1.        The primary outcome is pain and the primary outcome measure is the visual analogue scale (VAS).

2.        It is established from previous studies that the MCID for post-surgical pain using the VAS is 2.0.

3.        It is established from previous studies that the expected standard deviation in VAS in this population pain is 1.5.

4.        A 2-tailed sided calculation is chosen since both possibilities are of clinical interest.

5.        A power level of 0.9 (i.e. 90%) is chosen.

6.        A, with a significance Type-I error rate of 0.01 is chosen.

7.        A dropout loss to follow-up rate of 25% is expected.

8.        The above parameters are entered into sample size calculation software, with the result that each study group must enroll 24 participants for a total of 48 participants.

N.B. Some elements may not be applicable depending on the nature and risks involved in the research

 Title of research project

The consent form should be:

• Printed on CHEO letterhead (the logos of other participating institutions can also appear on the letterhead). 

• Include the names of the Primary CHEO Site Investigators, and CHEO Co-investigators, their Division or PSU and contact information as well as the name of the study Sponsor (if any). 

• Clearly indicate that individuals are being asked to participate in a research study. 

• Broken down into subsections: Why is the study being done?, How many people will take part in the study?, What is the Current Standard of Treatment for this disease?, What are the risks of the study and how are the risks different from standard of care?, etc.     

• Include visual schemata (tables and flowcharts) to organize complex information such as the schedule of study visits & drug toxicities.

• Include in the footer the page numbers as well as the version number and date of both the consent and assent forms and the protocol. 

• Written in the second person, in language understandable to someone who has not yet completed high school (i.e.; approximately Grades 6 to 9).  Contain simple declarative statements throughout.  Jargon should be avoided as much as possible and acronyms explained.  The following online medical dictionaries can be used to simplify medical terms (e.g., http://www.online-medical-dictionary.org/ or http://cancerweb.ncl.ac.uk/omd/). 

• The following steps can be used to obtain a global estimate of the readability of consent materials in Microsoft Word:

• Create a document of the consent form in which you have previously removed any technical terms that are unavoidable (e.g., names of drugs, the condition under study), and the investigator’s name.

• Go to "Tools", "Spelling & Grammar", and then to "Options".  Select "Show Readability Statistics".  The grade level will then be displayed upon completion of spell checking your document.

Why is this study being done?

The informed consent document should outline the scientific/clinical rationale for the proposed study, and the potential additional risks and benefits (compared to “standard” therapy) that might occur as a consequence of participating in the trial. 

 This description should include the following elements:

• Current disease/diagnosis

• “Standard” therapy for the disease that would be used on a child not participating in the trial

1. Success rate for current therapy
2. Side effects/toxicity of current therapy

• Research therapy:  Why it might be better than current therapy

1. Higher cure rate than standard therapy and/or
2. Fewer side effects/toxicity than current therapy

• Additional risks/benefits/discomforts (compared to standard therapy) that will/might arise as a consequence of participating in this trial.

1. Risks:  Known or unknown (totally new therapy, or new use of an established treatment).
2. Benefits:  Higher cure rate/less toxicity/earlier pick up (more intensive monitoring), unknown.
3. Discomforts: 

1.  Additional tests:  discomfort (blood tests), risks (general anaesthetics), etc.

2. Extra time taken for additional tests.

For example, Why is this study being done?, ‘You are being invited to join this study because your child has CNS tumour, which cannot be fully resected.  Standard therapy for young children with ‘non-resectable tumours of the central nervous system have traditionally involved chemotherapy.  The problem with this therapy is that … The purpose of this study is to see if the novel intervention can get rid of the cancer while avoiding some of these side effects.  It is not know if this new therapy will be as effective.  It is also not know if this new therapy will produce other side effects that we currently don’t know about… The difference between standard treatment and study participation in this case involves the use of the novel intervention, which is not always used across hospitals and is not proven to be better.  We do not know if the novel intervention is better (or worse) than standard therapy in terms of success rate or side effects.  The purpose of this study is to find this out…’

How many people will take part in this study?

• The number of subjects participating in the research should be specified both at CHEO, nationally and/or internationally.

 What is the Current Standard of Treatment for This Disease?

• Routine vs. supplementary procedures should be clearly delineated.  Whenever possible, supplementary procedures should be appended to routine tests.

• A lay explanation of randomization should also be included.  It is often wise to explain that the treating physician is typically blinded to the subject assignment, and cannot influence this process.  You will be 'randomized' into one of the study groups described below.  Randomization means that you are put into a group by chance.  Neither you nor your doctor can choose the group you will be in.  You will have an equal (one in ?) chance of being placed in any group.  The purpose of randomization is to ensure that those receiving the study medication and those receiving placebo are identical in every other respect.  That way, we can know for certain that any differences that we observe between the two groups are due to the study medication and nothing else.  It is often useful to include a table summarizing the study procedures, for example.

	Day 1	Day 2	Day 3	Day 4
Blood work	o	o	o	o
Blood pressure		o		o

 

What are the risks of the study and how are the risks different from treatment?

• A fair description of any risks and inconveniences (including time commitment) to participating in the study should be included. 

• For Clinical Trials, please outline in an attachment the study procedures and clearly identify how these differ (if at all) from standard care. 

• Whenever possible, the drug toxicities should be summarized in table form.  It is often easier for subjects to retain this information if it is organized on the basis of probability

 

• The subject should be advised what action to take to manage toxicities.  He / she should also be provided with a clear course of action to take if the symptoms worsen.

• Any supportive care should be specifically described.

• Subjects should be advised that the risks and inconveniences of the study are believed to be equivalent across the different study arms (clinical equipoise), e.g., ‘The purpose of this study is to compare two or more treatments. Based on our current knowledge, we do not know if any (either) of the treatments being studied are significantly better than the other(s) in terms of either effectiveness or side effects. The study would be stopped if we learned that this was not in fact, true.’

• Any costs of participating in the study should be outlined.  Subjects should be aware of what, if any, study-related expenses will be covered by the Sponsor or Investigator.

• The injury clause as outlined in the standard phrasing: In the event that you suffer injury as a direct result of participating in this study, normal legal rules on compensation will apply.  By signing this consent form you are in no way waiving your legal rights or releasing the investigator and the sponsor from their legal and professional responsibilities.

Are there benefits to taking part in the study?

• Individuals should be told if any direct benefit will come to them as a result of participating in the study.  You may or may not benefit from participating in this study; however, our hope is to change clinical practice or to take better care of our patients in the future.

If I chose, how would I withdraw from the study?

• Subjects should be told how they can withdraw from the study. 

• They should also be told under what circumstances their participation could be discontinued without their permission.

• Individuals should be assured that their decision to participate or not in the study will not influence the care they receive at CHEO.