TCPS 2 - Chapter 11
The TCPS 2 (2018) has replaced TCPS 2 (2014) as the official human research ethics policy of the Agencies.
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- A. Key Concepts
- B. Clinical Trial Design and Registration
- C. Assessing Safety and Minimizing Risk
- D. Financial Conflicts of Interest
- E. Analysis and Dissemination of Clinical Trial Outcomes
This chapter focuses on the ethical issues involved in the design, review and conduct of clinical trials (as defined below). In particular, it addresses clinical trial design, therapeutic misconception, research-attributable risk, and other issues that may be unique to clinical trials. As clinical trials are, perhaps, the most regulated type of research – subject to provincial, national and international regulatory bodies – reference will be made to these regulations, where appropriate. However, the emphasis in this chapter is on ethical guidance, grounded in the core principles of this Policy: Respect for Persons, Concern for Welfare, and Justice. As is the case throughout this Policy, the welfare of participants takes precedence over the interests of researchers and sponsors.
For the purposes of this Policy, a clinical trial (a form of clinical research) is any investigation involving participants that evaluates the effects of one or more health-related interventions on health outcomes. Interventions include, but are not restricted to, drugs, radiopharmaceuticals, cells and other biological products, surgical procedures, radiologic procedures, devices, genetic therapies, natural health products, process-of-care changes, preventive care, manual therapies and psychotherapies. Clinical trials may also include questions that are not directly related to therapeutic goals – for example, drug metabolism – in addition to those that directly evaluate the treatment of participants.
Clinical trials are most frequently undertaken in biomedical research, although research that evaluates interventions, usually by comparing two or more approaches, is also conducted in related disciplines, such as psychology. The researcher leading a clinical trial is often (but not always) a clinician, that is, a health care provider (e.g., physician, dentist, naturopath, nurse, physiotherapist). Although various types and forms of clinical trials have methodological differences, the ethical principles and procedures articulated in this Policy are applicable, and can be adapted as needed. Researchers and research ethics boards (REBs) should consult the other chapters of the Policy for additional guidance on principles, norms and practices applicable to all research.
This chapter will require periodic revision, particularly in light of the ongoing efforts to develop provincial, national and international guidance for new methods and emerging areas of clinical research, including, but not limited to, clinical trials. Though much clinical research is observational and evaluative such that previous chapters provide relevant guidance, there are plans to develop additions to the Policy that include both interventional clinical research (i.e., clinical trials) and encompass the fuller spectrum of non-interventional clinical research (e.g., public health research, epidemiology). This is in keeping with a commitment to the continued evolution of this Policy.
A. Key Concepts
Risk and Proportionate Approach
Clinical trials, like other research covered by this Policy, are subject to a proportionate approach to research ethics review: trials that pose greater foreseeable risk to participants will receive proportionately greater scrutiny (see Chapters 1 and 2). Not all clinical trials are high risk and care should be taken to avoid an automatic classification of this nature. However, because clinical trials often involve large numbers of people, and may include people who are in vulnerable circumstances due to health issues, the risk of serious harm or death must be considered. The majority of clinical trials are classified as above minimal risk, and are reviewed accordingly. This is consistent with the principle of Concern for Welfare.
As discussed in Chapter 2, Section B, the evaluation of possible harms that participants may experience due to their involvement in research is of primary importance. The magnitude and probability of these harms are described as foreseeable risks. In keeping with the principle of Respect for Persons, it is the responsibility of researchers to clearly describe all foreseeable risks and potential benefits of their research to prospective participants in the consent process (see Articles 11.4 and 11.5). It is the responsibility of the REB to weigh the foreseeable risks to participants against the potential benefits of the trial in the context of a proportionate approach to research ethics review, and to discuss with the researcher additional ways to eliminate or minimize risks.
In trials where participants are randomly assigned to different groups (e.g., treatment A; treatment B; no treatment), ethical issues relevant to the principle of Justice arise when one group may fare better or worse than another (see Article 11.2 on placebo-controlled clinical trials). For this reason, clinical equipoise may be considered as a starting point for the design and review of clinical trials. Clinical equipoise means a genuine uncertainty exists on the part of the relevant expert community about what therapy or therapies are most effective for a given condition. This uncertainty necessitates the conduct of research to determine the comparative therapeutic merits of existing interventions (not all of which may be represented in a given clinical trial). Clinical equipoise provides a link between the duty of care of a clinician with the need to do research to ensure that the therapies or interventions offered are demonstrably safe and effective.
Duty of Care, Therapeutic Misconception and Dual Roles
Because clinical trials often involve clinicians and patients who have become participants, the related issues of duty of care, therapeutic misconception and dual roles must be carefully considered at the design and conduct stages by researchers, and at the review stage by REBs.
Duty of Care
The duty of care in a medical context is the obligation of clinicians to act in the best interests of patients. In the context of clinical trials, researchers are concerned with the welfare of individual participants, but are also focused on the generation of new knowledge that may or may not confer direct benefits on participants. Nevertheless, researchers do have a duty of care to ensure that the foreseeable risks to participants are justified by the potential benefits, and that the safety of participants is an integral part of the research design and conduct (see Articles 11.7 and 11.9). Duty of care also includes the researchers’ responsibility to communicate any information relevant to individual participants’ health to their primary clinician. Clinician-researchers (clinicians who also conduct research) need to manage any conflict that may arise from their dual role (see below) and they must also be particularly sensitive to the issue of therapeutic misconception.
Although clinical trials may provide benefits to some participants, the purpose of a clinical trial is to evaluate an experimental therapy or intervention, not to provide therapy. Therapeutic misconception occurs when trial participants do not understand that research is aimed primarily at producing knowledge and may not provide any therapeutic benefit to them. It also occurs when participants enter trials without understanding the ways in which elements of a clinical trial design may interfere with their own health care objectives.
With the exception of some phase I trials, clinical trials usually involve individuals in need of treatment, for whom the experimental therapy is hoped to be effective. Even when foreseeable risks, potential benefits and treatment alternatives are explained to them, it is common that clinical trial patient-participants do not fully appreciate the differences between clinical care and research participation. As a result, some patient-participants may assume that there must be therapeutic value in the research procedures they are undergoing, or that they have been invited to participate because their clinician believes it would contribute to their health.
Dual Roles of Clinician-Researchers
Research has shown that clinician-researchers may conflate their clinical practice with their clinical trial research. Some may be overly optimistic about the prospects of an experimental intervention and overstate potential benefits or understate foreseeable risks to prospective participants. This can foster therapeutic misconception among patients and influence the recruitment and consent process (see Chapter 3 and Article 11.6). Clinicians must take care not to create unrealistic expectations among participants with respect to the potential benefits of the research.
To preserve the trust on which their professional relationships with patients and colleagues reside, researchers should take all necessary measures to separate their role as researcher from their role as clinician (e.g., enlist associates to recruit participants, rely on colleagues to determine when a patient should be withdrawn). It is important REBs appreciate the potential conflicts between these roles and the possible impact on the welfare of prospective participants.
In studies involving more than one researcher, particularly multi-site studies, the researcher who has overall responsibility for the ethical conduct of the study, and for the actions of any member of the research team, is known as the principal investigator (PI). The PI is responsible for communicating any changes to the study, material incidental findings, new information, and/or unanticipated events to their own REB as well as to local site researchers, who must then inform their local REBs.
B. Clinical Trial Design and Registration
This section discusses ethical issues associated with the design and registration of clinical trials. Guidance for the most common types of clinical trials (pharmaceuticals, medical devices) as well as other types of trials (natural health products, psychotherapy and surgery), is provided in sub-sections of the Application of Article 11.1. Though not all possible clinical trial designs are represented in this section, the guidance provided can be applied and adapted as needed. Researchers are advised to consult the relevant provincial, national and international regulatory documents to design their clinical trial (see References at the end of the chapter). In all clinical trials, researchers and REBs should be aware of ethical issues including, but not limited to, registration, safety, selection and recruitment of participants, undue inducement, consent, dissemination of findings, and real, potential or perceived conflicts of interest.
In the design and review of a clinical trial, researchers and REBs shall consider the type of trial (e.g., pharmaceutical, natural health product, medical device, psychotherapy), its phase (if appropriate) and the corresponding particular ethical issues associated with it, in light of the core principles of this Policy.
Each type of clinical trial has specific ethical issues that correspond to the risks faced by the participants. In a proposal submitted for research ethics review, the researcher shall clearly specify the type of trial proposed (and, where relevant, its phase), identify the foreseeable risks and potential benefits to participants, and show how this information will be clearly communicated to participants in the consent process (see Article 3.2).
REBs reviewing clinical trials need to be familiar with the ethical issues raised by different phases, and by different types, of clinical trials. If an REB does not have members with the appropriate expertise to review a particular trial, then it shall seek out someone with the necessary expertise to consult as an ad hoc advisor (see Article 6.5).
This guidance applies equally to continuing research ethics review, including requests to make changes to the method, statistical procedures, inclusion/exclusion criteria, or other elements of approved research, as required by this Policy (see Article 6.14 and 6.16).
Clinical trials involving pharmaceutical products are commonly categorized into four phases, each of which gives rise to particular ethical issues. Detailed descriptions of the phases of clinical trials are provided in other guidance documents (see References). The ethical concerns described are most likely to arise in a specific phase of a clinical trial. Some issues may arise at any phase of a clinical trial.
Safety concerns are particularly acute in phase I research because it may be the first time participants are exposed to the new drug (“first-in-human” trials), and there may be little or no experience with the drug. Phase I trials often depend on healthy participants who are offered incentives for their participation, though this is not usually the case in, for example, cancer trials. Increasingly, phase I trials include participants with specific diseases for whom conventional therapy has failed. The combination of clinical risk with uncertain or no likelihood of clinical benefit, and the often substantial incentives offered to participants, raises ethical concerns about safety, the selection and recruitment of participants, and the consent process. For safety, it is important to ensure that the drug is initially given to a small number of participants and that dosing is increased in clearly defined increments only after participants’ responses to the initial dose is known. Recruitment and consent procedures shall ensure that participants are aware of the untested nature of the therapy and that participants do not accept, because of the incentives being offered, risks they would otherwise refuse.
Phase II or combined phase I/II clinical trials raise particular ethical concerns, because they are often conducted with populations whose therapeutic options have been exhausted. Examples include patients with cancer that is incurable by standard therapies and HIV/AIDS, or people with conditions that cause them acute or chronic pain. These circumstances may affect the perceptions of patients and their families as to the balance between the risks and potential benefits of the trial and thus may affect their decision whether to participate. Additionally, because participants in phase II trials may include patients who are unwell and frequently not working, the REB should ensure incentives for participation are not coercive, and patients do not accept risks they would otherwise refuse because of the incentives being offered. Researchers should be encouraged to consult with the REB at an early stage about any recruiting, consent or safety issues that arise.
During the course of a phase II clinical trial, patients will have access to a new drug that may be efficacious (provide clinical benefit). Researchers shall: a) as part of the consent process, provide details on access to the new drug upon trial completion; and b) make reasonable efforts to secure continued access to the drug following the phase II trial, for those patients for whom the drugs appear to be efficacious.
The REB should carefully examine phase III clinical trials to ensure that the care of patient-participants is not compromised in the random assignment to any arm of the trial (including the placebo arm – see Article 11.2). Researchers should also provide a plan for interim analysis of data, early unblinding of clinicians and/or patients, and/or ending the trial if the drug should prove effective or harmful. The REB should evaluate such plans with due consideration for the welfare of the participants and the group which is the focus of the research (see Article 3.2 [l]).
Researchers and the REB should also address the issue of continuing access to the experimental therapy after the trial closes. If the treatment benefits participants and is safe, the proposal should state whether it will continue to be provided and under what conditions. REBs should be concerned about what provisions are possible to ensure that participants continue to receive adequate treatment.
Phase IV trials can be valuable for assessing the long-term safety and effectiveness of marketed drugs and devices. Earlier-stage trials are of limited duration, and subsequent research can identify side effects, toxicities, drug interactions and overall tolerance that may only emerge over time. However, in some cases, phase IV trials may be designed to serve primarily as marketing initiatives to encourage the prescription and continued use of an approved drug. For example, a clinician may be paid a per capita fee by a sponsor to collect data on the side effects and acceptance by patients of a drug being marketed by that drug’s sponsor. REBs should carefully consider the financial terms between sponsors and investigators associated with these trials as they may create problems such as inappropriate prescription practices, billing practices and/or inappropriate utilization of public resources (e.g., diagnostic services and medical imaging). Researchers and REBs must ensure that trials are undertaken for a bona fide scientific purpose, which includes a design and objective(s) that are scientifically, rather than commercially, driven. Phase IV trials designed with the primary goal of increasing sales do not constitute legitimate research.
Natural Health Product Trials
Natural Health Products (NHPs) may be viewed as safe simply because they are natural. Some NHPs, however, can pose serious health risks. NHPs may also be part of a multi-treatment therapeutic approach (e.g., a herbal medicine added to a conventional medicine or to a complementary alternative therapy). A research proposal for an NHP clinical trial shall clearly identify the known effects of the product under investigation and its possible contraindications. REBs should ensure that NHP clinical trial proposals are reviewed with the appropriate level of scrutiny as indicated by the foreseeable risks to the participants.
In evaluating the research design REBs should consider the history of the NHP as provided in the literature review contained in the researcher’s brochure and/or in a monograph (such as those published by Health Canada setting out approved uses and cautionary information). For NHPs with an established safe history of human use, the researcher does not have to present the findings of prior testing with animals, if the proposed conditions of use in the trial do not differ from approved uses. However, if the NHP is a new product without an established safe history of human use, prior animal testing may be necessary before it can be approved for first-in-human trials.
Since 2004, the conduct of clinical trials involving NHPs has been subject to regulations under the Food and Drugs Act and the Natural Health Products Directorate (NHPD) of Health Canada. Researchers and REB members are responsible for knowing how these regulations affect the design and conduct of NHP clinical trials.
Medical Device Trials
Medical devices may take many forms (e.g., a magnetic resonance imaging machine, a cardiac pacemaker, a hip implant). The term “medical device” covers a wide range of instruments used in the prevention, diagnosis, mitigation, or treatment of a disease or abnormal physical condition or the restoration, correction or modification of body function or structure. The conduct of clinical trials involving medical devices is subject to regulations under the Medical Devices Bureau of Health Canada. Researchers and REB members are responsible for knowing how these regulations affect the design and conduct of medical device clinical trials.
Researchers are responsible for providing up-to-date information about the device, for example, any feasibility studies it has been subject to in Canada or in other countries, and its risk classification. If an REB does not have enough safety information about the device to consider in its review of the trial, the researcher should be advised to work with the manufacturer of the device to provide appropriate risk information in the research proposal.
In any case, REBs should satisfy themselves (with the assistance of external expertise, if necessary) that the use of the device in the trial is appropriate and that the foreseeable risks to participants are justified by the potential benefits.
A clinical trial testing a psychotherapeutic approach to behavioural disorders or other mental illness may compare the outcomes of two or more patient populations with the same diagnosis but receiving different therapies; or a trial may compare the outcome of those who have received a therapy with those who are on the waiting list for treatment. Often a trial will compare a behavioural therapy approach with a pharmaceutical treatment approach or some combination of both. REBs should have a member knowledgeable in the relevant area to assess the ethical issues specific to the type of therapy involved.
REBs should be aware that trials involving psychotherapy may be more focused on effectiveness in real world conditions than on efficacy under tightly controlled conditions. For example, the research question may be how participants undergoing a particular therapy are functioning in their daily lives. The duration of these trials may be longer as a function of the therapeutic approach and the characteristics of the condition to which it is applied. Particular areas of concern are whether the principal investigator or others on the research team are sufficiently trained to provide the investigational therapy and whether there is any risk of a negative impact on participants’ mental health.
Issues of participant privacy and confidentiality may receive closer scrutiny in cases where people with specific psychological profiles are being recruited from the same institution as the researchers. Researchers shall indicate how recruitment, data collection and management, and compensation procedures have been designed to protect participant confidentiality (see Chapter 5).
Some of the issues surrounding the comparison of different surgical techniques are the appropriateness of the technique to the participants, whether the technique has been validated, whether the tools required have been approved for use in Canada, how well the experimental procedures have been explained to prospective participants, and whether it is appropriate to employ a control group that undergoes sham surgeries. When there is a crossover from medical to surgical treatment it can be difficult to assess whether participants’ health outcomes were due to the surgical intervention. The risk of subjecting participants to a potentially scientifically inconclusive trial needs to be weighed against the risk of subjecting them to a potentially harmful placebo intervention.
REBs should be aware that it is possible that the principal investigators of surgical clinical trials need not, themselves, be a surgeon or technician trained in the procedure. For example, a biomechanical engineer who has developed a new type of skin graft material to aid in surgical repair, may conduct a surgical clinical trial, with the assistance of a surgical team, to compare the new material with an existing material.
A clinical trial in which one or more intervention arms are compared with a placebo control group raises specific ethical issues. Where there is an established effective treatment, use of a placebo may deprive participants of needed therapy. It is the responsibility of the researcher or sponsor to provide justification to the REB for the choice of a placebo control group, as opposed to the other possible choices of control group (e.g., active control, wait-list control, dose-response and combination therapies). The following article sets out criteria for the use of a placebo control group to ensure that this type of clinical trial design is used only in situations that do not compromise the safety and welfare of participants.
- A new therapy or intervention should generally be tested against an established effective therapy.
- As with all alternative choices of a control, a placebo control is ethically acceptable in a randomized controlled clinical trial only if:
- its use is scientifically and methodologically sound in establishing the efficacy or safety of the test therapy or intervention; and
- it does not compromise the safety or health of participants; and
- the researcher articulates to the REB a compelling scientific justification for the use of the placebo control.
- For clinical trials involving a placebo control, the researcher and the REB shall ensure the general principles of consent are respected and that participants or their authorized third parties are specifically informed (see Article 3.2):
- about any therapy that will be withdrawn or withheld for purposes of the research; and
- of the anticipated consequences of withdrawing or withholding the therapy.
All clinical trials involve risk to participants. For all approved trials: a) the welfare of the participants needs to be upheld under the specific conditions of the trial; and b) the trial needs to be scientifically sound. Risks to the safety of participants can come from lack of efficacy or from undesirable side effects. These risks must be assessed for each treatment arm, including the experimental and control arm(s). The choice of control arm, which may range from currently approved treatments to placebo, placebo add-on, or no treatment, should, like all research, meet an acceptable risk-benefit ratio. As with other aspects of the trial design, the choice of control arm must be justified based on scientific, medical and methodological reasons.
According to Article 11.2, researchers should consider a proven effective therapy as a control if one is available. The implications of various choices of trial design directly affect the interpretability of trial results, and a trial that cannot return useful information is by definition not ethical. Good science is a necessary, albeit insufficient, condition for good ethics. To properly assess the ethics of a placebo-controlled superiority design vs. an active controlled non-inferiority design, an appreciation of the interplay of ethics and science is required (see Article 2.7). Conditions that work against carrying out a non-inferiority trial successfully include low and/or variable response to treatment, and high placebo response. The researcher must provide adequate justification for the use of a non-inferiority design.
Participants in the test arm of a trial of a new therapy are not receiving proven effective therapy. Risks to the safety of participants can come from lack of efficacy or from undesirable side effects. These risks should be assessed for each treatment arm, including the experimental and control arm(s).
The use of an active treatment comparator in a clinical trial of a new therapy is generally the appropriate trial design when an established effective therapy exists for the population and clinical indication under study.
Great care should be taken to avoid abuse of placebo comparators. However, they are acceptable in any of the following situations:
- there are no established effective therapies for the population or for the indication under study;
- existing evidence raises substantial doubt within the relevant expert community regarding the net therapeutic benefit of available therapies;
- patients are resistant to the available therapies by virtue of their past treatment history or known medical history;
- the trial involves adding a new investigational therapy to established effective therapies: established effective therapy plus new therapy vs. established effective therapy plus placebo;
- patients have provided an informed refusal of established effective therapy, and withholding such therapy will not cause serious or irreversible harm.
The determination of response satisfaction and refusal of treatment must take place outside the context of recruitment for the clinical trial and prior to offering trial participation to the prospective participant, and both must be documented.Footnote 1
The use of a placebo comparator in situation (5) is permitted because prospective trial participants are not using established therapies and therefore are not benefiting from therapy. For that reason, such participants would not be further disadvantaged if enrolled in a placebo-controlled trial than participants in a trial for whom there are no established effective therapies for the indication under study. Research proposals submitted to REBs shall include sufficient support and justification of the trial design and use of placebo comparator.
Clinical Trial Registration
There are compelling ethical reasons for the registration of all clinical trials. Registration improves researchers’ awareness of similar trials so that they may avoid unnecessary duplication and thereby reduce the burden on participants. Registration also improves researchers’ ability to identify potential collaborators and/or gaps in research so that they may pursue new avenues of inquiry with potential benefits to participants and to society. Perhaps of most concern is the danger that some researchers or sponsors may only report trials with favourable outcomes. Failing to report the outcome of a trial or withholding negative findings is more difficult when all trials must be registered.
The registration of clinical trials upholds the principles of Respect for Persons, Concern for Welfare, and Justice, by ensuring that the efforts of all participants in clinical trials are acknowledged, and by reducing the potential for endangerment of others through publication bias.
All clinical trials shall be registered before recruitment of the first trial participant in a publicly accessible registry that is acceptable to the World Health Organization (WHO) or the International Committee of Medical Journal Editors (ICMJE).
Clinical trial registries are intended to increase transparency and accountability by providing a record of clinical trials at the recruitment stage that can be used to locate publications of trial results (see Article 11.12). This helps prevent publication bias, that is, the selective publication of only those trials that yield results in support of an intervention. These registries, in addition to agency policies, editorial policies, ethical policy reforms, and revised national and institutional ethics policies and results disclosure requirements, contribute to a multi-faceted approach to eliminate non-disclosure. The collective goal is to reduce publication bias, and prevent the suppression of data in clinical research.
Clinical trials shall be registered in a publicly accessible registry that is acceptable to the World Health Organization (WHO) or the International Committee of Medical Journal Editors (ICMJE). All fields outlined in the WHO Trial Registration Data Set (TRDS) must be completed in order for a trial to be considered fully registered. A registration with missing information or uninformative fields in the TRDS is unacceptable. Researchers shall provide the REB with the number assigned to the trial upon registration.
C. Assessing Safety and Minimizing Risk
Participants enrolled in clinical trials are commonly exposed to investigational therapies, interventions, drugs or devices, each of which carries specific, and possibly unknown, risks. Because of the nature of clinical interventions, the potential harms can be physical, psychological or social, and may cause lasting, irreparable damage. In accordance with the core principles, it is the responsibility of researchers and REBs to ensure that (a) foreseeable risks to participants are minimized, and appropriately evaluated alongside potential benefits, (b) participants are clearly informed as to the nature of these foreseeable risks and potential benefits, (c) participant safety is monitored and accurately reported, and (d) any new information that may impact on the welfare of participants, or their decision to remain involved in a trial, be shared appropriately.
Researchers and REBs should ensure that the foreseeable risk to participants in clinical trials is: (a) justified by the potential benefits to be gained; and (b) appropriately minimized.
The researcher has a responsibility to present the proposed research in the context of a systematic review of the literature on that topic. Clinical trials should not be conducted unnecessarily on questions that have already been definitively answered.
The proportionate approach to research ethics review (see Chapter 2, Section B) dictates that trials deemed to be of greater risk should be subject to proportionately greater scrutiny. In all clinical research, the REB should carefully evaluate previous laboratory, animal and human research with a drug or other therapy, and/or have an expert evaluation undertaken on its behalf, to ensure that the foreseeable risk from its use is: (a) justified by the potential benefits to be gained; and (b) appropriately minimized.
Where appropriate, based on reports of safety issues arising in the trial, an REB may discontinue the trial at its institution, require the disclosure of relevant safety information to existing and future participants (see Articles 6.3 and 6.15), or take other steps that are reasonably necessary to promote the safety of participants, such as unblinding.
When describing the foreseeable risks and potential benefits of research involving participants who are undergoing high-risk therapies, researchers should clearly indicate which risks are attributable to the research (including cumulative risks), and which risks the participants would normally be exposed to in the course of their clinical care.
In their evaluation of risk, REBs should ensure that they are evaluating only those risks that are attributable to the research (including cumulative risks), and not compounding them with the risks attributable to clinical care.
The evaluation of foreseeable risk to participants in a clinical trial can be complicated if the prospective participants are already exposed to risks in the course of their clinical care. It is the researcher’s responsibility to clearly distinguish in their research proposal between the risks due to clinical care and the foreseeable risks of the clinical trial.
The REB must take into consideration the ethical implications of recruiting patients, particularly those receiving high-risk therapies, into clinical trials that may offer additional risk. In accordance with Articles 4.1 and 4.7 on vulnerability and inclusion/exclusion criteria, patients who are receiving high-risk clinical care should not be inappropriately included in, or excluded from, participating in research.
The REB may approve clinical trials involving participants who are exposed to risk in their usual clinical care, where the REB finds a favourable balance between the foreseeable risks attributable to the research and the potential benefits.
In addition to describing any other available treatments (including no treatment), researchers must ensure that prospective participants are informed of the foreseeable risks and potential benefits attributable to the research, as distinct from those arising from their clinical care. REBs should ensure that all consent materials reflect this distinction.
REBs and clinical trial researchers should be conscious of the phenomenon of therapeutic misconception, and ensure that procedures for recruitment and consent emphasize which specific elements of a clinical trial are required for research purposes, as well as the differences between research and the standard clinical care patients might otherwise receive.
When treating clinicians conduct research with their patients, special efforts may be required, as part of the consent process, to distinguish between their dual role – clinician and researcher – and to ensure that patients who become participants understand the differences between the goals of health care and the goals of research.
It is important that clinician-researchers take care not to overplay the benefits of research participation to patients in vulnerable circumstances, who may be misled to enter trials with false hopes. Research has shown that clinicians can affect how well their patients appreciate the uncertainty of research, the seriousness and magnitude of risks, and the possibility that participation may not result in any direct benefits to their own health status.
Article 3.2 describes the requirements for consent to research participation. It indicates that participants shall be provided with relevant information, including a clear description of those elements of participation that are experimental in nature and those not primarily intended to benefit the participant directly.
In general, therapeutic misconception can be minimized by ensuring that the clinicians who provide the patient’s regular care are involved as little as possible in the recruitment and the consent process. Ideally, treatment and research functions should be performed by different people. However, there may be instances in which participants’ best interests are served by having their primary care clinician involved in recruitment and consent. In these cases, the research proposal shall indicate what other measures will be taken to minimize therapeutic misconception.
Monitoring Safety and Reporting New Information
In accordance with the core principle of Concern for Welfare, it is a key responsibility of researchers and REBs to ensure that, as clinical trials proceed, the risks to participants remain in the acceptable range, and the safety of participants is monitored. Articles 11.7 and 11.8 address researchers’ responsibility to include a safety monitoring plan in their proposal submitted for REB review, and their responsibility to ensure that any new information that may affect participant welfare or consent is shared with the REB and participants (see also Articles 6.15 and 6.16). Article 11.9 addresses the REB’s responsibility to have procedures in place to receive and respond to reports of new information, including, but not limited to, safety data, unanticipated issues and newly discovered risks (see the Application of Article 11.8 for an expanded definition).
In the case of clinical trials, there are provincial, national and international guidelines that govern safety monitoring and reporting of new information. It is the responsibility of researchers to be aware of the guidelines that apply to their research (see References) and to adhere to them for the safety and benefit of participants.
Roles and Responsibilities in the Sharing of New Information
Typically, researchers in charge of a trial at a particular site are responsible for communicating new information to their REB, to participants and, in the case of multi-site research, to the principal investigator. In single-site clinical trials, such researchers will likely be the principal investigator (the leader of the trial who is responsible for its ethical conduct). In this chapter, the term “researcher” is used in the context of communication with REBs and participants, and the term “principal investigator” is used in the context of communication among researchers involved in a multi-site trial.
Trials may also have sponsors who can be a source of new information. Sponsors may be the principal investigator (investigator-initiated trials), a research institution or another type of organization (e.g., private company, not-for-profit association). When principal investigators receive new information, from the sponsor or any other source related to the trial, they are responsible for communicating this new information to their own REB, as well as to local site researchers, who must then inform their local REBs.
The extent to which new information is shared with participants depends upon the nature of the information, and the REB’s evaluation of whether it affects the welfare or consent of some or all participants. In the case of multi-site trials (also known as multi-jurisdictional trials), the roles and responsibilities of the principal investigator, researchers and sponsor may vary depending on the model of research ethics review in use (see Chapter 8).
Researchers shall provide the REB with an acceptable plan for monitoring the safety of participants, including a plan for the tabulation, analysis and reporting of safety data, and the sharing of other new information in a form that permits REBs to interpret and respond appropriately.
Researchers and REBs must ensure that every clinical trial proposal includes a plan to assess safety concerns and protect the ongoing safety of participants. The responsibility of establishing a safety monitoring plan is the responsibility of the researcher. This plan shall include the requirement that researchers provide REBs with clear and up-to-date information about the safety of participants taking part in clinical research. These summary reports should be provided promptly and include information about the context and significance of reported data to permit a fair interpretation and meaningful review by the REB for the protection of participants. When the REB requires additional information, the researcher shall provide it. If necessary, the REB may require that this evaluation shall be conducted by a qualified source, independent of any sponsor, who has no conflict of interest (see Chapter 7).
Any safety monitoring plan should include a mechanism by which researchers may remove participants for safety reasons and by which clinical trials may be stopped or amended if they are found to be unsafe, or for reasons of futility (e.g., it is determined that the trial is unlikely to produce valid results) or efficacy (e.g., one or more interventions are found to be successful).
A safety monitoring plan may (but need not) include the establishment of a data safety monitoring board (DSMB) or data safety committee (DSC).
A DSMB is normally a multidisciplinary, expert advisory group that is responsible for safeguarding the interests of participants, by reviewing emerging data, assessing the safety and efficacy of trial procedures, and monitoring the overall conduct of a trial. Researchers must indicate, in their proposal for REB review, whether they or a DSMB will be communicating any new information to the REB over the course of the trial. Researchers must ensure that DSMB reports are sent to REBs in a timely manner.
The appointment of a DSMB does not alter the responsibilities of researchers and REBs to monitor participant safety. In the context of multi-site trials, when new information at one site may be relevant to participant welfare and consent at other sites, principal investigators must ensure that this information is shared with researchers at each site, and researchers must ensure that the REB also receives these reports (Article 11.8). The REB must be prepared to act upon these reports, especially where urgent action is required (see Article 11.9).
Researchers shall promptly report new information that may affect the welfare or consent of participants, to the REB, and to other appropriate regulatory or advisory bodies. New information must be submitted to the publicly accessible trial registry along with reports of findings once the trial is completed. Where possible, this information can be reported earlier to the registry in descriptions of study design, intervention, or an equivalent data field. When new information is relevant to participants’ welfare, researchers shall promptly inform all participants to whom the information applies (including former participants). Researchers shall work with their REB to determine which participants must be informed, and how the information should be conveyed.
In the course of any type of clinical trial, new information may arise that is relevant to participants’ welfare and/or their ongoing consent to participate (see Article 2.8, Article 3.3, Articles 6.15 and 6.16, and Article 11.8). This new information may arise from unanticipated issues (e.g., adverse reactions to interventions) or from routine evaluations of participant health that occur in the context of the trial. It may pertain to all participants, or only to those in one arm of a trial, or only to one participant with a particular health issue. It may be information that arises from other related research that has repercussions for ongoing trials. To understand the particular relevance of new information, it should be considered from the perspective of the participant. Article 11.8 outlines the continuing duty of researchers to share new and relevant information regarding clinical trials with the REB, the publicly accessible registry where the trial is registered, other relevant bodies, and with participants and their primary care clinicians, as indicated by the nature of the information. The more relevant, serious and urgent the information, the more promptly it should be disclosed.
New information that arises outside the trial (e.g., new findings in other related research) must also be disclosed when that information is relevant to the participant’s ongoing consent to participation. Researchers should also promptly share new information about an intervention with other researchers or clinicians administering it to participants or patients, and with the scientific community – to the extent that it may be relevant to the general public’s welfare. New information thus covers a range of matters that includes, but is not limited to, the following:
- changes to the research design;
- evidence of any new risks;
- unanticipated issues that have possible health or safety consequences for participants;
- new information that decisively shows that the benefits of one intervention exceed those of another;
- new research findings, including relevant non-trial findings;
- unanticipated problems involving lack of efficacy, recruitment issues or other matters determined to be serious enough to warrant disclosure; or
- closure of trials at other sites for reasons that may be relevant to the welfare or consent of participants in the ongoing trial.
The duty to report new information to the REB, along with the necessary analysis and evaluation to make the new information interpretable, lies with the researcher. In the case of newly discovered risks or unanticipated issues, the report shall also include a plan to eliminate or mitigate any increased risks to participants. The REB should encourage researchers to raise potentially relevant developments with the REB at an early stage to better determine the appropriate scope and timing of information sharing with participants and regulatory authorities.
When new information is relevant to the welfare of all participants, then researchers and REBs have a duty to ensure that all participants are informed. Where new information affects only current participants in the trial, the REB may decide that former participants need not be informed. However, researchers may decide to voluntarily share this information with all participants if they choose.
In multi-site clinical trials, when new information arises at one site that may affect participant welfare or consent at other sites, the researcher in charge of that site shall promptly inform the principal investigator of the trial. The principal investigator shall inform researchers at all other sites of the trial. It is the responsibility of the researcher in charge of each site to ensure their REB receives this information in a timely fashion.
The welfare of participants must also be considered when a trial is unexpectedly discontinued. When a researcher, a sponsor or other body (institution, funding agency, regulatory body) stops or unblinds a clinical trial, or a part of a clinical trial, the principal investigator has an ethical and a regulatory responsibility to inform both clinical trial participants and the REB of the discontinuance or unblinding and the reasons for it. Researchers must update the publicly accessible trial registry with any changes to the trial that require REB review and approval, adverse events that occur during a trial, and decisions taken to end a trial early. In the case of a trial that has stopped early, an explanation must be provided as part of the update to the registry. Where no specific field for this information exists, this update can be added to descriptions of study design and/or intervention (or an equivalent data field). Any risks to participants that may arise from the closing of the trial must be communicated in writing to the REB and the participants, and the researcher shall indicate any measures that will be taken to mitigate these risks.
New information affecting the welfare of former participants may arise after the completion of the trial or after the participants’ involvement is finished. If so, the researcher should share the information with the REB and other appropriate regulatory or advisory bodies. The REB and the researcher should consider whether, given its nature and urgency, the information would be relevant to any former participants’ welfare and informed choices, as well as to ongoing research elsewhere, and the general public. If so, reasonable steps should be taken by researchers to inform former participants, and to publicly disclose the information, in a meaningful and timely manner.
REBs shall develop procedures to review safety reports and other new information arising from clinical trials that may affect the welfare or consent of participants, and to take appropriate steps in response.
In accordance with Articles 11.7 and 11.8 and Articles 6.15 and 6.16, REBs can expect to receive safety reports and new information, including, but not limited to, unanticipated issues, changes to the research design and newly discovered risks. The reports are usually submitted by the local site researcher, who may also be the principal investigator, or by an established safety monitoring body, such as a DSMB (see Article 11.7). REBs should be aware that researchers are also required to update the publicly accessible trial registry where their trial is registered (see Article 11.8).
It is the REB’s responsibility to establish procedures for reviewing safety reports and new information, to determine how they will respond to increased risks to participants, and to be ready to implement these responses as needed. Responses shall be relative to the seriousness and likelihood of the risk to the welfare of participants within their jurisdiction. REBs may advise researchers as to the steps they must take to eliminate or mitigate newly reported risks, and how this information should be shared with participants (see Article 11.8). In exceptional cases, REBs may decide to suspend new recruitment, or to suspend all participant involvement in a trial pending further investigation.
D. Financial Conflicts of Interest
Clinical trials can be affected by all types of conflict of interest: personal, professional and/or institutional (as described in Chapter 7). Article 11.10 deals specifically with financial conflicts of interest that are of concern for sponsored clinical trials.
Researchers and REBs should be aware of, and consider the possibility of, financial conflicts of interest. They should ensure that clinical trials are designed to meet appropriate standards of participant safety in accordance with the core principles of this Policy. Financial considerations shall not affect these standards or the scientific validity and transparency of trial procedures.
Researchers should not benefit financially from pharmaceutical or biotechnology companies, or other types of sponsors. Financial incentives have the potential to distort researchers’ judgment in ensuring the design and conduct of the trial is ethical. Some clinical trials are conducted under contract with companies that have a profit motive in order to secure marketing approval for the drug, device or product being tested. Because these companies operate on a profit-based model, the financial benefits of demonstrating efficacy and safety in a novel therapy may have the effect of compromising standards of participant protection and scientific validity (see Chapter 7). Financial conflicts of interest are not a feature of all sponsored research. However, REBs shall consider the potential for conflicts of interest in clinical trials because it has been empirically established as a risk of some sponsored research and can undermine the ethical conduct of research.
Clinical Trial Budgets
Budgets for clinical trials are usually calculated based on per capita costs – that is, the sponsor pays the researcher a fixed sum for each participant, based on the duration and complexity of the trial and the tests and procedures it requires.
REBs shall ensure that clinical trial budgets are reviewed to ensure that conflicts of interest are identified and minimized, or otherwise managed.
REBs may delegate the review of clinical trial budgets to an appropriate institutional body. The body should ensure financial conflicts of interest are reported to the REB. When no such institutional body exists, the REBs shall review clinical trial budgets for financial conflicts of interest.As a general guide, payments for clinical trial procedures should be no greater than the usual amounts charged by health care providers for the provision of comparable services. Researchers should disclose all kinds and amounts of payment to the REB (see Article 7.4).
A particular concern in the context of clinical trials is the use of inappropriate incentives by the sponsor to encourage researchers to recruit participants quickly and without regard to their suitability for the trial. Differential incentives paid for different levels of recruitment, such as higher per-participant payments for those recruited above a set target, may also encourage inappropriate recruitment practices and should be prohibited. The REB can assist the researcher in identifying these and other types of financial conflicts and managing them appropriately (see Article 7.4).
E. Analysis and Dissemination of Clinical Trial Outcomes
The rights of sponsors with respect to the analysis of data, interpretation of results and publication of findings, and ownership thereof, are typically described in sponsor-researcher contracts (often referred to as clinical trial agreements), which are reviewed by the institution. These contracts
may seek to place restrictions on the publication of findings, either directly or through provisions that seek to protect, in favour of the sponsor, the intellectual property of research procedures, data or other information. It is the responsibility of the institution to ensure that these contracts are in compliance with the guidance of this Policy, and in particular Article Article 11.12.
With respect to research findings:
- Institutions and REBs should take reasonable measures to ensure that sponsors, researchers and institutions publish or otherwise disseminate the analysis of data and interpretation of clinical trial results (i.e., the findings) in a timely manner without undue restriction.
- Any prohibition or undue limitation on the publication or dissemination of scientific findings from clinical trials is ethically unacceptable.
- Institutions should develop reasonable written policies regarding acceptable and unacceptable clauses in clinical trial research contracts relating to confidentiality, publication and access to data.
To justify the involvement of participants, and the risks and other burdens they are asked to bear, research must be valuable. That is, it must have a reasonable likelihood of promoting social good. If research findings and the research materials and research data they are based upon, are not disseminated (e.g., published in a peer-reviewed journal, added to a publicly available clinical trials database) within a reasonable time, their value may be diminished or lost, betraying the contributions and sacrifices of participants. For this reason, and based on respect for participant expectations and protection of the public good, researchers, research sponsors and institutions have an ethical responsibility to make reasonable efforts to publicly disseminate the findings of clinical trials in a timely manner by publications and by the inclusion of the findings (where possible), or information about where to access findings (e.g., lists of publications, links to publications or to the trial website) in the publicly accessible registry where the trial has been registered. In publications, researchers have the obligation to report trial details (for example, method, all planned outcomes, and harms as defined by the Consolidated Standards of Reporting Trials). Furthermore, any new information that has an effect on the welfare of participants that comes to light at, or after, the end of the trial should be reported in subsequent publications.
However, negative findings of research are not always published or otherwise disseminated. Clinical trial registries do not currently require dissemination of findings. Failing to publish negative findings could lead to publication bias and thus contribute to a series of risks, including misinformed clinical decision making based on incomplete or skewed data, inappropriate and potentially harmful clinical practices and injury to health, needless and wasteful duplication of research with associated risks to participants, fraud or deception in the clinical trials process, and erosion of public trust and accountability in research.
Although it is beyond the scope of the Policy to provide guidance for journal editors and publishers, both have ethical obligations with regard to the publication of the findings of research. Both negative and positive findings should be published. Sources of funding, any restrictions regarding public disclosure of trial data, institutional affiliations and conflicts of interest should be declared in publications.
Researchers are encouraged to make their data available for further analysis or verification by their peers. When sharing participant data with peers, researchers must be mindful of their responsibility to safeguard participant privacy and confidentiality (see Articles 3.2, 5.1 and 5.5A) and may have to code or anonymize the data to do so.
Confidentiality clauses and publication restrictions in research contracts
Institutions and REBs should require the satisfactory amendment or removal of any confidentiality clauses or publication restrictions in research contracts that unduly limit either the content of the scientific information that may be disseminated or the timing of dissemination. Contracts should also ensure that principal investigators have the necessary access to original trial data, and the opportunity to analyze them, to ensure that they can report trial findings fairly and accurately, particularly with respect to both efficacy and safety.
Institutional and REB policies should ensure that sponsors’ legitimate interests are reasonably balanced against the researcher’s ethical and legal obligations to participants, and to the scientific and public good to disseminate data and research findings (see Chapter 7 with respect to Conflicts of Interest). It shall be understood that the welfare of participants takes precedence over the interests of both researchers and sponsors.
Such policies should require that clinical trial research contracts be examined to ensure that contractual provisions comply with institutional policy standards. They should do all of the following:
- require that confidentiality and publication clauses be submitted to a responsible authority (e.g., the REB or research administration) for a determination of their consistency with the policy;
- require that any ethical concerns arising in the review be referred to the REB as an integral part of the research ethics review process;
- provide that any proposed restrictions on publication include an ethically acceptable justification;
- provide that all confidentiality and publication clauses:
- be consistent with the researcher’s duty to share new information from clinical trials with REBs and trial participants in a timely manner (Section D);
- be reasonable in terms of any limitations or restrictions on the publication or other dissemination or communication of information;
- permit principal investigators to access all trial data;
- permit researchers to access all trial data collected at their respective sites; and
- permit all researchers to access all trial data in cases where no principal investigator is named.
In the interests of transparency and accountability, it is necessary for researchers to have access to trial data. Normally, it is the responsibility of the named PI to examine the entire trial data set and to ensure that data are not inappropriately excluded from analyses and disseminations of findings. If a PI is not named to avoid sharing the entire data set of a multi-site trial, this would be contrary to ethical clinical trial reporting in accordance with TCPS 2. To promote transparency and accountability, TCPS 2 requires that, in the absence of a named PI, all site researchers shall be entitled to access the entire data set.
Review of ethical aspects of researcher-sponsor contracts should be undertaken by an REB, or by or under the auspices of another competent institutional authority as an integral part of the research ethics review process. If done under the latter process, the review of contracts should be conducted in a manner that: (1) conforms to the special ethical duties, mandate and purposes of REB review; and (2) consults with the REB when necessary.
In the review process, the onus to justify restrictions on dissemination or access to data should lie with the one seeking such restriction, usually the researcher or sponsor. The reasonableness of restrictions on either the content or timing of dissemination should be measured against the written institutional policies. For example, some existing institutional policies deem unacceptable any publication restrictions that exceed a time limit of three to six months after the close of the trial. Such policies should also address restrictions on the dissemination of particular kinds of information, such as information that may be considered proprietary or trade secrets. Restrictions on information that participants would reasonably consider relevant to their welfare (see Articles 11.7 and 11.8), or that are required to give appropriate context to a manuscript or other publication, are seldom, if ever, justified.
- Canada. Food and Drugs Act. Natural Health Products Regulations, Part 4: Clinical Trials Involving Human Subjects (SOR/2003-196) 5 June 2003.
- Canadian Institutes of Health Research. Open Access Policy (January 2013)
- Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada, Access to Research Results: Guiding Principles.
- Consolidated Standards of Reporting Trials: CONSORT Statement, and Explanation and Elaboration document.
- Council of Europe. Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. 1997.
- Council for International Organizations of Medical Sciences (CIOMS). International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: 2002.
- Health Canada. Therapeutic Products Directorate. Medical Devices Bureau. Guidance documents.
- International Conference on Harmonisation. Guidance for Industry: Good Clinical Practice – Consolidated Guidelines, ICH Topic E6: Technical Requirements for the Registration of Pharmaceuticals for Human Use. 1996. Adopted by Health Canada in 1997.
- Ottawa Hospital Research Institute. Ottawa Statement on Trial Registration.
- United States. Food and Drug Administration. Food and Drug Administration Amendments Act of 2007. September 2007.
- United States. National Institutes of Health. NIH Policy for Data and Safety Monitoring. Released 1998.
- Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials. Released 2000.
- World Medical Association. Declaration of Helsinki – Ethical Principles of Medical Research Involving Human Subjects. 2008.
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