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Revised Draft 2nd Edition of the TCPS (December 2009)

Chapter 11

CLINICAL TRIALS

A. Overview

A clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Clinical trials may also be referred to as interventional trials. 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, and manual, behavioural and psychological therapies, etc.1 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 study participants.

Clinical trials are most frequently undertaken in biomedical or health research, although research that evaluates interventions, usually by comparing two or more approaches, is also conducted in related disciplines, such as psychology. Clinical trials commonly involve testing new drugs or testing established drugs for new indications. For this reason, and for convenience, references in this chapter are made primarily to drug testing. The guidance provided in this chapter also applies, as appropriate, to trials involving other therapies or interventions.

Clinical trials take many forms, ranging from “n of 1” studies to multi-centre randomized controlled trials. Although the various types and forms of clinical trials have methodological differences, the ethical principles and procedures articulated in this Policy apply to and can be adapted for each of them. The primary focus of the chapter is on randomized controlled trials.

In addition to this Policy, national regulations and international guidelines provide direction on ethical principles and regulatory requirements for conducting clinical trials. For example, researchers undertaking clinical trials intended for use in seeking regulatory marketing approval in Canada must comply with Health Canada regulations.2 Researchers, specifically undertaking clinical trials pertaining to investigation in respect of a drug, should also respect the International Conference on Harmonization Good Clinical Practice Guidelines (ICH-GCP),3 which have been adopted by Health Canada, and other applicable policy or guidance documents. At the international level, the Declaration of Helsinki provides guidance for physicians conducting research.4 The European Convention on Human Rights and Biomedicine5 and The Council for International Organizations of Medical Sciences’ International Ethical Guidelines for Biomedical Research Involving Human Subjects6 provide general guidance on medical research on humans. These international guidelines have similar substantive aims but may employ different mechanisms for achieving such aims.

Clinical trials may draw participants from a variety of geographically diverse places. Data collected from all of the trial sites are pooled for analysis. Issues relating to such multi-site clinical trials are discussed in Chapter 8.

This chapter provides guidance on the ethical issues that are relevant specifically to clinical trial research. Clinical trial research is also subject to the general guidelines that are applicable to research involving humans. These guidelines are set out and discussed in Chapters 3 through 7.

B. Assessing Safety and Minimizing Risk

Participants enrolled in clinical trials are commonly exposed to experimental therapies, interventions, drugs or devices, each of which carries specific risks.

Article 11.1 Research ethics boards (REBs) should ensure that the risk to participants from drugs and other interventions in clinical trials is: (a) justified by the potential benefits to be gained; and (b) appropriately minimized.

Application The approach of proportionate review (see Chapter 2) dictates that studies deemed to be of greater risk should be subject to proportionately greater scrutiny. In all clinical trial research, the REB should carefully evaluate previous laboratory, animal and human research with the drug or other therapy, and/or have an expert evaluation undertaken on its behalf, to ensure that the 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 study, an REB may discontinue the study at its institution, require the disclosure of relevant safety information to existing and future participants (see Section D below), or take other steps reasonably necessary to promote the safety of participants.

Monitoring Safety and Reporting Adverse Events

A key responsibility of researchers and REBs is to ensure that, as a clinical trial proceeds, the risks to participants remain in the acceptable range and the safety of participants is monitored. It is the basis of the requirement for the reporting of serious adverse events or serious adverse drug reactions.

The following definitions are drawn from the ICH-GCP, which has been adopted by Health Canada:

  • Adverse event – “ … any unfavourable and unintended sign … symptom, or disease temporally associated with the use of a medicinal … product, whether or not related to the medicinal … product … ”7

  • Serious adverse event/serious adverse drug reaction – “any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.”8

Principal investigators must comply with Health Canada’s reporting requirements. These include the need to immediately report any safety problems and all serious adverse events to the sponsor and participants, as well as the need to report unexpected serious adverse events to the regulatory authorities and REBs. Sponsors also have responsibilities to expeditiously report all unexpected serious adverse events suffered by participants at any site to the regulatory body, the researchers and REBs at all institutions taking part in the research.

Assessing Research-Attributable Risk

Article 11.2 In clinical trials, an REB may approve a study that involves high-risk therapies if the research-attributable risk is no greater, or only minimally greater, than that to which patient-participants would routinely be exposed in their usual clinical care. Full REB review is the default level of review unless it is determined that delegated review may be appropriate.

Application As part of their ongoing medical care, patients with serious medical conditions are often treated with therapies or undergo interventions or procedures having significant risks. These patients are sometimes invited to participate in clinical trials. Some kinds of standard or recognized treatments themselves pose significant risks (e.g. surgery, chemotherapy or radiation therapy). An REB may approve a study that involves high-risk therapies if there are no other reasonable alternative therapies available to patient-participants and if the research-attributable risk is no greater, or only minimally greater, than that to which patient-participants would routinely be exposed. (See Chapter 2 Section B). Such risks may be regarded as within the range of minimal risk for these patient-participants, since they are inherent in the treatment that patients undergo as a part of their everyday life.

Eligible participants for such studies are those patients:

  • who are routinely exposed to similarly high-risk treatments in the course of their usual care and for whom there is a favourable balance of risk to potential benefits;

  • for whom there are no other reasonable treatment options available and for whom there is a favourable balance of risk to potential benefits; or

  • for whom the incremental risk of research interventions (the research-attributable risk) is minimal.

Because these populations are often vulnerable as a result of being exposed to relatively high levels of risks, full REB review is often warranted. REBs should asses these trials to determine if they are appropriate for delegated review.

Informed consent to such studies must include a description of the risks involved as well as a description of any available alternative treatments – including no treatment. REBs should also seek to ensure that participants are informed of the risks and potential benefits attributable to research, as distinct from those arising from indicated therapy. (See Chapter 2, Article 2.9 dealing with a proportionate approach to REB review).

Article 11.3 Researchers shall provide the REB with an acceptable plan for monitoring the safety of trial participants, including a plan for the tabulation, analysis and reporting of safety data in a form that permits REBs to interpret and act upon the data.9

Application REBs must ensure that every clinical trial protocol includes a plan to assess safety concerns and protect the ongoing safety of research participants. Such a plan should include the requirement that researchers, sponsors and/or Data Safety and Monitoring Boards (DSMBs), provide REBs with clear and up-to-date information about the safety of participants taking part in clinical trials. Such 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 trial participants. Where possible, REBs should be provided with individual serious adverse event reports, accompanied by an evaluation, by the sponsor, of their relevance and significance to the trial and its participants.

A safety monitoring plan should include a mechanism by which participants may be withdrawn for safety reasons and by which studies may be stopped or amended if they are found to be unsafe, or for reasons of futility or efficacy. For some trials, the researcher may be expected to perform this monitoring function. Depending on the circumstances of the trial, safety reports may be submitted on an annual or semi-annual basis, supplemented by prompt notices of serious safety threats to participants requiring urgent consideration. All information supplied to the REB should include an analysis of its significance and sufficient context to permit meaningful determinations to be made by the REB.

Data Safety and Monitoring Boards

A DSMB or Data Safety Committee (DSC) is a multi-disciplinary, independent expert advisory group that is responsible for safeguarding the interests of participants in randomized controlled trials, assessing the safety and efficacy of study procedures and monitoring the overall conduct of a study. It is composed of scientists with expertise in the clinical area, statisticians, pharmacists and individuals with expertise in ethics. Where the size and complexity of the trial support the establishment of a DSMB, it plays an important role in ensuring the safety of study participants, although its responsibilities differ from those of an REB.

These responsibilities include:

  • ensuring the overall safety of participants based on a review of the totality of evidence and the principle of the emergence of evidence that is likely to influence clinical practice;

  • advising the principal investigator and steering committees about the conduct of the trial and the integrity of the data, so as to protect the validity and scientific credibility of the trial;

  • developing and operating under a DSMB Charter governing the activities of the DSMB.

Although the DSMB reports its findings and recommendations to the principal investigator, it should act independently of the sponsor and of the investigator. The DSMB has intermittent access to the accumulated unblinded trial data, and it also audits unblinded safety reports from all sites taking part in the trial. Based on that information, and in accordance with its trial-specific stopping rules, the DSMB can recommend that the study be stopped early for reasons of safety, efficacy or futility. The DSMB will also be responsible for making appropriate recommendations about informing participants of safety concerns. The DSMB can also recommend that the principal investigator change the procedures, methods or consent form information to ensure the safety of participants and the validity and reliability of the data being collected.

Article 11.4
REBs shall develop procedures to review safety reports and to take appropriate steps in response.

Application
For more complex trials, an external DSMB may be appointed to provide a more comprehensive mechanism to monitor and address trial safety. Should the REB desire copies of DSMB reports and recommendations, they should liaise with the principal investigator or steering committee. A DSMB must be independent of the trial and its members free of conflicts of interests with the study therapy, the trial sponsor, and the outcome of the research. Even when there is a DSMB, the sponsor still has a responsibility to provide reports of serious adverse events directly to the REB, upon which the REB may be obliged to act urgently. The existence of a DSMB does not mitigate the responsibilities of the sponsor, investigator or REB to monitor and address trial safety.

Article 11.5 Investigators shall inform participants, immediately, of serious adverse events as they pertain to the participant’s health and/or willingness to continue to participate in the trial. They should also report these events to the REB.

Application For the purposes of this Policy, adverse event includes adverse drug reactions.10

Investigators in multi-site trials should be encouraged to inform other site investigators of serious adverse events. Where a sponsor has discontinued or unblinded a clinical trial or a part of a clinical trial, the investigator has regulatory responsibility to inform both clinical trial participants and the REB of the discontinuance or unblinding and the reasons for it, and also to advise them in writing of any risks to the health of participants.
Investigators should feel free to use their discretion in communicating other adverse events to participants as they think beneficial. Adverse events should be communicated to individual participants based on the extent to which the adverse event may be relevant to the participant’s health, safety and ongoing consent. REBs should encourage communication of adverse events among site investigators.

Reports on adverse events should provide the necessary detail for REBs to contextualize the report and understand the impact of the adverse event on the health and safety of participants.

C.     Phases of Clinical Trials

This section discusses the ethical issues pertaining to the different phases of clinical trials, primarily those involving drugs. The guidance provided in this section may also apply, as appropriate, to trials involving other therapies or interventions. Clinical trials involving pharmaceutical products are commonly categorized into four phases, each of which gives rise to particular ethical issues.11 In all phases of such clinical trial research, REBs should be aware of ethical issues including but not limited to safety, selection and recruitment of participants, undue inducement, consent, and real, potential or perceived conflicts of interests.

Article 11.6 When reviewing a clinical trial protocol, the REB should be aware of its phase and the special ethical issues that different phases of research may raise.

Application  Some ethical issues are most likely to arise in a specific phase or phases of a clinical trial. Other issues may arise at any phase of a clinical trial.

Phase I 

In Phase I clinical trials, researchers test a new drug or treatment in a small group of people, often for the first time, to evaluate its toxicity and other side effects, and to determine a safe dosing range. Participants in Phase I clinical trials are usually healthy volunteers or patients who have failed conventional therapy. Pharmacokinetic studies (the study of the absorption, distribution, metabolism, and elimination of a drug or ingested compound) are one example of Phase I clinical trials.

Ethical Concerns – Safety concerns are particularly acute in Phase I research because it may be the first time human 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. 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 should 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.

Although there are clear benefits to conducting Phase I trials on healthy volunteers, Phase I clinical trials now increasingly include participants with specific diseases for whom conventional therapies have failed. Such studies may be designated as Phase I clinical trials, but the boundaries between trial phases are not always clear. Such studies may be designated as combined Phase I/II or pure Phase II clinical trials (see below).

Phase II 

Phase II clinical trials primarily examine the safety (e.g. short-term side effects) and efficacy of new drugs. They are conducted in populations with the disease or condition sought to be treated by the drug.

Ethical Concerns: 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. Patients with cancer that is incurable by standard therapies and HIV/AIDS are examples. These circumstances may affect the perceptions of patients and their families as to the balance between the risks and potential benefits of the study and thus may affect their decision whether to participate. Additionally, because participants in Phase II trials include patients who are often unwell and frequently not working, the REB should ensure incentives for participation is 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). Investigators should: 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.

Phase III  

The drug or treatment is given to a large group of patients, often at several sites. Phase III trials determine the drug or treatments’ efficacy by comparing it with commonly used treatments, monitoring for side effects and collecting additional information to evaluate the overall risk-benefit relationship of the drug. This information will help support the safe use of the drug or treatment. These studies may lead to a new drug being marketed in Canada or to the use of an approved drug for a new indication.

Ethical Concerns: 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 study (including the placebo arm). The REB should also address the issue of continuing access to the experimental therapy after the trial. If the treatment benefits participants and is safe, will it continue to be provided? If so, for how long and at what cost? If not, what provision will be made to ensure that participants continue to receive adequate treatment? The REB should be aware that numerous safety standards (e.g. mechanical and electrical) apply to medical devices, and the REB should be assured that these standards will be met.

Phase IV 

Phase IV clinical trials, also known as post-regulatory approval studies, primarily examine the long-term effectiveness and toxicity of already-marketed drugs. They may also be designed to determine the effectivenessof the treatment or intervention in different populations, or to look at quality-of-life issues.

Ethical Concerns: Phase IV studies can be extremely valuable for assessing the long-term safety and effectiveness of marketed drugs and devices. Earlier-stage studies are of limited duration, and subsequent research can identify toxicities and drug interactions that 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 physician 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. However, the financial terms associated with these trials may create problems such as inappropriate prescription practices, billing practices or utilization of public resources (e.g. diagnostic services and medical imaging). Researchers and REBs must examine Phase IV clinical trials in light of these potential conflicts to 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.

D.    Sharing New Information

In the course of a clinical trial, new information may arise that is relevant to participants’ ongoing consent to participate in the research. Section B above addresses the REB’s obligation to ensure that the safety of participants is monitored and protected. Section D describes the obligations of researchers and REBs to ensure that any new information, including information about newly discovered risks and toxicities, changes to the research protocol, and information that may affect the participants’ welfare and willingness to enter or continue in the trial be promptly disclosed.

Article 11.7 Researchers shall promptly share information that may be relevant to participants’ ongoing consent to participate in the research with the REB, the participants, and other appropriate regulatory or advisory bodies.

Researchers should also promptly share new information with former participants in the research to the extent that it may be relevant to their welfare.

Application Article 11.7 outlines a researcher’s continuing duty to share new and relevant information from the clinical trial.

New information requires disclosure if it may affect the willingness of participants to continue in the trial, or is otherwise relevant to participants’ welfare or consent. (See Articles 2.8, 3.3, 3.4, and 6.15). To understand its particular relevance, the information should be considered from the perspective of the participant. New information that arises outside the trial (e.g. new findings in other related research), should also be disclosed when that information is relevant to the participant’s ongoing consent to participation. New information thus covers a range of matters that includes, but is not limited to, the following:

  • changes to the research protocol;

  • evidence of new risks, determined to be serious enough to warrant disclosure;

  • new information that decisively shows that the benefits of one intervention exceed those of another;

  • new research findings, including relevant non-trial findings; or

  • unanticipated problems involving lack of efficacy, recruitment issues, or other matters determined to be serious enough to warrant disclosure.

Researchers must promptly share new information with the REB and trial participants. What constitutes prompt disclosure may be set out in regulatory documents, such as Health Canada’s Food and Drug Act and Regulations, or in the absence of regulatory requirements, the REB may provide guidance. If sponsors fail to report new and significant information that is relevant to the welfare of participants, then researchers and/or REBs have a duty to do so. The more relevant, serious and urgent the information, the more promptly it should be disclosed. Researchers should also promptly share new information with other physicians administering the treatment and the scientific community to the extent that it may be relevant to the general public’s welfare.

The duty to report such new information to the REB, along with the necessary analysis and evaluation to make the new information interpretable, lies with the researcher and the sponsor. 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.

Significant 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 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 the ongoing research elsewhere and the general public. If so, reasonable steps should be taken to inform such participants, and publicly disclose the information, in a meaningful and timely manner.

E.    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 refers to the tendency of trial participants to believe that the primary intention of research tests and interventions is to provide a therapeutic benefit to the patient-participant. With the exception of some Phase I studies, clinical trials usually involve individuals in need of treatment, for whom the experimental therapy is hoped to be effective. Even when research risks, potential benefits and alternatives are explained to them, it is common that 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 physician believes it would contribute to their health. This may be particularly true when the researcher is the patient-participant’s own physician or care provider. Often the patient’s physician, or someone associated with the patient’s physician, makes the initial approach or provides preliminary information about trial participation. Research has shown that participants may confuse the purposes of research and therapy.

Article 11.8 REBs and clinical trial researchers should be conscious of the phenomenon of therapeutic misconception and ensure that procedures for recruitment and informed consent emphasize which specific elements of a clinical study are required for research purposes, as well as the differences between research and the standard clinical care they might otherwise receive.

Application Article 3.2 describes the requirements for informed 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. When a treating clinician conducts research on his or her patients, special efforts may be required, as part of the consent process, to distinguish between these two roles – clinician and researcher – and to ensure that patient-participants understand the research elements of the study. While the physician is ultimately responsible for patient care and safeguarding the patient’s health, patient-participants should understand that a physician who conducts research is acting in a capacity that is outside the traditional physician-patient relationship.

One way to minimize therapeutic misconception is to ensure that the health care professionals who provide the patient’s regular care are involved as little as possible in recruitment and the consent process, to ensure that clearly different people perform treatment and research functions.

Clinician-Researchers and Therapeutic Misconception

“Clinician” is defined as any health care provider. Research has shown that clinician-researchers may conflate research and clinical practice. Some clinicians may be unrealistically optimistic about an experimental intervention’s prospects. Clinicians may overstate the potential benefits and understate the risks of participation in a clinical trial when speaking with potential participants. Clinicians who conflate research and individual therapy may foster therapeutic misconception among patient-participants that may influence recruiting and the consent process. (See Chapter 3). They should take care not to create unrealistic expectations among participants with respect to the potential benefits of the research.

F.    Financial Conflicts of Interests

Real, potential or perceived financial conflicts of interests are a feature of some clinical trials. Clinical trials may also be subject to other forms of conflict of interests. (See Chapter 7).

Industry-Sponsored Research

Article 11.9 REBs should be aware of and consider the possibility of financial conflicts of interests. They should ensure that clinical trial research is designed to meet appropriate standards of participant safety and respectful treatment, and that financial considerations do not affect these standards or the scientific validity and transparency of study procedures.

Application  Researchers should not benefit financially from pharmaceutical or biotechnology companies. Financial incentives have the potential to distort researchers’ judgment in ensuring the design and conduct of the trial is ethical. Clinical trials are commonly undertaken under contract with pharmaceutical or biotechnology companies in order to secure marketing approval for the drug, device or product being tested. 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 human protection and scientific validity. (See Chapter 7). Financial conflicts of interests are not a feature of all industry-sponsored research. However, REBs shall consider the potential for conflicts of interests in clinical trials because it has been empirically established as a feature of some industry 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 research participant, based on the duration and complexity of the study and the tests and procedures it requires.

Article 11.10 REBs shall ensure that clinical trial budgets are reviewed to ensure that conflicts of interests are identified and appropriately managed.

Application  REBs may delegate the review of clinical trial budgets to an appropriate institutional body. The body should ensure financial conflicts of interests are reported to the REB. When no such institutional body exists, the REBs should review clinical trial budgets for financial conflicts of interests. 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. Budgets should also be examined to ensure that no inappropriate payments are to be made, such as incentives for identifying and recruiting participants or other unexplained expenses that may raise questions about conflict of interests. Further, payment provisions should be scrutinized to ensure they do not create ethically inappropriate incentives to recruit quickly, at the expense of a careful review of the suitability of potential participants. 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. Unreasonable payments or undue inducements may place the researcher, and sometimes the institution, in a conflict between maximizing financial remuneration on the one hand and protecting participants and meeting the scientific requirements of the study on the other. Disclosure of the kinds and amounts of payments and other budgetary details assists the REB to assess potential conflicts of interests and encourages the researcher to identify and manage them appropriately. Management by institutions and/or REBs may include prohibiting certain forms of payment.

G.    Placebo-Controlled Studies

With respect to establishing the efficacy of a new drug, the most compelling trial design is considered to be a Randomized Controlled Trial (RCT). There are many possible variations and choices of control groups for RCTs, including but not limited to active control, placebo control, dose-response, multiple arms and combination therapies. It is the responsibility of the trial sponsor to provide justification for the choice of control group. The International Conference on Harmonization: E-10 Choice of Control Group and Related Issues in Clinical Trials (ICH E10)12 guidance outlines the issues that must be considered when designing an RCT, as well as the implications of various design choices. Where there is an established effective treatment, use of a placebo may deprive participants of needed therapy. The following article is designed to ensure that placebo controls are used only in situations that do not compromise the safety and welfare of participants.

Clinical Equipoise

Clinical equipoise means a genuine uncertainty on the part of the relevant expert community about the comparative therapeutic merits of each arm of a clinical trial. The tenet of clinical equipoise provides a clear moral foundation to the requirement that the health care of individuals not be disadvantaged by their participation in research.

Article 11.11

(a) A new therapy or intervention should generally be tested against an established effective therapy.

(b) 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 to establish 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 valid scientific justification for the use of the placebo control.

(c) For clinical trials involving a placebo control, the researcher and the REB shall ensure the general principles of informed consent are respected (see Article 3.2 ) and that participants or their authorized third parties are specifically informed:

  • 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.

Application All clinical trials involve risk to participants. For all approved trials: a) the welfare of the participants need 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 should be justified based on scientific, medical and methodological reasons.

According to Article 11.11, one should consider a proven effective therapy as control if one is available. A superiority trial with an active control is a straight forward and uncomplicated design. However, superiority against an active control may not always be a realistic expectation in a test therapy. A non-inferiority trial on the other hand is not as straight forward. There are many methodological requirements that need to be considered in the design of a non-inferiority trial. As a result, a non-inferiority trial may not be feasible or interpretable in some therapeutic areas for the management of certain conditions. Sponsors, researchers, and REBs should refer to ICH E-10 and be familiar with concepts such as assay sensitivity, historical evidence of sensitivity to drug effects, and choosing the non-inferiority margin. 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 placebo vs. active controlled non-inferiority trials, an appreciation of the interplay of ethics and science is required. Conditions that work against carrying out a non-inferiority trial successfully include low and/or variable response to treatment, and high placebo response.

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 study 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:

  1. there are no established effective therapies for the population or for the indication under study;

  2. existing evidence raises substantial doubt within the community of treating physicians regarding the net therapeutic benefit of available therapies;

  3. patients are resistant to the available therapies by virtue of their past treatment history or known medical history;

  4. the study involves adding a new investigational therapy to established effective therapies: established effective therapy plus new therapy vs. established effective therapy plus placebo;

  5. 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 potential participant, and both must be documented.13

The use of a placebo comparator in situation (5) is permitted because potential 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 is no established effective therapies for the indication under study. Research protocols submitted to REBs should include sufficient support and justification of the study design and use of placebo comparator.

The following scenarios, while not exhaustive, may be used as guide for assessing the ethics and choice of trial designs:

Scenario 1

  • no proven effective therapy available;
  • efficacy can be established with a placebo controlled superiority trial.

Scenario 2

  • available treatment highly and consistently effective;
  • efficacy can be established with an active controlled non-inferiority trial;
  • consider adding a placebo arm if acceptable ethical conditions are met.

Scenario 3

  • available treatment modest and inconsistent;
  • new treatment expected to be more effective than available treatment;
  • efficacy can be established with an active controlled superiority trial;
  • consider adding a placebo arm if acceptable ethical conditions are met.

Scenario 4

  • available treatment modest and inconsistent;
  • new treatment expected to be more effective than available treatment;
  • relatively high placebo response;
  • a case for placebo controlled superiority trial to establish efficacy;
  • acceptable ethical conditions must be met or perform an active controlled superiority trial.

Scenario 5

  • available treatment is modest and inconsistent;
  • new treatment is not expected to be more effective than available treatment;
  • strong case for placebo controlled superiority trial to establish efficacy;
  • acceptable ethical conditions must be met or perform an active controlled superiority trial.

H.    Analysis and Dissemination of the Data and Results of Clinical Trials

The rights of sponsors with respect to the ownership, analysis, interpretation and publication of study data are typically described in industry-researcher contracts (often referred to as clinical trial agreements or clinical study agreements), which may not always be available for REB review. These contracts may also 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 study procedures, data or other information.

Article 11.12 With respect to research findings:

(a)  Institutions and REBs should take reasonable measures to ensure that sponsors, researchers and institutions share clinical trial research results and publish or otherwise disseminate the analysis and interpretation of clinical trial research findings in a timely manner without undue restriction.

(b)  Any prohibition or undue limitation on the publication or dissemination of scientific findings from clinical trials is ethically unacceptable.

(c)  Institutions should develop reasonable written policies regarding acceptable and unacceptable clauses in clinical trial research contracts relating to confidentiality, publication and access to data.

Application To justify the involvement of human 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 are not disseminated 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 and institutions have an ethical responsibility to make reasonable efforts to publicly disseminate the results of clinical research in a timely manner.

However, negative results of research are not always published or otherwise disseminated. Failing to publish such results 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, and 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 results of research. Both negative and positive results should be published. Sources of funding, institutional affiliations and conflicts of interests should be declared in publications.

REBs should require the satisfactory amendment or removal of any confidentiality clauses or publication restrictions that unduly limit either the content of the scientific information that may be disseminated, or the timing of dissemination. Contracts should also ensure, as far as reasonably possible, that principal investigators have the necessary access to original trial data, and the opportunity to analyze them, to ensure that they can report study findings fairly and accurately, particularly with respect to both efficacy and safety. When access to original trial data is not possible, the sponsor should provide the REB with the reason for restricting access to trial data.

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.

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:

  1. 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;

  2. require that any ethical concerns arising in the review be referred to the REB as an integral part of the ethics review process;

  3. provide that any proposed restrictions on publication should include an ethically acceptable justification;

  4. provide that all confidentiality and publication clauses:

    (a) are consistent with the researcher’s duty to share new information from clinical trials with REBs and trial participants in a timely manner (Section D, above);

    (b) are reasonable in terms of any limitations or restrictions on the publication or other dissemination or communication of information; and

    (c) permit researchers to access all study data.

Review of ethical aspects of researcher–industry contracts should be undertaken by a duly composed REB, or by or under the auspices of another competent institutional authority as an integral part of the 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 Article 11.7), or that are required to give appropriate context to a manuscript or other publication, are seldom if ever justified.

Clinical Trial Registration

Clinical trial registries permit web-based access to information about ongoing clinical trials so that anyone may have information about trials and their results.

Article 11.13 All clinical trials within the scope of this Policy shall be registered with a recognized and easily web-accessible public registry.14

Application Clinical trial registration is the international standard. Registration of all clinical trials is strongly encouraged, including trials that are not subject to this Policy. Clinical trial registries are one way to help ensure that negative trial results are widely available. These, in addition to editorial policies,15 ethical policy reforms, and revised national and institutional ethics policies, contribute to a multi-faceted approach to combating non-disclosure, publication bias, and the suppression of data in clinical research.

Clinical trials (as defined in Chapter 11 “Overview”) should be registered before recruitment of the first trial participant in a registry acknowledged by the World Health Organization (WHO) or International Committee of Medical Journal Editors (ICMJE). Researchers should provide the REB with the number assigned to the trial upon registration.

Endnotes


[1] This definition is drawn in part from World Health Organization, International Clinical Trials Registry Platform (ICTRP), www.who.int/ictrp/en

[2] Part C, Division 5 of the Food and Drug Regulations, www.laws.justice.gc.ca/eng/C.R.C.-C.870/page-2.html#anchorbo-ga:l_C-gb:l_5 and Medical Devices Regulations (SOR/98-282), www.laws.justice.gc.ca/eng/SOR-98-282/index.html

[3] International Conference on Harmonization, Guidance E6: Good Clinical Practice – Consolidated Guideline (of ICH Technical Requirements for the Registration of Pharmaceuticals for Human Use) 1996, adopted by Health Canada in 1997,
www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/efficac/e6-eng.php

[4] World Medical Association, Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects, October 2008, www.wma.net/en/30publications/10policies/b3/index.html

[5] 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) http://conventions.coe.int/Treaty/EN/Treaties/Html/164.htm

[6] The Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines for Biomedical Research Involving Human Subject, November 2002, www.cioms.ch/frame_guidelines_nov_2002.htm

[7] See note 3 above, Section 1.2.

[8] See note 3 above, Section 1.50.

[9] The NIH has developed guidance on data and safety monitoring of clinical trials, www.grants.nih.gov/grants/guide/notice-files/not98-084.html and www.grants.nih.gov/grants/guide/notice-files/not-od-00-038.html

[10] Part C, Division 5 of the Food and Drug Regulations, www.laws.justice.gc.ca/eng/C.R.C.-C.870/page-2.html#anchorbo-ga:l_C-gb:l_5

[11] The description of the clinical trial phases above has been adapted from the U.S. National Library of Medicine of the National Institutes of Health, “FAQ: What are clinical trial phases?” www.nlm.nih.gov/services/faqctgov.html

[12] International Conference on Harmonization, Guidance E10: Choice of Control Group and Related Issues in Clinical Trials, 2000
www.ich.org/LOB/media/MEDIA486.pdf

[13] These conditions are drawn from the recommendations of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Canada, July 2004. www.cihr-irsc.gc.ca/e/25139.html with minor amendments approved by the CIHR Standing Committee on Ethics.

[14] CIHR requires that randomized clinical trials be registered with an International Standard Randomized Controlled Trial Number (ISRCTN) at www.controlled-trials.com
and World Health Organization, International Clinical Trials Registry Platform (ICTRP) at
www.who.int/ictrp/en

[15] International Committee of Medical Journal Editors, Sponsorship, Authorship and Accountability, www.icmje.org/update_sponsor.html

References

  • US Food and Drug Administration, Food and Drug Administration Amendments Act (FDAAA) of 2007, September 2007.
  • World Medical Association, Declaration of Helsinki: Ethical Principles of Medical Research Involving Human Subjects, October 2008, www.wma.net/en/30publications/10policies/b3/index.html
  • 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, http://conventions.coe.int/Treaty/EN/Treaties/Html/164.htm
  • The Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines for Biomedical Research Involving Human Subjects, November 2002, www.cioms.ch/frame_guidelines_nov_2002.htm