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Draft 2nd Edition of the TCPS (December 2008)

Chapter 11

CLINICAL TRIALS

A. Overview

A clinical trial is “an investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.”[5]

Clinical trials are most frequently undertaken in biomedical or health research, although other clinically related disciplines, such as psychology, also conduct research that evaluates interventions, usually by comparing two or more approaches.

Clinical trials may include questions that are not directly related to therapeutic goals - for example, cost effectiveness or drug metabolism - in addition to those that directly evaluate the treatment of study participants. They may take the form of “n of 1” studies or multi-centre randomized controlled trials. Although the various types and forms of clinical trials naturally have methodological differences, the ethical principles and procedures articulated in this Policy can be adapted for each of them.

Clinical trials most commonly involve testing new drugs or testing established drugs for new uses. For this reason, and for convenience, references in this chapter are made primarily to drug testing. However, clinical trials also involve medical devices, biologics, radiopharmaceuticals, genetic therapies and natural health products, as well as behavioural and psychological therapies. The guidance provided in this chapter applies also, as appropriate, to trials involving these other therapies or interventions.

Researchers undertaking clinical trials intended for use in seeking regulatory marketing approval must comply with Health Canada regulations[6] and should also respect the ICH Good Clinical Practice Guidelines,[7] which have been adopted by Health Canada, and other applicable policy or guidance documents.

The accelerating pace of new pharmaceutical drug and device development in Canada, as well as increasing clinical trial activity in non-traditional research venues, including physicians’ offices and contract research organizations, brings the need for heightened vigilance in the clinical trial review process. Research ethics boards (REBs) must carefully monitor all aspects of clinical trials, including free and informed consent, confidentiality, safety and recruitment.

With respect to the recruitment of participants for clinical trials, it is often not possible to recruit, within a reasonable time, sufficient numbers of eligible participants from a single clinical site. It may also be desirable to draw participants from a variety of geographically diverse places to avoid bias. So, it is common that clinical trials are carried on at a number of different sites and that data collected from all of the sites are pooled for analysis. Ethical issues relating to such multi-centre clinical trials are discussed in Chapter 8 (“Multi-jurisdictional Research”).

B. Phases of Clinical Trials

Clinical trials are commonly categorized into four phases, each of which gives rise to particular ethical issues. [8]

Article 11.1 When reviewing a clinical trial protocol, the research ethics board should be aware of its phase and the special ethical issues that different phases of research may raise.

Application 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.

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 compensated 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 compensation made to participants, raises ethical concerns about safety, the selection and recruitment of participants, and the process of free and informed consent. 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 compensation being paid, risks they would otherwise refuse.

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 efficacy of new drugs and their short-term side effects. They are conducted in populations with the disease or condition sought to be treated by the drug.

Ethical Concerns: 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 harms and benefits of the study and thus may affect their decision whether to participate. Researchers should be encouraged to consult with the REB at an early stage about any recruiting, consent or safety issues that arise.

Phase II and III clinical trials, unlike combined Phase I/II clinical trials, often include a placebo control to help detect and quantify the toxicity and efficacy of an experimental drug or device. In such studies, and in addition to the other ethical concerns raised for Phase II clinical trials, the use of placebos (discussed in Section G [“Placebo-Controlled Studies”]) makes it particularly important for researchers to assess and monitor the safety of participants and ensure that the quality of their treatment is not compromised by participation in the study.

Phase III The drug or treatment is given to a large group of patients to confirm its efficacy, monitor side effects, compare it with commonly used treatments, and collect information that will allow the drug or treatment to be used safely. These studies may lead to a new drug’s being marketed in Canada or to the use of an approved drug for a new indication.

Ethical Concerns: The REB must 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), that there are no conflicts of interest in the selection and recruitment of participants (see Article 7.4 in Chapter 7 [“Conflict of Interest”], that payments by sponsors to researchers are reasonable, and that no financial incentives in the nature of finder’s fees are made or offered for the recruitment of participants. The REB should also address the issue of continuing access to the experimental therapy after the trial. If the treatment proves to be effective and reasonably safe for participants, will it continue to be provided? 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 (for example, 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 look at the use of 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 sponsor. However, the financial terms associated with these trials may compromise physicians’ professional integrity by skewing prescription practices and encouraging finders’ fees, as well as encouraging improper billing practices, inappropriate utilization of public resources, and other problems. 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, that free and informed consent is given, that physician-researchers have the requisite expertise or experience, and that potential conflicts of interest are adequately addressed.

C. Assessing Safety and Minimizing Risk

Participants enrolled in clinical trials are commonly exposed to experimental medications or devices, each of which carries specific risks. Indeed, the most severe research-related harms often arise in clinical trial research.

Article 11.2 Research ethics boards should ensure that drugs and other therapies used in clinical trials do not pose undue risk to human participants.

Application The approach of proportionate review (Chapter 2 [“Scope and Approach”]) dictates that studies with greater risks 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, or have an expert evaluation undertaken on its behalf, to ensure that the risk of harm from its use (a) is justified by the potential benefits to be gained, and (b) is 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 [“Sharing New Information”], below), or take other steps reasonably necessary to promote the safety of participants.

Monitoring Safety and Reporting Adverse Events

The ICH-GCP defines an adverse event as “any unfavourable and unintended sign, symptom or disease temporally associated with the use of a medicinal product, whether or not considered related to the product.” For research carried on at a single site, the principal investigator is obliged to report any safety problems and serious adverse events to the local REB, the sponsor, and regulatory authorities. Where clinical trials are carried on at multiple sites, Health Canada and ICH-GCP require that unexpected serious adverse events suffered by participants at any site be reported to the regulatory body, the researchers and REBs at all institutions taking part in the research.

In practice, these reports have proved challenging for many REBs, because the reports often lack context, informed analysis or explanation of their significance to the safety of participants. In addition, in many clinical trials, researchers at individual sites do not have access to detailed safety data, such as the rates of similar events at other sites or the background epidemiology necessary to determine whether an adverse event is truly unexpected. It is important, then, that mechanisms be put in place to ensure the safety of trials. In some cases, a researcher’s plan for reporting safety data to the REB and acting on it may serve this purpose. A Data and Safety Monitoring Board (DSMB) is another such mechanism.

DSMBs are multi-disciplinary expert panels organized to monitor clinical trials, particularly large, late-stage multi-centre trials involving randomized designs. They are composed of scientists with expertise in the clinical area, statisticians, pharmacists and individuals with expertise in ethics. Although the DSMB reports its findings and recommendations to the sponsor, it should act independently of the sponsor. 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 can also recommend that sponsors 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 11.3 Researchers should provide the research ethics board (REB) with an acceptable plan to monitor the safety of trial participants, including a plan for the tabulation, analysis and reporting of safety data to the REB.[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 REBs be provided, by researchers, sponsors and/or DSMBs, with clear and up-to-date information about the safety of participants taking part in clinical trials. Such reports should be provided in a timely way 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 adverse event reports, accompanied by an evaluation, by the sponsor, of their relevance and significance to the trial.

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 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.

Article 11.4 Research ethics boards should develop procedures to review safety reports and to take appropriate steps in response.

Application For more complex trials, an institutional or external DSMB may be appointed to provide a more comprehensive mechanism for monitoring the safety of multi-centre clinical trials. The REB should be satisfied that it will receive copies of all DSMB reports and recommendations. A DSMB must be independent of the trial and its members free of conflicts of interest with the study therapy, the trial sponsor, and the outcome of the research. Where a DSMB has been appointed to oversee a clinical trial, it will be mostly responsible for reviewing safety data and making appropriate recommendations about informing participants of safety concerns or stopping the trial for safety, futility or efficacy. Even when there is a DSMB, the researcher still has a responsibility to provide reports directly to the REB of serious adverse events at his or her site, upon which the REB may be obliged to act urgently.

Balancing Risks

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 may be invited to participate in clinical trials.

Article 11.5 In clinical trials, with appropriate scientific and clinical justification, it may be acceptable to allow research involving higher risk interventions with patient-participants in which such heightened risk is primarily attributable to the therapy and not to the research, or which is consistent with the risk normally undertaken by participants in their usual clinical care.

Application Some kinds of standard or recognized treatments (for example, surgery, chemotherapy or radiation therapy) themselves pose substantial risks. An REB may approve a study that involves such 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 participants would routinely be exposed. 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:

  • 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.

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 aware of the risks and benefits attributable to research, as distinct from those arising from indicated therapy. (See Article 2.7 in Chapter 2 [“Scope and Approach”], dealing with comparative risk.)

D. Sharing New Information

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

Article 11.6 Researchers should share with the research ethics board, the participants and other appropriate regulatory or advisory bodies, in a timely manner, information that may be relevant to participants’ continuing consent to participate in the research.

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

Application Researchers should share with the REB and trial participants, in a timely manner, new information relating to the safety and efficacy of the study therapy, significant changes to study procedures, and other relevant information. Article 11.6 outlines a researcher’s continuing duty to share new and relevant information from the clinical trial. The more serious and urgent the information, the more promptly it should be disclosed.

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 free, informed and continuing consent (see Articles 2.8, 3.3, 3.4). To understand its particular relevance, the information should be considered from a participant-centred perspective. New information that arises outside the trial (for example, new findings in other related research), when that information is relevant to the participant’s informed and continuing participation, should also be disclosed. 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.

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. If so, reasonable steps should be taken to inform such participants in a meaningful and timely manner.

When sponsors refuse 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 stronger is the duty to report. Before REBs or researchers act on such duties, they should afford sponsors a reasonable opportunity to report the information to the appropriate regulatory authorities.

E. Therapeutic Misconception

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. In addition, 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.

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 welfare. 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. Even when research risks, benefits and alternatives are explained to them, it is common that trial participants do not fully appreciate the differences between clinical care and research participation. This may be particularly true when the researcher is the participant’s own physician.

Article 11.7 Research ethics boards 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 Chapter 3 (“Free and Informed Consent”) describes the requirements for informed consent to research participation. In particular, Article 3.2 provides that participants must 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. One way to help avoid therapeutic misconception is to ensure that the health-care professionals involved in the patient’s care are involved as little as possible in recruitment, to ensure that clearly different people perform treatment and research functions.

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 and to ensure that patient-participants understand the research elements of the study. While the physician is ultimately responsible for patient care, participants should understand that a physician who conducts research is acting in a capacity that is outside the traditional physician-patient relationship.

F. Financial Conflicts of Interest

Industry-Sponsored Research

Clinical trials are commonly undertaken under contract with pharmaceutical or biotechnology companies in order to secure marketing approval for the drug being tested. These companies make drugs and devices in order to generate profits. This may be a source of conflict with researchers’ obligations of scientific integrity and participant welfare.

Article 11.8 Research ethics boards 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 Clinical trial research raises special challenges for the protection of human participants and the validity of research results because of the financial considerations associated with clinical trials. The profit motive of commercial research can conflict with participant protection and the scientific validity of clinical trials. 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 [“Conflict of Interest”]).

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 11.9 Research ethics boards should ensure that clinical trial budgets are reviewed to ensure that conflicts of interest are identified and appropriately managed.

Application 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. Budgets should also be examined to ensure that no inappropriate payments are to be made, such as finder’s fees or other unexplained expenses that may raise questions about conflict of interest. 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 compensation 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. 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 interest and encourages the researcher to manage them appropriately.

G. Placebo-Controlled Studies

In studies of new drugs or other therapies, a placebo study arm allows the researcher to control for factors that may confound a valid assessment of the value of an experimental therapy, and it also has other methodological advantages over non-placebo designs. Placebo-controlled studies have long been the gold-standard design for testing the efficacy and safety of new drugs and other clinical interventions. However, the primacy of the placebo-controlled study has been challenged, and opinions differ as to its methodological superiority for all types of clinical trials. In addition, 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 of participants.

Article 11.10

  1. A new therapy or intervention should generally be tested against an established effective therapy.
  2. As with all alternative choices of a control, a placebo control is ethically acceptable in a randomized controlled clinical trial if:
    1. its use is scientifically and methodologically sound to establish the efficacy or safety of the test therapy or intervention;
    2. it does not compromise the safety or well-being of participants; and
    3. the researcher articulates to the research ethics board (REB) a valid scientific justification for the use of the placebo control.
  3. For clinical trials involving a placebo control, the researcher and the REB must ensure that participants or their surrogate decision-makers are well informed:
    1. about any therapy that will be withdrawn or withheld for purposes of the research; and
    2. of the anticipated consequences of withdrawing or withholding the therapy.

Application 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.

However, a placebo comparator is acceptable in any of the following situations:

  1. There are no established effective therapies for the population or for the indication under study, and existing evidence raises substantial doubt within the community of treating physicians regarding the net therapeutic benefit of available therapies.
  2. Patients are refractory to the available therapies by virtue of their past treatment history or known medical history.
  3. The study involves adding a new investigational therapy to established effective therapies - established effective therapy + new therapy vs. established effective therapy + placebo.
  4. Patients have determined that the response to the established effective therapies for their condition is unsatisfactory to them.*
  5. Patients have previously refused established effective therapies for their condition.*

* For (4) and (5), 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 they must be documented in a standardized manner.[10]

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 11.11 With respect to research findings:

  1. Institutions and research ethics boards should take necessary measures to ensure that researchers and institutions share research results and publish or otherwise disseminate the analysis and interpretation of research findings in a timely manner without undue restriction.
  2. Any prohibition or undue limitation on the publication or dissemination of scientific findings from clinical trials is ethically unacceptable.
  3. Institutions should develop reasonable written policies regarding acceptable and unacceptable clauses in research contracts relating to confidentiality, publication and access to data.

Application To justify the use 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 may lead to publication bias and thus contribute to a series of harms, 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.

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 that researchers have the necessary access to 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.

Article 11.11 requires (a) that REBs and institutions take reasonable steps to ensure that research findings are published in a timely way, (b) that such publication may be done without undue limitation, and that (c) institutions and REBs adopt reasonable written, publicly available policies with respect to the publication and dissemination of results. Contracts and relevant documents for proposed research should be reviewed for consistency with these policies and principles. Such 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 (for example, 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:
    1. 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 [“Sharing New Information”]);
    2. Are reasonable in terms of any limitations or restrictions on the publication or other dissemination or communication of information; and
    3. Permit researchers to access 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 11.6), 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 11.12 All clinical trials should be registered with a recognized and easily web-accessible public registry.[11]

Application Clinical trial registries are one way to help ensure that negative trial results are widely available. These, in addition to editorial policies,[12] 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.


Endnotes

[5] Part C, Division 5 of the Food and Drug Regulations http://gazetteducanada.gc.ca/partII/2001/20010620/html/sor203-e.html.

[6] See note 1 and Medical Devices Regulations (SOR/98-282). http://laws.justice.gc.ca/en/f-27/sor-98-282/text.html.

[7] 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. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/efficac/e6_e.html.

[8] 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?” http://www.nlm.nih.gov/services/faqctgov.html.

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

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

[11] The CIHR requires that randomized clinical trials be registered with an International Standard Randomized Controlled Trial Number (ISRCTN) at www.controlled-trials.com .

[12] International Committee of Medical Journal Editors, Sponsorship, Authorship and Accountability. http://www.icmje.org/sponsor.htm .