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Recommendations – Researchers’ Continuing Duty to Share New Information in Clinical Trials; Confidentiality Clauses in Ethics Review; Continuing Consent Duties and REB Purpose and Functions

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Submitted by the

Working Committee on Clinical Trials Information: a Working Committee of the Interagency Advisory Panel on Research Ethics (PRE)

Members

  • Pierre Deschamps
  • Anne Dooley
  • Barry Hoffmaster
  • Peter Venner

Secretariat on Research Ethics

  • Derek Jones (up to July 2007)
  • Mary Fraser Valiquette (as of September 2007)

February 2008

The content and views expressed in this document are those of members of this committee, and do not necessarily reflect those of the Interagency Advisory Panel or Secretariat on Research Ethics.

The Panel and Secretariat welcome your comments: reports@pre.ethics.gc.ca


TABLE OF CONTENTS


Purpose

The following provides recommendations for change to the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS).

Background

In 1993, Dr. Nancy F. Olivieri was working as a hematologist and researcher at the Hospital for Sick Children and professor of medicine at the University of Toronto when she entered into multiyear clinical trial agreements with the pharmaceutical company Apotex Inc. to conduct research on deferiprone, a potential new drug to counteract iron overload in thalassemic1patients.

After a couple of years, Dr. Olivieri had concerns about the efficacy and safety of the drug. When she attempted to inform her patients of these possible side effects, she was reminded of the agreements she had signed that indicated that all findings and data were to remain confidential and were the property of Apotex without expressed permission for disclosure, and she was advised any violations would be legally pursued.

A cascade of disputes followed.

In October 2001, the Canadian Association of University Teachers (CAUT) published a report in which a number of recommendations were made. Some recommendations were directed towards the Agencies, in particular to address non-disclosure clauses in contracts and agreements in the TCPS. In May 2003, the Agencies directed the Interagency Advisory Panel on Research Ethics (PRE) through a Presidential Reference (Appendix A) to develop proposals for change in the TCPS. PRE struck the Working Committee.

The Duty to Share Information: A Foundation for the Recommendations

The following recommendations generally address related responsibilities aimed at more explicitly incorporating into the TCPS modern standards that bear on the sharing of new information that arises in clinical trials.

The recommendations are based on a review of the leading Olivieri reports2, pertinent national and international documents, and the interdisciplinary literature relevant to the Presidents’ Reference.

Consistent with the Presidents’ Reference, the Committee gave priority attention to Recommendations 1 and 25 of the CAUT Olivieri Report but looked at and addressed others as well (Appendix B). The Committee agrees with the general tenor of the CAUT recommendations. It finds that they address an ethical issue central to most of the reports that the Olivieri saga has inspired: namely, the researcher’s timely sharing of new information that arises in the clinical trial process.

The Olivieri incident raises a general question: Does/should an investigator have a duty to share new information that arises in the course of a clinical trial, with trial participants, REBs or related entities? Whether it is grounded on a paramount concern for patient safety, autonomy, informed consent, and associated principles of doing no harm, or a researcher’s fiduciary duty, most reports and much of the literature agree that investigators have a duty to share new risk information on a timely basis. The Committee shares this view.

Technical dialogue and targeted public consultations on the draft working recommendations generally revealed strong support for their general direction and underlying principles. They underscored some ambiguities, questions and sub-issues. As a result, the recommendations have benefited from clarification and strengthening. Most issues raised in the technical and targeted consultations have been incorporated into the recommendations. A summary of some leading clarifications, revisions or issues follows. The numbers refer to line items in the recommendations below.

  1. Contract Review: Indicate that if a university contract research officer reviews clinical trial contracts and channels the results to the REB, he/she does so with the special ethics duties of the REB.
  2. Suppression: Endorse a multi-faceted approach to non-suppression of data.
  3. Researcher/REB Conflict: What happens if a researcher and an REB disagree over the need to share new information with participants in the clinical trial? Response: I ncorporate reference to REB appeals, and insert a precautionary principle to guide conflicted decision-making.
  4. Reporting to Regulatory Authorities: Should theTCPS impose a new researcher and/or REB duty to report adverse events to regulatory authorities? The recommendations include two options to address this in a new article.
  5. DSMBs: Recognize the role of independent data safety monitoring boards (DSMB) in the objective interpretation and monitoring of new information.
  6. Harms: Summarize the harms that may flow from suppression of research results.
  7. What length of time should be indicated as a reasonable period of delay for sponsors’ review of data, publications drafts or patent issues for university policies? Response: Amend the example of a reasonable period of delay from 6-12 months in the initial draft to 3-6 months in the revised draft. The amendment is based on new institutional policies in Canada , persuasive trends and harmonization with policies in the United States , and the literature, as noted in Appendix C below.
  8. Consent: Amend art. 2.4 of the TCPS on informed consent to include a researcher’s duty to disclose measures to be taken to publish and disseminate research results.
  9. Conflict of Interest: Beyond amending article 7.3, the Committee agrees that t he TCPS should give further explicit direction to REBs and institutions to identify and manage conflicts of interests. Accordingly, the Working Committee urges, as a matter of priority, the PRE to undertake a review and update of chapter 4 of the TCPS to address modern conflict of interest (COI) matters.
  10. Purpose of REB Review: In underlining the role of REBs in protecting participants’ rights, safety and welfare, clarify that the protective function arises in a diversity of research contexts, ranging from biomedical to critical social science research.
  11. Broader Research Suppression: Recommendation: The dissemination of research data and/or results should be recognized as an important university issue beyond clinical trials.
  12. Health Canada Recommendation: Health Canada norms regarding a researcher’s duty to share information with the REB would benefit from clarification.
  13. Adverse Events: PRE should signal the need for urgent action to address the flood of paperwork and uncertainty surrounding adverse events reports to REBs.
  14. Ethical Principle of Dissemination of Research Results: The Committee has proposed text to include this principle in the TCPS Ethics Framework.

Overview of Recommendations

The Committee debated whether the TCPS should specify an investigator’s duty to share timely information that arises in a clinical trial. As Appendix C indicates, the existing TCPS does refer to an investigator’s responsibilities to share information as part of continuing consent and clinical trials duties. However, it may not provide optimal guidance, because it sketches responsibilities without clarity and specificity. Indeed, the Committee finds that the TCPS lacks the kind of explicit standard and specificity of the 1987 Guidelines of the former Medical Research Council of Canada, and lacks the precision and details found in other leading national and international documents.

To respond to these limitations and recommendations 1 and 25 of the CAUT Report, the Committee proposes recommendations for four related sections of the TCPS. The working recommendations are intended to clarify the investigator’s duty to share timely information in clinical trials, by clarifying the investigator’s continuing consent duties, by specifying the REB role in reviewing contracts that unduly restrict the sharing of information, and by clarifying one of the REB’s basic functions in initial and ongoing ethics review of clinical trials.

  • Section 7: Clinical Trials: To make explicit a researcher’s ongoing duty to share new risk/benefit information from the clinical trial process with REBs and/or participants on a timely basis. The urgency of the timing should be proportionate to the potential seriousness of the risk raised by the information.
  • Section 7: Clinical Trials: To make explicit the need to review confidentiality clauses in contracts between investigators and industry, as part of research ethics review, and to do so on the basis of reasonable written institutional policies about such clauses and publication bans.
  • Section 2: Informed Consent: To make explicit a researcher’s continuing consent duties and participants’ reasonable expectations that research results will normally be published or otherwise publicly disseminated.
  • Section 1: REB Purpose, Review and Ongoing Review: To make more precise the REB’s purpose and its duties to manage new information as part of ethics review, and to make these duties an explicit part of ongoing REB review.
  • Ethical Framework : To make explicit reference to the principle of public dissemination of the results of research, as part of the values of science, scholarship and accountability to participants, peers and society.

The bulk of the proposed amendments focus on the Clinical Trials section of the TCPS with complementary amendments to the Free and Informed Consent and Ethics Review sections.

RECOMMENDATIONS FOR SECTION 7: CLINICAL TRIALS

Nota: Underlined Text = New Recommended Text;

  1. Clinical Equipoise
  2. Phases of Pharmaceutical Research
  3. Budgets, Contracts and Agreements
  4. Multicentre Clinical TrialsD
  5. Placebo-Controlled Studies
  6. Sharing New Information
  7. Analysis and Dissemination of the Data and Results of Clinical Trials

C. Budgets, Contracts and Agreements

Article 7.3

REBs shall ensure that budgets, contracts and investigator agreementsregarding clinical trials are properly examined to assure that ethical duties concerning conflict of interest are respected.

Budgets for clinical trials are usually calculated on per capita costs, that is, the sponsor pays the researcher a fixed sum for each research subject recruited, based on the length of time that the subject is on the study and the tests required by the trial. Unreasonable payments or undue inducements raise ethical concerns because of the potential to place the researcher in a conflict between maximizing economic remuneration and serving the best health interests of subject-patients, especially if the researcher also holds a therapeutic or clinical or other fiduciary relationship with the subjects. Disclosure of the kinds and amounts of the payments, and other budgetary details, will assist the REB, or other delegated body within the institution, to assess potential conflicts of interest, and may also assist the researcher in resolving them. As a general guide, payments should be comparable to the physician’s or researcher’s usual professional fee for the provision of comparable services. When trials take place within a public institution, such as a hospital or a long-term care facility, recovery of utilization costs for institutional and other resources (such as radiological and diagnostic services) should be considered essential, and should be in addition to any overhead charge stipulated by the institution.

The independent review of the investigator-industry contract should be undertaken by a duly composed REB, or by or under the auspices of another competent institutional authority that shares the results with the REB, as an integral part of the ethics review process. If done under the latter process, the review of contracts should be conducted (i) in a manner that conforms to the special ethical duties, mandate and purposes of REB review, and (ii) in consultation with the REB when necessary.

F. Sharing New Information

Article 7.5

(a) If, in the course of a trial, new information arises that may be relevant to participants’ free, informed and continuing consent to participation in the research, investigators should share the information, in a timely manner, with the REB and participants. The urgency of the timing should be commensurate with the potential seriousness of the risk raised by the information. In some circumstances, new information that arises after a trial may also need to be shared.

Article 7.5 outlines an investigator’s continuing duty to share new and relevant information from the clinical trial process with the REB and research participants. “New information” is information that may affect the willingness of a participant to continue in the trial, or that is otherwise relevant to participants’ free, informed, and continuing consent. (See articles 2.1, 2.4.f) To understand its particular relevance, the information needs to be considered from a participant-centered perspective. This sharing may also include new information that arises outside the trial when that information is relevant to the participant’s informed and continuing participation. “New information” thus covers a range of matters that includes, but is not limited to, the following:

  • changes to the research protocol;
  • new risk information, such as adverse events or safety data;
  • new information which shows benefits of one intervention over another;
  • new findings, including important non-trial information;
  • unanticipated problems involving therapeutic efficacy or recruitment issues.

Duties to report such new information to the REB lies with the sponsor and the investigator. The REB’s interdisciplinary advice should help structure the breadth and timing of sharing the information with participants. The more serious and urgent the information, the more promptly it should be shared.

In those circumstances when significant risk/benefit information arises after the trial, and which may well affect the well-being or safety of former participants, the investigator should share the information with the REB. The REB and investigator should consider whether, given the nature and urgency of the information, a reasonable former participant would, under the circumstances, consider the information relevant to his or her well-being and informed choices. If so, then reasonable steps should be taken to share the information in a meaningful and timely manner with former participants.

In the event that a researcher and REB were to disagree over the sharing of new information with participants, attempts to resolve the disagreement should involve recourse to the REB appeals process (see articles 1.10-1.11, above). The REB process should be cognizant of, and sensitive to, the urgency of the matter. Attempts to resolve disagreement about the scope and reach of disclosure should be guided by a paramount principle of protecting the safety and welfare of trial participants.

(b)

Nota: This proposed sub-article 7.5(b) outlines two options regarding a TCPS duty to share new clinical trial information with regulatory authorities. Both options address researcher and sponsor disagreement over reporting the new information to relevant regulatory authorities. Option A recognizes that the duty may arise, as a matter of professional conscience, given a number of factors. Option B outlines a special duty to report the information when a sponsor refuses to do so.

Option A (Good Conscience Clause): In exceptional instances of intractable disagreement, where all other reasonable measures have been exhausted, the principle of protecting the safety and welfare of patients should further guide researchers and REBs about the lengths to which they should go to share new, relevant and important information. If, in good conscience, a researcher or REB, exercising independent and professional judgment, were to determine that sharing information likely would prevent significant harms to research participants, then the researcher or REB may reasonably conclude that there is an ethical duty to do so, despite objections. The scope of the duty—what new information should be disclosed, when it should be disclosed, and to whom it should be disclosed—should be proportionate to the seriousness and urgency of the potential harm.

Option A addresses exceptional circumstances that might arise, for example, if a research sponsor were to refuse to report to regulatory authorities new and significant information. In such circumstances, should the researcher or REB report the new information to regulatory authorities? In their deliberations on such matters, researchers and REBs should consider such factors as: whether the information is novel and significant or duplicative; the objective quality and nature of the information; the direct relevance of the information to participants’ safety, welfare and continuing consent; whether relevant entities (sponsors, data safety monitoring boards, and REBs) have been afforded a reasonable opportunity to discharge their duties with respect to the information, and relevant regulatory duties.

Option B (Special Duty to Report to Regulatory Authorities): In exceptional circumstances, beyond those required under existing regulations, the ethical principles of avoiding harm and respecting participants’ informed consent impose on researchers or REBs a special duty to share new safety-efficacy information with regulatory authorities. When sponsors refuse to report new and significant information that is relevant to the safety and welfare of participants, then researchers and/or REBs have a duty to do so. The more objectively relevant and urgent the information, the stronger the duty. Before REBs or researchers act on such duties, they should afford sponsors a reasonable opportunity to report the information to the appropriate regulatory authorities.

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

Article 7.6

(a) Institutions and REBs should develop reasonable written policies regarding confidentiality clauses and publication clauses in research contracts between investigators and industry.

A reasonable institutional policy should:

  1. require that confidentiality and publication clauses be submitted to the responsible authority (e.g. REB, research administration) for a determination of their adherence to the written policy of the institution;
  2. require that the results of the review be shared with the REB as an integral part of the ethics review process.
  3. provide that all confidentiality and publication clauses:
    • be consistent with the investigator’s duty to share new information from the clinical trial setting with REBs and trial participants in a timely manner, under articles 7.5 and 2.1(a);
    • be reasonable in terms of any limitations or restrictions on the dissemination or communication of information;
    • address data sharing/ownership; and
    • address publication rights and authorship of the initial and subsequent reports in multicentre trials.

(b) Absolute bans on the dissemination of scientific information from clinical trials are ethically unacceptable. Confidentiality clauses or publication limitations that impose unduly broad limitations on either the content of the scientific information that may be disseminated or on the timing of that dissemination are presumed to be ethically unacceptable.

In many clinical trials, the sponsors have contractual rights to the initial analysis and interpretation of the resultant data. These provisions are typically found in industry-investigator contracts3 that may not always be part of an REB review. To incorporate the analysis of these contractual provisions into modern interdisciplinary ethics review, articles 7.6(b) and 7.3 require (a) that institutions and REBs adopt reasonable written policies regarding such provisions; and (b) that contracts and relevant documents for proposed research be independently reviewed for their consistency with these policies and principles.

Article 7.6 is intended to ensure that any such contractual rights be reasonably balanced against the investigator’s ethical and legal obligations to participants in trials and the scientific and public good in the dissemination of the data and results of research. For example, where stopping rules are in place, monitoring of the interim results must be done independently, for example, by an independent data safety monitoring board (DSMB). Properly composed and duly accountable DSMBs play an important role in ensuring independent overall analysis of clinical trial data and complement the role of the REB.4It should also be remembered that, with a stopping rule in place, long-term positive or negative effects might be masked by short-term harms or benefits.

Measures necessary for the effective discharge ofthe duties of researchersand institutions to share new information and disseminate the analysis and interpretation of their results to the research community may need to be undertaken. Based on the principles of scientific process, respect for participant expectations and the protection of the public good, research scientists and institutions have an ethical responsibility to make reasonable efforts to disseminate publicly the results of research in a timely manner.5Unfortunately, however, negative results and outcomes of research frequently are not published or disseminated. Silence on such results may lead to data suppression and publication bias6 and thus contribute to a series of harms: misinformed decision-making based on a mis-weighing of risks and benefits, inappropriate and potentially harmful clinical practices and injury to health, needless and wasteful duplication of research interventions on participants, fraud or deception in the clinical trials process and erosion of public trust and accountability in research. Research journalists, journal editors, members of editorial peer review boards, sponsors and regulators should continue to address this as an issue of scientific and ethical urgency . Clinical trials registries,7 editorial policies,8 ethical policy reforms, and revised national and institutional ethics policies all contribute to a multi-faceted approach to combating the ills of non-disclosure and the suppression of data in clinical research.

In the review process, the onus to justify significant restrictions on dissemination should lie on the researcher and, when appropriate, the sponsor. The reasonableness of the restrictions on either the content or timing of dissemination should be measured against the standards of the written institutional policies. For example,some existing university policies deem publication restrictions that exceed a reasonable time limit, e.g ., 3-6 months after the close of the trial, to be unacceptable. Such written institutional policies should also address restrictions on the dissemination of particular kinds of information, such as information that may be considered proprietary/trade secret and information that participants would reasonably consider relevant to their welfare or safety. Consistent with Articles 2.1 and 7.5, restrictions on the latter are seldom, if ever, justified.

RECOMMENDATIONS FOR SECTION 2: FREE AND INFORMED CONSENT

Nota: To complement the working recommendations on clinical trials, the underlined text, below, proposes clarifying and bringing technical amendments to the Free and Informed Consent section of the TCPS. They are intended to make explicit what is implied and dispersed throughout the existing articles and commentary: namely, a researcher’s ongoing duty throughout the research project to share information relevant to a participant’s informed participation in the research. The amendments would affect the title, add a new clause to article 2.4, and insert new text in articles (2.1 and 2.4) of the section.

A. Requirement for Free, Informed and Continuing Consent

Article 2.1

Free and informed consent encompasses a process that begins with a researcher’s initial contact with participants and that continues through to the end and sometimes beyond the research project. Throughout the process, researchers have a continuing duty to provide participants and REBs information relevant to the participant’s free and informed consent to participate in the research.

(a) Research governed by this Policy (see Article 1.1) may begin only if:

(1) prospective subjects, or authorized third parties, have been given the opportunity to give free and informed consent about participation, and

(2) their free and informed consent has been given and is maintained throughout their participation in the research. Articles 2.1(c), 2.3 and 2.8 provide exceptions to Article 2.1(a).

(b) Evidence of free and informed consent…

As used in this Policy, the process of free and informed consent refers to the dialogue, information sharing and general process through which prospective subjects choose to participate in research involving themselves.

Article 2.1(a) states the requirement in both ethics and law: to protect and promote human dignity. Ethical research involving humans requires free and informed consent. As elaborated more fully below, free and informed consent is exercised by an authorized third party for those who lack legal competence.…

Article 2.4

Researchers shall provide, to prospective subjects or authorized third parties, full and frank disclosure of all information relevant to free and informed consent. As part of a researcher’s continuing duties throughout the free and informed consent process, the researcher must ensure that prospective subjects are given adequate opportunities to discuss and contemplate their participation. Subject to the exception in Article 2.1(c), at the commencement of the free and informed consent process, researchers or their qualified designated representatives shall provide prospective subjects with the following:

  1. Information that the individual is being invited to participate in a research project;
  2. A comprehensible statement of the research purpose, the identity of the researcher, the expected duration and nature of participation, and a description of research procedures;
  3. A comprehensible description of reasonably foreseeable harms and benefits that may arise from research participation, as well as the likely consequences of non-action, particularly in research related to treatment, or where invasive methodologies are involved, or where there is a potential for physical or psychological harm;
  4. An assurance that prospective subjects are free not to participate, have the right to withdraw at any time without prejudice to pre-existing entitlements, and will be given continuing and meaningful opportunities for deciding whether or not to continue to participate; and
  5. The possibility of commercialization of research findings, and the presence of any apparent or actual or potential conflict of interest on the part of researchers, their institutions or sponsors.

The measures to be undertaken to publish or otherwise make publicly available the results of the research.

Excerpts from Existing Commentary to Article 2.4

Under the normal process of obtaining written consent, the prospective subject should be given a copy of the consent form and any relevant written information. The consent of the participants shall not be conditional upon, or include any statement to the effect that, by consenting, subjects waive any legal rights.

In light of (b) and (c), REBs may require researchers to provide prospective subjects with additional information, such as that detailed in Table 1 below.

…Article 2.4(d) also requires that researchers specifically ascertain continuing consent from subjects on the basis of new information.

Article 2.4(f) requires that researchers provide a reasonable explanation of the measures to be undertaken to publish and otherwise disseminate the results of the research. Beyond the ethical obligation to do so in such areas as clinical trials (see articles 7.6(a) and 7.6(b) below), this requirement is grounded on the reasonable expectation of participants in research that the results will be published or otherwise disseminated in the public domain to advance societal knowledge.

Table 1: Additional information that may be required for some projects

  1. An assurance that new information will be provided to the subjects in a timely manner whenever such information is relevant to a subject’s decision to continue or withdraw from participation;
  2. The identity of the qualified designated representative who can explain scientific or scholarly aspects of the research;
  3. Information on the appropriate resources outside the research team to contact regarding possible ethical issues in the research;
  4. An indication as to who will have access to information collected on the identity of subjects, descriptions of how confidentiality will be protected, and anticipated uses of data;
  5. An explanation of the responsibilities of the subject;
  6. Information on the circumstances under which the researcher may terminate the subject’s participation in the research;
  7. Information on any costs, payments, reimbursement for expenses or compensation for injury;
  8. In the case of randomized trials, the probability of assignment to each option;
  9. For research on biomedical procedures, including health care interventions: information about (a) foregoing alternative procedures that might be advantageous to the subject, (b) which aspects of the research involve the use of procedures that are not generally recognized or accepted; and (c) particularly in trials of therapeutic interventions, the care provided if the potential subject decides not to consent to participation in the study;
  10. How the subjects will be informed of the results of the research.

RECOMMENDATIONS FOR SECTION 1: ETHICS REVIEW

Nota: The underlined language below recommends amendments to clarify and make explicit the fundamental purpose and function of REB review. The amendment would address Olivieri matters, and harmonize the TCPS with leading international standards. It is also recommended that researchers’ continuing consent and information sharing duties be cross-referenced with the REB’s duties concerning ongoing review (art. 1.13).

B1. Purpose and Authority of the REB

Article 1.2

(a) The primary purpose of REB review is to protect the dignity, well-being, rights and safety of research participants.

(b) The institution in which research involving human subjects is carried out shall mandate the REB to approve, reject, propose modifications to, or terminate any proposed or ongoing research involving human subjects which is conducted within, or by members of, the institution, using the considerations set forth in this Policy as the minimum standard.

Article 1.2(a) indicates the primary purpose of human research ethics review. Respecting the dignity and protecting the rights of participants reflect fundamental values in research ethics. Those values will sometimes conflict with others, such as the societal good that may derive from research. The value conflict is endemic in REB review, as recognized in the ethics framework of the TCPS. Under the framework, the functions of REB review need to be exercised and applied thoughtfully to diverse research contexts. Those contexts range from the safety risks posed by health science research to critical social sciences research the purpose of which is to critique those under study.

F. Review Procedures for Ongoing Research

Article 1.13
  1. Ongoing research shall be subject to continuing ethics review. The rigour of the review should be in accordance with a proportionate approach to ethics assessment.
  2. As part of each research proposal submitted for REB review, the researcher shall propose to the REB the continuing review process deemed appropriate for that project.
  3. Normally, continuing review should consist of at least the submission of a succinct annual status report to the REB. The REB shall be promptly notified when the project concludes.

As part of continuing ethics review , researchers should fulfill their responsibilities for continuing consent and the reporting of new information that arises in clinical trials, consistent with Articles 2.1 and 7.5.

Beyond scrutinizing reports, the REB itself should not normally carry out the continuing ethics review, except in specific cases where the REB believes that it is best suited to intervene. For research posing significant risks, the REB should receive reports on the progress of the project at intervals to be predetermined. These reports should include an assessment of how closely the researcher and the research team have complied with the ethical safeguards initially proposed.

In accordance with the principle of proportionate review, research that exposes subjects to minimal risk or less requires only a minimal review process. The continuing review of research exceeding the threshold of minimal risk that is referred to in Article 1.13 (b), in addition to the annual review (Article 1.13 (c)) might include:

  • a formal review of the free and informed consent process,
  • the establishment of a safety monitoring committee,
  • a periodic review by a third party of the documents generated by the study,
  • a review of reports of adverse events,
  • a review of patients' charts, or
  • a random audit of the free and informed consent process.

Other models of continuing ethics review may be designed by researchers and REBs to fit particular circumstances.

The process of a continuing ethics review should be understood as a collective responsibility, to be carried out with a common interest in maintaining the highest ethical and scientific standards. Research institutions should strive to educate researchers on the process of continuing ethics review through workshops, seminars and other educational opportunities.

Recommendations for the TCPS Ethics Framework: Ethical Responsibilities and the Dissemination of Research Results

Nota: To complement the proposed amendments to article 2.4(f) and existing references in the commentary to article 7.6(a), regarding an ethical responsibility to make publicly available the results of research in a timely manner, an amendment is offered for an addition to the TCPS Ethics Framework. The amendment proposes to incorporate reference to the ethical principle of dissemination of the results of research, as part of the public values of science, scholarship and accountability. (See also the Committee’s commentary following the proposed textual insert).

TCPS ETHICS FRAMEWORK

Academic Freedoms and Responsibilities

Researchers enjoy, and should continue to enjoy, important freedoms and privileges. To secure the maximum benefits from research, society needs to ensure that researchers have certain freedoms. It is for this reason that researchers and their academic institutions uphold the principles of academic freedom and the independence of the higher education research community. These freedoms include freedom of inquiry and the right to disseminate the results thereof, freedom to challenge conventional thought, freedom from institutional censorship, and the privilege of conducting research on human subjects with public monies, trust and support. However, researchers and institutions also recognize that with freedom comes responsibility, including the responsibility to ensure that research involving human subjects meets high scientific and ethical standards. The commitment of researchers and institutions to the advancement of knowledge through scientific and scholarly inquiry entails duties of honest and thoughtful inquiry, rigorous analysis and accountability to participants, peers and society. That broad accountability includes a responsibility to make reasonable efforts to disseminate or otherwise make publicly available the results of research, in a manner respectful of disciplinary and cultural contexts.

Peer review of research proposals, research findings and their interpretation contribute to accountability, both to colleagues and to society. Review of the ethics of research helps ensure a more general accountability to society. Accountability, moreover, requires that the whole process should always be open to critical assessment and scientific and public debate.


  1. Thalassemia is a form of anemia which in its severe form requires a patient to undergo repeated blood transfusions. However, blood transfusions can cause excess iron stores in the body, which in turn can be harmful. [back]
  2. Naimark et al. Clinical Trials of L1 (Deferiprone) at The Hospital for Sick Children: A Review of Facts and Circumstances, Dec. 1998 (Naimark Report); Hospital for Sick Children. Research Policy Review Task Force Report, Dec. 1999; Thompson, Baird & Downie . Report of the Committee of Inquiry on the Case Involving Dr. Nancy Olivieri, The Hospital for Sick Children, the University of Toronto, and Apotex Inc. Canadian Association of University Teachers (CAUT), Oct 2001 ; A Commentary by Arnold Naimark, Bartha Knoppers and Frederick Lowy on the CAUT Report , Dec. 2001 (Naimark Supplement); Thompson, Baird & Downie. Supplement to the Report of the Committee of Inquiry on the Case Involving Dr. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Inc. CAUT, Jan. 2002. (Thompson et al. Supplement). [back]
  3. Steinbrook R. Gag Clauses in Clinical-Trial Agreements. NEJM, 2005;352:2160-62; Mello MM, Clarridge BR, Studdert DM. Academic Medical Centers’ Standards for Clinical Trial Agreements with Industry, NEJM, 2005; 352:2202-10. Schulman KA, Seils DM, Timbie JW et al. A National Survey of Provisions in Clinical-Trial Agreements between Medical Schools and Industry Sponsors. NEJM, 2002; 347:1371-1375. Editorial. The Controlling Interests of Research. CMAJ 2002; 167 (11). [back]
  4. Council of International Organizations of Medical Sciences (CIOMS), Management of Safety Information from Clinical Trials: Report of CIOMS Working Group VI. CIOMS: Geneva , 2005; 265-27; Slutsky AS, Lavery JV. Data Safety and Monitoring Boards. NEJM, 2004; 350 (11):1143-7. [back]
  5. See article 2.4f, and accompanying commentary, above. Accord: Council of Europe , Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research, 2005, art. 28. [back]
  6. See, e.g., Chan AW, Krleza-Jeric K, Schmid I et al. Outcome Reporting Bias in Randomized Trials Funded by the Canadian Institutes of Health Research . CMAJ, 2004; 171(7):735-740. [back]
  7. See, e.g., International Committee of Medical Journal Editors, Is this Clinical Trial Fully Registered? — A Statement from the International Committee of Medical Journal Editors, NEJM, 2005; 362:2436-2439; Krleza-Jeric K, Chan AW, Dickersin K, Sim I et al. Principles for International Registration of Protocol Information and Results from Human Trials of Health Related Interventions: Ottawa Statement (Part I). BMJ 2005; 330:956-958 . Moher D, Bernstein A. Registering CIHR-funded Randomized Controlled Trials: A Global Public Good.CMAJ, 2004; 171:750-751; Eu ropean Union, Clinical Trials Directive, 2001, art. 11; www.clinicaltrials.gov. [back]
  8. International Committee of Medical Journal Editors (ICMJE), Statement on Conflicts of Interest, 2001. [back]