InfoMail for March 5, 2002

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Commentary by Vera Hassner Sharav

March 5, 2002 

Placebo Trials and Tribulations

FYI

An interesting article by Dr. Charles Weijer addresses thedebate about the ethics of conducting placebo controlled clinical trials inpatients, and the disparate application of regulatory protections in researchinvolving human subjects in Canada.

As he points out, the Declaration of Helsinki and theCanadian Tri-Council Policy Statement (equivalent in authority to the CommonRule in the U.S.) prohibit the use of placebo when a standard accepted treatmentexists. However, as in the U.S., Canadian institutional review boards (REB inCanada) wield enormous discretionary authority, often disregarding theTri-Council Policy Statement.

Dr. Weijer cites the example of a multi site, SSRIantidepressant trial that was rejected by some REBs and approved by others.

The placebo issue is complicated when antidepressant drugsare involved because their efficacy has been brought into question—as has theintegrity of the clinical trials in which they were tested. See, for example,Moncrieff, Joanna. (2001). Are antidepressants overrated? A review ofmethodological problems in antidepressant trials. Journal of Nervous and MentalDisease, 189(5), 288-295. See also, March 1 AHRP InfoMail, re: Brown Universityfinding: http://www.brown.edu/Administration/News_Bureau/2001-02/01-091.html

This poses an interesting dilemma for the manufacturersand purveyers of psychiatric drugs: if antidepressant drugs are not effective,it’s perfectly ethical to test one against placebo. But if the drugs are aseffective as those who prescribe and market them claim, then placebo controltrials are unethical.

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http://www.cma.ca/cmaj/vol-166/issue-5/0603.asp

Canadian Medical Association Journal CMAJ Home

Placebo trials and tribulations By Charles Weijer CMAJ2002;166(5):603-4 [PDF]

The most divisive debate within psychiatric research todayinvolves the proper role of placebo controls in clinical trials that test theeffectiveness of new drugs. Canada’s Tri-Council Policy Statement carefullydefines the conditions under which placebo controls may be used legitimately.1Article 7.4 stipulates that "[t]he use of placebo controls in clinicaltrials is generally unacceptable when standard therapies or interventions areavailable for a particular patient population." This is not anidiosyncratic position. Indeed, the most recent revision of the Declaration ofHelsinki (paragraph 29) similarly prohibits the use of a placebo control wheneffective therapy exists for the medical condition being studied.2 But ethicalguidelines are only as good as their application in practice. Are Canada’sresearchers, research institutions and government abiding by these requirements?

Unfortunately, at least in some cases, it appears that theanswer is no. Consider the following ongoing clinical trial for which I servedas an external reviewer for a local research ethics board (REB). The study is amulticentre, randomized controlled trial comparing a new selective serotoninreuptake inhibitor, paroxetine, and placebo in the treatment of major depressivedisorder. Given the existence of proven, effective treatment for majordepressive disorder,3 the local REB concluded that the use of a placebo controlwas inappropriate and, in accordance with the Tri-Council Policy Statement andparagraph 29 of the Declaration of Helsinki, rejected the study. The local REB’sdecision placed it in the minority of Canadian REBs that had considered the samestudy: 16 other REBs approved the protocol for use by 19 investigators.4

In order to explain this disparity, each of the manylevels of Canada’s regulatory system that is designed to protect researchsubjects must be examined. The first level of protection for research subjectsis provided by the clinical investigator and by each subject’s own physician.When may the responsible physician offer trial enrolment to her or his patient?Clinical equipoise provides the most widely accepted answer to this question.5According to this concept, there must exist at the start of the trial a state ofhonest, professional disagreement in the community of expert clinicians as tothe preferred treatment. Under these circumstances a state of clinical equipoiseis said to exist, and the physician may offer trial enrolment to his or herpatients legitimately.

Placebo controls may be used when there is no availabletreatment for a disorder, or when an adjunctive treatment is being tested, sothat all participants receive the standard treatment.6 Second-generationtreatments, however, must be tested against the best available therapy.6 In thecase of depression, the effectiveness of drug treatment is well established.3 Insuch cases, the scrupulous clinician cannot offer participation in aplacebo-controlled trial ethically to his or her patients.3

The second level of protection for Canada’s researchsubjects is the research institution, be it a university or hospital. Researchinstitutions that receive funds from the Canadian Institutes of Health Research,the Natural Sciences and Engineering Research Council or the Social Sciences andHumanities Research Council must uphold the ethical standards for research laidout in the Tri-Council Policy Statement.1 Lack of compliance may be associatedwith serious consequences: "The Councils will consider funding (orcontinued funding) only to individuals and institutions which certify compliancewith this policy regarding research involving human subjects."1 The REB’srole is to ensure that research meets the standards set by the Policy Statement.

The protocol described earlier was approved by REBs from anumber of Canada’s leading universities and their teaching hospitals. Thissuggests a lack of clarity on a national level regarding the need for adherenceto the Tri-Council Policy Statement. The funding councils themselves may haveperpetuated this state of affairs. To date, the councils have failed to cautionor suspend funding to any institution for failing to adhere to the PolicyStatement.

The third level of protection for Canada’s researchsubjects is the government. All research for the licensing of new drugs,including the protocol described here, is conducted under the aegis of HealthCanada’s Therapeutic Products Directorate (TPD), which was part of theTherapeutic Products Programme (TPP) until April 2001. The TPD does notofficially endorse the Tri-Council Policy statement. Rather, new drug researchmust comply with the guidelines of the International Conference on Harmonization(ICH), an international standard-setting body for the licensing of new drugs.7,8Obviously, any discrepancy between ICH guidelines and the Policy Statement willtranslate into a double standard for Canadian research subjects.

Further problems are posed by the fact that the ICHdocuments give conflicting guidance about the conduct of placebo-controlledtrials. At one point, ICH guidelines take a relatively permissive stance on theuse of placebo controls, allowing them when effective treatment exists as longas subjects are not exposed to the risk of death or permanent morbidity (Section2.1.3).7 At another point, however, ICH guidelines require that "[c]linicaltrials should be conducted in accordance with … the Declaration of Helsinki…" (Section 2.1) and, thus, prohibit the same trials that other ICHguidelines permit.8 Clearly, this regulatory conflict must be resolved.

The TPD relies on arms-length review by the REBs to ensurethat research is conducted ethically. In some cases, these REBs are notaffiliated with any institution (and as such are not bound by the Tri-CouncilPolicy Statement) and charge for ethics review. These "for profit"REBs are neither accredited by government nor are they subject to governmentoversight despite the obvious conflict of interest posed by "forprofit" ethics review.9 At least 2 of the REBs that reviewed the protocoldescribed here are "for-profit" REBs.4

The TPD must itself avoid the appearance of conflict ofinterest. After the local REB rejected the protocol under discussion, itreceived a copy of a letter from the then TPP written to a project manager at aresearch centre and forwarded by a researcher at the same centre that stated thefollowing:

We believe judicious use of placebo controlled trials toestablish unequivocally the efficacy of a new drug, together with acomprehensive risk management protocol and appropriate informed consent, isethical. To use an inconclusive trial design when a conclusive trial design ispossible, is unethical.10 REB review must be independent and it was, therefore,inherently improper for the TPP to tell an REB what is ethical. The facts ofthis case are problematic for 2 reasons. First, whether a particular practice isethical or not is a matter set forth in national and international guidelines tobe interpreted by REBs. The TPP should not have promulgated idiosyncratic views.Second, though the letter from the TPP made its way to the REB indirectly andthe TPP may not have been aware of the investigator’s intention to so distributeit, the TPP ought to have made it clear that this action by the investigator wasinappropriate and should have reassured the REB that the TPP had no intention ofinterfering with the REB review process. I raised this issue in a letter to theTPP’s then Acting Director General, Dr. Robert Peterson, dated Sept. 27, 2000.11I wrote, "For the TPP to attempt to influence the decision of a particularREB, or for it to even appear to do so, is a violation of proper procedure, andundermines the REB’s role as a societal mechanism to protect Canadians inresearch."11 To date, I have not received a reply.

The placebo-controlled trial is a litmus test for theadequacy of Canada’s regulatory system for research. The case discussed herereveals the need for change at all levels. Clinician investigators must reaffirmtheir commitment first and foremost to the well-being of their patients. REBsmust follow the ethical guidance given by the Tri-Council Policy Statement. Thefunding councils must enforce these standards. Finally, the TPD must formallyadopt the Policy Statement to ensure that all Canadians who give of themselvesto further research are afforded the highest level of protection.

This article has been peer reviewed.

Dr. Weijer is Associate Professor of Medicine, Departmentof Bioethics, Dalhousie University, Halifax, NS.

Competing interests: None declared.

Acknowledgements: I am grateful to Mr. Anthony Belardo and2 anonymous reviewers for their helpful comments on a draft version of thispaper.

Professor Weijer’s research is supported by a CIHR NewInvestigator Award and Operating Grant, as well as a Dalhousie UniversityClinical Research Scholar Award.

Correspondence to: Dr. Charles Weijer, Associate Professorof Medicine, Department of Bioethics, Dalhousie University, 5849 UniversityAve., Halifax NS B3H 4H7; fax 902 494-3865; charles.weijer@dal.ca

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The World Medical Association recently offered a "Note of clarification onparagraph 29" that seems to allow for limited use of placebo controls when"compelling and scientifically sound methodological reasons" exist orwhen subjects will not be placed at "any additional risk of serious orirreversible harm." The interpretation of this development is hindered bythe fact that these "clarifications" of paragraph 29 in factcontradict it. Nonetheless, Dr. Delon Human, Secretary General of the WMA, seemsto suggest that research on common psychiatric conditions would not fall intothese exceptions. According to Human, the exceptional use of placebo controls isonly acceptable "where research is done to find more effective treatmentsfor a minor condition, such as baldness or allergic rhinitis. For this type ofclinical situation there would be no additional risk or irreversible harm forthe control group, who would be receiving placebo (no treatment)" [emphasisadded] (www.wma.net/e/press.html [accessed 2002 Feb 4]). The reader should notethat all the events discussed in this commentary occurred before the note ofclarification was published. This article arose from a solicited manuscriptsubmitted to the Journal of Addiction and Mental Health (JAMH), a publication ofthe Centre for Addiction and Mental Health at the University of Toronto, in May2000. The author received an extensively edited and revised version of the paperfor approval. In Dr. Weijer’s view, the alterations so fundamentally altered hiscriticism of placebo-controlled trials in psychiatric research that he feltcompelled to withdraw the manuscript. CMAJ became aware of the manuscript whenthese events were reported in the Globe and Mail last year (2001 May 1; SectA:6). We invited Dr. Weijer to submit the paper to us. An edited versionapproved by the author is published here.

——————————————————————————————References 1. Canadian Institutes of Health, Natural Sciences and EngineeringResearch Council of Canada, and Social Sciences and Humanities Research Councilof Canada. Tri-council policy statement: ethical conduct for research involvinghumans. Updated 2000 Nov 21. (accessed 2002 Jan 23). 2. World MedicalAssociation. Declaration of Helsinki. 2000. (accessed 2002 Jan 23). 3. WhooleyMA, Simon GE. Managing depression in medical outpatients. N Engl J Med2000;343(26):1942-50. [MEDLINE] 4. Email correspondence from Roopa Ganapathy,Astra Zeneca, to Helen Begin, St. Joseph’s Health Care, Hamilton, Ont., reapproval given by ethics boards. 2001 June 18. 5. Freedman B. Equipoise and theethics of clinical research. N Engl J Med 1987;317:141-5. [MEDLINE] 6. Weijer C.Placebo-controlled trials in schizophrenia: Are they ethical? Are theynecessary? Schizophr Res 1999;35:211-8. [MEDLINE] 7. International Conference onHarmonisation of Technical Requirements for Registration of Pharmaceuticals forHuman Use. ICH Harmonised Tripartite guideline: choice of control group andrelated issues in clinical trials (E10). 2000. (accessed 2002 Jan 23). 8.International Conference on Harmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human Use. ICH Harmonised Tripartiteguideline: guideline for good clinical practice (E6). 1996. (accessed 2002 Jan23). 9. Lemmens T, Freedman B. Ethics review for sale? Conflict of interest andcommercial research review boards. Milbank Q 2000;78:547-84. [MEDLINE] 10.Letter from Dr. Siddiki Mithani, Manager, Clinical Trials & Special AccessProgramme, Health Canada, Ottawa, to Ms. Lorelei Audas, Project Manager, QueenElizabeth II Health Sciences Centre, Halifax, re placebo-controlled trials. 2000Aug 15. 11. Letter from Dr. Charles Weijer, Dalhousie University, Halifax, toDr. Robert Peterson, Acting Director General, Therapeutic Products Programme (TPP),Health Canada, Ottawa, re TTP policy concerning placebo-controlled trials. 2000Sept 27.

Copyright 2002 Canadian Medical Association or itslicensors

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