Pan-Canadian study on variations in research ethics boards' reviews of a research project involving placebo use.

• Author: Patenaude, Johane

Introduction

In Canada, since 1996, researchers have abided by ethical norms (2) intended to protect research subjects without unduly hindering the functioning of research projects. To this end, research ethics boards [REBs] have been entrusted with the responsibility for overseeing the protection of research subjects under the terms of recognized norms, including the Tri-Council Policy Statement [TCPS]. (3) One of the objectives of TCPS policy was "to harmonize the ethics review process. The Agencies expect that REBs will benefit from common procedures within a shared ethical framework". (4) Moreover, since 1997, when reviewing clinical trials, REBs have also been able to turn to the Good Clinical Practice [GCP] guidelines. (5)

Since these norms were implemented, the need has emerged to review, modify, and harmonize them. In the fall of 2001, Health Canada and the Canadian Institutes of Health Research [CIHR] set up the National Placebo Working Committee "to help determine the appropriate use of placebos in clinical trials in Canada." (6) One of this group's objectives was to harmonize Good Clinical Practice (E10) (7) [GCP (E10)] with the TCPS, (8) in particular as it related to the diversity of terms employed regarding placebo use in clinical trials.

GCP (E10) allows for the possibility of offering a placebo in these situations:

2.1.3 Ethical Issues.... In cases where an available treatment is known to prevent serious harm, such as death or irreversible morbidity in the study population, it is generally inappropriate to use a placebo control. There are occasional exceptions, however, such as cases in which standard therapy has toxicity so severe that many patients have refused to receive it. In other situations, when there is no serious harm, it is generally considered ethical to ask patients to participate in a placebo-controlled trial, even if they may experience discomfort as a result, provided the setting is noncoercive and patients are fully informed about available therapies and the consequences of delaying treatment. (9) Like GCP (E10), article 7.4 of the TCPS forbids the use of a placebo "when standard therapies or interventions are available for a particular patient population". However, exceptions to this prohibition are identified:

Consistent with clinical equipoise, a placebo may be used as the control treatment in a clinical trial in the following circumstances: (a) There is no standard treatment; (b) Standard therapy has been shown to be no better than placebo; (c) Evidence has arisen creating substantial doubt regarding the net therapeutic advantage of standard therapy; (d) Effective treatment is not available to patients due to cost constraints or short supply (this may only be applied when background conditions of justice prevail within the health care system in question; for example, a placebo-controlled trial is not permissible when effective but costly treatment is made available to the rich but remains unavailable to the poor or uninsured.); (e) In a population of patients who are refractory to standard treatment and for whom no standard second-line treatment exists; (f) Testing add-on treatment to standard therapy when all subjects in the trial receive all treatments that would normally be prescribed; or (g) Patients have provided an informed refusal of standard therapy for a minor condition for which patients commonly refuse treatment and when withholding such therapy will not lead to undue suffering or the possibility of irreversible harm of any magnitude. (10) REBs' ethical review of the acceptability of placebo use is based on two factors: their familiarity with the principal sets of norms for Canada, namely the TCPS and GCP (E10), and how they interpret these norms. At present, the great divergences among REBs' decisions result in the approval in some institutions of research projects for clinical trials involving placebo use that are rejected by others. For researchers, this inconsistency can mean differing requirements to modify a research project from one REB to another, a circumstance that is extremely undesirable in the context of multicentre research. Several studies (11) have assumed the existence of significant divergences in the way REBs apply purportedly shared norms.

Our study is intended to document these potential divergences. Our objective is not to forge a normative approach to revisit the legitimacy of placebo use. Rather, we wish to know whether Canadian REBs proceed homogeneously in their reviews, or whether, on the contrary, divergences exist that make substantive change to existing norms appropriate.

Methodology

Between January 2003 and June 2003, a mock research protocol based on real protocols was submitted to Canadian biomedical REBs that volunteered to participate. This mock protocol was accompanied by a brief questionnaire designed to elicit the decision-making criteria that underlay the REBs' review processes. Participating REBs were requested to follow their usual method of operation in the processing and ethical review of the documents.

The mock protocol presented a double-blind, Phase II multicentre study designed to evaluate the safety and antiviral efficacy against hepatitis B of three doses of the medication under study. The project provided for 85 patients with hepatitis B to be divided into four groups: three groups of 25 patients receiving 10, 20, and 50 mg doses respectively, and one group of ten patients receiving an inert substance. All participants would have previously been receiving treatment with a standard medication, the only one recognized so far for the treatment of hepatitis B. Patients agreeing to...