Research governance lessons from the National Placebo Initiative.

• Author: Sampson, Heather

1. Introduction

   For at least the last two decades, Canada has been an international leader in research ethics. Canadian scholars have written seminal articles that now fill standard texts in the field. For example, in the authoritative collection Ethical and Regulatory Aspects of Clinical Research, fully eighteen of 86 articles included in the volume were authored in Canada. (1) In the realm of research ethics policy, Canada's contributions are also many. The Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2) (TCPS), introduced a decade ago and currently under revision, is widely admired for its scope and substance. More recently the Canadian Institutes of Health Research Guidelines for Research Involving Aboriginal People (3) attracted considerable interest as a potential roadmap for effective research partnerships between aboriginal communities and researchers.

   The National Placebo Initiative (NPI) was established in 2002 with a mandate to broker consistent guidance on the use of placebos in clinical research in Canada. Although the recommendations set forth in its Final Report (2004) (4) have the potential to renew Canada's role as an international leader in research ethics, they have yet to be acted upon by the Canadian Institutes of Health Research and Health Canada. In this paper we discuss the history of the placebo question in Canada, describe the recommendations made by the NPI, and attempt to identify some of the reasons for their lack of uptake.

2. Historical Background

   Since the 1980s, Canada has been at the center of scholarly work on the ethics of randomized controlled trials (RCT). (5) Early work focused on the ethics of randomization. It is widely acknowledged that the physician owes her patient a duty of care that requires the physician to act and advise in accordance with the patient's best medical interests. In a RCT, the participant is allocated by chance to an experimental or control treatment. How, critics asked, could offering a patient enrollment in a RCT ever be consistent with the physician's duty of care? Benjamin Freedman provided the most widely accepted answer to this question with his concept of "clinical equipoise." (6) According to Freedman, a physician may legitimately offer a patient RCT enrollment provided that each of the treatment arms to which she may be allocated is consistent with competent medical care. In other words, clinical equipoise requires that at the start of a RCT [t]here exist ... an honest, professional disagreement among [the community of] expert clinicians about the preferred treatment." (7)

   Generally, a placebo control is appropriate when there is no proven treatment for the study condition. However, once proven treatment exists, an active control (i.e., standard treatment) ought to be used. Not only does this ensure that patients enrolled in a clinical trial will not go untreated when a proven therapy is available, but comparison to an active control provides valuable information on comparative efficacy. If the new drug eventually receives regulatory approval, information on comparative efficacy is essential for informed decision making by policy makers, clinicians, and patients.

   Clinical equipoise has clear implications for use of placebo controls in RCTs. In a 1990 article in the journal IRB, Freedman laid out circumstances in which a placebo control may be used consistently with clinical equipoise, namely when:

1. there is no standard treatment;

2. standard treatment is no better than placebo;

3. standard treatment is placebo;

4. the net therapeutic advantage of standard treatment has been called into question by new evidence; or,

5. effective treatment exists but is not available due to cost or short supply. (8)

   Two further circumstances in which a placebo control is licit are entailed by Freedman's list. First, a placebo control may be used in a population of patients who don't respond to standard treatment, provided no effective second-line treatment exists (there is no standard treatment). Second, a treatment added to a standard regimen might be compared to placebo provided that all patients in the trial receive the standard regimen (no one is denied standard treatment).

   The impact of clinical equipoise on research ethics policy has been profound. The Tri-Council Working Group (1994-1998) appealed to clinical equipoise repeatedly in early drafts of the TCPS and used the concept to justify its restrictive stance on placebo controls. For instance, the April 1998 draft of the TCPS states: "The use of placebos in clinical trials is ethically unacceptable where clearly effective therapies or interventions are available." The commentary on this article goes on to say:

   Researchers and REBs should be cautious concerning the use of placebos in clinical trials. Such use may be appropriate when a new or currently used intervention is in clinical equipoise with no intervention or a placebo, and when no clearly effective therapy is available for the study population. In the same vein, it is inappropriate to withhold a clearly effective intervention...