Canadian group studies ethical use of placebos

More stringent requirements recommended

When should placebos be used in clinical research? Can subjects with a medical condition be asked to consent to withdraw from their current medications and take an experimental medication — with the 50/50 chance that what they actually receive will be no medication at all?

Or should placebos only be used in trials of a therapy in which there is no acceptable alternative, or the currently accepted therapy is not effective?

That’s the dilemma tackled by a group of ethicists, attorneys, clinicians, pharmaceutical representatives, and lay volunteers who agreed to work on Canada’s National Placebo Initiative.

Launched in 2001, the initiative was charged with resolving an essential difference in the two placebo policies used in Canadian research and make recommendations for a common uniform placebo policy.

"The policy used by Health Canada differs significantly from the policy used by the three major funding agencies sponsoring clinical research," explains Kathleen Cranley Glass, LLB, BCL, DCL, director of the biomedical ethics unit at McGill University in Montreal, and a member of the committee charged with developing recommendations on the new policy.

Currently, the research governance and standards for the review of clinical trials in Canada can follow one of two approaches. One approach is the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, published in 1998 as a joint policy initiative by the Medical Research Council of Canada (now Canadian Institutes of Health Research, CIHR), the Social Sciences and Humanities Research Council of Canada (SSHRC) and the Natural Sciences and Engineering Research Council of Canada.

The other approach, used by Health Canada, is to follow Canada’s Clinical Trial Regulations and international guidelines, such as those produced by the International Conference on Harmonisation (ICH), a 1990 international agreement on human subjects protections developed by representatives from the United States, Japan, and Europe.

Essentially, the funding agencies have taken the approach of requiring "clinical equipoise" in research — permitting the use of placebo only when there is no "established effective therapy" for the condition being studied, Glass says.

The approach supported by Health Canada — and reflective of the ICH policy — is one that considers the "level of risk" and would allow the withdrawal of commonly accepted therapy to subjects, provided subjects are given full informed consent and will not face risk of death or serious injury during the trial.

To study the issue, Health Canada and CIHR established a joint initiative in the spring of 2001 and established the National Placebo Initiative and the National Placebo Working Committee (NPWC). The NPWC brought together an expert group of interested individuals who researched, discussed and debated the placebo issue in an attempt to arrive at a consensus around recommendations about the appropriate policy for Canada.

The members of the NPWC included a clinical trial nurse, a citizen representative, an ethicist, a health attorney, a patient advocate, a designated person with process experience in conflict resolution, a representative from the pharmaceutical industry, a principal investigator, a representative from the regulatory and public health sectors, a member of a research ethics board (the equivalent of IRBs in the United States), a statistician, and ex officio representation from Health Canada and CIHR.

The committee then established six subcommittees to address the different issues in the debate. These six subcommittees were dedicated to: citizen issues, scientific issues, ethics, legal perspective, regulatory perspective, and a research ethics board subcommittee.

Each subcommittee provided a section of the final report giving background, history, and perspective on the issues in its area related to placebo use and making policy recommendations based on its perspective.

The NPWC then combined all perspectives and developed overall draft policy recommendations.

Background

According to the background provided in the Canadian report, the beginning of the debate on the use of placebos in research largely began in 1964, when the World Medical Association published its Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. The declaration recognized that research is often conducted in the context of clinical care, the report notes.

The declaration also addressed the issue of withholding established therapies by requiring that "in any medical study, every patient — including those of a control group, if any — should be assured of the best proven diagnostic and therapeutic method." While the word "proven" was the cause of some controversy and confusion, read literally, the requirement would have prohibited new research, since "unproven" therapies could not be tested. However, the intent of the statement is clear, that is, that effective therapy should not be withheld from patients seeking care, the report states.

For almost two decades after that declaration, research ethics followed a doctrine of clinical equipoise — the rationale that patients should not be disadvantaged by entering a trial in which treatment is randomized when there is no consensus in the expert community about the preferred treatment for the patient population under study, making the arms of the trial medically and morally equivalent. This means that a placebo arm is acceptable if there is no established, effective therapy.

However, achieving a consensus among experts on what therapies are established has never been easy, Glass notes. And over the years it has become increasingly clear that clinical trials featuring the use of placebo — even when other common therapies were available — often were occurring.

The 1960s and 1970s saw an increase in the quantity of regulation surrounding all aspects of new medical products. In the 1980s, the International Conference on Harmonization (ICH), a group including regulatory authorities and representatives from industry from the United States, Japan, and Europe, established the rules that currently act as guidelines for Health Canada regulators.

The ICH-E10 guideline limits the use of placebo controls to trials in which there is no known proven effective treatment that is "lifesaving or known to prevent irreversible morbidity."

In 2002, in a controversial move, the World Medical Association also added a "Note of Clarification" on paragraph 29 of the Declaration of Helsinki, allowing for the use of placebo controls even if "proven therapy" is available, "where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm."

NPI recommendations

The NPWC published its initial draft report in April and has since revised the draft once based on comments it received. The changes, though, were largely to clarify what was stated and no substantive changes in the recommendations were made, Glass says.

Overall, the committee has recommended more of a return to the doctrine of clinical equipoise and a shift away from the concept that participants in a clinical trial could ethically withdraw from their current medications if no serious harm would result, she adds.

It is the approach that Glass finds most appropriate, given that clinical research does most often take place within the context of clinical care.

"Obviously, I come from a background in ethics and the law, and do not have a background in pharmaceutical development, science, or medicine," she notes. "But I have studied the law and the ethical perspective, both here and in the United States, and I could not find any perspective which would allow a physician to step back from his or her moral obligation to provide care and permit the withholding of appropriate treatment — even if the patient/subject were to knowingly consent."

She was surprised, however, at the diversity of opinion within the members of the committee — particularly the patient and citizen representatives, both of whom expressed opposite opinions.

The patient representative supported an environment in which placebos could only be used when physicians determined that no other effective therapy for the condition was available. However, the citizen representative wanted the opportunity to participate in placebo-controlled trials under any circumstances, as long as full informed consent was given about the risks and the actual availability of other therapy.

"His attitude was that he should be given all of the information about the trial, its purpose, what other therapies were available, etc., then the decision about whether to participate should be left up to the individual subjects who might be enrolled," Glass says.

Experts across the spectrum shared the citizen representative’s opinion, from regulators to clinical investigators to pharmaceutical representatives, she says.

"I think people honestly differ in opinion on this matter — aside from any financial incentives to further research," she notes. "It is not as if the pharmaceutical industry and others, motivated by profit, is pushing for more use of placebos."

The difference in opinion between the two community members of the committee indicates that the public also is divided on the issue, she notes.

However, Grass says, the committee ultimately felt that there had to be some limit to what patient subjects could consent to, and it was the responsibility of REBs and IRBs to first consider whether a placebo-controlled arm would be appropriate before allowing subjects to be asked to consent.

"Our approach believes that the first step should be for the REB to determine, Is this an appropriate study to conduct in humans? Is it morally appropriate to use placebo in this case?’" she notes. "The second step should be full informed consent, whereas the other approach places informed consent first."

The NPWC currently is working on a final draft of the report to given to Canadian authorities.

The proceedings are being closely watched by the research community in the United States, which also is debating the ethical use of placebo, says Howard Mann, MD, associate clinical professor of radiology at the University of Utah School of Medicine and a member of the school’s IRB.

Guidance from the U.S. Food and Drug Administration and the Office of Human Subjects Research Protections supports the broader "level of risk" school of thought promoted by the Health Canada approach and the ICH, though the use of placebos is still controversial, he says.

Advocates for the withholding, or withdrawing, of effective therapy under certain circumstances include ethicists such as Franklin G. Miller at the National Institutes of Health and Michigan State University’s Howard Brody (who have both called for the abandonment of the concept of clinical equipoise in randomized controlled trials), as well as drug regulators in the United States and Europe, and pharmaceutical and biotechnology companies, he adds.

According to Mann, the most compelling aspects of the recent Canadian effort were: a clarification of the notion of "established effective therapy" by the clinical epidemiologist and trialist David Sackett and a call for the use of systematic literature reviews in establishing whether "established effective therapy" for a particular condition exists; and literature reviews to support the choice of a control intervention for a randomized controlled trial; and a detailed clarification (and revision) to the guidance concerning the permissible use of placebos in trials.

The NPWC approach, which sought input and perspective from members of the public not associated with the research community or the pharmaceutical industry, also was interesting, Mann says.

"The perspectives of patient and health care consumers is generally not solicited when considering the social value of proposed biomedical research, or in informing research design, such as the choice of appropriate outcome measures for trials," he points out. "This is a pity. We [in the United States] need to encourage the creation of consumer organizations, such as Consumers for Ethics in Research in the United Kingdom, that will provide substantive input into the formulation, design, and conduct of clinical trials."

The draft report of the National Placebo Initiative is available on-line at: www.cihr-irsc.gc.ca/ e/services/19301.shtml.