DO THE RIGHT THING
McGill ethicists help ensure that medical research conforms to the highest scientific and ethical standards
by Dr. Charles Weijer, BA'93, MSc'95

Research ethics is one of medicine's newest and fastest growing disciplines. Situated neither fully within medicine nor within the humanities, it rests in a transitional zone where scientific fact and moral principle have equal weight. For the last five years, the Clinical Trials Research Group (CTRG) has devoted itself to disentangling the complicated issues dealing with the testing of new medical interventions, such as pharmaceutical drugs or medical devices (e.g., artificial joints). To date, our group is known for advocating more open access to clinical trials as well as arguing against the use of placebos. Since you may one day be asked by your doctor to participate, it is worthwhile to understand the clinical trial procedure.

Clinical trials are conventionally divided into three phases. Early-stage clinical trials (phase I) evaluate the safety of new treatments in humans. Usually these studies involve healthy volunteers who may be recruited through advertisements. Later studies (phase II) test if the drug works in a specific group of patients. If the first two phases of drug evaluation show the treatment to be promising, then a large-scale study, called a phase III study, involving hundreds or even thousands of patients, is initiated to compare the new treatment with the best available therapy. Patients may be asked to participate by their own doctor at the phase II or III stage.

Far from being "guinea pigs," recent studies suggest that study participants may actually receive better treatment for their illness. In a 1989 editorial in the prestigious British Medical Journal, cancer specialist Charles Stiller reviewed the results of studies that compared the survival rates of cancer patients treated in research studies with those treated in clinical practice. The result was surprising: cancer patients in research studies lived longer.

Although the results await definitive confirmation, the finding seems to support the long-held suspicion of many cancer specialists that superior treatment is given in research studies. The advantages conferred by research participation seem to be due to the careful manner in which treatment and follow-up are delivered. Treatments within research studies are controlled by a protocol -- a finely detailed plan of action -- which defines when treatments are to be given, how much will be given, and when the intensity of treatment should be reduced. Patients in research studies are also followed more closely: frequent follow-up examinations are set out by the study protocol to measure the effect of treatment and to detect side-effects as early as possible. If study participation does offer benefit to patients, research ethicists must ensure that patients are not unjustly denied access to research studies.

Armed with the belief that more patients might benefit from research, McGill philosopher Benjamin Freedman, cancer researcher Abraham Fuks, BSc'68, MD'70 (now McGill's Dean of Medicine), and biostatistician- epidemiologist Stanley Shapiro launched the Clinical Trials Research Group in 1990 to study ethical issues in medical research.

At the time the group began looking into the issue, it was widely believed that the ethical requirement for written informed consent -- a document which details, among other things, all the possible risks of treatment -- discouraged many from participating in clinical trials. Others speculated that individual physicians, reluctant to participate in research, prevented patients from signing up for studies. The CTRG's investigation revealed that neither of these factors was the most important. The biggest deterrent against enrolment turned out to be the criteria for trial eligibility within the studies themselves, a checklist by which each potential subject is evaluated before being allowed into a study. Eligibility criteria are written by the persons designing a clinical trial and at times it seems trial designers, in an attempt to make a study maximally "scientific," are overly zealous in restricting the people eligible to participate. Indeed, the CTRG found that while some of these criteria are essential (e.g., criteria defining the disease to be studied), it concluded that many are not (e.g., criteria excluding older persons and women of reproductive age from participation). A more open-door policy to trial enrolment, the CTRG argued, would both allow more patients to participate and, by virtue of greater diversity within studies, would make study results more relevant to clinical practice.

Clinical trials came to the attention of the Canadian public with the 1994 case of Dr. Roger Poisson, a well- respected breast cancer surgeon at Hopital St-Luc in Montreal, who falsified data on 99 women participating in clinical trials for the treatment of early-stage breast cancer. Although Dr. Poisson claimed that he was just trying to do the best for his patients by giving them an opportunity for a new treatment, an investigation by the U.S. Office for Research Integrity revealed that three patients with a history of heart disease were exposed to a chemotherapy drug known to cause heart damage. Moreover, it seems that several of the women were not properly informed that they were participating in a research study.

Why would a researcher engage in fraud and endanger patients? We can only speculate as to the motivation in this specific case. As research funding has become more and more restricted over the last decade, many researchers have felt under pressure to "get results." Furthermore, substantial rewards await the successful researcher: authorship of articles in prestigious journals, increased research funding, the respect of one's peers, and even fame. Part of the job description of the ethicist, then, must also be to ensure that the subjects of human experimentation are protected. This means ensuring that research participants are properly informed about the nature of the study and that the medical care of research participants is never disadvantaged. The task, then, of research ethics is rather like that of Ulysses, to chart a course between the Charybdis of harming research subjects and the Scylla of over-protecting them.

The Clinical Trials Research Group was later joined by other investigators from disparate backgrounds, including lawyers Kathleen Cranley Glass, LLB'80, BCL'80, DCL'91, and Trudo Lemmens, LLM'95, theologian Karen Lebacqz, nurse-clinician Myriam Skrutkowska, BSc(N)'85, CertHMgt'92, and myself, a physician pursuing graduate work in experimental medicine. These additions reflect founder Freedman's belief that the complex problems posed by medical research would admit no simple solution: satisfactory answers could only come from a multidisciplinary approach. Achieving multidisciplinarity, though, has proven to be one of the greatest challenges facing the group. Putting people from differing backgrounds in the same room is easy; communicating effectively is something else entirely. In order to work together, each of the group members has been forced to learn the language of the other disciplines: the lawyer has had to learn the language of the statistician; the philosopher, the language of the physician; and the theologian, the language of the lawyer. As a result, each group member is constantly under pressure to broaden his or her own academic scope. Group meetings are, according to one experienced member, at times, "like going back to school."

Funded by both the Medical Research Council and the Social Sciences and Humanities Research Council, the Clinical Trials Research Group meets once every one to two weeks in Benjamin Freedman's office. Each meeting is generally devoted to discussing one of the group's ongoing projects. The members present their work on a specific question; discussion and criticism from other group members follows. When research questions involve highly specialized research areas, the CTRG will frequently invite experts from those research areas to advise and collaborate. For example, the research group is currently examining issues in genetic research and recently met with McGill geneticist Roberta Palmour.

One contentious issue that the Clinical Trials Research Group has recently struggled with well illustrates the challenges -- and rewards -- of a multidisciplinary approach. The controversy centres on the use of placebos ("sugar pills") in medical research. In Canada and the United States, new drugs must be proven safe and effective before licensure. The evidence comes from carefully conducted phase III clinical trials in which two groups of patients are compared: one group that receives the new drug, and the other that receives a "control" treatment. When effective treatment exists for a disease, the control treatment is usually the best treatment available. If no treatment currently exists for a disease, patients in the control group may be given a placebo.

Research examining new treatments for mental illness has tested new drugs against placebos since the 1950s. This practice was unproblematic -- and, indeed, necessary -- in the early days of psychiatric research for the simple reason that few good treatments existed. However, after four decades of research, many clearly effective treatments have been found for a range of psychiatric disorders, including acute schizophrenia, depression and manic depression. Problematically, many psychiatric researchers continue to insist that all new drugs for mental illness be tested against placebo, even if it means depriving some patients with treatable mental illnesses of therapy for a period of weeks or months. Good science, they say, demands it.

Concerned that patients with mental illness might be harmed by participating in such studies, three members of the Clinical Trials Research Group (Freedman, Glass and myself) set out to challenge the inappropriate use of placebos in medical research, including psychiatry. We maintained that no single approach -- ethical, legal, or statistical -- can comprehensively address such a complex problem. Each of the three members challenged the necessity (and permissibility) of placebos from his or her base discipline. As the statistician, I argued that placebos are not required by science; indeed, comparing new treatments to standard therapy gives more useful information to the physician. The philosopher argued that international codes of ethics, including the influential World Medical Association's Declaration of Helsinki, forbid the use of placebo when proven therapy exists. The lawyer argued that denying patients effective treatment may constitute medical malpractice. Thus, the three separate strands of argumentation converged on a single point: psychiatric researchers must kick the placebo habit.

The Clinical Trials Research Group is mindful both of its obligation to ensure that patients are not unjustly deprived of the benefits of research participation and of its duty to protect research subjects. In fulfilling these obligations, the CTRG is continuing to help researchers, at McGill and internationally, to "do the right thing." The right thing for science, and, most important of all, the right thing for patients.

Recent publications:

Dr. Charles Weijer, BA'93, MSc'95, graduated from the University of Alberta in medicine and came to McGill to study philosophy and bioethics. He is currently a doctoral student in the Division of Experimental Medicine at McGill and has a fellowship from the Medical Research Council of Canada.