The debate over placebo controls continues
Should they be used if proven therapy exists?
In the Sept. 20, 2001, issue of the New England Journal of Medicine (NEJM), two editorials addressed a hot topic among clinical researchers — the ethics of using placebo-controlled studies.
"The debate over placebo-controlled trials is implicitly and inextricably linked to concern about withholding treatment — specifically, withholding proven or standard treatment — in the course of investigating new therapies," wrote Patricia Huston, MD, MPH, and Robert Peterson, MD, PhD, of Health Canada in Ottawa.
When designing clinical trials, researchers can use at least two different standards when deciding the ethical concerns of using placebo controls. One is the Declaration of Helsinki, a statement of ethical principles developed by the World Medical Association (WMA) in France to provide guidance to physicians and other participants in medical research involving human subjects. The WMA was founded in 1947; the first Declaration was issued in 1964 and descends in large part from the Nuremberg Code.
In its October 2000 edit, principle 29 of the Declaration caught the attention of many researchers. "The benefits, risks, burdens, and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods," it says. "This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic method exists."
The "diverse interpretations and possible confusion" of principle 29, however, led WMA to issue a note of clarification in October 2001. The association said it reaffirms its position that "extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy." However, a placebo-controlled trial may be ethically acceptable, even if a proven therapy is available, under the following circumstances:
• 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.
• 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.
The FDA’s position
The Food and Drug Administration (FDA), however, is not as strict in the use of placebo controls when a proven therapy exists. Instead, FDA says it is generally inappropriate to use a placebo in cases where an available treatment is known to prevent serious harm, such as death or irreversible morbidity in the study population.
This guidance is located in the "E10 Choice of Control Group and Related Issues in Clinical Trials," developed within the Expert Working Group (Efficacy) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. In situations where there is no serious harm, the guidance says, it generally is considered ethical to ask patients to participate in a placebo-controlled trial, even if they may experience discomfort as a result. The setting must be noncoercive and patients must be fully informed about available therapies and the consequences of delaying treatment.
Control groups have different problems, says Robert Temple, MD, director for medical policy, Center for Drug Evaluation and Research, Food and Drug Administration. "The placebo control is always informative, but there are some circumstances in which you can’t ethically use it. An active control equivalence trial or noninferiority trial [in which an investigational drug is compared with a known active drug] usually is not an ethical problem, but there are a lot of circumstances in which it is simply not interpretable."
Failure to show a difference between treatments may not tell you that the new one works and may mean you don’t have any evidence of effectiveness, he says. "You have to have effectiveness to be approved. That is a requirement of law."
Are placebo controls necessary?
Placebo controls are needed to test certain types of drugs, adds George J. Wright, PhD, an independent consultant in West Chester, OH. Wright has a number of years’ experience in clinical research. He offers the example of antidepressants. "There are quite a number of drugs that have an influence on the progression of the depressive state," he says. "On the other hand, depression is a cyclical disease. An individual often will effectively become cured for a short time with no treatment at all. You then have to sort out whether the drug was responsible for the regression of the disease or the individual was just in one of those cyclical states." Side effect profiles with antidepressants can be difficult to determine in the absence of placebo controls, as well, he adds.
"People like the fact that drugs only have the intended action. And drugs don’t," Wright says. "Any drug that is truly effective under certain circumstances will cause other things that you don’t want it to do. Some of these side effects are serious."
If the disease is life-threatening and an effective drug (one that will at least prolong life) exists, however, researchers are obligated to use the drug that they know will have some effect. "Then you try to add to that effectiveness with the new drug," Wright says. "Maybe the next time you don’t want to use that other drug. But you never leave [patients] untreated."
In a situation where no drug is truly effective, then researchers almost have to have an untreated group to discern that the new drug will or will not have an effect, he says. "The fact that the disease is untreated already tells you that no one has been terribly effective at finding a drug that does work."
Does a middle ground exist?
The second editorial in the NEJM that addressed placebo controls suggests that a middle ground exists between the positions of the Declaration of Helsinki and the FDA. "We propose a middle ground in which placebo-controlled trials are permitted but only when the methodologic reasons for their use are compelling, a strict ethical evaluation has made it clear that patients who receive placebo will not be subject to serious harm, and provisions have been made to minimize the risks associated with the receipt of placebo," write Ezekiel J. Emanuel, MD, PhD, and Franklin G. Miller, PhD, of the National Institutes of Health in Bethesda, MD.
Temple says the people writing the NEJM try very hard to say, "There are extremists on either side and we are in the middle."
"That is distorted," he continues. "The only disagreement they have with FDA is that they think there may be degrees of discomfort so extreme that you wouldn’t want to put people into a trial. I don’t disagree with that. That may be true. I don’t think it’s an ethical question. I think people just wouldn’t be in the trial."
The writers say they are proposing a middle ground, but they really are in near total agreement with the FDA and the contents of the guidance, Temple continues. "They make a big deal about the fact that we define the degree of discomfort or harm in several different ways. Then they use the term serious harm’ and say serious harm is a matter of judgment. They are just as vague about it as anyone."
A crucial component in the argument is that people are volunteering, he says. "You are not forcing someone to be in a study. If someone says, I am willing to endure pain for an hour or two to see if this new drug or placebo is better,’ then they ought to be considered intelligent enough to make that decision."
People sometimes act as if there is no decision to make when you are using an active control trial, Temple says. "That’s silly. You are either getting a standard drug that everyone knows works or you are getting a new drug that might have risks that aren’t known."
Every time someone enters a trial, there is a decision to be made, he adds. "The whole idea of carrying out trials is dependent on the idea that people can make intelligent decisions if you tell them the truth about what you know. We don’t see much difference in these symptomatic conditions between an active control trial and a placebo-controlled trial."
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