The Double Blind Placebo Controlled Trial: The Fool's Gold Standard

The blind allegiance to what I call the "fool's gold standard" lives on. Any one with even a passing interest in bioethics knows it is unethical to conduct a double blind placebo controlled trial where standard therapy exists, except under limited circumstances. Still sponsors and researches continue to design and conduct such trials, providing the familiar excuse: "The FDA made us do it." Indeed, in at least one case I have brought on behalf of an injured subject, I have seen the minutes of a meeting with an FDA official who advised the drug company that only a placebo controlled trial would be acceptable even though the drug company advised the official that standard therapy existed and there might be a risk of harm to the subject during the placebo phase. Even more startling is the response I have received in depositions of physician/principal investigators who believe such trials are the gold standard and are perfectly acceptable in the context of medical research as long as the subject signs the informed consent.

The reason such trials pose ethical issues are obvious. For research to be ethical in design, what is known as "clinical equipoise" must exist between the two arms of the study. This means that the researchers must not believe that the subjects in one arm of the study are getting any better or worse therapy than the subjects in the other arm. Thus, where standard therapy exists, the researchers must believe that the subjects in both arms are getting therapy at least equal to standard best therapy. Obviously, no state of clinical equipoise can exist where one arm of the study receives a nontherapeutic placebo unless no therapy considered standard exists for the disease or ailment.

The Declaration of Helsinki speaks directly to this issue. The World Medical Association had adopted a resolution on human experimentation in 1954 based largely on the Nuremberg Code. In 1964, after several revisions, the World Medical Assembly in Helsinki adopted the document now known as the Declaration of Helsinki. Like the Nuremberg Code out of which it arose, the Declaration of Helsinki recommended a worldwide minimal standard for human subject research. It has since been revised not only to include a requirement for ethical review committees, such as IRBs, but also to expressly preclude the use of a placebo when a proven therapeutic method exists and where the absence of therapy poses a risk to the subject. It states in relevant part:

29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists. See footnote.

Footnote: Note of clarification on paragraph 29 of the WMA Declaration of Helsinki

The WMA hereby 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 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; 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.

All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review.

See here.

Similarly, the IRB Guidelines, developed by the Office of Human Research Protection ("OHRP") outline the following standard for placebo-controlled trials.

Placebos. Placebos may be used in clinical trials where there is no known or available ( i.e, FDA-approved) alternative therapy that can be tolerated by subjects. IRBs should scrutinize studies that propose to use placebos to ensure that subjects are not deceived into believing that they have received an active agent.

. . .A design involving a placebo control should not be used where there is a standard treatment that has been shown to be superior to placebo by convincing evidence [Freedman (1990)]. It has been argued that placebo controls must be used, however, when the experimental treatment is of "dubious efficacy" or when there are known serious side effects [Freedman (1990); Levine (1985), 1986)]. The use of placebos in controlled clinical trials must be justified by a positive risk-benefit analysis, and subjects must be fully informed of the risks involved in assignment to the placebo group. There is a consensus that continued assignment of subjects to placebo is unethical once there is good evidence to support the efficacy of the trial therapy. Clinical trials should be stopped or their protocols modified when there is sufficient evidence of either a beneficial therapeutic effect or unacceptable side effects. Monitoring for such information during the course of the trial is discussed in Guidebook Chapter 3, Section E, "Monitoring and Observation."

See here.

It makes no difference whether the subject has signed on to the trial knowing a coin flip might result in no therapy. Informed consent does not make a trial ethical if it is unethical by design. Why the FDA continues to tell sponsors and researchers that they need the results of such trials for approval of the drug is troubling but beside the point. Even if the only way to prove efficacy to the FDA is by such a trial, this would not justify conducting unethical research. If the result is that the drug is delayed in coming to market, that is the price we as a society pay for requiring that research on human subjects be conducted in an ethical manner.

It is not just the "placebo" aspect of the "gold standard" that I find troubling, I have questioned researchers and their sponsors about the double-blinding as well. I accept the proposition that some subjects might manifest a placebo response to a therapy only because they think it must be beneficial. And I accept the proposition that bias might consciously or unconsciously cause researchers to skew the results of a trial one way or the other. But neither of these propositions is an absolute in every trial. In certain trials, the results might be so objective as to not be susceptible to either a placebo response or researcher bias. One such case I brought involved severe psoriasis where the results were obtained by some technician counting the skin plaques. It is difficult to conceive that the double blinding was necessary for the purpose of legitimizing the results.

Why then insist on double blinding?

Suppose subjects recruited for a trial exploring some great new therapy find out on day one that the coin flip placed them in the placebo arm. Is there any doubt the subjects would then opt out of the trial and return to standard therapy. Similarly, if the physician finds out his or her longtime patient has been randomized into the placebo arm, is there any doubt medical ethics or simply fear of a malpractice claim would compel the recommendation to withdraw? In fact, one physician candidly admitted at deposition that, had he known the patient had been randomized into the placebo arm, he would have recommended a return to standard therapy.

The point is that double-blinding is ethical only if it serves a scientific purpose. If its real purpose is to keep subjects in the trial when it is not in their best therapeutic interest to remain--a conflict of interest if ever there was one --then the blinds should be lifted. As the poet said, sometime we are all "a little too blind to see."

The exceptions are where (1) there is no risk of harm if the patient forgoes treatment during the placebo phase such as in a trial for a drug that seeks to cure hair loss or impotence; (2)the standard therapy carries such severe side effects that patients might choose to avoid it or (3) the standard therapy is otherwise of questionable efficacy.

See, e.g., Ezekiel J. Emanuel, M.D., Ph.D. and Franklin G. Miller, Ph.D., "The Ethics of Placebo-Controlled Clinical Trials - A Middle Ground," New England Journal of Medicine, Vol. 345:915-919, (September 20, 2001), at http.// 345/12/915?query=TOC; Samuel Hellman, "Of Mice But Not Men: Problems of the Randomized Clinical Trial," New England Journal of Medicine, Vol 324 (May 30, 1991); Robert J. Levine, "The Use of Placebos in Radndomized Clinical Trials," IRB - A Review of Human Subject Research, Vol. 7, No.2, (March/April 1985); Sissela Bok, "The Ethics of Giving Placebos," Scientific American, Vol. 231, No. 5 (November 1974)