The Myth of Equipoise in Phase 1 Clinical Trials

Adil E. Shamoo, PhD

Disclosures

Medscape J Med. 2008;10(11):254 

In This Article

The Beginning of the Myth

Freedman, in his 1987 article,[2] offered the concept of "clinical equipoise" to resolve the ethical dilemma pointed out by Fried[20]and Marquis[21]when conducting an RCT. RCTs have a group that receives placebo, thus offering no potential for benefit to those subjects. Freedman was dogmatic in that: "Equipoise is an ethically necessary condition in all cases of clinical research...equipoise must exist between all arms of the trial...If equipoise is disturbed during the course of a trial, the trial may need to be terminated." [2]

Freedman justified this by saying: "[I]t is necessary that the clinical investigator be in a state of genuine uncertainty regarding the comparative merits of treatments A and B for a population. If a physician knows that these treatments are not equivalent, ethics requires that the superior treatment be recommended."[2] In reality, we do not know the outcome before the experiment (by the definition of a phase 1 trial) is completed. It might be more appropriate to say: If during the course of the experiment a statistically significant difference between critical groups is found, ethically the trial should be stopped.

In his extension of Fried's 1974 concept of treatment equipoise, Freedman conflated the doctor's therapeutic obligations to the patient with the researcher's obligation to acquire new knowledge to serve the public good. Fried used the term "equipoise" to justify the use of placebo in RCTs. Freedman may have intended in his treatment to mean only phase 2and phase 3trials, but the concept of equipoise never excluded phase 1 trials, as mentioned earlier.

Research has no therapeutic intent to the individual subject, and we should not invent one to justify it. Invoking "clinical equipoise" enhances therapeutic misconception, clouds the drive to develop a moral concept among researchers of professional integrity, obfuscates the true concept of informed consent, and muddles the moral conflict between the best interest of the patient and the interest of society in research. For nearly 20 years, Paul Appelbaum and his colleagues[6]have argued against the perpetuation of the therapeutic misconception of research on human subjects in clinical treatment. Miller and Brody[1]contend that justification of "clinical equipoise" is nothing but an "ethical obfuscation." In their article, they argue that the ethics of clinical trials must start with the realization that medical research and medical treatment are 2 distinct activities, governed by different ethical principles. Because they are different, we may be able to analogize to transplantation in which 2 teams (one to treat, the other to harvest) are used. Is it not conceivable that in such trials we would have 2 physicians each responsible for their particular interest.

Strict application of "clinical equipoise" would rule out the widely used and accepted "placebo-controlled" trials and the use of healthy subjects in phase 1 clinical trials. Research with human subjects can be considered no different than research with animals, plants, or chemicals -- they are experiments.[22] Unfortunately, even Miller and Brody[1] fall into the therapeutic misconception trap when they cite Braunholtz and colleagues: "Patients receive more favorable medical outcomes in many clinical trials." This may be true in individual cases, after the fact of conducting the trial, but the overall potential risk to human subjects as they enroll in a research study is certainly much higher than when they are treated as patients. Otherwise, we are claiming that a scientific experiment is more certain than a completed study where the drug is already on the market.

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