Education and debate

Clinical equipoise and not the uncertainty principle is the moral underpinning of the randomised controlled trial

FOR

AGAINST

Clinical equipoise and not the uncertainty principle is the moral underpinning of the randomised controlled trial

The ethical basis for entering patients in randomised controlled trials is under debate. Some doctors espouse the uncertainty principle whereby randomisation to treatment is acceptable when an individual doctor is genuinely unsure which treatment is best for a patient. Others believe that clinical equipoise, reflecting collective professional uncertainty over treatment, is the soundest ethical criterion. Here doctors from two Canadian centres discuss their positions.

FOR

Charles Weijer, assistant professor of medicine, ^a Stanley H Shapiro, professor, ^b Kathleen Cranley Glass, assistant professor. ^c

^a Department of Bioethics, Dalhousie University, Halifax, NS B3H 4H7, Canada, ^b Department of Epidemiology and Biostatistics, McGill University, Montreal H3A 1A2, Canada, ^c Biomedical Ethics Unit, Department of Human Genetics and Department of Pediatrics, McGill University

Correspondence to: C Weijer charles.weijer{at}dal.ca

On what ethical grounds may a physician offer trial participation to his or her patient? The answer seems to depend greatly on which side of the Atlantic you reside. In the United Kingdom, the uncertainty principle is widely endorsed. ^{1 2} However, in North America, clinical equipoisereflecting collective uncertaintyis the dominant ethical basis.³ Which of these principles offers the preferred moral underpinning for the randomised controlled trial?

It is widely acknowledged that physicians have a primary duty to promote their patients' welfare. When physicians become investigators, however, other ends such as recruiting enough subjects and retaining them in the trial may conflict with this duty.⁴ How can the physician maintain fidelity to the patient and further the ends of a randomised controlled trial? The uncertainty principle offers an appealing solution to this problem.

Uncertainty principle

Physicians who are convinced that one treatment is better than another for a particular patient cannot ethically choose at random which treatment to give, they must do what they think best for the patient. For this reason, physicians who feel they already know the answer cannot enter their patients into a trial. If they think, whether for a wise or silly reason, that they know the answer before the trial starts, they should not enter any patients.²

On the other hand, if the physician is uncertain about which treatment is best for a patient, offering the patient randomisation to equally preferred treatments is acceptable and does not violate his or her duty. The uncertainty principle has been successfully used as a key eligibility criterion for large, simple trials. ^{1 5 6}

But is the uncertainty principle a solid moral basis for the randomised controlled trial? We think not. Under the uncertainty principle it would be difficult, if not impossible, to conclude that a physician ever errs in enrolling a patient in a trial. So long as the physician claims he or she was uncertain, even if madly or incompetently so, he or she cannot be said to be wrong. Recent articles on the uncertainty principle have added "reasonably" and "substantially" to qualify uncertainty. ^{1 6} But who decides what counts as reasonable or substantial uncertainty? If it is the individual physicianand the uncertainty principle certainly maintains that the proper normative locus for decision making is the individual physicianwe are left with the same problem.

Clinical equipoise

Clinical equipoise, on the other hand, recognises explicitly that it is not the individual physician but the community of physicians that establishes standards of practice. According to Freedman, the

ethics of medical practice grant no ethical or normative meaning to a treatment preference, however powerful, that is based on a hunch or anything less than evidence publicly presented and convincing to the clinical community. Persons are licensed as physicians after they demonstrate the acquisition of this professionally validated knowledge, not after they reveal a superior capacity for guessing.³

Competent medical practice is defined widely as that which falls within the bounds of standard of carethat is, practice endorsed by at least a respectable minority of expert practitioners. The innovation of clinical equipoise is the recognition that study treatments, be they the experimental or control treatments, are potentially consistent with this standard of care. Thus, a physician, consistent with his or her duty to the patient, may offer trial enrolment when there "exists . . . an honest, professional disagreement among expert clinicians about the preferred treatment."³

Clinical equipoise may arise in several ways. Evidence may emerge from early clinical studies that a new treatment offers advantages over standard treatment. Alternatively, there may be a split within the clinical community, with some physicians preferring one treatment and other physicians preferring another. This last scenario is well documented in the published report and calls for a randomised controlled trial to settle which is the better treatment.⁷ Clinical equipoise does, however, permit these important randomised controlled trials. It would have physicians respect the fact that "their less favoured treatment is preferred by colleagues whom they consider to be responsible and competent."³

Convincing results

The second part of clinical equipoise states: "the trial must be designed in such a way as to make it reasonable to expect that, if it is successfully concluded, clinical equipoise will be disturbed. In other words, the results of a successful trial should be convincing enough to resolve the dispute among clinicians."³ Clinical equipoise, therefore, generally requires a trial design that will "compare two treatments under the conditions in which they would be applied in practice [and] answer the questionwhich of the two treatments should we prefer?"⁸ In short, clinical equipoise supports a pragmatic approach to the design of randomised controlled trials.

Clinical equipoise . . . recognises explicitly that it is not the individual physician but the community of physicians that establishes standards of practice

Simplicity

The implications of this are just beginning to be explored. It has already been argued that some trials have too many eligibility criteria, are insufficiently generalisable to the patient population at large, and fail to compare new drugs to best available standard treatment. ^{9 10 11} Questions related to the determination of sample size and the interim analysis have yet to be explored using the lens of clinical equipoise. For instance, must randomised controlled trials be designed to ensure convincing negative as well as positive results? Might clinical equipoise provide a sound moral basis for decisions to stop trials early? While questions remain, it is already clear that clinical equipoise will lead randomised controlled trial design in the direction of larger, simpler trials.Charles Weijer, Stanley Shapiro, Kathleen Cranley Glass

Acknowledgments

We thank Françoise Baylis, Robert Crouch, and Carl Elliott for helpful comments on the paper.

Footnotes

Funding: CW's work is funded by a grant and scholar award from the Canadian Institutes of Health Research and a clinical research scholar award from Dalhousie University. SHS and KCG are members of the Clinical Trials Research Group, which is supported by the Social Sciences and Humanities Research Council of Canada and the Canadian Institutes of Health Research.

Competing interests: None declared.

References

1.	Peto R, Baigent C. Trials: the next 50 years. BMJ 1998; 317: 1170-1171[Free Full Text].
2.	Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976; 34: 585-612[Medline].
3.	Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141-145[Abstract].
4.	Hellman S, Hellman DS. Of mice but not men: problems of the randomized clinical trial. N Engl J Med 1991; 324: 1585-1591[Medline].
5.	Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med 1984; 3: 409-420[Medline].
6.	Collins R, Doll R, Peto R. Ethics of clinical trials. In: Williams CJ, ed. Introducing new treatments for cancer: practical, ethical and legal problems. New York: Wiley, 1992.
7.	Taylor KM, Margolese RG, Soskolne CL. Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 1984; 310: 1363-1367[Abstract].
8.	Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutic trials. J Chron Dis 1967; 20: 637-648[CrossRef][Medline].
9.	Fuks A, Weijer C, Freedman B, Shapiro S, Skrutkowska M, Riaz A. A study in contrasts: eligibility criteria in a twenty-year sample of NSABP and POG clinical trials. J Clin Epidemiol 1998; 51: 69-79[CrossRef][Medline].
10.	Weijer C, Crouch RA. Why should we include women and minorities in randomized controlled trials? J Clin Ethics 1999; 10: 94-101.
11.	Weijer C. Placebo-controlled trials in schizophrenia: Are they ethical? Are they necessary? Schizophrenia Res 1999; 35: 211-218[CrossRef][Medline].

AGAINST

Murray W Enkin, professor emeritus. 

Departments of Obstetrics and Gynaecology, Clinical Epidemiology, and Biostatistics, McMaster University, Hamilton, ON, Canada L8N 3Z5

enkin{at}fhs.mcmaster.ca

Uncertainty on the part of all participants is the principle, moral and practical, required to justify ethically a randomised controlled trial. According to Freedman: "The ethics of clinical research requires equipoise, a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in the trial."¹ But humans have preferences. Equipoise, with its etymological connotation of an equal balance between or among the alternatives to be tested, is a theoretical ideal, almost always impossible to achieve in practice. Freedman recognised that the concept "presents almost insuperable obstacles to the ethical commencement or continuation of a controlled trial." He went on neatly to cut the Gordian knot by rejecting what he called "theoretical equipoise," which he recognised as inherently fragile, difficult to attain, and impossible to maintain, and redefining "clinical equipoise" as a failure of consensus within the clinical community.¹ Thus defined, and thus used by Weijer et al above, "clinical equipoise" is one special case of the uncertainty required to justify a controlled trial. It refers to collective uncertainty among the body of clinicians.

Clinical equipoise [is] a failure of consensus within the clinical community

Individual and group morality

Morality, however, is an attribute of individuals as well as of groups. If we grant moral authority to the medical community as a whole, we devalue the responsibility of individual clinicians. Like individuals, the medical community is fallible. While it is often certain, it is not always right, and "certainties" change. Some examples of reversals in my own clinical field of obstetrics include the 19th century belief in the therapeutic value of blood letting and the unwarranted 20th century reliance on pubic shaving and routine enemas for women in labour to reduce the risk of infection. ^{2 3} It took passionate individuals a long time to shake the complacent collective certainty. Individuals count.

Patient comes first

An ethical physician must do what is best for his or her patients. She cannot participate in a controlled trial if she is certain that one arm is superior to the others and that some of her patients will receive an inferior treatment by participating in the trial. It does not matter whether her certainty is based on formal scientific studies, on personal experience, on anecdote, on tacit understanding, or rules of thumb.^4-6 Whether her certainty is in accord with or diverges from the view of the medical community is irrelevant. Uncertainty is a moral prerequisite for a controlled study. If we know what we should do, we should do it, not study it. Controlled studies are possible and necessary, however, because even though clinicians usually have hunches that one treatment arm is more effective than another, they are often not certain that their hunches are correct. The boundaries (confidence interval) on their hunch may range from much better, through marginally better, down to ineffective, or even frankly harmful. When this is the case "it is time for a trial, and that trial is ethical."⁷

The principle of uncertainty applies even more strongly when it refers to an individual patient, who should not be entered into a trial if any of the treatments that might be allocated would be inappropriate for her.⁸ David Sackett illustrates this most poignantly with his confession of the one and only time he felt it necessary to "cheat." Faced with a desperately ill patient, he gave her the treatment that he sincerely and wholeheartedly believed that she needed. His responsibility for the patient's welfare was in direct conflict with his responsibility to the internal validity of the trial. Looking back from the vantage point of today, he justified his action succinctly: "I believe that my action was right in particular, wrong in general." The conflict arose because he "knew" that his patient needed the treatment, and this conviction is just as relevant when it is wrong as when it is right.⁸ It could have been avoided if the principle of uncertainty had been incorporated into the trial protocol.

Resolving uncertainty

Herein lies the main lesson. Moral principles are intellectually attractive but ethically deceptive. Sometimes they are in conflict, and sometimeslike all evidence based guidelinesthey may not be appropriate. When we are morally certain, we know what to do. When we are uncertain, a controlled trial may help to resolve our uncertainty.Murray W Enkin

Footnotes

   Competing interests: None declared.

References

1.	Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141-145.
2.	Siddall AC. Bloodletting in American obstetric practice 1800-1945. Bull History Med 1980; 54: 101-110.
3.	Garforth S, Garcia J. Hospital admission practices. In: Chalmers I, Enkin MW, Keirse MJNC, eds. Effective care in pregnancy and childbirth. Oxford: Oxford University Press, 1989.
4.	Enkin MW, Jadad AR. Using anecdotal information in evidence-based care: heresy or necessity? Ann Oncol 1998; 9: 963-966[Abstract/Free Full Text].
5.	Polanyi M. The tacit dimension. New York: Doubleday, 1966.
6.	Nisbett RE, Ross L. Human inference: strategies and shortcomings of social judgement. Englewood Cliffs, NJ: Prentice-Hall, 1980.
7.	Sackett DL. Why randomized controlled trials fail but needn't. 1. Failure to gain "coal-face" commitment and to use the uncertainty principle. Can Med Assoc J 2000; 162: 1311-1314[Abstract/Free Full Text].
8.	Peto R, Baigent C. Trials: the next 50 years. BMJ 1998; 317: 1170-1171.