An apparent ethical dilemma arises when physicians consider enrolling their patients in randomized clinical trials. Suppose that a randomized clinical trial comparing two treatments is in progress, and a physician has an opinion about which treatment is better. The physician has a duty to promote the patient's best medical interests and therefore seems to be obliged to advise the patient to receive the treatment that the physician prefers. This duty creates a barrier to the enrollment of patients in randomized clinical trials.1-10 Two strategies are often used to resolve the dilemma in favor of enrolling patients in clinical trials

Don Marquis

Freedman B

Gifford R

Markman M

Spodick DH

Wikler D

English

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How to Resolve an Ethical Dilemma Concerning Randomized Clinical Trials

Marquis, Don

KU ScholarWorks

 SOUNDING BOARD Volume 341 Number 9 · 691 Sounding Board H OW   TO  R ESOLVE   AN  E THICAL  D ILEMMA  C ONCERNING  R ANDOMIZED  CLINICAL TRIALSN apparent ethical dilemma arises when physi-cians consider enrolling their patients in ran-domized clinical trials. Suppose that a randomizedclinical trial comparing two treatments is in progress,and a physician has an opinion about which treat-ment is better. The physician has a duty to promotethe patient’s best medical interests and thereforeseems to be obliged to advise the patient to receivethe treatment that the physician prefers. This dutycreates a barrier to the enrollment of patients in ran-domized clinical trials.1-10 Two strategies are oftenused to resolve the dilemma in favor of enrolling pa-tients in clinical trials. THE “EITHER YOU KNOW WHICH IS BETTER OR YOU DON’T” STRATEGYAccording to one strategy, physicians should notrecommend one treatment over another if they donot really know which one is better, and they do notreally know which treatment is better in the absenceof data from randomized clinical trials.11 Data fromuncontrolled studies are often influenced by the de-sire on both the investigator’s part and the patient’spart to obtain positive results.12 Journal editors aremore likely to publish reports of studies with posi-tive results than reports of studies with negative re-sults.13 A treatment recommendation based on weak-er evidence than that obtained from a randomizedclinical trial is like a recommendation based on amere hunch or an idiosyncratic preference.14 Thus,according to this argument, in the absence of datafrom a randomized clinical trial, evidence that pro-vides an adequate basis for recommending a treat-ment rarely exists, and the enrollment dilemma isbased on a mistake.This strategy for resolving the dilemma is simplis-tic. It assumes that evidence available to physicianscan be only one of two kinds: gold-standard evi-dence or worthless prejudice. But clinical judgmentsmay be based on evidence of intermediate quality,including physicians’ experience with their own pa-tients, their conversations with colleagues concern-ing their colleagues’ experience, their evaluation ofthe results of nonrandomized studies reported in theliterature, their judgment about the mechanism ofaction of one or both treatments, or their view ofthe natural history of a given disease. Evidence neednot be conclusive to be valuable; it need not be de-finitive to be suggestive. Because all good physiciansAallow evidence of intermediate quality to influencetheir professional judgment when a relevant random-ized clinical trial is not being conducted, it is unrea-sonable to claim that such evidence has no worthwhen a relevant randomized clinical trial is beingconducted. Therefore, the “either you know whichis better or you don’t” strategy for dealing with theenrollment dilemma is not persuasive.ADOPTING A LESS STRICT THERAPEUTIC OBLIGATIONThe dilemma about enrolling patients in random-ized clinical trials is generated by the claim that a phy-sician has a strict therapeutic obligation to inform thepatients of the physician’s treatment preference, evenwhen the preference is based on evidence that is notof the highest quality. The dilemma could be resolvedif the physician’s therapeutic obligation were lessstrict. This strategy was developed by Freedman.14,15He argued that the standard for determining wheth-er a physician has engaged in medical malpractice orcommitted some other violation punishable by aprofessional disciplinary body is the standard of goodpractice as determined by a consensus of the medicalcommunity. There is no consensus about whichof two treatments being compared in a randomizedclinical trial is superior. (Otherwise, why conductthe trial?) Therefore, enrolling a patient in the trialdoes not violate the physician’s therapeutic obliga-tion to the patient, regardless of the physician’s treat-ment preference. In addition, a patient who consultsa physician with a preference for treatment A couldhave consulted a physician who preferred treatment B.Therefore, enrolling a patient in a randomized clin-ical trial in order to be randomly assigned (perhaps)to treatment B does not make such a patient worseoff than he or she would otherwise have been.Despite these points, compelling arguments for thestricter interpretation of therapeutic obligation re-main. In the first place, consider what physicians ex-pect when they seek professional advice from theirmalpractice attorneys, their tax advisors, or for thatmatter, their own physicians. Surely they expect —and believe they have a right to expect — not merelyminimally competent advice, but the best profes-sional judgments of the professionals they have cho-sen to consult. In the second place, patients choosephysicians in order to obtain medical advice that is,in the judgment of those physicians, the best avail-able. If physicians do not provide such advice, thenthey tacitly deceive their patients, unless they dis-close to their patients that they are not bound bythis strict therapeutic obligation. Physicians shouldadopt the strict therapeutic obligation.A RESOLUTION The clash between a strict therapeutic obligationand a less strict one is only apparent. On the oneThe New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF KANSAS MEDICAL CENTER on February 11, 2015. For personal use only. No other uses without permission.  Copyright © 1999 Massachusetts Medical Society. All rights reserved. 692 · August 26, 1999The New England Journal  of  Medicinehand, the less strict therapeutic obligation is sup-ported by the argument that it is morally permissibleto offer to enroll a patient in a randomized clinicaltrial. On the other hand, the strict therapeutic obli-gation is supported by the arguments concerningtreatment recommendations. Recommending is dif-ferent from offering to enroll. A recognition of thisdifference provides the basis for a solution to the di-lemma. Suppose that a randomized clinical trial is beingconducted to compare treatments A and B and thata physician prefers A and informs the patient of thispreference. All physicians have an obligation to ob-tain their patients’ informed consent to treatment. Aphysician has respected this right only if he or sheexplains to the patient the risks and benefits of rea-sonable alternatives to the recommended treatmentand offers the patient an opportunity to choose analternative, if that is feasible. Either treatment B orenrollment in the trial comparing A and B is a rea-sonable alternative to treatment A, because presum-ably, A is not known to be superior to B. Indeed,there is some evidence that enrollment in a random-ized clinical trial is a superior therapeutic alternativewhen a trial is available.16 Respect for a patient’s val-ues is a central purpose of informed consent. A par-ticular patient may place a greater value on partici-pation in a study that will contribute to medicalprogress and to the well-being of patients in the fu-ture than on the unproved advantages of followingthe physician’s recommendation. Therefore, a physi-cian can both recommend a treatment and ask wheth-er the patient is willing to enroll in the randomizedclinical trial.This resolution is based on the recognition thatthere can be evidence of the superiority of a treat-ment that falls short of the gold standard for evi-dence but is better than worthless. It also takes intoaccount the good arguments for the view that phy-sicians have a strict obligation to recommend thebest treatment on the basis of their professionaljudgment, even when the recommendation is basedon evidence that falls short of the gold standard.Nevertheless, because all physicians have an obliga-tion to take informed consent seriously, because re-spect for informed consent entails offering a patientthe reasonable alternatives to the recommended treat-ment, and because enrollment in an appropriate ran-domized clinical trial is often a reasonable therapeu-tic option, one could argue that offering a patientthe opportunity to be enrolled in a clinical trial isnot only morally permissible but, in many cases, alsomorally obligatory, if a relevant trial is being con-ducted and if enrollment in it is feasible. Taking in-formed consent seriously resolves the dilemma aboutwhether to enroll patients in randomized clinical trials. Is this analysis clinically realistic? Some may arguethat if clinicians inform their patients that they prefertreatment A, then few of their patients will consentto participate in a trial comparing A with B. Further-more, many clinicians may be unwilling to invest thetime necessary to explain the option of enrollmentin a trial, particularly if it seems unlikely that a pa-tient, knowing the physician’s preference for one ofthe treatments, will choose to participate in the trial. On the other hand, in recent years the public hasbeen exposed to a barrage of medical informationand misinformation. Explaining to patients the dif-ference between solid scientific evidence of the mer-its of a treatment and weaker evidence of its meritsis worthwhile, whether or not a relevant randomizedclinical trial is being conducted. When a relevant tri-al is being conducted, offering the patient enroll-ment in the trial should not impose on the physiciana large, additional burden of explanation. Physicianscan promote enrollment by explaining that theirpreference is based only on limited evidence, whichmay or may not be reliable. They can also explainthat data from randomized clinical trials have oftenshown that the initial studies of new treatments wereoverly optimistic.17 In addition, using this informed-consent strategyto resolve the enrollment dilemma may not be mor-ally optional. My analysis is based on two importantobligations of physicians. The first is the strict obli-gation to recommend the treatment that is, in thephysician’s professional judgment, the best choicefor the patient. The second is the obligation to ob-tain the patient’s informed consent to the recom-mended treatment. The duty of obtaining informedconsent implies that the physician is obligated to of-fer the patient the opportunity to enroll in a clinicaltrial when one is available, even if the physician hasa treatment preference. The physician owes this dutyto the individual patient, not simply to future pa-tients who may benefit from advances in medicalknowledge. Thus, the informed-consent strategy forresolving the dilemma about enrolling patients inrandomized clinical trials leads to the conclusionthat physicians have a greater duty to offer their pa-tients enrollment in trials than has previously beenrealized. A strict, thoroughly defensible, therapeuticobligation need not interfere with the conduct ofrandomized clinical trials.DON MARQUIS, PH.D.University of KansasLawrence, KS 66045I am indebted to Erin Fitz-Gerald, Nina Ainslie, Stephen Wil-liamson, Sarah Taylor, Jerry Menikoff, Don Hatton, and RonStephens for their criticisms.REFERENCES1. Chalmers TC. The ethics of randomization as a decision-making tech-nique and the problem of informed consent. Report of the 14th conference The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF KANSAS MEDICAL CENTER on February 11, 2015. For personal use only. No other uses without permission.  Copyright © 1999 Massachusetts Medical Society. All rights reserved. SOUNDING BOARDVolume 341 Number 9 · 693of cardiovascular training grant program directors, June 3–4, 1967. Bethes-da, Md.: National Heart Institute, 1967:87-93.2. Shaw LW, Chalmers TC. Ethics in cooperative clinical trials. Ann N Y Acad Sci 1970;169:487-95.3. Kolata GB. Clinical trials: methods and ethics are debated. Science 1977;198:1127-31.4. Wikler D. Ethical considerations in randomized clinical trials. Semin Oncol 1981;8:437-41.5. Schafer A. The ethics of the randomized clinical trial. N Engl J Med 1982;307:719-24.6. Marquis D. Leaving therapy to chance. Hastings Cent Rep 1983;13:40-7.7. Gifford R. The conflict between randomized clinical trials and the ther-apeutic obligation. J Med Philos 1986;11:347-66.8. Hellman S, Hellman DS. Of mice but not men: problems of the ran-domized clinical trial. N Engl J Med 1991;324:1585-9.9. Gifford R. Community equipoise and the ethics of randomized clinical trials. Bioethics 1995;9:127-48.10. Markman M. Ethical difficulties with randomized clinical trials involv-ing cancer patients: examples from the field of gynecologic oncology. J Clin Ethics 1992;3:193-5.11. Spodick DH. Ethics of the randomized clinical trial. N Engl J Med 1983;308:343.12. Passamani E. Clinical trials — are they ethical? N Engl J Med 1991;324:1589-92.13. Altman L. Negative results: a positive viewpoint. New York Times. April 29, 1986:B6.14. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141-5.15. Idem. A response to a purported ethical difficulty with random-ized clinical trials involving cancer patients. J Clin Ethics 1992;3:231-4.16. Davis S, Wright PW, Schulman SF, et al. Participants in prospective, randomized clinical trials for resected non-small cell lung cancer have im-proved survival compared with nonparticipants in such trials. Cancer 1985;56:1710-8.17. Sacks H, Chalmers TC, Smith H Jr. Randomized versus historical con-trols for clinical trials. Am J Med 1982;72:233-40.©1999, Massachusetts Medical Society.The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF KANSAS MEDICAL CENTER on February 11, 2015. For personal use only. No other uses without permission.  Copyright © 1999 Massachusetts Medical Society. All rights reserved. 

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How to Resolve an Ethical Dilemma Concerning Randomized Clinical Trials

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