ResearchEthics and Misguided M o d Intuition

he term “therapeutic misconception” was coined by Paul Appelbaum and his colleagues to describe T the tendency of patients enrolled in clinical trials

to confuse research participation with the personal clinical attention characteristic of medical care.’ It has not been recognized that an analogous therapeutic misconception pervades ethical thinking about clinical research with patient-subjects. Investigators and bioethicists often judge the ethics of clinical research based on ethical standards appropriate to the physician-patient relationship in thera- peutic medicine. This ethical approach to clinical research constitutes a misconception because it fails to appreciate the ethically si@icant differences between clinical research and clinical care.

In this article I argue that the assumption that the ethical principles governing the practice of therapeutic medicine should also apply to clinical research with patient- subjects produces incoherence in research ethics and erroneous guidance concerning certain controversial research designs. The conflation between the ethics of clinical research and the ethics of clinical medicine is traced to an error in ethical judgment and reasoning derived from misguided moral intuition. In what follows I illustrate and diagnose this therapeutic misconception about the ethics of clinical research, offer some hypotheses to suggest why it has taken hold in ethical thinking, and reply to objections to h s critique.

I”cE IN THE ETHICS OF CLINICAL &!SEARCH: THE DXURATION OF mINKI

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JoumalofLaw, Medicine6 Etbkx, 32 (2004): 111-116. 0 2004 by the American Society of Law, Medicine & Ethics.

the ethics of clinical medicine is notably manifested in 7he Declaration of Hekink, which stipulates “ethical principles for medical research involving human subjects.”* Principle number 3 states, “The Declaration of Geneva of the World Medical Association binds the physician with the words, ‘The health of my patient will be my first consideration.”’ This is certainly a sound principle for the ethics of thera- peutic medicine; however, its appearance in the leading international code of ethics for clinical research is puzzling. It implies that clinical research should be governed by the patient-centered therapeutic beneficence characteristic of medical care.

The Declaration also contains principle number 5 stating that “In medical research on human subjects, considerations related to the well-being of the human sub- ject should take precedence over the interests of science and society.” This provides sound guidance for clinical research insofar as it directs investigators to avoid exploit- ing research subjects and seriously compromising their well-being for the sake of science. However, if consider- ations relating to the well-being of research subjects should always take precedence over the interests of science and society, how can any research risks be justified that are not compensated by potential medical benefits to the subjects? It is generally considered ethical for physician-investiga- tors to perform nontherapeutic research interventions, such as blood draws, lumbar punctures, and imaging proce- dures, in studies of pathophysiology of disease and to measure outcomes of clinical trials. Although these research risks are often no more than minimal, they potentially threaten subjects’ well-being. An ethical code for guiding a practice is incoherent if it stipulates principles the applica- tion of which would make the practice impossible.

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DIFFERmm- CUNICALRESEARCHAND CLINICALMEDICINE

context of clinical research. Conflating the ethics of clinical research with the ethics of clinical medicine can be seen in intuitive moral judgments concerning controversial research practices. Consider the following three scenarios: Physicians in clinical practice aim at providing optimal

medical care for individual patients who seek their help. The prospect of medical benefits for individual patients justifies the risks of medical interventions. Clinical medi- cine, accordingly, is governed ethically by the principles of therapeutic beneficence and therapeutic nonmaleficence.

Clinical research is not a therapeutic activity devoted to the personal care of particular patients. It is designed to answer scientific questions by producing generalizable knowledge, Physician-investigators design and conduct scientific experiments to learn about disease and its treat- ment in groups of patients, with the ultimate aim of improving medical care. Basic features of randomized clical trials, often erroneously described as “therapeutic re~earch,”~ exhibit the ethically significant differences between clinical research and clinical care. Treatments being evaluated are selected by chance, not by an individualized assessment of what is best for a particular patient. To produce interpretable data and valid conclusions, double- blind conditions and often placebo controls are employed. For similar reasons, scientific protocols governing clinical trials typically restrict flexibility in dosing of study drugs and use of concomitant medications. Trials often include drug washouts before randomization to establish a drug- free baseline to assess treatment efficacy and avoid confounding the effects of study drugs with those of treat- ments taken prior to trial participation. Research interventions such as blood draws, lumbar punctures, imaging procedures using radiation, and biopsies, are often administered to measure trial outcomes. These drug washouts and research interventions pose risks to partici- pants that are not compensated by medical benefits to them.

Given the purpose and characteristic methods of clini- cal research, it is misguided to treat clinical research as governed by the principles of therapeutic beneficence and therapeutic nonmaleficence. Clinical research, which is not aimed at personal medical benefit, would be impossible if all the risks of research interventions had to be justified by their potential benefits for participants. These differences in purpose and method make risk-benefit assessment sig- nificantly different in clinical research than in clinical medicine. In virtually all cases of clinical research, at least some of the risks are justified not by medical benefits to participants but by the anticipated knowledge to be gained.

MISGUIDED MORAL I”IoN

1. Ciical trials that test the efficacy of a new treatment for a disorder against a placebo control when proven effective treatment is clinically available for that disorder. Use of sham suxgery as a control intervention in a randomized clinical trial to evaluate rigorously a new or clinically available surgical procedure. Psychiatric “challenge” studies that administer phannacologic agents or psychological stimuli to patients that are likely to provoke characteristic symptoms for the purpose of investigating the pathophysiology of psychiatric disorders.

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Each of these scenarios is likely to evoke the intuitive judgment that “Doctors shouldn’t do that!” The moral think- ing behind these judgments of the three scenarios might be elaborated as follows. First, physicians are obligated to offer treatment to patients according to “the standard of care” in professional medical practice, and therefore should not enroll patients in placebecontrolled trials when proven effective treatment is available. Second, surgeons have the license and privilege to invade the body only for the sake of healing or providing needed treatment. Therefore, it is unethical to perform a fake operation as a control inter- vention in clinical trials. Third, in contrast to low-risk nontherapeutic research, symptom-provoking challenge studies in patients appear counter-therapeutic. Physicians should not deliberately make patients sick for the sake of scientific investigation. Hence, symptom-provoking studies are morally problematic, if not unethical.

These sorts of moral intuition about what physicians should and should not do are used in research ethics in two ways. They underlie ethical prescriptions absolutely prohibiting certain research practices, as in the prevailing bioethical positions concerning placebo controls when proven effective treatments exist! and the use of sham surgery.5 Alternatively, they may be understood as indica- tors that certain research practices are morally problematic and stand in need of compelling justification. I shall criticize both applications of these moral intuitions with respect to the three scenarios by arguing that absolute prohibitions of these practices are not juait?ed, and that inso- far as these practices are morally problematic it is notbecause they depart from the ethics of therapeutic medicine.

Before undertaking a critique of these moral intuitions, it is worth noting their plausibility or “face validity.” Physi- cian-investigators are physicians as well as scientists. Many research participants are patients in the sense that they are being studied because they have a medical condition.

The therapeutic misconception about the ethics of clinical research leads to erroneous moral judgments about specific types of research practices, which transpose moral evaluation appropriate to clinical medicine to the different

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Moreover, it is likely that in volunteering for clinical trials, these patient-subjects are seeking medical benefit. Physi- cians in clinical practice have an obligation to offer patients treatment that conforms to the professional standard of care. This therapeutic obligation invokes the principle of beneficence. As a rule, physicians practicing medicine are justified in exposing patients to risks of harm only insofar as these risks are reasonably believed to be compensated or outweighed by the potential benefits of medical inter- ventions. This medical risk-benefit ratio invokes the principle of nonmaleficence.

Are intuitive moral judgments that are appropriate to the domain of clinical medicine also accurate when ap- plied to clinical research with patient-subjects? One test of accuracy is to see if their role in grounding absolute prohi- bitions of research practices, as in the three scenarios, can withstand critical scrutiny. A single counterexample rehtes an absolute prohibition. Consider three specific cases fall- ing under the three generic scenarios:

1. A placebo-controlled trial of a new treatment for allergic rhinitis, despite the fact that proven effective treatments exist. A sham-controlled trial of arthroscopic surgery for arthritis of the knee. A symptom-provoking study of patients with panic disorder that administers CO, to elicit panic attacks.

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A thorough ethical analysis of each of these three cases would require an account of the social or scientific value of the questions or hypotheses investigated by these three studies and the scientific rationale for the respective study designs6 Presuming that a persuasive account of scientific merit could be provided, I shall focus on the key question of whether there is a favorable risk-benefit ratio justLfying the conduct of these studies. Is it ethically acceptable for investigators to invite patients to be exposed to the level of risk involved in these studies for the sake of generating knowledge that may improve patient care?

To answer this question involves four steps: (1) iden- tifying the risks posed to subjects; (2) determining whether the risks have been minimized; (3) judging that the risks not balanced by medical benefits to the subjects fall within an acceptable threshold; and (4) assessing whether these risks are justified by the potential benefits of scientitic knowl- edge to be gained from the research. What, then, are the risks to patient volunteers with allergic rhinitis randomized to placebo, of sham arthroscopic knee surgery, and C0,- induced panic attacks? Short-term lack of pharmacologic treatment for allergic rhinitis owing to placebo assignment may produce mild symptomatic discomfort; however, it poses no threat to health, provided that the trial adopts reasonable eligibility criteria, participant monitoring pro- cedures, and rules for stopping participation and initiating

treatment in the event of significant symptomatic worsen- ing. The risks of sham arthroscopic knee surgery as performed in a recently reported landmark study derived from three onecentimeter skin incisions after receiving a tranquilizer and opioid drug.’ The sham surgery thus posed minor risks of discomfort, complications from a minimally invasive procedure, and the side effects of safe anesthetic agents. Finally, challenge experiments administering CO, provoke a transient panic attack lasting at most a few minutes in most, but not all, patients diagnosed with panic disorder.” Though associated with psychic distress, these symptoms are familiar to the patients. No data exist indicating that such experimental panic provocation produces intolerable discomfort or any lasting harm.

Each of these three studies exposes patient volunteers to risks of mild to, at most, moderate discomfort and mini- mal, or slightly more than minimal, risk of serious, lasting harm without compensating medical benefit. Whether the risks have been minimized depends on detailed consider- ation of the study design and procedures in place to protect participants. For the sake of the argument, let us assume that the risks in each of these studies have been minimized in the sense that there is no alternative, sufficiently rigor- ous study design that presents less risk. I submit that the level of risks to participants is not excessive and the value of the knowledge to be gained by these studies - from rigorous testing of treatment efficacy in the first two cases and insight into the pathophysiology of panic disorder in the third - justifies the relatively minor risks to which patients are exposed. If this research risk-benefit assess- ment is sound, then these three cases represent counterexamples to an absolute prohibition of the three scenarios.

According to the argument, the three scenarios are not inherently unethical because cases exempllfylng each of them are ethically justifiable. Alternatively, should they be considered as morally problematic practices that stand in need of justification? If so, what makes them problematic is not departure from the ethics of therapeutic medicine. Rather, the types of research design involved in the three scenarios could be considered morally problematic in specific cases if there is reason to doubt their scientific merit or the justification of risks to which research subjects are exposed. It follows that ethical evaluation of these three scenarios should not be considered different in principle from the assessment of any research involving procedures that pose risks to subjects without compensating medical benefits: for example, a blood draw in an exploratory genetics study and a positron emission tomography scan, using lowdose radiation, to study abnormal brain func- tion. The key ethical issues in evaluating these and other research designs are whether they are necessary to answer valuable scientific questions and whether the knowledge gained by the research can justlfy the risks.

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Although indispensable to ethical thinking, moral in- tuitions are fallible. Kekes notes that one of the main causes of fallibility of moral intuitions is “to rely on them in the wrong ~ontext.”~ Moral intuitions about the appropriate conduct of doctors providing patient care often give erro- neous guidance when applied to the different context of clinical research, as in the case of the three scenarios.

REASONS FOR CONFIATION

Although the differences between clinical research with patient-subjects and clinical medicine in purpose and method are familiar, their ethical significance has not been sufficiently appreciated. What, then, accounts for the misguided moral intuitions that conflate the ethics of these two domains? The universal experience in developed societies of being a patient under the care of a doctor and the socialization of investigators as physicians give rise to deep-seated expectations about the ethical deportment of physicians. These expectations are readily, but erroneously, transported to the context of clinical research. The idea that physicians are devoted to the health and well-being of patients is so deeply ingrained that it is difficult to grasp that clinical research conducted by physicians in clinical settings is not also devoted to the health and well-being of patients enrolled in research.

In addition, medical ethics is much older and better understood than the ethics of clinical research. Moreover, the leading contemporary approach to medical ethics, which appeals to four principles - autonomy, nonmaleficence, beneficence, and justicelo- may be understood by many investigators and bioethicists in a way that conflates the ethics of clinical research and the ethics of clinical medi- cine. Each of these principles applies to medical care and clinical research. Because these principles are more famil- iar in the context of therapeutic medicine, it may be presumed that they have essentially the same meaning in guiding and jusufying ethical judgments in clinical research. However, the meaning or “specification” of beneficence and nonmaleficence is very different in these two domains. In the case of medical practice, beneficence and nonmaleficence are specified in terms of the personalized therapeutic purpose of medical care. Physicians providing medical care aim at promoting the health of particular patients and avoiding interventions that pose risks to patients that are not justified by their potential for thera- peutic benefit. In contrast, clinical research aims to benefit future patients and society and permits risks to subjects that are justified by the value of scientific knowledge. The misguided moral intuition about research designs is paral- leled on the level of principle by the presumption that the therapeutic understanding of beneficence and nonmaleficence in the case of medical care should also apply to clinical research.

h Y “0 OQJECTIONS

Distinguishing the ethics of clinical research from the ethics of clinical medicine is subject to at least three objec- tions that merit critical attention. First is the concern that without appeal to norms drawn from medical ethics, there are no ethical grounds for protecting research subjects. The argument that therapeutic beneficence and therapeu- tic nonmaleficence do not properly apply to clinical research opens the door to rampant exploitation under a utilitarian ethic, which sanctions sacrificing the well-being of research subjects for the sake of scientific progress. Specifically, among the twenty-two cases of research abuses noted by Beecher in his classic expos6 were three cases under the heading “Known Effective Treatment Withheld.””

Because research ethics is not properly governed by therapeutic norms, it does not follow that “anything goes.” that there are no ethical constraints on scientific investiga- tion to protect research participants. Emanuel, Wendler, and Grady explicate seven ethical requirements of clinical research, which together ground stringent protection of research subjects: (1) scientific or social value; (2) scientific validity; (3) fair subject selection; (4) favorable risk-benefit ratio; ( 5 ) independent review; (6) informed consent; and (7) respect for enrolled research participants.I2 These requirements can, and should, be understood in a way that does not imply that research is governed by the ethics of therapeutic medicine. Critical to an accurate ethical understanding of clinical research is recognizing that risk- benefit assessment, as suggested above, is different in this domain than in clinical medicine. The ethics of clinical research permits risks to subjects that are not compensated by medical benefits to them, provided that these risks are minimized in the context of valid research design, are not excessive, and are justified by the knowledge to be gained by the research.

In other words, to argue that investigators do not have the same therapeutic obligations to patients in the context of clinical research as in medical care does not imply that they have no obligation to protect research participants from harm and exploitation. Beecher’s three cases woutd all be unethical by virtue of having an unfavorable re- search risk-benefit ratio. In these cases, the withholding of treatment - penicillin for rheumatic fever and chloram- phenicol for typhoid fever - in untreated control groups posed known serious risks of mortality and morbidity that could not be justified by the scientific value of the research. Nevertheless, withholding known effective treatment in scientifically valuable and well-designed clinical trials is not inherently unethical and may be justified if the risks to participants are not excessive.

A second objection is that assessing the risks involved in placebo controls when proven effective treatment exists, and in other such departures from the standard of

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care in clinical medicine, presupposes application of the principle of therapeutic benefi~ence.’~ It is true that an understanding of the standard of care in medical practice is usually necessary to identlfy risks from placebo controls. The major research risks of pill placebos derive from with- holding clinically available effective treatment. However, risk assessment that relies on comparison of a placebo control with the standard of care in medical practice does nor entail that investigators have a therapeutic obligation to ensure that research participants receive treatment in accordance with the standard of care. Placebo controls and other research interventions that depart from the stan- dard of care in medical practice should be evaluated in terms of whether they are methodologically indicated, their risks are not excessive, and they are justified by the poten- tial benefits of scientific knowledge accruing from their use. In sum, therapeutic beneficence and nonmaleficence do not govern risk-benefit assessment in clinical research.

Thirdly, it may be objected that clinical research with patient-subjects is inextricably bound up with clinical care. Patients may shuttle back and forth between clinical care and trial participation under the supervision of the same physicians. Research observations are often tacked on to treatment according to the standard of care. Patients may be offered “treatment optimization” after completing a clinical trial and before being discharged. Hence, it is unrealistic and unreasonable to attempt any strict separa- tion between the ethics of clinical research and the ethics of clinical medicine.

Ethical clarity depends on discriminating those activi- ties in the context of research that involve care directed by therapeutic standards from research interventions that do not. Admittedly, this is likely to be easier at the stages of planning and ethical review of research protocols than in the midst of conducting clinical research. Especially in the context of research with severely ill patients, physician- investigators have a responsibility to provide appropriate medical attention and care at the same time that they are engaging in scientific investigation. Nonetheless, profes- sional integrity of investigators requires an ability to discern whether their activities are devoted to patient care, guided by therapeutic norms, or to scientific investigation, guided by norm appropriate to clinical research.’*

The fact that medical knowledge and skill are needed for clinical investigation - to conduct valid science, protect research subjects, and provide ancillary medical care - does not imply that physician-investigators performing research activities are governed by the principles of therapeutic beneficence and therapeutic nonmaleficence. The ethical imperative of investigators to use medical knowl- edge and slull to protect patients from undue risks of harm in the context of research is distinct from the obligation to do what is best therapeutically for patients. The latter is a guiding principle of medical care, including medical care

provided in the context of research; the former is an ethical constraint on the pursuit of clinical research that is necessar- ily devoted to a nontherapeutic purpose.

CONCLUSION Misguided moral intuition leads to erroneous ethical judg- ments that condemn justifiable research practices. Research practices that depart from therapeutic norms are not inher- ently unethical. Transporting ethical judgments appropriate to clinical medicine to the different context of clinical research produces incoherence in research ethics. More- over, clinical research is impossible to conduct in accordance with the principles of therapeutic beneficence and thera- peutic nonmaleficence. We cannot have it both ways: endorsing clinical research as a socially valuable enterprise, which is markedly different from medical care, while insisting that physician-investigators should be guided by the ethics of therapeutic medicine.

ACKNO- The author thanks Dan Brock, Donald Rosenstein, and Dave Wendler for helpful comments on previous drafts of this article.

DKIAlMER

The opinions expressed are those of the author and do not necessarily reflect the position or policy of the National Instimtes of Health, the Public Health Service, or the Department of Health and Human Services.

REFERENm 1. P.S. Appelbaum et al., “False Hopes and Best Data: Con-

sent to Research and the Therapeutic Misconception,” Hastings Center Report 17, no. 2 (1987): 20-24.

World Medical Association, “Declaration of Helsinki: Ethi- cal Principles for Medical Research Involving Human Subjects,” JAM4 284 (2000): 3043-3045.

R.J. Levine, Ethics and Regulation of Clinical Research, 2nd edition (New Haven: Yale University Press, 1986): at 8-10,

See B. Freedman, K.C. Glass, and C. Weijer, “Placebo Orthodoxy in Clinical Research 11: Ethical, Legal, and Regulatory Myths,” Journal of Law, Medicine &Ethics 24 (1996): 252-259; and T.L. Beauchamp and J.F. Childress, Principles of Biomedical Ethics (New York: Oxford University Press, 2001): at 327.

See P.A. Clark, “Placebo Surgery for Parkinson’s Dis- ease: Do the Benefits Outweigh the Risks?” Journal of law, Medicine &Ethics 30 (2002): 58-68; and C. Weijer, “I Need a Placebo Like I Need a Hole in the Head,” Journal of Law, Medi- cine &Ethics 30 (2002): 6F72.

See E.J. Emanuel and EG. Miller, “The Ethics of Pla- cebo-Controlled Trials -A Middle Ground,” N. Engl. J. Med. 345 (2001): 915-919; S. Horng and F.G. Miller, “Is Placebo Surgery Unethical?” N. Eng1.J. Med. 347 (2002): 137-13% and F.G. Miller

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and D.L. Rosenstein, “Psychiatric Symptom-Provoking Studies: An Ethical Appraisal,” Biological Psychiatry 42 (1997): 403-403.

J.B. Moseley et al., “A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee,” N. Engl. J. Med. 347 (2002): 81-88.

Y. Rassovsky and M.G. Kushner, “Carbon Dioxide in the Study of Panic Disorder: Issues of Definition, Methodology, and Outcome,” Journal of Anxiety Disordets 17 (2003): 1-32.

J. Kekes, “Mordl Intuition,” American Philosophical

T.L. Beauchamp and J.F. Childress, prlnc@ks of Bio-

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medical Ethics, 5th edition (New York: Oxford University Press, 2001).

11. H.K. Beecher, “Ethics and Clinical Research,” N. Engl. J. Med. 274 (1W): 1354-1360.

12. EJ. Emanuel, D. Wendler, and C. Grady, “What Makes Clinical Research Ethical?” JAMA 283 (2000): 2701-271 1.

13. T.F. Ackerman, “Therapeutic Beneficence and Placebo Controls,” A?n&can Journal of Bioethics 2, no. 2 (2002): 21-22.

14. F.G. Miller, D.L. Rosenstein, and E.G. DeRenzo, “Profes- sional Integrity in Clinical Research,”J’ 280 (1998): 1449-1454.

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