Ethical Dilemmas in Medical Innovation and Research: Distinguishing Experimentation From Practice Norman Fost
The words research and experimentation continue to have the power to evoke fear in potential subjects. But much of standard practice, particularly in critical care settings, involves interventions of unknown efficacy and safety. Innovation also abotmds in practice settings, typically unchecked by prospective or retrospective review. Historical attention has focused on the conflict of interest of the physician/investigator, but contemporary safeguards have reduced the risks of research and increased the likelihood that the patient/subject will have the opportunity to make an informed choice. Innovation and untested interventions in practice, in contrast, are often unknown to the patient and lack institutional safeguards. Some common cliches that suggest that research is more to be feared than standard practice will be examined, leading to the following conclusions: defining an intervention as experimental may be less important in ethical terms than the quality of prospective and retrospective review and the standards for informed consent, and the concerns that led to regulation of research should now be directed toward unproven interventions and innovation in the practice setting. Copyright 9 1998 by W.B. Saunders Company
As long as you promise not to learn anything from what you're doing, you don't have to go through an institutional review board.
I need permission to give a new drug to half my pa- tients but not to give it to all of them.
"When I use a word, " Humpty Dumpty said, in rather a scornful tone, "it means just what I choose it to mean--neither more nor less." "The question is, "said Alice, "whether you can make words mean so many different things." "The question is," said Humpty Dumpty, "which is to be master--that's all."
--Lewis Carroll 3
l ' f all you knew about human experimentation was what you read or heard in the mass me- dia, you might think that clinical research in- volves ethical problems that are more common, more serious, or more worrisome than standard practice.
There are several possible sources of such a viewpoint. Much of the modern bioethics move- ment had its origins in concerns about unethical experimentation involving human beings, begin-
ning with the disclosures at the Nuremberg tri- als. 4 Beecher 5 and others increased awareness of egregiously unethical research involving patients in the United States in the 1950s and 1960s. In 1973, hearings by Senator Ted Kennedy brought the infamous Tuskegee study 6 to public attention as well as other upsetting, if not unethical, stud- ies, such as studies on midtrimester fetuses kept alive after elective abortions for the purpose of nontherapeutic research. 7 Many of these exam- ples involved interventions of no conceivable or intended benefit to the subjects, confirming popular impressions that to be a research subject means to be used as a guinea pig, or to use Kant's more elegant phrase, being treated solely as a means.
Although the present federal rules and insti- tutional review boards have greatly reduced the chance of seriously unethical research, occa- sional scandals and further exposition of old scandals keep fear alive. The activities and report of the "Radiation Commission ''s received exten-
From the Departments of Pediatrics and History of Medicine, and the Program in Medical Ethics, University of Wisconsin School of Medicine, Madison, WI. Address reprint requests to Norman Fost, MD, MPH, Department of Pediatrics, University of Wisconsin Hospital, 600 Highland Ave, Madison, WI 53792. Copyright 9 1998 by W.B. Saunders Company 0146-0005/98/2203-0007508.00/0
Seminars in Perinatology, Vol 22, No 3 (June), 1998: pp 223-232 223
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sive press coverage, although most of the activi- ties occurred decades ago, before the current system of protections was in place. Legitimate controversies about research design, such as the use of placebos, are compared with the Tuskegee study, 9 even though there are few morally rele- vant points of comparison, a~ A recent change in the federal rules allowing consent to be waived in special situations in which experimental treat- ment may benefit unconscious patients in emer- gency settings was compared with the Nazi exper- iments) 2
Whether or not there are more serious or more common ethical problems in practice or research settings is partly an empirical question, but it also involves questions of definition. How we define words such as experimentation would seem critical to assessing how common it is, as well as a prerequisite to controlling it. The pur- pose of this article is to review some of the diffi- culties in defining and distinguishing experi- mentation, research, and standard practice by identifying and responding to several common misconceptions on the topic. But first, a few gen- eral observations about the limits of definitions in bioethics.
The Limits o f Def init ions
There is a tradition in the brief history of bio- ethics to appeal to definitions to solve complex moral problems. For many years, debates about withholding or withdrawing life-sustaining treat- ment, for example, focussed on whether or not the treatment involved extraordinary means. If it did, the argument went, there was no moral duty to treat. The problem, of course, was that the definition of extraordinary was elusive and not amenable to consensus. It also became ap- parent that some were using their own defini- tions as a short cut to justify actions, avoiding the difficult work involved in finding justifica- tions. In the early years of the "Baby Doe" de- bate, physicians reported that they commonly withheld standard treatment, such as repair of duodenal atresia, from infants with Down syn- drome, claiming that such treatment involved using extraordinary means, la The same physi- cians would argue that the use of the same treat- ment was quite ordinary, and obligatory, if the child did not have Down syndrome and was oth- erwise normal. 14 It was apparent that the means was not the morally relevant factor, but some-
thing about the intelligence and presumed qual- ity of life of the patient.
The same problem surfaces recurrently in the reliance on fetal viability as a morally relevant variable in judgments about the justifications for abortion and other prenatal and neonatal inter- ventions. 15 The concept is central to the land- mark United States Supreme Court decision in Roe V Wade) 6 But the court did not give us a clear definition of viability, stating only that it referred to a point at which the fetus "has the capability of meaningful life outside the mother's womb." This definition, of course, avoids the serious dis- cussion regarding what is meant by "meaningful life," as well as the ambiguity in what is meant by " the" mother. New reproductive technologies allow fertilized eggs to survive outside of the mother 's womb, if "mother" refers to the woman whose egg became fertilized, suggesting that all fertilized eggs are viable and therefore protectable by the state's important interest in potential life. My point is only that the court's simple definition of viability neither settles the complex moral questions nor even provides clear legal guidance.
A more contemporary example is the interest in defining some medical interventions as futile as a way of avoiding the difficulty involved in deciding whether treatment is owed to a patient. Although physicians are competent and war- ranted in making judgments regarding whether a treatment would be physiologically futile, ie, has no reasonable prospect of achieving its physi- ological purpose, the word is more commonly used to justify withholding treatments that are likely to be effective but are considered inappro- priate for social, economic, or other reasons. This kind of justification is not a matter of medi- cal expertise, and therefore cannot be defined by a physician) 7
The longstanding debate about distinguish- ing experimental care from standard practice is in this tradition. Whether a proposed interven- tion is experimental or not has important impli- cations for several policy questions: Must it be reviewed by an institutional review board? Should third-party payers offer reimbursement? What are the standards for informed consent? Many commentators have wrestled with defini- tions of key words--exper imentat ion, research, practice, and so on- - in the hope that clear definitions would make a major contribution to resolving some of the moral, legal, and policy
Ethical Dilemmas in Medical Innovation 225
questions. Although such analysis can be helpful in understanding the issues at stake, many of the critical questions cannot be resolved by defini- tions. I will try to illustrate this by analyzing a series of common myths or misunderstandings.
Definitions cannot do moral work, but they are necessary for communication. The defini- tions proposed by Levine, TM drawing mainly from standard dictionaries, seem useful: To experi- ment means to test something or try something out. Paraphrasing Moore 19 and Levineff much of standard practice involves experimenting. For example, a physician who sees a patient with a sore threat conducts an experiment: He swabs the throat, transfers the material to an agar dish, incubates it, and sees what grows. Depending on the result of that experiment, he may conduct another, involving an antibiotic, to see if it im- proves the patient's condition, and so on. All of this experimentation is done primarily in the interests of enhancing the well-being of the pa- tient.
Research, in contrast, is done primarily for the purpose of developing generalizable knowl- edge for the benefit of others. Research usually involves experimentation, as when the investiga- tor does something to the patient, such as admin- istering a new test or treatment. It need not in- volve new treatments; it may involve comparing standard treatments. Or it may involve interven- tions with no expected benefit to the patient, as in so-called nontherapeutic research studies, designed to advance knowledge about normal or pathological states. And research need not involve doing anything to the patient, as in medi- cal record review or studies of unidentified sam- ples.
Although these definitions are sensible, many use the word experimentation when referring to research as defined above, and use the word practice to refer to interactions that are intended to benefit the patient with no regard to the ad- vancement of knowledge. Despite the impurity of these uses, I will generally use the words exper- imentation and research as they are commonly used, to refer to activities that are intended to advance knowledge, and practice and treatment to refer to diagnostic and therapeutic activities designed primarily for the benefit of the patient.
With that as background, let us now turn to some popular truisms about claimed distinctions between research and experimentation, on the one hand, and standard practice on the other.
Alleged Truisms About the Distinction Between Experimentation and Treatment
1. Research involves trying new interventions of unknown benefit and risk; standard practice involves tested procedures with known benefits and risks.
Much of standard practice involves interventions that have never been adequately tested for safety or efficacy. It has been estimated that 80% of drugs prescribed by pediatricians have never been systematically studied in children. It has been a longstanding concern that clinical trials of new drugs generally exclude women, appar- ently because of concerns of pharmaceutical companies over possible fetal effects. The result is that drugs are approved and then prescribed and become part of standard practice without adequate information about appropriate doses or adverse effects on women or fetuses. Not only may drugs be used on populations in whom they have never been studied; they can be used for clinical purposes that have never been studied on any population. The Food and Drug Adminis- tration (FDA) does not prohibit or discourage physicians from using drugs for unapproved pur- pose. The FDA regulates the suppliers, not the prescribers, and accordingly restricts marketing practices, not use.
The use of unproven interventions is partic- ularly problematic in settings where the most seriously ill patients are treated; namely, emer- gency rooms and intensive care units. Some systematic reasons why clinical research has historically been less likely to occur in these settings are the pressure of clinical work leaves less t ime for clinicians to pursue scholarly in- terest, physicians attracted to these clinical spe- cialties may be more incl ined to action than study, and the imminence of death and the urgent nature of decisions makes it more diffi- cult to contemplate unfamil iar interventions or placebo-control led trials. Until recently, federal rules allowed little leeway for research in emergency settings when informed consent could not be obtained f rom the pat ient or his or her representatives.
Whatever the reasons, the history of neona- tology is replete with interventions that be- came standard practice over many years with- out adequate testing of safety or efficacy and were later found to cause harm without com-
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pensating benefits. 2~ A few examples will make the point.
A. Sulfonamides were given to many newborns for treatment or prevention of serious infec- tions before studies showed that the drug in- creased the risk of free bilirubin diffusing into the brain, causing kernicterus. 22
B. Chloramphenicol was also widely used for treatment of serious infection before studies showed that babies were dying of the "gray baby syndrome," a consequence of the in- ability of the immature liver to metabolize the drug. 2a
C. Exchange transfusion was performed on tens of thousands of otherwise healthy full-term newborns over a period of 30 years because of the unproven assumption that a serum bili- rubin above 20 mg% was associated with the risk of kernicterus. Many infants died of un- necessary procedures, and untold numbers developed complications, including transfu- sion-acquired infections. It is now clear that most of these infants were at no risk for devel- oping kernicterus. 24
D. Concentrated bicarbonate solutions were given intravenously to premature infants af- flicted with hyaline membrane disease to counter the respiratory acidosis brought on by carbon dioxide retention. Odell argued in vain that such therapy made no physiological sense, because the bicarbonate would bind with free hydrogen ions, and produce H2coa, which would dissociate into H~O and CO2, which could not be dissipated through the lungs. Despite animal studies showing the fu- tility of such treatment, the "Usher regimen" of ad...