Ethical dilemmas in medical innovation and research: Distinguishing experimentation from practice

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 o f 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 o f prospective and retrospective review and the standards for informed consent, and the concerns that led to regulation o f 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.

- -Lie tman 1

I need permission to give a new drug to half my patients but not to give it to all of them.

--Smithells 2

"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 h u m a n exper imenta t ion was what you read or heard in the mass me-

dia, you might think that clinical research involves 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 m o d e r n bioethics move- men t had its origins in concerns about unethical exper imenta t ion involving h u m a n beings, begin-

ning with the disclosures at the Nuremberg trials. 4 Beecher 5 and others increased awareness of egregiously unethical research involving patients in the Uni ted States in the 1950s and 1960s. In 1973, hearings by Senator Ted Kennedy b rought the infamous Tuskegee study 6 to public at tention as well as o ther upsetting, if not unethical, studies, such as studies on midtr imester fetuses kept alive after elective abortions for the purpose of nontherapeut ic research. 7 Many of these examples involved interventions of no conceivable or in tended benefi t to the subjects, conf i rming popula r 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 institutional review boards have greatly reduced the chance of seriously unethical research, occasional scandals and fur ther exposition of old scandals keep fear alive. The activities and repor t of the "Radiat ion 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

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sive press coverage, a l though most of the activities occurred decades ago, before the current system of protections was in place. Legit imate controversies about research design, such as the use of placebos, are compared with the Tuskegee study, 9 even though there are few morally relevant points of comparison, a~ A recent change in the federal rules allowing consent to be waived in special situations in which exper imenta l treat- m e n t may benefi t unconscious patients in emergency settings was compared with the Nazi experiments ) 2

Whether or not there are more serious or more c o m m o n 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 exper imenta t ion would seem critical to assessing how c o m m o n it is, as well as a prerequisi te to controll ing it. The purpose of this article is to review some of the diffi- culties in defining and distinguishing experi- mentat ion, research, and standard practice by identifying and responding to several c o m m o n misconcept ions on the topic. But first, a few general observations about the limits of definitions in bioethics.

T h e Limi t s o f Def in i t ions

There is a tradition in the br ief history of bioethics to appeal to definitions to solve complex moral problems. For many years, debates about withholding or withdrawing life-sustaining treatment , for example, focussed on whether or not the t rea tment involved extraordinary means. I f it did, the a rgument 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 apparen t that some were using their own definitions as a short cut to justify actions, avoiding the difficult work involved in finding justifications. In the early years of the "Baby Doe" debate, physicians repor ted that they commonly withheld standard t reatment , such as repair of duodenal atresia, f rom infants with Down syndrome, claiming that such t rea tment involved using extraordinary means, la The same physicians would argue that the use of the same treat- men t was quite ordinary, and obligatory, if the child did not have Down syndrome and was otherwise normal. 14 It was apparen t that the means was not the morally relevant factor, but some-

thing about the intelligence and p resumed quality of life of the patient.

The same p rob lem surfaces recurrently in the reliance on fetal viability as a morally relevant variable in judgments about the justifications for abort ion and o ther prenatal and neonatal interventions. 15 The concept is central to the landmark Uni ted States Supreme Court decision in Roe V W a d e ) 6 But the court did not give us a clear definit ion 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, o f course, avoids the serious discussion regarding what is mean t by "meaningfu l life," as well as the ambiguity in what is mean t by " t h e " mother . New reproductive technologies allow fertilized eggs to survive outside of the mothe r ' s womb, if " m o t h e r " refers to the woman whose egg became fertilized, suggesting that all fertilized eggs are viable and therefore protectable by the state's impor tan t interest in potential life. My point is only that the court 's simple definition of viability nei ther settles the complex moral questions nor even provides clear legal guidance.

A more con temporary example is the interest in defining some medical interventions as futile as a way of avoiding the difficulty involved in deciding whether t rea tment is owed to a patient. Although physicians are compe ten t and war- ranted in making judgments regarding whether a t rea tment would be physiologically futile, ie, has no reasonable prospect of achieving its physiological purpose, the word is more commonly used to justify withholding t reatments that are likely to be effective but are considered inappro- priate for social, economic, or o ther reasons. This kind of justification is not a mat ter of medical expertise, and therefore cannot be def ined by a physician) 7

The longstanding debate about distinguishing exper imenta l care f rom standard practice is in this tradition. Whether a p roposed intervention is exper imenta l or not has impor tan t impli- cations for several policy questions: Must it be reviewed by an institutional review board? Should third-party payers offer re imbursement? What are the standards for in formed consent? Many commenta to rs have wrestled with definitions of key words - - expe r imen ta t ion , research, practice, and so o n - - i n the hope that clear definitions would make a major contr ibut ion to resolving some of the moral, legal, and policy

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questions. Although such analysis can be helpful in unders tanding the issues at stake, many o f the critical questions cannot be resolved by definitions. I will try to illustrate this by analyzing a series of c o m m o n myths or misunderstandings.

Definitions cannot do moral work, but they are necessary for communicat ion. The definitions p roposed by Levine, TM drawing mainly f rom standard dictionaries, seem useful: To experi- m e n t 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 pat ient 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 exper iment , he may conduct another , involving an antibiotic, to see if it im- proves the pat ient 's condition, and so on. All of this exper imenta t ion is done primarily in the interests o f enhancing the well-being of the patient.

Research, in contrast, is done primarily for the purpose of developing generalizable knowledge for the benefi t of others. Research usually involves exper imentat ion, as when the investigator does something to the patient, such as administering a new test or treatment. It need not involve new treatments; it may involve compar ing standard treatments. Or it may involve interventions with no expected benefi t to the patient, as in so-called nontherapeut ic research studies, designed to advance knowledge about normal or pathological states. And research need not involve doing anything to the patient, as in medical record review or studies of unidentif ied sam- ples.

Although these definitions are sensible, many use the word exper imenta t ion when referr ing to research as def ined above, and use the word practice to refer to interactions that are in tended to benefi t the pat ient with no regard to the advancement of knowledge. Despite the impurity of these uses, I will generally use the words exper- imentat ion and research as they are commonly used, to refer to activities that are in tended to advance knowledge, and practice and t rea tment to refer to diagnostic and therapeut ic activities designed primarily for the benefi t of the patient.

With that as background, let us now turn to some popula r truisms about claimed distinctions between research and exper imentat ion, 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 est imated 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 pharmaceut ical companies over possible fetal effects. The result is that drugs are approved and then prescribed and become par t o f s tandard practice without adequate informat ion about appropr ia te doses or adverse effects on women or fetuses. Not only may drugs be used on populat ions in whom they have never been studied; they can be used for clinical purposes that have never been studied on any populat ion. The Food and Drug Adminis- tration (FDA) does not prohibi t or discourage physicians f rom using drugs for unapproved purpose. The FDA regulates the suppliers, not the prescribers, and accordingly restricts market ing practices, not use.

T h e use of u n p r o v e n in tervent ions is part ic- ularly p rob lema t i c in sett ings where the mos t seriously ill pat ients are t reated; namely, emer - gency rooms and intensive care units. Some systematic reasons why clinical research has historically been less likely to occur in these sett ings are the pressure of clinical work leaves less t ime for clinicians to pursue scholarly interest, physicians a t t rac ted to these clinical spe- cialties may be m o r e incl ined to act ion than study, and the i m m i n e n c e of dea th and the u rgen t na ture of decisions makes it m o r e difficult to c o n t e m p l a t e unfami l ia r in tervent ions or p lacebo-con t ro l l ed trials. Until recently, federa l rules allowed little leeway for research in e m e r g e n c y sett ings when i n f o r m e d consen t could no t be ob t a ined f rom the pa t i en t or his or he r representat ives .

Whatever the reasons, the history of neona - tology is rep le te with in tervent ions tha t became s tandard pract ice over m a n y years without adequa te test ing of safety or efficacy and were la ter f ound to cause h a r m wi thout com-

2 2 6 Norman Fost

pensat ing benefits. 2~ A few examples will make the point .

A. Sulfonamides were given to many newborns for t reatment or prevention of serious infections before studies showed that the drug increased the risk of free bilirubin diffusing into the brain, causing kernicterus. 22

B. Chloramphenicol was also widely used for t reatment 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 per formed on tens of thousands of otherwise healthy full-term newborns over a period of 30 years because of the unproven assumption that a serum bilirubin above 20 mg% was associated with the risk of kernicterus. Many infants died of unnecessary procedures, and untold numbers developed complications, including transfusion-acquired infections. It is now clear that most of these infants were at no risk for developing 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 futility of such treatment, the "Usher reg imen" of administering concentra ted solutions of sodium bicarbonate was standard practice for 15 years or more until Simmons showed that concentra ted bicarbonate caused fluid shifts resulting in intracerebral hemorrhage. 25 The practice has been largely abandoned.

E. Oxygen inhalation for hypoxic newborns was used for decades without regard to dose because it was thought unnecessary to assess toxicity for a naturally occurring substance, until Patz established the association between oxygen therapy and retrolental dysplasia.

F. Newborn screening for phenylketonuria (PKU) was mandated by legislation in most states without adequate studies assessing the

toxicity and efficacy of the screening test and the phenylalanine-restricted diet. The result was failure to appreciate that many infants falsely identified as having PKU in fact had a benign form of hyperphenylalaninemia and were exposed to toxic, and sometimes lethal, restrictions of an essential amino acid. The result was general protein malnutrit ion, causing severe brain damage in otherwise normal infants, and occasional deaths due to a kwashiorkor-like s t a t e . 26

In summary, many widely accepted standard practices involve interventions associated with considerable harm and little benefit. Although research interventions commonly involve new and completely untested practices, that is not always the case. Phase III randomized controlled trials may involve comparing two standard treatments to determine which, if either, is superior. The patient may not be exposed to any greater risk than would be the case if he or she were receiving standard care. In some settings, being a research subject may involve less risk than would be the case if the same treatment were being administered under the rubric of standard practice, because the moni tor ing for adverse effects and the oversight f rom the review process may lead to more careful patient follow-up.

It should be noted that clinical trials involving unapproved drugs will generally present the pa- t ient with much higher prospects for risk than benefit. The great majority of drugs that enter phase I testing never become approved.

2. Whether or not an intervention is research or standard practice is an objective question. The correct classification can be determined by answering a series of questions such as whether or not there is an intent to advance knowledge, whether patients will be randomized, whether there is an intent to disseminate the results, or whether the intervention deviates from standard practice.

As chair of an Institutional Review Board (IRB), I am frequently asked whether a proposed innovative procedure requires review and approval, ie, whether it is research. It would be helpful to have a litmus test that could resolve the question, but the answer is often elusive. One common approach relies on the intent of the physician. If his or her purpose is to help the patient, even


if using an innovative, untested, or unproven technique to do so, then he or she is engaging in the practice of medicine. As stated most pun- gently by Lietman, 1 as long as the physician promises not to learn anything f rom what he is doing, he does not need to submit his plan to the IRB.

This reliance on intent is problemat ic because it relies on the integrity of the physician/investigator, whose potential conflicts at interest are at the root of the need for external review. Most physicians are presumably hones t and want to do the right thing, and will also generally defer to IRB review for their own legal protection. But the occasional outlyer can avoid prospective peer review by claiming that he seeks only the welfare of his patients, acknowledging that he may not be able to avoid learning f rom his experiences. He may acknowledge that if a review of his records later uncovers some pat tern or b roader interest, he may disseminate such results through a presentat ion at a scientific meet ing or a scholarly publication. These activities, particularly review of the medical records, might consti- tute research, but not of the sort typically requir- ing IRB review or in formed consent f rom the patients. The would-be investigator could also argue that the future possibility of chart research does not change the nature of the innovative intervention, which was in tended for the benefi t o f the pat ient and not for the creation of new knowledge.

To avoid these ambiguities, some prefer a more objective test of whether an intervention is research, such as whether or not the intervention deviates f rom standard practice or whether patients are being randomized. Deviation f rom standard practice is obviously not a sufficient reason to classify an intervention as research, because much of standard practice is innovative. The Food and Drug Administrat ion (FDA) regulations explicitly allow approved drugs to be used for unapproved purposes if the intent is to benefit the patient. I f the defining feature of research is the search for new knowledge, knowing that a physician is deviating f rom standard practice does not tell us whether he is doing so for the sole benefi t of the pat ient before him, or for the benefi t o f future patients.

Using randomizat ion as a basis for deciding what t rea tment will be offered or given will generally be a valid indicator that there is a major research motive, but in rare instances a physician

may justifiably claim that he is randomizing treatments for some other reason. Such an occasion arose when the director of an infertility clinic was concerned about fairness in allocating a scarce r e sou rce - -name ly , fresh s e m e n - - t o women seeking artificial insemination f rom a donor o ther than their partners. At the time, fresh semen was considered to be more effective than frozen semen, but there was no scientific evidence for this. To avoid bias and unfairness in distributing what he thought was a valuable ser- vice, the physician p roposed randomizing fresh versus frozen semen, with each woman (with appropr ia te consent) given the oppor tuni ty to receive fresh semen in al ternate cycles. The physician realized that randomizat ion would open the possibility for medical record review and the possible discovery of relative benefi t in a way that would be publishable and of benefi t to future patients, but he claimed that his purpose was not research but only to treat his patients in a fair and equitable way.

He eventually published a landmark pape r on the relative efficacy of fresh versus frozen semen. 27 He was later sued by a woman who was exposed to semen f rom a donor who became HIV positive some months after he had donated semen. He was HIV negative on the day of dona- tion, but in re t rospect was possibly infected at the time. The suit was not based on negligence with regard to HIV testing, because the physician was following published standards of practice at the time, but was based on the claim that she was a research subject without having been in- fo rmed of that, and that the physician had failed to comply with laws requir ing institutional review of clinical research. He argued at his trial that there was no intent to do research, and that randomizat ion did not establish such an intent, and the jury suppor ted his view.

There is one o ther criterion sometimes used to de te rmine whether an intervention is experimental , namely, whether it is re imbursed by third-party payors. This is problemat ic in two re- gards. First, it is tautological, because insurers need not, and usually do not, provide a coheren t explanat ion of how they de termine that something is experimental . Second, to the degree that one can discern the underlying basis, it does not seem to be coherent . Sometimes the insurer seems to base the definition on the l ikelihood of a good outcome; eg, if a t rea tment cured a given cancer 5% of the time, it would be consid-

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ered experimental , even if it had been proven in a well-designed trial to have that benefit, and even if it had been standard practice for an ex- tended time. In these cases, the insurer appears to be making a j u d g m e n t on some other grounds, such as cost versus effectiveness, and using the word exper imenta l as a cover. The absence of a coheren t definition may account for the failure of insurance companies to withstand legal attacks on their policies. 2s

My own view is that there is no correct definition, but that the essential e lement , the factor that best captures most of the ethical concerns, has to do with the intent ion of collecting informat ion for the benefi t of others. It is therefore not helpful to refer to highly innovative, untested changes in health care delivery, such as managed care organizations, as "massive experiments . " They may be unwise or immoral for a variety of reasons, but it is not because h u m a n beings are being used to advance knowledge. As I will conclude, there are good arguments for studying innovations like this in formal ways. Such research projects are less likely to be morally problematic than unstudied innovations.

3. Research is more tightly regulated than practice because experimental interventions raise more serious ethical issues than standard practice; being a research subject is generally more risky than being a patient.

Academicians are sometimes understandably perp lexed that clinical research is so tightly regulated as compared with s tandard practice. They point out that the research subject is protected by multiple layers of oversight, including the compet i t ion and review process for funding of clinical studies; federal regulations, with their high standards for institutional review and in- fo rmed consent; the scrutiny of the local IRB; the review of submit ted manuscripts; and the open discussion of results when they are published. In addition, the investigator is likely to work in an academic center, sur rounded by knowledgeable and critical colleagues, and in- quisitive residents and students, and is more likely to be aware of current developments than his counterpar t engaged in pure clinical practice. The practit ioner, in contrast, may have little oversight of his activities, whether they be untested standard practices or adventures in innovative treatment. The major protect ion for the pat ient in the practice setting seems to be the

tort liability system, which most injured patients do not use because they are unaware that they may have been a victim of negligence. Why then is clinical research so much more tightly regulated than standard practice?

One reason is the historical discovery of egregiously unethical conduct by physician-investigators in the Nazi camps dur ing World War II , 4'29

and later studies of a larming misconduct by American researchers. 5 The latter disclosures in particular suggested that physicians who took ex- emplary care of their patients when acting in a clinical role lost their moral compass when they took on the role of researchers. Examples include the studies of Dr Chester Southam in 1963 at the Jewish Chronic Disease Hospital in New York, in which he injected cancer cells into chronically ill patients, without their knowledge or consent, to learn about the role of the im- m u n e system in the deve lopment of clinical cancer. ~~ Other studies, revealed by Beecher and others, include the dispensing of placebos to women who thought they were receiving bir th control pills.

These examples suggested that otherwise hu- mane, sensitive, caring physicians ceased to act in a fiduciary role when they took on the role of researcher. The conflicting in te res t s - -serv ing the needs of the present pat ient as well as those of future possible patients and the wider social g o o d - - a p p a r e n t l y distracted the physician f rom his otherwise single-minded at tention to the interests of the pat ient before him.

Another reason for the relatively greater regulation of research is because it is a discretionary activity. Although tight regulation of research may inhibit or slow down the rate of progress, with the consequence of suffering and death that would otherwise not occur, progress, it was argued, was optional. 31 Causing ha rm is worse than failing to do good; virtually all societies have strict prohibit ions against causing harm, whereas p romot ion of the good or the advancement of knowledge are seen as optional activities.

Finally, research is tightly regulated because it can be. The requirements for funding, as well as the need for FDA approval o f new drugs and devices, presents the would-be researcher with a toll gate through which he or she must pass before he or she can use a pat ient as a subject. IRBs can review all proposals for clinical research. Clinical care, in contrast, is so extensive that such oversight is logistically impractical. Pro-


spective review and approval for all clinical interventions is impossible. Thus, the need to rely on more general forms of oversight, such as peri- odic reviews of privileges and recertification, and reliance on posthoc corrections, such as malpractice litigation and suspension of licensure.

These are historical, practical, and partly philosophical reasons for the tight regulation of research. But the protest of the academician is probably correct, ie, there are almost certainly more f requent and more serious ethical transgressions in the practice setting than in the research setting. This is partly because of the success of the existing research regulations, and also because of the profoundly greater volume of clinical practice.

Nonetheless, public fears of being a research subject seem to exceed the fears of being a patient. Transgressions in the research arena continue to attract the interest of the mass media in a way that seems disproport ional to the magni- tude of the relative problems. Thus, a Presiden- tial Commission 8 exploring injuries to patients exposed to radiation mostly several decades ago, before the establishment of the current research regulations, evoked widespread press coverage. An apology to the victims of the admittedly unethical Tuskegee study also attracted major press attention. In contrast, there has been no comparable attention to the presumably much larger n u m b e r of people who have been unknowingly injured by malpractice, misconduct, or o ther transgressions in the practice setting.

4. Research differs from standard practice in that the physician has serious conflicts of interest.

One of the more remarkable observations in the history of research involving h u m a n subjects is how sensitive, caring physicians can apparent ly undergo a Jekyll-Hyde t ransformation when acting as a researcher. Beecher 's classic repor t was remarkable in the n u m b e r as well as the outra- geousness of some of the studies. 5 One of the early questions was how could a physician who was otherwise widely acknowledged to embody the best qualities of respect and caring for his patients become t ransformed when he assumed the role of researcher. One explanat ion is that the physic ian/ researcher is no longer jus t a physician, whose sole purpose is to help the pat ient before him, but also a scientist with ano ther larger constituency, namely, the larger group of

future patients who can benefi t f rom his work as a scientist. The phys ic ian/ researcher is a double agent, and is at risk of seeing the potential bene- ficiaries of his research as a more impor tan t cli- ent, in par t because there are so many more of them.

There are personal benefits, as well, for the successful researcher. These include material gains, including academic promot ion , lecture fees, and invitations to travel to meetings in ap- pealing locales. For some, career survival may be at stake, because funding for one ' s basic salary may depend on obtaining grants, which depends on showing success as an investigator. Success does not necessarily mean showing that a new drug is more effective than the old, but it does mean recruit ing adequate numbers of patients into the study to allow for meaningful conclusions. It is this pressure to enroll subjects that may tempt the physician to understate the risks, exaggerate the benefits, or a t t empt interventions beyond those he would consider if his economic welfare were not at stake.

These potential conflicts o f interest do not always materialize in ways that are adverse to the present pat ient 's interests. Indeed, these o ther interests of the investigator are often congruen t with, not in con f i c t with the pat ient 's interests. Many patients, particularly those with untreat- able conditions, want to be research subjects and are pleased that there are rewards and incentives for doctors to be researchers.

Conflicts of interests are not unique to researchers, of course. The physician involved in s tandard practice may also be distracted f rom his pat ient 's welfare by a variety of potential conflicts of interests, including incentives to provide unnecessary and dangerous care in fee-for-ser- vice systems, or providing too little care in capi- tared systems. These pressures are increasing in both the private sector and in academia, as managed care organizations br ing more "bo t t om line" thinking to clinical practice, and as academic depar tments become more dependen t on clinical income for their survival. "You eat what you kill" is becoming a familiar expression a m o n g physicians who once relied on guaran- teed salaries to protec t them f rom financial conflicts in making clinical decisions.

Whether or not the research subject or the pat ient is in a more precarious position because of the potential conflicts of interest of the physician is not self-evident. It depends on the facts

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of the case. Tha t is why many patients, women and member s of ethnic minorit ies as an example, may complain as bitterly about being ex- cluded f rom some research projects as they do about being included in others. It depends on their clinical situation, the benefits and risks of s tandard t reatment , the particularities of the physicians involved, their financial resources, and many other variables.

5. Barriers to experimentation protect patients from harm.

The ability of the lay press and politicians to generate high levels of anxiety by exposing alleged misconduct in exper imenta t ion suggests that the public is generally more fearful of exper- imentat ion than of standard practice. This may be partly because of the failure to distinguish so-called therapeut ic research, studies that offer some possibility of benefi t to the subject, f rom nontherapeut ic research, studies that offer no conceivable medical benefi t to the subject. The latter, particularly when strict standards of consent are not followed, feed the image of the research subject as guinea pig, exposed to discom- fort and risk with no possible benefit.

There is a more c o m m o n misconcept ion about the relationship between exper imenta t ion and harm, namely, that a typical pat ient has more to fear f rom exper imenta l than standard treatment. As noted above (Truism No. 1), standard practice, particularly in settings where the sickest patients present, may be domina ted by untested, unproven interventions with risks that may greatly exceed benefits. The practicing physician is not only free to use age-old unproven treatments, he or she is also free to innovate, using approved drugs for unapproved purposes, with none of the checks and balances that sur- round the explicit researcher.

The assumption that patients exposed to exper imenta t ion were more likely to suffer ha rm seemed to be at the root of much of the objec- tion to recent changes in the federal rules involving a waiver of consent for research studies in emergency settings. In 1996 the FDA and DHHS regulations were modif ied to allow research studies to include patients unable to consent, and without relatives able to consent, unde r specified conditions; namely, a l ife-threatening condit ion for which existing t reatments are unsatisfactory, and for which there is a promising exper imenta l t reatment. ~2

One of the more c o m m o n examples of such a condit ion is severe head injury, affecting hun- dreds of thousands of people each year, with a high incidence of poor outcomes. Although FDA rules allowed unapproved drugs and devices to be used without consent in such a situation, the justification had to be based on the need of the pat ient for such exper imenta l intervention. This principle prec luded placebo-control led studies, because no pat ient needs a placebo. The consequence was a succession of exper imenta l interventions, some, such as hypothermia, crani- otomy, or high dose barbiturates, involving considerable risk. The prohibi t ion of placebo controls prec luded prospective studies designed in a way that could adequately assess benefi t and risk. Instead, patients were compared with non- comparable groups, ei ther historical controls or patients treated in o ther settings, with unknown variables in their t rea tment or unknown differ- ences in severity of injury and other relevant variables.

The new rule allows for such patients to be randomized into placebo-controlled studies in which all patients would receive standard treatment , but half would receive the promising new treatment. This was in contrast to the pr ior rules, unde r which all patients could receive the new treatment , also without consent, but with fewer safeguards; namely, no requi rements for review by an IRB, and less chance for the results to be interpretable in a way that would allow for meaningful conclusions. Confused investigators have repeated Smithell 's complaint , " I need permission to give a new drug to half my patients but not to give it to all of them."2

Critics seemed to assume that giving the exper imenta l t rea tment to all patients, without their consent, unde r the rubric of innovative therapy, exposed them to less harm than giving it to half the patients, without consent, with the protect ions of the many layers of review that necessarily accompany research. 33 The effect of this review is that every c o m p o n e n t of the experimental i n t e rven t i on - - t he qualifications of the clinician, the inclusion criteria, the dose, the moni tor ing for adverse effects, and the assess- men t for bene f i t - - i s assessed. In the absence of the research protocol, unde r the more restrictive rules, the identical t rea tment could be given by the most jun io r clinician, at any dose, for any indication, with no requirements for assessing benefits or risks. Under ei ther system, uncon-

Ethical Dilemmas in Medical Innovation 2 3 1

senting patients receive innovative treatments. In the research context, the physician is constrained by procedures designed to minimize the risks and maximize the benefits. 34 In the practice setting, the physician is constrained only by his or her imagination and the low risk of a malpractice suit.

C o n c l u s i o n

Human experimentation has a troubled history, justifying the attention it has received. In the past 25 years, broad public disclosure of prior transgressions, coupled with increasingly de- tailed regulation and increasing oversight by local IRBs and federal agencies, has been associated with a virtual disappearance of the egregiously unethical research that was once common. Twenty-five years ago patients had reason to fear being victimized by overzealous unchecked researchers. Today, patients are as likely to complain about exclusion from research pro- tocols as they are about inclusion.

Experimentation in the form of innovative therapy continues to be widespread. But public and political attention and the tightening of regulations are addressed primarily to the physician whose innovations are most carefully considered, most subject to review, and most likely to respect the highest standards of informed consent.

All innovative treatment involves uncertain risks and benefits. Because of this, the standards for consent should be generally be high, regard- less of whether the intervention is part of a well- designed, well-reviewed protocol. High standards for consent are separate from the question of whether the intervention is research or investi- gational. ~5

If the purposes of moral discourse and regulations are to protect patients from harm, maximize their interests, and give them or their rep- resentatives the greatest opportunity to make informed choices about their medical care, then regulation of research involving human subjects may have come close to a point of diminishing returns. If further gains are to be made in achieving these goals, attention should turn to the kind of experimentation and innovation that occurs outside of careful scrutiny, essentially unknown to scientists or patients.

A c k n o w l e d g m e n t

Ryan Westergard and Leslie Klein provided valuable research assistance. Dr Alan Fle ischman m a d e helpful comments .

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Documents

Ethical dilemmas in medical innovation and research: Distinguishing experimentation from practice