Are There Ethical Exceptions?Author(s): Carol LevineSource: IRB: Ethics and Human Research, Vol. 11, No. 4 (Jul. - Aug., 1989), pp. 5-7Published by: The Hastings CenterStable URL: http://www.jstor.org/stable/3564171 .

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July/August 1989

Military Medical Research: 1. Are There Ethical Exceptions? by Carol Levine

Webster's dictionary defines "dilemma" in several senses: the one most pertinent to the topic at hand is "a choice between equally unsatisfac- tory alternatives." The problem is this: if nerve gas were to be used against U.S. soldiers, not an improbable scenario in today's world, there are no antidotes proven to be safe and effective that could be administered. Therefore, a priority of military medical research is to develop such an antidote. However, before the Food and Drug Administration can approve an agent for use in humans, it must have evidence of safety and efficacy. Subjecting humans to the high risk of the debilitating effects of nerve gas to test an antidote is unethical. Therefore, the antidote cannot be demonstrated to be safe and efficacious, and the FDA cannot approve it.

The "unsatisfactory alternatives" in this dilemma appear to be: (1) expose humans to the nerve gas, despite the high risk, in order to test the antidote; (2) use the antidote without evidence of its therapeutic or adverse effects. Although both alternatives may be unsatisfactory, they are not equally so. Setting aside the specific situation temporarily, it may be helpful to look at the broader issues raised by military medical research. The question: Are there ethical exceptions for military research? may be answered in two ways: no and a qualified yes.

The Limits to the Military Rationale

The regulations and ethical codes under which both civilian and military research are conducted today originated in the Nuremberg period. The trials of the Nazi doctors conducted after World War II revealed a series of horrendous experiments conducted on unconsent- ing individuals-Jews, gypsies, enemy prisoners, and others deemed "unfit for life." These experiments were conducted not by sadistic SS guards but by some of the most respected and highly trained German doctors. Their rationale for

conducting these experiments was that they were necessary for military reasons.

Here are a few examples from the indictment against Karl Brandt, the primary defendant:

High-Altitude Experiments. From about March 1942 to about August 1942 experiments were conducted at the Dachau concentration camp, for the benefit of the German Air Force, to investigate the limits of human endurance and existence at extremely high altitudes. The experiments were carried out in a low-pressure chamber in which the atmospheric conditions and pressures prevailing at high altitudes (up to 68,000 feet) could be duplicated. The experimental subjects were placed in the low-pressure chamber and thereafter the simulated altitude therein was raised. Many victims died as a result of these experiments, and others suffered grave injury, torture, and ill- treatment.... Freezing Experiments. From about August 1942 to about May 1943 experiments were conducted at the Dachau concentration camp, primar- ily for the benefit of the German Air Force, to investigate the most effective means of treating persons who had been severely chilled or frozen. In one series of experiments the subjects were forced to remain in a tank of ice water for periods up to 3 hours. Extreme rigor developed in a short time. Numerous victims died in the course of these experiments. After the survivors were severely chilled, rewarming was attempted by various means. In another series of experi- ments, the subjects were kept naked outdoors for many hours at temper- atures below freezing. The victims screamed with pain as parts of their bodies froze....' In summarizing these and other

similar experiments, Brig. Gen. Telford Taylor, the Chief Prosecutor, explained:

A sort of rough pattern is apparent on the face of the indictment. Exper- iments concerning high altitude, the effect of cold, and the potability of processed sea water have an obvious relation to aeronautical and naval combat and rescue problems. The mustard gas and phosphorous burn experiments, as well as those relating

to the healing value of sulfanilamide for wounds, can be related to air-raid and battlefield medical problems. It is well known that malaria, epidemic jaundice, and typhus were among the principal diseases which had to be combated by the German Armed Forces and by German authorities in occupied territories....

Fanatically bent upon conquest, utterly ruthless as to the means or instruments to be used in achieving victory, and callous to the sufferings of people whom they regarded as inferior, the German militarists were willing to gather whatever scientific fruit these experiments might yield.2 Although Taylor denied that the

experiments produced any scientifically valid data, some of the data gathered in the experiments, particularly in the field of hypothermia research, are being cited today. Many commentators believe that it is unethical to cite these findings, with or without qualifications about the unethical manner in which they were obtained; others believe that it would be equally unjustifiable not to use evidence that already exists.3

Presenting the defense for Karl Brandt, Dr. Robert Servatius pointed to the "hard necessity" of the state as justification for the experiments:

...in addition to the care for the population-the lives of soldiers were at stake, soldiers who had to be protected from death and epidem- ics...Biological warfare was immi- nent, even praised abroad as cheaper and more effective than the atomic bomb.4 Dr. Servatius was skeptical about

testimony at the trials that wartime experiments conducted in American prisons to develop antimalarial drugs used true volunteers, and that more volunteers than could be used offered to participate.

There may be people who realize that the community has the right to ask them for a sacrifice....But what if in the emergency of war the convicts, and those declared to be unworthy to serve in the armed forces, refuse to accept such a sacrifice voluntarily, and only prove an asocial burden to the state and community and bring about the downfall of the community? Is not compulsion by the state then admissible as an additional expia- tion?... Voluntariness is a fiction; the emergency of the state, hard reality.5 Although in no way comparable to the

Nazi experiments in extent or deliberate infliction of harm, the CIA's experiments with mind-altering drugs in the 1950s were defended with the same rationale. In these experiments, in which no

Carol Levine is Executive Director of the Citizens Commission on AIDS for New York City and Northern New Jersey, and Managing Editor of IRB: A Review of Human Subjects Research. This article is based on a paper presented at the Symposium on Safety & Efficacy in Military Medical Research, sponsored by the Office of the Post Chaplain, Fort Detrick, MD, September 30, 1988.

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MD _ military physicians were involved, LSD was given to soldiers and civilians without their knowledge to study the drug's behavioral effects. One civilian subject became psychotic and jumped from a tenth-story window to his death. These experiments came to light only in 1975.

The CIA has only recently agreed to settle a lawsuit filed by nine Canadians who had been unwitting subjects in mind-control experiments conducted by the late Dr. D. Ewen Cameron, a psy- chiatrist at McGill University in Mont- real. These patients were subjected to powerful electric shocks, prolonged periods of drug-induced sleep, and heavy doses of LSD and barbiturates. Although the agency has agreed to a settlement, it continues to maintain that "its actions were appropriate at the time."6

Soviet interest in LSD was reported to be a "strong motivating factor" in the CIA experiments. A government- sponsored study addressing the use of LSD in field conditions concluded that "in intelligence, the stakes involved in the interest of national security may permit a more tolerant interpretation of moral- ethical values, but not legal limits, through necessity."7

One military officer compared these experiments to a combat operation:

You start taking casualties in combat, and you don't stop. You press on. You take the objective. That is the way it was in these experiments. They were very important to national security, and we pressed on. It's unfortunate that somebody died. But we had to know what these drugs could do to people and how we could use them.8 These examples indicate that the

military rationale can be used to justify egregious abuses of autonomy and respect for human welfare. Current ethical standards and regulations of human subjects research would not permit such use of drugs or devices on unconsenting subjects, or even on consenting ones.

The Department of Defense policy for the conduct and review of human subjects research, which applies to all elements of the Department and to its contractors and grantees, "requires that the fundamental rights, welfare, and dignity of human subjects in DoD- supported research be protected to the maximum extent possible, and estab- lishes this as a responsibility of the military chain of command.

The Department adheres to the pro- tections established by the Department of Health and Human Services (45 CFR 46) and the Food and Drug Administra- tion (21 CFR 50 and 56). In addition to

review by local human use committees, there are additional layers of review at the command and services level.9

Some may claim that a soldier, like a prisoner, is incapable of true voluntary consent because the context (the armed forces or the prison) is inherently coercive. While there are certainly coercive elements in both settings, just as there are in medical schools and first- year college psychology classes, individ- uals do not lose their autonomy simply by virtue of being a soldier, prisoner, or medical student. Protocols can be constructed to enhance the key proc- esses of selection of subjects and informed consent.

Thus, if the question "Are there ethical exceptions for military medical research?" concerns the level of permis- sible risk to subjects and suspension of voluntariness, the answer is "No."

The Use of Unproven Therapies

If, however, the question concerns the use of agents whose safety and efficacy have not been thoroughly investigated, the answer may be a qualified "Yes." There may be situations in which different and lesser standards of evi- dence may have to suffice precisely because it would be unethical to create the risky situation in order to expose subjects to it.

Like the Department of Defense's policy on the use of human subjects, the FDA's standards have relevant historical antecedents. The thalidomide episode in the early 1960s was a critical event. A cautious stance by Frances Kelsey of the FDA staff blocked the introduction into the U.S. of a sedative that caused severe deformities in the newborns of pregnant women in Europe and Australia. Leg- islation amending the Food and Drug Act mandated a stringent pre-marketing review of all drugs to prevent such a tragedy from occurring in the U.S.

Twenty years later, as a result of pressures to release drugs more quickly and the advent of AIDS, as well as other social and political factors, the agency is loosening many of its restrictions and speeding up what remains a relatively lengthy approval process. The proce- dures may change, but the FDA's basic responsibility continues to be the pro- tection of the American people, includ- ing the military, from unsafe and ineffective drugs.

Given this more flexible but still stringent regulatory stance, several elements are significant to a decision about approval of use without evidence from human testing.

What is the purpose of the drug or device? Is it intended to be used in a

situation that is likely to occur or is it only a remote possibility?

What evidence exists concerning safety and efficacy? Are there studies using appropriate animal models? Lab- oratory studies that provide suggestive evidence? Is there a solid theoretical justification for the use of this agent in a particular situation?

Are there alternatives to this drug? If so, what are their shortcomings? Are these sufficiently compelling to warrant using a less-than-fully tested drug?

Is the agent an entirely new com- pound? Or are there related drugs that might offer comparable data?

Are there analogous situations in which the agent can be tested, such as industrial accidents or radiation expo- sures? Are there populations that are at risk of being subjected to biological warfare in which the agent could be tested in the event of such a disaster?'0 Can the agents be tested in these situations and in these populations with a reasonable expectation of providing benefit? Is it possible to obtain consent or to defer consent? Can adequate scientific data be obtained and reported in such situations?

Are there regulatory exceptions that can be applied, such as emergency exemptions or the Treatment IND process? Can a limited approval be granted, with the option of withdrawal if early use shows unacceptable levels of toxicity?

On balance, it would be more harmful to withhold a potentially beneficial agent to soldiers exposed to severe risk than to allow the use of drugs or devices that had not passed the most stringent testing. However, each of these judg- ments-what is potentially beneficial, what is risk, what is proof of efficacy- involves not just scientific judgments but also ethical determinations.

While there may be no inherent ethical (or legal) barrier to the use of untested agents in battlefield situations, a conclusion about a specific agent depends on the validity of the scientific rationale and evidence from sources other than human tests. A partial exemption from full standards of evi- dence is not a warrant for inadequate documentation and presentation of poorly assembled evidence. Such a cae calls, in fact, for the most "thordugh presentation, precisely because some pieces of the picture are of necessity missing.

The political dimension must also be considered. The public will make harsh judgments if American soldiers are. harmed by inadequately tested agents administered by military physicians and approved by regulators. Those who

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2. Proving the Safety and Effectiveness of a Nerve Gas Antidote: A Legal View by Richard M. Cooper

When the issue in question relates to the authority of a governmental agency to grant an approval based on its exercise of professional judgment or discretion, sometimes the most useful contribution the law can make is to get out of the way, so that professional expertise can be applied; and the most useful service a lawyer can provide is to show that the law is in fact out of the way. I firmly believe that the law governing drug approvals has made that contribution to the issues that concern the testing and approval of drugs to serve as antidotes to nerve gas (and other chemical and biological agents that may be used in warfare). My task, therefore, is to show that the law has made it.

I will discuss the requirements for determining the safety and effectiveness of such antidotes for use by the Army under conditions of war. The Army and FDA have a memorandum of under- standing that sets forth their mutual intent that drugs developed for military use will be subjected to the safety and effectiveness standards applied by FDA under the Federal Food, Drug, and Cosmetic Act.' Those standards gener- ally require that safety and effectiveness be demonstrated in controlled clinical trials conducted under therapeutic conditions. Plainly, such trials cannot be conducted on a nerve gas antidote because nerve gases cannot ethically be administered to human subjects and because it does not appear possible to

devise a suitable and ethical control regimen for persons who may be exposed to a nerve gas in actual warfare, by accident, or otherwise outside a planned trial. How, then, can an antidote ever be approved?

The issue, of course, is broader than nerve gas antidotes. It might arise with respect to drugs for treating poisonous snake bites, rabies, and many other diseases or conditions that are serious and rare. It is hard to think of any circumstances in which it would be ethical to induce a serious disease in human subjects in order to test the safety and/or effectiveness of new medicine to treat it. Nevertheless, on any given day numerous ethical human clinical trials of drugs for serious diseases are under way.

What creates the special problem for nerve gas antidotes is not that nerve gas is used in a military context, or that it is a serious harm intentionally inflicted on some human beings by other human beings (in that respect it is similar to gunshot wounds, which could be the subject of a clinical trial). Rather, the special problem arises from the com- bination of facts that nerve gas is seriously harmful and that there are too few cases of nerve gas exposure that occur in the course of life to be the basis for a clinical trial. That is, nerve gas poisoning is a nonexistent or extremely rare condition in normal times for American civilians and military person- nel; nevertheless, it is important to find a safe and effective antidote for it because, in wartime, many military personnel or even civilians might be exposed to it. How does the law bear on this special problem?

The generally applicable legal require- ments for approval of a new drug are

reasonably clear. The Federal Food, Drug, and Cosmetic Act requires that certain showings be made with respect to the drug's safety and effectiveness.2

For a new drug to be approved, its sponsor must present to FDA "adequate tests by all methods reasonably appli- cable"-note that phrase: "reasonably applicable"-to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the labeling thereof."3 It is required that such tests show that the drug is safe.4 A drug is safe "when the expected therapeutic gain justifies the risk entailed by its use."5 It is well recognized that "[f]ew if any drugs are completely safe in the sense that they may be taken by all persons in all circumstances without risk."6 Plainly, in some circumstances, one of the risks that may be considered-and accepted-in reaching a judgment that a drug is safe is that arising from the fact that the adequate tests reasonably applicable to assess safety are quite limited and, indeed, do not include clinical trials.

FDA's statutory authority to make judgments about safety in the absence of data is not wholly unconstrained, however. The statute does provide that it is a ground for denying approval of a drug if "upon the basis of the infor- mation submitted to [the Commissioner] as part of the application, or upon the basis of any other information before him with respect to [the] drug, he has insufficient information to determine whether such drug is safe for use under such conditions...."' So, the agency must decide whether it has enough informa- tion to assess safety.

Is the standard for determining the sufficiency of the information an abso-

Richard M. Cooper is a partner in the law firm of Williams & Connolly, Washington, DC. He was chief counsel for ED.A. from 1977-1979. This paper was presented at the Symposium on Safety & Efficacy in Medical Research, sponsored by the Office of the Post Chaplain, Fort Detrick, MD on September 30, 1988.

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July/August 1989

make the decision to employ what is, I believe, a theoretically permissible exception, will have to defend it. They should have prepared the best possible defense; that will also be the best insurance that the exception is truly justified. REFERENCES 'United States v. Karl Brandt, Trials of War

Criminals Before the Nuremberg Military Tribunals, Volumes I and II, the Medical Case. Washington, DC: Government Printing Office,

1948. Excerpts reprinted in Katz, J.: Experimen- tation with Human Beings. New York: Russell Sage Foundation, 1972, p. 293.

2Katz, p. 295. 3Moe, K. Should the Nazi research data be cited?

Hastings Center Report, 1984; 14(6):5-7; also see letters commenting on this article in the Hastings Center Report, 1985; 15(4):31-32.

4Katz, p. 303. SKatz, p. 303-04. 6C.I.A. near settlement of lawsuit by subjects of

mind-control tests, New York Times, October 6, 1988.

7USAINTC staff study, material testing program EA

1729, October 15, 1959, p. 34; cited in Senate Select Committee on Intelligence Activities, Testing and Use of Chemical Biological Agents by the Intelligence Community 1976; and quoted by Howe, EG: Ethical issues regarding mixed agency of military physicians, Social Science and Medicine, 1986; 23(8):809.

'Howe, p. 809. 9Winter, PE.: Human subject research review in

the Department of Defense. IRR A Review of Human Subjects Research, 1984; 6(3):9-10.

10Altman, L.: Pbison gas attacks: Why a diagnosis is so difficult, New York Times, September 28, 1988, p. A14.

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