The Interim Rule and Its Alternatives

Issues Associated with the Interim Rule

Question A-2 asks, "Are there circumstances under which the use of the Interim Rule would be justified? If so, what are those circumstances?" Several bioethicists, as noted above, answer this question with an absolutist position: The Nuremberg Code provides no basis for exceptions to informed consent on human subjects of research, and thus the Interim Rule is not justified. An absolutist position, however, does not take into account the existence of foreign enemies, the possibilities such enemies might generate, the options appropriate for response, or the qualified nature of investigational that is invoked under the terms of the Interim Rule. As a factual matter, the possible use of CW/BW agents against U.S. military personnel in future conflicts cannot be ruled out. Neither can the possibility of thousands of American casualties be ruled out if medical treatment is not available among the several protective measures used against CW/BW agents. In such circumstances, the obligation of the U.S. military to its personnel is to protect individuals, ensure the safety of units, and maintain the military capability to conduct war. The use of investigational drugs for treatment, not research, to protect these personnel is justified, in our view, as is a policy authorizing waiver of informed consent for such use.

Two questions--A-3 and A-8(b)--ask about the feasibility of obtaining informed consent in certain military combat exigencies. Question A-3 asks the following:

The Interim Rule is based on the premise that informed consent is not feasible in military combat exigencies because if a soldier were permitted to say "no," this could jeopardize the accomplishment of the combat mission. DoD has alleged that it is not an option to excuse a nonconsenting soldier from a military mission. Given the experience in the Gulf War, does this rationale still hold?

Should the authority to make the "feasibility determination" (i.e., whether obtaining informed consent is "not feasible") under the Interim Rule be vested in persons or entities other than the Commissioner of FDA?

Question A-6 asks a general question: "If the Interim Rule is needed, are there changes that should be made to it based on experiences during and following the Gulf War? If so, what are these changes and why should they be made?" Our response deals with the issue of need and then with that of specific changes. First, the fact that DoD has concluded that the rule is needed should not be taken lightly: The military requested that the authority to waive informed consent be established in 1990; in 1991, after the Gulf War, it requested that rule making be completed and the Interim Rule made final; and it regards the Interim Rule as an important legal-regulatory policy today.

Looking backward, the needs of the military at the time of the Gulf War were: to proceed with adequate authorization, which meant not risking the creation ad hoc of an exclusively DoD-based authority but seeking the imprimatur of FDA; to have authorization tailored to perceived military requirements, i.e., with an exception from full compliance with FDA regulations; and to assure military personnel, including many civilian reservists, and the American public that it was taking its responsibilities to protect such personnel very seriously. Therefore, any negative answer to the question about need ought to argue, at the very least, that DoD is wrong militarily.

Second, the implications of a negative answer to this question are also discussed below under "Revocation." Revocation would not be a return to the pre-Interim Rule status, but would, instead, constitute a denial of the authority to waive informed consent for CW/BW defensive use of investigational drugs. A policy that progressed from silence to affirmation to negation (a reversal of affirmation) could create the possibility of a war-related controversy at some future time. In our view, this would be unfortunate if it forced a choice between protecting U.S. troops and complying with FDA regulations.

Regarding specific changes that might be made in the rule, many are discussed below. Question A-8, for example, asks the policy question, "If the rule were to be reproposed," then breaks this down into a number of specific questions; the greater part of this section is devoted to discussing these specific questions. Other questions, such as Question A-7, which asks, "Can or should the Interim Rule be narrowed in scope? If so, how?," are left for the rule-making process and specific recommended changes. Finally, the general issue of oversight and accountability asked by Question A-8(f), "Should the rule contain additional procedures to enhance understanding, oversight, and accountability? If so, what are these procedures?," is dealt with in Chapter Five.

Question A-8(a): IRB Independent of DoD.

Should there be a requirement that DoD's proposed use of the investigational product(s) be approved by an IRB that is independent of DoD? If so, why should DoD be held to a requirement not imposed on other institutions, and what should be the requirement for that independent IRB? Can this be accomplished without compromising military or national security? (Request for Comments.)

Edgar and Rothman (1995), in a general review and critique of the IRB system unrelated to DoD, the Interim Rule, and ODS, ask, regarding the proliferation of such committees, "Is it truly the case that a `one size fits all' approach works well?" They elaborate in the following way:

Are the same general procedures for appointing members and defining their obligations appropriate for reviewing research conducted not only at the Central Intelligence Agency (CIA), the Bureau of Prisons, and the National Institutes of Health (NIH), but also at for-profit hospitals, local community hospitals, and university-affiliated tertiary-care centers? Does it make sense to give the leadership of an institution, which by its very nature cannot survive without the funds and fame brought in by clinical research, the responsibility for appointing the membership of a monitoring committee?

After reviewing the history of medical experimentation that abused human subjects, and the resultant conclusion that review by a body other than the investigator was necessary to ensure ethical treatment of such subjects, Edgar and Rothman review the assumptions underlying the dependence on local IRBs. They find all of them to be less compelling today, criticize continued reliance on "one size fits all," and make the following recommendations. First, they argue that "public visibility" and time for "political choice" are required to protect the public "from the ends [i.e., objectives] of research" and the development of new medical technologies and that a national monitoring system of a "super" committee or committees ought to be considered. Second, they argue that the newly entrepreneurial character of academic medical research raises conflict-of-interest questions that are "the appropriate object for formal legal rules." Third, they recommend that reform should "strengthen the `outside' elements of IRBs, while leaving the review based in the institution itself." Finally, they recommend "far more effective oversight mechanisms" than currently exist.

This critique by Edgar and Rothman of reliance on local IRBs is cited for two reasons. First, it makes clear that there are enough questions of public policy importance to justify a thorough and overarching review of the entire system. Indeed, this is perhaps the main reason the National Bioethics Advisory Committee was created. Second, the Edgar and Rothman review is directed to the research enterprise, not to situations in which treatment is the primary issue. Thus, the applicability of their critique to the DoD situation in ODS is a matter deserving independent consideration.

In the case of the Gulf War, the review by an IRB of the waivers requested under the Interim Rule was described by Dr. Edward Martin, then Principal Deputy ASD(HA), in testimony to the Presidential Advisory Committee on Gulf War Veterans' Illnesses:

The Department of Defense (DoD) IRB review for ODS was accomplished through The Army Surgeon General's Human Subjects Research Review Board (HSRRB). The HSRRB was established in 1975, replacing the review functions of three other committees which existed at that time: the Army Investigational Drug Review Board, the Contract Review Board, and the Clinical Investigations Committee. The HSRRB is administered by the Human Use Review and Regulatory Affairs Division (HURRAD) of the U.S. Army Medical Research and Materiel Command. The HURRAD was established in 1974 as the Human Use Review Office during the same time frame that the Office for Protection from Research Risks (OPRR) was established at the National Institutes of Health (NIH). The HURRAD performs similar functions for the Office of The Army Surgeon General (OTSG) as does the OPRR for NIH. The HSRRB acts for OTSG as an IRB, ethics advisory board and human research policy board. The HSRRB recommends protocols for approval by OTSG and may also recommend revisions to, or disapproval of, protocols. The HSRRB provides both a second level IRB review and acts as the sole IRB for selected protocols, especially those from institutions which do not have their own IRB, or for contingency or mobilization type protocols. The Army serves as the DoD executive Agent for Biological and Chemical Defense Programs.

At the time of ODS, the HURRAD and the HSRRB were well experienced in the regulatory processes and the ethics of the human subject experience with INDs.[1] The Acting Chairman of the HSRRB at that time was a physician with approximately ten years experience as Acting Chairman. The HSRRB acted as the sole IRB in this case to centralize the process for several different INDs coming from different sources. In the situation with ODS, the HSRRB acted for the Army, the Army being the DoD Executive Agent for the Biological and Chemical Defense Programs.

The HSRRB and later the FDA deliberated these ethical issues on each individual IND on a case-by-case basis. The medical risks versus the benefits of using the specific INDs were weighed against the risks of not using the INDs. The primary decision put before the HSRRB was whether or not the autonomy of an individual Service member to make his/her own decision outweighed the need to protect that Service member and/or fellow Service members in potentially life-threatening situations. Based on the long history of human use of the approved drug, Pyridostigmine Bromide (MestinonR), and also that of the IND Botulinum Toxoid vaccine, and the human safety and animal efficacy, these INDs were determined to be the best medical protective measures available against the threat of potential exposure to certain nerve agents and botulinum toxins. The HSRRB recommend the approval of the use of these two products for medical pretreatment and prophylaxis without the requirement of informed consent. The FDA required the epidemiological follow-up for collecting adverse event data, where possible. These recommendations represented the best medical treatment decisions at the time for the protection of our Service men and women. (Martin, 1996.)

Financial conflict of interest is the threat to impartiality of judgment that Edgar and Rothman suggest is the institutional conflict likely to confront academic IRBs in the contemporary world of biomedicine. The latter is addressed only by the requirement that there be one IRB member who has no ties to the institution in question, a very weak protection. More complicated is the conflict of interest stemming from intellectual bias. This matter was addressed briefly in an Institute of Medicine study (1992) of FDA advisory committees several years ago, in which such conflict was described as "the subtly and perhaps even overtly biasing effects on objectivity of a scientist's prior research and public positions, particularly positions taken in formal administrative or judicial proceedings." This area, however, is essentially uncharted territory, and the issues that might arise here are hardly any different in the military than in a civilian context.

Substantively, the IRB question in a Gulf War-type situation is precisely that posed by Martin in his PAC testimony:

The medical risks versus the benefits of using the specific INDs were weighed against the risks of not using the INDs [emphasis added]. The primary decision put before the HSRRB was whether or not the autonomy of an individual Service member to make his/her own decision outweighed the need to protect that Service member and/or fellow Service members in potentially life-threatening situations. (Martin, 1996)

Assume for this discussion that a judgment is reached favoring an independent IRB on the grounds that a DoD IRB is incapable of impartial judgment when confronted with a request for waiver of informed consent under the Interim Rule. There are then a number of complicated questions to be addressed, including the appointing authority (the FDA Commissioner, the Secretary of Health and Human Services, the President?), the criteria for selection of members (no veterans, some veterans, former enlisted men, former officers, all civilians with no prior military service, and what other kinds of expertise?), and the circumstances that would trigger the convening of this extraordinary IRB (after a congressional declaration of war, a presidential declaration of emergency?). In the last analysis, an independent IRB does not resolve the need to appoint human beings to exercise their best judgment about vexing issues in time of national emergency.

In the Gulf War situation, there is no evidence that the DoD IRB was not in compliance with all pertinent laws and regulations of the FDA and the DHHS regarding protection of human subjects. Even if such evidence existed, are there no remedies short of creating an independent IRB? Perhaps, following Edgar and Rothman, oversight might be strengthened; the members might be reminded of their obligations to uphold the law; and, if necessary, sanctions might be brought against them or against the IRB. Or perhaps several outside members, drawn from a pool of experts identified by DHHS and FDA, could be selected to ensure that the IRB does not subordinate its judgment to actual or perceived preferences of military authority. In any event, such remedies should be explored, as a policy based solely on distrust provides little basis for arguing for an IRB that is independent of DoD.

However, if distrust should prevail and provide a policy basis for establishing an independent IRB, could a policy be adopted that would leave any institution, whether a department or agency of the federal government or a research university, immune from challenge that it was unable to exercise impartial judgment because of institutional conflict of interest. Here we return to the general critique Edgar and Rothman developed. A recent congressional hearing (U.S. House, 1997) took several DHHS agencies--the NIH, CDC, and FDA--to task for research that did not adequately protect human subjects. Interestingly enough, the Director of OPRR was not present at that hearing, suggesting an institutional interest in his absence. Similarly, the scientific literature and popular press report from time to time on experimentation at universities that suggests lax IRB review or that the IRB might be subject to undue influence by prominent academic investigators. If a special rule requiring an independent IRB is crafted for DoD, why not apply the same logic to other federal agencies or to universities that stray from sanctioned behavior? In this context, one might also ask why the OPRR, a regulatory entity, is housed in the Office of the Director of the NIH, an agency whose primary mission is to support and conduct scientific research.

In short, any number of institutional conflict-of-interest questions might be raised, only some of which would apply to DoD. All human institutions are second best, including IRBs. Treating DoD separately from other agencies, absent compelling evidence of noncompliance with law and regulations, appears to be driven, in part, by an ill-defined search for a "best" arrangement without regard for the implications for all other "second-best" arrangements.

Question A-8(b): Determination That Informed Consent Is "Not Feasible"

Should the authority to make the "feasibility determination" i.e., whether obtaining informed consent is "not feasible") under the interim rule be vested in persons or entities other than the Commissioner of FDA? [Request for Comments]

The Interim Rule provides the second exception in a way that is more specific, formal, and less subject to abuse. The language of the Interim Rule states that the commissioner may determine that obtaining informed consent is not feasible

when the Assistant Secretary of Defense (Health Affairs) requests such a determination in connection with the use of an investigational drug (including an antibiotic or biological product) in a specific protocol under an investigational new drug application (IND) sponsored by the Department of Defense (DoD).

to facilitate the accomplishment of the military mission, preservation of the health of the individual and the safety of other personnel require that a particular treatment be provided to a specified group of military personnel, without regard to what might be any individual's personal preference [emphasis added] for no treatment or for some alternative treatment

A third exception [21 CFR 50.24], adopted in 1996, authorizes the waiver of informed consent for emergency use. The extensive deliberations surrounding this exceptions are set out in great detail in the NPRM (60 FR 49086, September 21, 1995) and in the final rule (61 FR 51498, October 2, 1996). Parenthetically, the deliberative process followed in this case may provide a model for the DoD-FDA consultation discussed below.

The first and third exceptions derive from life-threatening individual emergencies. In these cases, the commissioner is acting with respect to clinical situations that arise, however infrequently, in the familiar context of civilian medical care. The meaning of "not feasible" in this context is "not technically possible." The exception provided by the Interim Rule, however, flows from a national security emergency, not an individual emergency. In the situation addressed by the Interim Rule, "not feasible" goes beyond "not technically possible" to mean that it is not feasible to obtain informed consent and maintain military discipline.

Largely unspoken in official documents and discussions, but hardly unimportant, "not feasible" also has an intelligence dimension within the national security context. It was argued, for example, that General Schwarzkopf did not disclose in advance to General Belihar, his Command Surgeon, the identity of the military units that were to receive the anthrax and botulinum toxoid vaccines. This information was withheld to protect against the possibility that such "order of battle" information might be transmitted to the Iraqis and thus might identify to the enemy those units designated for the advance attack group. How would such information be obtained and conveyed? It takes little imagination to develop a scenario in which Iraqi informers were operating in and around coalition forces in Saudi Arabia for the express purpose of obtaining intelligence. So "not feasible" in the Gulf War context not only goes beyond "not technically possible" to embrace the issue of military discipline but, further, implies strategic considerations of an intelligence nature.

The question, then, of whether the FDA Commissioner should make the "not feasible" decision needs to be disaggregated into three distinct parts: DoD compliance with the requirements of the FDCA; FDA determination of medical aspects of "not feasible"; and DoD determination of military aspects of "not feasible." More specifically,

• The compliance issue stems from the facts that FDCA governs the use of investigational drugs, that DoD acknowledges FDA's authority in this regard, and that DoD has found it necessary to obtain FDA's determination that its actions under the Interim Rule were not in violation of the FDCA.

• The medical feasibility issues that the FDA Commissioner is clearly qualified to address include the safety and effectiveness of a drug, the "context" in which it will be administered, the nature of the disease or condition for which it will be used, and the information to be provided to a drug's recipients about "the potential benefits and risks of taking or not taking the drug."

• The military feasibility issues that DoD is most qualified to address include the risk of adverse health effects if lethal CW/BW agents are used; the military intelligence assessment of the probability that such agents will be used; the appropriate response, both military and ethical, to uncertainty about use of such agents; considerations about who in the chain of command makes what decisions regarding use of investigational drugs for CW/BW defensive purposes; and the battlefield impact of requiring consent.

Question A-8(c) and A-8(d): Information to Military Personnel

Should the rule be more specific in describing the information that must be supplied to military personnel, or should FDA have wide latitude to make such determinations on a case-by-case basis? [Request for Comments]

Should additional measures be taken to insure that information required by FDA is effectively conveyed to the affected military personnel? If so, in what way? [Request for Comments]

With respect to the above questions, three things can be said. First, a final rule could usefully indicate a requirement that any request for a waiver under the rule be accompanied by DoD submission of the information that it proposes to provide to military and appropriate civilian personnel. It could also include a feature for DoD reporting back to FDA on the experience. Such a declarative statement should be general and brief, leaving the details to be addressed in a specific situation.

Second, in general, for certain investigational products, such as those used in the Gulf, the information requirements can conceivably be addressed separately from a specific IND. In Chapter Five, under "DoD-FDA Interactions," the argument is developed that a range of general issues should be addressed in ways that are not subordinate to particular applications. The FDA regulatory process, as suggested earlier, has developed over more than three decades with respect to the commercial pharmaceutical industry. If DoD use, or prospective use, of investigational drugs, differs from commercial drug development in important ways, as we believe it does, then it is worth considering a more systematic process for dealing with general issues as opposed to specific applications.

Third, with respect to "additional measures," the equivalent of a checklist of such measures might be indicated in the rule, with the details left for specification in direct interaction between FDA and DoD in the review of specific applications. This would be prescriptive as to additional measures to be considered but discretionary as to content.

Pendergast, in her testimony of July 29, 1997, before the Presidential Advisory Committee, indicated that FDA was considering a conference focused on special topics as part of its rule-making process. Later, we argue that such a conference should be held; here we simply argue that the question of information to military and appropriate civilian personnel should be one item on the agenda of such a conference.

Question A-8(e): Adequate Record Keeping

Should the rule address what constitutes adequate recordkeeping and adequate long-term follow-up of individuals who receive investigational products? If so, in what way? [Request for Comments]

Furthermore, record keeping is a topic that could be considered in the conference that FDA has indicated it might hold as part of the current rule making. It is also a matter for continuing discussion between DoD and FDA, independent of a specific application for a waiver.

Question A-8(g): Procedures to Track Noncompliance

Standards of Approval

Question B. "When is it ethical to expose volunteers to toxic chemical and biological agents to test the effectiveness of products that may be used to provide potential protection against those agents?" [Request for Comments]

Question C. "If products that may be used to provide potential protection against toxic chemical and biological agents cannot be ethically tested in humans, what evidence would be needed to demonstrate their safety and effectiveness?" [Request for Comments]

DoD and FDA are addressing the scientific and clinical issues regarding Question C in relation to a BLA in the case of the BT vaccine and in relation to an NDA for PB. The general issue, however, deserves consideration should FDA decide to hold a conference as part of the current rule-making process.

Alternatives to the Interim Rule

• "Should the agency revoke [emphasis added] the interim rule? If so, why?"

• "Instead of waiving the requirement for informed consent, is it feasible to obtain anticipatory consent [emphasis added] from military personnel during peace time for the future use of investigational products during a military conflict? If it is feasible, would such consent be valid as `informed consent'? What would be the needed consent algorithm to make it valid and feasible."

• "Instead of waiving the requirement for informed consent, is it feasible to obtain anticipatory consent [emphasis added] from military recruits (prior to their recruitment into the military) for the future use of investigational products during a military conflict? If it is feasible, would such consent be valid? What would be the needed consent algorithm to make it valid and feasible."

Revocation

What would the implications of revocation be? That depends on how FDA chose to take such a step. If revocation was accompanied by a statement that FDA requirements, which were not developed for military contingencies, did not apply in circumstances like those of the Gulf War, DoD might have a freer hand to respond within the context of the military contingencies it confronted. If, on the other hand, FDA stated or implied that there would be no exemptions from FDA requirements, even for CW/BW agents in a Gulf War situation, that would be potentially dangerous.

If in such a situation, PB and BT vaccine were, as in 1990, the best available preventive and therapeutic drugs available for defensive purposes, even though investigational, the question would confront the President in his role as Commander in Chief. This scenario, in our judgment, is one that we believe should be avoided. We return to this issue at greater length below.

Anticipatory Consent

The FDA Request for Comments asks about two forms of anticipatory consent, an undefined form of consent that currently does not exist in statute or regulation. These two forms are, first, consent by military personnel during peacetime and, second, consent before recruitment into the military. We consider anticipatory consent with reference to three potential situations, which embrace the FDA's two situations: consent at recruitment, consent during basic training, and consent before deployment to a theater of operations where the prospect of active conflict or exposure to CW/BW toxins is high.

The analysis of anticipatory consent is addressed with respect to the following issues: a plausible scenario for the situation; implications of the timing of the request; the scope or range of investigational products for which consent is sought; the duration that consent is presumed to be valid; and the effect of refusal of consent.

In general, the timing of the request for consent is the characteristic that differentiates informed consent as it is currently understood from the undefined anticipatory consent. The principal unknown is what is the effect of divorcing consent from the actual moment of decisionmaking. One can hypothesize the following effects on an individual's decision under such circumstances: The individual subject dismisses the significance of the decision to consent because it bears no direct relationship to actual conflict; fear is induced in the individual and overrides reason regarding risks and benefits, simply because the potential intervention is described as investigational; subtle (or not so subtle) coercion occurs in the way consent is sought; or information is provided to military personnel in an unbalanced way, in a setting that does not encourage individuals to ask questions of others, or in a way that does not stimulate discussion among troops.

Closely related to timing is the question of the content of the information that is provided to service personnel. How are the risks and benefits of an investigational drug to be presented in relation to the risk of an enemy's potential use of CW/BW agents? Should the risk-benefit calculation restrict itself to a civilian context of risk of investigational drug versus no treatment, and rule out consideration of enemy threat, or should it also include consideration of such a threat?

If an enemy threat is to be considered, are all potential enemies to be included, or only some, the most probable? Or is consent to a hypothetical conflict sufficient? If enemy capabilities and intentions are assessed at the time consent is given, what might the content of such information include, say, in April 1990 with respect to Saddam Hussein and Iraq?

The issue of scope or range of investigational products to which military personnel might be asked to give consent for use is also not straightforward if the consent decision is divorced from the actual situation. Should military personnel be asked about all investigational products that are in the DoD pipeline at the time of asking--drugs, vaccines, and medical devices? or only those that are most likely to be used? On what basis might a distinction be made between all and some? Should consent be obtained for all, for some, or only for the "most probable," however defined? Do self-administered products pose issues that differ from medic-administered products?

The question of the duration for which consent is valid is also complicated. The Interim Rule restricts waivers granted under it to a maximum of 12 months or cessation of conflict, whichever comes first. If a decision to consent is given at any time other than close to deployment, for how long is it valid? for the entire tour of duty? for three years? for one year? A consideration that is related to duration and timing also bears on scope: What are the implications of obtaining consent about a set of investigational products at a time when no alternative therapies exist, if things change and--at deployment--a better therapy has emerged, but is itself still investigational?

Finally, there is the issue of the effect of refusal to consent. Under normal civilian circumstances, there is no penalty to an individual who refuses to provide consent. In a military situation, however, might an individual be allowed to "join the military" and then, by refusing to consent to the use of investigational drugs, be exempted from service in the war-fighting part of the military?

We next consider each of the three possibilities for obtaining consent--at recruitment, in basic training, and at time of deployment to an active or potentially active theater of operations--in relation to the above questions.

Anticipatory Consent at Time of Recruitment. One plausible scenario might occur in the recruiting office of a military service. Recruiters are available at specified hours to interview individuals who come in to discuss joining the military. Another scenario might involve the recruiter visiting a high school or college campus to interview prospective candidates. Neither recruiters nor potential recruits have any illusions about the encounter: Both expect that information will be provided to the potential recruit; but both also understand that the recruiter's purpose is clearly to obtain enlistments.

This "before enlistment" situation appears quite problematic for obtaining informed consent for the use of investigational drugs. The situation is confounded by the fact that the U.S. military is today an all-volunteer military, conscription having been confined to the history books for the present time. The decision by an individual to enlist, coupled with military efforts to recruit, is a contractual decision when compared to conscription. The reasons for voluntarily joining the military range from a desire "to grow up," to obtain discipline, to obtain education, to learn an occupational specialty for a postmilitary career, or to seek a military career. For the individual, a decision to join the military involves a priori acceptance of the possibility that he or she might be placed in harm's way.

One can only speculate about the likely effects of seeking consent under such circumstances. Is the desire to join the military likely to override concerns about the hypothetical possibility that one might be asked to take investigational drugs? Or are individuals more likely to rethink and turn away from a decision to join? Problems arise in either direction.

Moreover, military recruiters may not be the most appropriate persons in whom DoD should vest the responsibility to explain the risks and benefits of investigational drugs. They probably lack the educational training that would equip them to provide good information and explanations. Their defined role is to recruit. Thus, they are likely to minimize risk in favor of obtaining another recruit. It is also not feasible, to take an alternative possibility, for medics to sit at recruitment offices.

Finally, consent at this stage would be to some hypothetical conflict situation and with respect to the then-current state of research knowledge about certain investigational products. It is difficult to regard this as informed, and it is clearly quite different from informed consent in the civilian context.

The scope of the consent requested is also problematic, as the questions and discussion above suggest. Absent a consent decision that is related in real time to the actual possibility of conflict, there is no apparent way to obtain consent for some investigational products but not for all. What is quite likely, however, is that only some products will be relevant in an actual conflict situation but that these will be known only in relation to that situation. Moreover, the differences between self-administered and medic-administered drugs may enter here.

The duration of a valid consent is also a complicated issue. It is difficult to believe that consent obtained at recruitment would withstand challenge, including possible legal challenges, at the time active or potentially active conflict was under consideration.

Finally, the effect of refusal to consent, if it carried no penalty, would provide an incentive for those who wished to benefit from military service but to do so without accepting the danger inherent in such service. This seems a pernicious set of incentives for organizing the military, given the dubious benefits of the approach. If refusal to consent meant, however, that an individual could not join unless they signed a consent form, they might respond, "OK, I'll sign anything to get in." In which case, the issue of coercion arises.

Anticipatory Consent During Basic Training. Many of the concerns expressed above about obtaining consent pertain to the basic training situation. However, basic training does have the advantage of being a good period during which information about the subject of chemical and biological warfare threats and countermeasures, including medical countermeasures, can be usefully introduced to military personnel in education and training sessions. If such information is part of training, hypotheticals are quite appropriate, and the scope can be comprehensive with respect to both threats and countermeasures. The issues of duration and the effects of refusal need not arise if consent is not sought. The crowded basic training schedule may make this option infeasible.

Anticipatory Consent Before Deployment. Of the three anticipatory approaches, this is the most attractive. The timing of the request for consent would be related to the actual situation of threat and current status of investigational products. (This begs the question, however, of how to define "before deployment," a nontrivial issue.) The scope would be limited to products actively being considered for use. The duration would similarly be limited to the specific conflict situation or to a 12-month period.

However, several problems exist with this approach. First, the question regarding the use of investigational drugs for CW/BW defense is the precise timing of administration. PB is self-administered and was handed out at the unit level to be taken in advance of an expected attack on orders of the unit commander. In the predeployment situation, when is consent to be obtained? on introduction to the theater? for each packet? or when a confirmed incoming Scud missile believed to be carrying nerve agent is confirmed? In the last case, a field commander is likely to respond on short notice with the command to "Take your medicine," especially if a drug such as PB with reversible effects is involved. Vaccines differ, since these are typically administered by field medics and require a period of time for immunity to develop. The full anthrax dose requires six shots over 18 months, three in the first six weeks and three more at six-month intervals, although DoD is seeking to modify the dose requirement of the first three shots. BT vaccine also requires a series of shots, which cannot be turned on and off. When is consent to be obtained? And when and how is it necessary to have the field commanders involved?

Second, if there were no penalty for refusal to consent, an incentive would be created on the eve of conflict for individual military personnel to opt out of the obligations they had apparently assumed. If opting out of deployment were allowed, teams that trained together would be impaired, if not destroyed, with attendant loss of military effectiveness. An individual opting out of taking the medication, but being deployed, might place himself or herself at risk and place comrades in jeopardy. Third, strategic considerations might also enter the policy discussion, as discussed in the "not feasible" section above.

Finally, we note that there are certain to be differences between active duty forces and reserve forces for all options but that of seeking consent at time of deployment to a theater of operations in which potential or active conflict exists. We have made no effort to examine those differences here, but they clearly should be examined in the event that consent at recruitment or in basic training are pursued. These differences, in our judgment, argue strongly for consent at time of deployment when the actual nature of risks and benefits are much clearer.

Other Possible Arrangements

A military-purposes approach might be limited to drugs and vaccines developed for responding to military exigencies, such as CW/BW threats, and to endemic infectious diseases in countries to which troops might be deployed. The military may be unique in sending people into danger involuntarily. Public safety personnel, for example, police, fire, or other emergency personnel, always have the option of quitting their jobs. But inherent command authority in the military provides the basis for telling troops to wear their gas masks, to put on their MOPP gear, or to take their pills.

This military-purposes approach would require a rigorous process for evaluating the evidence of safety and efficacy. A critical question is whether the standards of approval for military purposes would be the same as for commercial drug approval purposes. One component of this question is whether human efficacy data are needed for approval. If so, how might they be obtained? If not, what data might be satisfactory as a substitute? Would nonhuman primate challenge data be acceptable? Would surrogate endpoints, such as antibody levels achieved after vaccination, be satisfactory?

A "limited purposes" approach that addressed both military and nonmilitary might also be considered, with nonmilitary referring, for example, to terrorist attacks against U.S. civilian populations. The approach would derive its rationale from an assessment of the threat of bioterrorism and from the reasonable expectation that any organized response involving public health authorities or emergency authorities (e.g., the Federal Emergency Management Agency) would probably confront as much, if not more, confusion as the DoD did in the Gulf War. A limited-purposes approach would allow the addition of categories as the need arose, could impose marketing restrictions, and could require special reporting.

Both the military-purposes and the broader limited-purposes approaches would require extensive public discussion and debate of the issues, including constitutional concerns for "the common defense" and "the general welfare." The discussion would have to lay out relative roles and responsibilities of military and civilian authorities, officials, and agencies, and legislation would undoubtedly be required to establish either and to ensure an adequate legal foundation for administrative behavior.

[1]This quotation does not distinguish between an IND, which is the application to test an investigational drug, and the drug itself. It is clear from the context that reference is to the latter.

[2]In the period since this report was written, legislative developments have made this discussion moot. See the Postscript for a summary of those developments.