The MOU also states that FDA and DoD "will continue to cooperate in meeting the requirements of the Federal Food, Drug, and Cosmetic Act and its implementing regulations without jeopardizing the mission of the DoD." This involves agreement that FDA will expeditiously review special DoD requirements to meet national defense considerations, including review of available data on a drug, biologic, or device under IND or investigational device exemption (IDE) to determine whether stockpiling for future use or use in an expanded military population is appropriate.
Finally, the MOU addresses circumstances when DoD might find it necessary, "for reasons of national security," to establish security classification for the clinical testing of a drug, biologic, or medical device. Although the general policy of DoD is not to classify medical research and development, classification, if necessary, is solely a DoD determination. If classified studies are required, DoD will submit classified INDs or IDEs, as appropriate, to FDA officers having the required clearances, and FDA will be responsible for maintaining "an appropriate cadre of personnel" with such clearances.
The 1987 MOU summarized the experience under this agreement as indicating
that the DoD and FDA have a record of cooperation; that human subject concerns have been adequately addressed in DoD-sponsored studies; that the DoD has been able to carry out effectively its responsibilities for national security without compromising the intent of the above-cited statutes and regulations; and that certain exemptions, relieving the DoD from the need to meet the ordinary requirements of the Investigational New Drug (IND) and Investigational Device Exemption (IDE) regulations are no longer necessary.We discuss the MOU mainly because it did not provide a policy framework for dealing with use of investigational drugs for CW/BW defense in the Gulf War. Its scope is restricted to DoD clinical testing of investigational new drugs (including biologics) and devices under basically peacetime circumstances. It states as DoD official policy that military research related to drug, vaccine, and medical device development will be conducted under the same rules as civilian research with respect to the protection of human subjects. But the MOU refers to potential national security responsibilities related to the use of INDs only in very general terms and is silent on any contingencies that may arise related to CW/BW defense. Thus, as we will discuss later in this report, the MOU may deserve to be revisited in light of the Gulf War.
deliberated carefully before enabling, through rule making, DoD to take pyridostigmine bromide (PB) and botulinum toxoid (BT) vaccine as pretreatments for possible CBW agents without FDA approval of the products for that purpose. (PAC, 1996b, Executive Summary.)The agencies, the PAC stated, had undertaken "an urgent and orderly course of action under the circumstances to devise a means to address the real threat of chemical and biological warfare in the Gulf War." (p. 23) The importance of a publicly open process of deliberation cannot be overemphasized, especially since some critics of the Interim Rule have argued that it violates the Nuremberg Code. (JAMA, 1996.) The Nuremberg Code was adopted at the end of World War II in response to the outrageous wartime Nazi experiments on concentration camp prisoners, which were conducted in the secrecy of the German war machine.
That DoD did not do so may be attributable to the urgency of the moment, to its desire to have the decision to use INDs ratified by a civilian agency of government, and to the reluctance of FDA to sanction such action formally. In any event, the decision that was reached had the effect of framing the discussion in terms of FDA regulations, the adequacy of those regulations for dealing with the Iraqi threat, and the DoD's perceived need for an exemption on the issue of informed consent.
We focus here on the discussions between DoD and FDA. Although there were a number of meetings between DoD and FDA, two such meetings indicate both the complexity of the issues and that they were clearly understood early in the discussions. An August 30 meeting reviewed the issues associated with the unusual military medical needs of ODS, especially possible deployment of IND status medical products (Lehman, 1990).
The major issue discussed dealt with the DoD request for waiver of the requirement of informed consent. DoD had reviewed the detailed Code of Federal Regulations (CFR) requirements for use of investigational drugs and had concluded that the requirement for informed consent (21 CFR 50) could not be met "in armed conflict and in circumstances of potential armed conflict for deployed and deployable units." It requested immediate relief from this requirement, either by waiver or by a new regulation.
FDA regulates drugs (including biologics) and medical devices (a) produced in the United States and shipped in interstate commerce for use in this country; (b) produced in the United States and exported for overseas distribution and use; and (c) produced overseas and imported to the United States. The first (a) must comply with all regulations governing INDs in the investigational stage and must meet the criteria of safety and effectiveness for approval of an NDA. The last (c) must meet the safety and effectiveness criteria for NDA approval. Drugs and devices produced overseas for distribution to and use in other countries do not fall under authority of the U.S. FDA.
In this context, FDA responded to DoD at the time with two main possible courses of action. First, for IND products exported from the United States and used overseas, the export licensing requirement (21 CFR 312.110), under which informed consent and investigational labeling are not required, was deemed "the quickest and most feasible approach." In such cases, FDA would review each product for safety and, under the MOU, would review available data to determine the appropriateness of use in an expanded military population.
Second, for investigational products used in the United States, for example, to vaccinate troops before overseas deployment, an amendment to the regulations (21 CFR 50) signed by the Secretary of Health and Human Services (HHS) would be necessary. This might require Office of Management and Budget (OMB) clearance and could take weeks. Time would not permit the publication of an NPRM. Therefore, a public announcement before completion of such an amendment was thought to be necessary. Drafting of an amendment was under way at FDA. Both options were considered necessary, on the assumption that IND products would need to be used both in the United States and in the theater of operations. FDA also made clear that reviews of investigational products would proceed on a case-by-case basis. FDA raised the question of who would resolve "the impasse if FDA decides that it is inappropriate to deploy a particular investigational product that Defense wants to deploy," which was not resolved at this meeting. We address this important policy issue toward the end of this report.
Although the informed consent issue was the primary concern, much discussion focused on the detailed requirements regarding INDs and their use. Those not familiar with FDA and its regulations may find it difficult to appreciate the level of detail that is involved. But we summarize the minutes of this August 30 meeting to convey a sense for precisely this aspect of the issue. Moreover, this detail is important because the actual difficulty DoD had in the Gulf War in complying with these requirements became a focus of the later attack on the merit of the Interim Rule itself. The following topics, derived directly from the Code of Federal Regulations, were considered:
The most important issue was whether the contemplated DoD use of INDs in support of ODS was research or treatment and whether IND use for treatment was precluded by Title 10 USC 980. "The key legal issue," a memorandum by the Assistant General Counsel of DoD read, "is whether the potential uses contemplated constitute `research involving a human being as an experimental subject' within the meaning of this provision." In DoD's judgment, "the potential drug uses are not human subjects research." (Gilliat, 1990.)
Title 10 USC 980 had been added to a DoD appropriations bill in 1972, and its language expressly precluded DoD from using appropriated funds "for research involving a human being as an experimental subject" unless one of two conditions had been met: Either the informed consent of the subject had been obtained in advance; or, for research intended to benefit the subject, the informed consent of the subject "or a legal representative of the subject" [emphasis added] had been obtained in advance. Therefore, if the contemplated use was for research, informed consent would be required.
How did DoD justify its proposed use of INDs as treatment? The drugs and biologics under consideration for use in ODS, the Gilliat memo argued, were neither "remarkably novel nor experimental in a scientific or medical sense." Some had been subjected to "extensive research" and some had been approved for uses that were not substantially different from the potential military need confronted in ODS. That need was for defense against "the potential unprecedented use of chemical and biological products" in the Gulf. The proposed use of these INDs could include the administration of one or more of them to "very large numbers of U.S. forces" as pretreatment for threatened CW/BW attack. Given the circumstances, the memo argued, "it is clear that the proposed uses are not in any usual sense of the word for `research' purposes, but rather to assure the best possible preventive and therapeutic treatment possible for all contingencies presented." It was also the case that no alternative therapeutics were available.
Notwithstanding this argument, the Gilliat memo continued, a possible "technical legal" question remained about whether such products must be legally classified as "research" because FDA had not "fully approved," i.e., licensed, them for general treatment. Lacking such approval, these products were legally classified as INDs under FDCA, thus restricting their use to investigational purposes only.
The Gilliat memo then discussed in some detail the authority of FDA (under 21 CFR 312.34) to permit the use of INDs for treatment under certain limited circumstances for individuals not in an approved clinical trial being conducted under a treatment protocol. Although such authority existed, it was tightly restricted: The trials had to have progressed through certain stages; the drug had to be needed to treat "serious or immediately life-threatening disease"; and it was essential that no satisfactory alternative treatment was available. Where investigational drugs were used under a treatment IND, it was recognized that the primary purpose was treatment; obtaining additional data on safety and effectiveness was clearly secondary. Such authority had been used to approve the use of drugs for patients with HIV disease, for example, while clinical trials continued and while the drugs in question were still investigational. Although use of treatment IND authority required informed consent of subjects under the provisions of 21 CFR 50, this requirement could be waived if obtaining consent was "not feasible."
The memo summarized the DoD position regarding the potential application of the treatment IND regulations in this way:
In connection with the potential need in Operation Desert Shield for certain treatment uses of the several drugs classified as INDs, it is clear that very unusual circumstances are present. The drugs have all progressed through FDA's IND process sufficiently to establish a high level of confidence on the part of the DOD medical community; the potential effects of the chemical and biological weapons widely reported as available to the Iraqi military are deadly; and the proposed uses, if approved by the FDA, will reflect the best scientific and medical judgment of the U.S. Government. (Gilliat, 1990.)Returning to 10 USC 980 on the question of whether the proposed ODS uses constituted "research involving a human being as an experimental subject," the memo argued that "the proposed uses of the drugs in question are, in fact, primarily treatment uses, not uses primarily for investigational or research purposes." It was appropriate to give legal recognition to this distinction in light of the basic purposes of 10 USC 980, which were narrowly restricted to clear research efforts, and given the necessity to assure DoD's ability "to provide to the forces involved in Operation Desert Shield the best preventive and therapeutic treatment available."
Moreover, this distinction had previously been established in a 1983 DoD Directive on "Protection of Human Subjects in DoD-Supported Research," which defined research as "a systematic investigation . . . designed to develop or contribute to generalizable knowledge." (DoD, 1983.) That directive had authorized the secretaries of the military departments to determine that "unique military requirements dictate the use of drugs or devices not officially approved by the FDA." DoD had an established interpretation that some drugs and devices FDA deemed "investigational" were not considered as "research" under 10 USC 980.
The legislative history of 10 USC 980 also made clear that Congress, in enacting the provision, "did not have in mind the potential military need for very large scale preventive and therapeutic treatment to deal with battlefield chemical or biological weapon attacks." Rather, the memo argued, referring to the remarks of Sen. Edward Kennedy on the Senate floor in 1972, that Congress was attempting to remedy evils related to clinical research projects, not problems associated with protection of troops in combat situations. The examples cited in 1972 had been the Public Health Service syphilis experiments in Alabama; brain surgery experiments on prisoners to alter their behavior; a test of a birth control pill on women, mostly Mexican-American; withholding of penicillin from patients with strep throat; and whole-body radiation of terminal cancer patients.
Finally, the memo referred again to the precedent in FDA regulations for treatment INDs for distinguishing between use of INDs for research and treatment purposes. The DoD memo had "no trouble concluding that the proposed treatment uses of these drugs--separate from the ongoing clinical trials--are not part of the research program within the meaning of 10 USC §980." Consequently, DoD did not regard 10 USC 980 as
an obstacle to your [ASD(HA)] efforts to work out with FDA officials appropriate means, including but not necessarily limited to `treatment use' approvals under FDA regulations, to assure the maximum preparedness of U.S. Forces in Operation Desert Shield.The FDA response to this argument in the September 14 meeting was to state that it did not wish DoD to proceed under the treatment IND authority of 21 CFR 312.34, but that treatment use should be by "open protocols" under the regular provisions of 21 CFR 312. More important, FDA committed itself again to writing a new regulation to determine that informed consent was "not feasible" in certain military situations. However, this regulation still had to be reviewed by the Commissioner of DHHS (including NIH's Office for the Protection of Research Risks), and OMB. DoD would have the opportunity to see and comment on it before it became final. The regulation would give the FDA Commissioner authority to determine on a product-by-product, protocol-by-protocol basis whether to waive the requirement of informed consent for the use of INDs for certain military uses as "not feasible." DoD would then have to request waivers under this authority for each product, explaining why such consent was not feasible. The DoD IRB would have to consider proposed waiver requests before they were sent to FDA. FDA would consider the DoD request and any other relevant factors. It could then grant a waiver of informed consent for a limited time, i.e., for one year or until the end of the military emergency.
The minutes of these meetings, which reflect only some of the discussions between DoD and FDA, make clear that all the issues associated with the subsequent issuance of the Interim Final Rule were identified and the subject of careful deliberation. In support of these deliberations, DoD provided FDA with a list (see Table 1) of IND medical products under consideration for use in Operation Desert Shield. This list shows that, although PB and BT were the primary subjects of discussion, they were not the only investigational products under consideration for use.
DoD Requests Authorization to Waive Informed Consent
The military assessment of the Iraqi CW/BW threat and DoD's discussions with FDA led the U.S. Army Medical Research and Development Command to recommend to the ASD(HA) on October 11, 1990, that DoD seek a waiver of informed consent for the use of PB and BT in ODS. This recommendation became the basis for a letter of October 30, 1990, from Dr. Enrique Mendez, Jr., ASD(HA), to the Assistant Secretary of Health, DHHS. At the request of DoD, this letter was reprinted in its entirety in the preamble to the Interim Rule (55 FR 52814).
The Mendez letter set forth the DoD rationale for seeking authority to waive informed consent for the use of certain INDs in specific military exigencies. It noted that the DoD-FDA MOU recognized that there were "special DOD requirements to meet national defense considerations," and that such requirements were presented by ODS. Contingency planning for ODS had to consider endemic diseases in the Persian Gulf area, a factor whenever troops were deployed overseas, as well as the unusual threats raised by Iraq's "well-publicized capabilities" in CW/BW weapons. Regarding the latter, DoD had determined "that the best preventive or therapeutic treatment calls for the use of products now under `investigational new drug' protocols of FDA."
These drugs, although not identified by name, were described as "not exotic new drugs," but ones that had "well-established uses," although for contexts different from DoD requirements, and were "believed by medical personnel in both DoD and FDA to be safe." Examples included "a special intramuscular injector" for ready use on the battlefield, a vaccine the CDC have long recognized as the "primary preventive treatment for a particular disease," and a licensed drug in common use at a dosage level higher than the DoD intended to use, although not approved by FDA for DoD's proposed use.
Explicit FDA assistance was sought "on the issue of informed consent." Under the FDCA, Mendez noted, the "general rule" required that any use of an IND, whether for research or treatment, "must be preceded by obtaining informed consent from the patient." The law allowed for exceptions, however, when professionals administering an IND "deem it not feasible" to obtain informed consent. The heart of the DoD argument was the following:
Our planning for Desert Shield contingencies has convinced us that another circumstance should be recognized in the FDA regulation in which it would be consistent with the statute and ethically appropriate for medical professionals to "deem it not feasible" to obtain informed consent of the patient, that circumstance being the existence of military combat exigencies, coupled with a determination that the use of the product is in the best interests of the individual. By "military combat exigencies," we mean military combat (actual or threatened) circumstances in which the health of the individual, the safety of other personnel and the accomplishment of the military mission 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 for no treatment or for some alternative treatment. [emphasis added]In all peacetime applications, the letter continued, DoD believed strongly "in informed consent and in its ethical foundations." In such cases, DoD readily agreed to tell military personnel, in accordance with FDA regulations, that research was involved, that risks or discomforts might be experienced, that participation was voluntary, and that refusal to participate carried no penalty. "But military combat is different" [emphasis added], Mendez argued, setting forth the doctrine of military authority in the following way:
If a soldier's life will be endangered by nerve gas, for example, it is not acceptable from a military standpoint to defer to whatever might be the soldiers' personal preference concerning a preventive or therapeutic treatment that might save his life, avoid endangerment of the other personnel in his unit and accomplish the combat mission. Based on unalterable requirements of the military field commander, it is not an option to excuse a non-consenting soldier from the military mission, nor would it be defensible militarily or ethical to send the solider unprotected into danger.Regarding this last point, the Mendez letter noted that a number of Supreme Court cases had established "that special military exigencies sometimes must supersede normal rights and procedures that apply in the civilian community." Long-standing military regulations made clear that military personnel might be required to submit to medical care judged necessary to "preserve life, alleviate suffering or protect the health of others." However, the nature of military command authority carried special responsibility for the well-being of military personnel. Consequently, the following procedural limitations were proposed for the "not feasible" determination: that waiver decisions be made on a case-by-case basis by the Commissioner of FDA, thus "assuring an objective review outside of military channels"; that written justification be provided for the intended uses of IND drugs and biologics and the specific military circumstances involved; that no satisfactory alternative treatment is available; that available safety and efficacy data support the proposed use of the drug or biologic; that each request be approved by the applicable DoD IRB; and that waivers have time limits.
FDA Rule Making
The Mendez letter set in motion the formal rule preparation processes of FDA, which ended when FDA issued the Interim Rule, "Informed Consent for Human Drugs and Biologics; Determination that Informed Consent is Not Feasible" (55 FR 52814), on December 21, 1990. In a lengthy preamble that included the Mendez letter, FDA explained its rationale for the rule. It acknowledged its responsibility to protect human subjects exposed to IND drugs, "the central role that informed consent plays in ensuring that protection," and that only "the narrowest of exceptions" to this requirement were consistent with FDA responsibilities. However, the agency had concluded that under the special circumstances that might be created by troops in conflict, the agency "may narrowly expand" the authority of the commissioner to determine that obtaining informed consent is "not feasible." It agreed with DoD that obtaining informed consent might not be feasible "in certain combat-related situations" and that withholding IND drugs for treatment would be "contrary to the best interests of military personnel involved."
FDA recognized DoD's "right and responsibility" to make the command decision to send troops into combat and its concomitant responsibility to protect those troops, both individually and collectively. This protection, FDA acknowledged, might include prevention or treatment with an investigational drug. Coming to the heart of its rationale, FDA stated:
FDA will consider investigational products proposed for military use on a case-by-case basis, and the agency is prepared to waive the requirement of informed consent where it can be documented that use of these agents in combat-related situations serves the best interests of individual soldiers and the military combat units in which they serve. Since these individual soldiers may be required to be exposed to combat, permitting them to choose whether to receive an investigational product that is the only available satisfactory protection against life-threatening conditions, is contrary to their individual best interests and to the welfare of the other soldiers involved. FDA therefore believes that such an exercise of the Commissioner's discretion is ethically justified. (Preamble to the Interim Rule.)The detailed provisions of the regulation included FDA review of all products for safety and "expanded availability" to a military population. Importantly, the use of IND products would be monitored by DoD and reported to and reviewed by FDA. Since not all combat situations would create the need to waive informed consent, DoD and FDA must determine the justification for a waiver of informed consent for a particular drug, after IRB approval of the use and the waiver, and make a judgment that anticipated use complied with the limited circumstances outlined in the regulation.
DoD and FDA compliance with established ethical principles was addressed explicitly as it bore on the limitations of the rule. The preamble to the Interim Rule read:
DoD and FDA also emphasize that accepted ethical principles permit waiver of informed consent only where the preventive or treatment is in the best interests of the individuals involved. Therefore, it is not sufficient as an ethical matter to waive informed consent in the military context where obtaining informed consent is "not feasible," unless it is also the case that withholding the treatment would be contrary to the best interests of the individuals involved.Consequently, the commissioner would waive informed consent only on a product-by-product basis after a finding that there "is no available satisfactory alternative therapy for the intended diagnosis, prevention, or treatment of the disease or condition." The Commissioner would consider the information provided to recipients of the IND drug about potential risks and benefits; known adverse effects; the risks of failing to take the drug in combat situations; whether the disease or condition (i.e., the military threat) was life-threatening, contagious, or highly debilitating; and how the drug was to be administered. Only written DoD requests for waivers would be considered, and these would have to specify a protocol for use of the IND in question, justification for use, and indication of IRB review and approval. Finally, waivers would expire after one year or when DoD informed FDA that the specific military operation creating the need for the investigational drug had ended, whichever was earlier. DoD could then reapply for a waiver if the need continued beyond the year, but this would not preclude the commissioner from revoking or modifying the waiver on the basis of "changed circumstances."
As summarized in enclosure 1 and supported by documentation in the IND file, available evidence supports the safety and effectiveness of pyridostigmine pretreatment, in conjunction with other drugs, for this purpose. If threatened with these chemical weapons, the interests of individual service personnel and the overall needs of the military service will require that pyridostigmine be used by all threatened personnel. No satisfactory alternative regimen involving investigational or approved drug products is available to deal with these life-threatening weapons. Under these circumstances, withholding pyridostigmine from any threatened individual would be contrary to that individual's best interests. The recommendation for use of pyridostigmine without informed consent has been concurred in by a duly constituted institutional review board. (Mendez, 1990b.)A similar statement was included in the BT letter. (Mendez, 1990a.)
The DoD PB waiver request was reviewed by the Center for Drug Evaluation and Research (CDER). The review group memorandum read, in part:
The CDER concludes, based on its review of the safety and effectiveness data, that pyridostigmine 30 mg tablets, in conjunction with atropine and pralidoxime, is the only potentially useful pretreatment to reduce mortality after exposure to chemical weapons involving organophosphorous nerve agent. There is no ethical means of carrying out a relevant human efficacy study. In the absence of human data, there is less than full certainty as to pyridostigmine's effectiveness in man at the recommended dose, but the extrapolation from rhesus monkey and other animal data is not unreasonable, and pyridostigmine has been protective to at least some extent in other species studied.CBER followed a similar process, which resulted in a similar recommendation for BT.
On January 8, 1991, the FDA Informed Consent Waiver Review Group (ICWRG), in a memorandum to the FDA Commissioner (ICWRG, 1991), recommended approval of the DoD-requested waiver of informed consent for use of PB for ODS. The memorandum noted that "pertinent safety data in both animals and humans" existed and that the recommended daily dose of 90 mg (one 30 mg tablet taken every 8 hours, for a total of 90 mg per day) for Gulf War pretreatment was only 10 to 15 percent of the typical daily dosage of 900 mg or greater prescribed for the treatment of myasthenia gravis. However, the review group expressed concern that DoD instructional materials (FM 8-285 and TM 90-4) implied that PB pretreatment use had been proven to be effective in human studies. "Efficacy data are based wholly on studies in animals," the memo stated. DoD then submitted a supplemental information sheet stating that PB had been shown to be effective in animal studies, and FDA concurred with this statement. A similar recommendation was made with respect to BT.
On January 8, 1991, Commissioner Kessler concurred in the recommendations and signed waivers of informed consent for the use of PB for nerve agent pyridostigmine bromide pretreatment and for BT to immunize against botulism, each limited to a 12-month period. One week later, on January 15, the United Nations' deadline for Iraq to withdraw from Kuwait was reached. Withdrawal did not occur, and coalition forces in the Gulf, led by the United States, attacked Iraqi forces. The coalition forces overwhelmed Iraq by massive air assaults, followed by ground attacks. Within six weeks, President Bush ordered a halt to active hostilities. In less than two months, the engagement with the Iraqis was over. In mid-March, Dr. Mendez informed the FDA Commissioner that hostilities had ended and that the waivers were no longer needed.
The Interim Rule became effective immediately on publication. Although "notice and comment" were deemed impracticable under the circumstances, a 30-day public comment period was provided. The comment period resulted in 21 letters to FDA, some of which supported the rule, others of which were highly critical of it. More important was the discussion in the bioethics literature and, to some extent the popular press, followed by litigation in the federal courts.
John Doe and Mary Doe v. Louis Sullivan and Richard Cheney, USDC, District of Columbia, 756F. Supp.12, January 31, 1991
In his opinion, Judge Harris summarized the case as follows. The plaintiffs' challenge to the Interim Final Rule (55 FR 52817), codified at 21 CFR 50.23(d)) argued that the regulation violated the FDCA limitations on the use of unapproved drugs on unconsenting humans; that it was a marked departure from long-standing FDA regulations regarding the feasibility of obtaining informed consent; that DoD was planning to exceed the scope of its authority, which prohibited the use of DoD funds for research on involuntary human subjects; and that use of unapproved drugs on military personnel without their informed consent violated their Fifth Amendment right to due process.
Judge Harris held, first, that the plaintiffs' motion was not likely to prevail on its merits; that the decision to use unapproved drugs was "a military decision"; that a long line of cases supported the defendants' claim that courts were ill-equipped to, and therefore should not, intrude on the relationship between enlisted military personnel and their superior officers; and that the Constitution expressly delegated oversight of the armed forces to Congress, which had enacted "comprehensive statutes regulating military life." Regarding the plaintiffs' motion, he wrote:
It would be difficult to think of a clearer example of the type of governmental action that was intended by the Constitution to be left to the political branches directly responsible--as the Judicial Branch is not--to the electoral process. Moreover, it is difficult to conceive of an area of governmental activity in which courts have less competence. The complex, subtle, and professional decisions as to the composition, training, equipping, and control of a military force are essentially professional military judgments, subject always to civilian control of the Legislative and Executive Branches. The ultimate responsibility for these decisions is appropriately vested in branches of the government which are periodically subject to electoral accountability. (USDC, DC, 756F. Supp. 12, January 31, 1991.)Judicial interference "in this type of strategic decision," Harris declared, would be improper and, for that reason, dismissed the request for a preliminary injunction.
The judge went on to say that, even if the plaintiffs' claim were subject to judicial review, the Court would deny its motion for preliminary injunction. Two arguments of the plaintiffs involved statutory construction (or meaning): that the regulation violated the FDCA and that DoD was planning to exceed the scope of its statutory authority. The criteria for judging such arguments were that, where the language of a statute was clear, no resort to legislative history was necessary and that, where a statute was silent, courts defer to the agency responsible for its administration. In this case, the statute was silent and the issue turned, therefore, on "whether the agency's answer is based on a permissible construction of the statute."
For DoD, the act in question was the 1985 DoD Appropriations Act, which prohibited the use of DoD funds "for any research involving a human being as an experimental subject" unless that individual's informed consent was first obtained. The plaintiffs argued that the DoD use of unapproved drugs [in ODS] constituted "research," that under FDA regulations DoD must collect data on the efficacy of such drugs, and that any use of unapproved drugs was research per se. Harris held the contrary:
Plaintiff's definitional argument is not persuasive in light of the DoD Act's plain meaning. The DoD's use of unapproved drugs does not involve the type of scientific investigation under controlled circumstances that "research" connotes. On the contrary, the DoD has responded to very real circumstances and chosen what it views as the best alternative given current knowledge. The primary purpose of administering the drugs is military, not scientific. The fact that the DoD will collect information on the efficacy of the drugs does not transform the strategic decision to use the unapproved drugs in combat into research.Moreover, he continued, FDA has interpreted the FDCA to permit use of unapproved drugs in a treatment-investigational setting, indicating that Congress did not intend to embrace all uses of such drugs under the term research.
On whether the Interim Final Rule violated the FDCA, the district court also held for the defendants. FDA had adopted §50.23(d) under authority of the statute that allowed exceptions to the informed consent requirement when obtaining such consent was deemed "not feasible" or "contrary to the best interests" of the individuals in question. FDA was not required under the statute to define "not feasible" so narrowly as to mean "impossible," as the plaintiffs argued. In response to the plaintiffs' argument that it was feasible to obtain informed consent in the combat situation for which DoD sought a waiver, Harris stated that FDA's interpretation was entitled to deference unless "arbitrary, capricious, or manifestly contrary to the statute."
On deprivation of due process under the Fifth Amendment, the court held that there were legitimate government interests in preventing unnecessary danger to all troops and in ensuring the accomplishment of the military mission and that these interests were a "counterbalance [to] an individual's interest in being free from experimental treatment without giving informed consent."
Thus the district court concluded that the DoD plan to administer unapproved drugs in ODS and the FDA's interim rule authorizing such use without informed consent constituted "strategic military decisions," and ones that the court declined to second guess. Even if reviewable, however, the court would have dismissed the motion. The plaintiffs' request for injunction was denied and the defendants motion for dismissal was granted.
Doe v. Sullivan, 938 F.2d 1370, No. 91-5019, USApp DC 111, heard March 18, 1991, decided July 16, 1991
The appeal to the U.S. Court of Appeals for the District of Columbia Circuit was argued on March 18, 1991, and decided on July 16. Writing for the court, Judge Ruth Bader Ginsburg joined by Judge Patricia Wald, held with the plaintiffs that the court had jurisdiction over the issue, but that the government was well within its authority under the law to issue the rule and authorize waivers under the rule. The court did so by a 2-to-1 vote, Judge Clarence Thomas dissenting in support of the government's arguments that the case was moot.
On mootness, even though hostilities had ended with President Bush's declaration on February 17, 1991, the court agreed with the plaintiffs that the controversy was one "capable of repetition, yet evading review." Although the two waivers for PB and BT had been terminated by the time the circuit court heard the case, the rule remained in existence; the government had no intention of withdrawing it; and "interim" rules had often remained in effect for lengthy periods in prior instances. Thus, the case clearly met the "evading review" criterion. On whether it was "capable of repetition," the court held that the likelihood of encountering chemical and biological warfare threats again against U.S. military personnel fell "in the middle ground between cases in which the recurrence prospect is nonexistent or extremely remote, and those in which the probability of repetition is high." The judicial review began when combat was imminent and both the court and Congress, in determining the need, if any, for legislative change subsequent to Desert Storm, "can consider the question Doe tenders most calmly and effectively after the battle fire is extinguished and before it is rekindled."
On the issue of judicial review, the appellate court held that the challenge to Rule 23(d) was "a straightforward one with a commonplace cast," not a "military action" that bars such review. Doe's challenge simply asks "whether the law that governs FDA action permits the measure which that non-military agency has taken." This issue was clearly within the jurisdiction of the court.
On the merits of the plaintiff's petition, however, the appellate court agreed with the district court:
the FDA's Rule 23(d), we hold, is within that agency's rule-making authority under the governing section of the FDC Act, and is not barred by the 1985 Department of Defense Authorization Act or the due process clause of the Fifth Amendment.Thus, it upheld the lower court's dismissal of the complaint.
However, during active Gulf War hostilities, which began within days of approval of the PB and BT waivers, the administration of these investigational drugs differed appreciably from expectations based on the DoD policy and the DoD-FDA discussions that led to the Interim Rule. Some U.S. troops received PB tablets, some were vaccinated with botulinum toxoid vaccine (BT), and some were vaccinated against anthrax (AX). In general, record keeping was quite poor.
For PB, a 21-tablet blister pack was dispensed to those service personnel at highest risk of nerve agent exposure. The dosage prescribed was one 30 mg tablet every 8 hours. PB was used by over 250,000 service personnel, but variation in use occurred as a function of unit commander orders. One of the better quality data reports was that of Keeler et al. (1991) on the experience of the XXVIII Airborne Corps. This unit instructed 41,650 solders (6.5 percent women) to take PB at onset of ODS in January 1991. (Keeler et al., 1991.) Individual service members took from one to 21 tablets over periods ranging from 1 to 7 days, with 34,000 soldiers reportedly taking the medication for 6 to 7 days. Reported side effects of PB were experienced by about half the troops, but were considered tolerable; the most common complaints were about side effects that are normal consequences of PB. Intolerance to PB, which was perceived as the need for medical attention, resulted in 483 aid station or clinic visits related to PB. Of these clinic visits, 313 were gastrointestinal; 150 were for frequency or urgency of urination; and there were other manifestations in a few others. As a demonstration of the data problems, the Defense Science Board Task Force on Persian Gulf War Health Effects reported in June 1994 that PB was issued as a nerve agent pretreatment "to nearly all US troops, as well as 45,000 participants from the United Kingdom," (Defense Science Board, 1994, p. 52), a figure later understood to be incorrect.
According to DoD, BT administration was restricted to relatively few units that were thought to be at highest risk; only about 8,000 doses were administered, hardly any to reservists. This vaccine was produced by the Michigan State Department of Public Health.
Information provided to service members and to health care providers was inadequate. Such information was available in training manuals. Information sheets were prepared for both PB and BT. But the actual distribution of information to the troops was highly variable, and postwar testimony by many veterans revealed that the information they received was unsatisfactory, at least in retrospect. This deficiency is perhaps the most telling of all, since authority to waive informed consent throws a heavy burden on the obligation to inform.
Record keeping was also very poor. This was particularly true for PB, which is self-administered. Without medics to record consumption of medication, there is very little way to overcome this deficiency. In the case of BT, which was administered by medics, record keeping in an individual's yellow shot card was quite uneven. Some record entries were for vaccine A, others for vaccine B, but individuals were not told what they had received. Others were told, and the entries were anthrax vaccine or BT. But there was no uniformity of record keeping during the conflict, which generated substantial criticism afterward.
The disparities between actual events and prior expectations stem from at least four sources. First, time was extraordinarily short. Rule making, which took place in record time, required three months. But only one week was available between the granting of the waivers and actual hostilities. Preparation for orderly processes was next to impossible.
Second, communication flows were quite complicated: They proceeded in the first instance from the ASD(HA) to FDA, then from FDA within DHHS, and from FDA back again to Health Affairs; they then went from Health Affairs to J-4 (Logistics, which includes Medical Readiness) in the Joint Staff; and J-4 was in communication with Central Command (CENTCOM) and BG Robert Belihar, Command Surgeon for CENTCOM during the war. The faithful transmission of complicated information is difficult under normal circumstances. In preparation for active conflict, it is likely to be very, very difficult.
Third, discretion was exercised in the theater of operations that overrode policy that had been agreed upon in Washington. This occurred, for example, in the case of BT administration. Although a waiver of informed consent had been approved for BT, the actual supply of the vaccine that was available for use in the Gulf was limited and inadequate to vaccinate all military personnel. Consequently, informed consent was used as the basis for allocating a scarce resource. As General Belihar later testified,
We did not have enough vaccine to vaccinate everybody. . . Now the question is, well, if we have people who are at risk and we don't have enough vaccine to vaccinate everybody, why make it mandatory. So we added the consent factor to it. . . it seemed reasonable to give them the choice, based upon the fact that you gave the information upon which to base a choice." (PAC meeting, January 12, 1996 transcript.)In the case of PB, which individual service members self-administered, informed consent was waived. The decision to order troops to take this medication, however, was made by the local unit commander. This occasioned a question at the January 1996 PAC meeting. Ms. Knox, a PAC member, asked General Belihar, "Can you help me understand, too, why the order for PB was a unit command?" Belihar responded:
I think you cannot, in the moment of battle, coordinate through your component commander up through the CINCCENT [Commander in Chief, U.S. Central Command] to the [Command] surgeon. There are certain things that must be empowered at the unit level.This response can be understood in two ways, either as an override of FDA-based expectations for some uniformity of the decision to administer PB or, on the other hand, as the exercise of time-honored, and legally protected, exercise of battlefield discretion within the chain of command.
Finally, the administration of these investigational drugs in the Gulf derived from strategic "order of battle" considerations. Again, it is useful to quote General Belihar:
Well, we had quite a bit of anthrax vaccine, but we did not have nearly enough botulinum toxoid to vaccinate everyone. So we went to the Commander in Chief [Schwarzkopf] and said, "Sir, there's a lot of information that we don't have. We have to go on a best guess. How do we utilize this botulinum toxoid?" I said, "Sir, you've got to make the call because you know the order of battle, I don't." And I will tell you, this whole order of battle is very closely held. I said, "Sir, you make the decision."He continued a few minutes later with this same theme:
There was a question that we kept this thing top secret because we wanted to shield the Allies from the fact that we were going to vaccinate. That is not true. . . The reason for the classified nature here is because of the order of battle, because the patterns of vaccine administration would indicate, perhaps, how those troops were going to be employed, and we didn't want to do that.
After the war, PB was implicated as a possible risk factor in Gulf War veterans' illnesses, especially when used in combination with diethyl-m-toluamide (DEET), a pesticide used in the Gulf War by deployed troops. BT and AX were also cited as possible causes for some veterans' illnesses. Most pertinent, however, is the fact that the manner of control and administration of these drugs has been used to call into question the merit of the initial policy embodied in the Interim Rule.
In addition, the PAC meeting on January 12, 1996, in Kansas City, Missouri, heard testimony from a number of witnesses. This meeting, chaired by PAC member Arthur Caplan, received testimony from Brig. Gen. Robert Belihar, Chief Surgeon to GEN Norman Schwarzkopf, theater commander in the Gulf War; David Bales, a physician who had served under Belihar; Edward Martin, then-Deputy Assistant Secretary of Defense for Professional Affairs and Quality Assurance, Health Affairs; Edmund G. Howe, director of programs in medical ethics and Professor of Psychiatry, Uniformed Services University of the Health Sciences; Nightingale, Associate Commissioner for Health Affairs, FDA; and Alta Chara, Professor of Law and Medical Ethics, University of Wisconsin-Madison.
On the bases of these meetings, the PAC, in its Interim Report of February 1996, drew three conclusions. First, it noted, as indicated above, that DoD and FDA had
deliberated carefully before enabling, through rulemaking, DOD to take pyridostigmine bromide (PB) and botulinum toxoid (BT) vaccine as pretreatment for possible CBW agents without FDA approval of the products for that purpose.Second, the report criticized FDA for having "failed, in the five years since the Gulf War, to devise better long-term methods governing military use of drugs and vaccines for CBW defense." (PAC, 1996b, Executive Summary.) The text also criticized FDA for not having "been proactive in addressing public comments on the interim final rule." (PAC, 1996b, p. 23.) The PAC further argued that when a waiver of informed consent is granted, "the government has a strong obligation to conduct long-term follow-up of military personnel who receive investigational products." (PAC, 1996b, p. 23.) Third, the PAC "also found DOD's inability to produce records of who received PB or BT indicative of much need for wholesale improvement in the government's performance on medical recordkeeping during military engagements." (Executive Summary). The body of the report extended this criticism to include anthrax vaccine and, rather ruefully, noted that there was "little possibility now of developing reliable data about which or how many persons received these products." (PAC, 1996b, p. 23.) The report also criticized DOD's rationale for keeping vaccination records secret. "This requirement," it stated, "confused and complicated recordkeeping procedures and hindered systematic follow-up of health issues." (PAC, 1996b, p. 23.)
Consequently, the Interim Report contained the following two recommendations:
develop enhanced orientation and training procedures to alert service personnel they could be required to take investigational drugs or vaccines not fully approved by FDA if a conflict presents a serious threat of exposure to CBW agents. (PAC, 1996c, p. 20.)The Final Report noted that FDA "is now considering the Interim Final Rule in conjunction with guidelines for CBW agent prophylaxis approval," but also expressed concern about the amount of time--nearly six years--that FDA was taking "to move forward with opening up the Interim Final Rule . . . for public comment." (PAC, 1996c, p. 20.)
The PAC Final Report had two findings pertaining to the use of investigational drugs. First, it noted that FDA "is moving toward soliciting public comment on alternatives [emphasis added] to the Interim Final Rule" but again expressed serious concern about the amount of time that had been taken. (PAC, 1996c, p. 27.) Second, it found that DoD had not been responsive to the recommendation that it should routinely inform recruits and troops, through orientation and training, about "the possible use of investigational drugs or vaccines for chemical and biological warfare purposes." This lack of response, the PAC concluded, "contributes to the perception of many that U.S. troops were inappropriately subjected to investigational drugs or vaccines during the Gulf War." (PAC, 1996c, pp. 27-28.)
The PAC then made the two recommendations. It again recommended that DoD "develop enhanced orientation and training procedures" (p. 52). It also recommended that "FDA should solicit timely public and expert comment on any rule [emphasis added] that permits waiver of informed consent for use of investigational products in military exigencies." Among the areas it recommended be revisited were the adequacy of disclosure to service personnel; the adequacy of record keeping; long-term follow-up of individuals who receive investigational products; review by an IRB outside of DoD; and additional procedures to enhance understanding, oversight, and accountability. (PAC, 1996c, p. 52.)
The departments of Defense, Health and Human Services, and Veterans Affairs responded to the PAC Final Report through the Persian Gulf Veterans' Coordinating Board on March 7, 1997 (PGVCB, 1997). FDA concurred with the PAC recommendation. It indicated that it had "carefully evaluated" the PAC recommendations since its Interim Report, had discussed the issues with DoD, and noted that the issues raised "are complex and require extensive coordination." FDA was preparing to solicit public comment on whether it should "finalize the Interim Rule, modify it, or eliminate it completely." One part of this process involved exploration of "the approval mechanisms that should be applied to drug and biological products that may be used in military or civilian exigencies." (PGVCB, p. 12.)
The DoD concurred with the PAC recommendation about the need for enhanced orientation and training. It acknowledged that, although medical personnel who participated in ODS were thoroughly briefed about the side effects of PB, this information "did not, in most cases, get down to the individual service member." Some service members' concerns could have been alleviated, DoD responded, "had they known that the side effects they experienced were, in fact, attributed to the known side effects of PB, and which in most cases would go away as the service member became tolerant to those effects of PB." (PGVCB, p. 13.) Consequently, all new and existing stockpiles of PB "will contain appropriate labeling" informing the individual service member of potential side effects and warnings for use.
Regarding orientation and training, DoD responded that it already conducts such programs for new troops "on the chemical and biological threat and on the countermeasures which may be needed." (PGVCB, p. 13.) It acknowledged that "more needs to be and will be done" within the coming year. The stated goal of the DoD is
that every service member is fully informed during orientation and training of the health risks, benefits, and proper use of all medical countermeasures, and, that when used, such countermeasures are documented and maintained as part of the individual's health record.Given the potential for CW/BW threats in future conflicts, the DoD sees having a fully informed service member as critical to troop protection. The troop information program and a new DoD medical surveillance policy, DoD asserted, will contribute to enhanced soldier welfare.
Finally, given that the Interim Rule was still in effect, DoD indicated that it would prepare orientation and training procedures
to alert service personnel [that] they may be required to take drugs or vaccines not fully approved by FDA if a conflict presents a serious threat of chemical and biological warfare. (PGVCB, p. 13.)The PAC was extended through October 1997, during which time it continued to hold hearings around the country. On July 29, 1997, at a public meeting in Buffalo, New York, Mary Pendergast, Deputy Commissioner of FDA, announced the agency's intention to complete the rule-making process. Step One of that process was to publish a formal "Request for Comments" in the Federal Register. A possible Step Two was to convene a conference focused on issues raised in the comments. The next step would be to issue an NPRM. The final step would be issuance of a final rule.
Initially executed by the Department of Health, Education, and Welfare and DoD in 1964, the MOU was revised in 1974 to indicate the procedures that would be followed "to ensure that the requirements of the Federal Food, Drug, and Cosmetic Act and its implementing regulations are fully met without jeopardizing or impeding the requirements of national security." It was revised again in 1987, and it is this version that is currently in force.
FDA participants included Dr. Stuart Nightingale, Associate Commissioner for Health Affairs (HA); Mr. Duncan, Deputy Associate Commissioner (HA); Margaret Porter, Chief Counsel (OGC); Ms. Witt (OGC); Ms. Wion (OGC); Mr. Geyer (OGC); Dr. Carl Peck, Director, Center for Drug Evaluation and Research (CDER); Dr. James Bilstad, Director, Office of Drug Evaluation II (CDER); Dr. Botstein, Deputy Director, Office of Drug Evaluation I (CDER); Dr. Elaine Esber, Deputy Director, Center for Biologics Evaluation and Research (CBER); Mr. Hoeting, Office of Compliance; and others. DoD participants included Dr. Ronald Clawson, Lt. Col. Lehmann, Lt. Col. Berezuk, Dr. Brandt, and Mr. Winchester.
The autoinjectors for administering diazepam to treat seizures for individuals exposed to PB actually constituted a third possibility, since they were produced overseas and shipped directly to the ODS theater of operations.
DoD participants included ADM (Dr.) Edward Martin, Health Affairs; John Casciotti, Office of General Counsel; and LTC George H. Sisson, Command Judge Advocate. FDA participants included Dr. Stuart Nightingale, Associate Commissioner, Health Affairs; Margaret Porter, Chief Counsel; and Dr. Carl Peck, Director, CDER.
This authority allows the "off label" use by a physician of a drug approved for one indication for a nonapproved indication.
One reviewer (Richard A. Merrill) of the draft version of this report wrote:
DoD's conclusion that the use of the two agents did not fall under 10 USC §980 seems entirely reasonable [and] should have influenced judgments about whether it was necessary for DoD to comply with or obtain an exemption from the FDA regulations for investigational use. Viewed as an initial matter, particularly given the specificity of the congressional policy reflected in 10 USC 980, one could argue that DoD must comply with the FDA requirements only when it is also obliged to comply with 10 USC §980.The PB request was simultaneously filed as an amendment to IND 23,509; the BT request was filed as an amendment to BB-IND 3723.
The anthrax vaccine, a licensed biologic, was administered to about one-third (150,000) of the troops deployed in the theater. It was also produced by the Michigan State Department of Public Health, and has been extensively used for years by civilian wool factory workers and laboratory workers, and its safety is well documented.
Participants included George Annas, Boston University; Edward Martin, Health Affairs; Edmund Howe, the Uniformed Services University of the Health Sciences, DoD; Stuart Nightingale, FDA, Gary Ellis, the Office for the Protection of Human Subjects; his predecessor, Charles McCarthy (who was in that position at the time of the Gulf War); Joan Porter, PAC staff; and others.
TBE vaccine is used against an endemic infectious disease, not against a BW agent, and thus its clinical testing does not raise the same questions as do PB and BT.