One threat the United States faced in the Gulf War was that Iraq might use chemical warfare (CW) and/or biological warfare (BW) agents. The Department of Defense's (DoD's) defensive measures against CW/BW weapons, imperfect as they are, included detection, protection, and medical measures (including both prophylactic and therapeutic interventions).
Several medical products were available to DoD for potential defensive and prophylactic use in response to CW and BW attacks. But the FDA had not approved these products for these indications. Thus, the FDA regulatory framework designated these products as investigational new drugs (INDs). Pyridostigmine bromide (PB), a drug for pretreatment against certain nerve agents, had been approved long ago for the treatment of myasthenia gravis in larger doses and for longer times than the anticipated Gulf War use. Thus, there was a prima facie case for safety based on experience in humans; there were also animal studies that supported its effectiveness. Botulinum toxin (BT) was a vaccine used routinely in occupational settings in which workers were at risk of botulism. Both the U.S. Army and the Centers for Disease Control also registered BT as an IND.
DoD wished to be in a position to use PB and BT, if necessary, but also wished to act either in compliance with FDA regulations governing INDs or with formal FDA concurrence that it could act without FDA approval. DoD and FDA recognized that neither DoD statutory or administrative authority nor the federal Food, Drug, and Cosmetic Act (FDCA) or its implementing regulations had been written with the contingency of the Gulf War in mind. The DoD-FDA discussions foreclosed the possibility of DoD action independent of FDA. This led DoD to request that FDA waive informed consent and other requirements of the IND regulations. Consequently, after several months of discussion, and within weeks of active combat, the Secretary of Health and Human Services and the Commissioner of Food and Drugs jointly issued an Interim Rule establishing the authority of the Commissioner to waive IND requirements in certain military exigencies (55 FR 52814, December 21, 1990).
The provisions of the Interim Rule included the following:
that a military combat exigency exists because of special military combat (actual or threatened) circumstances in which, in order 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 for no treatment or for some alternative treatment.
The DoD Gulf War experience in the use of PB and BT was characterized by poor record keeping, inadequate data collection, and other violations of the terms agreed to in the FDA waivers. This experience raised questions for FDA about the DoD's ability to administer the waivers and, for the critics of the Interim Rule, called the wisdom of the rule itself into question.
After the war, many Gulf War veterans reported a number of poorly diagnosed illnesses. A variety of hypotheses have been advanced regarding the exposure of military personnel to various chemical, biological, and environmental agents and the possible relationship between these exposures and the veterans' reported illnesses. PB and BT were among the agents that some, especially veterans, believed to have caused some of the Gulf War veterans' illnesses. The above factors, especially poor administration and the hypothesized (although not supported by data) relationships between the PB and BT and Gulf War veterans' illnesses, deterred FDA completion of the rule-making process.
The completion of rule making regarding the Interim Rule has taken a very complicated course in the eight years since the rule's issuance. First, the U.S. District Court of the District of Columbia upheld the rule on the grounds that the issue was not reviewable but that, if it were, the court would defer to the administrative agency implementing the rule (John Doe and Mary Doe v. Louis Sullivan and Richard Cheney, USDC, District of Columbia, 756F. Suppl. 12, January 31, 1991). The U.S. Circuit Court of Appeals for the District of Columbia, on appeal, held that the issue was reviewable, but that FDA acted within its authority in issuing the rule (Doe v. Sullivan, 938 F.2d 1370, No. 91-5019, USApp DC 111, July 16, 1991). In early 1991, then, FDA was ready to proceed to a final rule, especially after the courts upheld the Commissioner's authority. However, other, more normal, FDA priorities asserted themselves after the Gulf War ended, and delay set in. The emergence of sharply differing points of view within FDA on the merits of the Interim Rule reinforced the delay.
Second, the Presidential Advisory Committee (PAC) on Gulf War Veterans' Illnesses, formed in late 1995 and operating in 1996 and 1997, in its Interim Report (PAC, 1996b), its Final Report (PAC, 1996c), and in a letter report subsequent to the Final Report, recommended completion of the rule-making process. The PAC did not take a position on the controversial substantive issues surrounding the Interim Rule but did criticize DoD's implementation of the rule in the actual combat situation.
Third, FDA, prodded by successive recommendations of the PAC, published a request for comments on the merits of the Interim Rule in mid-1997, asking that respondents address the options of issuing it as a final rule, modifying it, or revoking it entirely (62 FR 40996, July 31, 1996). This published request was an antecedent action before FDA published its own proposed final rule. By mid-1998, it was known that FDA had proposed to revoke the authority the Interim Rule established, that DoD had objected to revocation, and that the matter was under discussion at the Office of Management and Budget (OMB).
Finally, in the summer of 1998, language (known as the Byrd amendment) was inserted into the Defense Authorization Act for Fiscal Year 1999 that would have required the Secretary of Defense to submit waiver requests, with the written concurrence of the President and with notification of the relevant congressional committees (S. 2057, July 20, 1998). Previously, under the Interim Rule, the Assistant Secretary of Defense (Health Affairs) was to submit such requests. The proposed legislation assumed the continuance of the Interim Rule, at least in some form. However, FDA revocation of the rule would nullify the effect of the legislation, because no one would have the authority to receive such a request. Consequently, the legislation actually adopted in October 1998 (Sec. 731, National Defense Authorization Act for Fiscal Year 1999, Public Law 105-261, October 17, 1998) modified the original language from the summer and vested the authority to grant waivers solely in the President of the United States. The criteria to be used in granting the waivers were the same as those of the Interim Rule. Hence, the policy conflict was resolved by statute, and OMB told the FDA and DoD to resolve their differences within the frame of the new legislation. That process is now under way.
This report reviews the history of the Interim Rule, including the deliberations between DoD and FDA in late 1990, the litigation that occurred in 1991, the actual Gulf War experience with PB and BT, and the work of the PAC. It also addresses the substantive issues raised by the Interim Rule, especially the ethical questions surrounding the waiver of informed consent as authorized by the Interim Rule. It then analyzes the issues FDA outlined in its 1997 request for comments (62 FR 40996, July 31, 1996), including the independence of the investigational review board in reviewing waiver requests, the determination that informed consent is "not feasible" in certain combat situations, the information about investigational drugs that is provided to military personnel in Gulf War-like situations, record keeping, procedures to track noncompliance, and alternatives to the Interim Rule. The report also discusses the question of authority stemming from the absence in the Constitution, in DoD statutes and regulations, and in the FDCA and its regulations of provisions for a contingency of the Gulf War type.
This report was written before the Byrd amendment was proposed and adopted. Therefore, although it refers to these legislative developments, the analysis of the Interim Rule reflects the issues as they were presented in 1997.