WASHINGTON, April 15, 1999 (GulfLINK) In 1990, when Iraq invaded Kuwait and the U.S. mobilized for combat, the threat of exposure to chemical and biological weapons was very high. Several medical products were available for use as pre-treatments for these threats, but were not approved for these purposes. The Department of Defense wanted to use these drugs, but would not do so without Food and Drug Administration approval.

The RAND report,"Military Use of Drugs Not Yet Approved by the FDA for CW/BW Defense," released today, chronicles the complex nature of the approval process. It reviews the history of the FDA's "interim rule," one of three exceptions to the general requirements for informed consent of the participants taking an investigational drug. It describes the deliberations between the Defense Department and the FDA in 1990; the litigation that followed in 1991; the actual Gulf War experience with pyridostigmine bromide and botulinum toxoid and the work of the Presidential Advisory Committee on Gulf War Veterans' Illnesses. The publication also addresses in great detail the ethical questions raised by the waiver of informed consent as authorized by the interim rule and analyzes subsequent issues identified by the FDA in its 1997 request for comments.

"We commissioned this review of DoD and federal health policies because of the continuing concerns of veterans," said Bernard Rostker, the special assistant for Gulf War illnesses. "During the Gulf War, troops received very little information regarding the use of investigational new drugs and some veterans believe these drugs may be related to their illnesses. The required record-keeping was poor and administration was inconsistent from unit to unit. This clearly is an area that required a closer look."

The RAND report noted that improvements are needed in record-keeping, risk communications and vaccine stockpiling in preparation for future deployments.

"Looking at this issue was lot like peeling an onion. The decision-making process was deliberate and careful, but it had many layers. It was also often easily misunderstood," Rostker said. "This review documents the actions taken by the Defense Department prior to the Gulf War, explains why they were taken and what happened after approval was given. It provides an objective review on a very serious subject."

An area of significant discussion when RAND began the review was the question about waiver of informed consent that is, for DoD to give troops investigational new drugs without obtaining their individual approval. While the research was underway in 1998, the issue of authority for granting a waiver of informed consent was decided by legislation. Now, by statute, the president with full knowledge of the relevant congressional committees is the final authority for such waivers.

Since 1987 the Defense Department has had a memorandum of understanding with the FDA allowing the "investigational use of new drugs, antibiotics, biologics, and medical devices conducted within DoD facilities, or by a contractor or grantee." The DoD had agreed to follow FDA regulations governing investigational new drugs and to comply with informed consent and institutional review board requirements when conducting research. However, the agreement did not provide a policy framework for dealing with the use of investigational new drugs for protection against chemical or biological weapons outside the research arena such as in the Gulf War. The report points out that the agreement referred to "national security responsibilities" in very general terms but was silent on any contingencies that might arise related to chemical warfare or biological warfare defense.

Consequently, the DoD engaged in careful deliberations with the FDA soon after Iraq invaded Kuwait. The report cites an August 30, 1990, meeting where DoD reviewed the issues associated with the unusual military medical needs of then Operation Desert Shield, in particular, the use of drugs to counter the chemical and biological threat. While the issue of informed consent was a primary focus, a great deal of discussion considered the detailed requirements associated with the use of investigational new drugs. This includes issues such as labeling, reporting, sponsor requirements, monitoring, record keeping and retention, disposition of unused supplies and IRB review.

The Defense Department's efforts were part of a public process, but even that was problematic. Even basic terminology represented a problem. In particular, the term "investigational" was then and today still is often misunderstood. Part of the difficulty, the report notes, is that the term is imprecise. Rather than defining, it establishes a "gray zone" wherein some activities include both research and treatment, and in others, solely treatment.

Furthermore, the term "investigational" is not synonymous with "experimental," although some commentators have used the terminology in this way. The report explains that an FDA classification is use-specific. A drug may be approved by the FDA and sold for use to treat one disease, but be in an investigational status for use as a new treatment for a different disease or condition. Drugs remain in an investigational status until they have completed the FDA review and approval process. For example, in 1990, pyridostigmine bromide was licensed for two civilian uses, treatment of myasthenia gravis, a neuro-muscular disorder, and for reversing the effects of some anesthetic drugs. The investigational status of pyridostigmine bromide signified that it had not been formally approved for labeling, marketing, and general use as a preventive measure against nerve agent exposure.

Pyridostigmine bromide is considered to be investigational when used as a pre-treatment against chemical warfare agents. It had been under investigation for such use since 1984, when the Army filed an application with the FDA. The report also explains that the safety of the drug in military use had been established on the basis of many well-controlled animal and human studies, including 25 studies in five different animal species in single doses and for as long as 34 weeks. But claims about the effectiveness of the pre-treatment drug were based solely on animal studies because it is unethical to intentionally expose people to lethal nerve agents in order to test the effectiveness of a drug. Based on these studies, the United States had decided to stock the tablets in 1986 as a wartime contingency pre-treatment.

The FDA also classified the botulinum toxoid vaccine as investigational at the time of the Gulf War. Like pyridostigmine bromide, that classification remains today. The vaccine had been used routinely since 1970 by people in certain at-risk occupations under investigational new drug status held by the Centers for Disease Control. However, with no commercial requirement, there is no effort to seek FDA licensure and this vaccine will most likely remain in an investigational status indefinitely.

The report concludes with eight points, beginning with a call for advanced planning. "Although policymaking in the shadow of war may involve careful deliberation, it is better to have an adequate policy in place beforehand. The policy needs to be broad enough to respond to a number of contingencies and yet narrow enough to avoid abuse or confusion."

Furthermore, those in the regulatory arena must recognize that the threatened use of chemical and biological warfare agents has permanently altered the context in which the use of investigational drugs is being considered. There are important differences between military drug development and commercial drug development for a civilian market, the report says, and revocation of the existing rule could be potentially very dangerous in operational terms

Finally, the report calls for a process of continual interaction within DoD to ensure the "integration of the medical, operational, and intelligence aspects associated with the use of investigational drugs," as well as interaction between the DoD and the FDA.

"Military drug development shares many features with civilian drug development for commercial purposes, but it also has distinct characteristics," the report said.

RAND is a non-profit institution working to improve policy and decision making through research and analysis. Its 50 years of experience and long history of working with the Department of Defense make the organization very well qualified to carry out this type of research, Rostker said.

The author of the report is a health policy and health services researcher who has served as a member of the professional staff of the Institute of Medicine, on FDA advisory committees and as director of the Forum on Drug Development.

This paper, as well as the first RAND literature review on oil well fires and another on depleted uranium released today is posted on the GulfLINK website ( http//www.gulflink.health.mil ). Literature reviews dealing with chemical and biological weapons, pesticides, pyridostigmine bromide, immunizations, infectious diseases and stress are still in preparation and are expected to be released over the next year. As each report is released, it will be posted on GulfLINK.

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