Waiving Informed Consent

The 1991 Gulf War raised a number of ethical and policy questions regarding the use of investigational drugs to defend against chemical and biological warfare (CW/BW) agents: What is the difference between "research" and "treatment"? Can informed consent be waived? If so, under what circumstances, and who has the authority to grant waivers? Richard Rettig explores these and related policy issues raised by the Gulf War experience in Military Use of Drugs Not Yet Approved by the FDA for CW/BW Defense: Lessons from the Gulf War.

Genesis of the Interim Rule

Historically, the Department of Defense (DoD) has agreed to comply with all civilian Food and Drug Administration (FDA) regulations concerning the development and use of new pharmaceuticals, including requirements to obtain informed consent before administering investigational new drugs (INDs) to research subjects. At the time of the Gulf War, two of the most promising pharmaceuticals available for defending against CW/BW agents—pyridostigmine bromide (PB) and botulinum toxoid vaccine (BT)—were still classified as INDs. Therefore, to comply with FDA regulations, DoD would have been required to obtain informed consent for use of PB and BT from every service member deployed to the Gulf. As a practical matter, it would have been extremely difficult for DoD to do so in the short time before troop deployment. More importantly, permitting military personnel to refuse drugs intended for their own protection would jeopardize the combat mission: Those choosing not to take the drugs would have to either leave the combat situation (thus reneging on their military obligations) or remain without protection, thereby placing themselves at risk, increasing the danger to other service personnel, and reducing the likelihood of a successful mission. To avoid this situation, DoD requested that FDA both establish authority to waive informed consent requirements and grant waivers for administration of PB and BT.

FDA had already licensed PB in 1955 for treating myasthenia gravis at daily, lifetime doses up to six times higher than those DoD proposed. However, because PB was not licensed as a pretreatment for nerve agent exposure, it was designated as an IND for that purpose. BT has been in routine use since the 1980s under IND status to protect agriculture workers from botulism. Because no significant market for BT exists, it has not attracted a sponsor willing to underwrite the additional clinical trials required for licensing; thus, it remains unlicensed.

After reviewing DoD's request and its proposed uses for PB and BT, FDA agreed that obtaining informed consent might not be feasible "in certain combat-related situations" and that withholding potentially life-saving INDs in such situations would be "contrary to the best interests of military personnel involved." Therefore, FDA issued the Interim Rule, "Informed Consent for Human Drugs and Biologics; Determination that Informed Consent is Not Feasible," which established the authority of the Commissioner of Food and Drugs to waive informed consent under certain military exigencies. Under this new authority, FDA subsequently granted DoD permission to waive informed consent for administration of PB and BT.

Ethical Issues

The Interim Rule and the waivers immediately sparked controversy, much of it centered on the distinction between "research" and "treatment." Those opposed to the waivers argued that the use of any IND was, by definition, "research" because the consequences, risks, and benefits of use were unknown. Therefore, informed consent was required under all circumstances. To support this position, critics pointed to a long line of ethical guidelines, such as the Nuremberg Code and the Belmont Report, that make no exception for waiving informed consent for research conducted under wartime conditions. These critics further argued that the intent to use an IND to "benefit, treat, or prevent harm" could not "transform an experimental investigation into therapy." Otherwise, researchers could simply change their stated intentions and redefine an experimental intervention as treatment, thereby evading informed consent requirements. Finally, the critics argued that the decision to seek a waiver of the informed consent requirements was, in and of itself, an admission that use of PB and BT constituted research, not treatment.

Proponents of the waivers argued that DoD had an ethical responsibility to protect its service members to the greatest extent possible. During the Gulf War, the best protection DoD could offer its personnel included use of PB and BT, which were the only preventive or therapeutic treatments available for defense against certain CW/BW agents. Although legally designated as "investigational," PB and BT were neither "remarkably novel nor experimental in a scientific or medical sense." They had been subjected to "extensive research" and, in the case of BT, had been approved for uses that were not substantially different from those the military proposed. Under the circumstances, the proponents argued, it was clear that the proposed uses of PB and BT did not constitute "research." Moreover, documents like the Nuremberg Code and the Belmont Report were written with human experimentation in mind, in which the outcome of the research was in doubt and could result in serious harm to the subject. They clearly did not anticipate the ethical issues surrounding the use of drugs that would provide the only available means of avoiding death or serious disability under combat situations. Finally, the proponents noted that, under the doctrine of military command authority, DoD could have justifiably chosen to act on its own, without FDA approval, but sought waivers to avoid even the appearance of impropriety.

Alternatives to and Proposed Modifications of the Interim Rule

Unfortunately, poor record keeping, inadequate data collection, and other violations of the terms of the FDA waivers characterized the administration of PB and BT during the Gulf War. These shortcomings called into question DoD's ability to administer informed consent waivers and the wisdom of the Interim Rule itself. A lengthy six-year debate followed, resulting in FDA publication of a "Request for Comments" to determine whether the Interim Rule should be revoked, modified, or replaced with an alternative means of obtaining informed consent for the use of INDs in combat situations.

Given the likelihood of facing CW/BW agents in the future and the need to defend against such agents, Rettig's analysis concludes that revoking the Interim Rule altogether would not be prudent. That said, some modifications to the Interim Rule—such as specifying the general requirements for record keeping, providing information to military personnel, and training the medics and commanders responsible for overseeing administration of INDs—appear to be necessary. Although alternatives to the Interim Rule exist, the most frequently discussed alternative—some form of "anticipatory" consent that could be obtained at recruitment, during basic training, or immediately before deployment—poses numerous ethical and logistical issues of its own: For example, what range of INDs should anticipatory consent cover? For how long would the anticipatory consent be valid? What penalties, if any, would attach to refusal to consent?

Despite arguments to retain the Interim Rule, FDA was poised to revoke it. Revocation would have immediately reopened the question of whether authority to grant waivers of informed consent existed, and if so, who was authorized to exercise it. Congress has since decided this question by vesting authority to approve waivers in the President alone. However, as of the publication of this report, many of the implementation issues raised above remain unresolved.