Renouncement of Informed Content

Non-FDA-Approved Drugs in Military Combats

The 1991 Gulf War raised many ethical and political questions about the use of research medicines to combat chemical and biological warfare: what is the difference between “research” and “treatment”? Can informed consent be waived? If yes, under what conditions and who is entitled to grant a waiver?

Richard Rettig addresses these and other policy questions arising from the Gulf War experience in his book Military Use of FDA-Approved Drugs for War/Defence: Lessons from the Gulf War.

The emergence of the interim rule

The Department of Defense (DoD) has traditionally agreed to comply with all Food and Drug Administration (FDA) civilian regulations governing the development and use of new drugs, including requirements for informed consent prior to the issuance of Investigational New Drugs (INDs) to research participants. At the time of the Gulf War, two of the most promising drugs available to combat armed and belligerent agents, pyridostigmine bromide (PB) and botulinum toxin vaccine (BT), were still classified as investigational drugs.

In order to comply with FDA regulations, the Department of Defense would have to obtain informed consent from each soldier deployed in the Gulf for the use of PB and BT. In practice, it would be very difficult for the MoD to do this in the short time before troops are deployed. More importantly, soldiers who might refuse to take the drugs in self-defence would thereby jeopardise the combat mission: those who chose not to take the drugs would either have to leave the combat situation (and thus lose their military duties) or be left unprotected, which would endanger them, increase the risk to other soldiers and reduce the chances of success of the mission. To avoid such a situation, the DoD has requested that the FDA confirm the authority to waive informed consent requirements and grant exceptions to the issuance of PBs and BTs.

The FDA had already approved the use of PB for the treatment of myasthenia gravis in 1955 at daily and lifetime doses up to six times higher than those proposed by the DoD. However, since PB was not approved as a pre-treatment for nerve agent exposure, it was designated as an IND for this purpose. BT has been routinely used as an IND since the 1980s to protect agricultural workers against botulism. In the absence of a significant market for BT, it has not found a sponsor willing to fund the additional clinical trials needed to obtain an IND, and therefore remains unauthorised.

After reviewing the DoD application and the proposed uses of PB and BT, the FDA agreed that in some combat situations ‘informed consent cannot be obtained’ and that denial of a potentially life-saving IND in such situations would be ‘contrary to the interests of the military personnel involved’. Therefore, the FDA published an interim rule entitled “Informed Consent for Human Drugs and Biologics; Determination that Informed Consent is Not Feasible”, which provides the authority of the Administrator of the Food and Drug Administration to waive informed consent in certain military situations. Under this new authority, the FDA subsequently granted the Department of Defense the authority to waive informed consent for the issuance of PB and BT.

Ethical issues

The interim rule and the exemptions immediately sparked controversy, mainly because of the distinction between “research” and “treatment”. Opponents of the exemption argued that the use of any indication method is in itself “research”, since the consequences, risks and benefits of its use are unknown. Informed consent was therefore required in all cases. In support of this view, critics cited long-standing ethical guidelines such as the Nuremberg Code and the Belmont Report, which do not provide an exception for the waiver of informed consent in the case of war research.

These critics further argued that the Agency’s use of medicines “for the purpose of benefit, cure or prevention of harm” cannot “turn experimental research into a cure”. Otherwise, researchers could simply change their stated intentions and redefine experimental interventions as treatment, thereby avoiding informed consent requirements. Finally, critics argued that the decision to exempt from the informed consent requirements was itself an acknowledgement that the use of PB and BT is research and not treatment.

Proponents of the exemptions argued that the MoD has an ethical duty to protect its service members to the greatest extent possible. During the Gulf War, the DoD was able to provide the best possible protection for its personnel by using PB and BT, the only preventive or curative agents available to protect against certain chemical pathogens. Although PB and BT are legally defined as ‘experimental’, they were not ‘scientifically or medically significant, novel or experimental’. They were ‘thoroughly investigated’ and, in the case of BT, approved for uses not similar to those proposed by the military.

In these circumstances, it was clear that the proposed uses of PB and BT were not ‘research’, the proponents argued. Moreover, documents such as the Nuremberg Code and the Belmont Report were prepared for human testing, the outcome of which was uncertain and could cause serious harm to the test subjects. They clearly did not foresee the ethical problems associated with the use of drugs, the only means available to prevent death or serious injury in combat situations. The proponents concluded that the Department of Defense could legitimately decide, under the military doctrine of command and control, to act only without FDA approval, but would seek an exception to avoid even the appearance of impropriety.

Options and proposed changes to the interim rule

Unfortunately, the administration of PB and BT during the Gulf War was marred by deficient record keeping, inadequate data collection, and other violations of the terms of the FDA exemption. These deficiencies call into question the ability of the Department of Defense to administer the exemption for informed consent and the reasonableness of the interim rule itself.

This was followed by six years of debate, culminating in the FDA’s issuance of a ‘request for comments’ to determine whether the interim rule should be rescinded, modified, or replaced with an alternative means of obtaining informed consent for the use of INDs in a combat situation.

Given the likelihood of future exposures to CW/BW agents and the need for protection against them, the Rettig analysis concludes that a complete repeal of the interim rule would not be prudent. However, some changes to the interim rule appear to be necessary, such as clarification of general record keeping requirements, notification of military personnel, and training of commanders responsible for supervising medical personnel and dispensing medications.

While there are several options for interim regulation, the most controversial option – some form of ‘prior’ consent that could be obtained at the recruitment stage, during basic training or immediately prior to deployment – raises a number of ethical and logistical questions: for example, which type of IND should be subject to prior consent? How long should prior consent last? What are the potential consequences of refusing consent?

Although there are arguments for maintaining the interim rule, the FDA was willing to repeal it. Withdrawal would immediately reopen whether there is a right to refuse informed consent and, if so, who is competent to exercise it. Congress has resolved this issue by giving the power to grant a waiver exclusively to the President. However, at the time of publication of this report, many of the implementation issues noted above had not been resolved.