FDA Comment: Investigational new drugs, informed consent, and the militaryment: Investigational new drugs, informed consent, and the military

In 1997 the Food and Drug Administration solicited public comment regarding the waiver of informed consent for the military use of investigational new drugs. Waiver of informed consent in this context means that troops serving in the US armed forces can be ordered to take investigational drugs without having been informed about the risks the drugs may entail. FDA granted such a waiver to the Department of Defense during the Gulf War, which enabled the military to administer pyridostigmine bromide (PB) to US troops without their informed consent.
The following is the entire comment sent by HEAL's Governing Board to FDA regarding this matter.

October 27, 1997
TO: FDA
Docket Management Branch HFA-305

FROM: The Governing Board, Human Ecology Action League, Inc.

RE: Food and Drug Administration Docket 90N-032

Determination under the interim rule that informed consent is not feasible for military exigencies. 21CFR Part 50

The Governing Board of the Human Ecology Action League, Inc. wishes to make the following recommendations in this matter.

# 1. Should FDA revoke the interim rule? If so, why?

The FDA should, at a minimum, suspend the interim rule waiving informed consent until such time as the Agency has established a method whereby the propriety of such waiver is justified (see recommendation at #2).

Discussion

In the case of pyridostigmine bromide (PB) used in this fashion in the Gulf War, the mere fact of the threat of a war against an enemy known to possess, and to have used, chemical weapons in the past, was insufficient justification for the wholesale distribution and unregulated ingestion of a drug with known limited capacity to protect against nerve agent poisoning, and with unknown capacity to cause or contribute to ill-health in those who were obliged to take it.

However, there may be times when the Agency determines that there are overriding reasons why military requests for use of drugs not approved for civilian use should be considered. This seems to have been the case in the Persian Gulf War: The threat of chemical weapons exposure made the military request for use of PB as a pretreatment seem both urgent and rational at the time. In such situations, the military may argue persuasively that since in combat situations informed consent cannot be obtained, therefore the requirement that informed consent be obtained should be waived.
We believe that such arguments do not in themselves justify invocation of the interim rule.

#2. Under what circumstances is invoking the interim rule justified?

When the Agency finds what it believes to be compelling reason to consider military requests for invoking the interim rule waiving informed consent for the administration of investigational new drugs, the Agency should be very clear about on whose behalf it is acting.

The Governing Board of the Human Ecology Action League, Inc. is convinced that
the Agency should regard itself as acting, not on behalf of the military, but on behalf of the troops -- US citizens serving in the armed forces.

In situations involving military exigencies, the Agency should put in place stringent requirements to be met by the military before the Agency permits military distribution of and use by the armed forces (without informed consent) of drugs not approved for civilian use, or drugs not approved for the purpose for which the military intends to use them.

These requirements should serve as a surrogate for the informed consent that the troops will not be able to give, and should be formulated for the protection of the troops, not for the convenience of the military. In situations involving military exigency, the Agency should regard itself as an advocate for the health and safety of the troops, not as a handmaiden of the military.

We believe that requirements that must be met by the military in these circumstances include the following; this list may not be exhaustive.

• The military must be able to demonstrate that the threat intended to be offset by the use of the drug is actually demonstrably likely to occur. (In the case of PB use in the Gulf War, it would have been necessary for the military to demonstrate that attack with the nerve agent soman was likely to occur.) This is a question of military intelligence, for which standards of reliability may exist in the security services. It is not necessary for FDA to accept these standards as decisive, but it is necessary for the agency to know what these standards are. If this condition cannot be met with greater than 50% likelihood of troop exposure to the threat, the drug should not be approved for military use.

• The military must be able to produce reliable evidence that the drug for which the permission is requested is likely to be effective against the demonstrable threat noted above. (In the case of PB use in the Gulf War, there was reason to believe that PB would not offer enhanced protection from nerve agents other than soman; thus the belief on the part of the military that chemical weapons (unspecified) might be used would be insufficient justification for invoking the interim rule.) If this condition cannot be met, the drug should not be approved for military use.

• In the field, evidence of the presence of the threat intended to be countered by use of the drug is not heavily dependent on the perfect performance of unreliable devices and thus subject to varied interpretations. (The administration of PB in the Gulf War was dependent on the operation of chemical weapons detection systems that were said to have malfunctioned at the time, and which in any case were incapable of distinguishing between types of chemical weapons.) If this condition cannot be met, the drug should not be approved for use.

• Prior to Agency approval of the requested use of the drug by the military, the military, the Agency, and independent investigators must fully explore the interaction potential of the requested drug with other exposures likely to be encountered by troops taking the drug. Such exposures include other drugs being taken or used by the troops, likely environmental exposures, and occupational exposures determined by military procedures. Common or unavoidable exposures may determine whether or not a drug is approved for use by the military. If the combination of the drug and other exposures likely to occur appears to present more of a risk than the threat for which the drug is being requested by the military, the drug should not be approved for use.

• The military must demonstrate that it has and will deploy adequate medical personnel and sufficient medical materiel for treatment of combat casualties from all causes. (It is not justifiable to permit the military to use unapproved drugs without informed consent on the troops when the military has demonstrably neglected its own field medical infrastructure and staffing.) If this requirement cannot be met, the drug should not be approved for use by the military.

• The military must demonstrate that there will be sufficient numbers of appropriately-trained military medical personnel present in the field to oversee the administration, use and treatment of troops using the requested drug. This is also a quality of care standard. If this condition cannot be met, the drug should not be approved for use by the military.

• The Agency and the military must agree on a record-keeping system that can be implemented in the field, and the military must demonstrate that it has dedicated both doctrine and personnel to implementing this system on an ongoing basis. Records must include the name of the drug, its manufacturer's name and address, the drug lot number, and the unit to which the drug was delivered. This information may be vital in the event of untoward outcomes in troops taking unapproved drugs, as it will provide information not only about the drug but about where the drug was taken and by whom (in unit level groups). (Note that the manufacturer can encode most of this information on bar-coded tearoff labels. The labels can then be removed at the unit distribution level and placed unsorted into special labeled containers for later archiving.) If this condition cannot be met, the drug should not be approved for use by the military.

The Agency should acknowledge that it is a misnomer to call unapproved drugs used by the military "investigational new drugs" when it is clear that no investigation is actually to be undertaken. The Agency had reason to believe that the military use of PB in the Gulf War would not be an investigation, but rather an uncontrolled trial of an old drug being used for a new, unapproved purpose.

The Agency should also acknowledge that the administration of a drug to troops in combat situations may not yield information about the drug in non-combat situations. Thus whatever investigatory usefulness 'trials' of this sort might have may apply only to combat situations, or situations comparable to combat. (There is preliminary evidence that PB's ability to permeate the blood-brain barrier is enhanced by combat-related stress.

It is not known what extreme of stress is represented by the combat stress capable of causing a drug that normally acts only in the peripheral nervous system to cross over into the central nervous system. It is not known if there are situations in civilian peacetime life that give rise to similar stress levels. Thus the knowledge about PB's activity that has been gained by its use in the Gulf War may have very limited usefulness.)