The purposes of this report are (1) to examine historically the adoption in 1990, in the shadow of the impending Gulf War, of the Interim Rule (55 FR 52814, December 21, 1990), which authorized the Commissioner of Food and Drugs to waive informed consent for the use of investigational drugs and vaccines for certain military uses; how this authority was used for pyridostigmine bromide and botulinum toxoid; and the subsequent controversy surrounding the rule, its application, and its implications; (2) to analyze the issues the Interim Rule raised when investigational drugs are used for such purposes; and (3) to make recommendations.
Chapter Two examines the historical development of the Interim Rule. Chapter Three addresses the definitional issues surrounding investigational. In Chapter Four, the Interim Rule and its alternatives are considered. Chapter Five discusses several broader issues than the immediate regulatory questions the Interim Rule itself raised. Finally, in Chapter Six, conclusions are drawn and recommendations are made.
It was well known that the Iraqi military capability included both chemical warfare and biological warfare (CW/BW) agents. This threat was well publicized to U.S. troops deployed to Saudi Arabia and has since been confirmed in detail in 1995 and later the United Nations Special Commission (UNSCOM).
The CW threat by Iraq was the most serious since the use of mustard gas in World War I. Iraq had used CW agents in its war with Iran as well as against its own citizens. There are four types of CW agents: nerve, vesicant, blood, and pulmonary agents. Nerve agents are organophosphorous inhibitors of acetylcholinesterase; vesicants are skin-blistering compounds, such as mustards and arsenicals; and blood agents are the cyanides, inhibitors of cytochrome oxidase. (Keeler et al., 1991). Pulmonary agents, such as chlorine, phosgene, and diphosgene, irritate the eyes and injure the respiratory system and may cause pulmonary edema. (Sidell, Takafuji, and Franz, 1997.)
The Iraqi CW arsenal was believed to include nerve, vesicant, and blood agents (Keeler et al., 1991), but the primary threat was that of nerve agents. Nerve agents are effective for CW because they are extremely potent inhibitors of the enzyme acetylcholinesterase, a key regulator of cholinergic neurotransmission in tissue. When this enzyme is severely inhibited, the resulting buildup of acetylcholine is fatal. Nerve agents include three inhalation "G" agents--tabun, sarin, and soman--and VX, which can be absorbed through both the lungs and the skin. (Dunn and Sidell, 1989). G agents, which are liquids at moderate temperatures, are typically distributed by droplets or aerosol and evaporate and disperse over several hours under temperate conditions. Tabun, sarin, and soman are "nonpersistent." VX, an oily liquid, is persistent.
The Iraqi BW threat included anthrax, which is caused by a powerful and highly toxic microorganism, Bacillus anthracis, and botulism, a neurotoxin (botulinum toxin), which is produced by the bacterium Clostridium botulinum. Both are capable of inducing lethal effects to exposed humans and animals. The protective measures against these biological agents include vaccines--AX vaccine against anthrax and botulinum toxoid (BT) against botulism.
Both before and during ODS, the Department of Defense (DoD) gave substantial attention to countermeasures for protecting troops against CW/BW attack and maintaining military effectiveness. Protection against nerve agent exposure includes detection and warning devices, use of chemical protective masks and protective clothing, and medical management. Medical management of nerve agent exposure involves a three-drug regimen: pretreatment with pyridostigmine bromide (PB) before exposure and administration of two antidotes, atropine sulfate (Atropine) and pralidoxime chloride (2-PAM), intramuscularly by autoinjectors after actual exposure. (The antidotes are components of the Mark I Nerve Agent Antidote Kit.) The rationale for the use of PB as a pretreatment for anticipated nerve agent exposure is that it temporarily (i.e., reversibly) occupies the same tissue receptor sites as does nerve agent, thus blocking the nerve agent from permanently inhibiting acetylcholinesterase and achieving lethal effects. The blocking action of PB allows treatment by atropine, which blocks the effects of excess acetylcholine, and pralidoxime chloride, which pulls the nerve agent off acetylcholinesterase. In short, PB pretreatment is indicated because it offers sufficient protection against rapid-acting nerve agent to permit therapy to be administered.
The safety of a drug is to be based on "adequate tests by all methods reasonably applicable." [Sec. 505(d)(1), FDCA] The effectiveness of a drug is to be based on "substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof." [Sec. 505(d)(5), FDCA] Substantial evidence is defined as
evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. [Sec. 505(d)]Under the law, the Secretary of Health and Human Services is required to issue regulations exempting those drugs "intended solely for investigational use [emphasis added] by experts qualified by scientific training and experience to investigate the safety and effectiveness of drugs" from the regulations applying to approved drugs. These regulations require that an investigational new drug (IND) application[4] be filed with FDA by the sponsor of a drug or biologic "before any clinical testing of a new drug is undertaken"; that sponsors agree on supervision of investigators, record keeping, and filing of reports; and that written informed consent be obtained from individual subjects (or patients) receiving such drugs. IND regulations govern the initial studies of toxicity or safety (Phase I clinical trials) and later studies of effectiveness (Phase II and Phase III trials).
When a sponsor[5] of a drug or biologic concludes that the evidence of safety and effectiveness from well-controlled studies (Phase III) is adequate to secure FDA approval for marketing, a New Drug Application (NDA) is submitted for a drug, or a Product Licensing Application (PLA) and an Establishment Licensing Application (ELA) are submitted for a biologic.[6] FDA then evaluates the NDA, or the PLA/ELA, and either approves or disapproves the application. FDA approval means that the drug or biologic in question satisfies the criteria of being safe and effective and, therefore, may be sold and promoted in interstate commerce for the specific use or indication the FDA approved. FDA approval also carries with it other requirements, such as product labeling, manufacturing quality control, reporting of adverse effects, and sponsor advertising.
For drugs not yet approved, but used in clinical trials that are designed to obtain evidence for approval, FDA has established regulations regarding informed consent. The FDCA requires that "experts using. . .drugs for investigational purposes" certify to the sponsor of such investigations
that they will inform any human beings to whom such drugs, or any controls used therewith, are being administered, or their representatives, that such drugs are being used for investigational purposes and will obtain the consent of such human beings or their representatives, except where they deem it not feasible or, in their professional judgment, contrary to the best interests of such human beings. [Sec. 505(I)(3), FDCA]Specific FDA informed consent requirements implement this statutory language. In addition, FDA requirements conform to the Department of Health and Human Services (DHHS) informed consent regulations for the clinical research of the National Institutes of Health (NIH) and the Centers for Disease Control (CDC) (45 CFR 46); and to the "Common Rule." The last regulation applies to all federal agencies and requires that an Institutional Review Board (IRB) review and approve research protocols involving human subjects according to the following criteria: (1) risks to subjects are minimized; (2) risks to subjects are reasonable in relation to anticipated benefits; (3) selection of subjects is equitable; (4) informed consent will be sought from each subject in accordance with the general requirements for informed consent; (5) informed consent will be appropriately documented; (6) when appropriate, provision will be made for monitoring the data collected to ensure safety of subjects; and (7) when appropriate, provisions will be made to ensure privacy and confidentiality of subject data.
PB is licensed for two civilian uses. It was first synthesized in 1945 and, after extensive testing, was approved (i.e., licensed) by FDA in 1955 as safe for the treatment of myasthenia gravis (NDA No. 9829, April 7, 1955). Produced by Hoffman-LaRoche, it is prescribed as Mestinon for this indication for lifetime use and at average daily dosages as much as six times greater than those used in the Gulf War for nerve agent pretreatment. FDA has also approved PB for use in reversing some of the effects of some anesthetic formulations. In this form, it is known as Regenol.
However, today as in 1990, the FDA considers PB to be investigational for prophylactic use against CW agents. PB had not been approved as a pretreatment against nerve agents on the eve of the Gulf War, although it had been under investigation for such a use since the U.S. Army filed an IND application with the FDA in 1984 (IND No. 23509, March 1984). The proposed addition of the drug to the U.S. therapeutic regime as a pretreatment for nerve agent poisoning was based on supporting studies conducted in the 1980s and earlier (Dunn and Sidell, 1989). The safety of PB for 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 PB as a pretreatment were based solely on animal studies. The reason for this is clear. It is unethical to expose individuals to lethal nerve agents in order to test the effectiveness of a pretreatment. The United States decided to stock PB tablets (30 mg) in 1986 as a wartime contingency pretreatment (Dunn and Sidell, 1989).
FDA also classified the BT vaccine as investigational at the time of the Gulf War, and this classification remains so today. BT vaccine has been used routinely since the 1980s by individuals in certain agricultural occupations at risk of botulism under an IND held by the Centers for Disease Control (Bureau of Biologics IND #161, November 23, 1965). Although this use of the vaccine is likely to continue, the threat of botulism is infrequent and a significant market for BT vaccine does not exist. Thus, it is unlikely to attract a commercial sponsor and will probably remain in an unlicensed, and therefore investigational status indefinitely.[7] Again, as with PB, the FDA has not approved the BT vaccine for prophylactic use against botulism in the case of a BW attack. Thus, since there are no specific FDA-licensed uses for the BT vaccine, its distribution and use are governed by the regulations that apply to investigational drugs.
However, the meaning of the term investigational requires clarification. It is a legal term FDA uses to distinguish between licensed and unlicensed drugs. Although there are scientific bases for the term, investigational is not synonymous with experimental, even though it is often used in that way by many commentators. Normally, informed consent is required in advance for the use of investigational drugs, whereas this is not an FDA requirement for FDA-approved drugs.
| List Date | Category, Product | IND #, Sponsor | Manufacturer | IND Listed Indication | ODS Status | Scheduled Availability | |
| Drug products | IND # | ||||||
| 8/31/909/19/90 | Diazepam autoinjector | 33,358 USA OTSG |
Duphar BV Amsterdam, Netherlands | Preventing nerve agent induced convulsions | Immediate requirement | 9/26/90 On schedule | |
| 8/31/909/19/90 | Ribavirin injection | 16,666 USA OTSG |
Viratech | Hemorrhagic fever with renal syndrome | Immediate requirement | 10/7/90 | |
| 8/31/909/19/90 | Atropine sulphate inhalation aerosol | 27,594 3M Pharmaceuticals |
NDA# 20-056 USA OTSG |
3M Riker developed product; mfr for gov�t TBD | Anticholinergic antidote for organophosphate poisoning | Decision pending | 5�11 weeks after decision to procure |
| 8/31/909/19/90 | Pyridostigmine bromide30 mg tablets | ANDA# 89-572 Kalipharma USA OTSG |
Duphar BVAmsterdam, Netherlands | ANDA for myasthenia gravis; for ODS, pretreatment nerve agent | On site per 1983 letter (classified); contract to Duphar for more | 9/21/90 | |
| 9/19/90 | Multi Shield | Reg. status under FDA review; mfr has asked reclassification from cosmetic to device | Interpro, Inc., Haverill, MA | ODS topical skin protectant | Procurement under consideration | 2 weeks after decision to procure | |
| Biologic products | #BB-IND | ||||||
| 8/31/909/19/90 | Hepatitis A vaccine inactivated | 3200 Smith-Kline-Beecham; 3252, Merck |
Smith-Kline-Beecham; Merck | Prevent disease caused by Hep A virus | Not an immediate requirement | Pending, undetermined | |
| 8/31/909/19/90 | Botulinal toxoid | 161, CDC | Michigan Dept of Public Health | Active immunization against botulism | Immediate requirement | 10/1/90 | |
| 8/31/909/19/90 | J-5 monoclonal antibody (Centoxin) | 2283, Centocor |
Centocor | Treatment of septic patients | Immediate requirement | 9/10/90 |
| List Date | Category, Product | IND #, Sponsor | Manufacturer | IND Listed Indication | ODS Status | Scheduled Availability |
| Device products | 510(k) # | |||||
| 9/19/90 | Field medical oxygen generating and distribution system | K903411Guild Associates, Inc. | Guild Associates, Inc. | Produce medical grade oxygen | No immediate requirement | 5 prototype on call for shipment to Saudi Arabia |
| 9/19/90 | Litter, folding, rigid pole, decontam-ination | K901760 USA MMDA |
Arizona Industries for the Blind | Evacuate and decontamin-ate chemical casualties | Immediate requirement | Production of 720 completed; 800 more being procured |
| 9/19/90 | Drawover anesthesia device | K901117A USA MMDA |
Ohmeda | Deliver anesthetic drugs in field medical units | Immediate requirement for 15 units | |
| 9/19/90 | Liquid oxygen system, Genox Model CT-1 | K904002 USAOTSG |
Pacific Consolidated Industries | Produce medical grade oxygen | 2 systems on site; 2 more may be procured |
SOURCE:Department of Defense (1990)
FDA responded to this request by issuing an Interim Rule, published in the Federal Register on December 21, 1990, "Informed consent for human drugs and biologics; determination that informed consent is not feasible for military exigencies," (55 FR 52814, 1991).[8] Under this rule, DoD then requested waivers of the informed consent requirement for two investigational drugs: PB and BT. These were granted on January 8, 1991.
The Interim Rule, which became effective immediately, did not go unchallenged. Concurrently, FDA also requested public comments on it, of which many were favorable but some were quite opposed. The rule was also contested in the U.S. District Court for the District of Columbia in January 1991 (Doe v. Sullivan, 1991). Judge Stanley S. Harris, ruled against a request for a preliminary injunction filed by John Doe, a service member in the Gulf War, and Mary Doe, his wife, on the grounds that this was not a reviewable issue for the courts, and, if it were, Harris would reject the request on its merits. Harris granted the U.S. government's motion to dismiss. The ruling was upheld in July 1991 by the U.S. Circuit Court of Appeals for the District of Columbia, stating the matter to be reviewable but upholding the government on the merits of its case. Some critical commentary also appeared in the popular press and the medical and bioethics literature in early 1991. But by and large, the rule occasioned only limited comment.
After active conflict ended in the spring of 1991, DoD asked FDA to complete the rule-making process and convert the Interim Rule to a final rule. Although apparently disposed to do so initially, FDA did not act immediately. As the Gulf War receded in public consciousness, the urgency associated with rule making also receded, and differences of view emerged within FDA about the appropriate course of action. FDA had not completed rule making by February 1996, when the Presidential Advisory Committee on Gulf War Veterans' Illnesses (PAC) issued its Interim Report. The PAC urged the FDA to complete the rule-making process, a suggestion it repeated in its Final Report of December 1996.
Then, in late July 1997, FDA announced plans to complete the rule-making process with publication of a "Request for Comments" on the Interim Rule (62 FR 40996, July 31, 1997). In testimony to the PAC on July 29, then-Deputy Commissioner Mary Pendergast indicated that the agency was also considering a public meeting in early 1998 that would focus on specific issues highlighted by the comments (Pendergast, 1997). She also stated that FDA expected to issue a Notice of Proposed Rule Making (NPRM) in the first half of 1998 after analyzing the comments received. The NPRM would propose a final rule that would modify or revoke the Interim Rule. Thus, resolution of the legal, regulatory, and ethical issues associated with the Interim Rule may occur within the not-too-distant future.[9]
Finally, a third set of broader, longer-term issues deals with possible conflict (or tension) between the constitutional authority of the President as Commander in Chief and the authority of the Secretary of Health and Human Services under the FDCA, the delegation of that authority to the Commissioner of Food and Drugs under the FDCA, and the interactions between DoD and FDA as they pertain to military drug development and use. This conflict arises from the fact that neither FDCA nor its implementing regulations were developed with respect to the special needs of military drug development and use. They certainly were not developed for the contingency that arose in the Gulf War, where the DoD concluded it needed to use investigational drugs for prophylactic, nonresearch purposes. Moreover, although military drug development has been conducted in full compliance with FDA regulations, it has faced difficult problems in adapting to those regulations with respect to prophylactic or therapeutic drugs for defense against CW/BW agents. Finally, it is worth noting that Congress has not enacted clear statutory directives, and the courts have not issued clear interpretations, of how this complex relationship between military drug development and use and the FDA should be organized.
These three sets of issues have both internal and external dimensions for DoD. The internal dimension pertains to those matters over which DoD has control, such as information to military personnel about the risks and benefits of the investigational drugs in question; training of military personnel, both medical and nonmedical, in the administration of IND drug; and record keeping, as well as threat analysis, production, logistics, and the like. These internal matters, however, do influence the debate over the merit of various policies. For example, DoD implementation of the waivers of informed consent for PB and BT was not well-executed in the Gulf War and, consequently, has reflected badly on the policy itself. (See the discussion in Chapter Four, especially regarding Questions A-8c, 8d, 8e, 8f, and 8g.)
The external dimension lies in the reality that policy regarding the potential combat use of investigational drugs does not currently lie within DoD authority but requires the participation and concurrence of FDA and DHHS in both the legal framework governing use and the actual use of drugs within that framework.
Section 50.23 [21 CFR Part 50], "Exception from general requirements," is amended by adding new paragraph (d) to read as follows:(d)(1) The commissioner may also determine that obtaining informed consent is not feasible when the Assistant Secretary of Defense (Health Affairs) requests such a determination in connection with the use of an investigational drugs (including an antibiotic or biological product) in a specific protocol under an investigational new drug application (IND) sponsored by the Department of Defense (DOD). DOD's request for a determination that obtaining informed consent from military personnel is not feasible must be limited to a specific military operation involving combat or the immediate threat of combat. The request must also include a written justification supporting the conclusions of the physician(s) responsible for the medical care of the military personnel involved and the investigator(s) identified in the IND 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 written request must also include a statement that a duly constituted institutional review board has reviewed and approved the use of the investigational drug without informed consent. The Commissioner may find that informed consent is not feasible only when withholding treatment would be contrary to the best interests of military personnel and there is no available satisfactory alternative therapy. (2) In reaching a determination under paragraph (d)(1) of this section that obtaining informed consent is not feasible and withholding treatment would be contrary to the best interests of military personnel, the Commissioner will review the request submitted under paragraph (d)(1) of this section and take into account all pertinent factors, including, but not limited to: (i) The extent and strength of the evidence of the safety and effectiveness of the investigational drug for the intended use; (ii) The context in which the drug will be administered, e.g., whether it is intended for use in a battlefield or hospital setting or whether it will be self-administered or will be administered by a health professional; (iii) The nature of the disease or condition for which the preventive or therapeutic treatment is intended; and (iv) The nature of the information to be provided to the recipients of the drug concerning the potential benefits and risks of taking or not taking the drug. (3) The Commissioner may request a recommendation from appropriate experts before reaching a determination on a request submitted under paragraph (d)(1) of this section. (4) A determination by the Commissioner that obtaining informed consent is not feasible and withholding treatment would be contrary to the best interests of military personnel will expire at the end of 1 year, unless renewed at DOD's request, or when DOD informs the Commissioner that the specific military operation creating the need for the use of the investigational drug has ended, whichever is earlier. The Commissioner may also revoke this determination based on changed circumstances.
| James S. Benson Deputy Commissioner of Food and Drugs |
Louis W. Sullivan Secretary of Health and Human Services |
| Friday, December 21, 1990 |
[1]The abbreviation ODS will be used throughout to refer to both Operation Desert Shield and Operation Desert Storm; the specific meaning will be clear in context.
[2]Desert Storm involved 41 days of intensive bombing in the air campaign and 100 hours of a ground attack. (Scales, 1993.)
[3]Under the FDCA, as amended [Ch. 2, Sec. 201[321](g)(1)], the term drug means
(A) articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of many or other animals; and (D) articles intended for use as a component of any articles specified in clause (A), (B), or (C); but does not included devices or their components, parts, or accessories."Biological products, including vaccines, are defined as "any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man." [21 Code of Federal Regulations (CFR) Part 600, ¤ 600.3(h)] For purposes of evaluating safety and effectiveness, the term drug applies both to drugs (usually chemical entities) and to biological products, also known as biologics. Drugs and biologics are regulated in basically the same way; devices are regulated somewhat differently; the distinction does not concern us in this report.
[4]Technically, an Investigational New Drug (IND) is an application to the FDA for approval to conduct clinical investigations related to the safety and effectiveness of a drug or biologic. The term is also used to refer to an investigational drug that is being tested in humans under an FDA-approved IND. The meaning in this report will be clear in the context of its use.
[5]Sponsors of Phase III drugs and biologics are usually, but not always, commercial drug firms; sponsors of Phase I and Phase II studies often include academic institutions and investigators as well.
[6]As one aspect of Reinventing Government, the PLA and ELA distinction was eliminated in 1997 in favor of a Biologic Licensing Application (BLA), which includes both product and establishment considerations and is consistent with the NDA nomenclature for drugs.
[7]A major reason these drugs remain investigational, although not the only one, is that FDA requires human efficacy data for approval of drugs. Obtaining such data for drugs intended for prophylactic use against CW/BW agents has been regarded as unjustifiable on the ethical grounds that it would involve exposing human beings to lethal doses of such agents, then determining the effectiveness of the prophylactic and therapeutic drugs in question to prevent death or serious injury. The issue raised by this prohibition has been how to evaluate drugs intended for CW/BW defense. However, in July 1997, FDA asked whether there were scientific and ethical ways "to expose volunteers to toxic chemical and biological agents to test the effectiveness of products that may be used to provide potential protection against those agents?" [62 FR 41001, July 29, 1997] This question is discussed in Chapter Four, with respect to Question B.
[8]The text of the Interim Rule appears at the end of this chapter.
[9]Pendergast, who had been FDA Commissioner David Kessler's principal deputy, left FDA for the private sector in early 1998. Moreover, the agency has been without an appointed successor to Kessler since the spring of 1997. In this context, the rule making timetable suggested here may appear optimistic, even unrealistic.