| Primary Issue | Secondary Issues |
| Integration of medical, operational, and intelligence functions | Incorporating DoD-FDA agreements, including FDA regulations, into DoD doctrine, policies, and procedures for both peacetime and wartime implementation Establishing and maintaining DoD effective communication among and between medical, operational, and intelligence entities and authorities |
| Threat analysis | Routine threat analysis (ongoing, periodic, episodic) Crisis threat analysis Validation of CW/BW threat and use Public understanding of threat |
| Availability of drugs and vaccines | Budgetary allocations Assessment of need (short and long term) Development process (long term) Licensing policies, procedures, and practices (short, mid, and long term) Production (sources, capacity, security) Stocks (inventories and shelf life) and storage capabilities Logistics |
| Implementation of actual use | Allocation decisions Logistics of administration (capability, supply, allocation criteria, schedule, dosage, discretion of local command authority) Information to personnel Informed consent Record keeping (individuals, units) |
The integration of external policies, such as the FDA Interim Rule, into DoD doctrine, policies, and procedures, is a major problem identified in the wake of the Gulf War. This issue has two dimensions: (1) the incorporation of DoD-FDA agreements into DoD doctrine, policy, and procedures during peacetime for implementation in wartime and (2) the establishment of effective communication among and between DoD medical, operational, and intelligence entities and authorities.
The discrepancy between the strictures of the Interim Rule and behaviors of military commanders in the Gulf War highlights the integration problem. The primary communication channel in the formulation of the policy ran from DoD medical, which included the offices of AASD(HA) and the Surgeon General of the Army, to FDA. Communication channels running to the theater of operations led from ASD(HA) to the Joint Staff, and through J-4 to Central Command (Schwarzkopf) and his chief surgeon. No one directly involved in policy formulation was in direct communication with those responsible for implementation. Given that less than one month elapsed between the Interim Rule and the start of hostilities and only one week between the waivers and hostilities and that the U.S. force consisted of nearly 600,000 personnel, it is hardly surprising that communication problems occurred.
The matter of remedies for this internal communication problem is not easy. However, in the discussion below regarding the question of authority, we propose that the Secretary of Defense submit waiver requests, under the Interim Rule or under a modified version of the rule, to the Secretary of Health and Human Services, rather that having ASD(HA) submit them to the FDA Commissioner (see below). The rationale for this proposal is that such a submission route would force internal DoD staffing to address the request that would involve medical, operational, and intelligence activities.
The assessment of worldwide CW/BW threats obviously must be a continuous function. On the other hand, once a thorough assessment of capabilities has been conducted, the primary task is monitoring for changes and anomalies and maintaining intelligence regarding intentions of potential enemies. The appropriate balance between routine and special assessments and short- and long-term assessments is beyond the scope of this report, as is allocation of resources for threat assessment; for a responsive research and development program; and for production, licensing, and logistics capabilities.
One issue that deserves attention in this context is the degree to which threat assessment information is held tightly as secret information or is publicly discussed in open session with Congress and the press. The nuclear threat was widely discussed in the press and before Congress over a period of decades, with confidential information protected in well-established ways. That threat was also the subject of many books and articles in the open literature, with Herman Kahn's On Thermonuclear War marking the start of a major public discourse, and the subject of many graduate school courses. One result of this public attention was a public much better informed about nuclear warfare and its prospects and implications than is the case for chemical and biological warfare possibilities. An item on the DoD agenda, then, might be the benefits of a more open discussion for purposes of securing a more informed citizenry and for providing a deeper understanding of the issues underlying such policies as the FDA's Interim Rule.
In general, command authority as established in the Constitution and by statute is an adequate basis for the conduct of military operations, both in peacetime and in war. This authority extends to requirements of training, uniforms to be worn, relations between officers and enlisted personnel, obligations to protect vital national security information from unauthorized personnel, and many other features of military life. The authority to direct soldiers to take medications or vaccines, to wear a uniform of a certain type, to train to use a particular weapon, although not spelled out in Title 10, U.S. Code, inheres in command authority; detailed applications of that authority exist in a number of Supreme Court cases, as the government's brief in the 1991 Gulf War litigation before the U.S. Court of Appeals makes clear (938 F.2d 1370, No. 91-5019, US App DC 111, July 16, 1991).[1] In active military conflict, command authority conveys great discretion to field commanders, who must make the tactical decisions that implement broad strategic and policy considerations.
One thing made abundantly clear by the Gulf War is that military command authority was not developed with reference to the use of investigational drugs as a defense against CW/BW agents. In actual or potential combat situations that may involve the use of CW/BW agents by an enemy, the military confronts three related needs: to protect individual service members against such agents, to ensure that the behavior of individuals does not jeopardize their immediate fellow soldiers and impair unit integrity, and to maintain an effective war-fighting capability overall. Refusal to consent may cause problems in all three areas. Accomplishing these purposes requires an array of countermeasures against CW/BW threats, including detection equipment, protective clothing and masks, and prophylactic and therapeutic medications. FDA-approved medications pose no problem for military use. Drugs and vaccines classified as investigational also pose no problems if informed consent is obtained from soldiers before they are used and if no penalty attaches to refusal of consent. But when some countermeasures are investigational drugs, and the military concludes that it is not feasible to obtain informed consent for their use, the question arises as to the authority needed for DoD to use such drugs and vaccines.
More important, in our judgment, are the mechanisms to accommodate conflicting interests. In the case of DoD and FDA with respect to the development and use of drugs and vaccines, we may identify the following mechanisms that represent accommodation of these different interests.
Two questions from the July 31, 1997, FDA Request for Comments indicate how this conflict of authority arises in the context of that agency's decision to complete rule making:
If answered negatively, however, the question becomes, "If not the FDA Commissioner, then whom?" The answer depends on whether one thinks the issue is a medical or a political-military one. If one accepts the view that the Interim Rule is both a medical and a political-military policy, and that requests for waivers under the rule require both medical and political-military decisions, an argument exists for making decisions at the highest level of political authority--within DHHS, the Secretary, and within DoD, the Secretary of Defense.
This logic opens the door to requests for waiver of informed consent originating with the Secretary of Defense, being transmitted to the Secretary of Health and Human Services, and the determination of "not feasible" being made either by the Secretary of HHS or jointly by the Secretary of HHS and the Secretary of Defense. Such a course would not relieve the FDA of its obligation to review such a request, but it would do so now at the direction of the Secretary of HHS , the highest political authority in the department.
Neither would such a course relieve the ASD(HA), nor the Surgeons General of the military services, of their obligations to assess the threat and to recommend a request for waiver of informed consent. It would require that DoD base a waiver request recommendation on input from medical, operational, and intelligence agencies, including concurrence from the field command. Indeed, it is clear that there was a serious breakdown in the implementation of the Interim Rule in the Gulf War, especially with respect to information provided to the affected military personnel, the training of medical and nonmedical personnel, and record keeping. This breakdown stemmed, in part, we believe, from the fact that a policy seen primarily as medical required for its implementation the active input from both military operations and military intelligence.
Would time permit such a course of action to be followed? In the case of the Gulf War, nearly four months elapsed from the initial discussions of the need for what became the Interim Rule until its issuance. If rule making should result in reissuance in modified form of the Interim Rule, the issue becomes the processing of waiver requests under the rule. It is not clear that staffing for waiver requests with a rule in place would require any more time than it took to issue the Interim Rule in the first place.
The pertinent unresolved concerns about the incomplete accommodation of these two sources of authority in our national life, then, are these. Might a threat similar to what emerged in the Gulf War recur within the foreseeable future and, if it did, would the absence of a clear policy on the use of investigational drugs for CW/BW defense help or hinder the ability of the U.S. government to defend its national interest? If such a threat recurred, would the national interest be best served by having a settled policy or by being forced to make policy in the shadow of war? To answer these questions, it is necessary to address several other issues in greater detail.
A question raised during the fall of 1990 was whether DoD was obligated to submit to FDCA authority for issues related to military combat, such as using investigational drugs for CW/BW defense. Why should DoD not assert the inherent authority of command? This question was informally discussed within DoD, between DoD and FDA, and within DHHS. No definitive answer was forthcoming, because the question was not raised formally, and it remains untested legally and politically.[2]
Some DoD officials thought that it might be sufficient legally to assert inherent command authority without reference to FDCA but that, as a matter of policy, it was better to comply with the FDCA. Others considered the implications of full compliance with FDCA by using investigational drugs with informed consent and complying, or seeking to comply, with all the rest of the IND regulatory requirements. ASD(HA) Mendez took the view that DoD should submit to FDCA authority but should also not represent its action regarding PB and BT as research but as treatment, and therefore, compliance was accompanied by a request to FDA to establish authority to waive informed consent. The Mendez view prevailed and effectively answered the question at a practical level of whether DoD should act independently of FDCA.[3]
If DoD had been unable to obtain the FDA waiver authority of the Interim Rule, and the subsequent waivers for PB and BT, would it have acted on the basis of command authority regarding the use of PB and BT? The scenario response goes something like the following: In all likelihood, the question would have gone from the DoD General Counsel to the Secretary of Defense, who would have consulted the Chairman of the Joint Chiefs of Staff, GEN Colin Powell, and the Commander of Central Command, GEN Norman Schwartzkopf. If in the judgment of the Chairman of the Joint Chiefs and the CENTCOM it had been important to use PB and BT, or to have the authority to do so in the event that these drugs were needed, they would have then responded to the General Counsel with the query, "Can you defend this legally?" The General Counsel would then probably have gone forward with an argument about general command authority in the Constitution and Title 10, U.S. Code, the clarity of Supreme Court case law supporting command authority, and the absence of any "private cause of action" to challenge the FDCA other than by the Commissioner of the FDA. This is the hypothetical case in which DoD would rely exclusively on the authority of the Commander in Chief.
Three factors suggest that the above course of action, though possibly defensible on legal grounds, might have limited utility as a public policy. One consideration was that FDA review of the policy issue and of the specific waivers might benefit the DoD by counterbalancing military medical R&D thinking with an outside, independent view.[4] The second consideration was that a policy that might be legally defensible in time of war might not be politically sustainable in the postwar environment. The controversy surrounding the Gulf War, a short, militarily successful campaign, in the past five years, suggests that this is the case and underlines the importance of closely linking legal authority and political support if policy is to succeed.
The final consideration has to do with the costs, benefits, and risks of taking this kind of an issue to the President for resolution. He is, after all, the ultimate arbiter of disputes between cabinet-level departments and is the Commander in Chief. Such a course of action, however, is not to be considered lightly. The brief for the Secretary of Defense and the Secretary of Health and Human Services filed in the U.S. Court of Appeals for the District of Columbia Circuit in Doe v. Sullivan posed the issue in the following terms:
Doe's challenge to these actions [i.e., issuance of the Interim Rule and granting of waivers under the rule] is an extraordinary one. It represents an unprecedented attempt by a military serviceman during wartime to judicially countermand decisions by his superiors about the conduct of the war. It asks the courts, in the name of enforcing statutes regarding unapproved drugs, to interfere with the President's constitutional power as Commander-in-Chief to direct the battlefield activities of the armed forces while actually in combat. And it asserts statutory and constitutional claims which, if recognized, may imperil the lives of military personnel and civilians and jeopardize the prosecution of the war. [p. 20]
and later
if Section 505(I) [of the FDCA] were construed to foreclose DoD from administering investigational drugs for tactical purposes in a combat theater, a grave question would be presented concerning the impact of the statute on the President's constitutional powers as Commander-in-Chief. Whatever the ultimate scope of those powers may be, they clearly encompass the exclusive authority to determine (directly or through the President's subordinates) how a military campaign authorized by Congress is to be carried out in the field. Cf. Youngstown, 343 U.S. at 645 (Jackson, J., concurring) (courts "should indulge the widest latitude of interpretation to sustain [the President's] exclusive function to command the instruments of national force"). That authority cannot constitutionally be withdrawn or denied by Congress or the courts. Thus, insofar as Section 505(I) could possibly be construed to limit the President's discretion as Commander-in-Chief concerning the prophylactic use of investigational drugs as a defensive measure on the battlefield, it almost certainly would be a constitutional nullity as applied. Section 505(I) therefore should be construed to avoid the constitutional problems that would be presented by Doe's construction. [pp. 39-40]
Avoiding the potential conflict between inherent command authority and the authority of FDCA should be regarded as an important public policy objective. This leads to the question addressed in the following section: What mechanisms exist by which conflicts between DoD and FDA might be resolved in a Gulf War-like case, short of taking the matter to the President?
The laws and regulations of the FDA that pertain to the development of therapeutic products (drugs, biologics, medical devices) have been developed pursuant to the commerce clause of the Constitution for the primary purpose of ensuring that the safety and effectiveness of these products is established before their introduction to the commercial market. Drug regulation originates in the 1906 Pure Food Act, which required that drugs not be misbranded or adulterated; it was extended by the 1938 FDCA, which requires the evaluation of new drugs for safety, and by the 1962 amendments, which require evaluation for effectiveness. Evaluation of biologics originates in the Public Health Service Act (42 USC 262, 263), deriving from the public health nature of vaccine development for the control of infectious diseases. In recent years, evaluation of biologics has also been drawn under the authority of FDCA. Evaluation of medical devices stems from the Medical Device Amendments of 1976 to FDCA (21 USC 351, 352, 360), as later amended.
The FDCA, as it pertains to drug and biologic evaluation, was not written with military drug and vaccine development in mind. This poses no problem as long as military drug development is comparable to civilian drug development for the commercial marketplace. But military drug development differs at times from commercial drug development in several important ways.
First, the purpose of military drug development is essentially similar to civilian drug development for the most part, but it has the additional purpose to develop and use drugs to protect military personnel from threats that are peculiar to military action. The specialized needs of military medicine, e.g., vaccines developed for defense against potential BW agents and for endemic diseases in remote environments, mean that a dual-use (i.e., military and civilian) commercial market does not always exist for a number of the needed products. Consequently, some drugs are likely to remain in the IND status indefinitely, as is also the case for a number of CDC-developed vaccines, because they are unattractive to commercial sponsors who are unwilling to incur the costs of their further development through the licensing stage.
Second, the economics of commercial drug development involve substantial financial and human resource investments in scientific research, clinical trials, and regulatory affairs. The average development time for a new drugs has been 10-12 years at an estimated cost of $350 million or higher per FDA-approved product. Drug development teams are assembled for a new product, teams that provide continuity of attention, depth of knowledge, and a division of labor appropriate to the task of taking a new chemical entity or a new biologic from the IND stage through the NDA licensing stage. Resources to support drug development are derived from debt or equity financing, or from internal allocation of profits from other products, in anticipation of a profit stream that is sustained over the patent life of the drug.
By contrast, military drug development is characterized by less investment in both financial and human resources. Teams are smaller, seldom assigned to a single compound or biologic. Rotation of military personnel characterizes these teams. Fewer resources are devoted to the regulatory affairs side of licensing, as distinct from the aspects of research and clinical trials. Funds are derived from those appropriated to the DoD for research. In a time of declining budgets, which has been true for the past decade for DoD, scarce resources loom large as a constraint on military drug development and are unlikely to allow DoD to pursue licensing aggressively.
Finally, in addition to highly localized threats from endemic infectious diseases, military drug development confronts the threat of chemical and biological warfare more directly in the wake of the Gulf War than at any other time since World War I. The scientific and clinical problem, then, is not restricted to developing a drug or vaccine for use against a given disease conditions, but embraces the development of drugs for prophylactic purposes against lethal agents deployed by an enemy.
It is this emergence of the CW/BW threat that argues against a simplistic assumption that military drug development can be compared to civilian, commercial drug development. The decades-long process by which FDCA regulations were articulated through the Notice and Comment procedures required by the Administrative Procedures Act, with responses to proposed rules provided by a very large, very profitable, very powerful commercial pharmaceutical industry, does not provide a model for the development of policies related to military drug development in the face of CW/BW threats.
In the spring of 1991, after hostilities in the Gulf War had ended, ASD(HA), Dr. Enrique Mendez, wrote the Director of the Joint Staff of DoD regarding the use of the informed consent waiver for "specific Investigational New Drugs" in the Gulf War about the merit of "a formalization of the FDA approval process." His senior staff, he reported, had taken steps "to define the requirements for informed consent, and the utilization of investigational drugs, devices, and vaccines." Prior FDA approval, he noted, would provide "a responsive mechanism" for the use of investigational products in a military contingency. "Therefore," he wrote,
we plan to conduct an annual meeting [emphasis added] of appropriate representatives from DoD and FDA to review, identify and obtain contingency FDA approval of investigational products of specific military interest.Mendez may have overreached in his aspirations. FDA prefers, by reason of long-established custom, to deal with general issues in the context of rule making and to address specific issues in the context of reviewing specific IND and NDA applications. They argue, appropriately regarding the latter, that questions of safety and effectiveness, language about labeling, etc., can best be addressed with reference to specific proposals. Nothing has come of the annual meeting proposal.
However, some current interaction along the Mendez lines suggested has occurred. Specifically, a meeting of the CBER anti-virals advisory committee was held in 1996 to review with DoD representatives the studies that would be necessary for DoD to obtain licensing approval for BT vaccine. DoD is currently at work seeking to respond to the advice it received.
Importantly, FDA Deputy Commissioner Mary Pendergast, in testimony to PAC on July 29, 1997, indicated how the agency intended to proceed in rule making. Based on the information received in response to the Request for Comments, she stated, FDA may decide "to hold an open public meeting on a more limited subset of issues." Such a meeting would later be followed by publication of an NPRM. She then added: "Because of the complexity and controversial nature of the issues involved, it will be incumbent on the agency to forge consensus with [sic] the executive branch prior to taking final action."
It would be prudent for DoD to add its collective support for such a public meeting, even to endorse a joint meeting, to seek to assist in defining the issues to be considered, either by negotiation with FDA or by formal submissions to it, and to participate fully in the meeting. Although such a meeting, if held, will focus on issues associated with the Interim Rule, it might facilitate movement toward a regular annual meeting between DoD and FDA on general issues not addressed in rule making and broader than the specific issues of a particular IND or NDA application.
The main point of this section, in summary, is to suggest strongly that a more public and systematic mechanism of interaction is needed between DoD and FDA with respect to the special problems of military drug development than currently exists. The above analysis points to this conclusion.
[2]It is possible, however, that the question might be raised again in a slightly different way in the rule-making context at the time of this writing, i.e., under what circumstances might it be appropriate for DoD to act without FDA authorization.
[3]Interview with John Casciotti.
[4]This construction was provided by one participant who observed that Dr. Enrique Mendez saw FDA involvement as beneficial from the medical viewpoint, while the Office of General Counsel saw it as beneficial from the legal viewpoint.