Mr. Chairman, Members of the Committee, I am Dr. Randolph F. Wykoff, Associate Commissioner for Operations at the Food and Drug Administration (FDA or Agency). I am pleased to be here today to discuss the Agency's role in the medical, chemical, and biological warfare preparedness program of the Department of Defense (DOD). Specifically, the Committee asked that we address FDA's role in DOD's administration of the Anthrax Vaccine, Adsorbed; the Pentavalent (ABCDE) Botulinum Toxoid Vaccine; the Tick-Borne Encephalitis (TBE) Vaccine, and Pyridostigmine Bromide (PB). It should be noted, however, that DOD sponsors Investigational New Drug applications (IND) for a number of other proposals, with a focus on therapies for diseases endemic in foreign countries where the military may be deployed or exposed.
We begin with the recognition that DOD has an exceptionally difficult task. It must, on very short notice, be able to move large numbers of men and women into areas of the world where they face threats that are unknown in this country, both man-made and natural. It is an awesome challenge that poses substantial logistical obstacles, and we all benefit from DOD's commitment. That said, there are several aspects of DOD's IND vaccine and drug program that can, and must, be improved. FDA is dedicated to working with DOD so that these changes can be made. We feel that these changes will help DOD in its efforts to ensure success in its mission to protect our nation; will help FDA in our efforts to ensure success in our mission to protect the public health; and will help both FDA and DOD ensure success in our mutual mission to provide the medical products available to military personnel to ensure protection of our troops.
GENERAL BACKGROUND
FDA's Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) are responsible for evaluating the safety, purity, efficacy, and potency of the products they regulate. For CBER, these products include biological products such as vaccines, products derived from human blood, and many products produced by recent advances in biotechnology. CDER is responsible for both prescription and over-the-counter drugs. The scope of regulatory responsibility for both Centers extends to both licensed or approved products and unapproved products under investigation.
From a regulatory viewpoint, one can identify four stages in vaccine and drug development: the pre-IND development stage (before the product is used in people), the IND stage (where human use occurs under limited study conditions), the Product License Application (PLA) stage for vaccines and the New Drug Application (NDA) stage for drugs (where FDA reviews the results of the clinical studies), and the postlicensure stage (following approval of the product for marketing). Before a new vaccine or drug can be studied in people, a sponsor must submit an IND application to FDA.1 In the application, the sponsor: 1) describes the composition, source, and method of manufacture of the product and the methods used in testing its safety, purity, and potency; 2) provides a summary of all laboratory and preclinical animal testing performed; and 3) provides a description of the proposed clinical study and the names and qualifications of each clinical investigator. Once the sponsor submits the IND, FDA has 30 days to review the application to determine whether or not the study may proceed. FDA may prohibit a sponsor from conducting a study for a number of reasons, including when the study volunteers will be exposed to unwarranted risks, by putting the IND on "Clinical Hold."
The IND process generally is described as having three phases prior to product approval; however, the distinctions between these phases are not absolute. Phase 1 trials are focused on basic safety and, for vaccines, Phase 1 trials also usually evaluate the immune response elicited by the vaccine. These trials are usually small -- generally between 20 and 100 subjects -- and they are frequently done in healthy "normal volunteers" and may last just several months. Phase 2 trials often include several hundred subjects, are often randomized, and last anywhere from several months to several years. These trials usually include dose-ranging studies in the "target population," (i.e., individuals who are expected to receive the licensed or approved product). Unless severe reactions or a lack of effectiveness surface during the first two phases, the sponsor may decide to perform one or more Phase 3 studies that can include several hundred to several thousand people. These Phase 3 trials are intended to provide the definitive measure of effectiveness, as well as continue the evaluation of the product's safety. The size of the efficacy trial will be affected by the expected incidence of disease that the vaccine is intended to prevent or the drug product is intended to treat. If at the end of Phase 3 trials the manufacturer believes there are adequate data to show the vaccine or drug product is safe and effective for its intended use, the manufacturer submits a PLA or NDA to the Agency.
Licensing of a new vaccine is only one stage of FDA's oversight of vaccine safety. Following issuance of the license, there is continued surveillance of the product and of the manufacturer's production activities, including compliance with good manufacturing practices. Manufacturers generally submit samples of each licensed vaccine lot and the results of their own tests for potency, safety, and sterility to the Agency before each release of licensed product. In addition, licensed establishments are inspected regularly by FDA.
After NDA approval, drug products also are subject to post-marketing requirements, including good manufacturing practices to ensure the safety, consistency, and stability of drugs and inspection of manufacturing facilities.
FDA'S ROLE IN DOD'S VACCINE AND DRUG PROGRAM
An intrinsic part of the IND process is the assurance of informed consent, active review by a properly constituted and functioning institutional review board (IRB), full compliance with accepted ethical principles for the participation of human subjects in clinical studies, and FDA's review of the manufacturing methods and clinical protocols. Clinical trial sponsors must report all serious and unexpected findings during the IND process to FDA and must file an annual report with the Agency that includes a summary of final or interim results of clinical studies, findings of adverse events, manufacturing changes, and other required information.
An IRB is a group formally designated to provide ethical review, approve the initiation of, and periodically review the progress of biomedical research involving human subjects. The primary function of IRBs is to protect the rights and welfare of the people who are in clinical trials, and it is an integral part of the system that provides safeguards to human subjects during clinical trials. Similar to many organizations, DOD establishes its own IRBs to review the clinical investigations it conducts.
A careful and balanced system of safeguards has evolved over the years providing multiple levels of protection to research subjects. One of FDA's most important responsibilities is to evaluate whether the safeguards are met and to monitor the activities of research sponsors, researchers, IRBs, and others involved in the clinical trial, through its Bioresearch Monitoring Program. Each participant in a research effort -- the sponsor that supports the research, the clinical investigator who conducts the research, and the IRB -- is obligated to take steps to protect the rights and welfare of the people who are taking part in the experiments. DOD, in the context of its vaccine and drug programs, has interacted with FDA as a manufacturer, a clinical trial sponsor, and a clinical investigator.
The sponsor of a clinical investigation must: 1) select qualified clinical investigators; 2) design scientifically-sound protocols; and 3) make sure that the research is conducted consistent with acceptable scientific and human subject protection standards, as well as applicable IRB, IND, and informed consent regulations.
The primary regulatory obligations of the clinical investigator are to: 1) follow the approved protocol or research plan; 2) ensure that the study is reviewed and approved by an IRB that is constituted and functioning according to FDA requirements; 3) obtain and document informed consent by using a form and procedures that an IRB has approved; 4) maintain adequate and accurate records of study observations (including adverse reactions); and 5) administer test articles only to subjects under the control of the investigator.
In addition to interacting with DOD regarding its use of investigational and licensed products, in June 1990, the United States Army Medical Research and Development Command at Fort Detrick contracted with FDA's National Center for Toxicological Research (NCTR) for secure contingency vaccine storage. The original agreement, which included construction of a storage facility, was to extend through 1994. In 1992, the Army began storing vaccines at NCTR and, in 1993, the agreement was extended to September 1997. Between 1992 and 1997, NCTR stored, distributed to DOD research locations, or destroyed vaccines as per DOD's instructions. DOD has not stored any vaccines at NCTR since September 1997.
VACCINES
Let me now turn to the three vaccines of interest to the Committee.
Anthrax
The Anthrax Vaccine, Adsorbed (anthrax vaccine), manufactured by Michigan Biologic Products Institute (MBPI) (formerly the Michigan Department of Public Health (MDPH)), is approved and was licensed by FDA in November 1970. MBPI is the manufacturer of the only licensed anthrax vaccine in the United States.
Pre-exposure immunization with anthrax vaccine is intended to protect against disease caused by the anthrax agent. Anthrax is an infectious and potentially deadly disease that normally afflicts herbivore animals, especially cattle and sheep. Humans can develop anthrax when they are exposed through the skin, lungs, or gastrointestinal system. Most human disease is caused by skin contact, but the most severe disease follows respiratory exposure.
DOD's plan of administration for the anthrax vaccine to troops during the 1991 Gulf War was consistent with the licensed administration schedule. This schedule consisted of three inoculations 2 weeks apart, followed by three inoculations given at 6, 12, and 18 months, followed by an annual booster. Recently, DOD has proposed to vaccinate military personnel against possible exposure to anthrax. It is our understanding that DOD plans to use the licensed schedule. The approved anthrax vaccine labeling contemplates use in people between the ages of 18 and 65, and use in pregnant women "only if clearly needed."
TBE
The TBE vaccine used by DOD is an unlicensed vaccine in the United States. This vaccine is manufactured by Immuno A.G. of Austria and is licensed in Austria. In central Europe, approximately 30 million doses have been administered since 1980. The TBE vaccine is used to protect against disease caused by the TBE virus that is transmitted to humans via a bite from a tick. TBE is common in parts of Asia and Europe. As TBE does not occur in the United States, the only need for the TBE vaccine has been for persons who are traveling to those areas where TBE is prevalent.
DOD originally submitted an IND for TBE vaccine in 1983 to administer the vaccine prophylactically to its laboratory personnel. It since has used the vaccine periodically under the terms of the IND, including its use during troop deployment in Bosnia. As noted below, FDA has communicated with DOD regarding the Agency's concerns about how the IND process for the TBE vaccine was managed during the deployment in Bosnia.
Botulinum Toxoid
Pentavalent (ABCDE) Botulinum Toxoid vaccine is an investigational product intended as a prophylactic treatment against botulinum toxin poisoning (botulism). There is no satisfactory or feasible alternative product to prevent botulism. This vaccine has been provided for over 25 years to laboratory workers and public health professionals at risk of infection. This has been accomplished under an IND sponsored by the Centers for Disease Control and Prevention (CDC). According to the most recent annual report, more than 3,400 individuals have received the primary series of three immunizations, and more than 15,700 doses have been used under this IND between 1970 and 1996.
In 1990, DOD applied for an IND for the use of the Botulinum Toxoid vaccine in Operation Desert Storm/Desert Shield as a prophylactic against botulism. The data collected under the CDC IND provided support for the prophylactic use proposed by DOD. DOD administered the Botulinum Toxoid vaccine during Desert Storm/Shield, under an IND. The Botulinum Toxoid vaccine is a vaccine manufactured by MDPH. As the sponsor and clinical investigator of the IND, DOD was responsible for meeting the Agency's IND requirements.
The licensure of the Botulinum Toxoid vaccine was not pursued previously in part due to the difficulty of testing clinical efficacy in humans. A clinical "field" efficacy trial is not feasible for this vaccine because of the low incidence and sporadic nature of naturally occurring botulism, and human challenge/protection studies using the toxin are not ethically feasible.
On October 30, 1996, FDA's Vaccines and Related Biological Products Advisory Committee met in an open public session to consider the type of evidence it would need to conclude that the Botulinum Toxoid vaccine is effective for the purpose of licensure. DOD gave a very extensive presentation on a strategy to achieve licensure using animal challenge/protection studies and human antibody studies, and presented available data. The Advisory Committee agreed with the concept of using this type of data to support vaccine efficacy in this case. From the Advisory Committee's discussion, DOD has clear direction on the types of studies it must conduct to support the effectiveness of Botulinum Toxoid vaccine. FDA cannot consider the approvability of the botulinum toxoid vaccine, however, until DOD conducts these studies and submits a PLA to FDA. There is no such application currently pending with the Agency.
DOD DRUG PROGRAM
Pyridostigmine Bromide (PB) has been approved by FDA since 1955 for the treatment of myasthenia gravis, a chronic disorder characterized by muscle weakness. As a result, there is considerable human experience on its long-term use. DOD has been investigating the effects of PB pre-treatment on healthy soldiers under an IND application on file with FDA since 1984. No serious adverse reactions were reported in this population from this experience. The determination that PB could be administered safely to healthy soldiers during Operation Desert Storm under the IND was based primarily on the long experience with PB at doses considerably greater than those proposed as pre-treatment for organophosphate nerve agent exposure (30 milligrams [mg] three times a day for a maximum of 7 days). Patients with myasthenia gravis typically are treated with PB doses of up to 1500 mg a day for many years. While myasthenic gravis patients are not, of course, entirely healthy, we believed their experience was pertinent to the effects of PB in completely healthy individuals. Patients with myasthenia gravis have antibodies directed at skeletal muscle structures. They would be expected to differ from healthy persons with respect to effects of PB on skeletal muscle and would be less likely to develop muscle twitching and muscle cramps. In other respects their response should be similar. We knew from past experience with the use of this drug that side effects (e.g., abdominal cramps, nausea, diarrhea, rash, muscle weakness, dimmed vision) were possible, and these were described in DOD's Field Manual which was included in the IND submission.
The effectiveness of PB, given as pre-treatment in conjunction with the acute use of atropine and 2-PAM (the regimen being used in this instance), in decreasing toxicity of soman in humans has not been demonstrated. In monkeys, however, the regimen greatly increases the ability to withstand the lethal dose of soman compared to the lethal doses in untreated monkeys. Despite the lack of human data on protection (it would be unethical to administer toxic agents to subjects for such research), PB, in conjunction with the acute use of atropine and 2-PAM, is postulated by some to be the only available means of decreasing organophosphate soman toxicity. It has been available to North Atlantic Trade Organization armies and has been held in reserve by DOD for that use since 1986.
The Agency has reviewed Chemistry and Manufacturing Controls data for PB on a continuing basis. Additionally, under a long-standing agreement with DOD, Agency chemists periodically reviewed stability data from studies conducted on PB tablets stockpiled by DOD at various locations to be available in time of war for distribution and use by military personnel.
GENERAL EXCEPTIONS FROM INFORMED CONSENT REQUIREMENTS
There are currently two general "exceptions" to FDA's informed consent requirements. These are: 1) for a physician to preserve the life or health of an individual patient and 2) for the conduct of a narrow class of research in life-threatening emergency settings. These two "exceptions" are intended to strike a careful balance between assuring the protection of an individual's welfare as a participant of a clinical trial and providing that seriously ill patient a promising, but as yet unproven, therapy.
Preserving the Life of the Patient
According to the first exception (21 CFR 50.23 (a), (b) and (c)) which has been in effect since 1981, informed consent of the subject or his/her legally authorized representative is required unless the investigator or a physician, who is not otherwise participating in the clinical investigation certify, in writing before the test article's use, that: 1) the subject is confronted by a life-threatening situation necessitating the test article's use; 2) informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from, the subject; 3) time is not sufficient to obtain consent from the subject's legal representative; and 4) no alternative method of approved or generally recognized therapy provides an equal or greater likelihood of saving the subject's life.
The regulatory requirement for this exception "applies to individual situations and not to categories of studies as a whole" (46 FR 8945, January 27, 1981) and suggests that there should be great confidence in the effectiveness of the product, (i.e., the situation must "necessitate" the use of the product).
Conduct of Research in Emergency Settings
The second exception to informed consent is for emergency research (21 CFR 50.24). This provision of the regulations was promulgated in 1996 (61 FR 51498, October 2, 1996). At the same time, the Secretary of the Department of Health and Human Services (DHHS) announced a comparable waiver of informed consent requirements in certain emergency research subject to DHHS regulations (61 FR 51531, October 2, 1996). The emergency research rule provides a narrow exception to the requirement for obtaining and documenting informed consent from each human subject, or his or her legally authorized representative, prior to initiation of an experimental intervention. The exception applies to a limited class of research activities involving human subjects who are in need of emergency medical intervention but who cannot give informed consent because of their life-threatening medical conditions, and who do not have a legally authorized person available to represent them. FDA promulgated this rule in response to concerns that existing rules were making high quality acute care research activities difficult or impossible to carry out at a time when the need for such research is increasingly recognized.
These policies establish narrow limits for allowing research without informed consent in certain studies of emergency medical interventions and harmonize these standards throughout DHHS. We believe DHHS's new overall approach to emergency research situations may offer the best hope, in an ethical manner, to critically ill, generally unconscious persons who have no reasonably available legal representative who can give consent and who cannot be successfully treated through conventional means, but might benefit from a promising experimental intervention.
DOD Combat Exigencies On December 21, 1990, FDA published an interim final regulation amending its informed consent regulations at 21 CFR 50.23(d) in the Federal Register. This Interim Final Rule allowed the Commissioner of FDA to grant a waiver of informed consent to DOD, on a case-by-case basis, under certain defined circumstances.
The rule sets forth four additional factors that the Commissioner is to consider in making his determination. These factors are: (1) the extent and strength of the evidence of the safety and efficacy of the drug for the intended use, (2) the context in which the drug will be administered (e.g., battlefield or hospital), (3) the nature of the disease or condition for which the preventive or therapeutic treatment is intended, and (4) the nature of the information to be provided to the recipients of the drug concerning the potential risks and benefits of taking or not taking the drug.
On October 31, 1990, DOD submitted a protocol under the IND for PB 30-mg tablets and Botulinum Toxoid vaccine. By letter dated December 31, 1990, DOD submitted a request for waiver of informed consent for PB. DOD also submitted a protocol and requested a waiver of informed consent for Botulinum Toxoid vaccine in December 1990. (Subsequently, DOD submitted a waiver request for multi-shield topical skin protectant, but later withdrew this request.) PB was considered a potentially useful pretreatment against certain nerve gases; Botulinum Toxoid vaccine was accepted as offering protection against toxins produced by Clostridium Botulinum, which cause botulism.
Each application for waiver from the informed consent requirements was assessed by the appropriate FDA review division and by the Agency's Informed Consent Waiver Review Group (ICWRG). The ICWRG included senior management of CDER, CBER, the Office of General Counsel, the Office of Health Affairs, and NIH's Office of Protection from Research Risks. The ICWRG core was supplemented by technical experts as appropriate for the particular investigational drug being considered for exception. The ICWRG considered DOD's justification supporting the request for the waiver and the reviewing division's evaluation of the available safety and efficacy data. The ICWRG requested additional supporting information in some cases and required changes in the information to be provided to the troops in several rounds of iterative exchanges with DOD. This information on the drugs was written information that was intended to be used verbatim and either read or provided to the military personnel. The ICWRG then made a recommendation to the Commissioner regarding whether or not to grant the waiver. The Commissioner made a decision on the application and informed DOD in writing.
The Commissioner approved DOD's waiver requests for Botulinum Toxoid vaccine and PB 30-mg tablets on December 31, 1990, and January 8, 1991, respectively. Both products were administered to portions of the military personnel who participated in Operation Desert Storm.
Following the cessation of combat activities, the Assistant Secretary of Defense (Health Affairs) notified the Commissioner of FDA in a letter dated March 15, 1991, that DOD considered the two waivers granted under the interim rule to be no longer in effect. He also informed the Commissioner that DOD had ultimately decided to administer the Botulinum Toxoid vaccine on a voluntary basis.
Based on our review and evaluation of DOD's use of PB and the Botulinum Toxoid vaccine, under their respective INDs and the waivers of informed consent under the Interim Rule, our June 1997 inspection of Ft. Detrick which was related to the Bosnia TBE IND, and the information included in the General Accounting Office's report concerning DOD's efforts to develop a program for biological warfare defense, FDA has identified significant deviations from Federal regulations regarding DOD's use of INDs in deployments. In a July 22, 1997, letter to DOD, FDA identified the Agency's concerns, specifically including concerns about the use of TBE in Bosnia and Botulinum Toxoid vaccine and PB during Desert Storm/Desert Shield. The Agency requested specific additional information related to DOD's implementation and management of these INDs and requested that DOD conduct an in-depth review of the conduct and implementation of all of its INDs intended to provide protection to deployed military personnel for compliance with all FDA regulatory requirements, as well as good clinical practices.
On October 23, 1997, DOD responded to our July 22 letter. FDA reviewed DOD's response and concluded that it was not sufficiently responsive. On December 22, 1997, therefore, FDA sent DOD a letter that asked for additional information and clarification regarding DOD's implementation and management of the above-mentioned INDs. On January 22, 1998, DOD responded with a letter that pledged to address the issues contained in our July 22 and December 22 letters. An ongoing dialogue has been established between DOD and FDA, and we are committed to ensuring that changes are made.
On July 31, 1997, FDA published a notice in the Federal Register soliciting comments on: 1) the advisability of revoking or amending the interim rule that permitted FDA's Commissioner to determine that obtaining informed consent from military personnel for the use of investigational products was not feasible during the Persian Gulf conflict and 2) identifying the evidence needed to demonstrate safety and effectiveness for investigational drugs that cannot ethically be tested on humans. One hundred twenty-eight relevant comments were received. The rulemaking process is still ongoing.
JOINT EFFORTS
Since the issuance of the July 22, 1997, letter, FDA and DOD have met several times to discuss a range of topics relating to the use of investigational drug and biological products in Bosnia and during the Gulf War, including FDA's concerns about DOD's ability to effectively implement INDs in deployment situations in accordance with FDA's regulations. As a direct result of these discussions, FDA and DOD established a joint FDA/DOD working group that would work to improve the availability of drugs and vaccines.
The DOD participants in the working group are involved in DOD's development of drugs and vaccines for use in military operations and during military exigencies. The FDA participants will serve two major roles: 1) facilitate the potential approval of drug or biological products that are identified by DOD by providing scientific expertise to DOD on its drug development plans and 2) review DOD's proposed milestones to help determine whether they are efficient and required by the review and approval process. In addition, once DOD has identified a list of risks or diseases of concern to DOD from an operational standpoint, the working group may discuss potential sponsors of drug and biological products that could address the identified risks or diseases. FDA will facilitate DOD's efforts to work with specific sponsors. It is the mission of the group to address the outstanding drug and biological product development issues that are identified by FDA and DOD.
FDA, DOD, CDC, NIH, and the Department of Veterans Affairs recently have been participating in an interagency working group led by DHHS's Office of Emergency Preparedness (OEP). This group is working to resolve issues related to the availability and use of investigational drugs and vaccines during domestic terrorist situations in the event civilians are exposed to weapons of mass destruction. Specifically, the interagency working group is discussing OEP's use of biological and drug products in the event of a domestic terrorism situation or a civilian emergency.
CONCLUSION
FDA is committed fully to its mission to protect the public health including people who participate in clinical trials and to provide scientific review of the safety and effectiveness of experimental products. While we recognize many unique aspects of the mission of DOD, ultimately we hold it to the same standards as we hold any other product sponsors or clinical investigators. We are committed to working with DOD to help assure that clinical trials of the highest quality are carried out in such a way as to assure both the collection of the best possible data and, most importantly, to assure that those individuals who participate in the trials are not subjected to unnecessary or unreasonable risk. DOD has a difficult and challenging mandate, as does FDA. It is in the national interest that we both succeed.
I will be happy to take any questions you may have.
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