[Federal Register Volume 62, Number 147 (Thursday, July 31, 1997)]
[Proposed Rules]
[Pages 40996-41001]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-20311]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 50

[Docket No. 90N-0302]


Accessibility to New Drugs for Use in Military and Civilian 
Exigencies When Traditional Human Efficacy Studies Are Not Feasible; 
Determination Under the Interim Rule That Informed Consent Is Not 
Feasible for Military Exigencies; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is requesting written 
comments related to the advisability of revoking or amending the 
interim final rule that permitted the Commissioner of Food and Drugs 
(the Commissioner) to determine that obtaining informed consent from 
military personnel for the use of an investigational drug or biologic 
is not feasible in certain situations related to military combat. The 
agency is also soliciting written comments identifying the evidence 
needed to demonstrate safety and effectiveness for such investigational 
drugs that cannot ethically be tested on humans for purposes of 
determining their efficacy. FDA is seeking written comments from all 
interested parties, including, but not limited to: Consumers, patient 
groups, veterans and veteran groups, active-duty military personnel, 
organizations and departments, ethicists, scientists, researchers with 
particular expertise in this area, and health care professionals. The 
written comments are intended to provide FDA with information to help 
the agency in making policy decisions on the use of investigational 
products during military exigencies and the appropriate evidence needed 
to demonstrate safety and effectiveness for drug and biological 
products used in military or other exigencies when traditional human 
efficacy studies are not feasible.

DATES: Submit written comments by October 29, 1997.

ADDRESSES: Submit written comments on the questions identified in 
section II of this document (specifically referencing the number of the 
question(s) being addressed) to the Dockets Management Branch (HFA-
305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments are to be 
identified with docket number found in brackets in the heading of this 
document.

FOR FURTHER INFORMATION CONTACT: Bonnie M. Lee, Office of the Executive 
Secretariat (HF-40), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-4450.

SUPPLEMENTARY INFORMATION:

I. Background

    There will continue to be military combat situations in which there 
will be a threat to U.S. military personnel from the possible use of 
chemical and biological weapons. The Department of Defense (DOD), 
therefore, has a legitimate interest in protecting military personnel 
by using products which may provide protection from such chemical and 
biological agents. In order to support this interest of DOD, FDA issued 
an interim rule during the Persian Gulf War that permitted DOD to use 
specified investigational products intended to provide potential 
protection against chemical and biological warfare agents without 
obtaining informed consent. A copy of the interim rule that published 
in the Federal Register of December 21, 1990 (55 FR 52813), can be 
viewed on FDA's website at http://www.fda.gov.
    Specifically, following a request from the DOD, FDA granted waivers 
from its informed consent requirements for the use of two products in 
specific protocols in the Persian Gulf War: Pyridostigmine bromide and 
botulinum toxoid vaccine. FDA recognizes that the interim final rule 
did not work the way that the agency anticipated it would work; 
therefore, the agency is seeking broad public input to provide 
information to help FDA in making policy decisions on the future use of 
such investigational products and possible efficacy demonstrations for 
these products.
    In order to provide a context for the decisionmaking process on the 
use of pyridostigmine bromide and the

[[Page 40997]]

botulinum toxoid vaccine during the Persian Gulf War, the following 
information is provided.

A. The Regulatory Process

    FDA regulates the use of investigational drugs under provisions of 
the Federal Food, Drug, and Cosmetic Act (the act). In FDA terms, drugs 
not approved for marketing and drugs studied for treatment other than 
that identified in the approved labeling, are investigational. In order 
for clinical testing to proceed with unapproved products (or, in some 
cases, for testing approved products for unapproved uses), an 
investigational new drug (IND) application is filed with FDA. The IND 
must contain information sufficient to demonstrate that it is 
reasonable to study the drug in humans, including drug composition, 
manufacturing and control data, the results of animal studies and, if 
available, prior human testing, and the protocol for the planned study. 
The investigator must agree to a number of commitments including 
obtaining approval of an institutional review board (IRB) before 
proceeding, obtaining written informed consent from subjects, and 
reporting adverse effects that occur as specified in the protocol.
    The act requires that investigators inform subjects receiving drugs 
under an IND that the drugs are investigational and ``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.'' There have been few 
instances in which obtaining informed consent has not been considered 
feasible or contrary to patients' interests.
    During the months preceding the Persian Gulf War, DOD had 
discussions with FDA regarding the potential use of specific 
investigational products in military personnel serving in the Gulf. It 
was thought that the products discussed represented the best preventive 
or therapeutic treatment for diseases endemic to the area and in 
providing protection against possible chemical or biological weapons. 
DOD requested the assistance of FDA in allowing the use of these 
products in certain battlefield or combat-related situations in which 
they considered obtaining informed consent ``not feasible.'' DOD's 
explanation as to why obtaining informed consent would not be feasible 
under battlefield conditions included the following:
    (1) It is not acceptable from a military standpoint to defer to 
whatever might be the soldier's personal preference concerning a 
preventive or therapeutic treatment that might save his life, avoid 
endangerment of the other personnel in his unit and accomplish the 
combat mission.
    (2) Based on unalterable requirements of the military field 
commander, it is not an option to excuse a nonconsenting soldier from 
the military mission.
    (3) It would not be defensible militarily, or ethically, to send 
the soldier unprotected into danger.
    (4) Special military exigencies sometimes must supersede normal 
rights and procedures that apply in the civilian community and, thus, 
military regulations state that military members may be required to 
submit to medical care determined necessary to preserve life, alleviate 
suffering or protect the health of others.
    At the time, FDA gave considerable deference to the DOD's judgment 
and expertise regarding the feasibility of obtaining informed consent 
under battlefield conditions. Thus, in response to DOD's request, in 
the Federal Register of December 21, 1990 (55 FR 52813), FDA published 
an interim regulation amending its informed consent regulations at 21 
CFR 50.23(d).

B. The Interim Regulation

    The interim regulation allowed the Commissioner to determine, upon 
receipt of an appropriate request from DOD, that obtaining informed 
consent from military personnel for use of a specific investigational 
drug or biologic would not be feasible in certain circumstances, and to 
grant a waiver from the requirement for obtaining such consent.
    The exception applied, on a case-by-case basis, only to 
investigational drugs (including antibiotic and biological products) 
for use in a specific military operation involving combat or the 
immediate threat of combat. The regulation requires the request to 
include: (1) The justification for the conclusion (made by physicians 
responsible for the medical care of the military personnel involved and 
the investigators involved) that the use is required to facilitate the 
accomplishment of the military mission, and the use would preserve the 
health of the individuals and the safety of other personnel, without 
regard for any individual's preference for alternate treatment or no 
treatment; and (2) a statement that a duly constituted IRB has reviewed 
and approved the use of the investigational drug without informed 
consent.
    Under the interim rule, the Commissioner may find that informed 
consent is not feasible (and thus may be waived) ``only when 
withholding treatment would be contrary to the best interests of 
military personnel and there is no available satisfactory alternative 
therapy.'' 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. 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 expires 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. In addition, when 
the Commissioner has issued a waiver to DOD, he may revoke the waiver 
based on changed circumstances.
    The appropriate FDA review division and the Informed Consent Waiver 
Review Group (ICWRG) assessed each request for waiver from the informed 
consent requirements. The ICWRG included senior management of FDA and 
the National Institutes of Health's Office of Protection from Research 
Risks, supplemented by technical agency 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 identified changes needed in the 
information to be provided to the troops. The ICWRG then made a 
recommendation to the Commissioner regarding whether or not to grant 
the waiver. The Commissioner made a decision on the request and 
informed DOD in writing.
    On December 28, 1990, DOD submitted protocols under IND's and 
requests for waiver of informed consent for pyridostigmine bromide 30-
milligram (mg) tablets and botulinum toxoid vaccine. (Subsequently, DOD 
submitted a waiver request for multishield topical skin protectant, but 
later withdrew this request.) Pyridostigmine bromide was considered

[[Page 40998]]

a potentially useful pretreatment against certain nerve gases; 
botulinum toxoid vaccine is widely accepted as offering protection 
against toxins produced by Clostridium Botulinum, the bacterium that 
causes botulism.
    The Commissioner approved DOD's waiver requests for pyridostigmine 
bromide 30-mg tablets and botulinum toxoid vaccine 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 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 on a voluntary basis.

C. Comments Received on the Interim Rule

    Twenty-two written comments were submitted to the agency in the 
brief 30-day comment period following publication of the interim rule 
in the Federal Register of December 21, 1990. Comments were received 
from physicians, members of IRB's, organizations concerned with 
bioethical issues, patient advocacy groups, and private citizens. The 
majority of the comments were supportive of the rule, although often 
with some qualification or suggested change. However, a number of 
comments expressed vehement opposition to the interim rule, both on 
general principle and with regard to one or more of its provisions. For 
example, one comment stated that the request for waiver of informed 
consent is merely an expedient solution to a problem that should be 
solved much better in other ways. This comment suggested that FDA 
modify its drug approval process so that therapies such as those that 
were sanctioned for use under the interim rule could be granted 
marketing approval notwithstanding the absence of substantial evidence 
of their effectiveness against nerve gas or biological warfare agents. 
Several comments stated that the interim regulation did not provide for 
recipients of investigational therapies to receive appropriate 
information on the treatment to be administered. Two comments stated 
that the interim rule should be modified to require that the reviewing 
IRB be unaffiliated with DOD. Five comments stated that the interim 
rule is a violation of fundamental ethical principles. The comments 
described the rule as ``* * * a flagrantly immoral violation of human 
rights,'' adding that ``Wartime does not justify experimentation 
without consent,'' and ``No explanation, whatever it might be, is 
acceptable to justify these actions.''

D. Summary of Litigation Regarding the Interim Rule

    On January 11, 1991, Public Citizen Health Research Group filed 
suit against the Department of Health and Human Services in the United 
States District Court on behalf of an unnamed serviceman stationed in 
Saudi Arabia, his wife, and all others similarly situated. In the 
Complaint, the plaintiff (``Doe'') alleged that: (1) The interim rule 
was outside FDA's statutory authority under the act, (2) DOD's use of 
unapproved investigational drugs, under the informed consent waiver, 
could not be reconciled with language in the 1985 Defense Department 
Authorization Act, and (3) the Government's use of drugs on 
unconsenting persons was a deprivation of liberty in violation of the 
Fifth Amendment. The district court dismissed the Complaint holding 
that the Complaint questioned ``a military decision that is not subject 
to judicial review.'' (Doe v. Sullivan, 756 F. Supp. 12, 14 (D.D.C. 
1991)). In an alternative holding, the district court also rejected on 
the merits the statutory and constitutional challenges stated in the 
complaint.
    On appeal, a three-judge panel of the United States Court of 
Appeals for the District of Columbia Circuit affirmed by a two-to-one 
vote the district court's order dismissing the Complaint on the grounds 
that FDA's rule was within FDA's authority, and not barred by the 1985 
Department of Defense Authorization Act or the due process clause of 
the Fifth Amendment. The dissenting judge was of the opinion that the 
case was moot.

E. DOD's Experience With Pyridostigmine Bromide and Botulinum Toxoid

    Following the approval of the waiver requests, DOD dispensed 
pyridostigmine bromide tablets and administered botulinumtoxoid to U.S. 
troops involved in Operations Desert Shield and Desert Storm who were 
deemed to be at high risk for exposure to organophosphorus nerve agents 
or bacterial agents. As part of the legal requirements for the use of 
products under an IND, DOD was required to collect data on the safety 
and efficacy of the two agents. This information is summarized as 
follows:
1. Safety Data on Pyridostigmine
    U.S. troops who were deemed to be at high risk for exposure to 
organophosphorus nerve agents received pyridostigmine bromide tablet 
packages for self-administration use when ordered to take them as 
prophylaxis against nerve agents. Unit commanders had discretion on 
whether, and when, to order use of the pyridostigmine bromide, and 
could delegate this authority to the lowest level of field command. 
Documentation does not exist on how far down the command chain the 
authority was delegated in each unit, or whether or when each unit 
issued orders to begin taking the pyridostigmine, or who took 
pyridostigmine.
    The Department of the Army conducted three separate surveys in an 
effort to determine the incidence and severity of side effects 
associated with the use of pyridostigmine bromide as a nerve agent 
pretreatment.
    Survey I was a questionnaire sent to 42 selected medical personnel 
involved in Operation Desert Shield and Operation Desert Storm; 23 of 
these questionnaires were completed and returned. Among the 23 medical 
officers who returned the survey, 10 responded that their overall 
impression was that the drug was tolerated either very well or well. 
The most common side effects reported were gastrointestinal (abdominal 
cramps, nausea, and diarrhea). Less common side effects were weakness 
and light-headedness, exacerbation of asthmatic symptoms, fatigue, 
sleep disturbances, and reduced mental concentration. Of the 5,825 
medical personnel reported on, 8 were hospitalized for side effects 
that were attributed to pyridostigmine. The reasons listed for 
hospitalization included exacerbation of cholelithiasis, asthma, and 
allergic skin reaction.
    Survey II was a questionnaire given to an unspecified number of 
soldiers deployed in Operation Desert Storm; 149 of these soldiers 
responded. Of those individuals who took the drug, 37.5 percent 
experienced side effects. The most common side effects were 
gastrointestinal in nature. Nausea was reported most frequently (11 
percent of subjects), and headache was the second most frequent side 
effect reported (7.5 percent of subjects).
    Survey III was designed to document the effects of pyridostigmine 
on aviators' ability to carry out combat missions. One hundred eighteen 
aviators participated in the survey, 48 of whom were taking other 
medications concomitantly. The majority of those taking other 
medications were taking

[[Page 40999]]

the antibiotic ciprofloxacin. Twenty-six of the 108 aviators who 
indicated that they had taken the drug reported experiencing side 
effects they attributed to pyridostigmine, mainly headaches and 
diarrhea.
    The Journal of the American Medical Association published the 
result of one retrospective study that reported on the 18th Airborne 
Corps (Corps) use of pyridostigmine. The Corps instructed 41,650 
soldiers (6.5 percent women) to take pyridostigmine at the beginning of 
Operation Desert storm in January 1991. Approximately 30 medical 
officers (physicians and physician's assistants) provided their 
impressions of the incidence of physiologic responses and potential 
adverse effects to pyridostigmine. A total of 483 aid station or clinic 
visits were related to pyridostigmine administration; 313 of these 
visits were due to ``gastrointestinal disturbances severe enough to 
prompt medical attention.'' And ``[a]nother 150 soldiers had frequency 
or urgency of urination.'' Less than 5 percent of the 41,650 soldiers 
complained of headaches, rhinorrhea, diaphoresis, or tingling of 
extremities. The article reported that 1 percent of the troops 
perceived the need for a medical visit and less than 0.1 percent 
discontinued pyridostigmine based on medical advice (LTC Jill R. 
Keeler, et al., ``Pyridostigmine Used as a Nerve Agent Pretreatment 
Under Wartime Conditions,'' Journal of the American Medical 
Association, vol. 266, no. 5, August 7, 1991).
2. Safety and Efficacy Data on Botulinum Toxoid Vaccine
    As noted previously, DOD advised FDA that the military command in 
the theater of operations administered this vaccine on a voluntary 
basis. Approximately 8,000 service members were reported to have 
received the botulinum toxoid vaccine. Most of these individuals 
received two doses.
    The Department of the Army collected safety information through a 
retrospective survey on local and generalized reactions experienced by 
soldiers vaccinated with the botulinum toxoid vaccine. The survey, 
conducted on August 27, 1991, was given to individuals who received one 
or more doses of the vaccine (between January 3, 1991, and March 2, 
1991) in the Persian Gulf, and who had received no other vaccines 
against biological warfare agents. One hundred and twenty-one responses 
were received. With respect to local reactions, 84 percent of 
vaccinated individuals reported either no local reactions (72.5 
percent) or redness and/or swelling less than 6 inches in any dimension 
(11.57 percent). One individual reported post-vaccination injection 
site pain that temporarily (one half day) interfered with his ability 
to perform his duties but resolved quickly. With respect to systemic 
reactions to the vaccine, 97.52 percent of respondents reported having 
none. Of the three respondents who reported systemic reactions, two 
reported mild systemic effects such as headache and muscle aches, and 
the third also reported nausea, fever, and fatigue; none of these 
events were reported to have persisted or have resulted in limitations 
on activity.
    In 1992, DOD carried out a followup study, with informed consent, 
on 327 selected military personnel who received the botulinum toxoid 
vaccine during Operation Desert Shield and Operation Desert Storm. The 
objectives of this study were, in part, to evaluate the persistence of 
antibodies to botulinum toxoid vaccine received during the Gulf War 
and, to determine the serological response 30 days after a booster 
dose. The evaluation demonstrated that 35 of the 327 had measurable 
antibody 18 to 24 months following primary vaccination. The percentage 
of antibody varied depending on whether the individuals had received 1, 
2, or 3 primary vaccinations ((0/10 (0 percent), 27/244 (11.1 percent), 
and 8/73 (11 percent) of individuals who had received 1, 2, or 3 
primary vaccinations, respectively). This response was to be expected 
at this followup time point in individuals receiving anything less than 
the full primary immunization and booster dose. Thirty days after the 
booster dose was administered, 7/10 (70 percent), 238/244 (97.5 
percent), and 72/72 (98.6 percent) of individuals who had received 1, 
2, or 3 of the primary dose series, respectively, responded with a 
significant increase in toxin neutralizing antibody titer to botulinum 
type A.
3. Information Supplied to Military Personnel
    DOD has stated that its implementation of plans for providing 
service members with information about the investigational products was 
frustrated due to time limitations.
    In order to evaluate the effectiveness of its efforts to 
disseminate information to military personnel regarding the safety, 
risks, and possible benefits of pyridostigmine, the Army surveyed an 
unspecified number of personnel regarding their views on the adequacy 
of the information that they received. This was a part of Survey II 
described in section I.E.1 of this document. Those surveyed were asked 
whether they thought the training that they received was adequate and 
to comment about any problems with their training.
    One hundred forty-nine individuals responded to this survey. In 
response to the question ``Was training about pyridostigmine 
adequate?'', 43.7 percent of the respondents answered in the negative. 
Most of those who felt that the training was inadequate expressed a 
desire for more information on side effects, long-term effects, and the 
drug's mechanism of action. The following is a sample of some of the 
comments received (both by those who felt the training was inadequate 
and those who felt it was adequate but could have been better):
    (a) ``No standard side effects given.''
    (b) ``No training on side effects.''
    (c) ``People were worried about the drug's side effects. Many 
people avoided taking it. Some people would double dose after missing 
one.''
    (d) ``Not trained on drug action, but yes on side effects.''
    (e) ``Combat lifesavers brief it and said it was FDA approved.''
    (f) ``Many soldiers didn't take the tablets due to the fact that 
they weren't FDA approved or thought not.''
    (g) ``Didn't know what it did, what it was for. Disregarded 
instructions to take it.''
    (h) ``Training was not enough in layman's terms. You would need to 
know more about nerve agents.''
    Veterans made similar comments on the adequacy of the information 
they received at hearings before the Senate Committee on Veterans' 
Affairs and the Presidential Advisory Committee on Gulf War Veterans' 
Illnesses.
    As part of Survey I described in section I.E.1 of this document, 15 
of the 23 medical officers who returned the survey responded that to 
their knowledge, the information sheet on pyridostigmine bromide was 
not distributed to personnel instructed to take pyridostigmine bromide. 
Two respondents said that the information was distributed, and one 
respondent, whose unit was not instructed to begin pretreatment with 
pyridostigmine bromide, replied that he had the sheet available for 
distribution.
    Although FDA did not require the Army to attempt to evaluate the 
effectiveness of its educational efforts, the Army did so in an effort 
to monitor its own performance and perhaps learn about how education 
might be improved in the future. While it is difficult to evaluate the 
validity of the Army's findings (due to the difficulty of measuring the 
effect of response bias in Survey II), FDA is concerned about the high 
level of dissatisfaction expressed

[[Page 41000]]

by this small sample of military personnel. Their responses indicate 
that the information on pyridostigmine was not distributed as intended 
and the Army's educational activities were uneven and possibly 
inappropriate to the education level of all personnel. Their responses 
also indicate that because of the inadequate information provided to 
the soldiers, that at least some soldiers either took the wrong amount 
of pyridostigmine or disregarded orders to take it completely. Based on 
subsequent DOD statements, FDA has concluded that the information sheet 
on pyridostigmine was not provided and disseminated to military 
personnel in the Gulf as conditioned in the Commissioner's letter 
granting the waiver under the interim rule.
    With respect to botulinum toxoid vaccine, there is a lack of 
clarity as to whether the conditions of waiver were met and applied or 
whether informed consent was actually obtained.

F. Other Information Related to the Interim Rule

    There has been extensive examination of the use of the interim 
rule, pyridostigmine bromide, and the botulinum toxoid vaccine during 
Operation Desert Storm. This focused examination is, in part, the 
result of interest in determining the cause of a variety of health 
effects suffered by veterans who served in the Gulf War.
    On May 6, 1994, the United States Senate Committee on Veterans' 
Affairs held a hearing on ``Is Military Research Hazardous to Veterans' 
Health? Lessons From World War II, the Persian Gulf, and Today.'' The 
Chairman, in his opening statement, stated his view that the issue 
needed to be resolved. Witnesses at the hearing included ethicists, 
four veterans with stories of illnesses allegedly related to exposures 
they experienced either in the military or working for the military, 
and scientists and officials from the Department of Veterans Affairs, 
DOD, FDA, and the Department of Agriculture.
    The Presidential Advisory Committee on Gulf War Veterans' 
Illnesses' final report reviewed these issues extensively. In its 
interim report (February 1996), the committee described a number of 
shortcomings in DOD's use of investigational products during the Gulf 
War and recommended, among other things, that:
    If FDA decides to reissue the interim final rule as final, it 
should first issue a Notice of Proposed Rule Making. Among the areas 
that specifically should be revisited are: adequacy of disclosure to 
service personnel; adequacy of recordkeeping; long term followup of 
individuals who receive investigational products; review by an IRB 
outside of DOD; and additional procedures to enhance understanding, 
oversight, and accountability. (p. 24)
This report further stated:
    The activities of FDA and DOD related to the use of drugs and 
biologics intended to protect against [chemical and biological 
warfare] CBW remain an area of considerable interest to the 
Committee. In particular, we plan to explore with FDA possible 
alternatives to the interim final rule to help ensure troops are 
protected against CBW. Some observers have suggested an approval 
standard that recognizes surrogate endpoints and other data 
indicative of efficacy for vaccines, drugs, devices, and antibiotics 
intended for CBW defense might be a more appropriate policy than a 
waiver of informed consent. (p. 44)
    On May 7, 1996, Public Citizen, the National Veterans Legal 
Services Program, and the National Gulf War Resource Center, Inc., 
submitted a petition to FDA requesting that the Commissioner repeal the 
interim rule. The petition set forth a number of grounds for this 
request, including: The ethics of the rule continues to be questioned; 
the military did not provide the information regarding the effects of 
experimental drugs that FDA considered essential to permitting their 
use without informed consent; DOD failed to keep the necessary records 
on the administration and effects of the experimental drugs; the waiver 
of informed consent was not necessary (botulinum toxoid vaccine was 
ordered to be given on a voluntary basis and ``the fact that the PB 
tablets were self-administered by the troops underscores that it was 
possible to inform and obtain the consent of the military personnel who 
took these tablets''); the safety of the experimental drugs is still 
questionable; and administration of these drugs without informed 
consent was not limited to military personnel.
    The petition concluded with the following:
    The FDA should repeal the Interim Rule in light of all the 
problems encountered in its implementation. Not only did the Interim 
Rule fail to operate in the manner the FDA intended, but it also 
allowed the military to circumvent the safeguards the FDA offered to 
rationalize this departure from its ordinary rules on informed 
consent. The military did not follow through with many conditions 
that the FDA deemed crucial to granting a waiver of this critical 
requirement. (p. 26)
    On September 13, 1996, the Assistant Secretary of Defense, Health 
Affairs, provided DOD's comments on the petition to FDA and urged that 
it be denied. DOD's comments included the following statements:
    1. When the President commits U.S. military forces to a combat, 
peacekeeping, or humanitarian deployment, the U.S. Government has a 
duty to take all reasonable precautions to bring about a successful 
completion of the mission and a safe return of the deployed forces.
    2. The Government's duty to take all reasonable precautions to 
preserve the fighting force must include recognition of the 
startling proliferation of chemical and biological weapons among 
potential adversaries and terrorist organizations and an obligation 
to implement the best possible medical countermeasures.
    3. Implementation of the best possible medical countermeasures 
may require the standardized treatment use of an investigational new 
drug or vaccine for all personnel at risk in a military combat 
exigency, including those personnel who, for whatever reason or no 
reason at all, would prefer an alternate treatment or no treatment.
    4. The current rule is an extremely limited authority, requiring 
case-by-case justification, available only under extraordinary 
circumstances, and explicitly restricted to advancing the best 
interests of the military personnel concerned.
    5. The current rule is fully consistent with law and ethics.
    6. Overall, notwithstanding some problems in carrying out the 
designed treatment protocols, the two uses made of the current rule 
during the Persian Gulf War support the rule's continuation.
    7. Initiatives since the Gulf War, including current operations 
in Bosnia, have improved DOD's ability to implement medical 
countermeasures under the authority of the current rule, should that 
become necessary in the future.
This petition is pending before the agency.

II. Scope of Comments Requested

    In light of the many complex ethical, scientific, and public health 
issues associated with the use of investigational products during the 
Gulf War and the waiver of the requirement to obtain informed consent, 
FDA is soliciting broad public comment on the advisability of the 
agency: (1) Revoking or amending the interim final rule that permits 
the Commissioner to determine that obtaining informed consent from 
military personnel for the use of an investigational drug or biologic 
is not feasible in certain situations related to military combat, and 
(2) identifying the evidence needed to demonstrate safety and 
effectiveness for such investigational drugs that cannot ethically be 
tested on humans for purposes of determining their efficacy because 
they would involve administering a severely toxic substance to human 
volunteers. The agency encourages written comments from all interested 
parties, including, but not limited to, consumers, patient groups, 
veterans and veteran groups, active military personnel, organizations 
and departments, ethicists, scientists,

[[Page 41001]]

researchers with particular expertise in this area, and health care 
professionals.
    Interested persons may, on or before October 29, 1997, submit to 
the Dockets Management Branch (address above) written comments 
regarding the questions identified in section II of this document 
(referencing the number of the question(s) being addressed). Two copies 
of any comments are to be submitted, except that individuals may submit 
one copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. Received comments may be seen 
in the office above between 9 a.m. and 4 p.m., Monday through Friday.
    The agency specifically requests comments on the following:

A. The Interim Rule

    (1) Should the agency revoke the interim rule? If so, why?
    (2) Are there circumstances under which use of the interim rule 
would be justified? If so, what are those circumstances?
    (3) The interim rule is based on the premise that informed consent 
is not feasible in military combat exigencies because if a soldier were 
permitted to say ``no,'' this could jeopardize the individual soldier's 
life, endanger other personnel in his or her unit, and jeopardize the 
accomplishment of the combat mission. DOD has alleged that it is not an 
option to excuse a nonconsenting soldier from a military mission. Given 
the experience in the Gulf War, does this rationale still hold?
    (4) Instead of waiving the requirement for informed consent, is it 
feasible to obtain anticipatory consent from military personnel during 
peace time for the future use of investigational products during a 
military conflict? If it is feasible, would such consent be valid as 
``informed consent''? What would be the needed consent algorithm to 
make it valid and feasible?
    (5) Instead of waiving the requirement for informed consent, is it 
feasible to obtain anticipatory consent from military recruits (prior 
to their recruitment into the military) for the future use of 
investigational products during a military conflict? If it is feasible, 
would such consent be valid? What would be the needed consent algorithm 
to make it valid and feasible?
    (6) If the interim rule is needed, are there changes that should be 
made to it based on experiences during and following the Gulf War? If 
so, what are these changes and why should they be made?
    (7) Can or should the interim rule be narrowed in scope? If so, 
how?
    (8) If the rule were to be reproposed:
    (a) Should there be a requirement that DOD's proposed use of the 
investigational product(s) be approved by an IRB that is independent of 
DOD? If so, why should DOD be held to a requirement not imposed on 
other institutions, and what should be the requirement for that 
independent IRB? Can this be accomplished without compromising military 
or national security?
    (b) Should the authority to make the ``feasibility determination'' 
(i.e., whether obtaining informed consent is ``not feasible'') under 
the interim rule be vested in persons or entities other than the 
Commissioner of FDA?
    (c) Should the rule be more specific in describing the information 
that must be supplied to military personnel, or should FDA have wide 
latitude to make such determinations on a case-by-case basis?
    (d) Should additional measures be taken to insure that information 
required by FDA is effectively conveyed to the affected military 
personnel? If so, what should these measures be?
    (e) Should the rule address what constitutes adequate recordkeeping 
and adequate long term followup of individuals who receive 
investigational products? If so, in what way?
    (f) Should the rule contain additional procedures to enhance 
understanding, oversight, and accountability? If so, what are these 
procedures?
    (g) Should the rule contain additional procedures to track 
noncompliance?

B. When Is It Ethical 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?

    The agency recognizes that reliance on nonhuman studies will almost 
always give greater uncertainty about effectiveness than would studies 
in humans. Therefore, the agency is also seeking comments on the 
ethical and scientific considerations of conducting human efficacy 
trials with these products. For example, the agency is interested in 
receiving comment on whether it is ethical to conduct challenge studies 
in humans if, should the test product fail, there is strong reason to 
believe the effect of the challenge could be reversed or effectively 
treated. What if the effect of the challenge could not be reversed or 
effectively treated? What would be the needed risk/benefit assessment? 
Who could volunteer for such studies? Would it be ethically preferable 
to carry out such studies in people who could be exposed to the toxic 
substance? Should the agency further explore these issues in a separate 
public forum?

C. If Products That May Be Used to Provide Potential Protection Against 
Toxic Chemical and Biological Agents Cannot Be Ethically Tested in 
Humans, What Evidence Would Be Needed to Demonstrate Their Safety and 
Effectiveness?

    (1) Should FDA identify the evidence needed to demonstrate safety 
and effectiveness for drugs that cannot ethically be tested on humans 
to demonstrate efficacy when such tests would involve administering a 
severely toxic substance to human volunteers? If ``yes,'' what should 
constitute the evidence needed to demonstrate safety and efficacy? (The 
current statutory standard requires, among other things, there be 
``substantial evidence'' that the drug is effective; ``substantial 
evidence'' means evidence ``consisting of adequate and well-controlled 
investigations, including clinical investigations * * * on the basis of 
which it could fairly and responsibly be concluded by such experts that 
the drug'' is effective.)
    (2) If the agency were to identify the evidence needed to 
demonstrate safety and effectiveness of these products, would this 
preclude the need for the interim rule? What specific advantages would 
this offer over the interim rule?
    (3) Civilian populations may require products used in the 
prevention or treatment of the serious or life-threatening effects from 
exposure to toxic chemical or biological agents, e.g., in the event of 
exigencies such as the release of toxic chemical agents in the Tokyo 
subway system. Thus, should the agency consider identifying the 
evidence needed to demonstrate safety and effectiveness for these 
products which would apply to both civilian as well as military 
populations?

    Dated: July 7, 1997.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
[FR Doc. 97-20311 Filed 7-29-97; 10:58 am]
BILLING CODE 4160-01-F