[Federal Register Volume 64, Number 192 (Tuesday, October 5, 1999)]
[Rules and Regulations]
[Pages 54180-54189]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-25376]



[[Page 54179]]

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Part V





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Parts 50 and 312



Human Drugs and Biologics; Determination That Informed Consent Is NOT 
Feasible or Is Contrary to the Best Interests of Recipients; Revocation 
of 1990 Interim Final Rule; Establishment of New Interim Final Rule

  Federal Register / Vol. 64, No. 192 / Tuesday, October 5, 1999 / 
Rules and Regulations  

[[Page 54180]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 50 and 312

RIN 0910-AA89

[Docket No. 90N-0302]


Human Drugs and Biologics; Determination That Informed Consent Is 
NOT Feasible or Is Contrary to the Best Interests of Recipients; 
Revocation of 1990 Interim Final Rule; Establishment of New Interim 
Final Rule

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim final rule; opportunity for public comment.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is revoking its 1990 
interim final regulations 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. FDA also is issuing a new interim final rule addressing waiver 
of informed consent in military operations. FDA is taking these actions 
based on its analysis and consideration of all relevant facts, 
including its evaluation of the Department of Defense's (DOD) 
experience during the Persian Gulf War, its evaluation of the comments 
received by the agency in response to the agency's July 31, 1997, 
request for comments on whether the agency should revise or revoke the 
interim regulations, and the enactment of the Strom Thurmond National 
Defense Authorization Act for Fiscal Year 1999 (the Defense 
Authorization Act). Under the Defense Authorization Act, the President 
is authorized to waive the Federal Food, Drug, and Cosmetic Act's (the 
act) informed consent requirements in military operations if the 
President finds that obtaining consent is infeasible or contrary to the 
best interests of recipients and on an additional ground that obtaining 
consent is contrary to national security interests. In light of the 
enactment of the Defense Authorization Act, with an immediate effective 
date, and because the President could be called upon to make a waiver 
determination for military personnel engaged in a specific military 
operation at any time, the agency believes that it is critical to have 
in place adequate criteria and standards for the President to apply in 
making an informed consent waiver determination. Therefore, FDA is 
issuing a new interim final regulation with an immediate effective date 
to establish criteria and standards for the President to apply in 
making a determination that informed consent is not feasible or is 
contrary to the best interests of the individual recipients.

DATES: Effective October 5, 1999. Submit written comments by December 
20, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Bonnie M. Lee, Division of Compliance 
Policy, Office of Enforcement, Office of Regulatory Affairs (HFC-230), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-827-0415.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is revoking its interim final regulations related to informed 
consent for human drug and biological products that permitted 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. On a case-
by-case basis, the interim final rule authorized the Commissioner to 
make such a determination at the written request of the Assistant 
Secretary of Defense (Health Affairs). Any determination made with 
respect to the nonfeasibility of obtaining informed consent expired at 
the end of 1 year, unless renewal was requested, or when DOD informed 
the Commissioner that the military operation had ended, whichever was 
earlier.
    In the Federal Register of July 31, 1997 (62 FR 40996), FDA 
published a document entitled ``Request for Comments'' that discussed 
the use of investigational drugs and biologicals in military and other 
emergency settings to treat or prevent toxicity of chemical or 
biological substances (hereinafter referred to as the July 1997 request 
for comments). In this document, FDA provided extensive background on 
the development and implementation of the 1990 interim rule and DOD's 
experience during the Persian Gulf War. The agency's request for 
comments included specific questions in the three following subject 
areas.
    First, the agency asked whether its rule permitting waiver of 
informed consent in very limited circumstances involving military 
exigencies should be revoked or amended, and if so, how. In 1990, FDA 
issued an interim rule (``Informed Consent for Human Drugs and 
Biologics; Determination that Informed Consent is Not Feasible'' 
(Sec. 50.23(d) (21 CFR 50.23(d)) (55 FR 52814, December 21, 1990)), 
allowing the Commissioner to make the determination, in response to 
product specific requests from DOD, that obtaining informed consent 
from military personnel for the use of an investigational drug or 
biological product is not feasible in certain battlefield or combat-
related situations.
    Second, because information on a product's efficacy in reducing or 
preventing toxicity of chemical or biological substances is important, 
the agency also asked when, if ever, it is ethical to expose volunteers 
to toxic chemical and biological substances to test the efficacy of 
products that may be used to provide potential protection against those 
substances.
    Third, because these products are critically important, even if 
they cannot be ethically tested in humans to demonstrate efficacy, the 
agency asked what evidence of efficacy, other than that from human 
trials, would be appropriate to demonstrate the safety and efficacy of 
products that may provide protection against toxic chemical and 
biological substances.
    In a related document published elsewhere in this issue of the 
Federal Register, FDA has addressed the second and third issues in a 
proposed regulation that discusses the evidence needed to demonstrate 
efficacy of new drugs for use against lethal or permanently disabling 
toxic substances when definitive efficacy studies in humans cannot 
ethically be conducted. The agency believes that, if issued, this 
proposed rule may make it possible to develop evidence sufficient to 
support approval of such drugs and thus should help minimize the need 
to use investigational products in military exigencies.
    With respect to the first question, waiver of informed consent in 
military operations, FDA's decision to revoke the 1990 interim rule is 
based on consideration of all relevant facts, including FDA's 
evaluation of DOD's experience during the Persian Gulf War, FDA's 
analysis of the comments received in response to the first issue 
addressed in the July 1997 request for comments on whether the agency 
should revise or revoke the interim rule (62 FR 40996), and the recent 
enactment of the Defense Authorization Act.
     Section 731 of the Defense Authorization Act, amending 10 U.S.C.

[[Page 54181]]

1107(f), became effective on October 17, 1998. Under 10 U.S.C. 1107(f), 
the Commissioner of Food and Drugs no longer has the authority to make 
waiver of informed consent decisions in military operations because 10 
U.S.C. 1107(f)(1) explicitly vests the authority to waive the act's 
informed consent requirement in the President. Section 1107(f)(1) of 
Title 10 provides for such waiver in the case of the administration of 
an investigational new drug or drug unapproved for its applied use to a 
member of the armed forces in connection with the member's 
participation in a particular military operation. Section 1107(f)(1) of 
Title 10 authorizes the President to waive informed consent if the 
President finds that obtaining informed consent is: (1) Not feasible; 
(2) contrary to the best interests of the member; or (3) not in the 
interests of national security. The first two grounds (lack of 
feasibility or contrary to the best interests of recipients) are 
specified in section 505(i) of the act (21 U.S.C. 355(i)).
     Section 1107(f)(2) of Title 10 provides that, in making a 
determination to waive informed consent on the grounds that it is not 
feasible or contrary to the best interests of the armed services 
member, the President shall apply the standards and criteria that are 
set forth in the relevant FDA regulations for a waiver of the prior 
consent requirement on that ground.
     Because section 1107(f)(1) of Title 10 refers to waiver of 
informed consent in connection with military operations, the relevant 
FDA regulations referenced in section 1107(f)(2) of Title 10 would be 
any regulations dealing with waivers in this context. As discussed 
previously, FDA originally issued such regulations as an interim final 
rule in 1990 (55 FR 52814, December 21, 1990), at Sec. 50.23(d)(1) 
through (d)(4). These regulations consisted of procedures to be 
followed by the Assistant Secretary of Defense (Health Affairs) and the 
Commissioner of Food and Drugs (Sec. 50.23(d)(1)); standards and 
criteria for granting such waivers (Sec. 50.23(d)(1) and (d)(2)); a 
discretionary provision for consultation with advisory committees 
(Sec. 50.23(d)(3)) and time limits for such waivers (Sec. 50.23(d)(4)). 
These regulations conflict with section 1107(f)(1) of Title 10 in that 
they vest FDA's Commissioner with the authority to make such waiver 
decisions.
     As reflected in a number of the comments FDA received on the 1990 
interim rule, many people addressed the issue of whether waiver of 
informed consent in military operations involving military personnel is 
ever acceptable, and if so, when. In the Defense Authorization Act, 
Congress has addressed that issue by explicitly providing for waiver of 
the informed consent requirement by the President in certain 
situations. In light of the immediate effective date of the Defense 
Authorization Act, the agency believes that it is critical to have in 
place adequate criteria and standards for the President to apply in 
making an informed consent waiver determination.
     Based on the extensive examination of issues associated with the 
existing interim final rule during the last 8 years, the agency has 
developed a new rule consistent with the Defense Authorization Act that 
contains new strengthened criteria and standards that the President can 
use in making informed consent waiver determinations. The agency 
believes that it is in the public interest to have these new criteria 
and standards in place and available for use should the President be 
called upon to make a waiver determination while, at the same time, it 
solicits public comments on these criteria and standards. These new 
criteria and standards are discussed in greater detail later in this 
document.

II. Comments Received on Whether to Revoke or Amend the 1990 
Interim Rule

    The agency received 134 comments on whether it should revoke or 
amend the 1990 interim rule: Of these, 119 comments expressed 
opposition to the interim rule and recommended that it be permanently 
revoked, 7 comments recommended changes to the interim rule, 2 comments 
supported retention of the interim rule, and 6 comments misunderstood 
the scope of the interim rule and provided comments on a different 
regulation.

A. Summary of Comments Recommending That the Interim Rule Be Revoked

    The 119 comments that recommended the revocation of the interim 
rule were signed by 160 individuals including veterans, veterans' 
relatives, active military personnel, active military families, 
ethicists, physicians, other health care providers, and private 
citizens, as well as from an advocacy group for ailing Persian Gulf 
Veterans, an organization representing grassroots veterans' 
organizations in America and England, and a nonprofit public interest 
organization.
    Most of these comments opposed the agency's continued use of the 
interim rule after the experience of the Persian Gulf War. Many thought 
it should never have been used. Specifically, 114 comments stated that 
informed consent was absolutely essential and that military personnel, 
like other nonmilitary citizens, should receive adequate information 
about an investigational product before its use and have the right to 
refuse to receive it. Seventeen comments stressed the need for followup 
of possible adverse reactions to investigational products, and 15 
comments indicated that DOD could not fulfill its responsibilities even 
if FDA required adequate followup and other requirements as part of a 
new regulation. Five comments stated that DOD had shown itself to be 
incapable of adequate oversight and recordkeeping and three comments 
noted that the interim rule had not been implemented by DOD as had been 
intended. Several comments suggested that if the rule were to be used 
again, there must be an independent board of medical and ethical 
experts, there must be an institutional review board independent of 
DOD, and there must be proper monitoring that could only be done by 
non-DOD personnel.
     As described earlier in this document, The Defense Authorization 
Act answers the controversial question of whether waiver of informed 
consent in military operations is ever appropriate. In passing this 
legislation, Congress has concluded that the President may waive the 
informed consent requirement for military personnel engaged in a 
particular military operation in certain situations. The comments on 
the 1990 interim rule pointed out significant areas that needed to be 
strengthened, including: Provision of adequate information about an 
investigational product before its use; adequate followup to assess 
whether there are adverse health consequences that result from the use 
of the investigational product; adequate oversight, accountability, and 
recordkeeping when investigational agents are used; and involvement of 
non-DOD personnel in decisions to use investigational products without 
informed consent. All of these areas have been addressed in the new 
interim rule that establishes the criteria and standards for the 
President to use in making an informed consent waiver determination.

B. Summary of Comments Recommending Changes to the Interim Rule

    Seven comments recommended changes to the interim rule. Three of 
these comments recommended that the rule be suspended and reconsidered 
only if their modifications were adopted and adhered to by DOD.
     Two comments recommended that a process be established for the 
President

[[Page 54182]]

to authorize the use of investigational products without informed 
consent in military conflicts.
     The Defense Authorization Act establishes the President as the 
sole authority for making a waiver of informed consent determination 
for military personnel involved in a particular military operation. 
Thus, the process recommended by these comments has already been 
established through legislation. FDA will be involved in this process 
through its traditional role of reviewing specific protocols under its 
investigational new drug (IND) regulations.
    One comment recommended that the rule be amended to require: (1) 
That reasonable efforts be made to inform individuals in advance that 
investigational products are to be used, (2) that the extent and 
appropriateness of the information provided be determined by the 
Commissioner of FDA, (3) that all individuals exposed to 
investigational products be informed no later than 1 year after their 
use, and (4) that there be established a publicly accessible site for 
continuous access to the most updated scientific information on these 
products.
     The agency agrees with this comment and has incorporated the 
suggested requirements into the new interim rule. The interim rule 
requires that each member involved in the military operation be given, 
prior to the administration of the investigational new drug, a specific 
written information sheet. That information sheet is to include 
information (in addition to information required by 10 U.S.C. 1107(d)) 
concerning the investigational new drug, the risks and benefits of its 
use, potential side effects, and other pertinent information about the 
appropriate use of the product. Under 10 U.S.C. 1107(d), the 
information sheet is required to contain the following: (1) Clear 
notice that the drug being administered is an investigational new drug 
or a drug unapproved for its applied use; (2) the reasons why the 
investigational new drug or drug unapproved for its applied use is 
being administered; (3) information regarding the possible side effects 
of the investigational new drug or drug unapproved for its applied use, 
including any known side effects possible as a result of the 
interaction of such drug with other drugs or treatments being 
administered to the members receiving such drug; and (4) such other 
information that, as a condition of authorizing the use of the 
investigational new drug or drug unapproved for its applied use, the 
Secretary of Health and Human Services may require to be disclosed. FDA 
intends to review the information sheet as part of its review of the 
use of the investigational product under an IND in order to determine 
its adequacy. The interim rule also requires DOD to provide public 
notice in the Federal Register describing each waiver of informed 
consent determination, a summary of the most updated scientific 
information on the products used, as well as other pertinent 
information.
    One comment from an individual who was employed at the U.S. Army 
Medical Materiel Development Activity, Ft. Detrick, MD, during the Gulf 
War, and who served for 22 years as an Army officer, stated that ``[a]s 
the largest training organization in the United States, perhaps in the 
world, DoD clearly has the capacity and resources to provide adequate 
information to each service member before he or she takes or uses an 
investigational product.'' Based on this reasoning, the Army officer 
suggested that the rule be amended and that DOD could, and should, 
institute training programs early in each service member's military 
career. Specifically, this comment recommended that FDA demand adequate 
training as part of the informed consent process and require that DOD 
develop and validate training guidelines for the use of investigational 
products that might be used under a waiver during all phases of product 
development.
     The agency agrees with this comment. The interim rule now requires 
DOD to provide training to the appropriate medical personnel and 
potential recipients on the specific investigational new drug to be 
administered prior to its use.
    Two comments stressed that FDA should regard itself as acting on 
behalf of the troops, not on behalf of the military or the DOD. These 
comments recommended that the interim rule be suspended or revoked 
until the agency critically reviewed requests from DOD to waive 
informed consent that contained the following documentation: (1) 
Documentation from DOD that identified the threat, its nature, and its 
likelihood; (2) documentation from DOD that administration of the 
proposed treatment is likely to be effective against that threat; (3) 
documentation from DOD that detailed concurrent conditions (such as 
environmental and occupational conditions, treatment regimens that may 
be employed by troops serving in the forces to be treated) that could 
alter the effects of the proposed treatment; (4) documentation from DOD 
that demonstrated that military medical services are capable of 
delivering qualified personnel and adequate supplies of necessary 
medical material to the specific theater of operations; (5) 
documentation from DOD that establishes that the recordkeeping systems 
are capable of tracking the proposed treatment from supplier to point 
of administration; and (6) documentation that demonstrates that there 
are medical followup plans for troops receiving the proposed treatment. 
These comments stated that this documentation should be made public and 
public comment should be sought regarding the performance of both DOD 
and FDA. These comments stated that if these requirements could be met, 
adequate information would need to be provided to the troops by 
individuals with whom they have daily contact.
     The agency agrees with the suggestions for documentation contained 
in these comments and has incorporated them into the new interim rule. 
Under the new interim rule, each member involved in the military 
operation will be given, prior to the administration of the 
investigational new drug, a specific written information sheet. This 
information sheet is required, under 10 U.S.C. 1107(d), to contain 
specific information. The interim rule incorporates this requirement by 
reference and requires the disclosure of risks and benefits of the use 
of the investigational product, potential side effects, and other 
pertinent information about the appropriate use of the product.

C. Comments in Support of Retaining the Interim Rule

    The agency received two comments in support of retaining the 
interim rule as written--one from DOD and the other from a physician 
from academia. This latter comment stated that:
    [t]he organization and activities of the DOD are not meant to be 
either democratic or reliant upon informed consent. However, the 
goal of DOD activities in combat situations is victory, and with 
that end in sight, it is reasonable to expect that the condition of 
the troops is considered carefully by DOD leadership. Decisions 
pertinent to the use of investigational drugs without informed 
consent will most likely represent the best interests of military 
personnel and the nation.
    DOD's comments in support of maintaining the interim rule were 
similar to those expressed by DOD in requesting the interim rule 
initially (see the Assistant Secretary of Defense (Health Affairs) 
letter of October 30, 1990, to the Assistant Secretary for Health, HHS, 
quoted in the preamble to the interim rule (55 FR 52814), and in its 
September 13, 1996, response to the

[[Page 54183]]

May 7, 1996, petition to FDA requesting that the Commissioner repeal 
the interim rule (see summary in the July 1997 request for comments (62 
FR 40996 at 41000)).
     As previously stated, Congress now has passed legislation 
providing for waiver of the informed consent requirement by the 
President in certain military situations, thus, recognizing the need 
for waiver in limited situations. The agency, however, believes that 
the criteria and standards contained in the 1990 interim rule are not 
sufficient and has therefore established new criteria and standards for 
the President to apply in making an informed consent waiver 
determination.

D. Other Comments on the Interim Rule

    A comment from Chairman Arlen Specter and Ranking Minority Member 
John D. Rockefeller IV, Senate Committee on Veterans' Affairs, stated 
that whether the rule should be revoked or not ``* * * is a complex 
decision that needs to be carefully considered, with input from health 
care professionals, ethicists, active duty military personnel, 
veterans, and the general public.'' They urged FDA, if it decided not 
to revoke the rule, to ensure that a process is instituted to provide 
maximum protection to ``* * * the health and well-being of military 
personnel prior to, during, and subsequent to a combat situation.'' 
They stressed the importance of establishing a process prior to any 
combat situation that would: (1) Lay out how decisions would be reached 
in a timely manner; (2) require institutional review boards (IRB's) 
used during this process to consist of at least three persons 
independent of DOD because the IRB will be making decisions that result 
in the loss of rights of a large group of individuals and objectivity 
is essential; (3) require health surveillance data from well-designed 
data collection forms be used to assess the potential health 
consequences of the use of products and to modify decisions as 
information is gained; and (4) require compliance with mechanisms for 
review and sanctions be put in place.
     The agency agrees that the decisions associated with the interim 
rule have been complex and there is a need to institute a process that 
will provide maximum protection to military personnel. The Defense 
Authorization Act vests authority in the President to make a waiver of 
informed consent determination, and it vests in the President the 
process by which such decisions shall be made. FDA believes that this 
process, which includes use of the criteria and standards in the new 
interim final rule, will provide the protection of the health and well-
being of military personnel urged by the comments. As suggested by this 
comment, the new interim rule requires the IRB to include at least 
three nonaffiliated members who are not employees or officers of the 
Federal Government.
     In response to the suggestion that the rule require health 
surveillance to assess the potential health consequences of the use of 
the product and to modify decisions as information is gained, the new 
interim rule contains two provisions. One requires DOD to provide 
adequate followup to assess whether there are beneficial or adverse 
health consequences that result from the use of the investigational 
product. The second requires DOD to report to FDA and to the President 
any changed circumstances relating to the standards and criteria 
contained in the rule or that otherwise might affect the determination 
to use an investigational new drug without informed consent.
     In response to the comment's recommendation that the process 
require compliance with mechanisms for review and sanctions, the agency 
notes that the Defense Authorization Act requires the Secretary of 
Defense, if the President grants the requested waiver, to submit to the 
chairman and ranking minority member of each congressional defense 
committee a notification of the waiver, together with the written 
determination of the President and the Secretary of Defense's 
justification for the request for the waiver of informed consent (see 
10 U.S.C. 1107(f)(3)(B)). The new interim rule builds in accountability 
and compliance by requiring the Secretary of Defense to certify and 
document to the President that the standards and criteria in the rule 
have been met, including the criteria that use of the investigational 
drug without informed consent otherwise conforms with applicable law. 
Further, the new interim rule notes that ``[n]othing in these criteria 
or standards is intended to preempt or limit FDA's and DOD's authority 
or obligations under applicable statutes and regulations.'' The agency 
notes that the mechanisms for review and sanctions under the IND 
regulations apply to the DOD and its employees involved in the use of 
products subject to FDA regulation.
     In response to the comment's suggestion that the process include 
public disclosure, the new interim rule requires DOD to provide public 
notice in the Federal Register as soon as practicable and consistent 
with classification requirements describing each waiver of informed 
consent determination, a summary of the most updated scientific 
information on the products used, and other pertinent information.
    The agency has concluded that the issues associated with the 1990 
interim rule are very complex and difficult, as recognized by Senators 
Specter and Rockefeller. As described in detail in FDA's July 1997 
request for comments, there has been extensive examination of issues 
associated with the 1990 interim rule during the last 8 years. In 
addition to FDA's July 1997 request for comments, the issues have been 
examined in comments submitted to the agency in the 30-day comment 
period following the rule's publication in the Federal Register on 
December 21, 1990; in litigation (Doe v. Sullivan, 756 F. Supp. 12, 14 
(D.D.C. 1991)); in a May 6, 1994, United States Senate Committee on 
Veterans' Affairs hearing on ``Is Military Research Hazardous to 
Veterans' Health? Lessons From World War II, the Persian Gulf, and 
Today;'' reviews conducted by the Presidential Advisory Committee on 
Gulf War Veterans' Illnesses; and in the Public Citizen, the National 
Veterans Legal Services Program, and the National Gulf War Resource 
Center, Inc., May 7, 1996, petition to FDA requesting that the 
Commissioner repeal the interim rule.
    The agency believes that exceptions from the informed consent 
requirement should apply rarely and only when sufficient additional 
protections are provided to the military personnel affected.

III. Revocation of the 1990 Interim Rule

    The agency recognizes that there may be future military combat 
situations where U.S. military personnel are at risk of exposure to 
chemical and biological weapons and that DOD has a critical and 
legitimate interest in protecting military personnel from such chemical 
and biological agents. This was the basis for FDA's 1990 interim rule 
issued in anticipation of the Persian Gulf War that gave DOD the 
authority to use specified investigational products to provide 
potential protection against chemical and biological warfare agents 
without obtaining informed consent from individual service personnel.

A. DOD's Experience in Implementing the Rule During the Persian Gulf 
War

    DOD's experience during the Gulf War with pyridostigmine bromide 
and the botulinum toxoid vaccine was described in detail in the July 
1997 request for comments (62 FR 40996 at 40998 through 41000). A brief 
summary of this experience follows.

[[Page 54184]]

    In December 1990, DOD submitted protocols under IND's and requests 
for waiver of informed consent for: (1) Pyridostigmine bromide 30-
milligram tablets, a potentially useful pretreatment against soman, a 
nerve gas; and (2) the botulinum toxoid vaccine, potentially protective 
against toxins produced by Clostridium botulinum (the bacterium that 
produces the toxin that causes botulism). The Commissioner approved 
both of DOD's waiver requests and each product was administered to some 
of the military personnel who participated in Operation Desert Storm. 
FDA's agreement to waive the informed consent requirement was based, in 
large part, on DOD's agreement to provide and disseminate specified 
information on these products to military personnel and upon adherence 
to labeling and other prescribed requirements for the use of 
investigational products.
    Concurrent with the agency's request for comments on the interim 
rule, FDA was also evaluating DOD's experience in implementing IND's, 
as well as waivers under the interim rule, during the Gulf War in order 
to obtain specific factual information and to assess DOD's compliance 
with FDA requirements. In the agency's ongoing evaluation of the use of 
investigational products in the Persian Gulf, the agency identified 
significant deviations from Federal regulations published in Title 21, 
Code of Federal Regulations (CFR), parts 50 and 312 (21 CFR parts 50 
and 312). These deviations were set forth in a July 22, 1997, and a 
December 2, 1997, letter from the Lead Deputy Commissioner of the Food 
and Drug Administration to the Acting Deputy Secretary of Defense for 
Health Affairs (Refs. 1 through 3). The noted deviations, and the 
relevant observations that formed the basis for the conclusion that 
deviations had occurred, are summarized in the following paragraphs.
1. Pyridostigmine Bromide
     There was a failure to meet the conditions set by the Commissioner 
for granting a waiver from the informed consent requirements under the 
1990 interim rule for pyridostigmine bromide. FDA's agreement to waive 
the informed consent requirement at the time of the Gulf War was based, 
in large part, on DOD's agreement to provide and disseminate 
information on pyridostigmine to all military personnel. Based on DOD 
statements to FDA as well as FDA's own evaluation, FDA has concluded 
that the information sheet on pyridostigmine was not provided and 
disseminated to military personnel in the Gulf as required by the 
Commissioner's letter granting the waiver under the interim rule. 
Because inadequate information was provided to the soldiers, at least 
some soldiers either took the wrong amount of pyridostigmine or 
disregarded orders to take it completely.
     There was a failure to collect, review, and make reports of 
adverse experiences attributed to the use of pyridostigmine bromide in 
a timely manner. Although the agency waived the requirements of 
Sec. 312.32 in regard to the 3- and 10-day time limits for the 
reporting of adverse experiences, the agency expected DOD to make a 
reasonable effort to collect, review, and make reports of adverse 
clinical consequences attributed to the use of the product in as timely 
a manner as conditions permitted.
     There was a failure to label pyridostigmine bromide with 
investigational labeling as required by FDA regulations. FDA had 
agreed, as requested by DOD, to waive the provisions of Sec. 312.6 in 
order to allow DOD to employ the phrase ``For military use and 
evaluation'' in place of the statement ordinarily mandated for use on 
the immediate package of an investigational drug product, which reads 
``Caution: New Drug--Limited by Federal (or United States) Law to 
Investigational Use''. FDA's waiver of the standard statement was on 
condition that all of the product distributed to service members would 
carry the new ``military use'' labeling. Based on information provided 
to the agency, FDA believes that the pyridostigmine bromide distributed 
to military personnel in the Persian Gulf was not labeled as required 
by the conditions of the waiver.
2. Botulinum Toxoid Vaccine
     There was a failure to ensure that the investigation was conducted 
in accordance with the general investigational plan for the botulinum 
toxoid vaccine during the Gulf War. The protocol for the botulinum 
toxoid vaccine stated that each botulinum toxoid vaccine dose was to be 
recorded in the individual's permanent immunization record. This was 
not done.
     There was also a failure to maintain adequate records showing the 
receipt, shipment, and disposition of the investigational product 
botulinum toxoid vaccine as required by Secs. 312.57 and 312.59.
     On January 8, 1991, FDA granted DOD's request for a waiver of 
informed consent under the interim final rule for use of the botulinum 
toxoid vaccine during the Gulf War. However, following the cessation of 
combat activities DOD advised FDA in a March 15, 1991, letter that the 
military command in the theater of operations in the Persian Gulf 
decided to administer the botulinum toxoid vaccine on ``a voluntary 
basis.'' This letter did not state whether informed consent was 
obtained.
    The military command's decision to allow administration of the 
vaccine on a voluntary basis indicates that the criteria for granting a 
waiver under the interim rule was no longer met; specifically that ``* 
* * preservation of the health of the individual and the safety of 
other personnel require that a particular treatment [botulinum toxoid 
vaccine] be provided to a specified group of military personnel, 
without regard to what might be an individual's personal preference for 
no treatment or for some alternative treatment.'' If the criteria for 
waiver were not met, DOD was required to obtain and document the 
informed consent of military personnel receiving the vaccine in 
accordance with Secs. 50.25 and 50.27. Without signed consent forms to 
document that informed consent was obtained, and based on testimony 
from Persian Gulf War veterans that information on the vaccine was not 
uniformly given to military personnel, the agency has concluded that 
informed consent was not routinely obtained from military personnel who 
received the botulinum toxoid vaccine in accordance with FDA 
regulations.
     Experience with the use of the waiver provision of the 1990 
interim rule suggests two conclusions: (1) To the extent possible, 
military personnel should receive treatments whose safety and 
effectiveness have been fully evaluated; (2) where it is necessary to 
utilize investigational agents and to waive informed consent, new 
standards and criteria for doing so should be developed that will 
better ensure protection of the troops receiving the investigational 
product.

B. Future Use of FDA-Regulated Products by DOD

    FDA has concluded that there are important ways for the agency to 
contribute to DOD's mandate to protect military personnel that are 
consistent with FDA's mission and regulations. FDA's existing 
mechanisms for providing access to investigational products under an 
IND will continue to be available to any entity that complies with the 
agency's specified requirements. Both DOD and FDA recognize, however, 
that some of the IND requirements may not be feasible in certain combat 
situations. Based on the lessons from use of investigational agents 
during the Gulf War, the agency

[[Page 54185]]

believes that DOD's needs can best be met through DOD's support of drug 
development efforts leading to approval of products found to be safe 
and effective.
    FDA shares DOD's goal of getting the best products to military 
personnel. Thus, FDA is committed to working with DOD to resolve the 
safety and effectiveness questions that may allow FDA to approve the 
drug and biological products for use in military operations and during 
military exigencies. In order to provide pharmaceutical agents that are 
safe and effective in protecting military personnel, the agency 
believes that DOD must focus its efforts on drug development. The 
agency notes that under existing regulations it can expedite access to 
new drugs by accelerating approval (subpart H of 21 CFR part 314 and 
subpart E of 21 CFR part 601). In addition, consistent with the recent 
changes to the act on fast track products made in the Food and Drug 
Administration Modernization Act of 1997, FDA is committed to 
facilitating development and expediting the review of drugs for serious 
and life-threatening conditions that address unmet needs (section 506 
of the act (21 U.S.C. 356)). Moreover, FDA is proposing an additional 
mechanism for product approval that is described elsewhere in this 
issue of the Federal Register and that relates to the evidence needed 
to demonstrate safety and efficacy for drug and biological products for 
use against lethal or toxic substances when efficacy studies in humans 
cannot ethically be conducted.
    In order to minimize the need to use investigational products 
during military exigencies, DOD and FDA have formed a working group for 
the purpose of assisting DOD in its drug development efforts related to 
these products. DOD has agreed to identify those products that may 
provide protection to military members, develop appropriate drug 
development plans for each product, and establish a timeframe for 
completion.
     FDA recognizes, however, that in rare instances investigational 
products may need to be used by DOD in deployment situations. The 
enactment of the Defense Authorization Act reflects this fact and calls 
for the implementation of a process that will help ensure that when 
informed consent is waived it will be done under standards and criteria 
that will help protect the troops receiving the investigational 
product. Accordingly, FDA has issued this new interim rule.

 IV. Establishment of New Standards and Criteria

 A. Description of New Interim Rule

     As described earlier, under 10 U.S.C. 1107(f), the President may 
waive the prior consent requirement for the administration of an 
investigational new drug to a member of the armed forces in connection 
with the member's participation in a particular military operation. The 
statute specifies that only the President may waive informed consent 
and that the President may grant such a waiver only if the President 
determines in writing that obtaining consent: Is not feasible, is 
contrary to the best interests of the military member, or is not in the 
interests of national security. The statute further provides that in 
making this determination based on the grounds that it is infeasible or 
contrary to the best interests of the military member, the President 
shall apply the standards and criteria that are set forth in the 
relevant FDA regulations for a waiver of the prior informed consent 
requirements. This interim rule contains those standards and criteria. 
The statute is silent about the standards and criteria that the 
President is to apply in making a determination that obtaining consent 
is not in the interests of national security.
     The Defense Authorization Act authorizes the Secretary of Defense 
to request an informed consent waiver determination from the President. 
The interim rule requires the Secretary of Defense to certify and 
document to the President that the standards and criteria in the 
interim rule have been met.
     Section 50.23(d)(1)(i) through (d)(1)(iv) contain the fundamental 
information necessary to make an informed assessment of risks and 
benefits. Under these paragraphs, the Secretary of Defense must certify 
and document that: (1) The extent and strength of evidence of the 
safety and effectiveness of the investigational new drug in relation to 
the medical risk that could be encountered during the military 
operation supports the drug's administration under an IND; (2) the 
military operation presents a substantial risk that military personnel 
may be subject to a chemical, biological, nuclear, or other exposure 
likely to produce death or serious or life-threatening injury or 
illness; (3) there is no available satisfactory alternative therapeutic 
or preventive treatment in relation to the intended use of the 
investigational new drug; and (4) conditioning use of the 
investigational new drug on the voluntary participation of each member 
could significantly risk the safety and health of any individual member 
who would decline its use, the safety of other military personnel, and 
threaten the accomplishment of the military mission.
     The requirements for IRB review of protocols for military use of 
investigational drugs without informed consent have been strengthened 
and further specified. Following the Gulf War, the agency became aware 
that a military IRB, upon initial review of the proposed use of the 
botulinum toxoid vaccine in anticipation of the Gulf War, had 
recommended that the vaccine be provided with informed consent (Ref. 
4). The proposed use was subsequently reviewed by a different military 
IRB that approved its use without informed consent. It is not clear 
whether the conclusions of the initial IRB were shared with the 
subsequent IRB. In order to ensure adequate and meaningful IRB review, 
Sec. 50.23(d)(1)(v) requires the duly constituted IRB to be responsible 
for the review of the study and requires that the IRB review and 
approve the investigational new drug protocol and the administration of 
the investigational new drug without informed consent as a prerequisite 
for the study to proceed. It also requires DOD's request for a waiver 
to include the documentation of minutes of IRB meetings at which the 
protocol was reviewed. This documentation of minutes is required by 21 
CFR 56.115(a)(2).
     Section 50.23(d)(2) describes additional requirements that pertain 
to this IRB that are not contained in FDA's IRB regulations part 56 (21 
CFR part 56). The IRB must include at least 3 nonaffiliated members who 
are not employees or officers of the Federal Government (other than for 
purposes of membership on the IRB). The quorum required for a convened 
meeting must include a majority of the members including at least one 
member whose primary concerns are in nonscientific areas, and, if 
feasible, a majority of the nonaffiliated members. The minutes of IRB 
meetings at which the protocol is reviewed are to be provided to the 
Secretary of Defense for further review.
     Section 50.23(d)(3) describes additional review requirements that 
pertain to this IRB. For the study to be able to proceed, the IRB must 
review and approve the contents of the required written information 
sheet on the investigational product; the adequacy of the plan to 
disseminate information, including the information sheet and other 
information (e.g., in forms other than written), to potential 
recipients; the adequacy of the information and the plans for its 
dissemination to health care providers, including potential side

[[Page 54186]]

effects, contraindications, potential interactions, and other pertinent 
considerations; and an informed consent form, as required by part 50, 
in those circumstances in which DOD determines that informed consent 
may be obtained from some or all personnel involved. In addition, 
Sec. 50.23(d)(4) requires DOD to submit to FDA summaries of IRB 
meetings at which the proposed protocol has been reviewed.
     In order to help ensure that the President is provided all 
relevant information related to the effects of the investigational 
drug, Sec. 50.23(d)(1)(vi) requires the Secretary of Defense to certify 
and document in his or her request for a waiver determination under 
Sec. 50.23(d)(1) that DOD has explained: (1) The context in which the 
investigational drug will be administered; (2) the nature of the 
disease or condition for which the preventive or therapeutic treatment 
is intended; and (3) to the extent there are existing data or 
information available, information on conditions that could alter the 
effects of the investigational drug.
     In order to help ensure better recordkeeping than occurred during 
the Gulf War, Sec. 50.23(d)(1)(vii), (d)(1)(ix), and (d)(1)(x) require 
the Secretary of Defense to document and certify that DOD's 
recordkeeping system is capable of tracking, and will be used to track 
the proposed treatment from the supplier to the individual recipient; 
that medical records of members involved in the military operation will 
accurately document the receipt by members of the notification required 
by Sec. 50.23(d)(1)(viii) as well as any investigational new drugs in 
accordance with FDA regulations.
     In order to help ensure that each military member is provided 
adequate information on the investigational product, 
Sec. 50.23(d)(1)(viii) requires the Secretary of Defense to document 
and certify that each member involved in the military operation will be 
given, prior to the administration of the investigational new drug, a 
specific written information sheet containing specified information. 
Section 50.23(d)(1)(xiv) requires the Secretary of Defense to document 
and certify that DOD will provide training to the appropriate medical 
personnel and potential recipients on the specific investigational new 
drug to be administered prior to its use.
     In response to comments that DOD must provide adequate followup to 
determine whether there are adverse consequences to the use of 
investigational products, Sec. 50.23(d)(1)(xi) requires the Secretary 
of Defense to document and certify that DOD will provide adequate 
followup to assess whether there are beneficial or adverse health 
consequences that result from the use of the investigational product.
     Because the agency believes that exceptions to the informed 
consent requirement should be made rarely and in narrow circumstances 
and that it is preferable to establish the safety and efficacy of 
products before their general use in large populations, 
Sec. 50.23(d)(1)(xii) requires the Secretary of Defense to certify and 
document that DOD is pursuing drug development for the investigational 
drug (that could be used in a deployment situation), including a time 
line for such development, and marketing approval with due diligence. 
The rule contains two provisions to help ensure that informed consent 
waiver determinations continue to meet the standards and criteria of 
this rule after an initial waiver has been granted by the President. 
Section 50.23(d)(1)(xv) requires the Secretary of Defense to certify 
and document that DOD has stated and justified the time period for 
which the waiver is needed, not to exceed 1 year. For a waiver to 
exceed 1 year, this paragraph requires such a waiver to be separately 
renewed under the standards and criteria contained in Sec. 50.23(d). 
Section 50.23(d)(1)(xvi) places a continuing obligation on DOD to 
report to the FDA and to the President any changed circumstances 
relating to these standards and criteria or that otherwise might affect 
the determination to use an investigational new drug without informed 
consent.
     Section 50.23(d)(1)(xiii) has been included in order to ensure 
that FDA has completed its review of the investigational new drug 
protocol and concluded that it may proceed subject to a decision by the 
President on the informed consent waiver request. FDA will provide a 
written notification to DOD after it has completed its review of the 
investigational new drug protocol. This notification may either grant 
permission for the protocol to proceed subject to the President's 
decision on the informed consent waiver request or it may place the 
study on clinical hold. DOD should not proceed with a protocol under 
this rule until it has received notification from FDA that the protocol 
may proceed. As discussed later in this document, the agency has 
adopted a change in part 312 to help ensure that the IND review process 
is efficiently applied to the use of investigational products under 
this rule.
     In response to a number of comments, discussed previously, that 
encouraged public access to information about products for which an 
informed consent waiver is granted, the agency has included 
Sec. 50.23(d)(1)(xvii) in the rule. This paragraph requires DOD to 
provide public notice as soon as practicable and consistent with 
classification requirements through notice in the Federal Register 
describing each waiver of informed consent determination, a summary of 
the most updated scientific information on the products used, and other 
pertinent information.
     Finally, in order to help ensure that DOD adheres to applicable 
statutes and laws, Sec. 50.23(d)(1)(xviii) requires the Secretary of 
Defense to document and certify that the use of the investigational 
drug without informed consent otherwise conforms with applicable law. 
Section 50.23(d)(5) states that ``[n]othing in these criteria or 
standards is intended to preempt or limit FDA's and DOD's authority or 
obligations under applicable statutes and regulations.''

 B. Description of Conforming Amendments

     This interim rule necessitates a change to the regulations for 
human drugs so that those regulations are consistent with this rule. 
The agency is amending Sec. 312.42 to explicitly state that an 
investigation may be placed on clinical hold pending a determination by 
the President to waive the prior consent requirement for the 
administration of an investigational new drug. If the agency invokes 
this reason for a clinical hold, it will mean that the agency has 
completed its review of the protocol and has concluded that the study 
may proceed; however, subjects may not be enrolled in the study until a 
positive decision on the informed consent waiver request has been made 
by the President and FDA has provided written notification to DOD that 
the clinical hold has been removed.

V. Request for Comments

    Interested persons may, on or before December 20, 1999, submit to 
the Dockets Management Branch (address above) written comments 
regarding this rule. 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.
     FDA is revoking the December 21, 1990, interim rule and issuing a 
new interim rule in its place effective on date of publication in the 
Federal Register. FDA is proceeding without notice and comment 
rulemaking because of the

[[Page 54187]]

significant need to have regulations in place that are consistent with 
recently enacted legislation addressing waiver of informed consent in 
military operations and that provide adequate standards and criteria 
for such waiver determinations. As described in more detail in the 
following paragraphs, FDA finds, in accordance with section 553(b) of 
the Administrative Procedure Act, that it would be impracticable and 
contrary to the public interest to provide for notice and comment prior 
to the revocation of the December 1990 rule and the issuance of the new 
interim rule.
     The statutory provision in the Defense Authorization Act that 
vests authority for waiver decisions in the President overrides the 
1990 rule vesting authority for such waiver decisions in the 
Commissioner. Thus, it invalidates those parts of the 1990 regulation 
that are inconsistent with the Defense Authorization Act. The new 
interim rule corrects this inconsistency by acknowledging the existence 
of the Defense Authorization Act and its grant of waiver authority to 
the President. To require notice and comment to make this correction is 
unnecessary in that the new rule codifies in regulation a clear 
statutory mandate.
     Since the issuance of the 1990 interim rule, there has been 
extensive public discussion regarding the rule on numerous occasions 
(see discussion in section II of this document). After considering all 
the relevant facts, including the comments received on the July 1997 
request for comments, and FDA's evaluation of DOD's experience during 
the Persian Gulf War in implementing the 1990 rule, FDA has concluded 
that the rule did not work as intended. In light of the enactment of 
the Defense Authorization Act, with an immediate effective date and 
because the President could be called upon to make a waiver 
determination for military personnel engaged in a specific military 
operation at any time, the agency believes that it is critical to have 
in place adequate criteria and standards for the President to apply in 
making an informed consent waiver determination. Modifying the 1990 
rule to conform to the statute, without adding the additional 
protections provided in this new rule is contrary to the public 
interest because it would leave in place, during the comment period, 
procedures now considered insufficient. As discussed previously, FDA 
has developed new strengthened criteria and standards that the 
President can use in making informed consent waiver determinations. 
Accordingly, the agency believes it is in the public interest to have 
these new criteria and standards in place while, at the same time, it 
solicits public comment.
     It is, therefore, in the public interest, to establish quickly, 
through this new interim final rule, stringent criteria and standards 
for the President's application. Following the comment period, the 
agency intends promptly to publish a final rule.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Executive Order 12612: Federalism

    Executive Order 12612 requires Federal agencies to carefully 
examine regulatory actions to determine if they would have a 
significant effect on federalism. Using the criteria and principles set 
forth in the order, FDA has considered the impact of the interim rule 
on the States, on their relationship with the Federal Government, and 
on the distribution of power and responsibilities among the various 
levels of Government. FDA concludes that this rule is consistent with 
the principles set forth in Executive Order 12612.
    Executive Order 12612 states that agencies formulating and 
implementing policies are to be guided by certain federalism 
principles. Section 2 of Executive Order 12612 enumerates fundamental 
federalism principles. Section 3 of Executive Order 12612 states that, 
in addition to these fundamental principles, executive departments and 
agencies shall adhere, to the extent permitted by law, to certain 
listed criteria when formulating and implementing policies that have 
federalism implications. Section 4 of Executive Order 12612 lists 
special requirements for preemption.
    Section 4 of Executive Order 12612 states that an executive 
department or agency foreseeing the possibility of a conflict between 
State law and federally protected interests within its area of 
regulatory responsibility is to consult with States in an effort to 
avoid such conflict. Section 4 of Executive Order 12612 also states 
that an executive department or agency proposing to act through 
rulemaking to preempt State law is to provide all affected States 
notice and opportunity for appropriate participation in the 
proceedings. As required by the Executive Order in section 4(d) and 
(e), States have, through this notice of proposed rulemaking, an 
opportunity to raise the possibility of conflicts and to participate in 
the proceedings. Consistent with Executive Order 12612, FDA requests 
information and comments from interested parties, including but not 
limited to State and local authorities, on these issues of federalism.

VIII. Analysis of Impacts

    FDA has examined the impacts of the rule under Executive Order 
12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). If a rule would have a 
significant economic impact on a substantial number of small entities, 
the Regulatory Flexibility Act requires agencies to analyze regulatory 
options that would minimize these impacts. Title II of the Unfunded 
Mandates Reform Act (Public Law 104-4) (in section 202) requires that 
agencies prepare an assessment of anticipated costs and benefits before 
proposing any rule that may result in an expenditure in any 1 year by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100 million or more (adjusted annually for 
inflation).
     The agency believes that the revised rule is consistent with the 
regulatory philosophy and principles identified in the Executive Order 
and in these two statutes. The agency has determined that this rule is 
a ``significant regulatory action'' as defined in section 3(f)(4) of 
Executive Order 12866 because it raises novel policy issues. To the 
extent that any of the standards and criteria entail costs to the DOD, 
these standards and obligations are already assumed by DOD; they are 
enunciated here to stress their importance to safeguarding the health 
and welfare of military personnel to minimize the need to use this 
rule. With respect to the Regulatory Flexibility Act (5 U.S.C. 605(b)), 
any economic cost of the rule would be incurred only by DOD, which is 
not a small entity. Therefore, the agency certifies that the rule will 
not have significant economic impact on a substantial number of small 
entities. Under the Regulatory Flexibility Act, therefore, no further 
analysis is required. Similarly, because the rule does not impose any 
mandates on State, local, or tribal governments, or the private sector 
that will result in a 1-year expenditure of $100 million or more,

[[Page 54188]]

FDA is not required to perform a cost-benefit analysis under the 
Unfunded Mandates Reform Act.

IX. Paperwork

    This interim final rule contains no collections of information 
subject to the Paperwork Reduction Act of 1995.

X. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Letter from the Lead Deputy Commissioner, FDA, to the Acting 
Deputy Secretary of Defense for Health Affairs, July 22, 1997.
    2. Letter from the Army Surgeon General to the Lead Deputy 
Commissioner, FDA, responding to the July 22, 1997, letter, October 
23, 1997.
    3. Letter from the Lead Deputy Commissioner, FDA, to the Acting 
Deputy Secretary of Defense for Health Affairs, December 22, 1997.
    4. Memorandum for record, minutes of the October 4, 1990, 
ninety-third meeting of the U.S. Army Medical Research Institute of 
Infectious Diseases Human Use Committee, October 5, 1990.

 List of Subjects

 21 CFR Part 50

    Human research subjects, Prisoners, Reporting and recordkeeping 
requirements, Safety.

 21 CFR Part 312

     Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
50 and 312 are amended as follows:

PART 50--PROTECTION OF HUMAN SUBJECTS

    1. The authority citation for 21 CFR part 50 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 360, 
360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 241, 262, 263b-
263n.

    2. Section 50.23 is amended by revising paragraph (d) to read as 
follows:


Sec. 50.23   Exception from general requirements.

* * * * *
     (d)(1) Under 10 U.S.C. 1107(f) the President may waive the prior 
consent requirement for the administration of an investigational new 
drug to a member of the armed forces in connection with the member's 
participation in a particular military operation. The statute specifies 
that only the President may waive informed consent in this connection 
and the President may grant such a waiver only if the President 
determines in writing that obtaining consent: Is not feasible; is 
contrary to the best interests of the military member; or is not in the 
interests of national security. The statute further provides that in 
making a determination to waive prior informed consent on the ground 
that it is not feasible or the ground that it is contrary to the best 
interests of the military members involved, the President shall apply 
the standards and criteria that are set forth in the relevant FDA 
regulations for a waiver of the prior informed consent requirements of 
section 505(i)(4) of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 355(i)(4)). Before such a determination may be made that 
obtaining informed consent from military personnel prior to the use of 
an investigational drug (including an antibiotic or biological product) 
in a specific protocol under an investigational new drug application 
(IND) sponsored by the Department of Defense (DOD) and limited to 
specific military personnel involved in a particular military operation 
is not feasible or is contrary to the best interests of the military 
members involved the Secretary of Defense must first request such a 
determination from the President, and certify and document to the 
President that the following standards and criteria contained in 
paragraphs (d)(1) through (d)(4) of this section have been met.
     (i) The extent and strength of evidence of the safety and 
effectiveness of the investigational new drug in relation to the 
medical risk that could be encountered during the military operation 
supports the drug's administration under an IND.
     (ii) The military operation presents a substantial risk that 
military personnel may be subject to a chemical, biological, nuclear, 
or other exposure likely to produce death or serious or life-
threatening injury or illness.
     (iii) There is no available satisfactory alternative therapeutic 
or preventive treatment in relation to the intended use of the 
investigational new drug.
     (iv) Conditioning use of the investigational new drug on the 
voluntary participation of each member could significantly risk the 
safety and health of any individual member who would decline its use, 
the safety of other military personnel, and the accomplishment of the 
military mission.
     (v) A duly constituted institutional review board (IRB) 
established and operated in accordance with the requirements of 
paragraphs (d)(2) and (d)(3) of this section, responsible for review of 
the study, has reviewed and approved the investigational new drug 
protocol and the administration of the investigational new drug without 
informed consent. DOD's request is to include the documentation 
required by Sec. 56.115(a)(2) of this chapter.
     (vi) DOD has explained:
     (A) The context in which the investigational drug will be 
administered, e.g., the setting or whether it will be self-administered 
or it will be administered by a health professional;
     (B) The nature of the disease or condition for which the 
preventive or therapeutic treatment is intended; and
     (C) To the extent there are existing data or information 
available, information on conditions that could alter the effects of 
the investigational drug.
     (vii) DOD's recordkeeping system is capable of tracking and will 
be used to track the proposed treatment from supplier to the individual 
recipient.
     (viii) Each member involved in the military operation will be 
given, prior to the administration of the investigational new drug, a 
specific written information sheet (including information required by 
10 U.S.C. 1107(d)) concerning the investigational new drug, the risks 
and benefits of its use, potential side effects, and other pertinent 
information about the appropriate use of the product.
     (ix) Medical records of members involved in the military operation 
will accurately document the receipt by members of the notification 
required by paragraph (d)(1)(viii) of this section.
     (x) Medical records of members involved in the military operation 
will accurately document the receipt by members of any investigational 
new drugs in accordance with FDA regulations including part 312 of this 
chapter.
     (xi) DOD will provide adequate followup to assess whether there 
are beneficial or adverse health consequences that result from the use 
of the investigational product.
     (xii) DOD is pursuing drug development, including a time line, and 
marketing approval with due diligence.
     (xiii) FDA has concluded that the investigational new drug 
protocol may proceed subject to a decision by the President on the 
informed consent waiver request.
     (xiv) DOD will provide training to the appropriate medical 
personnel and potential recipients on the specific

[[Page 54189]]

investigational new drug to be administered prior to its use.
     (xv) DOD has stated and justified the time period for which the 
waiver is needed, not to exceed one year, unless separately renewed 
under these standards and criteria.
     (xvi) DOD shall have a continuing obligation to report to the FDA 
and to the President any changed circumstances relating to these 
standards and criteria (including the time period referred to in 
paragraph (d)(1)(xv) of this section) or that otherwise might affect 
the determination to use an investigational new drug without informed 
consent.
     (xvii) DOD is to provide public notice as soon as practicable and 
consistent with classification requirements through notice in the 
Federal Register describing each waiver of informed consent 
determination, a summary of the most updated scientific information on 
the products used, and other pertinent information.
     (xviii) Use of the investigational drug without informed consent 
otherwise conforms with applicable law.
     (2) The duly constituted institutional review board, described in 
paragraph (d)(1)(v) of this section, must include at least 3 
nonaffiliated members who shall not be employees or officers of the 
Federal Government (other than for purposes of membership on the IRB) 
and shall be required to obtain any necessary security clearances. This 
IRB shall review the proposed IND protocol at a convened meeting at 
which a majority of the members are present including at least one 
member whose primary concerns are in nonscientific areas and, if 
feasible, including a majority of the nonaffiliated members. The 
information required by Sec. 56.115(a)(2) of this chapter is to be 
provided to the Secretary of Defense for further review.
     (3) The duly constituted institutional review board, described in 
paragraph (d)(1)(v) of this section, must review and approve:
     (i) The required information sheet;
     (ii) The adequacy of the plan to disseminate information, 
including distribution of the information sheet to potential 
recipients, on the investigational product (e.g., in forms other than 
written);
     (iii) The adequacy of the information and plans for its 
dissemination to health care providers, including potential side 
effects, contraindications, potential interactions, and other pertinent 
considerations; and
     (iv) An informed consent form as required by part 50 of this 
chapter, in those circumstances in which DOD determines that informed 
consent may be obtained from some or all personnel involved.
     (4) DOD is to submit to FDA summaries of institutional review 
board meetings at which the proposed protocol has been reviewed.
     (5) Nothing in these criteria or standards is intended to preempt 
or limit FDA's and DOD's authority or obligations under applicable 
statutes and regulations.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    3. The authority citation for 21 CFR part 312 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42 
U.S.C. 262.

    4. Section 312.42 is amended by adding paragraph (b)(6) to read as 
follows:


Sec. 312.42   Clinical holds and requests for modification.

* * * * *
     (b) * * *
     (6) Clinical hold of any investigation involving an exception from 
informed consent under Sec. 50.23(d) of this chapter. FDA may place a 
proposed or ongoing investigation involving an exception from informed 
consent under Sec. 50.23(d) of this chapter on clinical hold if it is 
determined that:
     (i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this 
section apply; or
     (ii) A determination by the President to waive the prior consent 
requirement for the administration of an investigational new drug has 
not been made.
* * * * *

    Dated: May 25, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-25376 Filed 10-4-99; 8:45 am]
BILLING CODE 4160-01-F