[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]]
_______________________________________________________________________
Part V
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
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.
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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
