Mr. Chairman and Members of the Committee, I am Dr. William Raub, Deputy Assistant
Secretary for Science Policy at the Department of Health and Human Services (DHHS). I am
pleased to be here today to discuss Federal policies governing the administration of
investigational new drugs to U.S. military personnel, including the safeguards and
protections recently announced in the Executive
Order 13139 issued by the President and
the interim rule on waiver of informed consent issued by the Food and Drug Administration
(FDA or the Agency). The issuance of these documents represents a long, cooperative,
interagency effort aimed at providing the best protection possible for military personnel
needing investigational drugs during particular military operations.
DHHS was a party to this cooperative effort and believes that the resulting criteria take
into account the protection of individual military personnel while accommodating the
national security interests that arise during the conduct of military operations.
Protection of individuals receiving health care services, including those receiving
investigational new drugs, is an issue of paramount concern to DHHS. This stance is
reflected in the positions taken by DHHS concerning the Patient Bill of Rights, medical
data privacy, the allocation of human organs for transplantation and many other issues
involving the provision of medical care to individuals. This is particularly
appropriate in the use of investigational products. There may not be any FDA
approved medical products to treat or prevent certain diseases or conditions. The
lack of approved products becomes particularly critical in the context of military
operations when investigational products may constitute the best treatment for a
particular disease or exposure to a chemical or biological warfare agent. DHHS
believes, however, that exceptions from informed consent should apply rarely and only when
sufficient additional protections are provided to the military personnel affected.
We believe that the new interim rule and the Executive
Order provide those protections.
ESTABLISHMENT OF NEW STANDARDS AND CRITERIA UNDER THE 1999 INTERIM RULE
On October 5, 1999, FDA published in the Federal Register a new interim rule
that contains new strengthened criteria and standards the President can use in making
informed consent waiver determinations. Among other things, 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 providing full
information on the product. It also requires the Department of Defense (DOD) to provide,
consistent with classification requirements, public notice in the Federal Register
describing the waiver of informed consent determination, a summary of the most updated
scientific information on the products used, as well as other pertinent information. The
interim rule also 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.
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 if it is determined 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. If a determination is based on the grounds that
it is infeasible or contrary to the best interests of the military member, the President
must apply the standards and criteria that are set forth in the relevant FDA regulations
for a waiver of the prior informed consent requirements. Executive
Order 13139 also
specifies that the President will consider the standards and criteria even under grounds
of national security. This new interim rule contains those standards and criteria.
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) contains the fundamental information necessary to make
an informed assessment of risks and benefits within the context of the specific military
situation. Under these paragraphs, the Secretary of Defense must certify and document
- 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 investigational new
drug application (IND);
- 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;
- there is no available satisfactory alternative therapeutic or preventive treatment in
relation to the intended use of the investigational new drug; and
- 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.
In order to help ensure that the President is provided all relevant information related
to the effects of the investigational drug, the rule requires the Secretary of Defense to
certify and document in his or her request for a waiver determination that DOD has
- the context in which the investigational drug will be administered;
- the nature of the disease or condition for which the preventive or therapeutic treatment
is intended; and
- to the extent it is available, information on conditions that could alter the effects of
the investigational drug (21 CFR 50.23(d)(1)(vi)).
In order to improve record-keeping over that which occurred during the Gulf War, the
Secretary of Defense is required to document and certify that DOD's record-keeping system
is capable of tracking, and will be used to track, the proposed treatment from the
supplier to the individual recipient; and, that medical records of members involved in the
military operation will accurately document the receipt by members of the notification
required by Section 50.23(d)(1)(viii) as well as any investigational new drugs in
accordance with FDA regulations (21 CFR 50.23(d)(1)(vii), (d)(1)(ix), and (d)(1)(x)).
As noted earlier, the rule 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 written information sheet describing 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 (21 CFR
50.23(d)(1)(viii)). In addition, 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, 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 Secretary of Defense must 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 (21 CFR 50.23(d)(1)(xiv)). DOD must also
document and certify that DOD will provide adequate follow-up to assess whether there are
beneficial or adverse health consequences that result from the use of the investigational
product (21 CFR 50.23(d)(1)(xi)).
The requirements for Institutional Review Board (IRB) review of protocols for military
use of investigational drugs without informed consent have been strengthened and further
specified beyond those required for conventional INDs. The provisions of the interim rule
include the following:
- The duly constituted IRB is to be responsible for reviewing the study. It must 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 (21 CFR 50.23(d)(1)(v)).
- DOD's request for a waiver must include the documentation of minutes of IRB meetings at
which the protocol was reviewed (21 CFR 56.115(a)(2)).
- The IRB must include at least three nonaffiliated members who are not employees or
officers of the Federal Government (other than for purposes of membership on the IRB)
- 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; the
adequacy of the information and the plans for its dissemination to health care providers;
and an informed consent form in those circumstances in which DOD determines that informed
consent may be obtained from some or all personnel involved (Section 50.23(d)(3)).
The rule provides for FDA to complete its review of the investigational new drug
protocol and conclude that it may proceed subject to a decision by the President on the
informed consent waiver request (Section 50.23(d)(1)(xiii)). FDA will provide a written
notification to DOD after it has completed its review, either granting permission for the
protocol to proceed subject to the President's decision on the informed consent waiver
request or, if appropriate, placing the study on clinical hold.
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 one year. For a waiver to exceed one year, this
paragraph requires such a waiver to be separately renewed under the standards and criteria
contained in 21 CFR 50.23(d). Section 50.23(d)(1)(xvi) places a continuing obligation on
DOD to report to 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.
To encourage public access to information about products for which an informed consent
waiver is granted, Section 50.23(d)(1)(xvii) 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,
Section 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."
As noted above, DHHS 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. The new
rule, 21 CFR 50.23(d)(1)(xii), therefore requires the Secretary of Defense to certify and
document that it is pursuing drug development and marketing approval for the
investigational drug with due diligence.
ANTECEDENTS TO THE Executive
ORDER AND INTERIM RULE
As noted above, the interim rule was the result of much effort and took into account
the interests of all affected parties. It is important to understand the background of the
rule and the actions leading up to its promulgation.
The use of investigational drugs is regulated by provisions of the Food, Drug and
Cosmetic (FD&C) Act. In order for clinical testing to proceed with unapproved
products, an IND application must be filed with FDA. The IND must contain
information sufficient to demonstrate that it is reasonable to study the drug in humans,
including information on drug composition, manufacturing and control data, the results of
animal studies and, if available, prior human testing, and the protocol for the planned
study. More importantly, the investigator must agree to a number of commitments
designed to protect the rights and safety of human research subjects, including obtaining
written informed consent from subjects, obtaining
approval of an IRB before proceeding, and reporting to the sponsor of the study adverse
effects that occur in research subjects. An IRB is a board or Committee that
reviews, approves and provides continuing oversight of biomedical research involving human
subjects to ensure the right and welfare of the human subjects. (21 CFR Part 56).
Under the FD&C Act, sponsors must require investigators to certify that they will
inform subjects receiving drugs under an IND that the drugs are investigational and
"obtain the consent of such human beings or their representatives,
except where they deem it not feasible, or in their professional judgment, contrary to the
best interests of such human beings" (21 USC ?
505). There have been few instances in which obtaining informed consent has not been considered feasible or contrary to patients' interests.
There are three limited exceptions to FDA's informed consent requirements. These
exceptions are: 1) for a physician to preserve the life of an individual patient; 2) for
the conduct of a narrow class of research in emergency settings; and 3) for use by DOD of
specific investigational products in military operations. FDA regulations governing all
three of these informed consent exceptions are primarily focused on protecting the rights
and safety of patients. The third exception to our informed consent requirements, the use
of an investigational drug or biologic in certain situations related to military
exigencies is the focus of this hearing.
During the months preceding the Persian Gulf War, DOD had discussions with FDA
regarding the potential use of specific investigational products in military personnel
serving in the Gulf region. It was thought that the products discussed represented the
best preventive or therapeutic treatment for diseases endemic to the area and in providing
protection against the possible use of chemical or biological weapons.
Thus, in response to DOD's request, FDA published in the December 21, 1990, Federal
Register (55 FR 52813) an interim regulation amending its informed consent regulations at 21 CFR 50.23(d). The interim regulation allowed Commissioner of Food and Drugs to determine, upon receipt of an appropriate request from DOD, that obtaining informed consent from military personnel for use of a specific investigational drug or biologic would not be feasible in certain circumstances, and to grant a waiver from the requirement for obtaining such consent.
On December 28, 1990, DOD submitted protocols under INDs and requests for waiver of informed consent for pyridostigmine bromide 30-milligram (mg) tablets and the botulinum toxoid vaccine. Pyridostigmine bromide was considered a potentially useful pretreatment against certain nerve gases; the botulinum toxoid vaccine is widely accepted
as offering potential protection against toxins produced by Clostridium botulinum, the
bacterium that causes botulism. The Commissioner approved DOD's waiver requests for
pyridostigmine bromide 30-mg tablets and botulinum toxoid vaccine on December 31, 1990,
and January 8, 1991, respectively. Both products were administered to portions of the
military personnel who participated in Operation Desert Storm. Following the cessation of
combat activities, the DOD notified the Commissioner in a letter dated March 15, 1991,
that DOD considered the two waivers granted under the interim rule to be no longer in
effect. DOD also informed the Commissioner that DOD had ultimately
decided to administer the botulinum toxoid vaccine on a voluntary basis.
There has been extensive examination of the use of the 1990 interim rule during the
Persian Gulf War. The Presidential Advisory Committee on Gulf War Veterans'
Illnesses' final report reviewed these issues in detail. In its interim report
(February 1996), the Committee described a number of shortcomings in DOD's use of
investigational products during the Gulf War and recommended, among other things, that FDA
should issue a Notice of Proposed Rulemaking to revisit the adequacy of disclosure to
service personnel; adequacy of record-keeping; long term follow-up of individuals who
receive investigational products; and additional procedures to enhance understanding,
oversight, and accountability. The report further suggested that FDA should explore
possible alternatives to the 1990 interim final rule, such as an approval standard that
recognizes surrogate endpoints and other data indicative of efficacy for vaccines, drugs,
devices, and antibiotics to protect against chemical and biological warfare agents.
DOD's experience during the Gulf War with pyridostigmine bromide and the botulinum
toxoid vaccine was described in detail in the request for comments on the 1990 interim
rule. Concurrent with the request for comments on the interim rule, FDA was also
evaluating DOD's experience in implementing INDs, 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 ongoing evaluation of the use of
investigational products in the Persian Gulf, significant deviations were identified from
Federal regulations. These deviations were set forth in July 22, 1997, and December 2,
1997, letters from FDA to DOD.
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.
In the July 31, 1997, Federal Register (62 FR 40996), FDA published a
"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.
The public comments received 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 follow-up to assess whether there are
adverse health consequences that result from the use of the investigational product;
adequate oversight, accountability, and record-keeping 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.
The new interim rule also necessitates a change to the regulations for human drugs so
that those regulations are consistent with this rule. In the interim rule, 21 CFR 312.42
is amended 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 FDA invokes this reason for a clinical
hold, it will mean that review of the protocol is completed and FDA 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.
Section 731 of the Defense Authorization Act
Public Law 105-261, the Strom Thurmond National Defense Authorization Act for Fiscal
Year 1999 (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 President is established as the sole authority for making such a waiver of
informed consent determination. FDA will be involved in this process through its
traditional role of reviewing specific protocols under its investigational new drug
regulations. The Commissioner of Food and Drugs will also play a key role in reviewing the
waiver of informed consent request to the President.
Section 731 of the Defense Authorization Act, amending 10 U.S.C. 1107(f), became
effective on October 17, 1998. Under new 10 U.S.C. 1107(f), the Commissioner of Food and
Drugs no longer has the authority to issue a waiver of informed consent with respect to
military operations. Section 1107(f)(1) of Title 10 provides for the President to grant
such a 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 FD&C Act (21 U.S.C. 355(i)). Section 1107(f)(2)
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.
FDA's October 5, 1999, interim rulemaking coincided with the publication of Executive
Order 13139, entitled "Improving Health Protection of Military Personnel
Participating in Particular Military Operations" and implementing Section 1107 of
Order explicitly states the expectation that the United States
will administer products approved for their intended use by FDA. In the event that the
Secretary of Defense considers an investigational product to represent the most
appropriate countermeasure for diseases endemic to the area of operations or to protect
against possible chemical, biological, or radiological weapons, the product may, under
certain circumstances and strict controls, be administered to provide potential protection
for the health and well-being of deployed military personnel in order to ensure the
success of the military operation.
Under the Executive
Order, the Secretary of Defense shall develop the waiver request in
consultation with FDA. The Commissioner of FDA shall expeditiously review the waiver
request and certify whether the standards and criteria of the relevant regulations have
been adequately addressed and whether the investigational new drug protocol may proceed
subject to a decision by the President on the informed consent waiver request. FDA shall
base its decision on, and the certification shall include an analysis describing, the
extent and strength of the evidence on the safety and effectiveness of the investigational
new drug in relation to the medical risk that could be encountered during the military
operation. Finally the Executive
Order establishes FDA review of training and health risk
FUTURE USE OF FDA-REGULATED PRODUCTS BY DOD
There are important ways that FDA can contribute to DOD's mandate to protect military
personnel that are consistent with FDA's mission and regulations and also mesh with DHHS's
initiatives on bioterrorism and commitment to human subject protection. 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 military situations. Based on the lessons from use of investigational agents
during the Gulf War, DHHS 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. We share DOD's goal of getting the best products to military personnel. Thus,
we are 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, FDA believes that DOD must focus its efforts on drug development.
Under existing regulations FDA 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 FD&C Act on fast track products made in the Food and
Drug Administration Modernization Act of 1997 (FDAMA), FDA is committed to facilitating
development and expediting the review of drugs for serious and life-threatening conditions
that address unmet needs (§ 506, FDAMA (21 U.S.C. 356)).
Moreover, FDA has proposed an additional mechanism for product approval 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. FDA is proposing to amend its new drug and biological product
regulations to identify the information needed to provide substantial evidence of the
efficacy of new drug and biological products used to reduce or prevent the toxicity of
chemical, biological, radiological, or nuclear substances. This proposal would apply when
the traditional efficacy studies in humans are not feasible and cannot be ethically
conducted under FDA's regulations for adequate and well-controlled studies in humans. We
recognize the need for adequate medical responses to protect or treat individuals exposed
to these lethal or permanently disabling toxic substances.
In these situations, certain new drug and biological products that are intended to
reduce or prevent serious or life-threatening conditions could be approved for marketing
based on evidence of effectiveness derived from appropriate studies in animals, without
adequate and well-controlled efficacy studies in humans (21 CFR 314.126). Under the
proposed rule, FDA could rely on the evidence from animal studies where:
- There is a reasonably well understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention by the product;
- the effect is independently substantiated in multiple animal species, including species expected to react with a response predictive for humans;
- the animal study endpoint is clearly related to the desired benefit in humans, generally, the enhancement of survival or prevention of major morbidity; and;
- the data or information on the kinetics and pharmacodynamics of the product or other
relevant data or information in animals and humans allows selection of an effective dose
in humans, and it is therefore reasonable to expect the effect of the product in animals
to be a reliable indicator of its efficacy in humans.
In order to minimize the need to use investigational products during military
exigencies, FDA has been working with 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.
Mr. Chairman, we hope the information presented here is useful to the Committee in
examining the difficult issues surrounding the use of investigational drug products by the
armed forces. DHHS has learned an enormous amount through our experience with the waiver
of informed consent during the Persian Gulf War, and we are putting those lessons to work
as we prepare for future exigencies. Thank you.