[Federal Register Volume 64, Number 192 (Tuesday, October 5, 1999)]
[Proposed Rules]
[Pages 53960-53970]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-25377]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 601

RIN 0910-AA89
[Docket No. 98N-0237]


New Drug and Biological Drug Products; Evidence Needed to 
Demonstrate Efficacy of New Drugs for Use Against Lethal or Permanently 
Disabling Toxic Substances When Efficacy Studies in Humans Ethically 
Cannot Be Conducted

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (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

[[Page 53961]]

conducted under FDA's regulations for adequate and well-controlled 
studies in humans. The agency is proposing this action because it 
recognizes the need for adequate medical responses to protect or treat 
individuals exposed to these lethal or permanently disabling toxic 
substances.
DATES: 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. Submit written comments on the information 
collection requirements to the Office of Information and Regulatory 
Affairs, Office of Management and Budget (OMB), New Executive Office 
Bldg., 725 17th St., NW., rm. 10235, Washington, DC 20503, Attn: Desk 
Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Bonnie M. Lee, Division of Compliance 
Policy, Office of Enforcement, Office of Regulatory Affairs (HFC-230), 
Food and Drug Administration, Rockville, MD 20852, 301-827-0415.

SUPPLEMENTARY INFORMATION: 

I. Introduction

    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 when adequate and well-controlled efficacy 
studies in humans cannot be ethically conducted because they would 
involve administering a potentially lethal or permanently disabling 
toxic substance or organism to healthy human volunteers without a 
proven treatment and field trials (assessment of use of the product 
after accidental or hostile exposure to the substance) are not 
feasible. The agency is proposing that, 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: (1) 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; (2) the effect is 
independently substantiated in multiple animal species, including 
species expected to react with a response predictive for humans; (3) 
the animal study endpoint is clearly related to the desired benefit in 
humans, which is generally the enhancement of survival or prevention of 
major morbidity; and (4) 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. It is 
also expected that the data or information on the kinetics and 
pharmacodynamics of the drug or biological product will be sufficiently 
well understood in both animals and humans or there will be some other 
relevant data or information in animals and humans to allow selection 
of an effective dose in humans.
    Safety evaluation is not discussed in this proposal because the 
agency believes that, with one limitation, the safety of these products 
can be studied in human volunteers similar to the people who would be 
exposed to the product. The limitation is the inability to examine 
possible adverse interactions between the toxic substance and the new 
product. Safety and efficacy of a product are ordinarily studied 
together in the patient population at risk or with the condition to be 
treated. An interaction of the pharmacologic effects of the two should 
emerge in the animal studies of efficacy but certain kinds of effects 
are not easily detected in animals (e.g., effects on memory or 
cognitive function). Possible interactions between the product and 
underlying disease or another substance to which the user might be 
concomitantly exposed can be evaluated by studying safety in a 
population similar to the ultimate user population and under conditions 
approximating those in which the drug will be used. In section VII of 
this document, the agency seeks comments on the safety evaluation of 
these products.
    This proposal will not apply if product approval can be based on 
standards described elsewhere in FDA's regulations (e.g., accelerated 
approval based on human surrogate markers or clinical endpoints other 
than survival or irreversible morbidity).

II. Background

    In the Federal Register of July 31, 1997 (62 FR 40996), FDA 
published a document entitled ``Request for Comments'' (hereinafter 
referred to as the July 1997 request for comments) related to the use 
of drugs and biological products in military and other emergency 
settings to treat or prevent toxicity of chemical or biological 
substances. The July 1997 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 the Federal 
Register of December 21, 1990 (55 FR 52814), FDA issued an interim rule 
(``Informed Consent for Human Drugs and Biologics; Determination that 
Informed Consent is Not Feasible'') allowing the Commissioner of Food 
and Drugs (the Commissioner) to make the determination, in response to 
product specific requests from the Department of Defense (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 (62 FR 40996).
    Elsewhere in this Federal Register, consistent with the Defense 
Authorization Act of 1998, FDA has published an interim final rule 
revoking the 1990 interim final rule and establishing new criteria and 
standards for the President of the United States to apply in making a 
determination that informed consent is not feasible or is contrary to 
the best interests of the individual recipients. That document 
addresses the first issue. This notice addresses the second and third 
issues.

[[Page 53962]]

A. When Is It 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?

    In response to the July 1997 request for comments, FDA received 
nine comments on this question.
    Two comments stated that it is never ethical to expose volunteers 
to toxic chemicals or biological substances to test the efficacy of 
products that may be used to provide potential protection against those 
substances.
    Another comment, which appeared to conclude that human trials could 
perhaps be carried out in some cases, stressed that a ``volunteer'', by 
definition, must be fully aware of any harm that he or she may incur as 
a result of participation in such a study. All information regarding 
exposures must be relayed to the volunteer, and the volunteer should 
confirm that he or she accepts those risks. If data from animal testing 
are supplied, the volunteer must also be fully aware that the data may 
not be relevant to how a human may respond. This comment concluded that 
``[a]nimal testing, an abhorrent practice, often puts human health in 
peril via misleading data.'' The comment also suggested that the 
developers of these drugs, if they are confident that they are both 
safe and effective, should offer themselves for final testing of safety 
and efficacy. This comment also stated that it seemed more ethical to 
attempt antidote experiments on ``victims of such poisonings in regions 
where such abhorrent `weapons' are used to create morbidities'' rather 
than deliberately exposing any healthy individuals to such poisons for 
the purpose of testing antidotes, and concluded the comment with the 
suggestion that in vitro or computer-model testing would be preferable 
to human antidote testing unless one could ensure fully informed 
consent from a nonvulnerable population.
    A fourth comment stated that it is not ethical to conduct clinical 
testing with toxic chemical or biological substances unless there is 
certainty that their effects are fully reversible. Because it is not 
scientifically possible to prove that substances are completely safe 
and their effects fully reversible, such studies are not possible.
    Two comments did not appear to think such testing was impossible, 
but they pointed to significant difficulties. The comments noted that 
testing the efficacy of any product is never ethical unless the 
subjects truly volunteer with full informed consent. The comments 
suggested that one way to ensure voluntariness and informed consent 
would be to require that DOD and the Veterans Administration (VA) 
recruit only non-DOD and non-VA volunteers who are not otherwise 
``beholden'' to these agencies for their employment or pensions. The 
comments note that given the risks, it would be highly unlikely that 
anyone would volunteer, and, therefore, efficacy testing may not be 
possible.
    An additional comment, also apparently reflecting the view that 
studies might be possible, stated that volunteers should receive 
experimental products only after being counseled by medical, legal, and 
religious personnel, and only after being offered a nongovernment 
``second opinion.'' The comment stated that all issues of facts should 
be written, witnessed, and notarized, and each volunteer's family must 
have access to what, when, and where the individual was exposed to the 
experimental product.
    DOD strongly opposed testing of such products in humans and also 
stated that testing of sublethal doses of the toxic substances would be 
uninformative. DOD stated:
    The products under development are to be used to protect service 
members against lethal exposure to chemical and biological warfare 
agents. It is never ethical to expose volunteers to such lethal 
amounts of these agents in order to test the potential effectiveness 
of pretreatment, treatment or prophylactic products.
    Dose or concentration ranging studies are normally required for 
new or new-indication studies of drugs or biologics. Because 
response to treatment of sublethal doses of chemical or biological 
agents (weapons) could not be extrapolated to predict response to 
higher doses, a lethal dose would be necessary to test the 
effectiveness of the protective drug or biologic. If lethal doses 
were given to volunteers, a 100% effective rescue agent would need 
to be available, in case the protective agent failed and potentially 
fatal toxicity had to be reversed. Antidotes to probable threat 
agents do not currently exist.
    A public interest group recommended that FDA address the complex 
issues raised by these questions in a separate proceeding and a 
separate public forum, noting that the ethical issues raised by these 
questions are not limited to the evaluation of products for use in the 
military context, but also arise with respect to products designed to 
protect individuals who may be exposed to toxic substances in the 
workplace or in other situations (e.g., exposure to pesticides or 
industrial toxins).
    The agency has reviewed the comments and finds them in accord with 
its longstanding analysis. Therefore, FDA again concludes that it would 
be unethical to expose volunteers to potentially lethal or permanently 
disabling doses of toxic biological, chemical, radiological, or nuclear 
substances to test the efficacy of products that may be used to provide 
protection against those substances. Based on this conclusion and in 
recognition of the need to take all possible steps to protect 
individuals exposed to such agents, the agency has written this 
proposal. Section VII of this document discusses specific issues that 
deserve further consideration. The agency believes that the comments it 
has received thus far are sufficient for it to proceed with this 
proposal and that an additional public forum is not necessary before 
this proposal is issued for comment.

B. What Evidence Would Be Needed to Demonstrate Safety and Efficacy of 
Products That May Be Used to Provide Protection Against Toxic Chemical 
and Biological Substances That Cannot Be Ethically Tested in Humans?

    FDA received nine comments in response to this question in the July 
1997 request for comments. Most of the comments did not address the 
specific kinds of information that would be needed for approval.
    One comment expressed support for the idea of approving such 
``emergency'' drugs based on animal studies. Another comment stated 
that:
* * * [e]ffectiveness studies in animals and human phase I studies 
(pharmacokinetic/antibody response) should have resulted in 
plausible evidence that a protective product will have a reasonable 
risk/benefit ratio in a combat situation or during an attack on 
civilians. The phase one studies should include the generation of 
data in children and take into account anticipated combination(s) 
with other products and immunization schedules.
    A third comment recommended that FDA scientific advisory committees 
be used to advise, on a case-by-case basis, on data (e.g., nonclinical 
or surrogate markers of efficacy) required to demonstrate efficacy. 
Additionally, postmarketing clinical efficacy data could be obtained 
from, for example, incidents involving accidental exposures by at risk 
workers or operating forces, and this data could also contribute to the 
body of ``substantial evidence'' needed to demonstrate efficacy. This 
comment emphasized that, as with other FDA regulated products, data 
related to the safety and efficacy of medical products that DOD may 
want to give to its personnel should be considered on a case-by-case 
basis, taking into account

[[Page 53963]]

the intended indication and levels of medical supervision for product 
use.
    Two comments stressed that while it may not be ethical to test 
efficacy of these products in humans, this does not preclude testing to 
demonstrate their safety. (The agency notes that this proposal does not 
address trials required to demonstrate safety; the safety of these 
products will be studied under existing rules in human volunteers.) 
These comments stressed the importance of establishing a product's 
safety in the specific population ``at issue'' and at the proposed 
dosage levels. Further, when synergistic exposures or stresses are 
likely, these should be incorporated into the safety testing as much as 
possible. For pyridostigmine bromide, in particular, these comments 
stressed that its safety should be studied under high heat conditions 
and in combination with insecticides and pesticides, including DEET, 
Permethrin, Malathion and/or Dursban.
    The DOD's comment on this question addressed only the issue of 
relying on a human surrogate marker (already possible under current 
regulations at subpart H of part 314 (21 CFR part 314) and subpart E of 
part 601 (21 CFR part 601) (the Accelerated Approval regulations)) and 
did not consider the case where there is no human surrogate marker that 
is at least reasonably likely to predict clinical efficacy in humans. 
DOD added, however, that:
    In addition, other information should be obtained in order to 
better understand and perhaps predict the reactions of the drug or 
vaccine when given to a large group of DoD personnel. These might 
include metabolic and disposition pathways in both the animal model 
and in humans and population studies in humans to understand 
clinical covariates to predict response ranges in very large groups.
    The Public Citizen Litigation Group without further elaboration 
rejected as illegal the idea that animal data or other nonhuman data 
could serve as a basis for approval of an antidote and stated that both 
the ethical standards for informed consent as well as the standards for 
establishing safety and efficacy should apply equally to products used 
in military and civilian populations.

III. Introduction to the Rule

    FDA has determined that the requirement for human studies to 
demonstrate efficacy has the effect of preventing the development and 
availability of approved drug and biological products to reduce or 
prevent serious or life-threatening toxicity resulting from exposure to 
lethal or permanently disabling toxic biological, chemical, 
radiological, or nuclear substances.\1\ In reaching this conclusion, 
FDA considered two possible kinds of human efficacy studies: (1) 
Clinical studies in which the toxic substance is given to volunteers 
and harm is prevented because the product proves to be fully 
efficacious, and (2) field studies in which toxicity following an 
accidental or hostile exposure is reduced or prevented by the product. 
In many cases involving these products, however, the first kind of 
study cannot ethically be performed; and, as to the second, there may 
be no opportunity to conduct them, or such field studies may not 
provide adequate information.
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    \1\ The agency has expanded the scope of this proposal to 
include not only biological and chemical substances, but also 
radiological and nuclear substances in order to include all types of 
substances that could be lethal or permanently disabling.
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    Although such products may be used, and potentially used widely, 
under the investigational provisions of the Federal Food, Drug, and 
Cosmetic Act (the act), which, among other things, require informed 
consent, this is a suboptimal solution for many reasons. In truly 
emergent circumstances, where the population needing treatment cannot 
be identified in advance and may be large, obtaining informed consent 
may be impossible. Allowing a waiver of the informed consent 
requirement as ``not feasible'' in circumstances where the product is 
to be given to competent individuals has proved to be extremely 
controversial. (See, elsewhere in this issue of the Federal Register, 
FDA's interim final regulations for waiver of informed consent in 
certain situations related to military combat.) Thus, the agency is 
presented with two choices for this class of products: (1) Make no 
adjustments to its current regulations, which would likely severely 
restrict the ability to use such products; or (2) identify an 
alternative basis for establishing efficacy for such products, and if 
safety and efficacy are established, grant marketing approval for the 
product with appropriate restrictions and requirements, including 
patient-directed labeling describing the basis of the product approval 
to help assure the safest possible use. FDA believes that approval 
should not be withheld for a product that is intended to, and is being 
widely used to, reduce or prevent the lethal or permanently disabling 
toxic effects of chemical, biological, radiological, or nuclear 
substances, that has been fully studied for safety in humans, and that 
has been determined to be effective based on the best human and animal 
evidence that can be obtained ethically. Accordingly, FDA is proposing 
regulations that would describe how efficacy for these products can be 
demonstrated.
    FDA is proposing to amend part 314 by adding subpart I, consisting 
of Secs. 314.600 through 314.650, and to amend part 601 by adding 
subpart G, consisting of Secs. 601.60 through 601.65.

IV. Scope

    This proposal would apply to new drug and biological products to be 
used in the reduction or prevention of serious or life-threatening 
consequences resulting from exposure to lethal or permanently disabling 
toxic biological, chemical, radiological, or nuclear substances, where: 
(1) The products would be expected to provide meaningful therapeutic 
benefits to patients over existing treatment; (2) the conduct of human 
challenge/protection efficacy trials would be unethical because it 
would be necessary to administer a potentially lethal or permanently 
disabling toxic biological, chemical, radiological, or nuclear 
substance to human volunteers without a proven effective treatment; and 
(3) field trials\2\ are not feasible. This proposal would not apply to 
products that could be approved under standards described elsewhere in 
the regulations (part 314 or part 601), e.g., products for which 
traditional human efficacy studies could be conducted ethically or for 
which there is an acceptable human surrogate endpoint or for which 
accelerated approval would apply. As in past efforts to expedite access 
to new drugs by accelerating approval (subpart H of part 314 and 
subpart E of part 601) or facilitating access to investigational agents 
and speeding development and review of these products (21 CFR 312.34 
Treatment use of an investigational new drug), FDA proposes to apply 
these procedures where an important medical need is not adequately met 
by currently available therapies. If such a need does not exist, the 
agency believes that the usual procedures provide for the most 
appropriate and thorough approach to ensuring efficacy of drugs prior 
to marketing. This proposal is consistent

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with the recent changes in the act on fast track products made in the 
Food and Drug Administration Modernization Act of 1997. Consistent with 
these changes, FDA is committed to facilitating the 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)).
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    \2\ As used in this document, ``field trials'' are well-
controlled studies that can sometimes be conducted when the toxic 
substance is naturally occurring and there are individuals who are 
at risk for exposure to the toxic substance. For example, the 
anthrax vaccine was approved based on a successful well-controlled 
field trial in mill workers at high risk for anthrax exposure. In 
other cases, it is possible that accidental or hostile exposures to 
toxic substances could be treated and the effects observed. However, 
the ability to conduct such studies cannot usually be anticipated 
and their historically controlled nature makes them difficult to 
interpret.
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    Sponsors are encouraged to meet with FDA early in the drug 
development process to determine the nature of the regulatory review 
that FDA will apply.

V. Legal Authority

    In developing this rule, FDA considered the question of whether it 
has the authority to approve a product without determinative efficacy 
studies in humans when it would be unethical to conduct such studies. 
FDA also considered, assuming it has such authority, what data, other 
than determinative efficacy studies in humans, could constitute 
sufficient evidence of efficacy to support product approval. These 
questions have arisen recently because of concerns raised regarding the 
nation's ability to adequately respond to threats of chemical, 
biological, radiological, and nuclear agents that could be used to 
cause serious harm to humans. FDA has not previously addressed this 
issue in any of its regulations. As described in the next paragraphs, 
FDA has the authority to issue regulations describing the type of 
evidence that may be the basis of an efficacy determination for drugs 
and biological products that are therapies for toxic agents in 
situations where it would be unethical to conduct a clinical 
investigation in humans to demonstrate efficacy.
    FDA approves new drugs under the authority of the act and biologics 
under section 351 of the Public Health Service Act. The act authorizes 
the Secretary of Health and Human Services (the Secretary) to issue an 
order refusing to approve a new drug application if the Secretary finds 
that ``there is a lack of substantial evidence that the drug will have 
the effect it purports or is represented to have under the conditions 
of use prescribed, recommended, or suggested in the proposed labeling 
thereof * * *'' (section 505(d) of the act (21 U.S.C. 355(d).) The term 
substantial evidence is defined as:
* * * evidence consisting of adequate and well-controlled 
investigations, including clinical investigations, by experts 
qualified by scientific training and experience to evaluate the 
effectiveness of the drug involved, on the basis of which it could 
fairly and responsibly be concluded by such experts that the drug 
will have the effect it purports or is represented to have under the 
conditions of use prescribed, recommended, or suggested in the 
labeling or proposed labeling thereof.
Id.
    In interpreting the term ``substantial evidence,'' FDA has viewed 
the phrase ``adequate and well-controlled investigations, including 
clinical investigations'' as meaning that efficacy determinations must 
include studies of efficacy in humans. The agency's regulations did not 
contemplate situations in which efficacy studies cannot be ethically 
conducted in humans, and FDA believes that it would be inconsistent 
with the statute's public health objectives to conclude that FDA cannot 
use some other basis for considering the efficacy of such products. The 
legislative history does not address this issue. Concluding that such 
products cannot ever be approved because human efficacy trials cannot 
be conducted is contrary to the public interest and inconsistent with 
the act's purpose of public health protection. Courts have recognized 
that remedial statutes such as the act are to be liberally construed 
consistent with the act's overriding purpose to protect the public 
health. (United States v. An Article of Drug * * * Bacto-Unidisk, 394 
U.S. 784 (1968).)
    FDA has therefore tentatively concluded that, where definitive 
human efficacy studies cannot be ethically conducted because they would 
necessarily expose healthy subjects to a potentially lethal or 
permanently disabling substance, the statutory standard should be 
interpreted as permitting efficacy to be based on adequate and well-
controlled investigations that are not conducted in humans. This 
conclusion is consistent with the recognition by Congress of the 
importance of ethical behavior in the study of unapproved products. For 
example, Congress has acknowledged the need: (1) For informed consent 
in clinical research (section 505(i)(2) of the act); (2) to have due 
regard for patients in issuing regulations for investigational use of 
drugs (section 505(k) of the act); and (3) for experts to act ``fairly 
and responsibly'' in evaluating efficacy (section 505(d) of the act). 
Where human efficacy trials cannot be done ethically, experts are 
without human studies upon which to fairly and responsibly conclude 
that a product is effective. In the situations described previously, 
the agency believes that adequate and well-controlled animal studies 
may provide sufficient data to warrant approval. For FDA to approve 
products where definitive efficacy studies cannot be conducted in 
humans there must be sufficient data available to meet the statutory 
standard. The data must be such that experts are able to fairly and 
responsibly conclude ``that the drug will have the effect it purports 
or is represented to have * * *'' in humans. Where data from adequate 
and well-controlled animal studies meet this standard, FDA may approve 
the product. Unless such data exist, FDA will not approve the product.

VI. Elements of the Proposal

    For the limited types of products within the scope of this 
proposal, FDA would grant marketing approval for a new drug or 
biological product on the basis of adequate and well-controlled animal 
trials when it is scientifically reasonable to expect that the effect 
of the drug or biological product in animals is reasonably likely to 
predict clinical benefit in humans. Safety evaluation is not discussed 
in this proposed rule because the safety of these products can be 
studied in human volunteers. In order to provide for the safe and 
effective use of these products, similar restrictions, withdrawal 
procedures, postmarketing safety reporting requirements, and 
requirements pertaining to promotional materials contained in the 
accelerated approval regulations in subpart H of part 314 and in 
subpart E of part 601 are included in this proposal, with appropriate 
modifications. (The rationale and authorities for including these 
requirements remain unchanged and are described in the Federal Register 
of April 15, 1992 (57 FR 13234), proposed accelerated approval 
regulations.) Thus, the agency intends to require, under 
Secs. 314.610(a) and 601.61(a), postmarketing studies if a product 
approved under this subpart is used in a situation that makes such 
studies feasible and ethical. The agency may also require, for example, 
under Secs. 314.610(b) and 601.61(b) that: (1) The product be stored at 
the control and direction of competent military and civilian emergency 
governmental personnel; (2) the product be used at the direction of, 
and as ordered by, competent military and civilian emergency 
governmental personnel; and (3) applicants be obligated to followup on 
its use and report to FDA in Phase 4 reports and descriptions of 
adverse reactions. In addition, in order to assure public knowledge of 
products approved under this rule, the agency is proposing to add a new 
requirement pertaining to providing specific information on the product 
to its recipients (Secs. 314.610(c) and 601.61(c)). The agency also 
intends in most cases to consult on applications to market such 
products with an advisory committee, supplemented with

[[Page 53965]]

appropriate expert consultants, in meetings open to the public in order 
to receive expert advice on whether a particular set of animal data 
support efficacy of a product under this rule.
    Under the rule, FDA will rely on the efficacy evidence from 
adequate and well-controlled studies in animals only where: (1) There 
is a reasonably well-understood pathophysiological mechanism of the 
toxicity of the substance and its prevention by the product; (2) there 
is independent substantiation of the effect in multiple animal species, 
including species expected to react with a response predictive for 
humans; (3) the animal study endpoint is plainly related to the desired 
benefit in humans, which is generally the enhancement of survival or 
prevention of major morbidity; and (4) 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 FDA therefore concludes that the effect of the product 
in animals is reasonably likely to predict clinical benefit in humans. 
Where it is possible to conduct human efficacy studies of products, 
these will continue to be required. Safety evaluation of these products 
in humans will be required.
    To the extent possible, human experience that is potentially 
relevant should be obtained, such as effects on potential human 
surrogate markers or studies of low, sublethal doses of the toxic 
substance, where such doses may be defined and where the studies are 
sufficiently cautious in design and monitoring. If the surrogate 
endpoint effect is reasonably likely to predict clinical benefit, and 
it is possible to design postmarketing studies to confirm effectiveness 
(which could depend on the occurrence of an unpredictable toxic 
exposure), such that the drug could be approved under subpart H of part 
314 and subpart E of part 601, the accelerated approval regulations, it 
would not be considered under this proposal.

VII. Discussion

    In situations where definitive human efficacy studies cannot be 
ethically conducted, a possible means of demonstrating efficacy could 
be through animal studies. FDA seeks comments on the following issues:
    1. As indicated previously, the agency has never before permitted a 
sponsor to rely on animal studies to support a finding of ``substantial 
evidence'' and approval of a drug under section 505 of the act. 
Although the agency has attempted to propose a very narrow exception to 
the need for human studies in a situation where human studies seem 
truly impossible, the exception might be viewed by some as establishing 
the principle that animal studies may be relied on ``for good reason'' 
under the act; other ``good reasons'' might be advanced. What are the 
risks of the approach taken in this rule, if any, to the efficacy 
standard? To what extent, if any, would it diminish the efficacy 
standard? What impact would it have, if any, on how the agency might 
apply the efficacy standard to other drugs in the future?
    2. If the agency proceeds to finalize this rule, are there 
additional limitations that should be placed on any approval based on 
animal data? For example, should the agency place additional 
advertising restrictions on these products, and describe the 
restrictions and the legal basis for such restrictions?
    3. What would make animal data sufficiently predictive of efficacy 
in humans to warrant product approval based on such data? The agency 
has identified several elements that are important. These elements 
include consistency of results across species, and an effect on the 
same morbidity/mortality endpoint in animals that is of interest in 
humans together with a good understanding of the mechanisms of the 
effect of the toxin and the product. Information about the relative 
sensitivity of the species to the toxin or agent (compared to humans), 
and consistent dose-response and pharmacokinetic/pharmacodynamic 
relationships in various animal species might also make animal data 
more persuasive. Are there other elements that should be considered?
    4. How can the correct human dose be selected? Presumably, if 
multiple animal species show a consistent relation of protective effect 
to exposure (minimum blood levels, average concentration, etc.), a 
response of a pharmacodynamic marker, or measure of dose (e.g., 
milligram (mg)/meter2 dose, mg/kilogram dose, or cumulative 
dose), a similar human dose, or a human dose giving the same blood 
concentration or pharmacologic effect could be chosen. If species 
differ in their susceptibility to the toxic agent, what approaches 
could help identify the proper human dose of the drug? For example, 
would the largest dose (concentration) needed in any species be the 
best choice?
    5. What constitutes ``independent substantiation in multiple animal 
species'' (i.e., consistency of results across species)? How many 
species represent a reasonable number and should at least one primate 
species be included? In what situation(s) might a primate species be 
unnecessary? If efficacy results across species are not consistent, 
would a single unprotected species (without clear explanation) 
undermine the entire premise on which approval would be based? If the 
inconsistency would not undermine the premise, what are examples of 
situations where one could conclude a treatment will be effective in 
humans even though there is an unprotected species and no clear 
explanation of why it is unprotected?
    6. As discussed previously, safety evaluation is not discussed in 
this document because safety will be studied in human volunteers. If 
efficacy of a product were demonstrated through animal studies rather 
than studies in humans, are there special considerations that should 
apply to the safety data base? If so, what do these special 
considerations consist of and why should they be applied to the data 
base? To what extent should interactions with potential concomitant 
treatments and concomitant environmental exposures be studied?
    7. In the July 1997 request for comments, FDA requested comments 
on: When is it ethical to expose volunteers to toxic chemical and 
biological substances to test the effectiveness of products that may be 
used to provide potential protection against those substances? As 
described earlier in this document, the agency received nine comments, 
most of which expressed considerable doubt regarding whether it would 
be ethical to expose volunteers to toxic substances to test the 
efficacy of these products. Although the agency has concluded in 
proposing this rule that it will generally not be possible ethically, 
in the cases described, to conduct human studies, it is also true that 
it is critically important for a product intended to reduce or prevent 
lethal consequences to be effective when used. The agency therefore is 
requesting further comment on this issue. It would be helpful to 
receive information, with examples if available, on the value of 
studying sublethal doses of toxins in humans and evaluating the ability 
of these products to protect against the sublethal effects. This would 
not be equivalent to testing the product against a full dose of the 
toxin, but it could support the fundamental similarity of responses in 
animals and humans to the toxin and the product.

VIII. 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

[[Page 53966]]

the human environment. Therefore, neither an environmental assessment 
nor an environmental impact statement is required.

IX. 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 proposed rule's impact 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 proposal 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 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 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 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 an opportunity for 
appropriate participation in the proceedings. As required by the 
Executive Order, States have, through this notice of proposed 
rulemaking, an opportunity to raise the possibility of conflicts and to 
participate in the proceedings (section 4(d) and (e)). 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.

X. Analysis of Impacts

    FDA has examined the impacts of the proposed 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 has a 
significant economic impact on a substantial number of small entities, 
the Regulatory Flexibility Act requires agencies to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. 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 this proposed 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 
the Executive Order because it raises novel policy issues. However, the 
rule is not an ``economically significant'' rule as defined in section 
3(f)(1) of the Executive Order, as it will not have an annual effect on 
the economy of $100 million or more, nor will it impose material 
adverse effects. With respect to the Regulatory Flexibility Act (5 
U.S.C. 605(b)), this rule will permit products to be approved that 
could not be approved under existing regulations and very few products 
will need to meet the requirements of this rule. Therefore, the 
Commissioner certifies that the rule will not have a significant 
economic impact on a substantial number of small entities. Accordingly, 
under the Regulatory Flexibility Act, no further analysis is required. 
Similarly, because the rule does not impose any mandates on State, 
local, or tribal government, or the private sector that will result in 
a 1-year expenditure of $100 million or more, FDA is not required to 
perform a cost-benefit analysis under the Unfunded Mandates Reform Act.

XI. Paperwork Reduction Act of 1995

     This proposed rule contains information collection provisions that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A 
description of these provisions is given in the following paragraphs 
with an estimate of the annual reporting and recordkeeping burden. 
Included in the estimate is the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.
    With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: New Drug and Biological Products; Animal Efficacy Studies.
    Description: FDA is proposing to amend its new drug and biological 
product regulations to identify the evidence needed to demonstrate the 
efficacy of drug and biological products used to treat or prevent the 
toxicity of chemical, biological, radiological, or nuclear substances 
when definitive efficacy studies in humans cannot be ethically 
conducted because they would involve administering a lethal or 
permanently disabling toxic substance to healthy human volunteers 
without a proven treatment and when field trials are not feasible. In 
these circumstances, when it may be impossible to demonstrate efficacy 
through the adequate and well-controlled studies in humans, FDA is 
proposing that certain new drug and biological products to treat or 
prevent serious or life-threatening conditions could be approved for 
marketing based on studies in animals, without the traditional efficacy 
studies in humans. FDA is proposing this action because it recognizes 
the importance of improving medical response capabilities to the use of 
lethal or permanently disabling chemical, biological, radiological, and 
nuclear substances in order to protect individuals exposed to these 
substances.
    Respondent Description: Businesses and other for-profit 
organizations, and nonprofit institutions.

[[Page 53967]]



                                  Table 1.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
----------------------------------------------------------------------------------------------------------------
314.610(b)(3) and 314.630
601.61(b)(3) and 601.63                 1               1               1               5               5
 
314.610(c) and 314.640
601.61(c) and 601.64                    1               1               1             240             240
 
Total                                                                                                 245
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs with this collection of information.


                           Table 2.--Estimated Annual Disclosure/Recordkeeping Burden1
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                   Recordkeepers   Recordkeeping      Records      Recordkeeper
----------------------------------------------------------------------------------------------------------------
314.610(b)(3) and 314.630
601.61(b)(3) and 601.63                 1               1               1               1               1
 
314.610(c)
601.61(c)                               1               1               1               1               1
 
Total                                                                                                   2
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs with this collection of information.

    FDA estimates that only one application of this nature may be 
submitted every 3 years; however, for calculation purposes, FDA is 
estimating the submission of one application annually. FDA estimates 
240 hours for a manufacturer of a new drug or biological product to 
develop patient labeling, and to submit the appropriate information and 
promotional labeling to FDA. At this time, FDA cannot estimate the 
number of postmarketing reports for adverse drug or biological 
experiences associated with a newly approved drug or biological 
product. Therefore, FDA is using one report for purposes of this 
information collection. These reports are required under 21 CFR parts 
310, 314, and 600. Any burdens associated with these requirements will 
be reported under the adverse experience reporting (AER) information 
collection requirements. The estimated hours for postmarketing reports 
range from 1 to 5 hours based on previous estimates for adverse 
experience reporting; however FDA is estimating 5 hours for the purpose 
of this information collection.
    The majority of the burden for developing the patient labeling is 
included under the reporting requirements, therefore, minimal burden is 
calculated for providing the guide to patients. As discussed 
previously, no burden can be calculated at this time for the number of 
AER reports that may be submitted after approval of a new drug or 
biologic, therefore, the number of records that may be maintained also 
cannot be determined. Any burdens associated with these requirements 
will be reported under the AER information collection requirements. The 
estimated recordkeeping burden of 1 hour is based on previous estimates 
for the recordkeeping requirements associated with the AER system.

XII. Request for Comments

    Interested persons may, on or before December 20, 1999, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. 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.

List of Subjects

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 314 and 601 be amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN 
ANTIBIOTIC DRUG

    1. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 374, 
379e.

    2. Subpart I, consisting of Secs. 314.600 through 314.650, is added 
to read as follows:

Subpart I--Approval of New Drugs for Use Against Lethal or Permanently 
Disabling Toxic Substances When Efficacy Studies in Humans Ethically 
Cannot Be Conducted

Sec.
314.600  Scope.
314.610  Approval based on evidence of efficacy from studies in 
animals.
314.620  Withdrawal procedures.
314.630  Postmarketing safety reporting.
314.640  Promotional materials.
314.650  Termination of requirements.

Subpart I--Approval of New Drugs for Use Against Lethal or 
Permanently Disabling Toxic Substances When Efficacy Studies in 
Humans Ethically Cannot Be Conducted


Sec. 314.600  Scope.

    This subpart applies to certain new drug products that have been 
studied for their safety and efficacy in ameliorating or preventing 
serious or life-threatening conditions caused by exposure to lethal or 
permanently disabling toxic biological, chemical, radiological, or 
nuclear substances, where the products would be expected to provide

[[Page 53968]]

meaningful therapeutic benefits to patients over existing treatments 
(e.g., ability to treat a condition that has no current therapy, 
ability to treat patients unresponsive to, or intolerant of, available 
therapy, or ability to improve patient response compared to available 
therapy). This subpart applies only to those new drug products for 
which: Definitive human efficacy studies cannot be conducted because it 
would be unethical to deliberately expose healthy human volunteers to a 
lethal or permanently disabling toxic biological, chemical, 
radiological, or nuclear substance without a proven treatment; and 
field trials to study the product's efficacy after an accidental or 
hostile exposure are not feasible. This subpart does not apply to 
products that can be approved based on standards described elsewhere in 
FDA's regulations (e.g., accelerated approval based on surrogate 
markers or clinical endpoints other than survival or irreversible 
morbidity), nor does it address the safety evaluation for these 
products.


Sec. 314.610  Approval based on evidence of efficacy from studies in 
animals.

    FDA may grant marketing approval for a new drug product for which 
safety has been established and for which the requirements of 
Sec. 314.600 are met based on adequate and well-controlled animal 
trials when the results of those animal studies establish that the drug 
product is reasonably likely to predict clinical benefit in humans. FDA 
will rely on the evidence from studies in animals only where: There is 
a reasonably well-understood pathophysiological mechanism of the 
toxicity of the substance and its prevention or substantial reduction 
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. Approval under this subpart will be subject to three 
requirements:
    (a) Postmarketing studies. The applicant shall conduct 
postmarketing studies to verify and describe the drug's clinical 
benefit when such studies are feasible and ethical. Such postmarketing 
studies may not be feasible until an exigency arises that necessitates 
use of the product. When such studies are feasible, the applicant shall 
conduct such studies with due diligence.
    (b) Approval with restrictions to assure safe use. If FDA concludes 
that a drug product shown to be effective under this subpart can be 
safely used only if distribution or use is restricted, FDA will require 
such postmarketing restrictions as are needed to assure safe use of the 
drug product, commensurate with the specific safety concerns presented 
by the drug product, such as:
    (1) Distribution restricted to certain facilities or health care 
practitioners with special training or experience;
    (2) Distribution conditioned on the performance of specified 
medical procedures, including medical followup; and
    (3) Distribution conditioned on specified recordkeeping 
requirements.
    (c) Information to be provided to patients and potential patients; 
unit of use packaging. For drug products approved under this subpart, 
applicants shall prepare, as part of their proposed labeling, labeling 
to be provided to patients or potential patients. The patient labeling 
will explain that the drug's approval was based on efficacy studies 
conducted in animals alone, give the drug's indication(s), directions 
for use (dosage and administration), contraindications, a description 
of any reasonably foreseeable risks, adverse reactions, anticipated 
benefits, drug interactions, and any other relevant information 
required by FDA at the time of approval. For self-administered drug 
products, there shall be unit-of-use packaging and attached patient 
labeling containing this information. For drug products administered by 
health professionals, the patient labeling shall be available with the 
product to be provided to patients prior to administration of the drug 
product, if possible.


Sec. 314.620  Withdrawal procedures.

    (a) For new drugs approved under this subpart, FDA may withdraw 
approval, following a hearing as provided in part 15 of this chapter, 
as modified by this section, if:
    (1) A postmarketing clinical study fails to verify clinical 
benefit;
    (2) The applicant fails to perform the postmarketing study with due 
diligence;
    (3) Use after marketing demonstrates that postmarketing 
restrictions are inadequate to assure safe use of the drug product;
    (4) The applicant fails to adhere to the postmarketing restrictions 
applied at the time of approval under this subpart;
    (5) The promotional materials are false or misleading; or
    (6) Other evidence demonstrates that the drug product is not shown 
to be safe or effective under its conditions of use.
    (b) Notice of opportunity for a hearing. The Director of the Center 
for Drug Evaluation and Research (CDER) will give the applicant notice 
of an opportunity for a hearing on CDER's proposal to withdraw the 
approval of an application approved under this subpart. The notice, 
which will ordinarily be a letter, will state generally the reasons for 
the action and the proposed grounds for the order.
    (c) Submission of data and information. (1) If the applicant fails 
to file a written request for a hearing within 15 days of receipt of 
the notice, the applicant waives the opportunity for a hearing.
    (2) If the applicant files a timely request for a hearing, the 
agency will publish a notice of hearing in the Federal Register in 
accordance with Secs. 12.32(e) and 15.20 of this chapter.
    (3) An applicant who requests a hearing under this section must, 
within 30 days of receipt of the notice of opportunity for a hearing, 
submit the data and information upon which the applicant intends to 
rely at the hearing.
    (d) Separation of function. Separation of functions (as specified 
in Sec. 10.55 of this chapter) will not apply at any point in 
withdrawal proceedings under this section.
    (e) Procedures for hearings. Hearings held under this section will 
be conducted in accordance with the provisions of part 15 of this 
chapter, with the following modifications:
    (1) An advisory committee duly constituted under part 14 of this 
chapter will be present at the hearing. The committee will be asked to 
review the issues involved and to provide advice and recommendations to 
the Commissioner of Food and Drugs.
    (2) The presiding officer, the advisory committee members, up to 
three representatives of the applicant, and up to three representatives 
of CDER may question any person during or at the conclusion of the 
person's presentation. No other person attending the hearing may 
question a person making a presentation. The presiding officer may, as 
a matter of discretion, permit questions to be submitted to the 
presiding officer for response by a person making a presentation.
    (f) Judicial review. The Commissioner of Food and Drugs' decision 
constitutes final agency action from which the applicant may petition 
for judicial review. Before requesting an order from a court for a stay 
of action pending review, an applicant must first submit a

[[Page 53969]]

petition for a stay of action under Sec. 10.35 of this chapter.


Sec. 314.630  Postmarketing safety reporting.

    Drug products approved under this subpart are subject to the 
postmarketing recordkeeping and safety reporting applicable to all 
approved drug products, as provided in Secs. 314.80 and 314.81.


Sec. 314.640  Promotional materials.

    For drug products being considered for approval under this subpart, 
unless otherwise informed by the agency, applicants shall submit to the 
agency for consideration during the preapproval review period copies of 
all promotional materials, including promotional labeling as well as 
advertisements, intended for dissemination or publication within 120 
days following marketing approval. After 120 days following marketing 
approval, unless otherwise informed by the agency, the applicant shall 
submit promotional materials at least 30 days prior to the intended 
time of initial dissemination of the labeling or initial publication of 
the advertisement.


Sec. 314.650  Termination of requirements.

    If FDA determines after approval under this subpart that the 
requirements established in Secs. 314.610(b), 314.620, and 314.630 are 
no longer necessary for the safe and effective use of a drug product, 
it will so notify the applicant. Ordinarily, for drug products approved 
under Sec. 314.610, these requirements will no longer apply when FDA 
determines that the postmarketing study verifies and describes the drug 
product's clinical benefit. For drug products approved under 
Sec. 314.610, the restrictions would no longer apply when FDA 
determines that safe use of the drug product can be assured through 
appropriate labeling. FDA also retains the discretion to remove 
specific postapproval requirements upon review of a petition submitted 
by the sponsor in accordance with Sec. 10.30 of this chapter.

PART 601--LICENSING

    3. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 
241, 262, 263; sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 
355 note).

    4. Subpart G, consisting of Secs. 601.60 through 601.65, is added 
to read as follows:

Subpart G--Approval of Biological Products for Use Against Lethal or 
Permanently Disabling Toxic Substances When Efficacy Studies in Humans 
Ethically Cannot Be Conducted

Sec.
601.60  Scope.
601.61  Approval based on evidence of efficacy from studies in 
animals.
601.62  Withdrawal procedures.
601.63  Postmarketing safety reporting.
601.64  Promotional materials.
601.65  Termination of requirements.

Subpart G--Approval of Biological Products for Use Against Lethal 
or Permanently Disabling Toxic Substances when Efficacy Studies in 
Humans Ethically Cannot Be Conducted


Sec. 601.60  Scope.

    This subpart applies to certain biological products that have been 
studied for their safety and efficacy in ameliorating or preventing 
serious or life-threatening conditions caused by exposure to lethal or 
permanently disabling toxic biological, chemical, radiological, or 
nuclear substances, where the products would be expected to provide 
meaningful therapeutic benefits to patients over existing treatments 
(e.g., ability to treat a condition that has no current therapy, 
ability to treat patients unresponsive to, or intolerant of, available 
therapy, or ability to improve patient response compared to available 
therapy). This subpart applies only to those biological products for 
which: Definitive human efficacy studies cannot be conducted because it 
would be unethical to deliberately expose healthy human volunteers to a 
lethal or permanently disabling toxic biological, chemical, 
radiological, or nuclear substance without a proven treatment; and 
field trials to study the product's efficacy after an accidental or 
hostile exposure are not feasible. This subpart does not apply to 
products that can be approved based on standards described elsewhere in 
FDA's regulations (e.g., accelerated approval based on surrogate 
markers or clinical endpoints other than survival or irreversible 
morbidity), nor does it address the safety evaluation for these 
products.


Sec. 601.61  Approval based on evidence of efficacy from studies in 
animals.

    FDA may grant marketing approval for a biological product for which 
safety has been established and for which the requirements of 
Sec. 601.60 are met based on adequate and well-controlled animal trials 
when the results of those animal studies establish that the biological 
product is reasonably likely to predict clinical benefit in humans. FDA 
will rely on the evidence from studies in animals only where: There is 
a reasonably well-understood pathophysiological mechanism of the 
toxicity of the substance and its prevention or substantial reduction 
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. Approval under this subpart will be subject to three 
requirements:
    (a) Postmarketing studies. The applicant shall conduct 
postmarketing studies to verify and describe the biological product's 
clinical benefit when such studies are feasible and ethical. Such 
postmarketing studies may not be feasible until an exigency arises that 
necessitates use of the product. When such studies are feasible, the 
applicant shall conduct such studies with due diligence.
    (b) Approval with restrictions to assure safe use. If FDA concludes 
that a biological product shown to be effective under this subpart can 
be safely used only if distribution or use is restricted, FDA will 
require such postmarketing restrictions as are needed to assure safe 
use of the biological product, commensurate with the specific safety 
concerns presented by the biological product, such as:
    (1) Distribution restricted to certain facilities or health care 
practitioners with special training or experience;
    (2) Distribution conditioned on the performance of specified 
medical procedures, including medical followup; and
    (3) Distribution conditioned on specified recordkeeping 
requirements.
    (c) Information to be provided to patients and potential patients; 
unit of use packaging. For biological products approved under this 
subpart, applicants shall prepare, as part of their proposed labeling, 
labeling to be provided to patients or potential patients. The patient 
labeling will explain that the biological product's approval was based 
on efficacy studies conducted in animals alone, give the biological 
product's indication(s), directions for use (dosage and 
administration), contraindications, a description of any

[[Page 53970]]

reasonably foreseeable risks, adverse reactions, anticipated benefits, 
drug interactions, and any other relevant information required by FDA 
at the time of approval. For self-administered biological products, 
there shall be unit-of-use packaging and attached patient labeling 
containing this information. For biological products administered by 
health professionals, the patient labeling shall be available with the 
product to be provided to patients prior to administration of the 
biological product, if possible.


Sec. 601.62  Withdrawal procedures.

    (a) For biological products approved under this subpart, FDA may 
withdraw approval, following a hearing as provided in part 15 of this 
chapter, as modified by this section, if:
    (1) A postmarketing clinical study fails to verify clinical 
benefit;
    (2) The applicant fails to perform the postmarketing study with due 
diligence;
    (3) Use after marketing demonstrates that postmarketing 
restrictions are inadequate to assure safe use of the biological 
product;
    (4) The applicant fails to adhere to the postmarketing restrictions 
applied at the time of approval under this subpart;
    (5) The promotional materials are false or misleading; or
    (6) Other evidence demonstrates that the biological product is not 
shown to be safe or effective under its conditions of use.
    (b) Notice of opportunity for a hearing. The Director of the Center 
for Biologics Evaluation and Research (CBER) will give the applicant 
notice of an opportunity for a hearing on the CBER's proposal to 
withdraw the approval of an application approved under this subpart. 
The notice, which will ordinarily be a letter, will state generally the 
reasons for the action and the proposed grounds for the order.
    (c) Submission of data and information. (1) If the applicant fails 
to file a written request for a hearing within 15 days of receipt of 
the notice, the applicant waives the opportunity for a hearing.
    (2) If the applicant files a timely request for a hearing, the 
agency will publish a notice of hearing in the Federal Register in 
accordance with Secs. 12.32(e) and 15.20 of this chapter.
    (3) An applicant who requests a hearing under this section must, 
within 30 days of receipt of the notice of opportunity for a hearing, 
submit the data and information upon which the applicant intends to 
rely at the hearing.
    (d) Separation of function. Separation of functions (as specified 
in Sec. 10.55 of this chapter) will not apply at any point in 
withdrawal proceedings under this section.
    (e) Procedures for hearings. Hearings held under this section will 
be conducted in accordance with the provisions of part 15 of this 
chapter, with the following modifications:
    (1) An advisory committee duly constituted under part 14 of this 
chapter will be present at the hearing. The committee will be asked to 
review the issues involved and to provide advice and recommendations to 
the Commissioner of Food and Drugs.
    (2) The presiding officer, the advisory committee members, up to 
three representatives of the applicant, and up to three representatives 
of CBER may question any person during or at the conclusion of the 
person's presentation. No other person attending the hearing may 
question a person making a presentation. The presiding officer may, as 
a matter of discretion, permit questions to be submitted to the 
presiding officer for response by a person making a presentation.
    (f) Judicial review. The Commissioner of Food and Drugs' decision 
constitutes final agency action from which the applicant may petition 
for judicial review. Before requesting an order from a court for a stay 
of action pending review, an applicant must first submit a petition for 
a stay of action under Sec. 10.35 of this chapter.


Sec. 601.63  Postmarketing safety reporting.

    Biological products approved under this subpart are subject to the 
postmarketing recordkeeping and safety reporting applicable to all 
approved biological products.


Sec. 601.64  Promotional materials.

    For biological products being considered for approval under this 
subpart, unless otherwise informed by the agency, applicants shall 
submit to the agency for consideration during the preapproval review 
period copies of all promotional materials, including promotional 
labeling as well as advertisements, intended for dissemination or 
publication within 120 days following marketing approval. After 120 
days following marketing approval, unless otherwise informed by the 
agency, the applicant shall submit promotional materials at least 30 
days prior to the intended time of initial dissemination of the 
labeling or initial publication of the advertisement.


Sec. 601.65  Termination of requirements.

    If FDA determines after approval under this subpart that the 
requirements established in Secs. 601.61(b), 601.62, and 601.63 are no 
longer necessary for the safe and effective use of a biological 
product, it will so notify the applicant. Ordinarily, for biological 
products approved under Sec. 601.61, these requirements will no longer 
apply when FDA determines that the postmarketing study verifies and 
describes the biological product's clinical benefit. For biological 
products approved under Sec. 601.61, the restrictions would no longer 
apply when FDA determines that safe use of the biological product can 
be assured through appropriate labeling. FDA also retains the 
discretion to remove specific postapproval requirements upon review of 
a petition submitted by the sponsor in accordance with Sec. 10.30 of 
this chapter.

    Dated: May 25, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-25377 Filed 10-4-99; 8:45 am]
BILLING CODE 4160-01-F