[Federal Register: October 5, 1999 (Volume 64, Number 192)]
[Proposed Rules]
[Page 53960-53970]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05oc99-40]
=======================================================================
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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
[[Page 53964]]
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)).
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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