[Federal Register Volume 67, Number 105 (Friday, May 31, 2002)]
[Rules and Regulations]
[Pages 37988-37998]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-13583]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 601

[Docket No. 98N-0237]
RIN 0910-AC05


New Drug and Biological Drug Products; Evidence Needed to 
Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are 
Not Ethical or Feasible

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its new 
drug and biological product regulations to allow appropriate studies in 
animals in certain cases to provide

[[Page 37989]]

substantial evidence of the effectiveness of new drug and biological 
products used to reduce or prevent the toxicity of chemical, 
biological, radiological, or nuclear substances. This rule will apply 
when adequate and well-controlled clinical studies in humans cannot be 
ethically conducted and field efficacy studies are not feasible. In 
these situations, certain new drug and biological products that are 
intended to reduce or prevent serious or life-threatening conditions 
may be approved for marketing based on evidence of effectiveness 
derived from appropriate studies in animals and any additional 
supporting data.

DATES: This rule is effective July 1, 2002.

FOR FURTHER INFORMATION CONTACT:
    Wayne H. Mitchell, Center for Drug Evaluation and Research (HFD-7), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-594-2041;
    or Karen L. Goldenthal, Center for Biologics Evaluation and 
Research (HFM-475), 1401 Rockville Pike, suite 370 North, Rockville, MD 
20852, 301-827-3070.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In the Federal Register of October 5, 1999 (64 FR 53960), we (FDA) 
proposed to amend our new drug and biological product regulations to 
identify the information needed to provide substantial evidence of the 
effectiveness of certain new drug and biological products used to 
reduce or prevent the toxicity of chemical, biological, radiological, 
or nuclear substances. We are finalizing that proposed rule by adding 
subpart I to part 314 (21 CFR part 314) and subpart H to part 601 (21 
CFR part 601).
    This final rule provides for approval of certain new drug and 
biological products based on animal data when adequate and well-
controlled efficacy studies in humans cannot be ethically conducted 
because the studies would involve administering a potentially lethal or 
permanently disabling toxic substance or organism to healthy human 
volunteers and field trials are not feasible prior to approval. Under 
this rule, in these situations, certain new drug and biological 
products that are intended to reduce or prevent serious or life-
threatening conditions can be approved for marketing based on evidence 
of effectiveness derived from appropriate studies in animals, without 
adequate and well-controlled efficacy studies in humans (Sec. 314.126). 
In assessing the sufficiency of animal data, the agency may take into 
account other data, including human data, available to the agency. 
Under this rule, FDA can rely on the evidence from animal studies to 
provide substantial evidence of the effectiveness of these products 
when:
    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 demonstrated in more than one animal species 
expected to react with a response predictive for humans, unless the 
effect is demonstrated in a single animal species that represents a 
sufficiently well-characterized animal model (meaning the model has 
been adequately evaluated for its responsiveness) for predicting the 
response in 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 pharmacokinetics and 
pharmacodynamics of the product or other relevant data or information 
in animals and humans is sufficiently well understood to allow 
selection of an effective dose in humans, and it is therefore 
reasonable to expect the effectiveness of the product in animals to be 
a reliable indicator of its effectiveness in humans.
    All studies subject to this rule must be conducted in accordance 
with preexisting requirements under the good laboratory practices (21 
CFR part 58) regulations and the Animal Welfare Act (7 U.S.C. 2131 et. 
seq.).
    Safety evaluation of products is not addressed in this rule. 
Products evaluated for effectiveness under subpart I of part 314 and 
subpart H of part 601 will be evaluated for safety under preexisting 
requirements for establishing the safety of new drug and biological 
products. The agency believes that the safety of most of these products 
can be studied in human volunteers similar to the people who would be 
exposed to the product. FDA recognizes that some safety data, such as 
data on possible adverse interactions between the toxic substance 
itself and the new product, may not be available. This is not expected 
to keep the agency from making an adequate safety evaluation. FDA's 
procedures and standards for evaluating the safety of new drug and 
biological products are sufficiently flexible to provide for the safety 
evaluation of products evaluated for efficacy under subpart I of part 
314 and subpart H of part 601.
    This rule will not apply if product approval can be based on 
standards described elsewhere in our regulations (for example, 
accelerated approval based on human surrogate markers or clinical 
endpoints other than survival or irreversible morbidity).\1\
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    \1\ An example of a drug approval based on human surrogate 
markers is our August 30, 2000, approval of an efficacy supplement 
for ciprofloxacin. Ciprofloxacin HCl was approved for postexposure 
management of inhalational anthrax. The approval was based, in part, 
on human studies demonstrating that ciprofloxacin achieved serum 
concentrations reaching or exceeding levels associated with improved 
survival of animals exposed to aerosolized Bacillus anthracis 
spores. The results from these studies were combined with the 
knowledge of effectiveness in humans of ciprofloxacin for other 
bacterial infections, including pneumonia. The validity of the human 
surrogate marker was supported by animal studies.
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II. Comments on the Proposed Rule and Our Response

    We received comments on the proposed rule from two pharmaceutical 
companies and one physician affiliated with a university. We also 
received comments from the National Institutes of Health (NIH). The NIH 
comments were based on a prepublication draft of the proposed rule, but 
the comments were received too late to be addressed in the proposed 
rule. The NIH comments have been placed in the docket for this rule and 
are addressed in this document.
    In addition to the changes we have made in response to comments, we 
have changed the titles of subpart I of part 314 and subpart H 
(formerly subpart G) of part 601 to better describe the scope of the 
subparts. Subpart I of part 314 is now entitled ``Approval of New Drugs 
When Human Efficacy Studies Are Not Ethical or Feasible'' and subpart H 
of part 601 is now entitled ``Approval of Biological Products When 
Human Efficacy Studies Are Not Ethical or Feasible.'' Proposed subpart 
G has been redesignated as subpart H in the final rule because subpart 
G has since been designated for regulations on postmarketing studies. 
Proposed Secs.  601.60 through 601.65 have been renumbered Secs.  
601.90 through 601.95 in subpart H.
    We have also changed, on our own initiative, the requirements 
proposed in Secs.  314.610(c) and 601.61(c) (Secs.  314.610(b)(3) and 
601.91(b)(3) in this final rule). We have deleted the requirement that 
self-administered drug products approved under this rule be in unit-of-
use packaging with attached patient labeling. In addition, we have 
eliminated the distinction between self-

[[Page 37990]]

administered products and products administered by health 
professionals.
    Whether a product is self-administered or administered by a health 
professional, it is important to inform patient recipients that a 
product approved under this rule has not been studied for efficacy in 
humans because of ethical or feasibility reasons.\2\ It is also 
important that patient recipients receive information about 
indications, dosage and administration, contraindications, reasonably 
foreseeable risks, adverse reactions, anticipated benefits, and drug 
interactions. This rule requires that all of this information be 
provided to patient recipients of products approved under subpart I of 
part 314 and subpart H of part 601.
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    \2\ In some cases, however, such as with anti-infective drug 
products, it would usually be expected that human data on safety and 
effectiveness for other indications may be available.
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    We believe, however, that the proposed unit-of-use packaging and 
attached patient-labeling requirement could have had the unintended 
effect of hampering the distribution and dispensing of these products 
in the event of an emergency. The added bulk of unit-of-use packaging 
could have made stockpiling and transporting more difficult in many 
cases. The proposed requirement might also have hampered the speedy 
distribution of products for additional indications previously approved 
outside of this rule.
    Applicants may meet the requirements of new Secs.  314.610(b)(3) 
and 601.91(b)(3) in a variety of ways, as long as sponsors make 
provisions to get the information to patients. For example, the sponsor 
could provide reproducible master copies of labeling information or 
presentations for patient recipients that would be appropriate in the 
event of an emergency.
    We have also changed proposed Secs.  314.610(c) and 601.61(c) (Secs.  
314.610(b) and 601.91(b) in this final rule) to require that the 
patient labeling explain that, for ethical or feasibility reasons, the 
product's approval was based on efficacy studies conducted only in 
animals. This explanation will better inform patient recipients about 
the nature and ethical basis of the product approval under this rule 
and how that approval differs from approval of products based on 
standard human efficacy studies.
    Finally, we have added to Secs.  314.610(b)(1) and 601.91(b)(1) 
(proposed Secs.  314.610(a) and 601.61(a)) a requirement that 
applicants include a plan or approach to fulfilling postmarketing study 
commitments as part of their application. We recognize that such 
studies normally will not be conducted unless an emergency arises that 
requires the product's use. Furthermore, when the product is used in an 
emergency, it may not be feasible for sponsors to conduct postmarketing 
studies in a timely manner, nor is it our intention to require sponsors 
to send investigators into areas of exposure. We do, however, believe 
that applicants can plan a postmarketing study approach, in 
consultation with the agency, as part of an overall response to an 
event.
    The requirement to submit a plan for postmarketing studies is 
consistent with the requirements for sponsors under the accelerated 
approval process provided for in subpart H of part 314.
    The procedures in subpart H and in this rule are similar because, 
to assess efficacy, both allow use of an endpoint that is not a 
clinical endpoint showing a benefit. Instead the rules under subpart H 
allow for reliance on a clinical surrogate endpoint and this rule 
allows for the use of animal data as an endpoint.
    Postmarketing studies are critical in both of these situations to 
verify and describe the clinical benefit of the drug or biological 
product. The postmarketing studies may provide us with data that 
directly verify that the product provides the desired benefit in 
humans, such as increased survival or prevention of major morbidity.
    (Comment 1) One comment suggested that we define ``lethal'' and 
``permanently disabling.'' The comment expressed concern that without 
such definitions, subpart I of part 314 and subpart H of part 601 will 
be misapplied in situations where clinical testing can and should be 
carried out.
    The definitions of ``lethal'' and ``permanently disabling'' would 
seem to be well understood. Although we share the concern that too 
expansive an interpretation of ``lethal'' or ``permanently disabling'' 
could lead to attempts to apply this rule when human studies are, in 
fact, feasible, we are also concerned that too restrictive a definition 
of ``lethal'' or ``permanently disabling'' could lead to failure to 
apply subpart I of part 314 and subpart H of part 601 in situations 
where they should be applied to protect the public health. We believe 
that, as a general matter, we must rely on the good sense and 
responsibility of those health professionals who will be seeking to 
apply subpart I of part 314 and subpart H of part 601 in the future, 
and on responsible review of specific cases by FDA. Nevertheless, we 
can provide guidance for applying subpart I of part 314 and subpart H 
of part 601 by clarifying that a ``lethal substance'' is one that is 
likely to kill at least some of the humans who have been exposed to the 
substance and a ``permanently disabling substance'' is one that is 
likely to cause a permanent physical or mental impairment that 
substantially limits one or more of the major life activities in at 
least some of the humans who have been exposed to the substance.
    (Comment 2) One comment stated that the rule does not explicitly 
cover infectious substances and pointed out that not all infectious 
substances produce toxins. The comment suggested replacing ``toxic'' 
with ``toxic and/or infectious'' in proposed Secs. 314.600 and 601.60 
(Sec.  601.90 in this final rule).
    The rule is certainly intended to cover products for treatment of 
infections. At some level, an infectious agent that is lethal or 
permanently disabling is toxic to its host, even if that agent is not 
itself a ``toxin'' or a producer of ``toxins'' within a strict 
definition of the word. Because we do not use ``toxin'' in the rule, 
and ``toxic'' is accurate, we do not believe we need to replace 
``toxic'' with ``toxic and/or infectious'' to indicate that products 
for the treatment of infections may be approved under this rule.
    (Comment 3) One comment noted that the proposed rule did not 
discuss criteria that should be applied in determining if ``an 
important medical need is not adequately met by currently available 
therapies.'' The comment suggested that we state that we will use the 
criteria given in our guidance for industry entitled ``Fast Track Drug 
Development Programs--Designation, Development, and Application 
Review'' (September 1998).
    We have decided to eliminate the requirement that ``products would 
be expected to provide meaningful therapeutic benefits to patients over 
existing treatments,'' as well as the limitation that the toxic agent 
be ``without a proven treatment'' (proposed Secs. 314.600 and 601.60). 
Recent events involving the multiple exposures to anthrax in our 
population, and deaths resulting from those infections, have indicated 
a need for a wide range of therapeutic options that, in some instances, 
might be inappropriately limited by requiring new products to have a 
therapeutic benefit over existing treatments, or to be used only in the 
absence of a proven treatment. Availability of a variety of drug and 
biological products is important because, for example, patient 
recipients may be allergic to one product and require another, may be 
intolerant of a product because of side effects, or may respond more 
favorably to one product

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than another. We also believe that a wider variety of therapeutic 
choices will limit potential problems with availability, accessibility, 
and distribution of products. We have modified the final rule to 
address these concerns and help ensure the availability of more than 
one therapeutic option.
    (Comment 4) One comment requested that antivenin and antitoxin 
products of animal origin be considered for inclusion specifically on 
the list of new drugs and biological products to which the rule 
applies.
    There is no list of products that may be approved based on evidence 
of effectiveness from efficacy studies in animals. The rule provides 
criteria to determine if evidence of effectiveness from efficacy 
studies in animals may support approval of a product. If an antivenin 
or antitoxin product of animal origin meets the criteria specified in 
the rule, it may be approved on the basis of evidence of effectiveness 
from efficacy studies in animals.
    (Comment 5) One comment requested that we revise proposed 
Secs. 314.610 and 601.61 (Sec. 601.91 in this final rule) to state that 
substantiation in multiple animal species is required only where 
appropriate. The comment stated we should not limit ourselves to 
approvals only when there is substantiation in ``multiple'' animal 
species. The comment contended that where independent studies in a 
single species meet the general principles of independent 
substantiation as described in the guidance for industry entitled 
``Providing Clinical Evidence of Effectiveness for Human Drugs and 
Biological Products'' (May 1998), those studies are sufficient to 
substantiate effectiveness as a matter of science and a requirement of 
substantiation in multiple species would result in an unnecessary delay 
of agency approval. According to the comment, these concerns are 
particularly important where viruses have a narrow host range and 
conducting efficacy trials in more than one animal species in such 
cases either is not feasible or provides only limited additional 
information that is relevant to the full-blown disease in humans. The 
comment suggested that the requirement of substantiation in multiple 
species in a given case should depend on the known host range and the 
availability of animal model systems.
    We share some of the concerns expressed in the comment, but we 
believe the proposed remedy goes too far. Approval of the use of a drug 
lacking human evidence of effectiveness represents a significant 
departure from ordinary practice. There are countless examples of 
treatments with favorable effects in animals that did not prove 
effective in humans. Although this rule does, for good reason, allow 
reliance on animal studies when human studies cannot be conducted, in 
general we expect that the evidence, to be persuasive, should be 
developed in more than one animal species unless the effect is 
demonstrated in a single animal species that represents a sufficiently 
well-characterized animal model for predicting the response in humans. 
We recognize that conducting studies in more than one species can 
result in added expense, but we believe this is warranted because of 
the additional assurance they would provide.
    Furthermore, reliance on our guidance entitled ``Providing Clinical 
Evidence of Effectiveness for Human Drugs and Biological Products'' is 
misplaced. That guidance was drafted to provide advice on the quantity 
of data from clinical studies needed to support a finding of 
effectiveness and, specifically, on when the agency ought to rely on a 
single human study. The guidance addressed cases in which the issue is 
the credibility of the data itself, not the relevance of the data to 
humans. In this rule, the issue is the ability of results from animal 
studies to predict the human response, and not the credibility of the 
animal finding itself (although, of course, the animal studies should 
be replicated or substantiated in each species as needed to ensure 
credible results). The need for multiple species in certain cases is to 
enhance the likelihood that the data are pertinent to humans.
    We do recognize, however, that the multiple species requirement 
could be inappropriate or unnecessary in certain situations. For 
example, there may be only one species capable of reacting with a 
response predictive for humans. This would occur where there is only 
one nonhuman host for the targeted microorganism. There may also be 
other situations in which studies in a particular species are 
specifically well recognized as predictors of effectiveness in humans. 
Thus, circumstances in which the agency will rely on evidence from 
studies in one animal species to provide substantial evidence of the 
effectiveness of these products in humans would generally be limited to 
situations where the study model is sufficiently well-recognized so as 
to render studies in multiple species unnecessary. In addition, other 
human data for the product could provide support for such approvals.
    Accordingly, we have changed proposed Secs. 314.610 and 601.61 
(Sec.  601.91(c) in this final rule) to require that approval be based 
on studies in more than one animal species unless the effect is 
demonstrated in a single animal species that represents a sufficiently 
well-characterized animal model for predicting the response in humans. 
The agency believes that demonstrating effectiveness in studies 
conducted in a single animal species using a well-characterized animal 
model will most often be done for anti-infective drug products. The 
pathophysiological mechanisms of infectious diseases are usually very 
well understood, and animal models for many infectious diseases have 
been studied for years and are very well characterized.
    (Comment 6) One comment suggested we remove the requirement that 
there be a reasonably well-understood pathophysiological mechanism of 
the toxicity of the substance and its prevention or substantial 
reduction by the product. The comment stated it is hard to say when we 
understand something reasonably well and that, if we decide to retain 
the requirement, we should state at what level (e.g., cellular, 
molecular) the mechanism must be understood.
    A disease's or toxin's mechanism of action does not need to be 
understood before a safe and effective treatment or preventative can be 
devised. Quinine and Jenner's smallpox vaccine were both developed 
before the acceptance of the germ theory of disease. Neither is there a 
general requirement that an applicant who is relying on human testing 
to establish effectiveness demonstrate the mechanism of action of the 
drug or biological product that is the subject of the marketing 
application. It is generally sufficient to demonstrate that a product 
is safe and effective. It is generally not required that an applicant 
demonstrate how or why the product is safe and effective.
    It is true that a pathophysiologic understanding of a disease and 
treatment is not required when human studies are used to support 
approval. In the case of human drug or biological products approved on 
the basis of evidence of effectiveness from studies in animals, 
however, we are requiring an understanding of the mechanism of the 
toxic substance or infectious organism and its prevention or reduction 
by the product. This understanding helps provide assurance that the 
efficacy data from studies in animals can be applied to humans. We have 
not specified exactly what degree of pathophysiologic understanding is 
needed, and that will be a matter of judgment. The level of 
understanding could range from a complete understanding of how a toxic

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substance works at the cellular level in both human and animal cells 
together with a clear understanding of what the antidote does at the 
molecular level to a less complete understanding. The level of required 
understanding of the mechanism of action of the toxic substance or 
infectious organism and the product may vary from toxic substance to 
toxic substance or infectious organism to infectious organism and could 
even vary from one product to another intended to treat the same 
condition.
    (Comment 7) One comment suggested that an institutional review 
board (IRB) or other ethical scientific review body determine if it 
would be unethical to conduct studies in humans. The comment also said 
we do not mention who would make the determination that it would be 
unethical to conduct studies in humans.
    The final determination that it is unethical to conduct studies in 
humans will be made by the reviewing officials in FDA. We anticipate 
that in most cases the determination as to whether it would be 
unethical to conduct studies in humans will not be difficult. In those 
cases that are difficult, the views of one or more IRBs, individual 
ethicists and clinicians, and FDA advisory committees could be sought 
by a sponsor or FDA. A case where such a consultation could be useful 
is one in which a putatively subtoxic dose would be used in humans to 
establish at least a mechanism for protection, if not actual 
protection.
    (Comment 8) One comment noted that we said in the proposed rule:
    The agency also intends in most cases to consult on applications 
to market such products with an advisory committee, supplemented 
with 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 (64 FR 
53960 at 53964 and 53965).
    The comment asked us to consider requiring consultation with an 
advisory committee either before conducting the animal studies or 
before approval of the product, or both.
    We want to reiterate our statement in the proposed rule that we 
intend usually to consult with an advisory committee during the 
approval process. Indeed, we may consult with an advisory committee 
more than once on a single product if circumstances warrant it. 
Consultation with an advisory committee could occur early in the 
development process, to discuss whether the concept of using certain 
animal data to support efficacy is reasonable.
    Even though consultation with an advisory committee is generally 
desirable, it is not always practical. For example, products reviewed 
under this rule may be part of the response to a public health 
emergency; therefore, there may not be time to convene an advisory 
committee. Accordingly, we believe that it would be inappropriate to 
absolutely require consultation with an advisory committee.
    (Comment 9) One comment questioned whether patient labeling is 
adequate to inform patients that a product has been approved on the 
basis of animal efficacy data, particularly in situations where 
military personnel are ordered to take a product approved under this 
rule. The comment did not suggest an alternative to the provisions of 
the rule.
    Sections 314.610(b)(3) and 609.91(b)(3) provide that for products 
or specific indications approved under this rule, applicants must 
prepare, as part of their proposed labeling, labeling to be provided to 
patients or potential patients. The patient labeling, written in 
language that can be easily understood by the general public, must 
explain that, for ethical or feasibility reasons, the product's 
approval was based on efficacy studies conducted in animals alone. The 
labeling must give the product'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. If possible, the patient labeling must be 
available with the product to be provided to patients or potential 
patients prior to administration or dispensing of the product for the 
use approved under this rule. We intend that in interpreting 
Sec. Sec. 314.610(b)(3) and 601.91(b)(3), the word ``possible'' be 
given its ordinary and literal meaning. Situations in which it would be 
inconvenient or require some effort to make the labeling available for 
patients should not be equated with situations in which it would be 
impossible to do so.
    These provisions, coupled with communications within a health care 
provider-patient relationship should, as a general matter in both 
civilian and military contexts, adequately ensure that patients are 
informed that the product they are taking has been approved based on 
animal efficacy data.
    (Comment 10) One comment suggested that labeling a drug or 
biological product approved on the basis of evidence of effectiveness 
from studies in animals as ``FDA approved'' is misleading, because 
patients would assume that the product had been approved based on human 
studies. The comment suggested that we treat the product as an 
investigational new drug, but waive certain requirements generally 
applied to investigational new drugs, if those requirements would 
provide obstacles to the product's use in an emergency.
    We agree that the labeling would be misleading if information were 
not included to explain to patients or potential patients that the 
effectiveness of the product was demonstrated in animals not humans, 
and that this reliance on animal efficacy data was based on ethical and 
feasibility concerns. Therefore, under sections 502(a) and 701(a) of 
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352(a) 
and 372(a)) (and consistent with the legal authority cited in the 
preamble to the proposed rule (64 FR 53960 at 53964)), we have revised 
the language in Secs. 314.610(b)(3) and 601.91(b)(3) to require that 
this information be included in the patient labeling.
    Where the evidence of effectiveness comes from studies in animals, 
regulating new drug or biological products as investigational drugs 
presents several difficulties. These difficulties have led us to this 
rulemaking. The proposed rule describes our concerns with relying 
solely on the investigational new drug regulations (64 FR 53960 at 
53963) for such approvals. There may be cases, however, when an 
application does not meet the criteria of this rule, and approval of 
the product is not feasible. Should an emergency situation arise under 
such circumstances, it is conceivable that the product could be used 
under the investigational new drug regulations.
    (Comment 11) Another comment suggested that, unless ``lay persons'' 
may use the product, we prohibit advertising of drug or biological 
products approved on the basis of evidence of effectiveness from 
studies in animals. The comment further recommended stringent controls 
on the advertising of products that could be used by ``lay persons.''
    Such a sweeping prohibition would likely give rise to 
constitutional issues regarding the regulation of commercial speech. In 
addition, the suggestion presents serious public health concerns. A 
prohibition on advertising could limit health care providers' and 
public health and emergency preparedness officials' awareness of the 
products approved under this rule. Limiting awareness of these 
products, which are intended to

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reduce or prevent life-threatening or disabling toxicity, does not seem 
desirable or appropriate.
    We believe that the advertising provisions in Secs.  314.640 and 
601.94 of this rule provide adequate protection against false or 
misleading advertising, and no additional requirements are needed. As 
discussed in the preamble to the proposed rule (64 FR 53960 at 53964), 
we proposed the requirements pertaining to promotional materials in 
order to provide for the safe and effective use of these products. 
These requirements, along with others, are similar to those in the 
accelerated approval regulations in subpart H of part 314 and in 
subpart E of part 601. In issuing the accelerated approval regulations, 
we stated that the special circumstances under which those products 
would be approved and the possibility that promotional materials could 
adversely affect the sensitive risk/benefit balance justified review of 
promotional materials before and after approval (57 FR 58942 at 58949). 
Similarly, the special circumstances of all product approvals under 
subpart I of part 314 and subpart H of part 601 and the possibility 
that promotional materials could adversely affect the even more 
sensitive risk/benefit balance justifies advance review of promotional 
materials.
    We intend to review all such promotional materials under these new 
regulations promptly, and to notify the applicant of any identified 
problems as soon as possible (see also 57 FR 58942 at 58950). Also as 
with the accelerated approval regulations' requirements for promotional 
materials (Secs.  314.560 and 601.46), FDA may terminate the 
requirements for advance submission of promotional materials under 
these new regulations at Secs.  314.650 and 601.95 if the agency 
determines, on its own initiative or in response to a petition 
submitted by the sponsor, that the requirements are no longer necessary 
for safe and effective use of the product. When we remove the 
requirement for advance submission of promotional materials, we will 
continue to offer a prompt review of all voluntarily submitted 
promotional materials.
    (Comment 12) We received some comments addressing questions posed 
in section VII, ``Discussion,'' of the proposed rule. In this final 
rule, we have addressed comments that dealt with the rule itself. 
Comments that dealt with questions related to the application of this 
rule, rather than the requirements, will be addressed if and when we 
draft a guidance on this subject.

III. Legal Authority

    We did not receive any comments discussing our legal authority to 
approve new drugs and biological products based on evidence of 
effectiveness from studies in animals. We have concluded, for the 
reasons set out in section V of the proposed rule, ``Legal Authority,'' 
(64 FR 53960 at 53964), that we have the legal authority to approve new 
drugs and biological products based on evidence of effectiveness from 
studies in animals.
    (Comment 13) We received a comment asserting that under the court's 
holding in American Pharmaceutical Association v. Weinberger, 377 
F.Supp. 824 (D.C.D.C. 1974) aff'd sub nom. American Pharmaceutical 
Association v. Mathews, 530 F.2d 1054 (D.C. Cir. 1976) (per curiam), we 
do not have the legal authority to impose the distribution controls 
proposed in Secs. 314.610(b) and 601.61(b) (Secs.  314.610(b)(2) and 
601.91(b)(2) in this final rule). The comment asked that, if we 
disagree with their characterization of the law, distribution controls 
not be applied just because a product was approved under the provisions 
of this rule. The comment also asked that we give examples of 
situations where we would impose distribution restrictions.
    For a full discussion of FDA's authority to impose distribution 
restrictions to ensure the safe use of drug products, see the agency's 
proposed and final rules amending part 314 by adding subpart H on 
accelerated approval of new drugs for serious or life-threatening 
illnesses (proposed rule at 57 FR 13234, April 15, 1992; final rule at 
57 FR 59842, December 11, 1992). Those rules relied on sections 501, 
502, 503, 505, and 701 of the act (21 U.S.C. 351, 352, 353, 355, and 
372) as authority for FDA to issue regulations to help ensure the 
safety and effectiveness of new drugs.
    We agree with the comment that distribution controls should not be 
placed on a product solely because it is approved under the provisions 
of this rule. New Secs.  314.610(b)(2) and 601.91(b)(2) authorize 
distribution controls--they do not require them.
    We do not believe it would be useful to give examples of situations 
where distribution controls may be necessary to ensure safe use of the 
product. Products approved under this rule could be indicated for 
widely differing conditions, and those products could be used in unique 
circumstances presenting many distinct safety concerns. It would not be 
practical to try to devise a list of representative examples of 
situations where distribution controls would be appropriate.

IV. Environmental Impact

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

V. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

VI. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121)) and the Unfunded Mandates Reform Act of 1995 
(Public Law 104-4). 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). Unless the agency certifies that the rule is not expected to 
have a significant economic impact on a substantial number of small 
entities, the Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant economic impact 
of a rule on small entities. Section 202 of the Unfunded Mandates 
Reform Act (Public Law 104-4) requires that agencies prepare an 
assessment of anticipated costs and benefits before proposing any rule 
that may result in expenditure by State, local, and tribal governments, 
in the aggregate, or by the private sector, of $100 million in any one 
year (adjusted annually for inflation).

[[Page 37994]]

    The agency has determined that the rule is consistent with the 
principles set forth in the Executive order and in these statutes. FDA 
finds that this rule will not have an effect on the economy that 
exceeds $100 million in any one year (adjusted for inflation). The 
current inflation-adjusted statutory threshold is about $110 million. 
Therefore, no further analysis is required under the Unfunded Mandates 
Reform Act. Because this rule does not impose any new costs on small 
entities, FDA certifies that this rule will not result in a significant 
economic impact on a substantial number of small entities. Thus, the 
agency need not prepare a Regulatory Flexibility Analysis. The agency 
reached the same conclusions in its proposed rule. FDA has not received 
any new information or comments that would alter its previous 
determinations.

VII. The Paperwork Reduction Act of 1995

    This final 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). The title, 
description, and respondent description of the information collection 
provisions are shown below 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.
    Title: New Drug and Biological Products; Animal Efficacy Studies.
    Description: FDA is amending its new drug and biological product 
regulations to allow appropriate studies in animals in certain cases to 
provide substantial evidence of effectiveness 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 the studies would involve administering a potentially lethal or 
permanently disabling toxic substance or organism to healthy human 
volunteers and field trials are not feasible prior to approval. In 
these circumstances, when it may be impossible to demonstrate 
effectiveness through adequate and well-controlled studies in humans, 
FDA is providing that certain new drug and biological products intended 
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 taking 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.

                                                     Table 1.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                           Annual Frequency      Total Annual
                   21 CFR Section                     No. of Respondents     per Response          Responses      Hours per Response      Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.610(b)(2) and 314.630 601.91(b)(2) and 601.93             1                   1                   1                   5                   5
314.610(b) and 314.640 601.91(b) and 601.94                   1                   1                   1                 240                 240
                                                                                                                                     -------------------
Total                                                                                                                                       245
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


                                              Table 2.--Estimated Annual Disclosure/Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            No. of         Annual Frequency      Total Annual          Hours per
                   21 CFR Section                        Recordkeepers     per Recordkeeping        Records          Recordkeeper         Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
314.610(b)(2) and 314.630 601.91(b)(2) and 601.93             1                   1                   1                   1                   1
314.610(b) 601.91(b)                                          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 parts 310 and 
600 (21 CFR parts 310 and 600), and 314. 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 AER; 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.

[[Page 37995]]

    The information collection provisions in this final rule have been 
approved under OMB control number 0910-0423. This approval expires 
December 31, 2002. An agency may not conduct or sponsor, and a person 
is not required to respond to, a collection of information unless it 
displays a currently valid OMB control number.

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, 21 CFR parts 
314 and 601 are amended as follows:

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW 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, 355a, 356, 
356a, 356b, 356c, 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 When Human Efficacy Studies Are 
Not Ethical or Feasible

Sec.
314.600  Scope.
314.610  Approval based on evidence of effectiveness 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 When Human Efficacy Studies Are 
Not Ethical or Feasible


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. 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; and field trials to study 
the product's effectiveness after an accidental or hostile exposure 
have not been feasible. This subpart does not apply to products that 
can be approved based on efficacy 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 the products 
to which it does apply.


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

    (a) 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 
studies when the results of those animal studies establish that the 
drug product is reasonably likely to produce clinical benefit in 
humans. In assessing the sufficiency of animal data, the agency may 
take into account other data, including human data, available to the 
agency. FDA will rely on the evidence from studies in animals to 
provide substantial evidence of the effectiveness of these products 
only when:
    (1) There is a reasonably well-understood pathophysiological 
mechanism of the toxicity of the substance and its prevention or 
substantial reduction by the product;
    (2) The effect is demonstrated in more than one animal species 
expected to react with a response predictive for humans, unless the 
effect is demonstrated in a single animal species that represents a 
sufficiently well-characterized animal model for predicting the 
response in humans;
    (3) The animal study endpoint is clearly related to the desired 
benefit in humans, 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.
    (b) Approval under this subpart will be subject to three 
requirements:
    (1) Postmarketing studies. The applicant must conduct postmarketing 
studies, such as field studies, to verify and describe the drug's 
clinical benefit and to assess its safety when used as indicated when 
such studies are feasible and ethical. Such postmarketing studies would 
not be feasible until an exigency arises. When such studies are 
feasible, the applicant must conduct such studies with due diligence. 
Applicants must include as part of their application a plan or approach 
to postmarketing study commitments in the event such studies become 
ethical and feasible.
    (2) Approval with restrictions to ensure 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 ensure safe use of the 
drug product, commensurate with the specific safety concerns presented 
by the drug product, such as:
    (i) Distribution restricted to certain facilities or health care 
practitioners with special training or experience;
    (ii) Distribution conditioned on the performance of specified 
medical procedures, including medical followup; and
    (iii) Distribution conditioned on specified recordkeeping 
requirements.
    (3) Information to be provided to patient recipients. For drug 
products or specific indications approved under this subpart, 
applicants must prepare, as part of their proposed labeling, labeling 
to be provided to patient recipients. The patient labeling must explain 
that, for ethical or feasibility reasons, the drug's approval was based 
on efficacy studies conducted in animals alone and must 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. The 
patient labeling must be available with the product to be provided to 
patients prior to administration or dispensing of the drug product for 
the use approved under this subpart, if possible.


Sec. 314.620  Withdrawal procedures.

    (a) Reasons to withdraw approval. 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 ensure 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

[[Page 37996]]

    (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 functions. 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 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 requirements 
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 must 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 must 
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)(2), 314.620, and 314.630 
are no longer necessary for the safe and effective use of a drug 
product, FDA 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 ensured 
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, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).

    4. Subpart H, consisting of Secs. 601.90 through 601.95, is added 
to read as follows:

Subpart H--Approval of Biological Products When Human Efficacy 
Studies Are Not Ethical or Feasible

Sec.
601.90  Scope.
601.91  Approval based on evidence of effectiveness from studies in 
animals.
601.92  Withdrawal procedures.
601.93  Postmarketing safety reporting.
601.94  Promotional materials.
601.95  Termination of requirements.

Subpart H--Approval of Biological Products When Human Efficacy 
Studies Are Not Ethical or Feasible


Sec. 601.90  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. 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; and field trials to study 
the product's efficacy after an accidental or hostile exposure have not 
been feasible. This subpart does not apply to products that can be 
approved based on efficacy 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 the products to which it does 
apply.


Sec. 601.91  Approval based on evidence of effectiveness from studies 
in animals.

    (a) FDA may grant marketing approval for a biological product for 
which safety has been established and for which the requirements of 
Sec. 601.90 are met based on adequate and well-controlled animal 
studies when the results of those animal studies establish that the 
biological product is reasonably likely to produce clinical benefit in 
humans. In assessing the sufficiency of animal data, the agency may 
take into account other data, including human data, available to the 
agency. FDA will rely on the evidence from studies in animals to 
provide substantial evidence of the effectiveness of these products 
only when:
    (1) There is a reasonably well-understood pathophysiological 
mechanism of the toxicity of the

[[Page 37997]]

substance and its prevention or substantial reduction by the product;
    (2) The effect is demonstrated in more than one animal species 
expected to react with a response predictive for humans, unless the 
effect is demonstrated in a single animal species that represents a 
sufficiently well-characterized animal model for predicting the 
response in humans;
    (3) The animal study endpoint is clearly related to the desired 
benefit in humans, 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.
    (b) Approval under this subpart will be subject to three 
requirements:
    (1) Postmarketing studies. The applicant must conduct postmarketing 
studies, such as field studies, to verify and describe the biological 
product's clinical benefit and to assess its safety when used as 
indicated when such studies are feasible and ethical. Such 
postmarketing studies would not be feasible until an exigency arises. 
When such studies are feasible, the applicant must conduct such studies 
with due diligence. Applicants must include as part of their 
application a plan or approach to postmarketing study commitments in 
the event such studies become ethical and feasible.
    (2) Approval with restrictions to ensure 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 ensure safe 
use of the biological product, commensurate with the specific safety 
concerns presented by the biological product, such as:
    (i) Distribution restricted to certain facilities or health care 
practitioners with special training or experience;
    (ii) Distribution conditioned on the performance of specified 
medical procedures, including medical followup; and
    (iii) Distribution conditioned on specified recordkeeping 
requirements.
    (3) Information to be provided to patient recipients. For 
biological products or specific indications approved under this 
subpart, applicants must prepare, as part of their proposed labeling, 
labeling to be provided to patient recipients. The patient labeling 
must explain that, for ethical or feasibility reasons, the biological 
product's approval was based on efficacy studies conducted in animals 
alone and must give the biological product'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. The patient labeling must be 
available with the product to be provided to patients prior to 
administration or dispensing of the biological product for the use 
approved under this subpart, if possible.


Sec. 601.92  Withdrawal procedures.

    (a) Reasons to withdraw approval. 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 ensure 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 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 functions. 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. 601.93  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. 601.94  Promotional materials.

    For biological products being considered for approval under this 
subpart, unless otherwise informed by the agency, applicants must 
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 must submit promotional materials at least 30 
days prior to the intended time of initial dissemination of the 
labeling or initial publication of the advertisement.

[[Page 37998]]

601.95  Termination of requirements.

    If FDA determines after approval under this subpart that the 
requirements established in Secs. 601.91(b)(2), 601.92, and 601.93 are 
no longer necessary for the safe and effective use of a biological 
product, FDA will so notify the applicant. Ordinarily, for biological 
products approved under Sec. 601.91, 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. 601.91, the restrictions would no longer 
apply when FDA determines that safe use of the biological product can 
be ensured 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 23, 2002.
Lester M. Crawford,
Deputy Commissioner.
[FR Doc. 02-13583 Filed 5-30-02; 8:45 am]
BILLING CODE 4160-01-S