[Federal Register: December 2, 1998 (Volume 63, Number 231)]
[Rules and Regulations]
[Page 66631-66672]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02de98-24]

[[Page 66631]]

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Part II

Department of Health and Human Services

_______________________________________________________________________

Food and Drug Administration

_______________________________________________________________________

21 CFR Parts 201, 312, 314 and 601

Regulations Requiring Manufacturers to Assess the Safety and
Effectiveness of New Drugs and Biological Products in Pediatric
Patients; Final Rule

[[Page 66632]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 312, 314, and 601

[Docket No. 97N-0165]
RIN 0910-AB20

Regulations Requiring Manufacturers to Assess the Safety and
Effectiveness of New Drugs and Biological Products in Pediatric
Patients

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing new
regulations requiring pediatric studies of certain new and marketed
drug and biological products. Most drugs and biologics have not been
adequately tested in the pediatric subpopulation. As a result, product
labeling frequently fails to provide directions for safe and effective
use in pediatric patients. This rule will partially address the lack of
pediatric use information by requiring that manufacturers of certain
products provide sufficient data and information to support directions
for pediatric use for the claimed indications.

DATES: Effective date. The regulation is effective April 1, 1999.
    Compliance dates. Manufacturers must submit any required
assessments of pediatric safety and effectiveness 20 months after the
effective date of the rule, unless the assessments are waived or
deferred by FDA.

FOR FURTHER INFORMATION CONTACT: Khyati N. Roberts, Center for Drug
Evaluation and Research (HFD-103), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-6779, or Karen D. Weiss,
Center for Biologics Evaluation and Research (HFM-570), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-5093.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In the Federal Register of August 15, 1997 (62 FR 43900)
(hereinafter referred to as the proposal), FDA proposed to require that
manufacturers of certain new and marketed drugs and biologics conduct
studies to provide adequate labeling for the use of these products in
children. As described in the proposal, children are subject to many of
the same diseases as adults, and are, by necessity, often treated with
the same drugs and biological products as adults. However, many drugs
and biological products marketed in the United States that are or could
be used in children are inadequately labeled for use in pediatric
patients or for use in specific pediatric subgroups (Refs. 1 and 2).
Indeed, many of the drugs and biological products that are widely used
in pediatric patients carry disclaimers stating that safety and
effectiveness in pediatric patients have not been established (Refs. 2
and 3). Safety and effectiveness information for some pediatric age
groups is particularly difficult to find. For example, there is almost
no information on use in patients under 2 years of age for most drug
classes (Ref. 1).
    As described in more detail in the proposal, the absence of
pediatric labeling information poses significant risks for children.
Inadequate dosing information exposes pediatric patients to the risk of
adverse reactions that could be avoided with an appropriate pediatric
dose. The lack of pediatric safety information in product labeling
exposes pediatric patients to the risk of age-specific adverse
reactions unexpected from adult experience. The proposal cited reports
of injuries and deaths in children resulting from use of drugs that had
not been adequately tested in the pediatric population. The absence of
pediatric testing and labeling may also expose pediatric patients to
ineffective treatment through underdosing, or may deny pediatric
patients therapeutic advances because physicians choose to prescribe
existing, less effective medications in the face of insufficient
pediatric information about a new medication. Failure to develop a
pediatric formulation of a drug or biological product, where younger
pediatric populations cannot take the adult formulation, may also deny
pediatric patients access to important new therapies, or may require
pediatric patients to take the drug in extemporaneous formulations that
may be poorly or inconsistently bioavailable.
    The proposed rule described previous steps taken by FDA in recent
years to address the problem of inadequate pediatric testing and
inadequate pediatric use information in drug and biological product
labeling. FDA's Center for Drug Evaluation and Research (CDER) and
Center for Biologics Evaluation and Research have implemented a
``Pediatric Plan'' designed to focus attention on, and encourage
voluntary development of, pediatric data both during the drug
development process and after marketing. In addition, in the Federal
Register of December 13, 1994 (59 FR 64240) (hereinafter referred to as
the 1994 rule), FDA issued a regulation requiring manufacturers of
marketed drugs to survey existing data and determine whether those data
were sufficient to support additional pediatric use information in the
drug's labeling. Under the 1994 rule, if a manufacturer determines that
existing data permit modification of the label's pediatric use
information, the manufacturer must submit a supplemental new drug
application (NDA) to FDA seeking approval of the labeling change.
    Although the preamble to the 1994 rule recognizes FDA's authority
to require drug and biological product manufacturers to conduct
pediatric studies on a case-by-case basis, the rule does not impose a
general requirement that manufacturers carry out studies when existing
information is not sufficient to support pediatric use information.
Instead, if there is insufficient information to support a pediatric
indication or pediatric use statement, the rule requires the
manufacturer to include in the product's labeling the statement:
``Safety and effectiveness in pediatric patients have not been
established.''
    The response to the 1994 rule has not substantially addressed the
lack of adequate pediatric use information for marketed drugs and
biological products. Pediatric labeling supplements were submitted for
approximately 430 drugs and biologics, a small fraction of the
thousands of prescription drug and biological products on the market.
Of the supplements submitted, approximately 75 percent did not
significantly improve pediatric use information. Over half of the total
supplements submitted simply requested the addition of the statement
``Safety and effectiveness in pediatric patients have not been
established.'' Others requested minor wording changes or submitted
unorganized, unanalyzed collections of possibly relevant data.
Approximately 15 percent (approximately 65) of the supplements provided
adequate pediatric information for all relevant pediatric age groups,
and another 8 percent (approximately 35) provided adequate pediatric
information for some but not all relevant age groups.
    The absence of adequate pediatric use information remains a problem
for new drugs and biologics as well as for marketed products. The
proposal presented data from 1988 through the 1990's showing that the
percentage of new products entering the marketplace with adequate
pediatric safety and effectiveness information has not increased in the
last decade.
    For example, FDA compared the number of new molecular entities
(NME's) approved in 1991 and 1996

[[Page 66633]]

with potential usefulness in pediatric patients and looked at the
adequacy of pediatric labeling for those drugs. Fifty-six percent (9/
17) of the NME's approved in 1991 with potential usefulness in
pediatric patients had some pediatric labeling at the time of approval.
In 1996, only 37 percent (15/40) of the NME's with potential usefulness
in pediatric patients had some pediatric labeling at the time of
approval. For both 1991 and 1996, those drugs counted as having
pediatric labeling may not have been studied in all age groups in which
the drug was potentially useful. The manufacturers of an additional 7
of the 1991 drugs and 17 of the 1996 drugs promised to conduct
pediatric studies after approval. Since publication of the proposal,
figures for 1997 NME's have become available. In 1997, 39 NME's were
approved. Twenty-seven had potential usefulness in pediatric patients,
and 33 percent of these (9/27) had some pediatric labeling at the time
of approval. Postapproval studies were requested or promised for an
additional six. It is uncertain how many of the commitments made for
postapproval studies of the 1996 and 1997 drugs will result in
pediatric labeling. Of the seven NME's approved in 1991 for which
sponsors made commitments to conduct postapproval pediatric studies,
pediatric labeling has been added to only one. This figure reflects
both studies that resulted in positive labeling, i.e., safety and
dosing information, and studies that resulted in warnings against
pediatric use. It does not reflect studies that failed to provide any
useful information about pediatric use or studies that were completed
but the sponsor failed to seek a change in its pediatric use labeling.
    These data indicate that voluntary efforts have, thus far, not
substantially increased the number of products entering the marketplace
with adequate pediatric labeling. FDA has therefore concluded that
additional steps are necessary to ensure the safety and effectiveness
of drug and biological products for pediatric patients. This rule
requires the manufacturers of new and marketed drugs and biological
products to evaluate the safety and effectiveness of the products in
pediatric patients, if the product is likely to be used in a
substantial number of pediatric patients or would provide a meaningful
therapeutic benefit to pediatric patients over existing treatments.
    In addition to issuing this rule, FDA has initiated other actions
that it hopes will encourage the development of adequate pediatric use
information. FDA has issued a draft guidance document entitled
``General Considerations for Pediatric Pharmacokinetic Studies for
Drugs and Biological Products'' (November 30, 1998). FDA also plans to
develop additional guidance on how to develop effectiveness, safety,
and dosing information to support pediatric labeling. The agency also
supported a provision in the reauthorized Prescription Drug User Fee
Act (PDUFA) eliminating user fees for pediatric supplements to
encourage the submission of these supplements.
    Finally, FDA has issued a guidance document entitled ``Providing
Clinical Evidence of Effectiveness for Human Drug and Biological
Products,'' describing the kinds of studies that can support
effectiveness in supplemental or original applications. In that
document, FDA provides guidance to manufacturers on the circumstances
in which FDA may approve an initial or supplemental claim in which
substantiation of the results of an adequate and well-controlled trial
is provided by information other than a second adequate and well-
controlled trial precisely replicating the first trial, or the
circumstances in which studies without the extensive documentation
ordinarily required could be utilized. This guidance will often be
relevant to the data needed to support claims in a pediatric
population.
    Since the issuance of the proposal, Congress has enacted a bill
that has an impact on pediatric studies of certain drugs. The Food and
Drug Administration Modernization Act of 1997 (FDAMA) (Pub. L. 105-115)
contains provisions that establish economic incentives for conducting
pediatric studies on drugs for which exclusivity or patent protection
is available under the Drug Price Competition and Patent Term
Restoration Act (Pub. L. 98-417) and the Orphan Drug Act (Pub. L. 97-
414). These provisions extend by 6 months any existing exclusivity or
patent protection on a drug for which FDA has requested pediatric
studies and the manufacturer has conducted such studies in accordance
with the requirements of FDAMA. FDAMA also specifically recognizes
FDA's intention to require pediatric studies by regulation and extends
by 6 months any existing exclusivity or patent protection on a drug
whose manufacturer submits pediatric studies in compliance with this
rule, if the studies meet the completeness, timeliness, and other
requirements of section 505A. Under FDAMA, a manufacturer who submits
pediatric studies required under this rule may receive a 6-month
extension of exclusivity or patent protection granted to the
manufacturer for that drug.
    Although FDA expects the exclusivity offered by FDAMA to provide a
substantial incentive for sponsors to conduct some pediatric studies,
the agency nonetheless believes that this final rule is necessary to
significantly increase the number of drug and biological products that
have adequate labeling. Certain limitations on the scope and effect of
the exclusivity offered by FDAMA are likely to leave significant gaps
in pediatric labeling. For example, because FDAMA exclusivity applies
only to products that have exclusivity or patent protection under the
Drug Price Competition and Patent Term Restoration Act and the Orphan
Drug Act, it provides no incentive to conduct studies on certain
categories of products, including most antibiotics, biologics, and off-
patent products.
    In addition, the voluntary nature of the incentive provided by
FDAMA is likely to leave many drugs, age groups, and indications
unstudied. Given limited resources to conduct pediatric studies, it is
probable that manufacturers will elect to conduct pediatric studies
preferentially on those drugs for which the incentives are most
valuable, i.e., on drugs with the largest sales. This may leave
unstudied drugs that are greatly needed to treat pediatric patients,
but that have smaller markets. For similar reasons, manufacturers are
less likely to seek FDAMA exclusivity by conducting studies on drugs
that require studies in neonates, infants, or young children. The
youngest pediatric populations are more difficult to study and may
require pediatric formulations, making pediatric studies of these
groups more expensive, thereby reducing the value of the incentives
provided by FDAMA. Thus, where there is a great medical need for data
on drugs with relatively small markets or for studies on neonates,
infants, or young children, it may be necessary to require the
collection of such data, rather than rely on incentives.
    Finally, manufacturers are eligible for FDAMA exclusivity when they
submit a study to FDA that is consistent with FDA's written request for
such a study. The study results are not required to provide useful
information on pediatric use (e.g., the results may be inconclusive),
and the sponsor is not required to obtain approval of a supplement
adding the information gained in the study to the drug's label. Thus,
FDAMA provides no guarantee that the studies conducted under the
statute will result in improved pediatric labeling.

[[Page 66634]]

    For these reasons, FDA believes that there remains an important
need for this rule. FDA has concluded, however, that with respect to
already marketed drugs eligible for exclusivity under FDAMA, the
publication of the list required by section 505A(b) and the
availability of pediatric exclusivity may diminish the need to exercise
the agency's authority to require studies. Under the rule, FDA has
discretion whether to require studies of marketed drugs (see
Sec. 201.23 (21 CFR 201.23)). FDA believes that, in exercising its
discretion under Sec. 201.23, it is appropriate to determine whether
manufacturers will undertake the needed studies voluntarily. FDA will
therefore allow an adequate opportunity for manufacturers voluntarily
to submit studies for drugs listed by FDA as having a high priority.
If, following such an opportunity, there remain marketed drugs for
which studies are needed and the compelling circumstances described in
the rule are met, the agency will consider exercising its authority to
require studies. With respect to marketed drugs and biologics that are
not eligible for exclusivity under FDAMA, FDA intends to exercise its
authority to require studies as of the effective date of the rule in
the circumstances described in the regulation. FDA emphasizes that the
appearance of a drug or biologic on the list published under section
505A(b) carries no implication that FDA will require studies on that
drug or biologic under this rule. FDA intends to reserve its authority
to require studies of marketed drugs and biologics to situations in
which the compelling circumstances described in the regulation are
present.
    FDA intends to issue further regulations and guidance implementing
the pediatric exclusivity provisions of FDAMA, which will, among other
things, provide guidance on the interaction of this rule and FDAMA
exclusivity.

II. Highlights of the Final Rule

    This final rule is designed to ensure that new drugs and biological
products contain adequate pediatric labeling for the approved
indications at the time of, or soon after, approval. The final rule
establishes a presumption that all new drugs and biologics will be
studied in pediatric patients, but allows manufacturers to obtain a
waiver of the requirement if the product does not represent a
meaningful therapeutic benefit over existing treatments for pediatric
patients and is not likely to be used in a substantial number of
pediatric patients. The rule also authorizes FDA to require pediatric
studies of those marketed drugs and biological products that: (1) Are
used in a substantial number of pediatric patients for the claimed
indications, and where the absence of adequate labeling could pose
significant risks; or (2) would provide a meaningful therapeutic
benefit over existing treatments for pediatric patients, and the
absence of adequate labeling could pose significant risks to pediatric
patients.

A. Scope of Rule

    The proposed rule would have required an application for a drug
classified as a ``new chemical entity'' or a new (never-before-
approved) biological product to contain safety and effectiveness
information on relevant pediatric age groups for the claimed
indications. Based upon comments observing that changes in already
marketed chemical entities, such as new indications or dosage forms,
can have as much or more therapeutic significance for pediatric
patients than the original product, the final rule expands the scope of
the rule to include new active ingredients, new indications, new dosage
forms, new dosing regimens, and new routes of administration for which
an applicant seeks approval. The final rule does not, however, require
the submission of pediatric data for a drug for an indication or
indications for which orphan designation has been granted under section
526 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.
360bb).

B. Types of Studies Needed

    As described in the 1994 final rule, gathering adequate data to
establish pediatric safety and effectiveness may not require controlled
clinical trials in pediatric patients. Where the course of the disease
and the product's effects are similar in adults and pediatric patients,
FDA may conclude that pediatric safety and effectiveness can be
supported by effectiveness data in adults together with additional
data, such as dosing, pharmacokinetic, and safety data in pediatric
patients. The rule also does not necessarily require separate studies
in pediatric patients. In appropriate cases, adequate data may be
gathered by including pediatric patients as well as adults in the
original studies conducted on the product.
    The specific pediatric information needed in each case will depend
on the nature of the application, what is already known about the
product in pediatric populations, and the underlying disease or
condition being treated. The final rule requires an assessment of
safety and effectiveness in pediatric patients only for the indications
claimed by the manufacturer. It does not require a manufacturer to
study its product for unapproved or unclaimed indications, even if the
product is widely used in pediatric patients for those indications. In
the proposed rule, the pediatric study requirement for drugs was
contained in Sec. 314.50(g) (21 CFR 314.50(g)). In the final rule, the
requirement is located in new Sec. 314.55, because Sec. 314.50 does not
contain other specific study requirements. The location of the
requirement for biological products (Sec. 601.27 (21 CFR 601.27))
remains unchanged in the final rule.

C. Age Groups

    The final rule requires pediatric studies in each age group in
which the drug or biological product will provide a meaningful
therapeutic benefit or will be used in a substantial number of
pediatric patients for the indications claimed by the manufacturer. The
relevant age groups will, however, be defined flexibly, depending on
the pharmacology of the drug or biological product, rather than
following the fixed age categories defined in the 1994 rule and
identified in the preamble to the proposed rule. For drugs and
biological products that offer a meaningful therapeutic benefit, the
rule requires manufacturers to develop pediatric formulations, if
needed, for those age groups in which studies are required.
Manufacturers may, however, avoid this requirement if they demonstrate
that reasonable attempts to develop a pediatric formulation have
failed.

D. Not-Yet-Approved Products

1. Deferral of Studies Until After Approval
    The final rule permits the submission of pediatric information to
be deferred until after approval if there is an adequate justification
for deferral, e.g., because pediatric studies should not begin until
some safety and/or effectiveness information on adults has been
collected, or awaiting the completion of pediatric studies would delay
the availability of a product to adults. When trials should begin in
particular cases, and whether deferral will be necessary, will depend
upon the seriousness of the disease for which the drug or biological
product is indicated, the need for the product, the amount of safety
and effectiveness data available, and what types of pediatric studies
are needed.
    In general, FDA expects that studies of drugs or biological
products for diseases that are life threatening in pediatric patients
and that lack adequate

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therapy could begin earlier than studies of drugs that are less
urgently needed, ordinarily as early as the availability of preliminary
safety data in adults (frequently referred to as phase 1 data), even if
data from well-controlled studies are not yet available. For less
critical drugs and biologics, pediatric studies could ordinarily begin
when additional safety and/or effectiveness data from the initial well-
controlled trials in adults (frequently referred to as phase 2 data)
became available. Of course, studies of products for exclusively
pediatric diseases ordinarily need not await the development of adult
data. The timing of individual pediatric studies will, however,
necessarily depend on the specific information available about the
product in question. For example, a study of a noncritical drug in
adolescents might begin after the initial safety studies in adults, if
all the parties involved agreed that initiation was appropriate in
light of the results of the adult and animal safety studies.
    In other cases, studies should not begin in pediatric patients
until significantly more adult data are collected. For example, FDA
does not believe that early study or use in pediatric patients is
appropriate for some so-called ``me-too'' drugs that are expected to be
widely used but are members of a drug class that already contains an
adequate number of approved products with pediatric labeling. Such
drugs may not have been shown to provide any benefit over other
products in the same class, and may introduce new risks that are not
apparent until the drug has been in wide use after marketing. Studies
of such drugs will therefore usually be deferred until the safety
profiles of the drugs are well established through marketing
experience. To encourage use of properly labeled drugs in pediatric
patients, FDA may require the pediatric use section of the approved
labeling of such a me-too drug to contain a statement recommending
preferential use of other drugs that are adequately labeled for
pediatric use.
2. Waiver of the Study Requirement
    The pediatric study requirement applies to all applications for new
active ingredients, new indications, new dosage forms, new dosing
regimens, and new routes of administration, unless FDA waives the
requirement. Under criteria established in the rule, FDA may waive the
study requirement for some or all pediatric age groups. The burden is
on the sponsor to justify a waiver. A waiver will be granted if the
waiver request demonstrates that the product meets both of the
following conditions: (1) The product does not represent a meaningful
therapeutic benefit for pediatric patients over existing treatments,
and (2) the product is not likely to be used in a substantial number of
pediatric patients. There was some confusion in the comments on the
proposed rule over these waiver criteria. FDA emphasizes that the study
requirement applies to a product that offers a meaningful therapeutic
benefit even if it is not used in a substantial number of pediatric
patients, and vice versa.
    In response to comments, FDA has refined its definitions of
``meaningful therapeutic benefit'' and ``substantial number of
pediatric patients.'' To define meaningful therapeutic benefit for both
drugs and biologics covered by this rule, FDA has relied, in part, on
CDER's current administrative definition of a ``Priority'' drug,
applied to pediatric populations. The administrative definition of
``Priority'' products for biologics relies on different criteria (Ref.
2). Use of CDER's Priority drug definition to help define ``meaningful
therapeutic benefit'' is not intended to affect the administrative
definition of a Priority biologic. The Priority classification for
drugs is determined based on CDER's estimate, at the time of NDA
submission, of a drug's therapeutic, preventive, or diagnostic value. A
Priority drug is defined as one that, if approved, would be a
significant improvement in the treatment, diagnosis, or prevention of a
disease, compared to marketed products approved for that use. In
establishing meaningful therapeutic benefit for pediatric use, the
comparison will be to other products adequately labeled for use in the
relevant pediatric population. If there are no such products, a new
product would usually be considered to have a meaningful therapeutic
benefit. Improvement over existing products labeled for pediatric use
can be demonstrated by, for example: (1) Evidence of increased
effectiveness in treatment, prevention, or diagnosis of disease; (2)
elimination or substantial reduction of a treatment-limiting drug
reaction; (3) documented enhancement of patient compliance; or (4)
evidence of safety and effectiveness in a new subpopulation. Evidence
of improvement over existing therapies need not in all cases come from
head-to-head trials.
    To help ensure that pediatric patients have a sufficient range of
treatments available, a product will also be considered to provide a
meaningful therapeutic benefit if it is in a class of products or for
an indication for which there is a need for additional therapeutic
options, notwithstanding the fact that it might not be a priority drug.
In contrast to the range of therapies for a given indication often
available to adults, there are relatively few instances in which
therapeutic alternatives are studied and labeled for pediatric
patients. For some diseases, however, it is therapeutically important
to have a range of available treatment options, e.g., because there are
frequent treatment failures. The Priority definition would cover the
first product labeled for pediatric use, but might not cover the second
or third product for a given indication or in a given class, if the
subsequent product did not offer an advantage over existing therapies.
The specific number of products needed will depend upon such factors as
the severity of the disease being treated and the adverse reaction
profile of existing therapies. FDA will seek further guidance on
applying this criterion from a panel of pediatric experts.
    Thus, new products will meet the definition of a meaningful
therapeutic benefit if: (1) They provide a significant improvement over
existing adequately labeled therapies; or (2) if they are indicated for
diseases or conditions, or are in product classes, in which there are
currently few products labeled for pediatric use and more therapeutic
options are needed. FDA expects that over time, as the number of
products adequately labeled for pediatric patients grows, the number of
new products meeting the second criterion will diminish. FDA emphasizes
that the addition of the second criterion for defining meaningful
therapeutic benefit under this final rule is not intended to alter the
definition of a Priority drug, and that products meeting the second
criterion will not thereby be eligible for Priority status. FDA also
notes that the rule's definition of meaningful therapeutic benefit is
intended to apply only in the pediatric study context.
    FDA has also revised the proposed definition of ``a substantial
number of pediatric patients.'' Many comments argued that the number
chosen by FDA in the proposal (100,000 prescriptions per year or
100,000 pediatric patients with the disease) was arbitrary. Physician
mention data from the IMS National Disease and Therapeutic Index (Ref.
38), which tracks the use of drugs by measuring the number of times
physicians mention drugs during outpatient visits, shows that pediatric
use of drugs is generally grouped in two distinct ranges. Physician
mentions of drugs for pediatric use generally fall either below 15,000
per year or above 100,000 per year. Few drugs fall within the two
ranges. Thus, selecting a cut-off

[[Page 66636]]

for ``substantial number of pediatric patients'' in the middle of the
two ranges will provide a reasonable discrimination between products
that are widely used and those that are less commonly used, and the
specific number chosen will not arbitrarily include or exclude a
significant number of drugs. FDA has therefore chosen 50,000 as the
cut-off for a substantial number of pediatric patients. Because the
number of pediatric patients with the disease or condition is easier to
determine than the number of prescriptions per year, a substantial
number of pediatric patients will be defined as 50,000 pediatric
patients with the disease or condition for which the drug or biological
product is indicated. Although physician mentions per year does not
correspond exactly to the number of patients with the disease or
condition, they provide a rough approximation and the IMS data show
that the number of products included or excluded is relatively
insensitive to changes in the cut-off chosen. As proposed, a partial
waiver for a particular pediatric age group would be available under
this method if 15,000 patients in that age group were affected by the
disease or condition. This definition of ``a substantial number of
pediatric patients'' has not been codified, however, and FDA may modify
it, after consulting with a panel of pediatric experts. Any
modification will be issued in a guidance document with an opportunity
for comment.
    FDA will also waive the pediatric study requirement where: (1) The
applicant shows that the required studies on the product are impossible
or highly impractical because, for example, the population is too small
or geographically dispersed; (2) the product is likely to be unsafe or
ineffective in pediatric patients; or (3) reasonable efforts to develop
a pediatric formulation (if one is needed) have failed.
    To reduce the burden on manufacturers in applying for waivers and
deferrals, FDA intends to issue a guidance document providing a format
for a request for waiver or deferral.

E. Marketed Products

    The final rule is also intended to improve pediatric use
information for already marketed drugs and biological products. The
rule codifies FDA's authority, discussed in the 1994 rule, to require,
in the compelling circumstances described in the regulation, that
manufacturers of already marketed drugs and biological products conduct
studies to support pediatric-use labeling for the claimed indications.
The criteria for requiring studies of marketed products have been
revised slightly in response to comments.

F. Early Discussions and Pre- and Postmarket Reports

    The final rule contains provisions designed to encourage
discussions of the need for pediatric studies early in the drug
development process, as well as pre- and postmarketing reporting
requirements designed to assist FDA in determining whether pediatric
studies are needed for particular products and whether required studies
are being carried out with due diligence.

G. Pediatric Committee

    Many comments on the proposed rule urged FDA to form a committee of
outside experts to assist in various aspects of the implementation of
the rule. FDA has concluded that such a panel could provide useful
advice and experience. FDA will convene a panel of pediatric experts,
including at least one industry representative, and seek its advice on
a range of issues related to implementation of the rule, including: (1)
The agency's implementation of all aspects of the final rule, including
its waiver and deferral decisions; (2) which marketed drugs and
biological products meet the criteria for requiring studies; (3) when
additional therapeutic options are needed for a given disease or
condition occurring in pediatric patients; (4) ethical issues raised by
clinical trials in pediatric patients; (5) the design of trials and
analysis of data for specific products or classes of products; and (6)
issues related to the progress of individual studies.

H. Remedies for Violation of the Rule

    For violations of this rule, FDA would ordinarily expect to file an
enforcement action for an injunction, asking a Federal court to find
that the product is misbranded under section 502 of the act (21 U.S.C.
352) or is an unapproved new drug under section 505(a) of the act (21
U.S.C. 355) or an unlicensed biologic under section 351 of the Public
Health Service Act, and to require the company to submit an assessment
of pediatric safety and effectiveness for the product. Violation of the
injunction would result in a contempt proceeding or such other
penalties as the court ordered, e.g., fines. FDA does not intend,
except possibly in rare circumstances, to disapprove or withdraw
approval of a drug or biological product whose manufacturer violates
requirements imposed under this rule.

III. Comments on the Proposed Rule

    FDA received 54 written comments on the proposed rule from
pediatricians, professional societies, parents, members of the
pharmaceutical industry, organizations devoted to specific diseases,
and patient groups. A significant majority of the comments, primarily
those from pediatricians, professional societies, parents,
organizations devoted to specific diseases, and patient groups,
supported regulations requiring that drugs and biologics be studied in
children. Many of these comments described the problems faced by the
pediatric community and parents resulting from inadequate pediatric
labeling and the absence of pediatric formulations, and argued that a
pediatric study requirement was long overdue. Some comments, primarily
those from the pharmaceutical industry, opposed a pediatric study
requirement, arguing that existing voluntary measures and incentives
were sufficient to ensure adequate pediatric labeling. Finally, a
number of comments addressed FDA's legal authority to require pediatric
testing of drugs and biologics.
    FDA also held a day-long public hearing on October 27, 1997, in
Washington, DC, at which recognized experts in the field, members of
the pharmaceutical industry, and other interested parties were given an
opportunity to discuss the issues raised by the proposed rule. There
were three panels, each of which comprised representatives from
industry, the pediatric community, organizations devoted to specific
diseases, patient groups, and a bioethicist. The panels considered the
following three issues: (1) When pediatric studies are needed, (2) what
types of studies are needed, and (3) special challenges in testing
pediatric patients. Those who spoke were nearly unanimous in their
support for some kind of regulation requiring pediatric studies of some
drugs and biologics. There was, however, a wide range of views on which
drugs and biologics should be the subject of required studies and on
how the requirement should be implemented.
    Many written and oral comments raised specific issues for
consideration by the agency. These comments are addressed below.

A. Purpose of Rule

    1. FDA received many comments arguing that this rule is needed to
ensure adequate medical care for children. Many comments from
pediatricians stated that they regularly must prescribe to young
children drugs

[[Page 66637]]

that are not labeled for children under 6 or even 12, and for which
pediatric dosage forms do not exist. One comment stated that, without
adequate testing and labeling, physicians must estimate appropriate
pediatric doses, and that even at ``appropriate'' doses, it is not
known whether use in children is as safe as use in adults. One comment
argued that the absence of pediatric labeling puts children at greater
risk for adverse drug reactions (ADR's) and therapeutic failures than
adults. According to another comment, most common and severe ADR's in
pediatric patients would be eliminated by adequate testing, and that
perhaps 2 percent of all pediatric hospitalizations are due to ADR's.
One comment concluded that the failure to conduct pediatric studies
results in a different standard of care for children and adults in this
country.
    A comment from a pharmaceutical trade association argued, however,
that most of the toxicity problems identified by FDA as caused by
inadequate pediatric labeling were from the 1950's and that these
``dated'' examples are not relevant to current practice. As an example,
the comment cited chloramphenicol, a drug referred to by FDA in the
proposed rule because, when it was used in the 1950's in neonates
without adequate testing, it was responsible for many infant deaths
(Ref. 4). According to the comment, it is now known that
chloramphenicol can be used in neonates if the dose is correct. The
comment also stated that practicing physicians have access to adequate
dosing information from case reports in the medical literature.
    FDA agrees that the absence of adequate pediatric labeling puts
pediatric patients at risk for adverse drug reactions and ineffective
dosing. FDA believes that the reference to new dosing information that
permits use of chloramphenicol in infants illustrates the need for this
final rule. Had adequate safety and dosing information been available
earlier, many babies' lives could have been saved. Instead, adequately
supported dosing information was not available until after the drug had
been used in a large number of babies, with tragic consequences. FDA
also disagrees with the comment that the remaining reports cited in the
proposal of unexpected toxicity in pediatric patients from inadequately
tested drugs are ``dated.'' Contrary to the assertion in the comment, a
majority of these reports are from the 1980's and 1990's (Refs. 5
through 14).
    FDA also does not believe that case reports scattered through the
medical literature are an adequate substitute for organized and
complete pediatric labeling information. To the extent that published
experience is informative and credible, it should be used to improve
labeling. The comments received from pediatricians reflect their view
that there is often no adequately supported dosing and safety
information for the drugs they use routinely in their patients. Even
where case reports are available, they describe a limited number of
pediatric patients and cannot provide sufficient information to
establish the safety profile of a drug in pediatric patients.
    2. Some comments argued that pediatric studies are needed because
differences between children and adults can make extrapolation from
adult data treacherous. One comment pointed out that research on
antiarrhythmics in pediatric patients has revealed many surprises in
dosing and side effects. For example, drugs that bind to milk may cause
safety or effectiveness problems in pediatric patients not detected in
adults.
    FDA agrees that pediatric dosing cannot necessarily be extrapolated
from adult dosing information using an equivalence based either on
weight milligram/kilogram (mg/kg) or body surface area (mg/m \2\).
There are potentially significant differences in pharmacokinetics, or
unique drug-food interactions, that may alter a drug's blood levels in
pediatric patients. Moreover, there can be pharmacodynamic differences
between adults and pediatric patients.
    3. Several comments argued that voluntary measures have not
resulted in a significant increase in pediatric labeling, and that new
products continue to enter the market without adequate, or any,
pediatric labeling. Pediatricians, professional societies, parents,
organizations devoted to specific diseases, and patient groups provided
many examples of diseases and drug classes for which pediatric labeling
was long-delayed, inadequate, or nonexistent. Acquired immune
deficiency syndrome (AIDS) drugs were frequently cited as an example of
the industry's failure to obtain adequate pediatric labeling at or near
the time of approval. One comment pointed to protease inhibitors, which
are theoretically most effective in newborns but have not been tested
or approved for use in this group. Even for older children, the comment
observed that it has taken over a year after adult approval to obtain
pediatric labeling for these life-saving drugs. Another comment stated
that the absence of drugs for human immunodeficiency virus (HIV)
infection that are appropriately labeled and formulated for pediatric
patients causes parents to give children inappropriate doses, sometimes
giving up part of their own dose if the child's physician will not
prescribe it.
    Other comments pointed out that epilepsy is considered a pediatric
disease but claimed that many new epilepsy drugs are approved without
information for use in pediatric patients. These comments urged that
anti-epileptic drugs be added to the list of drug classes with
inadequate labeling. A comment from a specialist in pulmonary medicine
stated that although asthma is a common disease in pediatric patients,
adult formulations are often released first, leaving pediatric patients
without effective treatments. Other comments observed that not one of
the standard immunosuppressive medications used in pediatric patients
has been tested in pediatric patients. One comment contended that poor
information about the pharmacokinetics of these drugs in pediatric
patients has led to inadequate dosing to achieve effectiveness and
possibly unnecessary toxicity.
    The American Psychiatric Association commented that significant
psychiatric diseases are increasingly diagnosed in pediatric patients,
who may be treated with drugs despite the lack of pediatric labeling.
According to this comment, most psychoactive medications are
underutilized in pediatric patients due to the lack of pediatric
labeling and to fear of overdosing. In the case of anti-hyperactivity
drugs, however, the comment states that as many children are
overtreated as undertreated, especially among pre-school age children.
A comment from the National Institute of Mental Health (NIMH) stated
that the rule was much needed to provide essential data on the safety
and effectiveness of psychiatric medications in pediatric patients.
This comment attached seven NIMH reviews of the existing data on
psychotropic medications for pediatric patients, identifying many
critical knowledge gaps that remain to be addressed by pediatric
research.
    One comment stated that pediatric nephrologists frequently
prescribe drugs to pediatric patients for life-threatening conditions,
including antihypertensive medications, diuretics, lipid-lowering
agents, and immunosuppressive agents, even for pediatric patients less
than 2 years of age, without benefit of formal studies. This comment
further stated that drug therapy for chronic conditions like kidney
failure is currently based only on experience gained from drug usage in
children after approval for the indication in adults, and that

[[Page 66638]]

discovering ``inadequate dosing or severe side effects by empiric use
of these drugs is not desirable or safe.'' Another comment provided the
results of a survey of 4,898 pediatric patients with end-stage renal
disease on the medications they receive. Ninety-seven percent received
prednisone or prednisolone, 91 percent received cyclosporine, and 84
percent received azathioprine. According to the comment, none of these
drugs was studied in pediatric patients and no information on the
pharmacokinetics of these drugs in pediatric patients is available.
    In contrast, several comments from the pharmaceutical industry
argued that voluntary measures, the 1994 rule, and the incentives
provided by FDAMA are adequate to assure adequate pediatric labeling
and that FDA has not given these steps sufficient time to work. Several
comments argued that to obtain pediatric studies, FDA should use
encouragement and early discussion with sponsors, together with
incentives, rather than imposing new requirements. These comments
contended that sponsors should make ``phase 4 commitments''
(commitments to conduct pediatric studies after approval) and FDA
should track these commitments. According to one comment, these methods
have not been systematically used by FDA. According to another comment,
FDA did not describe its present experience in getting manufacturers to
conduct pediatric studies. Other comments argued that FDA has not
allowed the 1994 rule sufficient time to produce results and that the
agency should wait until it has reviewed and acted upon all supplements
submitted under that rule before imposing new requirements. One comment
contended that if the 1994 rule was successful in producing pediatric
labeling for marketed drugs, the new rule should apply only to new
drugs. One comment argued that incentives, including exclusivity,
waiver of user fees, tax credits, and expedited reviews of pediatric
supplements, and liability protection for research physicians,
Institutional Review Boards (IRB's), universities, pharmaceutical
firms, and parents, are the best means of obtaining pediatric labeling.
A few comments argued that excessive litigation will follow imposition
of this rule.
    Two comments argued that the 53 NME's approved in 1996 demonstrate
that pediatric labeling efforts by the industry are adequate, and that
new requirements are not needed. Although the figures used in the 2
comments do not agree exactly, these comments stated that 20 or 21 of
the 53 have potential for pediatric use. According to these comments,
of these, 4 have approved pediatric labeling, 14 have planned or
ongoing studies, 1 is switching to over-the-counter (OTC) use, and 1 or
2 have no immediate plans for pediatric labeling activities. One
comment contended that, between 1990 and 1997, a 28 percent increase
occurred in the number of new drugs in development for pediatric uses,
but provided no data to support this claim.
    FDA believes that the current state of pediatric labeling for drugs
and biologics in the United States, as amply illustrated by comments
from the pediatric community, is unsatisfactory. The agency's failure
to obtain a significant increase in labeling for either new or marketed
drugs or biologics through other measures implemented over the last
several years demonstrates the need for a requirement that sponsors
conduct pediatric studies of drugs and biologics that represent a
meaningful therapeutic benefit to pediatric patients or that will be
widely used in pediatric patients. As described in section I of this
document, the response to the 1994 rule has not produced a significant
improvement in pediatric labeling for marketed drugs. FDA received
labeling supplements only for a small fraction of the drugs and
biologics on the market. Of those supplements it did receive, over half
of the submissions merely sought to add a statement to the product's
labeling that ``safety and effectiveness in pediatric patients have not
been demonstrated,'' and less than a quarter provided adequate
pediatric information for some or all relevant age groups.
    The agency's experience in attempting to obtain pediatric labeling
for new drugs entering the marketplace through voluntary measures has
also been disappointing. As described in the proposal, the percentage
of NME's with adequate pediatric labeling has not increased since 1991,
when the agency began systematic efforts to obtain better pediatric
labeling. Although the number of requests by the agency and commitments
by sponsors to conduct phase 4 (postapproval) pediatric studies may
have increased, these requests and commitments have so far infrequently
resulted in pediatric labeling. Table 1 of this document displays the
results of commitments or requests to conduct pediatric studies
postapproval between 1991 and 1996. FDA notes that the table does not
reflect any labeling supplements under review. There are a total of six
pediatric labeling supplements currently under review for NME's
approved between 1991 and 1996. These supplements may or may not add
significant new labeling information; but, in any case, would not
substantially increase the number of successfully conducted
postapproval studies.

                                          Table 1.--Pediatric Labeling
----------------------------------------------------------------------------------------------------------------
              Status of pediatric labeling                 1991    1992    1993    1994    1995    1996   Totals
----------------------------------------------------------------------------------------------------------------
NME's approved..........................................      30      25      25      22      28      53     183
Pediatric studies not needed............................      14      11      11       7      14      13      70
Label includes some pediatric use information or
 pediatric studies complete at time of approval.........       9       4   \1\ 5   \1\ 6       5      15      44
Postapproval pediatric studies promised or requested....       7      10  \2\ 10  \2\<SUP>,\3
                                                                                    \ 10  \2\ 10      17      64
Pediatric labeling added after approval.................       1       0       2       4       2       2     11
----------------------------------------------------------------------------------------------------------------
\1\ In one case, pediatric use information provided for one of two approved indications.
\2\ In one case, pediatric data requested for second of two approved indications.
\3\ In one case, pediatric data requested for additional age groups.

    As Table 1 of this document reflects, FDA's figures disagree with
those of the comments for the number of 1996 NME's with potential for
pediatric use, the number with some pediatric labeling at the time of
approval and the number for which commitments or requests for
postapproval studies have been made. The comments did not identify
specific drugs, so it is not possible to determine why the two sets of
figures conflict. Nevertheless, the historical experience reflected in
the table suggests that most of the postapproval pediatric studies for
which commitments were made for the

[[Page 66639]]

1996 NME's will not result in pediatric labeling. Of the 17 commitments
to conduct pediatric studies in 1996, there have thus far been only 2
additions of pediatric labeling. Although some additional studies
supporting labeling changes may be submitted in the future, the
experience reflected in Table 1 of this document suggests that this
will not be a large number. For example, the 27 promised or requested
studies for the 1991 through 1993 cohorts have resulted in just 3
additions of pediatric labeling 5 to 7 years after approval. Thus, FDA
does not agree that the experience with 1996 NME's demonstrates the
adequacy of current efforts to obtain pediatric labeling.
    None of the comments claiming that the rule will result in
excessive litigation provided any evidence suggesting a relationship
between pediatric testing and increased litigation or liability. As
shown in the number of NME's with pediatric labeling at the time of
approval, a significant minority of drug and biologic manufacturers
already conducts pediatric testing. FDA is aware of no evidence that
excessive litigation has been associated with this testing.
    With respect to the argument that the incentives provided by FDAMA
will be sufficient to ensure adequate pediatric labeling, FDA believes
that a mixture of incentives and requirements is most likely to result
in real improvements in pediatric labeling. FDA is hopeful, e.g., that
the FDAMA incentives will make more resources available for pediatric
studies. As described earlier, FDA does not believe, however, that
incentives alone will result in pediatric studies on some of the drugs
and biologics where the need is greatest. The incentives provided by
FDAMA are available only for drugs already covered by the exclusivity
or patent protection provided by sections 505 and 526 of the act. Thus,
the FDAMA incentives are not available for many already marketed drugs,
or for many antibiotics or biologics. In addition, limited resources
available to conduct pediatric studies and fiduciary obligations to
shareholders may cause manufacturers to conduct pediatric studies
preferentially on those drugs where the incentives are most valuable,
rather than on those drugs or biological products where studies are
most needed.
    4. Two comments argued that the rule is inconsistent with a 1977
FDA document entitled ``General Considerations for the Clinical
Evaluation of Drugs in Infants and Children,'' which recommended, among
other things, that ``reasonable evidence of efficacy generally * * * be
known before infants and children are exposed to [a drug].''
    As described in more detail in section III.D of this document under
``Deferral,'' FDA expects that for drugs and biologics other than those
for life-threatening diseases without adequate treatment, clinical
trials in pediatric patients will ordinarily begin no earlier than when
initial data from well-controlled trials in adults (frequently referred
to as phase 2 data) become available to ensure that reasonable
preliminary evidence of safety and/or effectiveness is available before
pediatric patients are exposed to the drug or biological product. How
much evidence of safety or effectiveness is ``reasonable evidence''
that should be available before pediatric trials may begin will be
determined on a case-by-case basis. Thus, FDA believes that this rule
is substantially consistent with the 1977 document.
    FDA notes that the 1977 document was based upon a report prepared
for FDA under a contract with the American Academy of Pediatrics (AAP).
The AAP is currently developing proposed revisions to this document
concerning the types of data needed to support pediatric labeling. The
1977 document, which falls under the general category of guidance
documents, does not bind FDA or the public, but represents the agency's
current thinking on a particular issue. Alternative approaches may be
used if the alternative satisfies the requirements of the applicable
statute and regulations (62 FR 8961, February 27, 1997) (Good Guidance
Practices document). Until such time as an updated guidance on the
clinical evaluation of drugs in infants and children is published,
sponsors are encouraged to confer with the agency before initiating
pediatric studies.
    5. Several comments challenged FDA's use of the 1994 IMS National
Disease and Therapeutic Index (NDTI) data on the 10 drugs used most
frequently in pediatric patients without adequate labeling, arguing
that the data incorrectly imply that physicians have no labeling
information, when in fact prescribing information is now, or will be,
available for most of the 10 drugs listed.
    These comments misunderstand the purpose for which FDA cited the
1994 data. Those data provided a snapshot of the labeling information
available to physicians for 10 widely used drugs at a given point in
time. Even if additional information had been added to the labels of
these drugs in the 4 years since the survey was conducted, there was
none available during a year in which the drugs, together, were
prescribed to pediatric patients over 5 million times. FDA notes,
moreover, that, contrary to the suggestion in the comments, adequate
labeling has been added for only 1 of the 10 drugs for the age group
described in the proposal.
    6. Two comments disputed the estimated number of times their
products were prescribed to pediatric patients. One manufacturer argued
that the total units sold of Auralgan were less than the listed number
of prescriptions. Another manufacturer disputed the estimates of
Ritalin usage. This manufacturer also complained that it was not
contacted by FDA about use of Ritalin despite the statement in the
proposal that FDA had contacted the manufacturers of the top 10 drugs
used without adequate labeling in pediatric patients.
    Limitations on the data used to estimate number of prescriptions
may have resulted in the discrepancy noted by the manufacturers of
Auralgan or Ritalin. The number of prescriptions is estimated from data
provided by IMS America, Ltd. IMS NDTI surveys a sample of physicians
(more than 2,940 physicians representing 27 specialities) to determine
the number of times that, during patient contacts, physicians mentioned
specific drugs for particular age groups. Physician mentions may not
correlate exactly with actual usage. In addition, the NDTI numbers
taken from the sample of physicians are extrapolated to the nation as a
whole, using a given formula. With respect to the claim that FDA has
not contacted the manufacturer of Ritalin, FDA notes that it has
scheduled meetings with the manufacturer to discuss use of the drug in
children, which have been canceled at the manufacturer's request.
    7. One comment challenged FDA's use of quinolones as an example of
a class of drug that does not need to be studied in pediatric patients.
The comment claimed quinolones do need to be studied in pediatric
patients because of their important use in cystic fibrosis patients.
    FDA agrees that fluoroquinolones may provide important therapeutic
benefits to patients with cystic fibrosis. At present, all approved
fluoroquinolones are labeled with the following statement: ``Safety and
effectiveness in children and adolescents less than 18 years of age
have not been established.'' In addition, the label includes a
statement advising that the fluoroquinolones cause arthropathy in
juvenile animals. Historically, the agency has recognized a potential
therapeutic role for the fluoroquinolones in children with cystic
fibrosis and hematology/oncology

[[Page 66640]]

disorders. Indeed, FDA recently approved ciprofloxacin labeling
containing a discussion of cystic fibrosis experience in the pediatric
use subsection. These actions show that the agency recognizes that
there may be a need to study fluoroquinolones in some pediatric
patients.
    8. One comment from a pharmaceutical company argued that serious
ethical, legal, medical, and technical difficulties often prevent
conducting pediatric studies. The comment cited difficulties in
enrolling pediatric patients in sufficient numbers, unwillingness of
parents to enroll children, and the absence of pediatric patients with
the disease near convenient and qualified study centers. According to
the comment, studies have been successfully conducted in pediatric
patients in the past where there was a medical need for the drug in
pediatric patients, but this rule will require pediatric studies of
drugs intended for adults that may or may not be administered to
pediatric patients. The comment also contended that the rule will
necessitate a massive infusion of resources for industry, FDA, and
medical speciality organizations, and that the agency should start with
a small list of diseases with similar pathophysiology in adults and
children, and a small list of drug classes known to have similar
metabolism, and plan a graduated approach.
    Contrary to the suggestion in the comment, this rule is designed to
require studies only in those settings in which there is a significant
medical need or where usage among pediatric patients is likely to be
substantial. FDA acknowledges the difficulties encountered in some
cases, but agrees that where there is a need for studies these
difficulties have been overcome and that pediatric studies have been
successfully conducted in many situations. FDA believes that the number
of such studies already conducted each year, for example of
antibiotics, vaccines, and roughly 25 percent of NME's, support the
view that such studies are not medically, ethically, or technically
impossible. FDA also emphasizes that this rule will not require studies
in settings where ethical or medical concerns militate against studies.
As with all studies regulated by FDA, no pediatric study may go forward
without the approval of an IRB, which is responsible for ensuring that
the study is ethical and adequately protects the safety of the
subjects. In addition, the deferral provisions of the rule are
specifically designed to ensure that no pediatric study begins until
there are sufficient safety and effectiveness data to conclude that the
study is ethically and medically appropriate.

B. Scope

    The proposal would have covered only original applications for
those drugs classified as ``new chemical entities,'' including
antibiotics, and new biological products that had never been approved
for any indication. A ``new chemical entity,'' defined in 21 CFR
314.108(a), is a drug that contains no previously approved active
moiety. Under the proposal, chemical modifications that did not change
the active moiety, such as the formation of a different salt or ester
of the moiety, would not have required further study. New indications
or dosage forms of a previously approved moiety also would not have
required further studies. FDA sought comment on whether the requirement
should apply more broadly, e.g., to applications for minor chemical
variations of approved products, new indications, new dosage forms or
new routes of administration.
    9. A majority of those who commented on the scope of the rule
recommended that the final rule cover all new drugs and biologics,
including new dosage forms and indications, because modifications in
existing drugs may be as therapeutically significant to pediatric
patients as the original drug or biologic. These comments included
pediatricians, medical societies, one pharmaceutical company, and one
disease-specific organization. Several comments, including two
companies, an IRB, the AAP, a disease-specific organization, and a
professional society recommended including new indications and dosage
forms on a case-by-case basis, generally if their inclusion were
recommended by an expert panel. Several comments supported the narrow
scope of the proposal, including a pharmaceutical trade association, a
professional society, and several companies. The pharmaceutical trade
association suggested that the rule might also apply to new
formulations uniquely suited to pediatric patients.
    FDA has reconsidered the scope of the rule in light of the comments
and has concluded that, in some cases, the need for pediatric studies
is as great for modifications of existing products and new claims as
for the original products. A new indication or dosage form for a
previously approved drug, e.g., could be far more relevant to pediatric
patients than the originally approved product. From a public health
standpoint, FDA cannot justify the distinction in the proposal between
new chemical entities and never-before approved biologics, on one hand,
and significant modifications of those products, on the other hand.
Therefore, FDA has revised proposed Secs. 314.55 (proposed 314.50(g))
and 601.27(a) to cover applications for new active ingredients, new
indications, new dosage forms, new dosing regimens, and new routes of
administration. The final rule exempts from its coverage any drug for
an indication or indications for which orphan designation has been
granted under the Orphan Drug Act (21 U.S.C. 360bb). FDA believes this
exemption is appropriate because the purpose of the Orphan Drug Act is
to encourage the development of drugs for patient populations that are
so small as to make the manufacture and sale of the drug unprofitable
if not for the incentives offered by the Orphan Drug Act. Imposition of
a pediatric study requirement on an orphan drug could conflict with the
balance struck by the Orphan Drug Act, by further raising the cost of
marketing the drug. This exemption does not apply after marketing under
Sec. 201.23 of this final rule.
    FDA's decision to expand the scope of the rule does not mean,
however, that pediatric studies would always be needed for a new
product entering the marketplace, or for a new claim. The waiver
criteria will apply equally to modifications of existing drugs and
biological products. Thus, FDA will require studies only of those new
drugs and biologics that offer a meaningful therapeutic benefit to
pediatric patients or that are expected to be used in a substantial
number of pediatric patients. In many cases, moreover, new dosage forms
might need relatively little pediatric data, such as pharmacokinetic
data alone.
    10. One comment sought clarification of the applicability of the
rule to generic drugs. The comment argued that the collection of
pediatric data was unwarranted where a generic manufacturer was copying
a drug with an adult dose, and that FDA should require a pediatric
bioequivalence study only where the innovator submits a supplement for
a new dose or regimen in the pediatric population. Another comment from
a generic drug trade association argued that bioequivalence studies in
children should never be required to support approval of a generic
drug.
    This rule does not impose any requirements on studies submitted in
support of applications for generic copies of approved drugs that meet
the requirements of section 505(j) of the act. FDA also does not
currently require bioequivalence studies to be conducted

[[Page 66641]]

in children for generic drugs. FDA notes that petitions submitted under
section 505(j)(2)(C) for a change in active ingredient, dosage form, or
route of administration may be denied if ``investigations must be
conducted to show the safety and effectiveness of'' the change. Thus,
if a petition is submitted for a change that would require a pediatric
study under this rule, the petition may be denied.

C. Required Studies

    FDA proposed to amend its regulations related to the content of NDA
and biologic license applications (BLA's) to include required
information on pediatric studies for certain applications. Under the
proposal, an application for a new chemical entity or never before
approved biologic would have been required to contain data adequate to
assess the safety and effectiveness of the product for all pediatric
age groups for the claimed indications, unless FDA granted a deferral
or full or partial waiver of the requirement. As described in section
III.B of this document under ``Scope'', FDA has revised Sec. 314.55(a)
(proposed Sec. 314.50(g)(1)) and Sec. 601.27(a)) to cover applications
for new active ingredients, new indications, new dosage forms, new
dosing regimens, and new routes of administration. Under the final
rule, all covered applications will be required to contain data
adequate to assess the safety and effectiveness of the product, unless
FDA has granted a waiver or deferral of the requirement (see ``Waiver''
and ``Deferred Submission'' in section III.D and E of this document).
    Assessments required under this section for a product that
represents a meaningful therapeutic benefit over existing treatments
must be carried out using appropriate formulations for the age group(s)
for which the assessment is required, unless reasonable efforts to
produce a pediatric formulation had failed (see ``Waiver'' in section
III.E of this document). Comments on issues related to formulation are
addressed under ``Pediatric Formulations'' in section III.I of this
document.
    The proposal did not mandate particular types of studies. The
proposal recommended that the sponsor consult with FDA on the types of
data that would be considered adequate to assess pediatric safety and
effectiveness in particular cases.
    FDA received several comments on the design and conduct of clinical
trials in pediatric patients.
    11. One comment asked for clarification of what is meant by
``adequate evidence'' to demonstrate safety and effectiveness. The
comment argued that FDA should not require two adequate and well-
controlled trials for pediatric studies, and that the amount of
evidence required should depend on the ability of the data to be
extrapolated from adult to pediatric patients, the seriousness of the
illness to be treated, the ability to assess meaningful measures of
efficacy in pediatric patients, and the feasibility of conducting
adequate trials in relatively uncommon pediatric disease states.
Another comment claimed that the ability to extrapolate from adult
efficacy data is limited and argued that well-controlled trials in
pediatric patients should be the norm. This comment also stated that
safety cannot be extrapolated from adult data and recommended studying
300 pediatric patients for an adequate period to identify frequent
ADR's. Other comments questioned the appropriateness of extrapolating
from adult effectiveness data in a variety of settings. One comment
argued that in the area of blood products, in addition to extrapolating
from pharmacokinetic data, it may be appropriate to extrapolate from
adult data using relative blood volume replacement. Several comments
urged reliance on a variety of other sources of data, including
published studies and reports, and actual use information. One comment
urged FDA to rely on advanced scientific and statistical methods that
optimize safety, convenience, and informativeness, while minimizing
unnecessary or uninformative clinical trials.
    FDA agrees that ``adequate evidence'' of safety and effectiveness
for pediatric patients does not necessarily require two adequate and
well-controlled trials. One of two central purposes of the 1994 rule
was to make it clear that pediatric effectiveness may, in appropriate
circumstances, be based on adequate and well-controlled studies in
adults with supporting data in pediatric patients that permit
extrapolation from the adult data. FDA agrees, however, that
extrapolation from adult effectiveness data would not always be
appropriate and that it may not be appropriate to extrapolate pediatric
safety from adult safety data. FDA has specifically noted, in the FDA
guidance document entitled ``Providing Clinical Evidence of
Effectiveness for Human Drug and Biological Products,'' that if further
controlled trial data were needed in a population subset, it would
usually be sufficient to conduct a single additional controlled trial.
FDA also agrees that useful information can come from data other than
adequate and well-controlled trials, and encourages the submission of
valid and reliable data from a variety of sources. The type and amount
of data required in any particular case will depend upon many factors,
including those cited in the comments.
    12. One comment urged FDA, in the final rule, to encourage sponsors
to use Computer-Assisted Trial Design (CATD), allowing them to reduce
number of actual trials in pediatric patients.
    FDA encourages the use of any validated scientific method for
designing, conducting, or analyzing clinical trials.
    13. One comment questioned whether there will be a sufficient pool
of pediatric subjects to complete trials, in light of the increase in
the number of trials occasioned by the rule.
    FDA believes that with appropriate organization, the pool of
pediatric patients available for studies should be adequate. The
Pediatric Pharmacology Research Units (PPRU's), a network of groups
instituted to conduct pediatric research, some of which are located
outside of major population centers, have an established record of
recruiting pediatric patients and completing valid studies. Even where
the number of pediatric patients affected by a disease is small, valid
studies have sometimes been successfully conducted. It should also be
reemphasized that many of the studies contemplated under the rule are
pharmacokinetic studies, dose-response studies with short-term
endpoints (pharmacodynamic studies) and safety studies that are likely
to impose relatively little burden on individual patients. Where,
however, patient recruitment is so difficult as to make the study
impossible or highly impractical, the rule permits a waiver of the
study requirement (Secs. 314.55(c) and 601.27(c)).
    14. One comment urged that the final rule include a broader
research requirement, and sought to have drug interactions and drug
metabolism taken into consideration. Another comment sought to have the
final rule codify minimal requirements for studies, such as toxic
overdose and pharmacokinetic data. One comment urged FDA not to codify
specific requirements for clinical trials, but to establish these
requirements in consultation with an expert pediatric committee.
    FDA declines to codify specific requirements for pediatric studies.
Flexibility is necessary to assure that required studies are
appropriate for each product. FDA will, however, consult with a
pediatric committee on specific pediatric study issues.

[[Page 66642]]

    15. One comment from a professional pharmacy organization urged
that all protocols for pediatric studies be reviewed by pediatric
experts, including a pharmacist knowledgeable about pharmacodynamic
factors in each age group.
    FDA reviews protocols for pediatric studies submitted in
investigational new drug applications (IND's), and its reviewers
include experts in pediatrics and pharmacology.

D. Deferred Submission

    The proposal recognized that there would be circumstances in which
it would be appropriate to permit the submission of pediatric data
after approval. Two such circumstances were described in the preamble
to the proposal: (1) Where adult safety or effectiveness data need to
be collected before the product could be appropriately studied in
pediatric patients, and (2) where the product was ready for approval in
adults before studies in pediatric patients were completed. Although
not included in the text of the proposal, these examples have been
added to the final rule. Under the proposal, FDA would have the
authority to defer the submission of some or all of the required
pediatric data until after approval of the product for adult use, on
its own initiative or at the request of the applicant. Under the
proposed provisions, if the applicant requested deferral, the request
would be required to contain an adequate justification for delaying
pediatric studies. If FDA concluded that there were adequate
justification for deferring the submission of pediatric use studies,
the agency could approve the product for use in adults subject to a
requirement that the applicant submit the required pediatric studies
within a specified time after approval. It is important to appreciate
that deferred submission of pediatric data refers to the date on which
the data are submitted, not when the studies are initiated. Thus,
deferred studies will generally be initiated before approval, unless it
is concluded that the full adult data base or marketing experience are
needed before pediatric studies may appropriately begin.
    FDA stated in the proposal that it would consult with the sponsor
in determining a deadline for the deferred submission, but tentatively
concluded that it would require the submission not more than 2 years
after the date of the initial approval. To ensure that deferral would
not unnecessarily delay the submission of pediatric use information,
FDA proposed that a request for deferred submission include a
description of the planned or ongoing pediatric studies, and evidence
that the studies were being, or would be, conducted: (1) With due
diligence, and (2) at the earliest possible time. FDA sought comment on
the circumstances in which FDA should permit deferral, and on the
factors that should be considered in determining whether a given
product was one that should be studied in adults before pediatric
patients. FDA received many comments on the deferral provisions in the
proposal.
    16. A few comments stated that the deferral provisions are an
appropriate means of assuring that pediatric patients are not studied
before adequate safety data have been gathered. A number of comments
from the pharmaceutical industry asserted, however, that the proposal
would require concurrent testing in adults and pediatric patients
despite medical and ethical reasons for delaying testing pediatric
testing. For example, a comment from a pharmaceutical trade association
claimed that the rule:

    * * * would require testing of new medical compounds in children
before safety in adults has been studied adequately, before
effectiveness in adults has been established, and in young children and
neonates without adequate information about the effects of the drug in
older pediatric patients.

    These industry comments appear to have misunderstood the explicit
deferral provisions of the rule and perceived them as rare exceptions
to a usual requirement that adults and children be studied at the same
time. Nothing in the rule requires concurrent testing in adults and
pediatric patients, nor testing in infants and neonates before testing
in older children. As stated previously and in the proposal, the
deferral provisions were specifically included to, among other things,
ensure that pediatric studies could be delayed when necessary to assure
that appropriate safety and/or effectiveness data were available to
support pediatric testing.
    17. Most of the comments on deferral focused on whether the need
for safety and/or effectiveness data in adults before initiating
pediatric studies should be a basis for deferral. Comments from
disease-specific organizations, medical societies, including the AAP,
and pediatricians argued that deferrals should be granted rarely if at
all on this basis. One comment argued that delaying availability of
life-saving drugs to children cannot be rationalized scientifically,
legally, or ethically, and contended that deferral should not be
permitted for serious and life-threatening diseases where there is no
substantial difference between the disease or the anticipated effect of
the drug in children or adults. Another comment argued that deferral
should be used sparingly in all age groups, including infants and
neonates, and that its use should be evaluated in the context of the
seriousness of the condition to be treated, the therapeutic advance the
drug represents, and the likelihood that the drug will be given to
children as soon as it is approved. According to this comment, the
risks of research in pediatric patients may be outweighed by the risks
that the drug will be given to them without data.
    One comment argued that pediatric studies of important drugs should
be conducted in parallel to adult studies, especially in children under
12. Several comments from the pediatric community, however, supported
the development of some adult safety and/or effectiveness data before
initiation of pediatric studies. One comment from an organization
devoted to pediatric AIDS stated that while the general assumption
should be that pediatric studies will be submitted at the same time as
adult studies, it may be appropriate to have some testing in adults
before children. The AAP stated that it is appropriate to begin studies
in pediatric patients after phase 1 and phase 2 studies in adults have
defined routes of clearance and metabolic pathways. Thus, the comment
urged that pediatric studies be conducted during phases 2 and 3, not 4.
A comment from a nephrology organization argued that drugs for organ-
specific diseases should be studied in phase 3, as soon as phase 1 and
2 trials have shown safety in adults. This and another comment stated
that deferring studies until after approval compromises clinical trial
enrollment, citing the experience with recombinant erythropoietin.
According to these comments, erythropoietin was not studied in
pediatric patients until after its approval for adults, and enrollment
was so difficult that pediatric studies were not completed for 5 years.
    Several comments from the pediatric community also cited limited
circumstances in which they believed deferral to be appropriate. A
medical society argued that data should be collected after adult
studies only for drugs with narrow therapeutic indices, unusual
accumulation in the body, where the drug study requires extensive blood
sampling, or where the study design places young patients at risk for
limited information gain.
    Many comments from the pharmaceutical industry argued, in contrast,
that deferral should be the

[[Page 66643]]

rule, rather than the exception. Most of these comments contended that
it was unethical to begin studying drugs in pediatric patients, other
than those that are intended primarily for pediatric patients, until
the drugs are shown to be reasonably safe and effective in adult
patients. All argued that pediatric studies must not be initiated until
substantial data in adults are available, but cited different
initiation points, e.g., after phase 2, after safety and effectiveness
is established in adults and an approvable letter is received, after
approval, after 1 year of marketing.
    Although many of these industry comments argued that pediatric
studies should be conducted exclusively as phase 4 (postapproval)
commitments, a significant number of industry comments acknowledged
that pediatric studies could begin before approval, generally after
phase 2, and that there were circumstances in which deferral was not
appropriate. One comment argued that because early pediatric studies
often require pediatric formulations and because up to 50 percent of
drugs are abandoned before phase 3, it is wasteful to require companies
to manufacture a pediatric formulation and begin studies before the end
of phase 2. Another comment argued that no pediatric studies should
begin before the decision to proceed to phase 3, except where: (1) The
disease affects only pediatric patients; (2) the disease mainly affects
pediatric patients, or the natural history or severity of the disease
is different in pediatric patients and adults; or (3) the disease
affects both pediatric patients and adults and lacks adequate treatment
options. One comment urged that the final rule state that ``in most
cases, pediatric testing should not begin with any drug or biological
product until certain adult safety and/or effectiveness information has
been collected.'' According to this comment, there could be exceptions
where no other therapy was available and there was a potential for the
drug to be lifesaving. A pharmaceutical trade association argued for a
presumption that pediatric studies not begin until the end of phase 2
or 3, but listed circumstances in which deferral should not occur: (1)
Where the disease is life threatening and there is no alternative
therapy, (2) where the drug is intended for a pediatric indication, (3)
where the drug presents no major safety issues, (4) where the drug
class is well studied in pediatric patients, or (5) where a large
amount of ``off-label'' use in pediatric patients is anticipated.
    In general, FDA expects that some data on adults will be available
before pediatric studies begin, but that less data will usually be
required to initiate studies of drugs and biologics for life-
threatening diseases without adequate treatment than for less serious
diseases. Pediatric studies of drugs and biologics for life-threatening
diseases may in some cases be appropriately begun as early as the
initial safety data in adults become available, because the urgency of
the need for such products may justify early trials despite the
relative lack of safety and effectiveness information. In such cases,
deferral of submission of pediatric studies until after approval will
be unnecessary, unless drug development is unusually rapid and the
product is ready for approval in adults before completion of the
pediatric studies.
    Pediatric studies on products for less serious diseases should
generally not begin until more adult data have been collected,
ordinarily no earlier than the availability of data from the initial
well-controlled studies in adults. As noted earlier in this document,
there may occasionally be exceptions to this principle where all
parties agree that earlier initiation is appropriate. Whether deferral
of submission of the data until after approval will be necessary for
such products will depend upon when pediatric studies can
scientifically and ethically begin in each case and how difficult the
studies are to complete.
    In some cases, FDA expects that scientific and ethical
considerations will dictate that studies not begin until after approval
of the drug or biological product. For example, pediatric studies of
``me-too'' drugs that do not offer a meaningful therapeutic benefit and
that are members of a drug class that already contains an adequate
number of approved products with pediatric labeling may be deferred
until well after approval. In cases where a drug has not been shown to
have any benefit over other adequately labeled drugs in the class, the
therapeutic need is likely to be low and the risks of exposing
pediatric patients to the new product may not be justified until its
safety profile is well established in adults through marketing
experience. Because the basis for the deferral in such cases will be
concern that the drug presents risks to pediatric patients that will
not be known until there is widespread marketing experience, without
offsetting benefit, FDA may require, in appropriate cases, that such
drugs carry labeling statements recommending preferential use in
pediatric patients of products that are already adequately labeled.
Such a statement might read:

    The safety and effectiveness of this product have not been
established in children. There are alternative therapies that have
been shown to be safe and effective for use in children with
[indicated condition]. Ordinarily, products already labeled for use
in children should be used in preference to [name of this product].

FDA labeling regulations at 21 CFR 201.57 express the agency's
authority to ensure that drugs are safe for use under the conditions
prescribed, recommended, or suggested in their labeling, and to require
labeling identifying safety considerations that limit the use of drugs
to certain situations. Some drugs with no demonstrated advantage over
available therapy can nonetheless be expected to have wide use in
pediatric patients. Pediatric studies of such drugs should be initiated
relatively early, even if they are not completed at the time of
approval.
    18. A comment from a pharmaceutical company listed several
circumstances in which it argued FDA should permit deferral: (1) The
pediatric population is so small that enrollment and completion of
trials cannot be accomplished in parallel with adult trials, (2) the
natural course of the disease is different in adults and children, (3)
analytic tools and clinical methodologies cannot be easily adapted to
the pediatric population, (4) the drug has complex pharmacokinetic
properties in adults making it hard to extrapolate a pediatric dosage
range, (5) the scope and nature of nonclinical studies support only
adult clinical studies, (6) two or more attempts to develop a pediatric
formulation have failed, or (7) unique drug-drug or drug-food
interactions in children confound drug development. Another comment
added to this list: (1) Where fewer than 200,000 pediatric patients are
affected by the disease being treated, and (2) drugs with a low
therapeutic index.
    FDA agrees that some of these circumstances could make completion
of studies prior to approval in adults difficult, but does not agree
that they would make studies impossible or impractical in all cases.
The need for deferral must be considered case-by-case. A small
pediatric population, e.g., might make completion of controlled trials
very slow, but might not prevent obtaining pharmacokinetic data. Simply
citing a pediatric population under 200,000 will not be sufficient to
justify deferral; a small fraction of this number participating in
trials may be sufficient to support timely pediatric studies, depending
on the nature of the studies. As an example, over 70 percent of the
estimated 6,000 pediatric patients with cancer each year are enrolled
in clinical trials (Ref. 15). There does not seem to

[[Page 66644]]

be any reason to conclude that deferral is warranted solely because the
natural course of the disease is different in adults and children. FDA
also disagrees that deferral is necessarily warranted where analytic
tools and clinical methodologies cannot be easily adapted to pediatric
patients. Deferral may be necessary in some cases where the infants and
toddlers are unable to provide subjective outcome data, but it may also
be possible to utilize alternative endpoints or to extrapolate
effectiveness data from older pediatric age groups, obtaining
pharmacokinetic data from the younger age groups to determine an
appropriate dose. Drugs with a low therapeutic index that do not
fulfill an urgent need should, in general, be studied in pediatric
patients later in drug development.
    With respect to complex pharmacokinetic properties that prevent
extrapolation of adult data to pediatric patients, low-therapeutic
index drugs, and unique drug-drug or drug-food interactions in
pediatric patients, FDA believes that the need for pediatric studies
before approval is even greater where these conditions are present;
moreover, none of them represents a significant impediment to studies.
Recognizing that drugs and biologics approved for adults are regularly
prescribed to pediatric patients despite the absence of adequate dosing
and safety data, information positively suggesting that dosing and
safety cannot be extrapolated from adult data increases the importance
of conducting pediatric studies before the product is widely used in
pediatric patients. The absence of supporting nonclinical studies
(e.g., studies in young animals) should not usually be a basis for
deferral. These studies, if needed, are readily conducted. Moreover, a
full adult data base provides pertinent safety information that might
make further preclinical data unnecessary. Difficulties in developing
an adequate pediatric formulation may, in some cases, justify deferral
of studies in young pediatric patients. In other cases, however, it may
be appropriate to study a less-than-optimal formulation, e.g., an
injection, if one is available, in pediatric patients while awaiting
the development of a more desirable pediatric formulation.
    19. One comment argued that it was ``unacceptable'' to defer
pediatric studies to avoid delaying approval for adult use. Instead,
the comment urged FDA to provide a ``limited approval'' for adult use
until pediatric data are available and impose a monetary penalty for
failure to comply. Another comment argued that permitting deferral to
avoid delay in adult marketing could be applied to most applications,
creating a de facto situation in which pediatric data were understood
to be not required until 2 years after approval. One comment stated
that while pediatric dosing schedules are essential, pediatric studies
should not delay approval of drugs for a major population, adults.
    FDA continues to believe that deferral is appropriate where
awaiting the completion of pediatric studies would delay the
availability of a safe and effective drug or biological product for
adults. Granting a deferral does not automatically mean, however, that
pediatric studies need not be submitted for 2 years or that initiating
them should be long delayed. The proposal suggested 2 years as the
maximum period for a deferral. Where pediatric studies are supposed to
be nearing completion at the time a product is ready for approval in
adults, FDA expects that the period of deferral would be significantly
shorter than 2 years. Where some useful pediatric information, e.g.,
safety information, is available at the time of approval, even if some
required studies are not complete, FDA may require that the pediatric
use section of the product's labeling include that information, to the
extent consistent with 21 CFR 201.57(f)(9). FDA also notes that it has
no authority to impose a monetary penalty for failure to submit a
required study of a drug or biological product. FDA must ask a court to
impose such a penalty in a contempt proceeding.
    20. Several comments argued that pediatric trials should be
conducted sequentially, beginning with the oldest pediatric age group,
and ending with the youngest. One comment stated that IRB's would
question testing a drug in younger children before older children. The
AAP argued that there is little defense for studying pediatric patients
sequentially from oldest to youngest, and that such a policy will
result in approvals without data in neonates. This comment argued that
the timing of studies should give consideration to safety, but without
consideration of sequence. Another comment argued that FDA should not
routinely require that drugs for serious and life-threatening diseases
be studied sequentially. In HIV, according to this comment, drug
testing should be ``as simultaneous as possible'' because safety and
dosing may be initiated in each age group in a dose escalating manner
regardless of the results in previously tested groups.
    FDA agrees that age-dependent sequential studies are not
necessarily appropriate. Particularly were there is urgent need for a
product, there may be good reason to study older and younger children
at the same time.
    21. A few comments objected to FDA's tentative decision to require
the submission of studies ordinarily no later than 2 years after the
initial approval. One comment stated that deferral of up to 2 years was
excessive, citing the ``critical'' need to ensure timely performance of
pediatric studies in populations where the drug is likely to be used.
Another comment stated that 2 years may be adequate for collecting
pharmacokinetic data, but not necessarily for collecting safety data.
According to this comment, the size of the clinical data base will be
the principal determinant of when data should be submitted. A comment
from the American Red Cross stated that the extensive IRB review of
studies of blood products involving pediatric patients, and the
difficulty in enrolling such patients, makes the 2-year deferral
deadline unrealistic for this category of product.
    FDA agrees with the comments that the 2-year deadline suggested by
the proposal may not be appropriate, and that the length of the
deferral should be decided on a case-by-case basis. The timing of the
deferred submission will depend upon such factors as the need for the
drug or biologic in pediatric patients, when sufficient safety data
become available to initiate pediatric trials, the nature and extent of
pediatric data required to support pediatric labeling, and
substantiated difficulties encountered in enrolling patients and in
developing pediatric formulations. FDA may also extend the date for
submission of studies at the time of approval, e.g., where other drugs
in the class have been approved during the pendency of the NDA and the
new drug is no longer needed as a therapeutic option.

E. Waivers

    FDA does not intend to require pediatric assessments unless the
product represents a meaningful therapeutic benefit over existing
treatments or is expected to be used in a substantial number of
pediatric patients. FDA also does not intend to require pediatric
assessments in other situations where the study or studies necessary to
carry out the assessment are impossible or highly impractical or would
pose undue risks to pediatric patients. Thus, FDA proposed to add
Sec. 314.50(g)(3) (now Sec. 314.55(c)) and Sec. 601.27(c) to authorize
FDA to grant a waiver of the pediatric study requirement on its own
initiative or at the request of the applicant unless the product
represented a meaningful therapeutic benefit over existing

[[Page 66645]]

treatments, or was likely to be used in a substantial number of
pediatric patients. These provisions also require FDA to grant a waiver
if necessary studies were impossible or highly impractical, because,
e.g., the number of pediatric patients was very small or patients were
geographically dispersed, or there was evidence strongly suggesting
that the product would be ineffective or unsafe in some or all
pediatric populations. If a waiver were granted because there was
evidence that the product would be ineffective or unsafe in pediatric
patients, this information would be included in the product's labeling.
    An applicant could request a full waiver of all pediatric studies
if one or more of the grounds for waiver applied to the pediatric
population as a whole. A partial waiver permitting the applicant to
avoid studies in particular pediatric age groups could be requested if
one or more of the grounds for waiver applied to one or more pediatric
age groups. In addition to the other grounds for waiver, the proposal
would authorize FDA to grant a partial waiver for those age groups for
which a pediatric formulation was required (see ``Pediatric
Formulations'' in section III.I of this document), if reasonable
attempts to produce a pediatric formulation had failed.
    The proposal would require the applicant to include in the request
for a waiver an adequate justification for not providing pediatric use
information for one or more pediatric populations.
    FDA would grant the waiver request if the agency found that there
was a reasonable basis on which to conclude that any of the grounds for
a waiver had been met. If a waiver were granted on the ground that it
was not possible to develop a pediatric formulation, the waiver would
cover only those pediatric age groups requiring a pediatric
formulation.
    The agency also proposed two possible methods of determining a
``substantial number of patients.'' The first method would focus on the
number of times the drug or biologic was expected to be used in
pediatric patients, annually. Under this method, FDA tentatively
concluded that 100,000 or more prescriptions or uses per year in all
pediatric age groups would be considered a substantial number.
    The second proposed method for establishing whether there was a
substantial number of pediatric patients would focus on the number of
pediatric patients affected by the disease or condition for which the
product is intended. Under this method, FDA tentatively concluded that
100,000 pediatric patients affected by the disease or condition for
which a product was indicated would be considered a ``substantial
number'' of pediatric patients. FDA sought comment on the waiver
criteria and on these methods of calculating a substantial number of
pediatric patients. FDA also sought comment on whether cost to the
manufacturer should justify a waiver.
    FDA received many comments on the waiver provisions of the
proposal, and has made certain changes in response to the comments, as
described below.
    22. As proposed, new drugs and biologics are presumptively required
to be studied in pediatric patients, unless a waiver is granted. The
presumption in the proposal was supported by comments from
pediatricians, a pharmacy organization, disease specific organizations,
and medical societies, including the AAP. Several industry comments
argued, however, that new drugs and biologics should presumptively not
be covered by the rule, unless they were specifically identified by FDA
as needing to be studied. One of these comments stated that companies
should not have to waste the effort of applying for waiver for drugs of
no potential benefit to pediatric patients, which the comment estimated
as a majority of those developed.
    FDA continues to believe that it is appropriate to presume that
drugs and biologics should be studied in pediatric patients, and that
this presumption should be overcome only if there are clear grounds for
concluding that such studies are unnecessary. Pediatric patients are a
significant subpopulation, affected by many of the same diseases as
adults, and are foreseeable users of new drugs and biologics. The
agency has stated, in the context of pediatric studies and other
subpopulations, that an application for marketing approval should
contain data on a reasonable sample of the patients likely to be given
a drug or biological product once it is marketed (59 FR 64240 at 64243;
58 FR 39406 at 39409, July 22, 1993). FDA does not believe that the
cost of drafting a waiver request will be great, particularly where the
basis for the waiver is that the product has no potential use in
pediatric patients. To assist sponsors in preparing such waivers, FDA
has included in this document a partial list of diseases that are
unlikely to occur in pediatric patients and for which waiver requests
need include only reference to this document.
    23. FDA received many comments on the proposed criteria for waiving
pediatric studies. A few comments supported the proposed criteria. Many
comments from pediatricians, medical societies, and disease-specific
organizations argued that the proposed grounds for waiver were too
broad. Several of these stated that the rule should apply to drugs for
all conditions that affect pediatric patients unless there is a special
reason not to do so. One comment argued that waivers should be
available only for drugs known to be extremely toxic in pediatric
patients or to have no anticipated use in pediatric patients.
    Other comments from the pharmaceutical industry argued that the
waiver provisions were too narrow. One comment from a generic trade
association urged that pediatric studies be required only when there is
a significant public health concern with respect to the safety of a
drug product in pediatric patients or to the availability of adequate
pharmacological intervention for pediatric patients for the indication.
Another comment stated that the criteria in the proposal ``do not begin
to address the complexities associated with moving forward on a
clinical development plan'' and argued that additional criteria should
include: (1) The lack of correlative safety evidence, (2) liability
concerns, and (3) prohibitive cost (but the sponsor, not FDA, should be
allowed to determine the importance of cost).
    FDA believes that the criteria for waiver in the final rule strike
a careful balance. On the one hand, requiring studies for all new
products would have potentially severe resource implications for
manufacturers and the agency. On the other hand, obtaining studies only
where the studies impose no burden on the sponsor would continue to
expose millions of pediatric patients to unnecessary risks and
ineffective treatment. Requiring pediatric studies only of those drugs
or biologics that offer a meaningful therapeutic benefit or that are
expected to be used in a substantial number of pediatric patients
focuses limited resources on those products that are most critically
needed for the care of pediatric patients.
    24. Several comments addressed the definition of ``meaningful
therapeutic benefit.'' Some comments from the pharmaceutical industry
stated that ``meaningful therapeutic benefit'' should be defined as it
is used in 21 CFR 314.500. (That regulation applies to drugs ``that
provide meaningful therapeutic benefit to patients over existing
treatments (e.g., ability to treat patients unresponsive to, or
intolerant of, available therapy, or improved patient response over
available therapy).'') One of these comments

[[Page 66646]]

suggested that analogous cases in the pediatric context would be: (1)
Where the drug treats a pediatric disease for which no other treatments
exist; (2) where the drug treats patients who are unresponsive to or
intolerant of other drugs; or (3) where the drug produces a superior
response over other treatments. One industry comment argued that the
agency should consult with the sponsor, and the pediatric investigators
involved to assess whether the drug will provide a ``meaningful
therapeutic benefit.'' According to the comment, the assessment should
include the likely use of the product in a specific pediatric
population, the likely benefit without increased risk to patients
versus existing treatments, a ``definitive need'' for a new therapy in
very serious or life-threatening illnesses, and the cost and
feasibility of developing the necessary formulations and of conducting
studies. Another comment from a disease-specific organization argued
that ``meaningful therapeutic benefit'' should be a relative term,
depending on the severity of the illness, the potential risk posed by
the drug, and the availability of alternative treatments. One comment
from a medical society devoted to the treatment of psychiatric
disorders contended that ``meaningful therapeutic benefit'' should mean
that the product enables a child to function better, and participate in
age-appropriate activities, such as playing and going to school,
without undue pain and suffering from the disease or disorder. Another
comment argued that ``meaningful therapeutic benefit'' should mean
better response or ability to treat nonresponsive patients. Another
comment maintained that the presumption should be that a product
represents a meaningful therapeutic benefit in pediatric patients if it
is expected to provide a meaningful therapeutic benefit in adults.
    Several comments from the pharmaceutical industry contended that it
is not possible to define meaningful therapeutic benefit before
approval or that FDA should not be responsible for defining it. A
pharmaceutical trade association argued that meaningful therapeutic
benefit is the decision of the sponsor, not FDA, and that it is not
possible to determine meaningful therapeutic benefit until a drug has
been used for some period of time. Another comment maintained that FDA
must first have adult data to reach the conclusion that a drug offers a
meaningful therapeutic benefit. The same comment also argued that a
rigorous determination of meaningful therapeutic benefit would require
randomized, controlled trials in pediatric patients.
    FDA disagrees that it is impossible or beyond FDA's expertise to
reach a conclusion before approval about whether a product has the
potential to offer a meaningful therapeutic benefit. FDA routinely
estimates the therapeutic benefit of new drugs and biologics at the
time applications are first submitted, in order to determine whether to
assign ``Priority'' (expedited) status to the review of the
application. In assigning Priority status to new drug applications,
CDER determines whether the product, if approved, ``would be a
significant improvement compared to'' marketed (or approved, if such is
required) products, including nondrug products or therapies.
``Improvement can be demonstrated by, for example: (1) Evidence of
increased effectiveness in treatment, prevention, or diagnosis of
disease; (2) elimination or substantial reduction of a treatment-
limiting drug reaction; (3) documented enhancement of patient
compliance; or (4) evidence of safety and effectiveness in a new
subpopulation'' (Ref. 16). These criteria are similar to many of the
criteria suggested in the comments. FDA notes that demonstration of an
advantage over existing products may come from evidence other than
head-to-head comparisons of the new product and existing products. For
example, in some cases a new product could be shown to lack an adverse
effect associated with an existing product, or to have an effect on a
different outcome or on a different stage of disease than an existing
product, without a direct comparison of the two products.
    FDA has concluded that in determining whether a product offers a
meaningful therapeutic benefit, it will use the Priority definition,
with some modifications. First, in determining whether a product is
expected to be an improvement over other products, the comparison will
be made only to other products that are already adequately labeled for
use in the relevant pediatric population. Second, it is often
therapeutically necessary to have two or more therapeutic options
available, because some patients will be unresponsive to a given
therapy. Because the Priority definition would not cover more than the
first or second product for a given indication or in a given class
(unless the product offered an advantage over others for the indication
or in the class), a drug or biologic will also be considered to provide
a meaningful therapeutic benefit if it is in a class of drugs and for
an indication for which there is a need for additional therapeutic
options. The specific number of products needed will depend upon such
factors as the severity of the disease being treated, and the adverse
reaction profile of existing therapies. FDA has added this definition
of meaningful therapeutic benefit to Secs. 314.55(c)(5) and
601.27(c)(5). This rule's definition of meaningful therapeutic benefit
is intended to apply only in the pediatric study context and is not
intended to alter the definition of a Priority drug.
    25. Several comments addressed the definition of ``a substantial
number of pediatric patients.'' A few comments argued that it would be
difficult to estimate product use until after marketing. Several
comments argued that FDA should not base waivers on the number of
patients or prescriptions. Many other comments claimed that the
proposed numerical cut-offs are arbitrary. These comments maintained
that waivers should be decided on a case-by-case basis. Several
comments urged that FDA consult with an expert panel in deciding
whether pediatric use was substantial.
    Comments from the pediatric community contended that the numerical
cut-offs in the proposal were too high, and would preclude studies of
many serious diseases affecting fewer than 100,000 pediatric patients.
One comment, for example, voiced concern that pediatric patients with
less common seizure types may not benefit from the regulations because
the use is not sufficiently widespread. Another comment argued that
numerical cut-offs should not apply to drugs for serious and life-
threatening diseases, unless the number of pediatric patients was so
low as to make clinical study impossible. Another comment suggested
that studies be required not only for uses greater than 100,000
prescriptions, but for ``drugs used chronically for a defined, though
smaller group of pediatric patients, usually for organ-specific
diseases, such as kidney failure or hypertension.''
    Comments from the pharmaceutical industry argued that the numerical
cut-offs proposed by FDA were too low. Some of these comments argued
that 100,000 prescriptions per year translates to fewer than 100,000
patients, and that the resulting population could be so small that it
would be difficult to study. Several of these comments urged that cut-
off for substantial use be 200,000 patients with the disease, the
threshold established by the Orphan Drug Act for identifying rare
diseases.
    FDA has decided to revise its proposed method of defining a
substantial number of patients, in light of the comments. Physician
mention

[[Page 66647]]

data from the IMS National Disease and Therapeutic Index (Ref. 38),
which tracks the use of drugs by measuring the number of times
physicians mention drugs during outpatient visits, shows that pediatric
use of drugs is generally grouped in two distinct ranges. Physician
mentions of drugs for pediatric use generally fall either below 15,000
per year or above 100,000 per year. Few drugs fall within the two
ranges. Thus, selecting a cut-off for ``substantial number of pediatric
patients'' in the middle of the two ranges will provide a reasonable
discrimination between products that are widely used and those that are
less commonly used, and the specific number chosen will not arbitrarily
include or exclude a significant number of drugs. FDA has therefore
chosen 50,000 as the cut-off for a substantial number of pediatric
patients. Because the number of pediatric patients with the disease is
easier to determine than the number of prescriptions per year, a
substantial number of pediatric patients will be defined as 50,000
pediatric patients with the disease for which the drug or biological
product is indicated. Although physician mentions per year does not
correspond exactly to the number of patients with the disease, they
provide a rough approximation and the IMS data show that the number of
products included or excluded is relatively insensitive to changes in
the cut-off chosen. As proposed, a partial waiver for a particular
pediatric age group would be available under this method if 15,000
patients in that age group were affected by the disease or condition.
This definition of ``a substantial number of pediatric patients'' has
not been codified, however, and FDA may modify it, after consulting
with the pediatric panel discussed in section III.M of this document
(``Pediatric Committee''). Any modification will be issued as a
guidance document.
    In response to those comments that voiced concern that this
definition would exclude a number of serious diseases, FDA emphasizes
that the definition of ``meaningful therapeutic benefit'' assures that
drugs and biologics will be covered by the rule if they are medically
needed as therapeutic options because there are insufficient products
adequately labeled for pediatric patients for that indication or in
that drug class. Until there are enough adequately labeled products
available, many new drugs and biologics for serious and life-
threatening diseases will be considered to offer a meaningful
therapeutic benefit and thus will be required to be studied, even if
the products are not also used in a substantial number of pediatric
patients. This will be particularly true during the first few years
after implementation of this rule when few drugs and biologics will yet
be adequately labeled for use in pediatric patients, and a larger
proportion of new entrants into the marketplace will be considered to
be medically necessary therapeutic options.
    In response to the comments arguing that FDA's proposed numerical
cut-off is too low and will result in too many pediatric studies, FDA
expects to defer until after approval many of the studies of products
that will be used in a substantial number of pediatric patients but
that do not offer a meaningful therapeutic benefit. As described
previously in response to comments on the deferral provisions, studies
of new drugs and biologics that do not offer a meaningful therapeutic
benefit and are members of a class that is already adequately labeled
for pediatric patients are likely to be deferred until well after
approval of the product for adults.
    26. A few comments addressed the provisions that would permit
waiver if pediatric trials were impossible or impractical. One comment
argued that the provision authorizing waiver if the proposed population
was ``too small or geographically dispersed'' was too broad. This
comment urged that tests should be waived only if ``significant efforts
to recruit patients fail.'' The comment also argued that the
unsupported suggestion that tests are ``impractical'' should not be
accepted, and that evidence of due diligence should be required.
Another comment argued that waivers should never be granted because the
population is too small or dispersed. According to this comment, many
safety and pharmacokinetic studies are already performed in dispersed
populations, and the comment maintained that no experimental drug
should be administered to a child with a serious or life-threatening
disease without requiring that some safety data and pharmacokinetics
data be obtained. Another comment observed that although only 600 renal
transplants are performed each year in pediatric patients, pediatric
academic centers have been creative in forming collaborative efforts to
study these small groups. One comment from an organization devoted to
children with HIV stated that the ``impossible or highly impractical''
standard must be narrowly interpreted, and that a manufacturer should
show that all reasonable efforts to recruit patients have failed.
According to this comment HIV/AIDS drugs should be a benchmark of when
a waiver should not be granted: Any group as big or bigger than the
pediatric AIDS population should be considered big enough to study.
    Another comment argued that because of special difficulties
encountered in recruiting pediatric patients into studies of blood
products, such as parental fear of disease transmission, the inability
to obtain a sufficient number of test subjects should be added to the
criteria for waiver or to the definition of ``highly impractical.''
    FDA agrees with those comments urging that this ground for waiver
be interpreted narrowly and that unsupported assertions be rejected as
a basis for waiver. Although the number of patients necessary to permit
a study must be decided on a case-by-case basis, FDA agrees that there
are methods available to conduct adequate studies in very small
populations. Moreover, where only safety or pharmacokinetic studies are
required to support pediatric labeling, the size of the population or
geographic dispersion would only rarely be a sufficient basis to
consider trials impossible or highly impractical. Because of the speed
and efficiency of modern communications tools, geographic dispersion
will justify a waiver only in extraordinary circumstances and will
generally have to be coupled with very small population size. FDA is
not persuaded that inability to recruit patients because of parental
fears associated with administration of the drug is an adequate basis
to conclude that studies are impractical where there is also evidence
that similar products are regularly prescribed to pediatric patients
outside of clinical trials.
    27. Several comments responded to the request for comment on
whether cost should justify a waiver. Comments from the pediatric
community argued that cost to the manufacturer should never or rarely
justify a waiver. Two of these comments stated that the cost of failure
to study is always higher than the cost of research. Another comment
stated that cost may be a factor, but FDA must be careful not to allow
studies to be waived automatically because they ``cost too much.'' Two
comments from a pharmaceutical company and a pharmaceutical trade
association argued that FDA should not have responsibility for
assessing the costs of a study.
    In light of the comments, FDA has concluded that it does not have
an appropriate basis to evaluate and weigh cost in granting or
declining to grant a waiver. Therefore, cost will not ordinarily be a
factor in determining whether a waiver should be granted.

[[Page 66648]]

    28. One comment claimed that the proposal lacks adequate regulatory
procedures for timely processing of waiver requests and will result in
a new layer of bureaucracy.
    As described previously in response to comments on the deferral
provisions, preliminary decisions on whether to grant waivers will be
provided to the sponsor at the end of phase 1 for drugs and biologics
for life-threatening diseases and at the end of phase 2 for other
products. FDA does not agree that processing of waiver requests will
result in a new layer of bureaucracy. The decisions will be made by the
division responsible for reviewing the NDA or BLA. FDA intends to
ensure that the process is timely and fair. To reduce the burden on
manufacturers in applying for waivers and deferrals, FDA intends to
issue a guidance document providing a format for a request for waiver
or deferral.
    29. One comment asked that the rule clarify that the onus is on the
manufacturer to justify waivers. Another comment argued that the
proposed standard for granting a waiver (``reasonable basis'') places
an inadequate burden of proof on manufacturers. According to this
comment, manufacturers should be required to present ``persuasive
proof,'' and FDA should have to find that the grounds for waiver have
``in fact'' been met.
    FDA agrees that the burden is on the manufacturer to justify
waivers, but believes that the rule already adequately imposes that
burden. The rule requires both a certification from the manufacturer
that the grounds for waiver have been met and an adequate justification
for the waiver request. FDA believes that it would be inappropriate to
require ``proof'' that the grounds for waiver have ``in fact'' been met
because each ground requires a degree of speculation about the safety
and effectiveness of, or the ability to test, a product, in a
population in which it has not yet been tested.
    30. Many comments from pediatricians, disease-specific
organizations, a pharmacists' organization, a medical society, several
companies, a pharmaceutical trade association, and the AAP urged that
the decision to require pediatric studies be reviewed by a panel of
outside pediatric experts. Some of the comments recommended that the
panel include industry representatives. The comments were divided on
whether the panel would review only waiver requests or would be
responsible for identifying, in the first instance, those drugs that
need study. Some of these comments believed that the rule should
include no criteria for granting waivers and that the decision should
be made on a case-by-case basis in consultation with the expert panel.
    As described later in this document, FDA intends to convene a panel
of pediatric experts, which will include one or more industry
representatives, to assist the agency in implementing this rule. FDA
will bring before that panel some issues related to waivers. FDA does
not believe, however, that it is reasonable to bring every product
undergoing clinical studies before the panel for a decision on whether
pediatric studies are required. Because many dozens of drugs and
biologics reach the end of phase 1 and phase 2 each year, and the panel
could not realistically meet more than once every few months, insisting
that each product be brought before the panel would introduce
substantial delay into the development and review of drugs and
biologics. Moreover, many waiver decisions will be straightforward and
noncontroversial.
    FDA does, however, agree that it would be beneficial to have the
advice of pediatric experts on its administration of the waiver
provisions of the rule. FDA will therefore ask the panel, at least on
an annual basis for the first several years, to review the agency's
waiver decisions and provide advice on whether it believes that the
criteria used in making those decisions were appropriate. FDA will use
the advice it receives to modify future waiver decisions. FDA also
expects to consult with individual members of the panel on difficult
waiver decisions in their fields of expertise.
    31. One comment suggested that FDA identify diseases that are not
likely to occur in pediatric patients, such as prostate cancer, and
classes of drugs not likely to be used in pediatric patients, and grant
blanket waivers. Another comment listed the following product classes
as having no applicability to pediatric patients: Alcohol abuse agents,
Alzheimer's agents, Amyotrophic lateral sclerosis agents, antifibrosis
therapy, antiparkinsonian agents, fertility agents, gout preparations,
multiple sclerosis drugs, oral hypoglycemics, osteoporosis agents,
oxytocics, tremor preparations, uterine relaxants, and vasodilators
(including cerebral vasodilators).
    FDA agrees that there are some disease and drug classes that have
extremely limited applicability to pediatric patients and that waiver
is appropriate for these. The decision to grant a waiver in such cases
would be based on a conclusion that a disease does not have sufficient
significance in the pediatric population (either because of frequency
or severity) to constitute a meaningful therapeutic benefit for
pediatric patients or to be used in a substantial number of pediatric
patients. FDA emphasizes that this decision would not be intended to
prevent or impede studies of these diseases or drug classes in the
pediatric population, should a sponsor wish to conduct them.
    The agency has identified the diseases following for which waivers
will be likely to be granted. Some of the diseases listed in the
comment are included in FDA's list. Others, such as osteoporosis, gout,
multiple sclerosis, and tremors can develop in children, and are not
included in FDA's list. Waiver decisions on products for the listed
diseases are expected to be straightforward and noncontroversial. FDA
may add to or revise this list in the future by issuing guidance
documents. An applicant who wishes to obtain a waiver because the
product is indicated for a disease on the list may refer in the waiver
request to this Federal Register notice, or to any guidance document
modifying this notice. FDA's list follows:

1. Alzheimer's disease.
2. Age-related macular degeneration.
3. Prostate cancer.
4. Breast cancer.
5. Non-germ cell ovarian cancer.
6. Renal cell cancer.
7. Hairy cell Leukemia.
8. Uterine cancer.
9. Lung cancer.
10. Squamous cell cancers of the oropharynx.
11. Pancreatic cancer.
12. Colorectal cancer.
13. Basal cell and squamous cell cancer.
14. Endometrial cancer.
15. Osteoarthritis.
16. Parkinson's disease.
17. Amyotrophic lateral sclerosis.
18. Arteriosclerosis.
19. Infertility.
20. Symptoms of the menopause.

F. Pediatric Use Section of Application

    FDA proposed to add Sec. 314.50(d)(7), under which applicants would
be required to include in their applications a section summarizing and
analyzing the data supporting pediatric use information for the
indications being sought. FDA received no comments on this provision.
The new pediatric use section will be required to contain only brief
summaries of the studies together with a reference to the full
description of each provided elsewhere in the application.

[[Page 66649]]

G. Planning and Tracking Pediatric Studies

1. Sections 312.23(a)(3)(v), 312.47 (b)(1)(i), (b)(1)(iv) and (b)(2),
and 312.82--Early Discussion of Plans for Pediatric Studies
    In the proposal, FDA identified several critical points in the drug
development process, before submission of an NDA or BLA, during which
the sponsor and FDA should focus on the sponsor's plans to assess
pediatric safety and effectiveness. These time points include: Any pre-
IND meeting or ``end-of-phase 1'' meeting for a drug designated under
subpart E of part 312 (21 CFR part 312), the IND submission, the IND
annual report, any ``end-of-phase 2'' meeting, the presentation of the
IND to an FDA drug advisory committee, and any pre-NDA or pre-BLA
meeting. Of these, the pre-IND meeting, the ``end-of-phase 1'' meeting,
the IND submission, the IND annual report, the ``end-of-phase 2''
meeting, and the pre-NDA/pre-BLA meeting are codified in part 312,
FDA's regulations governing IND's.
    In a separate rulemaking, FDA has already amended the IND annual
report requirement to include discussion of pediatric patients entered
in trials (63 FR 6854, February 11, 1998). In the proposal, FDA
proposed to amend Secs. 312.23(a)(3)(v), 312.47 (b)(1)(i) and (b)(2),
and 312.82 (a) and (b) to specify that these meetings and reports
should include discussion of the assessment of pediatric safety and
effectiveness. To assist manufacturers in planning for studies that may
be required under this proposal, FDA also proposed to inform
manufacturers, at the ``end-of-phase 2'' meeting, of the agency's best
judgment, at that time, of whether pediatric studies would be required
for the product and when any such studies should be submitted. The
proposal also stated that, in addition to the discussions of pediatric
testing codified in the proposal, FDA would assist manufacturers by
providing early consultations on chemistry and formulation issues
raised by requirements under this rule.
    Because, as described previously, studies of drugs and biologics
for life-threatening diseases may begin as early as the end of phase 1,
FDA will, at the end-of-phase 1 meeting, provide the sponsor of such a
product the agency's best judgment, at that time, whether pediatric
studies will be waived or deferred. Section 312.82(b) has been revised
to include this requirement. Because studies of other products may
begin as early as the end of phase 2, FDA will, at the end-of-phase 2
meeting, provide the agency's best judgment, at that time, whether
waiver or deferral is appropriate. Although a formal request for
deferral or waiver is not required until submission of the NDA or BLA,
FDA has revised Sec. 312.47(b)(1)(iv) to state that a manufacturer who
plans to seek a waiver or deferral should provide information related
to the waiver or deferral in the advance submission required before the
end-of-phase 1 or end-of-phase 2 meeting, as appropriate.
    As described earlier, a pediatric study required under this rule
may be eligible for exclusivity under FDAMA, if such study ``meets the
completeness, timeliness, and other requirements of [section 505A].''
(See 21 U.S.C. 355A(i).) Among other requirements, a pediatric study
must, to be eligible for exclusivity, be responsive to a written
request for the study from FDA. To obtain a written request, a
manufacturer may submit a proposed written request to FDA that contains
the information described in a guidance document issued by FDA
entitled, ``Qualifying for Pediatric Exclusivity Under Section 505A of
the Federal Food, Drug, and Cosmetic Act.'' A manufacturer who has been
told in the end-of-phase 1 or end-of-phase 2 meeting that it is FDA's
best judgment at that time that it does not intend to waive the study
requirement may submit a proposed written request at any time
thereafter. FDA will issue a written request for a study required under
this rule promptly after an adequate proposed written request is
submitted.
    FDA also sought comment on the types of evidence that FDA should
examine to ensure that deferred pediatric studies are carried out in a
timely fashion. In response to comments, FDA has revised Secs. 312.47
(b)(1)(iv) and (b)(2) to require submission of information about
planned and ongoing pediatric studies.
    32. One comment supported the proposed provisions and the need for
early consultation with sponsors, stating that discussions should take
place as early as possible in drug development. The comment urged that
proposed Sec. 312.47(b)(1) be revised to acknowledge the possibility
that studies could already be underway.
    FDA agrees with this comment and has revised Sec. 312.47(b)(1) as
suggested in the comment.
    33. Several comments provided suggestions on how to assure that
deferred studies are carried out expeditiously. One comment urged that
the criteria to ensure deferred studies are carried out in a timely
fashion be modeled on the AIDS Clinical Trials Group (ACTG) system of
National Institute of Allergy and Infectious Diseases (NIAID). Another
comment recommended that evidence demonstrating that the required
studies were underway be submitted to FDA within 6 months of approval.
This comment suggested that the evidence should include: (1) A
finalized protocol, (2) evidence of sufficient entry of patients to
address the objective of the protocol, and (3) a time line for data
analysis and submission to FDA. Another comment argued that the burden
should be on manufacturers to provide evidence that studies are being
conducted with due diligence through submission of protocols, progress
reports and certifications by researchers. To hold manufacturers
accountable, this comment suggested that nonproprietary information
related to deferrals be made available to the public, including
deferral requests, FDA action, postmarketing status reports, and the
time line for deferred studies. One comment argued that FDA's current
procedures are adequate to track the timeliness of pediatric studies. A
pharmaceutical trade association argued that FDA should institute an
adequate tracking system and meet periodically with the sponsor to
discuss the progress of the studies, but that no new rules are needed.
    FDA agrees that an adequate system for ensuring that studies, both
deferred and nondeferred, are carried out in a timely manner requires
the submission of plans and progress reports from the sponsor at
defined intervals. As described previously, FDA will provide sponsors
with a preliminary decision on whether pediatric studies will be
required and their timing at the end-of-phase 1 meeting, for drugs and
biologics for life-threatening diseases, and at the end-of-phase 2
meeting, for other products. FDA has revised Sec. 312.47(b)(1)(iv) to
state that sponsors should submit, in the advance submission for the
end-of-Phase 2 meeting, a proposed time line for protocol finalization,
enrollment, completion, data analysis, and submission of pediatric
studies, or, in the alternative, information to support a planned
request for waiver or deferral. For drugs and biologics for life-
threatening diseases, the submission should be made in advance of the
end-of-Phase 1 meeting. FDA has also revised Sec. 312.47(b)(2)(iii) to
state that sponsors should submit, in the submission in advance of the
pre-NDA or pre-BLA meeting, information on the status of needed and
ongoing pediatric studies. The proposed language of Sec. 312.47 has
been slightly modified to

[[Page 66650]]

seek information on ``needed'' and ongoing studies rather than
``planned'' and ongoing studies. This change has been made because not
every sponsor elects to have an end-of-phase 1 or end-of-phase 2
meeting. In those cases, the need for a pediatric study may be
discussed for the first time at the pre-NDA or pre-BLA meeting. FDA has
also revised the title of Sec. 312.47(b)(2) from `` `Pre-NDA'
meetings'' to `` `Pre-NDA' and `pre-BLA' meetings.'' This is merely a
clarification, because part 312 is expressly applicable to products
subject to the licensing provisions of the Public Health Service Act,
as well to products subject to section 505 of the act and 21 CFR
312.2(a).
2. Sections 314.81(b)(2) and 601.37--Postmarketing Reports
    To permit FDA to monitor the conduct of postapproval studies to
ensure that they are carried out with due diligence, FDA proposed to
amend Sec. 314.81(b)(2) of the postmarketing report requirements to
require applicants to include in their annual reports: (1) A summary
briefly stating whether labeling supplements for pediatric use have
been submitted and whether new studies in the pediatric population to
support appropriate labeling for the pediatric population have been
initiated; (2) where possible, an estimate of patient exposure to the
drug product, with special reference to the pediatric population; (3)
an analysis of available safety and efficacy data in the pediatric
population and changes proposed in the label based on this information;
(4) an assessment of data needed to ensure appropriate labeling for the
pediatric population; and (5) whether the sponsor has been required to
conduct postmarket pediatric studies and, if so, a report on the status
of those studies. (Additional postmarketing reporting requirements are
described under ``Remedies'' in section III.L of this document.)
Although the proposal was intended to cover both drugs and biological
products, the proposal inadvertently omitted a postmarketing reports
requirement specifically applicable to biological products. In the
final rule, FDA has corrected this oversight and included an identical
postmarketing reports requirement in Sec. 601.37.
    FDA notes that FDAMA includes a provision requiring reports of
postmarketing studies in a form prescribed by the Secretary of Health
and Human Services (the Secretary) in regulations. (Section 506 of the
act (21 U.S.C. 356B).) At such time as regulations implementing this
provision are issued, FDA may modify or withdraw Secs. 314.81(b)(2) and
601.37 for consistency with the implementing regulations.
    34. Three comments from the pharmaceutical industry agreed that it
was appropriate to require postmarketing reports on the progress of
postapproval pediatric studies. One comment argued, however, that
collection of this information along with an adequate system to track
pediatric studies could preclude the need to finalize the rule. Another
comment argued that the required analyses of pediatric data ``may lead
to exposure of a larger number of children to an unapproved product.''
This comment also contended that estimates of patient exposure are
difficult to obtain and unreliable.
    FDA disagrees that postmarket reports and a tracking system are an
adequate means of assuring that drugs and biologics are appropriately
labeled for pediatric use. As shown above, even postmarket commitments
to conduct pediatric studies have infrequently resulted in pediatric
labeling submissions. FDA also disagrees that the analyses required
under Sec. 314.81(b)(2) require exposure of any new patients. The
analyses referred to in the provision are of already collected data.
Finally, the rule requires estimates of patient exposure ``where
possible.'' If there are no data on which to make such estimates, the
estimates are not required. FDA notes, however, that there are
commercial data bases designed to estimate use of marketed drugs.
    35. One comment argued that FDA should require postmarket
surveillance of approved drugs that do not have pediatric labeling, to
generate helpful comparative information and provide additional
information useful for analysis of adverse event profiles.
    The provisions of the final rule require manufacturers of approved
drugs without pediatric labeling to conduct postmarket surveillance on
their products and provide an analysis of available safety and efficacy
data in the pediatric population.

H. Studies in Different Pediatric Age Groups

    Because the pharmacokinetics and pharmacodynamics of a drug or
biological product may be different in different pediatric age groups
or stages of development, FDA proposed to require an assessment of
safety and effectiveness in each pediatric age group for which a waiver
was not granted. The following age categories for the pediatric
population were distinguished in the proposal: (1) Neonates (birth to 1
month); (2) infants (1 month to 2 years); (3) children (2 years to 12
years), and (4) adolescents (12 years to 16 years). The proposal stated
that the need for studies in more than one age group would depend on
whether the drug or biological product was likely to be used or offered
meaningful therapeutic benefit in each age group (see ``Waivers''
section III.E of this document), the metabolism and elimination of the
drug, and whether safety and effectiveness in one age group could be
extrapolated to other age groups. The proposal further stated that it
would not ordinarily be necessary to establish effectiveness in each
age group, but there would generally need to be pharmacokinetic data in
each group to allow dosing adjustments. The proposal recognized that
studies in neonates and young infants present special problems, and
sought comment on whether it is appropriate to require the assessment
of safety and effectiveness in this age group.
    36. Several comments addressed the requirement that all relevant
age groups be studied. Some comments opposed studies in more than one
age group. One comment contended that requiring safety data in each
pediatric group may place an unnecessary burden on the sponsor, and
that FDA should require safety data only in one group, presumably that
with the highest potential use. Another comment claimed that requiring
studies in all four age groups would almost never be justified. In most
cases, according to this comment, it should be possible to study a
single subgroup and extrapolate. Other comments argued that studies in
more than one age group could be necessary depending on the
pharmacokinetics of the drug, the disease, and expected use of the
drug. Most of these comments stated that the type and extent of studies
in different age groups must be decided on a case-by-case basis.
Several comments contended that drugs should be studied in each age
group in which they are expected to be used. One comment stated that
studies in toddlers are especially needed. A comment from an
organization devoted to pediatric AIDS argued that all age groups
should be studied unless the manufacturer provides compelling evidence
that it would be impossible or virtually impossible to study that
group.
    FDA continues to believe that studies in more than one age group
may be necessary, depending on expected therapeutic benefit and use in
each age group, and on whether data from one age group can be
extrapolated to other age groups.

[[Page 66651]]

    37. Many comments argued that the pediatric subgroups identified in
the proposal were arbitrary and that FDA should be flexible in
determining which age ranges or stages of development need to be
studied. A comment from a pharmaceutical trade association contended
that rigid age divisions for required studies were inappropriate, and
that the method by which the compound is cleared from the body must be
considered in light of what is known about physical development. The
AAP stated that the groups identified in the proposal provide
acceptable guidelines, but should not be adhered to rigidly. One
comment argued that the definition of pediatric patients should include
all subgroups of growth and development from 0 to 21 years.
    FDA agrees that the age ranges identified in the proposal may be
inappropriate in some instances and that it will be reasonable in some
cases to define subgroups for study using other methods, such as stage
of development. FDA has deleted the references in the rule to specific
age ranges.
    38. Several comments addressed inclusion of neonates in studies.
One comment maintained that because neonates are a special challenge,
they should not ordinarily be included in studies under this rule.
Another comment described the difficulties in conducting studies in
infants and neonates and recommended that before studies in this group
there be an assessment of ``the expected extent of use and potential
benefit in this patient population'' and an evaluation of safety data
in adults and older pediatric patients. One comment contended that
there are not many instances in which the benefit will outweigh the
risk of exposing neonates and young infants to drugs. This and another
comment also argued that it is not always possible to extrapolate from
data in older pediatric patients. A pharmaceutical trade association
maintained that validated end-points and ability to assess these by age
should determine which age groups to include, and that it may not be
possible to study certain end-points in very young pediatric patients.
One comment argued that early research on neonates raises special
ethical issues. Citing the 1977 FDA guideline, this comment asserted
that testing in neonates should occur only when substantial evidence of
benefit or superiority over accepted agents has been demonstrated in
older pediatric patients and adults.
    Other comments argued that neonates should not be excluded from
studies. According to one comment, study designs will be appropriate
and necessary ethical issues will be addressed if neonatologists are
included in the review of studies. Another comment stated that neonates
represent the greatest disparity in drug disposition compared to
adults, and that, on a scientific and ethical basis, they must
therefore be included in drug studies. The AAP stated that premature
infants, newborns, and infants are more difficult to study, but that
the difficulties do not outweigh the importance of studying them.
According to this comment, inadequate study of neonates has led to
frequent and severe toxicity. This comment agreed that it is
inappropriate to extrapolate from older pediatric patients to the
youngest age group.
    FDA agrees that the benefits and risks to premature infants,
neonates, and infants must be carefully weighed before these pediatric
patients are included in pediatric studies. Although the agency
believes that studies in these groups may be frequently waived or
deferred until adequate safety data have been collected, there will be
cases in which the drug or biologic is important and expected to be
used in these groups. In such cases, it will be appropriate to require
studies in these groups. To exclude them from study would be to subject
the most vulnerable patients to the risks of the drugs in clinical use
without adequate information about safety or dosing. FDA agrees that
studies in neonates and young infants raise special ethical issues, but
once these issues are addressed in each case, the studies should
proceed.

I. Pediatric Formulations

    As described in the proposal, testing of a product in pediatric
patients could require the development of a pediatric formulation. Many
young children are unable to swallow pills and may require a liquid,
chewable or injectable form of the product. A standardized pediatric
formulation also ensures bioavailability and consistency of dosing,
compared to alternatives such as mixing ground-up tablets with food,
and permits meaningful testing of safety and effectiveness. FDA
proposed in Secs. 201.23, 314.50(g)(1) (now 314.55(a)) and 601.27(a) to
require a manufacturer to produce a pediatric formulation, if one were
necessary, only in those cases where a new drug or new biological
product provided a meaningful therapeutic benefit over existing
treatments, and where the study requirement had not been waived in the
age group requiring the pediatric formulation. The proposal recognized
that the difficulty and cost of producing a pediatric formulation may
vary greatly depending upon such factors as solubility of the compound
and taste. FDA proposed to waive the requirement for pediatric studies
(see ``Waivers'' in section III.E of this document) in age groups
requiring a pediatric formulation, if the manufacturer provided
evidence that reasonable attempts to produce a pediatric formulation
had failed.
    FDA sought comment on whether it is appropriate to require a
manufacturer to develop a pediatric formulation, on whether the cost of
developing a pediatric formulation should ever justify a waiver of the
pediatric study requirement, and on how to define ``reasonable
attempts'' to develop a pediatric formulation.
    39. Many comments from the pediatric community argued that it is
appropriate to require manufacturers to produce pediatric formulations.
Several comments from pediatricians and parents described the
difficulties and uncertainties in attempting to administer adult
formulations to pediatric patients, and argued that pediatric
formulations are essential to assure bioavailability, accurate dosing,
and patient compliance, and to avoid wasting medications. The AAP
argued that FDA should require development of an appropriate
formulation for each age group for which the drug will be used, taking
into account ease of administration and ability to dose accurately.
    Comments from the pharmaceutical industry described technical
problems in producing pediatric formulations, including stability,
taste and palatability, and claimed that FDA underestimated these
difficulties. Some of these comments maintained that requiring
development of pediatric formulations during the investigational phase
will necessitate diversion of resources, increase the cost of the adult
formulation, and create a disincentive to produce drugs with pediatric
uses. One comment argued that it would be wasteful to require
development of a pediatric formulation before some evidence of
effectiveness has been collected and dose selection has been achieved,
because before that time the drug could be abandoned because of lack of
safety or effectiveness. A pharmaceutical trade association opposed a
pediatric formulation requirement, arguing that the government has no
right to tell manufacturers what products to market. This comment
stated that only if FDA successfully demonstrated that ``all attempts
to develop a voluntary solution have failed'' might the industry
consider other options. One comment stated that

[[Page 66652]]

a single drug could require more than one pediatric formulation for
different pediatric age group, such as a chewable tablet, a nonalcohol
containing liquid, and sprinkles. Counting failed attempts, this
comment claimed that producing a pediatric formulations may cost
millions of dollars.
    FDA believes that for drugs and biologics that offer a meaningful
therapeutic benefit to pediatric patients, it is essential to provide
pediatric formulations that ensure bioavailability and accurate dosing.
FDA disagrees that it is inappropriate for the government to require
manufacturers to produce pediatric formulations. As many comments
demonstrated, adult formulations of these drugs are frequently used in
pediatric patients because there is no other choice. Drug manufacturers
profit from these uses, but do not take responsibility for them. Where
a product is commonly being used in a subpopulation for an indication
recommended by the manufacturer, it is appropriate to require the
manufacturer to take steps to ensure that the use is safe and
effective.
    FDA agrees that producing a pediatric formulation can be difficult
or, rarely, impossible and has attempted to account for this problem by
permitting waiver of the pediatric study requirement where reasonable
attempts to produce a pediatric formulation have failed. FDA notes that
the pharmaceutical industry did not respond to FDA's request to help
define what should constitute such ``reasonable attempts.''
    To permit pediatric studies that may begin, for products for life-
threatening diseases, at the end of phase 1, or, for other products, at
the end of phase 2, it may be necessary to begin development of a
pediatric formulation before initiation of clinical trials. FDA does
not agree that it is wasteful to begin development of a pediatric
formulation at this stage. This rule is premised on the view that for
drugs and biologics that will have important use in pediatric patients,
it is the responsibility of the manufacturer to ensure that use is safe
and effective. Although some such products may ultimately prove to be
unsafe or ineffective, work on pediatric formulations of such products
is not necessarily more wasteful than work on adult formulations. FDA
does not agree that manufacturers will be required to develop several
pediatric formulations for different age groups. Even for a drug that
was to be used in all pediatric age groups, a liquid formulation, e.g.,
might be usable in all age groups.
    FDA has no basis to conclude that producing pediatric formulations
will increase the cost of adult formulations or create disincentives
for producing drugs and biologics with pediatric uses. No evidence was
submitted to support either of these assertions.
    40. Several comments discussed how to define ``reasonable
attempts'' to produce a pediatric formulation. The AAP argued that
difficulty in producing a pediatric formulation should be a basis for
waiver only if the sponsor provides data showing that formulation
experts encountered insurmountable problems of solubility, stability,
compatibility, or palatability using accepted methods, and that cost be
given only limited consideration. The AAP urged that such an assertion
be corroborated by a panel of pediatric experts and FDA as well as
formulation experts. Another comment agreed that formulations
appropriate for younger age groups should be developed unless the
manufacturer shows it would be virtually impossible. This comment
argued that if a manufacturer wants to show that the cost is
prohibitive, it should provide information allowing the financial and
other costs of development to be seen in terms of the entire drug
development process. Another comment argued that waivers should not be
based on whether reasonable efforts to develop a pediatric formulation
have failed because this ground for a waiver would permit small
companies to avoid producing pediatric formulations on cost grounds.
This comment urged that waivers be allowed only if a pediatric
formulation cannot be produced for scientific or technological reasons.
One comment argued that even if producing a pediatric formulation is
impossible, the manufacturer should be required to study the adult
formulation in pediatric patients, because it will be used in pediatric
patients.
    One industry comment urged that the decision to require a pediatric
formulation be made on a case-by-case basis. Another comment argued
that pediatric formulations should be required only if a panel of
pediatric experts concludes that there is a genuine pediatric need and
substantial benefit.
    FDA agrees that the burden should be on the manufacturer to provide
evidence that experts in formulation chemistry had encountered
unusually difficult technological problems in the development of a
pediatric formulation. In determining whether those problems were
sufficiently severe to warrant a waiver of pediatric studies, FDA will
consider the potential importance of the product for pediatric
patients. The more important the product, the more efforts should be
made to develop a pediatric formulation. FDA will also, at its
discretion, take to the Advisory Committee for Pharmaceutical Sciences
questions about whether ``reasonable attempts'' have been made to
produce pediatric formulations in particular cases. Although FDA
believes that it is appropriate to consider the cost to the
manufacturer in determining whether attempts to produce a pediatric
formulation have been reasonable, the agency received no helpful
guidance on how to assess whether the costs of producing a pediatric
formulation were unreasonable. In addition to any informative cost
information provided by the manufacturer, FDA will take into account
whether a product is still under patent or exclusivity protection. FDA
will assume that manufacturers can incur greater costs for products
that have significant patent life or exclusivity remaining.
    41. One comment contended that FDA chemistry requirements have
increased over the last 10 years. Another comment urged that FDA be
more flexible in its review of formulations, e.g., by permitting
generally recognized as safe (GRAS) substances in pediatric
formulations.
    FDA recently held a conference on pediatric formulations at which
the agency sought input from industry on identifying the regulatory
issues that affect the development of pediatric formulations for both
new and approved marketed drugs. At this meeting, FDA also requested
proposals for solutions to facilitate the development and approval of
pediatric formulations. FDA is committed to removing unnecessary
burdens on the review and approval of pediatric formulations.
    42. Two comments urged manufacturers to provide formulas in product
labeling for extemporaneous pediatric formulations made by pharmacists.
These comments stated that the current practice among hospital
pharmacies is to use unvalidated formulas, resulting in a lack of
consistency from one hospital to another, no stability testing, and, in
some cases, reluctance to produce pediatric formulations at all because
of the lack of guidance. One comment stated that information on
extemporaneous formulations should be provided only where: (1) A
commercial formulation is not possible or (2) the drug has extremely
limited use in pediatric patients.
    FDA is concerned that the availability of this approach may
undermine efforts to produce standardized pediatric formulations. There
are, however, one or two examples in which approved labeling carries
directions for producing

[[Page 66653]]

extemporaneous pediatric formulations. FDA will consider, on a case-by-
case basis whether such an approach is appropriate, e.g., where it has
not been possible to develop a stable commercial formulation.

J. Marketed Drug and Biological Products

    FDA proposed in Sec. 201.23 to codify its authority to require, in
certain circumstances, a manufacturer of a marketed drug or biological
product to submit an application containing data evaluating the safety
and effectiveness of the product in pediatric populations. FDA proposed
to impose such a requirement only where the agency made one of two
findings: (1) That the product was widely used in pediatric populations
and the absence of adequate labeling could pose significant risks to
pediatric patients; or (2) the product was indicated for a very
significant or life-threatening illness, but additional dosing or
safety information was needed to permit its safe and effective use in
pediatric patients.
    Before requiring a study under this section, FDA proposed to
consult with the manufacturer on the type of studies needed and on the
length of time necessary to complete them, and would notify the
manufacturer, by letter, of the agency's tentative conclusion that such
a study was needed and provide the manufacturer an opportunity to
provide a written response and to have a meeting with the agency. At
the agency's discretion, such a meeting could be an advisory committee
meeting. If, after reviewing any written response and conducting any
requested meeting, FDA determined that additional pediatric use
information was necessary, FDA proposed to issue an order requiring the
manufacturer to submit a supplemental application containing pediatric
safety and effectiveness data within a specified time. The proposal
referred to the order in one place as a letter. FDA has clarified the
final rule by stating that the manufacturer will receive ``an order, in
the form of a letter.'' A few other minor clarifying revisions have
also been made in this section.
    FDA sought comment on whether it should codify its authority to
require the manufacturers of marketed drugs and biologics to conduct
pediatric studies, and, if so, on the circumstances in which the agency
should exercise that authority.
    43. Many comments from the pediatric community agreed that FDA
should codify its authority to require pediatric studies on marketed
drugs. Several comments from the pharmaceutical industry argued that
FDA lacked authority to require studies of marketed drugs and that the
1994 rule sufficiently addressed pediatric labeling for marketed drugs.
Some comments argued that adding pediatric labeling for indications
applicable to pediatric patients should be at the sponsor's discretion.
Others claimed that incentives are better than requirements. One
comment contended that the proposed requirement forces manufacturers
``to take on unwanted liabilities in order to maintain an asset which
was created and earned under a different set of rules.'' Other comments
maintained that companies should not be required to conduct new
studies, and that pediatric labeling should be based on existing data,
such as marketing experience and dosing regimens generally accepted by
experts. A comment from a pharmaceutical trade association argued that
studies should not be required but that FDA should work with industry
and others to ``develop creative ways to obtain the needed labeling
information'' for marketed drugs.
    FDA believes that it has ample authority to require pediatric
studies of marketed drugs and biologics, as described in the preamble
to the 1994 rule (59 FR 64240 at 64243) and in ``Legal Authority''
section IV of this document. FDA has also concluded, as described
previously, that the response to the 1994 rule and other voluntary
measures have not produced a significant improvement in pediatric
labeling for many marketed drugs and biologics. In addition, as one
pharmaceutical company conceded, manufacturers are unlikely to initiate
clinical research on marketed drugs whose patents have expired, or are
about to expire. FDA has therefore concluded that where pediatric
information is critical to patient care, it is necessary to require
that pediatric studies be carried out. FDA notes that new requirements
are sometimes imposed on already marketed consumer products when such
requirements are necessary to protect the public health. FDA
emphasizes, however, that it will require studies of marketed products
only in the compelling circumstances described in the regulation.
    44. FDA received many comments on the grounds for requiring studies
of marketed products. Comments from medical societies, pediatricians,
and disease-specific organizations argued that the proposed grounds
were too narrow. One comment stated that pediatric studies should be
required of any marketed drug that is likely to be used in pediatric
patients. Several comments argued that the phrase ``very significant
illness'' was ill-defined. One comment stated that it was ``so open-
ended and subjective as to be impossible for use as a regulatory
standard.'' Another comment suggested that any definition of ``very
significant illness'' would be arbitrary and overbroad. Several
comments urged that the same criteria that are applied to not-yet-
approved drugs be applied to marketed drugs. One of these comments
argued that even if the criteria remain as proposed, ``widely used''
and ``significant risk'' should be defined in terms of the severity of
the illness. According to this comment, if the consequences of no
treatment are serious, the absence of labeling should be more readily
found to present a significant risk. One industry comment maintained
that the requirement should apply to marketed drugs only where there is
a ``compelling need'' for pediatric data. One comment argued that the
requirement should apply to all marketed drugs unless an expert panel
concluded that studies were not required, while other comments urged
that FDA utilize an expert panel to affirmatively identify and
prioritize marketed drugs that should be studied in pediatric patients.
Some of these comments suggested that there be no criteria and that the
panel should determine which drugs should be studied on a case-by-case
basis. One comment suggested that the list should be prioritized using
the number of pediatric prescriptions.
    FDA believes that criteria are necessary to assure consistency and
fairness in deciding which marketed drugs and biologics are studied.
FDA has reviewed the grounds for requiring pediatric studies of
marketed drugs and biologics and has revised them in light of the
comments. FDA has concluded that the phrase ``very significant
illness'' is not sufficiently defined and agrees that it would be less
confusing to use the same concepts that are used in defining which new
products will be subject to the pediatric study requirement. FDA has
therefore replaced the concept of ``very significant illness'' and
replaced it with ``meaningful therapeutic benefit.'' However, to ensure
that this authority is reserved for cases in which there is a
compelling need for studies, FDA has added the requirement (already
present in the first criterion) that FDA also find that the absence of
adequate labeling could pose significant risks for pediatric patients.
The second criterion will now read:

[[Page 66654]]

    * * * there is reason to believe that the drug product would
represent a meaningful therapeutic benefit over existing treatments
for pediatric patients for one or more of the claimed indications,
and the absence of adequate labeling could pose significant risks to
pediatric patients.

    FDA has also revised the first criterion to conform more closely to
the criteria for requiring studies in not-yet-approved drugs and
biologics, replacing ``widely used'' with ``used in a substantial
number of pediatric patients.'' FDA will use the same definition of
``substantial number'' for both marketed and not-yet-approved drugs and
biologics. The first criterion will, however, continue to include the
requirement that ``the absence of adequate labeling could pose
significant risks to patients.'' FDA believes that the pediatric study
requirement may impose greater burdens on the manufacturers of marketed
drugs and biologics than the manufacturers of not-yet-approved
products, and that it is appropriate to require such studies only in
the compelling circumstances described in the regulation. In
determining which marketed products ``could pose significant risks to
patients,'' FDA will consider such factors as the severity of the
illness and the consequences of inadequate treatment, the number of
pediatric prescriptions, and any available information on adverse
events associated with use of the product.
    FDA emphasizes that it intends to exercise its authority under
Sec. 201.23 only in compelling circumstances. FDA has estimated that it
will require studies of approximately two marketed drugs per year.
    FDA agrees that an expert panel can provide useful experience and
guidance in developing a prioritized list of marketed drugs and
biologics that meet the criteria for required studies. FDA intends to
seek advice on developing such a list from a pediatric panel, as
described in section III.M of this document (``Pediatric Committee'').
    FDA also notes that FDAMA requires the agency to publish a list of
marketed drugs for which ``additional pediatric information may produce
health benefits in the pediatric population.'' FDA published this list
within 180 days of the enactment of FDAMA, as required by that statute.
Although the products on the list designated as high priority may be
appropriate candidates for required studies under this rule, the list
of high priority products is not necessarily exhaustive. Other products
that might be subject to a requirement under this rule might not appear
on the list. FDA also emphasizes that there is no implication that the
agency will require studies of any particular product on the list. As
noted in the Introduction to this preamble, before imposing any
requirements under Sec. 201.23, FDA intends to allow manufacturers
eligible for FDAMA incentives an adequate opportunity to voluntarily
conduct studies of marketed drugs in response to those incentives. If,
following such an opportunity, there remain marketed drugs for which
studies are needed and the compelling circumstances described in the
rule are met, the agency will consider exercising its authority to
require studies.
    45. One comment claimed that the proposal requires studies only
from manufacturers of innovator drugs (sponsors of the original
application for the drug), while the major market share for many of
these drugs is now held by generic manufacturers. This comment argued
that a waiver should be granted if ANDA holders fail to share the costs
of required studies. Another comment argued that the pediatric study
requirement should apply only to the sponsor of the original
application.
    Where the agency requires pediatric studies on a multi-source
marketed drug, each manufacturer of that drug, whether innovator or
generic, will be responsible for satisfying the study requirement. To
avoid duplication of research, FDA will encourage all the manufacturers
to jointly fund an appropriate study. If, however, a joint study is not
agreed to, each manufacturer will be responsible for submitting
adequate studies.

K. Ethical Issues

    In the proposal, FDA noted that because pediatric patients
represent a vulnerable population, special protections are needed to
protect their rights and to shield them from undue risk. To address
ethical concerns in research on pediatric patients, both the AAP (Ref.
17) and the Department of Health and Human Services (DHHS), 45 CFR part
46, subpart D, have developed guidelines for the ethical conduct of
clinical studies in pediatric patients. FDA advised in the proposal
that sponsors should adhere to these guidelines for pediatric studies
conducted under this rule. The agency also sought comment on ethical
issues raised by the proposal.
    46. A few comments addressed appropriate ethical guidelines for
pediatric studies. Several comments said that existing ethical
guidelines provide an adequate framework for pediatric studies. A
comment from the AAP stated that ethical conduct should be guided by
the DHHS and AAP guidelines, and that IRB approval that explicitly
ensures protection of vulnerable subjects should be obtained. This
comment also stated that the AAP guidelines provide a means to ensure
ethical conduct of studies without impeding pediatric research. One
comment said that DHHS ethics regulations may not provide sufficient
protection for pediatric patients and suggested incorporating AAP
guidelines for ethical conduct of pediatric studies into FDA's human
subjects protections regulations. Another comment contended that
pediatric studies should strictly adhere to regulations currently in
effect for studies of human subjects who are unable to give consent,
and urged FDA to further define requirements for investigation in
vulnerable populations.
    FDA believes that adherence to the DHHS and AAP guidelines will
provide sufficient protection to pediatric patients from the risks of
research. FDA will, however, seek advice from a panel of pediatric
experts on whether additional protections are necessary.
    47. Several comments addressed the ethics of requiring pediatric
studies as described in the proposal. Two comments asserted that
children are overmedicated and that administering drugs to children is
unacceptable and ``ungodly.'' Comments from the pharmaceutical industry
claimed that the rule as drafted would result in unethical testing of
pediatric patients. One comment maintained that the regulations do not
adequately protect pediatric patients from the risks of research
because they impose a ``general rule that a deferral of testing in
pediatrics will only be granted in narrow and limited circumstances.''
    In contrast, comments from the pediatric community maintained that
far more serious ethical concerns are raised by using untested drugs in
pediatric patients than by conducting pediatric research. A comment
from the AAP stated that there is no greater ethical dilemma than
whether to give a drug with insufficient safety and effectiveness data
to a child, or to withhold treatment and let the disease progress
unabated.
    Some comments suggested specific points in drug development at
which pediatric testing becomes ethical. One comment argued that
testing in pediatric patients before efficacy is demonstrated in adults
may unnecessarily expose pediatric patients to a product's risks before
its benefits are established. Another comment contended that it is
unethical to begin studying drugs in pediatric patients that are not
intended primarily for pediatric patients until the drug is adequately
characterized in

[[Page 66655]]

adult patients, including choice of appropriate adult dose and
establishment of reasonable evidence of safety and efficacy with an
acceptable therapeutic margin. A pharmaceutical trade association
argued that it is unethical to begin trials in pediatric patients until
enough adult safety and effectiveness data have been gathered to
conclude that the drug ``is likely to be approved for use in adults.''
    FDA believes that some of the comments from the pharmaceutical
industry misstate the application of the rule. As described fully
previously, deferral of pediatric studies is specifically permitted in
those cases where data should be collected in adults before exposing
pediatric patients to the agent. There is no suggestion in either the
proposed or final rule that deferral will be granted only in ``narrow
and limited circumstances.'' FDA believes that, as drafted, the
deferral provisions of the rule permit ethical pediatric testing that
does not expose pediatric patients to inappropriate risks.
    48. A few comments urged that placebo-controlled trials in
pediatric patients be used rarely if at all. The AAP stated that
placebo controls should not be used where that design would impose a
substantial increase in risk to the child or would impede the ability
to perform useful clinical trials. This comment urged that alternatives
to placebo controls be used wherever possible and that where placebo
controls are used, the study design should incorporate safeguards to
avoid undue risk.
    The question of appropriate control group arises only when there is
a need for controlled trials to establish efficacy in the pediatric
population. FDA agrees that alternatives to placebo-controlled trials
should be used wherever they can provide sufficient information to
establish effectiveness. FDA often accepts data from active control
studies for certain therapeutic classes, such as anti-infectives and
oncologic drugs. (See 21 CFR 314.126.) In some cases, new treatments
can also be studied against a placebo together with a background of
existing therapy, i.e., studied in ``add-on'' trials.
    49. One comment argued that parents should not be given money or
equivalent compensation for participation in drug studies. This comment
suggested that any compensation could be put in the child's IRA.
    The IRB overseeing a research study, rather than FDA, is
responsible for determining whether compensation offered to the
subjects of the study is ethically appropriate.

L. Remedies

    If a manufacturer failed, in the time allowed, to submit adequate
studies to evaluate pediatric safety and effectiveness required under
proposed Sec. 201.23(c) or Sec. 314.55 (proposed Sec. 314.50(g)), FDA
proposed to consider the product misbranded under section 502 of the
act or an unapproved new drug under section 505(a) of the act (see
``Legal Authority,'' in section IV of this document). Although proposed
Sec. 201.23 expressly covered both drugs and biologics, FDA
inadvertently omitted in that section a reference to actions against
biologics that have not obtained a license under section 351 of the
Public Health Service Act. Such a reference has been added in the final
rule. When a product is misbranded or an unapproved new drug, sections
302, 303, and 304 of the act (21 U.S.C. 332, 333, 334) authorize
injunction, prosecution or seizure. FDA may also seek an injunction or
bring a prosecution under the Public Health Service Act. In the
proposal, FDA advised that it would bring an enforcement action for
injunctive relief for failure to submit a required assessment of
pediatric safety or effectiveness. Violation of the injunction would
result in a contempt proceeding or such other penalties as the court
ordered, e.g., fines. As noted in the proposal, FDA does not intend to
deny or withdraw approval of a product for failure to conduct pediatric
studies, except possibly in rare circumstances, because removal of a
product from the marketplace could deprive other patients of the
benefits of a useful medical product. Such circumstances might arise
where the predominant use of the product was in pediatric patients
rather than adults, and there were life-threatening risks associated
with use of the product in pediatric patients when used without proper
dosing and safety information in the labeling.
    To assist FDA in determining whether pediatric assessments are
needed or are being carried out with due diligence, FDA proposed to
amend Sec. 314.81(b)(2) (21 CFR 314.81(b)(2)) (annual postmarketing
reports) to require that annual reports filed by the manufacturer
contain information on labeling changes that have been initiated in
response to new pediatric data, analysis of clinical data that have
been gathered on pediatric use, assessment of data needed to ensure
appropriate labeling for the pediatric population, and information on
the status of ongoing pediatric studies. FDA also proposed to require
that, where possible, the annual report contain an estimate of patient
exposure to the drug product, with special reference to the pediatric
population.
    50. Several comments agreed with the agency that withdrawal or
denial of approval is infeasible and supported the use of injunctive
remedies. One comment argued that if FDA provides no incentives,
disincentives to avoid pediatric trials must be strong, and that
withdrawal and denial of approval must therefore be used as a remedy.
    FDA continues to believe that refusal to approve or removal from
the market is generally an unsatisfactory remedy from a public health
perspective because it denies adequately studied populations access to
safe and effective medicines.
    51. Several comments supported the imposition of monetary fines.
One comment urged that fines be imposed in the amount of a percentage
of the profits to ensure that large and small companies had an equal
disincentive. Several comments argued that fines should be used by FDA
to fund pediatric studies carried out by government or private
agencies. One comment contended that monetary penalties, such as fines
or shortening of exclusivity, are the only practical remedy because
industry and government are economically driven, but that injunctions
are too costly.
    Although FDA continues to believe that court-imposed fines are an
appropriate remedy for failure to submit pediatric assessments, the
agency has no authority itself to impose fines for violation of this
rule, to set the amount of such fines, or to take the fines and direct
them to specific activities.
    52. Two comments opposed treating violative products as
``misbranded'' because this could limit access to the drugs or could
delay availability of the products for adult use. According to one
comment, FDA should consider a misbranding charge only if the sponsor
failed to meet a phase 4 commitment. Another comment argued that
injunction or prosecution are appropriate only as a final response, and
that other, unspecified means are more efficient to elicit compliance.
This comment also argued that seizure would serve only to deprive
patients of safe and effective drugs.
    The comments arguing that a misbranding charge could limit access
or delay approval provided no basis for concluding that these results
would occur, and FDA is aware of none. FDA agrees that injunction and
prosecution are appropriate remedies only after the sponsor has been
given an adequate opportunity to meet its obligations under the rule.
FDA emphasizes, however, that providing adequate

[[Page 66656]]

pediatric labeling cannot be long-delayed without putting the health of
pediatric patients at risk and that the agency will not accept
unwarranted delays in submitting required studies. FDA also notes that
it does not intend ordinarily to use seizure as a remedy for failure to
conduct required studies.
    53. Some comments offered additional or alternative remedies for
failure to conduct required studies. One comment urged that failure to
provide information to support pediatric labeling result in highly
visible warnings on prescription and OTC labels that the drug has not
been approved by FDA for pediatric use. Two comments argued that the
label should disclose the status of pediatric studies, whether waivers
or deferrals had been requested or granted, and the timetable for full
compliance. Another comment contended that incentives are more
effective than penalties, and that FDA discussions with sponsors during
drug development will achieve the results sought in the proposal.
    FDA agrees that publicity can sometimes be a useful tool for
encouraging compliance. FDA does not believe, however, that it is
feasible to include in labeling detailed information on the status of
pediatric trials, because that information could change frequently. As
described in section III.M of this document, FDA will, in appropriate
cases, bring issues related to the progress of pediatric studies before
a panel of pediatric experts, and may utilize other forms of publicity
to provide the public with information about the status of required
pediatric studies. FDA notes, e.g., that FDAMA contains provisions
concerning disclosure of information on the status of postmarketing
studies. FDA may also consider the use of prominent warnings about the
absence of data on pediatric use, if necessary in particular cases.

M. Pediatric Committee

    A large number of comments recommended that FDA form a panel of
pediatric experts to provide advice on a range of topics related to
implementation of this rule. Two comments recommended that an expert
panel give advice on all facets of the rule. Several comments suggested
more specific roles for the panel. For example, the AAP recommended
that the panel provide advice on waiver requests, which marketed drugs
require study, whether a drug is ``widely used,'' whether to accept a
manufacturer's failure to develop a pediatric formulation, relevant age
groups for study, the appropriateness of deferral, and appropriate
timetables for completion of deferred studies. A disease-specific
organization urged that a pediatric committee assist in establishing
``pediatric guidelines and practice,'' including a list of drugs for
which studies would be required, protocol design, formulations, and age
ranges. Two industry comments recommended that the panel review which
drugs require testing and labeling, at what phase of drug development
pediatric patients should be exposed, when waivers should be granted,
what methods should be used to evaluate safety and effectiveness, the
economic burdens on industry, and liability issues. Several comments,
including comments from a pharmaceutical trade association, a disease-
specific organization, a medical society, and pediatricians,
recommended that the panel give advice on which drugs should be studied
in pediatric patients. One comment suggested that FDA appoint a
pediatric pharmacology expert to each of the existing drug advisory
committees, except possibly the Fertility and Maternal Health Advisory
Committee.
    FDA has concluded that a panel of pediatric experts could provide
useful advice and experience on several aspects of the implementation
of the rule. FDA will therefore convene a panel of pediatric experts,
including at least one industry representative, and seek its advice on
a range of issues. Such a panel may be composed of pediatric experts
appointed to each of FDA's existing drug advisory committees. As
described in section III.E of this document under ``Waivers,'' FDA does
not believe that it would be practical to ask such a committee to
review every waiver or deferral request. However, the agency will ask
the panel to provide annual oversight of the agency's implementation of
the final rule, including the agency's record of granting or refusing
waivers and deferrals. FDA will also seek the advice of the panel in
identifying specific marketed drugs and biological products that should
be studied in pediatric patients, and the age groups in which they
should be studied. FDA will also ask for advice on assessing when
additional therapeutic options are needed in treating specific diseases
and conditions occurring in pediatric patients. As described
previously, FDA will seek the panel's advice on ethical issues raised
by clinical trials in pediatric patients, and whether additional rules
should be implemented in this area. Where a manufacturer is not
carrying out required studies according to the agreed upon timetable,
FDA may seek the advice of the panel on whether the manufacturer is
acting with due diligence. In addition, FDA may bring before the panel
other issues that arise in the implementation of the rule, including
the design of trials and analysis of data for specific products and
classes of products.

N. Other Comments

    54. Several comments suggested various forms of oversight for the
implementation of the rule. One comment suggested that FDA establish a
plan to prospectively evaluate these regulations, including their
effect on the cost of drug development and on the time to new drug
approval, and the number and success of pediatric studies actually
performed. Another comment urged FDA to appoint a ``Children's Studies
Ombudsman.'' One comment asked that the rule include an appeals
mechanism to resolve disputes between sponsors and agency reviewers.
    As described previously, FDA intends to convene a panel of
pediatric experts, including at least one representative of the
pharmaceutical industry, to, among other things, review the agency's
implementation of the rule. FDA notes that it already has procedures
for resolution of disputes between sponsors and FDA reviewing
divisions, 21 CFR 312.48 and 314.103, and that these procedures will be
available for disputes that arise under this rule.
    55. Several comments contended that the rule is inconsistent with
requirements in Canada, Europe, and Japan for pediatric studies. These
comments argued that the rule was at odds with harmonization efforts
and urged FDA to harmonize its requirements with those of other
countries. One comment recommended that the United States, the European
Union (EU), and Japan adopt pediatric drug development as a topic for
global discussion and harmonization.
    Although FDA is not required to harmonize its labeling regulations
and enforcement with those of our International Conference on
Harmonization (ICH) partners, harmonization is a goal that the agency
strives to achieve. FDA intends to work through the ICH process to
harmonize methods for conducting pediatric studies.
    56. A few comments sought additional incentives for pediatric
studies. One industry comment suggested that FDA should provide: (1)
Priority reviews for applications containing pediatric data or ongoing
studies; (2) waiver of user fees for pediatric effectiveness
supplements; and (3) application of the subpart E

[[Page 66657]]

regulations (21 CFR part 312, subpart E) to pediatric development of
new drugs and biological products, to address the issues associated
with small sample size and therapeutic need.
    Since the publication of the proposal, two significant new
incentives have become available for pediatric research. First, as
described elsewhere in this document, FDAMA provides 6 months of
exclusive marketing to certain applicants who conduct pediatric
studies. Second, as a result of changes made during the reauthorization
of the PDUFA, user fees are no longer required for supplements that are
solely for the purpose of adding a new indication for use in pediatric
populations.

IV. Legal Authority

    In the proposal, FDA cited as authority for the requirements in the
rule sections 502(a), 502(f), 505(d)(7) of the act, and Sec. 201.5 (21
CFR 201.5), which require adequate directions for use and prohibit
false or misleading labeling; section 201(n) of the act, which defines
as misleading labeling that fails to reveal material facts related to
consequences of the customary or usual use of a drug; sections 201(p),
301(a) and (d) (21 U.S.C. 331(a) and (d)), and 505(a) of the act, which
subject a drug to enforcement action if it is not recognized as safe
and effective or approved for the conditions prescribed, recommended,
or suggested in the labeling; section 502(j) of the act, which
prohibits drugs that are dangerous to health when used in the manner
suggested in their labeling; sections 505(i) and 505(k) of the act,
which authorize FDA to impose conditions on the investigation of new
drugs, including conditions related to the ethics of an investigation,
and to require postmarketing reports; section 701(a) of the act, which
authorizes FDA to issue regulations for the efficient enforcement of
the act; and section 351 of the Public Health Service Act, which
formerly required biological products to meet standards designed to
insure their ``continued safety, purity, and potency.'' FDA notes that
section 351 was amended by FDAMA, and now requires biological products
to be ``safe, pure, and potent.''
    FDA has authority under section 302 of the act and under the Public
Health Service Act to seek an injunction requiring studies of certain
marketed drugs on the grounds that the absence of pediatric safety and
effectiveness information in the labeling renders the product
misbranded or an unapproved new drug. The act also authorizes seizures
of misbranded or unapproved drugs under section 304 of the act.
Misbranding drugs and introducing unapproved new drugs into interstate
commerce are prohibited acts under sections 301(a), (d), and (k) of the
act. The statutory definition of ``drug'' is set out at section 201(g)
of the act.
    57. Several comments agreed that FDA has authority to require
pediatric testing of drugs and biological products. One comment argued
that the act already gives FDA the authority to require that all drugs
be tested in pediatric patients, and that the rule, which permits
waivers and deferred testing in some cases, weakens the agency's
existing statutory authority. One comment contended a provision of
FDAMA granting exclusivity to ``any pediatric study [that] is required
pursuant to regulations promulgated by the Secretary [and that meets
certain other requirements]'' shows that Congress agrees that FDA has
authority to require pediatric studies. This comment also argued that,
to the extent that FDA's position on its authority to require pediatric
studies has changed, the change in position is justified because the
proposal articulates a reasoned basis for the change.
    FDA agrees that it has the authority to require pediatric testing
of drugs and biologics. For the reasons cited in the preamble to the
proposed and final rules, FDA has concluded that the requirements in
the rule appropriately balance the need for adequate pediatric labeling
and the limitations on resources available for pediatric testing and
agency review. FDA also agrees that the reference in FDAMA, which was
enacted after the proposal was issued, to pediatric studies required by
FDA, demonstrate that Congress is aware of FDA's position that it has
the authority to issue this rule and agrees that the agency has such
authority. Finally, FDA agrees that it has articulated a reasoned basis
for its position that the agency has authority to require pediatric
studies, but notes that FDA previously stated its position that it has
the authority to require pediatric studies in 1994 (59 FR 64240 at
64243).
    58. Several comments argued that FDA lacks authority to require
pediatric studies of drugs. A few comments cited remarks by former
Commissioner David Kessler during a 1992 speech. In that speech, David
Kessler stated his opinion that FDA does not have ``the authority to
require manufacturers to seek approval for indications which they have
not studied.'' Other comments argued that FDA has no authority to
require the study of any indications or populations other than those
proposed by the manufacturer. One comment challenged FDA's reliance on
section 201(n) of the act for not-yet-approved drugs, claiming that the
agency cannot know what will be the ``customary or usual uses'' of an
unmarketed drug. A few comments argued that the agency's legal theory
would authorize the agency to require studies of all off-label
indications.
    FDA disagrees that any of these arguments show that FDA lacks
authority to issue this rule. Under FDA's longstanding policy,
statements made in speeches, even by Commissioners, are informal
expressions of opinion and do not constitute a formal agency position
on a matter. As such they are not binding on the agency. (See, e.g., 21
CFR 10.85(k).)
    FDA also disagrees that it has no authority to require a drug or
biologic to be studied in a population that is expected to use the
product for the claimed indication, or that this is a new position. The
agency has repeatedly stated that an application for marketing approval
should contain data on a reasonable sample of the patients likely to be
given the product once it is marketed (59 FR 64240 at 64243; 58 FR
39406 at 39409). The agency has also previously asserted its authority
to require studies in pediatric patients and in other subpopulations
for both not-yet-approved products and marketed products. In the
preamble to the 1994 rule, FDA made the following statement:

    If FDA concludes that a particular drug is widely used,
represents a safety hazard, or is therapeutically important in the
pediatric populations, and the drug sponsor has not submitted any
pediatric use information, then the agency may require that the
sponsor develop and/or submit pediatric use information.
    If FDA has made a specific request for the submission of
pediatric use information because of expected or identified
pediatric use, and the sponsor fails to provide such information,
the agency may consider the product to be a misbranded drug under
section 502 of the act, or a falsely labeled biological product
under section 351 of the PHS Act, as an unapproved new drug or
unlicensed biological product. (See 21 U.S.C. 355 and 42 U.S.C.
262.)

(59 FR 64240 at 64248; see also 58 FR 39406 at 39409)

    The act and implementing regulations require drugs to be adequately
labeled for their intended uses. See sections 502(f) of the act and
Sec. 201.5. ``Intended uses'' encompass more than the uses explicitly
included in the manufacturer's proposed labeling. Id., 21 CFR 201.128.
In determining the intended uses of a drug for which it must be
adequately labeled, FDA may consider both the uses for which it is
expressly labeled and those for which the drug is commonly used,
Sec. 201.5.

[[Page 66658]]

FDA may also consider the actual uses of the drug of which the
manufacturer has, or should have, notice, even if those uses are not
promoted by the manufacturer, 21 CFR 201.128. Section 201(n) of the act
defines labeling as misleading if it fails to include material facts
about the consequences of ``use of the [drug] * * * under such
conditions of use as are customary or usual.'' Sections 201(p) and
505(d) of the act authorize FDA to require evidence establishing the
safety and effectiveness of uses ``suggested'' by the manufacturer's
labeling as well as those expressly recommended in the labeling. Thus,
the agency has authority to require a manufacturer to establish the
safety and effectiveness of, and adequately label its product for, use
of the product in a subpopulation for which the product is not labeled
if that use is common or suggested in the labeling.
    As described in the proposal, there is extensive evidence that
drugs and biologics indicated for diseases that affect both adults and
pediatric patients are routinely used in pediatric patients despite the
absence of pediatric labeling, and even in the face of disclaimers
stating that safety and effectiveness have not been established in
pediatric patients. FDA may therefore consider pediatric use to be
``customary or usual'' or ``commonly used'' where the drug is indicated
for a disease or condition that affects both adults and children, and
the drug is not contraindicated in pediatric patients. FDA may also
consider pediatric use to be ``suggested'' in a drug's labeling even
where such use is not expressly recommended or is even disclaimed. The
medical community generally expects that drugs and biological products
will behave similarly in demographic subgroups, including age and
gender subgroups, even though there may be variations among the
subgroups, based on, e.g., differences in pharmacokinetics. Thus, where
a drug or biological product is indicated for a disease suffered
equally by men, women, and children, and is not contraindicated in
women or pediatric patients, the product will be widely prescribed for
all three subgroups even if it were studied only in, or labeled only
for, men.
    FDA disagrees that it can know nothing, in advance of marketing,
about whether a drug or biological product will be used in pediatric
patients. The evidence cited in the proposal and confirmed by comments
from the pediatric community is overwhelming that products indicated
for diseases that affect both adults and children are and will be
commonly used in pediatric patients. Indeed, pediatricians often have
no choice but to use these products in pediatric patients. A drug
product that provides a meaningful therapeutic benefit either because
it represents a significant improvement in therapy or because it is a
necessary therapeutic option can be expected to be routinely used in
the treatment of pediatric patients. Under the rule, the decision that
a product will provide a meaningful therapeutic benefit or will be used
in a substantial number of pediatric patients is made on a case-by-case
basis, depending upon such factors as the number of pediatric patients
affected by the disease for which the product is indicated, the
availability and adequacy of other therapeutic options to treat
pediatric patients for the disease, and whether similar products, e.g.,
products in the same drug class, have been widely used in pediatric
patients.
    Finally, FDA emphasizes that this rule applies only where a product
is expected to have clinically significant use in pediatric populations
for the indications already claimed by the manufacturer. The record
before the agency documents widespread evidence of actual use of
products in the pediatric population for indications labeled for
adults. This record supports FDA's conclusion that it has authority to
require pediatric studies of drugs and biologics that have or are
expected to have clinically significant use among pediatric patients
for the claimed indications. The agency has not examined evidence
concerning the use of approved products for diseases or conditions not
in the label, and the rule does not apply in those situations.
    59. Two comments addressed the agency's reliance on section 701(a)
of the act. One comment argued that 701(a) of the act, in combination
with the substantive statutory provisions cited by FDA, authorizes this
rule because the agency has demonstrated that the rule is reasonably
related to the purposes of the act. Another comment argued that 701(a)
of the act does not authorize the agency to enforce requirements beyond
those imposed by the act.
    Section 701(a) of the act gives the Secretary authority to issue
regulations for the efficient enforcement of the act. Consonant with
the Supreme Court's determination that the language of the act should
not be read restrictively, but in a manner consistent with the act's
purpose of protecting the public health, a regulation issued under
section 701(a) of the act will be sustained so long as it is reasonably
related to the purposes of the act. United States v. Nova Scotia Food
Products Corp., 568 F.2d 240, 246 (2nd Cir. 1977). FDA believes that it
has demonstrated that this regulation is reasonably related to the
purposes of the act.

V. Implementation Plan

    FDA proposed that the rule would become effective 90 days after the
date of its publication in the Federal Register. For new drug and
biologic product applications submitted before the effective date of
the final rule, the agency proposed a compliance date of 21 months
after the effective date of the final rule (for a total of 2 years
after issuance of the final rule). For new drug and biologic product
applications submitted on or after the effective date of the final
rule, the agency proposed a compliance date of 15 months after the
effective date of the final rule (for a total of 18 months after
issuance of the final rule). FDA has revised the final rule to become
effective 120 days after publication in the Federal Register, to allow
additional time for comment on the revised information collection
requirements. FDA has also revised the compliance dates. All
applications will have a compliance date of 20 months after the
effective date of the rule (for a total of 2 years after publication of
the final rule).
    60. Two industry comments argued that the proposed effective dates
were too short. One of these suggested that 15 and 21 months were too
short to develop a pediatric program and formulation, conduct trials,
analyze data, and submit an application. Two comments asked that FDA
clarify what ``compliance'' means. According to one of these comments,
15 months would be adequate for initiation of discussions with a
sponsor about plans, but inadequate for completion of studies. This
comment also argued that it is not in children's interest to rush
through pediatric studies to meet an arbitrary deadline. Another
comment offered the example of Ritonavir, a drug to treat HIV
infection, for which pediatric studies reportedly took 21 months even
after development of a pediatric formulation. According to the comment,
it took 15 months to agree on a protocol, 3 months to recruit patients,
and 3 months to the first interim analysis of data. One disease-
specific organization argued that the effective dates were too long.
This comment proposed 12 months from the effective date of final rule,
which could be extended by 6 months if genuine difficulties occurred.
This comment also urged that compliance with the early discussion
requirements be immediate. One comment argued that pending applications
should be granted a full

[[Page 66659]]

waiver and treated as marketed products.
    ``Compliance,'' as referred to in the proposal, means the
submission of an assessment of pediatric safety and effectiveness under
Sec. 314.55(a) (proposed Sec. 314.50(g)(1) or 601.27(a)), unless a
waiver or deferral for all relevant age groups has been granted. FDA
has reconsidered the compliance dates and has concluded that
applications submitted on or after the effective date of the final rule
should be given 20 months from the effective date of the final rule to
achieve compliance. Although FDA does not believe that development of,
and agreement on, a protocol should take 15 months, protocol
development, recruitment, enrollment, and data analysis may together
take up to 2 years. There is no reasonable basis on which to
distinguish between an application submitted 1 day before the effective
date of the final rule, and one submitted a day later.
    All other provisions of the rule will become effective on the
effective date of the rule. One hundred twenty days from the date of
publication in the Federal Register is sufficient time to meet these
new requirements.

VI. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the
information collection requirements are shown below with an estimate of
the annual reporting 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
invited comment on: (1) Whether the proposed collection of information
is necessary for 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.
    OMB filed a Notice of Action, not approving the proposed collection
of information. OMB requested that, as part of the final rule, FDA
address all comments received on the information collection
requirements contained in the rule, particularly with respect to the
reporting burden imposed by the rule. FDA received one comment
concerning the proposed burden estimates of this rulemaking under the
PRA. The comment contended that FDA underestimated the time required to
comply with the annual reporting requirements of the proposed
rulemaking.
    The agency received several comments that questioned the accuracy
of FDA's estimate of the burden of the proposed collection of
information as being too low and requested changes. For example, one
comment requested changes in the burden estimate for manufacturers
requesting deferrals of submission of pediatric data as well as the
estimate for manufacturers to submit pediatric information in their
annual report. In addition, the estimate for manufacturers to submit in
their annual reports the analysis of available safety and efficacy data
conducted or obtained in the pediatric population as well as proposed
labeling was questioned. Based on these comments the agency increased
the proposed burden estimates. These issues are discussed in more
detail in the preamble to the final rule.
    Concerning Sec. 314.50(d)(7), the comment stated that in order to
comply with this requirement, ``one company'' estimated that, for one
pediatric reporting project, medical staff had spent at least 118
hours, rather than the 8 hours that FDA had estimated, reviewing the
medical literature and summarizing the findings. FDA does not believe
that this comparison is fully appropriate because Sec. 314.50(d)(7)
does not require an applicant to review the medical literature, or
other studies, de novo. It simply requires an applicant to provide a
brief summary of data that have already been fully reported and
analyzed elsewhere in the same application. However, because the data
to be summarized may be more extensive than originally estimated, FDA
has, in response to the comment, increased its estimate of the
reporting burden for this requirement from 8 hours to 50 hours.
    Concerning Sec. 314.55(a), the comment contended that FDA's
estimate of 10 companies submitting NDA's annually for NME's is too
low. The comment implied that, based on data for 1996, 50 companies
would be a more realistic estimate. The comment also contended that
FDA's estimate of 16 hours for a manufacturer to prepare the report of
the data supporting the safety and effectiveness of the drug for the
indication for the pediatric population is too low. In response to this
comment, FDA has revised its burden estimate from 16 to 48 hours. FDA
has also made a corresponding change in the estimate for
Sec. 601.27(a). FDA has revised the estimate of the number of companies
affected from 10 to 51 to reflect the broader scope of the rule.
    Concerning Sec. 314.55(b), the comment stated that FDA's estimate
of 9 manufacturers requesting deferrals of the submission of pediatric
study data and the estimate that this would take 8 hours to complete
are too low. In response to this comment, FDA has revised its burden
estimate from 8 hours to 24 hours. FDA has also made a corresponding
change in the estimate for Sec. 601.27(b). FDA has revised the estimate
of the number of companies affected from 8 to 51 to respond to the
comment and to reflect the broader scope of the rule.
    Concerning Sec. 314.81(b)(2)(i), the comment contended that FDA's
estimate of 1.5 hours for manufacturers to submit pediatric information
in their annual reports is too low. In response to this comment, FDA
has revised its burden estimate from 1.5 hours to 8 hours and has made
a corresponding change in its estimate for Sec. 601.27(c).
    Concerning Sec. 314.81(b)(2)(vi)(c), the comment contended that
FDA's estimate of 1.5 hours for manufacturers to submit in their annual
reports the analysis of available safety and efficacy data conducted or
obtained in the pediatric population as well as proposed labeling
changes is too low. The comment stated that even an estimate of 15
hours would be too low. Although the comment did not provide an
estimate of the hours required to satisfy Sec. 314.81(b)(2)(i) and
(b)(2)(vi)(c), FDA has increased its estimates to 8 and 24 hours,
respectively.
    Based upon these comments, FDA has decided to increase the agency's
proposed burden estimates. These revisions are reflected in the Table 2
of this document. In addition, the burden estimates for
Secs. 314.55(a), (b), and (c), and 601.27(a), (b), and (c), have
increased because of the new requirements in the final rule to include,
in addition to applications for new chemical entities and never-before-
approved biologics, applications for new active ingredients, new
indications, new dosage forms, new dosing regimens, and new routes of
administration. These estimates are based upon FDA's analysis of all
marketing applications and efficacy

[[Page 66660]]

supplements approved over the 5-year period of 1993 to 1997 and those
that would likely have needed additional pediatric data had this rule
been in effect by 1993 (see ``Analysis of Impacts,'' in section VIII of
this document). In addition, burden estimates have been added in Table
2 of this document for the new requirements in the final rule
concerning submissions for end-of-phase 1 and end-of-phase 2 meetings
under Sec. 312.47(b)(1)(iv) and submissions for pre-NDA meetings under
Sec. 312.47(b)(2). These estimates are based on FDA's records of the
number of these meetings held during 1997. Finally, burden estimates
have been added for new postmarket report requirements added for
biological products under Sec. 601.37 (a), (b), and (c), corresponding
to Sec. 314.81 (b)(2)(i), (b)(2)(vi)(c), and (b)(2)(vii). These
estimates are based upon FDA's records of the number of licensed
biological products.
    Title: Regulations Requiring Manufacturers to Assess the Safety and
Effectiveness of New Drugs and Biological Products in Pediatric
Patients.
    Description: This final rule includes the following reporting
requirements: (1) Reports on planned pediatric studies in IND's
(Sec. 312.23(a)(10)(iii)); (2) Reports for end-of-phase 1 and end-of-
phase 2 meetings (Sec. 312.47(b)(1)(iv)) and reports for pre-NDA
meetings (Sec. 312.47(b)(2)); (3) Summaries of data on pediatric safety
and effectiveness in NDA's (Sec. 314.50(d)(7)); (4) Reports assessing
the safety and effectiveness of certain drugs and biological products
for pediatric use in NDA's and BLA's or in supplemental applications
(Secs. 314.55(a) and 601.27(a)); (5) Requests seeking deferral of
required pediatric studies (Secs. 314.55(b) and 601.27(b)); (6)
Requests seeking waiver of required pediatric studies (Secs. 314.55(c)
and 601.27(c)); (7) Postmarketing reports of analyses of data on
pediatric safety and effectiveness (Secs. 314.81(b)(2)(vi)(c) and
601.37(a)(1)); (8) Postmarketing reports on patient exposure to certain
marketed drug products (Secs. 314.81(b)(2)(i) and 601.37(a)(2)); (9)
Postmarketing reports on labeling changes initiated in response to new
pediatric data (Secs. 314.81(b)(2)(vi)(c) and 601.37(a)(3)); and (10)
Postmarketing reports on the status of required postapproval studies in
pediatric patients (Secs. 314.81(b)(2)(vii) and 601.37). The purpose of
these reporting requirements is to address the lack of adequate
pediatric labeling of drugs and biological products by requiring the
submission of evidence on pediatric safety and effectiveness for
products with clinically significant use in children.
    Description of Respondents: Sponsors and manufacturers of drugs and
biological products.

                                 Table 2.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                              Annual        Total
               21 CFR section                    No. of      frequency      annual      Hours per    Total hours
                                              respondents  per response   responses     response
----------------------------------------------------------------------------------------------------------------
201.23......................................            2           1              2          48            96
312.47(b)(1)(iv)............................           27           1.2           32          16           512
312.47(b)(2)................................           36           1.3           46          16           736
314.50(d)(7)................................          213           1            213          50        10,650
314.55(a)...................................           51           1             51          48         2,448
314.55(b)...................................           51           1             51          24         1,224
314.55(c)...................................          176           1            176           8         1,408
314.81(b)(2)(i).............................          625           1            625           8         5,000
314.81(b)(2)(vi)(c).........................          625           1            625          24        15,000
314.81(b)(2)(vii)...........................          625           1            625           1.5         937.5
601.27(a)...................................            2           1              3          48           144
601.27(b)...................................            2           1              3          24            72
601.27(c)...................................            3           1              4           8            32
601.37(a)...................................           69           1             69           8           552
601.37(b)...................................           69           1             69          24         1,656
601.37(c)...................................           69           1             69           1.5         103.5
                                             -------------------------------------------------------------------
    Total...................................  ...........  ............  ...........  ............      40,571
----------------------------------------------------------------------------------------------------------------
\1\There are no capital or operating and maintenance costs associated with this collection of information.

    The information collection provisions of this final rule have been
submitted to OMB for review. Prior to the effective date of this final
rule, FDA will publish a notice in the Federal Register announcing
OMB's decision to approve, modify, or disapprove the information
collection provisions in this final rule. 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.

VII. 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.

VIII. Analysis of Impacts

A. Introduction and Summary

    FDA has examined the impacts of the final rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act (Pub. L. 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). Under the Regulatory
Flexibility Act, unless an agency certifies that a rule will not have a
significant economic impact on a substantial number of small entities,
the agency must analyze regulatory options that would minimize the
impact of the rule on small entities. The Unfunded Mandates Reform Act
(Pub. L. 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 by State, local, and tribal
governments,

[[Page 66661]]

in the aggregate, or by the private sector, of $100 million or more in
any one year (adjusted annually for inflation).
    The agency has reviewed this final rule and has determined that the
rule is consistent with the regulatory philosophy and principles
identified in Executive Order 12866, and in these two statutes. This
rule is an economically significant regulatory action, because of its
substantial benefits. It is also a significant regulatory action as
defined by the Executive Order due to the novel policy issues it
raises. With respect to the Regulatory Flexibility Act, the agency
certifies that the rule will not have a significant economic impact on
a substantial number of small entities. Since the rule does not impose
any mandates on State, local, or tribal governments, or the private
sector that will result in an expenditure of $100 million or more in
any one year, FDA is not required to perform a cost-benefit analysis
according to the Unfunded Mandates Reform Act.
    FDA is requiring that a limited class of important new drugs and
biologicals that are likely to be used in pediatric patients contain
sufficient data and information to support directions for this use. As
the approved labeling for many of these new products lacks adequate
pediatric information, their use in children greatly increases the risk
of inappropriate dosing, unexpected adverse effects, and suboptimal
therapeutic outcomes. This rule is designed to ensure that new drugs,
including biological drugs, that are therapeutically important and/or
likely to be used in a substantial number of children contain adequate
pediatric labeling at the time of, or soon after, approval.
    The agency estimated the costs to industry of the required new
pediatric studies by first determining what the annual costs would have
been in 1993 to 1997, had the rule become effective in 1993. The
methodology included: (1) Constructing a data base of all 583 NDA's and
efficacy supplements approved by the agency over that 5-year period for
drugs and biologicals likely to produce health benefits in the
pediatric population, (2) determining which of those applications would
have been required to conduct additional pediatric studies, (3)
calculating how many unapproved and already marketed drugs and
biologicals would have needed additional pediatric studies, and (4)
estimating the size and cost of the additional studies. The analysis
indicated that, on average, this regulation would have required an
estimated 378 additional pediatric studies on about 82 drugs and
biologicals per year. These studies would have involved a total of
10,860 pediatric patients, 7,408 in efficacy studies, and 3,452 in PK
studies. In addition, an estimated 33 of the 82 drugs and biologicals
needing new pediatric data each year may have needed new pediatric
dosage forms. FDA judges that the additional studies would have cost
about $45 million and the new dosage formulations about $33 million
annually, for a total annual cost of almost $80 million. The agency
found, however, that roughly 42 percent of the costs of the studies
would have been spent voluntarily had the extended pediatric
exclusivity provisions of the recent FDAMA statute been in place.
Adjusting for this effect lowers the agency's final cost estimate for
this rule to about $46.7 million per year.
    FDA could not develop a quantifiable estimate of the benefits of
this regulation, although numerous anecdotal examples illustrate the
current health problem. To consider some of the potential benefits, the
agency examined hospitalization rates for five serious illness (asthma,
HIV/AIDS, cancer, pneumonia, and kidney infections) and found
significantly higher rates for children than for middle-aged adults.
Although FDA can not estimate the extent to which these differentials
reflect the relative lack of pharmaceutical safety and efficacy
information for pediatric compared to adult use, the agency calculated
that a 25 percent reduction in these differentials would lead to direct
medical cost savings of $228 million per year. FDA also estimates that
about two-thirds of the approved applications needing pediatric studies
will be addressed by the incentives established by FDAMA. If the
estimated medical cost savings were adjusted by a similar ratio, the
analysis suggests that a 25 percent reduction in the pediatric/adult
hospitalization rate differentials would yield annual savings of $76
million for these five illnesses.

B. Number of Affected Products and Required Studies

    In the preamble to its proposal, FDA explained that neither the
precise number of drugs that would require additional pediatric studies
nor the cost of these studies could be predicted with certainty. To
develop plausible estimates of the number of new drugs and biologicals
that would be affected, the agency had examined the pediatric labeling
status at time of approval for each NME and important biological
approved from 1991 to 1995, and used these estimates to project the
number of drugs that would have required additional pediatric data had
the proposal been in place over that period.
    Several industry comments declared that FDA's analysis of the
proposal substantially underestimated the economic impact by
understating both the number and size of the studies that would be
required. Only two of the comments, however, included alternative
estimates. One suggested that each new drug could require the testing
of 300 or more pediatric patients for safety data alone. The other
comment estimated that, ``each new drug studied would probably require
a minimum of six clinical trials (two each in Phases I, II, and III),
for one indication and one formulation.'' This comment explained that
Phase I trials would include 20 patients, Phase II trials 50 patients,
and Phase III trials 100 patients. Assuming two trials for each phase,
the comment projected that 34,000 pediatric patients would need to be
studied each year (170 patients x 2 trials x 100 drugs).
    FDA agrees that some applications will require data from a
substantial number of pediatric patients. The agency believes, however,
that most studies will not include large numbers of pediatric patients.
For example, FDA does not necessarily require two pediatric studies for
each trial phase. Moreover, FDA's 1994 final rule (59 FR 64240)
explains that extrapolations from adult effectiveness data based on PK
studies and other safety data can be sufficient to provide the
necessary pediatric dosing information for those drugs and biologicals
that work by similar mechanisms in adults and children. The agency
expects that the majority of the studies will rely, to some extent, on
such extrapolations.
    On the other hand, the proposal primarily addressed drugs and
biologicals that contained no previously approved active moiety. The
final rule requires pediatric data for new active ingredients, new
indications, new dosage forms, new dosing regimens, and new routes of
administration that represent a meaningful clinical benefit over
existing treatments for children, or that are likely to be widely used
in children. The rule also requires pediatric studies for marketed
drugs and biologicals that are already widely used among children for
the claimed indications, if the absence of adequate labeling could pose
significant risks; or if the drug would provide a meaningful clinical
benefit over existing treatments for pediatric patients, but additional
dosing or safety information is needed to permit their safe and
effective use in children.
    To develop a revised estimate of the number of drugs and
biologicals that

[[Page 66662]]

would require additional pediatric data, FDA constructed a data base of
all 583 applications and efficacy supplements approved over the 5-year
period from 1993 to 1997 for drugs and biologicals for which pediatric
labeling would be likely to provide a significant health benefit. The
selected drugs and biologicals included all those for which the active
moiety was listed in the priority section in the Federal Register of
May 20, 1998 (63 FR 27733), document entitled ``List of Drugs For Which
Additional Pediatric Information May Produce Health Benefits in the
Pediatric Population'' (``List''). Mandated by FDAMA, this publication
includes the agency's priority list of drugs and biologicals that would
likely provide a significant benefit to the pediatric population. The
selection criteria used to prepare this priority list were almost
identical to those set forth in this final rule, i.e.,
    <bullet> The drug product, if approved for use in the pediatric
population, would be a significant improvement compared to marketed
products labeled for use in the treatment, diagnosis, or prevention of
a disease in the relevant pediatric population (i.e., a pediatric
priority drug); or,
    <bullet> The drug is widely used in the pediatric population, as
measured by at least 50,000 prescription mentions per year; or,
    <bullet> The drug is in a class or for an indication for which
additional therapeutic options for the pediatric population are needed.
    FDA then identified each of the 583 applications that would likely
have needed additional pediatric studies had this rule been in effect.
The number and type of studies needed were projected based on specific
decision rules derived from agency experience in reviewing drug
applications and developed strictly for the purpose of estimating the
regulatory costs of this rule. Although in practice, these rules would
have been subject to numerous exceptions, in the aggregate, FDA
believes that they provide plausible estimates of the total number and
type of pediatric studies that would have been required. The decision
rules were as follows:
    1. All New Chemical Entities (NCE's) and biologicals were assumed
to need both an efficacy study and a PK study for each age group
identified in the priority section of the ``List'' as needing pediatric
information, although FDA believes that this assumption overstates the
true number of efficacy studies that will be needed.
    2. For the following categories of applications, both an efficacy
and a PK study were assumed for each designated age group. Again, FDA
believes that this assumption may overstate the true number of efficacy
studies that will be needed:

Neurological drugs;
Oncology drugs;
Nausea agents;
Pulmonary agents;
NSAIDs--arthritis/pain;
AIDS/HIV agents;
Asthma drugs;
Anesthesia drugs;
Hormones;
Dermatological agents;
Acne agents

    3. A PK study alone was assumed sufficient for each relevant age
group for the following types of non-NCE applications:

Allergies;
Infectious diseases;
Cardiovascular diseases;
Imaging agents;
Hematology agents;
GI disorders;
Urologic drugs

    4. If pediatric labeling was already adequate as the result of an
approved application, additional applications for new dosage forms were
assumed to be exempt.
    5. If a second applicant sought approval for the same indication of
the same drug as a previous applicant that had already satisfied the
pediatric labeling requirements, the second applicant was considered
exempt from the pediatric labeling requirement.
    6. Because the regulation imposes requirements only on new NDA's or
efficacy supplements that specifically address an indication needing
pediatric data, no pediatric requirements were assumed for an NDA
supplement submitted for a new indication not identified as needing
pediatric data.
    7. Orphan drugs were excluded from additional research
requirements.
    The results of this analysis (see Table 3 of this document) show
that about 44 percent, or an estimated 255, of the total 583 drug and
biological applications for the products on the priority section of the
``List'' drugs approved over the 5-year period would have required
additional pediatric studies, had the rule been in effect starting in
1993. Assuming separate studies for each pediatric age group specified
in the ``List,'' indicates that an estimated 459 efficacy studies and
713 PK studies would have been required for these applications.
    These estimates understate the required research effort, however,
because they omit pediatric studies for drugs that fail to gain
approval. It is difficult to judge how much additional pediatric
research would be directed towards nonapprovable products. The agency
notes, however, that because only about 63.5 percent of all NME's that
enter phase III trials are eventually approved (Ref. 18), the number of
drugs entering phase III trials is about 58 percent greater than the
number of actual approvals (100/63.5 = 1.58). Moreover, there are two
additional complications. First, under the rule, FDA expects to defer
for several years the conduct of pediatric studies of ``me-too'' drugs
that do not offer a meaningful therapeutic benefit and that are members
of a drug class that already contains an adequate number of approved
products with pediatric labeling. No additional pediatric studies would
be expected for this group of never approved drugs. On the other hand,
applications for ``lifesaving'' drugs may need to begin pediatric
trials by the start of Phase II. On the assumption that these two
factors would roughly offset, FDA has retained the 58 percent figure as
a reasonable adjustment factor to account for the number of studies
conducted for drugs that fail to gain approval. Finally, each year, the
agency expects to identify about two ``already marketed'' drugs that
require additional pediatric efficacy data.
    As shown in Table 4 of this document, adjusting for the ``never
approved'' and the ``already marketed'' applications implies that, had
this rule become effective in 1993, about 1,892 new pediatric studies
would have been required over the 1993 to 1997 period. About 740 of the
studies would have been efficacy studies and 1,151 PK studies. Thus, on
average, each year, the rule would have required about 378 new
pediatric studies for about 82 NDA's and or NDA supplements--148
efficacy studies and 230 PK studies.

[[Page 66663]]

                Table 3.--Approved New Drug Applications and Their Supplements From 1993 to 1997
----------------------------------------------------------------------------------------------------------------
                                                Applications
                                  Applications     needing      Efficacy    PK studies     Total      New dosage
          Approval year           for ``List''    pediatric     studies      required     studies       forms
                                      Drugs        studies      required                  required
----------------------------------------------------------------------------------------------------------------
1993............................            77            43           63          122          185           12
1994............................            76            42           74          118          192           17
1995............................           107            38           69          107          176           13
1996............................           177            74          147          213          360           29
1997............................           146            58          106          153          259           19
                                 -------------------------------------------------------------------------------
    Total.......................           583           255          459          713        1,172           90
                                 -------------------------------------------------------------------------------
    Average.....................           117            51           92          143          234           18
----------------------------------------------------------------------------------------------------------------

                 Table 4.--All New Drug Applications and Their Supplements From 1993 to 1997 \1\
----------------------------------------------------------------------------------------------------------------
                                                Applications
                                  Applications     needing      Efficacy    PK studies     Total      New dosage
          Approval year           for ``List''    pediatric     studies      required     studies       forms
                                    Drugs \2\      studies      required                  required
----------------------------------------------------------------------------------------------------------------
1993............................           124            69          102          197          299           22
1994............................           123            68          119          190          310           32
1995............................           173            61          111          173          284           24
1996............................           286           119          237          344          581           54
1997............................           236            94          171          247          418           35
                                 -------------------------------------------------------------------------------
    Total.......................           942           411          740        1,151        1,892          167
                                 -------------------------------------------------------------------------------
    Average.....................           188            82          148          230          378          33
----------------------------------------------------------------------------------------------------------------
\1\ Includes estimates for ``unapproved'' and ``already marketed'' drugs.
\2\ Adjusted for ``unapproved'' and ``already marketed'' drugs.

C. Number of Pediatric Patients

    The number of pediatric patients needed varies with the particular
type of drug studied. However, based on agency experience, FDA
estimates that, for each pediatric age group studied, typical pediatric
PK studies may involve about 15 patients and typical efficacy studies
about 50 patients. For example, if 2 of the 4 age groups lack PK
studies, FDA assumed that a total of 30 subjects would be needed for
the studies. If 3 of the 4 age groups lack efficacy studies, a total of
150 subjects were assumed to be needed in all 3 age groups. These
assumptions indicate that, had this rule become effective in 1993, each
year, about 82 NDA's would have required additional pediatric studies;
7,408 pediatric patients in efficacy studies and 3,452 pediatric
patients in PK studies, for an annual total of about 10,860 pediatric
patients.

D. Costs of Compliance

1. Cost of Pediatric Studies
    FDA's analysis of the proposal assumed that new studies would cost
pharmaceutical firms from $5,000 to $9,000 per pediatric patient. Only
one comment, that of a large U.S. pharmaceutical company, submitted
actual estimates of the cost of conducting pediatric trials. This
comment stated that a PK or bioavailability/bioeqivalency study of 20
patients would cost at least $100,000, a Phase II trial of 50 patients
would cost a minimum of $150,000, and a Phase III trial of 100 patients
would cost $200,000. For its revised analysis, therefore, FDA assumes
that a PK study of 15 patients will cost $100,000 per affected age
group and that an efficacy study of 50 patients will cost $150,000 per
affected age group. Although a few trials may need to be larger and,
thus more expensive; others will require substantially fewer pediatric
patients. Thus, FDA believes these figures reasonably project the
average added costs.
    As FDA estimates that the regulation would have required
pharmaceutical companies to annually conduct an estimated 378
additional pediatric studies for 82 NDA's, 148 efficacy studies, and
230 PK studies; the above unit cost estimates imply total industry
costs of $45 million annually. Although the industry comment that
included the cost data projected clinical trial costs totaling over
$100 million per year, this estimate assumed the need for 34,000
additional pediatric patients. FDA found that had this rule been in
place over the 1993 to 1997 period, it would have required additional
data from about 10,860 patients per year.
2. Cost of New Formulations
    In its earlier analysis of the proposal, FDA calculated that about
30 percent of all NME's were available only in tablets or hard capsules
at the time of approval. Acknowledging the potential difficulties of
developing new formulations for certain drugs, FDA estimated that the
overall costs could average $1 million for each new formulation
developed. Several comments questioned the agency's estimates. Based on
an informal survey of its members, a major industry trade association
reported that the development of a pediatric formulation could take
from 5 months to 4 years and cost from $500,000 to $3.5 million. It
also objected to the agency's estimate of the number of drugs that
would require reformulation. The association, however, apparently
misunderstood FDA's methodology. The agency had found that 10 of 14
drugs per year would not need reformulation because a potentially
adequate dosage form (liquid, an injectable, a solution, a
dermatological, etc.) was already available. The association believed
that FDA has assumed that only tablets and/or capsules were available
for the ten drugs. None of these comments,

[[Page 66664]]

however, offered an alternative methodology for projecting the
aggregate value of these costs.
    To develop reasonable estimates of the number of new dosage forms
that would be needed, FDA again reviewed all of the 255 approved drug
applications that would likely have required new pediatric studies
during the 1993 to 1997 period, had this rule been in place. The agency
generally assumed that those drugs identified as having a meaningful
clinical pediatric benefit for the youngest three age groups, but
available only in tablets or hard capsules at the time of approval,
would have needed to develop an alternative dosage form. The agency
also assumed that a new pediatric formulation would not be counted if a
more appropriate pediatric dosage form was subsequently approved for
the same drug. FDA is aware that these estimates can not be considered
precise. For example, not all liquids are adequate for pediatric
populations. On the other hand, new formulations may not be needed if a
drug is used primarily for children between the ages of 8 and 12 years.
Nevertheless, as shown in Table 3 of this document, the results of this
methodology show that about 35 percent of the approved applications
needing studies, or about 18 per year, would have needed new dosage
forms. Table 4 of this document raises this estimate by 83 percent, or
to 33 per year, to account for the number of new dosage forms developed
for drugs not subsequently approved. While FDA cannot confidently
predict a typical initiation time for this effort, the 83 percent
adjustment calculation assumes that work on about 25 percent of all new
formulations would be initiated at the start of Phase 2 trials and 75
percent by the start of Phase 3 trials. (The probability of approval
was assumed to be .635 for a drug entering phase 3 trials and .31 for a
drug entering phase 2 trials (Ref. 18).)
    The development of some pediatric formulations will be difficult,
the development of others relatively straightforward and achieved
without substantial problem. The rule requires only that sponsors take
all reasonable steps to develop needed new formulations. Thus, while
acknowledging that the cost for particularly difficult formulations may
be higher, FDA has retained its average cost estimate of $1 million to
develop each new dosage form and projects this total industry cost at
nearly $33 million per year.
3. Cost of Added Paperwork Requirements
    The rule also requires additional industry effort for new or
expanded paperwork reporting. Section VI of this document describes
these reporting tasks, discusses the industry comment that questioned
the agency's estimate of the paperwork burden for the proposal, and
presents the agencies revised estimate for this final rule. As shown in
that section, FDA projects an annual burden of about 40,000 hours per
year. On the assumption that 25 percent of these hours will be for
upper management staff, 50 percent for middle management staff, and 25
percent for administrative and clerical support, at respective labor
costs of $52, $34, and $17 per hour, FDA estimates these total
paperwork costs at about $1.4 million per year.
4. Total Costs
    Table 5 of this document summarizes the agency's estimates of costs
for efficacy studies, PK studies, new dosage forms, and paperwork.
Because the expense of pediatric trials and dosage form development
will be spread over 2 or 3 years for any given drug, the total costs to
industry in any given year are unlikely to vary as much as shown in
Table 5. Most importantly, however, the average $80.1 million annual
cost figure reflects only what the rule would have cost had the rule
been in effect from 1993 to 1997. The incentives generated by the
additional 6-month marketing exclusivity offered by FDAMA will reduce
the future costs of the regulation.

                     Table 5.--Estimated Industry Costs--Compliance With Pediatric Labeling
                                                  [in millions]
----------------------------------------------------------------------------------------------------------------
                                                                            New dosage
                      Year                         Efficacy    PK studies      form      Paperwork      Total
                                                   studies                  developed
----------------------------------------------------------------------------------------------------------------
1993...........................................        $15.3         19.7         22.3          1.4         58.6
1994...........................................         17.9         19.0         31.6          1.4         69.9
1995...........................................         16.7         17.3         24.1          1.4         59.5
1996...........................................         35.6         34.4         53.9          1.4        125.2
1997...........................................         25.7         24.7         35.3          1.4         87.0
                                                ----------------------------------------------------------------
    Average Per Year...........................        $22.2        $23.0        $33.4         $1.4        $80.0
----------------------------------------------------------------------------------------------------------------

    FDA cannot develop precise adjustments for the forthcoming effects
of FDAMA, due to the complexity of the economic forecasting that would
be needed. Nevertheless, the agency developed rough projections of the
potential impact of this statute by comparing the estimated present
value of the 6-month exclusivity gain with the estimated cost of the
new pediatric studies, for each of the 85 drugs with applications
approved in 1993 and 1994 that would have needed new pediatric
labeling. (More recent years were not used, because the revenues of
newer drugs are far below their peak values.) Where the estimated
exclusivity gain exceeded the cost of all required studies, including
the development of new dosage forms, FDA concluded that the studies for
that drug would have been initiated voluntarily and their cost
attributable to FDAMA rather than to this regulation.
    The methodology assumed that a 6-month gain of marketing
exclusivity would be worth about 25 percent of a drug's annual sales
revenue during the year the exclusivity is needed, less 60 percent for
production, administrative, and marketing costs (Ref. 19). Costs of
conducting the required studies for each of the 85 drugs were based on
the cost estimates described previously ($150,000 for each efficacy
study, $100,000 for each PK study, and $1 million for each new dosage
form. The present value of the additional revenues (at a 7 percent
discount rate) were calculated from 1997 sales data published by IMS
America (Ref. 20). Because 1997 sales revenues probably underestimate
the sales revenues that will be realized at the time that the added
exclusivity is used, this methodology likely underestimates the effects
of FDAMA, hence overestimating the costs of the rule. In general,

[[Page 66665]]

however, this analysis was insensitive to the precise assumptions used.
For example, using an 11 percent rather than 7 percent discount rate
raises the cost totals by only $1.2 million per year.
    The analysis found that the necessary studies would have been
conducted voluntarily for 56 out of the 85 affected applications (66
percent). Adjusting estimates of only the approved applications by this
percentage (FDAMA was not assumed to affect studies for applications
not obtaining approval), FDA projects that the annual costs
attributable to this rule will be approximately $46.7 million, or about
42 percent below the non-FDAMA adjusted figure of $80 million.
    Further, although the agency has not yet evaluated the full
economic impact of the FDAMA legislation, it believes that the present
value of the net revenues expected from the 6 months of added
exclusivity granted under the new FDAMA legislation will greatly exceed
the additional costs imposed by this regulation. One industry
publication (MedAdNews, June 1998, p. 10) for example, reports that
products currently valued at $41 billion in annual sales will come off
patent between 1998 and 2008, or an average of $11 billion per year.
Alternatively, FDA estimates that the annual revenues for NCE's coming
off patent may average between $200 and $300 million each. If 25 NCE's
lose exclusivity each year, these annual revenues would range from $5
billion to $7.5 billion. If only 60 percent of these NCE's become
eligible for extended exclusivity, the methodology described above
implies that industry net incomes will increase from $300 to $450
million per year. Thus, FDAMA and this rule, taken together, will
provide critical pediatric information without diverting current
resources from pharmaceutical innovation.

*COM041**COM041*E. Benefits

    The rule addresses two major problems associated with the lack of
adequate information on the effects of drugs on pediatric patients: (1)
Adverse drug reactions in children due to inadvertent drug overdoses or
other drug administration problems that could be avoided with better
information on appropriate pediatric use; and (2) under use of safe and
effective drugs for children due to the prescribing of an inadequate
dosage or regimen, a less effective drug, or no drug at all because of
uncertainty over the drug's effect on children or the unavailability of
a pediatric formulation. By developing improved information on whether,
and in what dosage, a drug is safe and effective for use in children,
FDA believes that the regulation will result in fewer adverse drug
reactions and fewer instances of less-than-optimal treatment of
pediatric patients.
    Despite numerous reports of children endangered by the absence of
adequate drug labeling, FDA has found no systematic studies in the
literature that evaluate the overall magnitude of the harm that results
from the incomplete labeling of drugs for use in children. In the
preamble to the proposal, the agency specifically requested,
``information on any available studies or data related to the incidence
and costs of either undertreatment or avoidable ADE's in pediatric age
groups due to the lack of information on the effects of
pharmaceuticals.'' The comments received cited case after case of
children who have died or suffered because of the inadequate testing of
drugs in children, but the information was largely anecdotal and
related to particular instances of drug misuse or underuse.
    For example, physicians who care for HIV-infected patients
expressed frustration at their inability to treat children with drugs
known to be effective in adults. Pulmonary specialists described the
dearth of information on risks versus benefits of new antimicrobials
for pediatric patients, citing the example of ciprofloxacin, a
quinolone that may be valuable in treating cystic fibrosis, although
the safety and effectiveness of the drug in children has not been
established. Comments received from asthma specialists reaffirmed the
difficulties of administering medications, treating drug side effects,
or withholding treatment for children with asthma, due to the lack of
research on drug safety and effectiveness.
    In both written comments and in commentary at the public hearing in
October 1997, concerns were raised about the costs of not implementing
a requirement for pediatric labeling. Avoidable adverse outcomes, cited
in relation to pediatric dosage problems, included opportunistic
infections from too much immunosuppression, and loss of grafts in
pediatric renal transplant patients with too little immunosuppression.
Comments also cited added health care, including increased
hospitalizations, required as a result of less effective treatment for
pediatric patients. One comment estimated the cost of delayed access in
terms of infant deaths, attributing an additional 2,000 unnecessary
infant deaths over a 2-year period to the delay in access to AZT for
HIV-exposed infants. Another suggested using the Vaccine Injury
Compensation program figure of $250,000 per child as the value of an
avoided death resulting from an ADR. Other comments confirmed that many
adverse outcomes develop quickly and would be detected in early
clinical studies (e.g., ``gray syndrome'' in babies treated with
chloramphenicol).
    While clearly demonstrating the critical need for improved
pediatric information, these comments do not suggest a practical
methodology for quantifying the aggregate benefits of this rule. FDA,
also, has been unable to develop a precise assessment of the probable
regulatory benefits. The agency's approach to estimating regulatory
benefits therefore is framed in terms of the following two questions:
(1) Are data available to assess current differences in the safety of
drug therapy for adults versus children with the same condition? and
(2) Are data available to assess current differences in the
effectiveness of drug therapy for adults versus children with the same
condition?
    FDA first attempted to assess the safety of drug therapy by looking
for differences in the frequency and severity of ADR's for adults
versus children treated for the same condition. The available clinical
and health survey data, however, did not provide a reliable estimate of
the contribution of ADR's to pediatric as compared to adult rates of
mortality and morbidity. ADR-related data are limited by the lack of a
general requirement and a ready mechanism for the comprehensive
reporting of incidents directly attributable to ADR's (Ref. 21).
Moreover, most available studies have not addressed ADR rates and
associated death rates by age group within a treated condition (Refs.
22, 23, and 24). For example, one study of pediatric patients shows an
ADR-related admission rate in the range of only 2.0 to 3.2 percent,
well below the average for adult and pediatric studies combined.
Pediatric cancer patients, however, experienced a 22 percent ADR-
admission rate (Ref. 25), suggesting that pediatric risks may be
significantly greater within condition-defined subpopulations. In
addition, potential concerns about negative public attention (Ref. 26)
or liability inhibit reporting of ADR's. Finally, for many seriously
ill patients, it is very difficult to attribute a specific medical
outcome to a particular medication, as opposed to some other
complication in the patient's condition, or misadventure in the
patient's care. The agency found therefore that it could not rely on
available ADR studies to derive an assessment of the potential benefits
of this rule.

[[Page 66666]]

    Data to assess the effectiveness of drug therapy would indicate
differences in clinical outcomes, or in other health care utilization
concomitant with drug therapy. If drug therapies for children were less
effective than that for adults with the same condition, one might see
longer recovery times, or lower recovery rates, together with increased
health services use, assuming a similar prognosis and course of
illness. A limitation to this approach is that the prognosis and course
of illness may not be the same in children and adults with the same
serious health condition, even if the same drugs were included in best-
practice treatment. Moreover, differential patterns of health care
utilization may reflect variations in physician practice patterns,
insurance benefits, or patient and family behavior and preferences,
rather than measures of drug effectiveness. Notwithstanding such
limitations, comparisons of health care resource use for one
therapeutic approach compared to another are commonly used in
evaluations of therapy effectiveness in the field of pharmacoeconomics.
In this instance, FDA finds that health care utilization data may
provide at least an indirect indication of potential benefits.
Hospitalization rates, in particular, are the most extensively studied
measure of morbidity related to adverse drug reactions and of quality
of care for a number of chronic (e.g., asthma) and acute conditions
(e.g., pneumonia) (Refs. 27 and 28). While hospitalizations due to
adverse drug reactions or drug therapy undertreatment are not always
recognized, these admissions are routinely classified with a primary
diagnosis of the underlying disease. FDA therefore has relied on
diagnosis-related hospitalization rates to develop an order-of-
magnitude assessment of the potential benefits of this rule.
    For this assessment, the agency compared rates of hospitalization
of pediatric patients to rates of hospitalization of adult patients for
several important disease conditions. Next, the agency examined the
potential direct and indirect cost savings that would be realized by
diminishing any age-related disparities. The pediatric population was
defined to be all persons under the age of 15 and the comparison group
to be those adults between the ages of 15 and 44. (The exclusion of
older adult patients minimizes the confounding effect of the age-
related increased morbidity and mortality.) Comparisons were limited to
asthma, HIV/AIDS, cancer, pneumonia, and kidney infection, as these
conditions are life threatening, occur in both adults and children, and
comparable data are available for adult and pediatric patients.
Moreover, reports received in the FDA Spontaneous Reporting System
(SRS) in 1993 indicated that the therapeutic areas for which the
highest number of ADR's were reported for patients under age 15,
relative to the number reported for patients 15 to 44, included those
for anti-infectives, pulmonary drugs and oncology drugs.
    Direct costs were based on the estimated number of cases,
hospitalization rates, and length of stay for each of the selected
conditions. The number of cases reported were based on national health
survey (Ref. 29) and public surveillance data (Refs. 30, 31, and 32).
In 1994, the total number of cases for these 5 conditions, in patients
under age 15, was approximately 6.65 million. The total number of cases
for patients ages 15 to 44 was approximately 8.3 million. The number of
hospitalizations per year for which the selected condition was the
primary diagnosis was obtained from the National Hospital Discharge
Survey (Ref. 33). As shown in Table 6 of this document, the pediatric
hospitalization rate exceeded the adult rate for all five conditions.

          Table 6.--Hospitalization Rates per Patient per Year
------------------------------------------------------------------------
                                                                   Rate
                                                          Rate     for
                   Primary diagnosis                     under   ages 15-
                                                         age 15     44
------------------------------------------------------------------------
Asthma................................................     .045     .024
HIV/AIDS..............................................     .533     .233
Cancer................................................    4.247    3.903
Pneumonia.............................................     .147     .129
Kidney Infection......................................     .191     .073
------------------------------------------------------------------------

    The average length of hospital stay (ALOS) for patients with the
selected condition as the primary diagnosis (based on ICD-9 code) was
obtained from recent hospital survey data (Ref. 34), the average cost
per day of inpatient hospital care for each of the selected conditions
was based on hospital charge data reported in the survey (Ref. 35), and
the cost of physician services associated with each episode of
hospitalization was based on physician charge data (Ref. 36). Each
episode of care was assumed to include physician charges for emergency
room service, daily inpatient visits, and a postdischarge office visit.
For cancer hospitalizations, daily inpatient visits and a followup
office visit were included. The calculation of indirect costs assumed 8
hours of parental time away from work for each episode of
hospitalization and income and productivity losses based on average
employee compensation, as reported in the 1997 U.S. Statistical
Abstract. A detailed description of all assumptions, calculations, and
data sources is included in the full agency report (Ref. 37).
    The assumed hypothesis is that a substantial fraction of the
difference between pediatric and adult hospitalization rates for like
disease conditions are attributable to the greater range of drug
therapies and better information on drug dosages for adults. FDA cannot
estimate the precise magnitude of the relevant fraction. Nevertheless,
if the differentials between pediatric and adult hospitalization rates
were reduced by 25 percent, the resulting direct cost savings would be
$228 million, with indirect cost savings of $5.3 million per year. If
the differentials were reduced by as much as 50 percent, the direct
cost savings would be $456 million per year, with indirect savings of
$10.6 million. Even if the differentials were as low as 10 percent, the
resulting reductions in hospitalization would lead to direct cost
savings of $91.2 million, with indirect savings of $2.1 million per
year.
    The timing of the benefit after the rule's implementation is
uncertain. The previous values represent the potential benefit over
time as the safety and effectiveness of drugs are more extensively
tested, new and already marketed drugs become labeled for use in
children, and new formulations and dosage forms are developed to
facilitate therapy for children. The figures may overestimate the
impact for the selected conditions over the next few years, but may
underestimate the potential benefits for these patients in the longer
term if there is an increasing prevalence of asthma, cancer, and
respiratory and other infectious diseases in the pediatric population.
Thus, the lower reduction estimate may be more realistic in the near-
term, with the higher reduction estimates offering a better indication
of longer-term benefit.
    As discussed previously, FDA believes that the new FDAMA statute
will cause some of these pediatric studies to be conducted voluntarily.
In its assessment of costs, the agency found that about two-thirds of
the applications for approved drugs needing pediatric studies may be
undertaken voluntarily due to the incentives established by FDAMA.
Adjusting the previous medical cost savings by a similar ratio suggests
that if all of the new pediatric studies achieved a 25 percent
reduction in the pediatric/adult hospitalization differentials, the
additional studies prompted by this rule would yield

[[Page 66667]]

annual savings of $76 million for just those five diseases. This
estimate may represent a lower bound on the benefits to pediatric
patients, however, because a number of other disease conditions are
also common to children and adults, including such life-threatening
conditions as hypertensive disease and renal disease. These pediatric
populations also would experience significant benefits from increased
safety and access to drug treatments currently available only to adult
patients. Moreover, the analysis omits any quantification of benefits
for reduced pain and suffering and reduced pediatric mortality. Thus,
the full benefits of the rule could easily exceed $100 million per
year. Therefore, in accordance with the SBREFA, the Administrator of
the Office of Information and Regulatory Affairs of the Office of
Management and Budget (the Administrator) has determined that this rule
is likely to result in an annual effect on the economy of $100 million
or more and thus is a major rule for the purpose of congressional
review.

F. Small Entities

    The rule will impose a burden on relatively few small entities,
because new drug development is typically an activity completed by
large multinational firms. Only one industry comment questioned the
agency's determination that the rule would not have a significant
effect on a substantial number of small entities. That comment
indicated that about 1,500 small entities are conducting diagnostic and
therapeutic R&D in the United States and that ``[c]ontributions to new
drug approvals by the `biotech' and `small pharma' sector are
increasing year by year, and the pace of change will--almost
certainly--continue.''
    FDA agrees that small firms contribute substantially to the early
development of many new drugs and biologicals. Nevertheless, because of
the considerable resources needed for clinical testing and marketing,
the agency finds that very few of these small firms retain ownership
and control through the large-scale clinical testing and approval
stages. Moreover, many of the products that are sponsored by small
companies are eligible for orphan designation and therefore exempted
from this rule. To approximate the number of small firms that might be
significantly affected, FDA determined the sponsor company size for all
of the approved applications that may have required additional
pediatric studies had this rule been in place over the years from 1993
to 1997. The agency found that, on average, based on the Small Business
Administration's definition of a small firm, only three approved
applications per year were submitted by small companies. Multiplying by
the previously described 1.58 factor to account for unapproved
applications increases this estimate of the number of small entities
that may have been significantly affected by this rule to just five
small firms per year. Because the agency has certified that the rule
will not impose a significant economic impact on a substantial number
of small entities, the Regulatory Flexibility Act does not require the
agency to prepare a Regulatory Flexibility Analysis. Moreover, the
agency further points out that the required new studies will comprise a
very small part of the total cost of developing new drugs or biologics,
which is generally estimated in the hundreds of millions of dollars for
each new drug.

G. Regulatory Alternatives

    The agency carefully examined two major alternatives to the final
rule. The first alternative considered was the initial proposal, which
covered only NCE's. The estimated cost of this alternative, excluding
the FDAMA adjustment, would be about $40 million, or roughly 50 percent
of the cost of the final rule. The agency rejected this alternative
because of the predominant view of the medical community that
additional pediatric data were needed for all of the drugs and
biologicals that may be therapeutically significantly in pediatric
populations, not just for the new chemical entities.
    The other major alternative considered was to delay implementation
of the rule until the effects of the new FDAMA statute were reviewed.
FDA fully expects the FDAMA exclusivity provisions to provide a
substantial incentive to conduct large numbers of pediatric studies.
Nevertheless, the agency finds that relying on these incentives, alone,
would leave numerous gaps in many important areas of pediatric
labeling. For example, as described earlier in this preamble, voluntary
research may overlook studies for many important drugs, especially
where such studies require the development of new pediatric dosage
forms. Thus, notwithstanding FDAMA incentives, FDA has determined that
this regulation is necessary to protect the pediatric population and
that further delay is not warranted.

IX. References

    The following references have been placed on display in the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852, and may be seen by interested
persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Pina, L.M., Drugs Widely Used off Label in Pediatrics, Report of
the Pediatric Use Survey Working Group of the Pediatric Subcommittee,
in News Along the Pike, January 1997.
    2. Food and Drug Administration, Guidance for Industry: Standards
for the Prompt Review of Efficacy Supplements, Including Priority
Efficacy Supplements, May 1998.
    3. Population Division, United States Bureau of the Census, PPL-91,
Appendix a. Resident Population--Estimates by Age, Sex, Race, and
Hispanic Origin, Washington, DC 20233, 1998.
    4. Powell, D.A. et al., ``Chloramphenicol: New Perspectives on an
Old Drug,'' Drug Intelligences & Clinical Pharmacy, 16:295-300, 1982.
    5. Koren, G. et al., ``Unexpected Alterations in Fentanyl
Pharmacokinetics in Pediatric Patients Undergoing Cardiac Surgery: Age
Related or Disease Related?'' Developmental Pharmacology Therapeutics,
9:183-191, 1986.
    6. Gauntlett, I.S. et al., ``Pharmacokinetics of Fentanyl in
Neonatal Humans and Lambs: Effects of Age,'' Anesthesiology, 69:683-
687, 1988.
    7. Kauffman, R.E., ``Fentanyl, Fads, and Folly: Who Will Adopt the
Therapeutic Orphans?'' Journal of Pediatrics, 119:588-589, 1991.
    8. McCloskey J.J. et al., ``Bupivacaine Toxicity Secondary to
Continuous Caudal Epidural Infusion in Pediatric Patients,'' Anesthesia
Analgesia, 75:287-290, 1992.
    9. Fisher, D.M. et al., ``Neuromuscular Effects of Vecuronium (ORG
NC45) in Infants and Pediatric Patients During N<INF>2</INF>O Halothane
Anesthesia,'' Anesthesiology, 58:519-523, 1983.
    10. Agarwal, R. et al., ``Seizures Occurring in Pediatric Patients
Receiving Continuous Infusion of Bupivacaine,'' Anesthesia and
Analgesia, 75:284-286, 1992.
    11. Mevorach, D.L. et al., ``Bupivacaine Toxicity Secondary to
Continuous Caudal Epidural Infusion in Pediatric Patients,'' Anesthesia
Analgesia, 77:13005-1306, 1993.
    12. Editorial: ``Cystic Fibrosis and Colonic Strictures,'' Journal
of Clinical Gastroenterology, 21(1):2-5, 1995.
    13. Olkkola, K.T. et al., ``A Potentially Hazardous Interaction
Between Erythromycin and Midazolam,'' Clinical Pharmacology Therapy,
53:298-305, 1993.

[[Page 66668]]

    14. Hiller, A. et al., ``Unconsciousness Associated with Midazolam
and Erythromycin,'' British Journal of Anaesthesia, 65:826-828, 1994.
    15. Tejeda, H. et al., ``Representation of African-Americans,
Hispanics, and Whites in National Cancer Institute Cancer Treatment
Trials,'' Journal of the National Cancer Institute, 88(12):812-816,
1996.
    16. Center for Drug Evaluation and Research, Manual of Policies and
Procedures, Priority Review Policy, MAPP 6020.3, April 22, 1996.
    17. Committee on Drugs, American Academy of Pediatrics, Guidelines
for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric
Populations, Pediatrics, 95(2):286-294, 1995.
    18. DiMasi et al., ``Cost of Innovation in the Pharmaceutical
Industry,'' Journal of Health Economics, p. 127, 10:1991.
    19. Office of Technology Assessment, ``Pharmaceutical R&D: Costs,
Risks and Rewards, Washington, DC: U.S. Government Printing Office,''
Appendix G, February 1993.
    20. IMS America, ``1997 Retail Perspective and Provider
Perspective.''
    21. Bates, D.W., ``Drugs and Adverse Drug Reactions: How Worried
Should We Be?'' Journal of American Medical Association, vol. 279, No.
15, April 1998.
    22. Einarson, T.R. ``Drug-Related Hospital Admission'', The Annals
of Pharmacotherapy, vol. 27, pp. 832-840, July/August 1993.
    23. Lazarou, J., B.H. Pomeranz, and P.N. Corey, ``Incidence of
Adverse Drug Reactions in Hospitalized Patients'', Journal of American
Medical Association, vol. 279, No. 15, April 1998.
    24. Phillips, D.P., N. Christenfeld, and L.M. Glynn, ``Increase in
U.S. Medication-Error Deaths Between 1983 and 1993'', The Lancet, vol.
351, 643-644, February 1998.
    25. Mitchell, A.A., P.G. Lacouture, J.E. Sheehan, R.E. Dauffman,
and S. Shapiro, ``Adverse Drug Reactions in Children Leading to
Hospital Admission,'' Pediatrics, vol. 82, No. 1, July 1988.
    26. Bates, D.W., ``Drugs and Adverse Drug Reactions: How Worried
Should We Be?'' Journal of American Medical Association, vol. 279, No.
15, April 1998.
    27. National Committee for Quality Assurance (NCQA) HEDIS 2.5,
December 1995.
    28. Agency for Health Care Policy Research (AHCPR) Conquest 1.1.
    29. Vital and Health Statistics, Current Estimates From the
National Health Interview Survey, 1994, Series 10: Data From the
National Health Survey, No. 193, PHS 96-1521, December 1995.
    30. Center for Disease Control Wonder HIV/AIDS statistics.
    31. World Health Organization, Provisional Working Estimates of
Adult HIV Prevalence as of end of 1994 by Country.
    32. SEER 1989, Available Through CDC Wonder, ICD 140-239.
    33. Vital and Health Statistics, National Hospital Discharge
Survey: Annual Summary, 1995, Series 13, No. 133, PHS 98-1794, January
1998.
    34. Vital and Health Statistics, Detailed Diagnoses and Procedures,
National Hospital Discharge Survey, 1995, Series 13: Data From the
National Health Survey, No. 130, PHS 98-1791, November 1997.
    35. Statistics From the HCUP-3 Nationwide Inpatient Sample for
1994: Principal Diagnoses, http://www.ahcpr.gov/data/94dcchpr.htm,
current as of September 1997, AHCPR Pub. No. 97-0058.
    36. Health Care Financing Administration, Office of Research and
Demonstrations, Health Care Financing Review: 1997 Statistical
Supplement, November 1997.
    37. ``Potential Benefits of Pediatric Information,'' Economics
Staff, Office of Planning and Evaluation, FDA, April 1998.
    38. IMS, National Disease and Therapeutic Index, IMS America:
Plymouth Meeting, PA.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.

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, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR parts 201, 312, 314, and 601 are
amended as follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 358,
360, 360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262,
264.

    2. Section 201.23 is added to subpart A to read as follows:

Sec. 201.23  Required pediatric studies.

    (a) A manufacturer of a marketed drug product, including a
biological drug product, that is used in a substantial number of
pediatric patients, or that provides a meaningful therapeutic benefit
over existing treatments for pediatric patients, as defined in
Secs. 314.55(c)(5) and 601.27(c)(5) of this chapter, but whose label
does not provide adequate information to support its safe and effective
use in pediatric populations for the approved indications may be
required to submit an application containing data adequate to assess
whether the drug product is safe and effective in pediatric
populations. The application may be required to contain adequate
evidence to support dosage and administration in some or all pediatric
subpopulations, including neonates, infants, children, and adolescents,
depending upon the known or appropriate use of the drug product in such
subpopulations. The applicant may also be required to develop a
pediatric formulation for a drug product that represents a meaningful
therapeutic benefit over existing therapies for pediatric populations
for whom a pediatric formulation is necessary, unless the manufacturer
demonstrates that reasonable attempts to produce a pediatric
formulation have failed.
    (b) The Food and Drug Administration (FDA) may by order, in the
form of a letter, after notifying the manufacturer of its intent to
require an assessment of pediatric safety and effectiveness of a
pediatric formulation, and after offering an opportunity for a written
response and a meeting, which may include an advisory committee
meeting, require a manufacturer to submit an application containing the
information or request for approval of a pediatric formulation
described in paragraph (a) of this section within a time specified in
the order, if FDA finds that:
    (1) The drug product is used in a substantial number of pediatric
patients for the labeled indications and the absence of adequate
labeling could pose significant risks to pediatric patients; or
    (2) There is reason to believe that the drug product would
represent a meaningful therapeutic benefit over

[[Page 66669]]

existing treatments for pediatric patients for one or more of the
claimed indications, and the absence of adequate labeling could pose
significant risks to pediatric patients.
    (c)(1) An applicant may request a full waiver of the requirements
of paragraph (a) of this section if the applicant certifies that:
    (i) Necessary studies are impossible or highly impractical because,
e.g., the number of such patients is so small or geographically
dispersed, or
    (ii) There is evidence strongly suggesting that the product would
be ineffective or unsafe in all pediatric age groups.
    (2) An applicant may request a partial waiver of the requirements
of paragraph (a) of this section with respect to a specified pediatric
age group, if the applicant certifies that:
    (i) The product:
    (A) Does not represent a meaningful therapeutic benefit over
existing therapies for pediatric patients in that age group, and
    (B) Is not likely to be used in a substantial number of patients in
that age group, and
    (C) The absence of adequate labeling could not pose significant
risks to pediatric patients; or
    (ii) Necessary studies are impossible or highly impractical
because, e.g., the number of patients in that age group is so small or
geographically dispersed, or
    (iii) There is evidence strongly suggesting that the product would
be ineffective or unsafe in that age group, or
    (iv) The applicant can demonstrate that reasonable attempts to
produce a pediatric formulation necessary for that age group have
failed.
    (3) FDA shall grant a full or partial waiver, as appropriate, if
the agency finds that there is a reasonable basis on which to conclude
that one or more of the grounds for waiver specified in paragraphs
(c)(2) or (c)(3) of this section have been met. If a waiver is granted
on the ground that it is not possible to develop a pediatric
formulation, the waiver will cover only those pediatric age groups
requiring that formulation. If a waiver is granted because there is
evidence that the product would be ineffective or unsafe in pediatric
populations, this information will be included in the product's
labeling.
    (d) If a manufacturer fails to submit a supplemental application
containing the information or request for approval of a pediatric
formulation described in paragraph (a) of this section within the time
specified by FDA, the drug product may be considered misbranded or an
unapproved new drug or unlicensed biologic.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    3. The authority citation for 21 CFR part 312 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371; 42
U.S.C. 262.

    4. Section 312.23 is amended by redesignating paragraph
(a)(10)(iii) as paragraph (a)(10)(iv) and adding new paragraph
(a)(10)(iii) to read as follows:

Sec. 312.23  IND content and format.

    (a) * * *
    (10) * * *
    (iii) Pediatric studies. Plans for assessing pediatric safety and
effectiveness.
* * * * *
    5. Section 312.47 is amended by revising paragraph (b)(1)(i) and
the first sentence of paragraph (b)(1)(iv), by removing the fifth
sentence of paragraph (b)(1)(v) and adding two sentences in its place,
by revising the heading of paragraph (b)(2) and the second and last
sentences of the introductory text of paragraph (b)(2), and by
redesignating paragraph (b)(2)(iii) as paragraph (b)(2)(iv) and by
adding new paragraph (b)(2)(iii) to read as follows:

Sec. 312.47  Meetings.

* * * * *
    (b) * * *
    (1) End-of-Phase 2 meetings--(i) Purpose. The purpose of an end-of-
phase 2 meeting is to determine the safety of proceeding to Phase 3, to
evaluate the Phase 3 plan and protocols and the adequacy of current
studies and plans to assess pediatric safety and effectiveness, and to
identify any additional information necessary to support a marketing
application for the uses under investigation.
* * * * *
    (iv) Advance information. At least 1 month in advance of an end-of-
Phase 2 meeting, the sponsor should submit background information on
the sponsor's plan for Phase 3, including summaries of the Phase 1 and
2 investigations, the specific protocols for Phase 3 clinical studies,
plans for any additional nonclinical studies, plans for pediatric
studies, including a time line for protocol finalization, enrollment,
completion, and data analysis, or information to support any planned
request for waiver or deferral of pediatric studies, and, if available,
tentative labeling for the drug. * * *
    (v) Conduct of meeting. * * * The adequacy of the technical
information to support Phase 3 studies and/or a marketing application
may also be discussed. FDA will also provide its best judgment, at that
time, of the pediatric studies that will be required for the drug
product and whether their submission will be deferred until after
approval. * * *
    (2) ``Pre-NDA'' and ``pre-BLA'' meetings. * * * The primary purpose
of this kind of exchange is to uncover any major unresolved problems,
to identify those studies that the sponsor is relying on as adequate
and well-controlled to establish the drug's effectiveness, to identify
the status of ongoing or needed studies adequate to assess pediatric
safety and effectiveness, to acquaint FDA reviewers with the general
information to be submitted in the marketing application (including
technical information), to discuss appropriate methods for statistical
analysis of the data, and to discuss the best approach to the
presentation and formatting of data in the marketing application. * * *
To permit FDA to provide the sponsor with the most useful advice on
preparing a marketing application, the sponsor should submit to FDA's
reviewing division at least 1 month in advance of the meeting the
following information:
* * * * *
    (iii) Information on the status of needed or ongoing pediatric
studies.
* * * * *
    6. Section 312.82 is amended by revising the last sentence of
paragraph (a) and by removing the second sentence of paragraph (b) and
adding two sentences in its place to read as follows:

Sec. 312.82  Early consultation.

* * * * *
    (a) Pre-investigational new drug (IND) meetings. * * * The meeting
may also provide an opportunity for discussing the scope and design of
phase 1 testing, plans for studying the drug product in pediatric
populations, and the best approach for presentation and formatting of
data in the IND.
    (b) End-of-phase 1 meetings. * * * The primary purpose of this
meeting is to review and reach agreement on the design of phase 2
controlled clinical trials, with the goal that such testing will be
adequate to provide sufficient data on the drug's safety and
effectiveness to support a decision on its approvability for marketing,
and to discuss the need for, as well as the design and timing of,
studies of the drug in pediatric patients. For drugs for life-
threatening diseases, FDA will provide its best judgment, at that time,
whether pediatric studies will be required and whether their submission
will be deferred until after approval. * * *

[[Page 66670]]

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

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

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371,
374, 379e.

    8. Section 314.50 is amended by adding paragraph (d)(7) to read as
follows:

Sec. 314.50  Content and format of an application.

* * * * *
    (d) * * *
    (7) Pediatric use section. A section describing the investigation
of the drug for use in pediatric populations, including an integrated
summary of the information (the clinical pharmacology studies,
controlled clinical studies, or uncontrolled clinical studies, or other
data or information) that is relevant to the safety and effectiveness
and benefits and risks of the drug in pediatric populations for the
claimed indications, a reference to the full descriptions of such
studies provided under paragraphs (d)(3) and (d)(5) of this section,
and information required to be submitted under Sec. 314.55.
* * * * *
    9. Section 314.55 is added to subpart B to read as follows:

Sec. 314.55  Pediatric use information.

    (a) Required assessment. Except as provided in paragraphs (b), (c),
and (d) of this section, each application for a new active ingredient,
new indication, new dosage form, new dosing regimen, or new route of
administration shall contain data that are adequate to assess the
safety and effectiveness of the drug product for the claimed
indications in all relevant pediatric subpopulations, and to support
dosing and administration for each pediatric subpopulation for which
the drug is safe and effective. Where the course of the disease and the
effects of the drug are sufficiently similar in adults and pediatric
patients, FDA may conclude that pediatric effectiveness can be
extrapolated from adequate and well-controlled studies in adults
usually supplemented with other information obtained in pediatric
patients, such as pharmacokinetic studies. Studies may not be needed in
each pediatric age group, if data from one age group can be
extrapolated to another. Assessments of safety and effectiveness
required under this section for a drug product that represents a
meaningful therapeutic benefit over existing treatments for pediatric
patients must be carried out using appropriate formulations for each
age group(s) for which the assessment is required.
    (b) Deferred submission. (1) FDA may, on its own initiative or at
the request of an applicant, defer submission of some or all
assessments of safety and effectiveness described in paragraph (a) of
this section until after approval of the drug product for use in
adults. Deferral may be granted if, among other reasons, the drug is
ready for approval in adults before studies in pediatric patients are
complete, or pediatric studies should be delayed until additional
safety or effectiveness data have been collected. If an applicant
requests deferred submission, the request must provide a certification
from the applicant of the grounds for delaying pediatric studies, a
description of the planned or ongoing studies, and evidence that the
studies are being or will be conducted with due diligence and at the
earliest possible time.
    (2) If FDA determines that there is an adequate justification for
temporarily delaying the submission of assessments of pediatric safety
and effectiveness, the drug product may be approved for use in adults
subject to the requirement that the applicant submit the required
assessments within a specified time.
    (c) Waivers--(1) General. FDA may grant a full or partial waiver of
the requirements of paragraph (a) of this section on its own initiative
or at the request of an applicant. A request for a waiver must provide
an adequate justification.
    (2) Full waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section if the applicant
certifies that:
    (i) The drug product does not represent a meaningful therapeutic
benefit over existing treatments for pediatric patients and is not
likely to be used in a substantial number of pediatric patients;
    (ii) Necessary studies are impossible or highly impractical
because, e.g., the number of such patients is so small or
geographically dispersed; or
    (iii) There is evidence strongly suggesting that the drug product
would be ineffective or unsafe in all pediatric age groups.
    (3) Partial waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section with respect to a
specified pediatric age group, if the applicant certifies that:
    (i) The drug product does not represent a meaningful therapeutic
benefit over existing treatments for pediatric patients in that age
group, and is not likely to be used in a substantial number of patients
in that age group;
    (ii) Necessary studies are impossible or highly impractical
because, e.g., the number of patients in that age group is so small or
geographically dispersed;
    (iii) There is evidence strongly suggesting that the drug product
would be ineffective or unsafe in that age group; or
    (iv) The applicant can demonstrate that reasonable attempts to
produce a pediatric formulation necessary for that age group have
failed.
    (4) FDA action on waiver. FDA shall grant a full or partial waiver,
as appropriate, if the agency finds that there is a reasonable basis on
which to conclude that one or more of the grounds for waiver specified
in paragraphs (c)(2) or (c)(3) of this section have been met. If a
waiver is granted on the ground that it is not possible to develop a
pediatric formulation, the waiver will cover only those pediatric age
groups requiring that formulation. If a waiver is granted because there
is evidence that the product would be ineffective or unsafe in
pediatric populations, this information will be included in the
product's labeling.
    (5) Definition of ``meaningful therapeutic benefit''. For purposes
of this section and Sec. 201.23 of this chapter, a drug will be
considered to offer a meaningful therapeutic benefit over existing
therapies if FDA estimates that:
    (i) If approved, the drug would represent a significant improvement
in the treatment, diagnosis, or prevention of a disease, compared to
marketed products adequately labeled for that use in the relevant
pediatric population. Examples of how improvement might be demonstrated
include, for example, evidence of increased effectiveness in treatment,
prevention, or diagnosis of disease, elimination or substantial
reduction of a treatment-limiting drug reaction, documented enhancement
of compliance, or evidence of safety and effectiveness in a new
subpopulation; or
    (ii) The drug is in a class of drugs or for an indication for which
there is a need for additional therapeutic options.
    (d) Exemption for orphan drugs. This section does not apply to any
drug for an indication or indications for which orphan designation has
been granted under part 316, subpart C, of this chapter.
    10. Section 314.81 is amended by revising paragraph (b)(2)(i) and
(b)(2)(vii), and by adding paragraph (b)(2)(vi)(c) to read as follows:

Sec. 314.81  Other postmarketing reports.

* * * * *
    (b) * * *
    (2) * * *

[[Page 66671]]

    (i) Summary. A brief summary of significant new information from
the previous year that might affect the safety, effectiveness, or
labeling of the drug product. The report is also required to contain a
brief description of actions the applicant has taken or intends to take
as a result of this new information, for example, submit a labeling
supplement, add a warning to the labeling, or initiate a new study. The
summary shall briefly state whether labeling supplements for pediatric
use have been submitted and whether new studies in the pediatric
population to support appropriate labeling for the pediatric population
have been initiated. Where possible, an estimate of patient exposure to
the drug product, with special reference to the pediatric population
(neonates, infants, children, and adolescents) shall be provided,
including dosage form.
* * * * *
    (vi) * * *
    (c) Analysis of available safety and efficacy data in the pediatric
population and changes proposed in the labeling based on this
information. An assessment of data needed to ensure appropriate
labeling for the pediatric population shall be included.
    (vii) Status reports. A statement on the current status of any
postmarketing studies performed by, or on behalf of, the applicant. The
statement shall include whether postmarketing clinical studies in
pediatric populations were required or agreed to, and if so, the status
of these studies, e.g., to be initiated, ongoing (with projected
completion date), completed (including date), completed and results
submitted to the NDA (including date). To facilitate communications
between FDA and the applicant, the report may, at the applicant's
discretion, also contain a list of any open regulatory business with
FDA concerning the drug product subject to the application.
* * * * *

PART 601--LICENSING

    11. The authority citation for 21 CFR part 601 is revised to read
as follows:

    Authority: 15 U.S.C. 1451-1461; 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.

    12. Section 601.27 is added to subpart C to read as follows:

Sec. 601.27  Pediatric studies.

    (a) Required assessment. Except as provided in paragraphs (b), (c),
and (d) of this section, each application for a new active ingredient,
new indication, new dosage form, new dosing regimen, or new route of
administration shall contain data that are adequate to assess the
safety and effectiveness of the product for the claimed indications in
all relevant pediatric subpopulations, and to support dosing and
administration for each pediatric subpopulation for which the product
is safe and effective. Where the course of the disease and the effects
of the product are similar in adults and pediatric patients, FDA may
conclude that pediatric effectiveness can be extrapolated from adequate
and well-controlled effectiveness studies in adults, usually
supplemented with other information in pediatric patients, such as
pharmacokinetic studies. In addition, studies may not be needed in each
pediatric age group, if data from one age group can be extrapolated to
another. Assessments required under this section for a product that
represents a meaningful therapeutic benefit over existing treatments
must be carried out using appropriate formulations for the age group(s)
for which the assessment is required.
    (b) Deferred submission. (1) FDA may, on its own initiative or at
the request of an applicant, defer submission of some or all
assessments of safety and effectiveness described in paragraph (a) of
this section until after licensing of the product for use in adults.
Deferral may be granted if, among other reasons, the product is ready
for approval in adults before studies in pediatric patients are
complete, pediatric studies should be delayed until additional safety
or effectiveness data have been collected. If an applicant requests
deferred submission, the request must provide an adequate justification
for delaying pediatric studies, a description of the planned or ongoing
studies, and evidence that the studies are being or will be conducted
with due diligence and at the earliest possible time.
    (2) If FDA determines that there is an adequate justification for
temporarily delaying the submission of assessments of pediatric safety
and effectiveness, the product may be licensed for use in adults
subject to the requirement that the applicant submit the required
assessments within a specified time.
    (c) Waivers--(1) General. FDA may grant a full or partial waiver of
the requirements of paragraph (a) of this section on its own initiative
or at the request of an applicant. A request for a waiver must provide
an adequate justification.
    (2) Full waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section if the applicant
certifies that:
    (i) The product does not represent a meaningful therapeutic benefit
over existing therapies for pediatric patients and is not likely to be
used in a substantial number of pediatric patients;
    (ii) Necessary studies are impossible or highly impractical
because, e.g., the number of such patients is so small or
geographically dispersed; or
    (iii) There is evidence strongly suggesting that the product would
be ineffective or unsafe in all pediatric age groups.
    (3) Partial waiver. An applicant may request a waiver of the
requirements of paragraph (a) of this section with respect to a
specified pediatric age group, if the applicant certifies that:
    (i) The product does not represent a meaningful therapeutic benefit
over existing therapies for pediatric patients in that age group, and
is not likely to be used in a substantial number of patients in that
age group;
    (ii) Necessary studies are impossible or highly impractical
because, e.g., the number of patients in that age group is so small or
geographically dispersed;
    (iii) There is evidence strongly suggesting that the product would
be ineffective or unsafe in that age group; or
    (iv) The applicant can demonstrate that reasonable attempts to
produce a pediatric formulation necessary for that age group have
failed.
    (4) FDA action on waiver. FDA shall grant a full or partial waiver,
as appropriate, if the agency finds that there is a reasonable basis on
which to conclude that one or more of the grounds for waiver specified
in paragraphs (c)(2) or (c)(3) of this section have been met. If a
waiver is granted on the ground that it is not possible to develop a
pediatric formulation, the waiver will cover only those pediatric age
groups requiring that formulation. If a waiver is granted because there
is evidence that the product would be ineffective or unsafe in
pediatric populations, this information will be included in the
product's labeling.
    (5) Definition of ``meaningful therapeutic benefit''. For purposes
of this section, a product will be considered to offer a meaningful
therapeutic benefit over existing therapies if FDA estimates that:
    (i) If approved, the product would represent a significant
improvement in the treatment, diagnosis, or prevention of a disease,
compared to marketed products adequately labeled for that use in the
relevant pediatric population. Examples of how improvement might be
demonstrated include, e.g., evidence of increased effectiveness in
treatment, prevention, or diagnosis of disease;

[[Page 66672]]

elimination or substantial reduction of a treatment-limiting drug
reaction; documented enhancement of compliance; or evidence of safety
and effectiveness in a new subpopulation; or
    (ii) The product is in a class of products or for an indication for
which there is a need for additional therapeutic options.
    (d) Exemption for orphan drugs. This section does not apply to any
product for an indication or indications for which orphan designation
has been granted under part 316, subpart C, of this chapter.
    13. Section 601.37 is added to subpart D to read as follows:

Sec. 601.37  Annual reports of postmarketing pediatric studies.

    Sponsors of licensed biological products shall submit the following
information each year within 60 days of the anniversary date of
approval of the license, to the Director, Center for Biologics
Evaluation and Research:
    (a) Summary. A brief summary stating whether labeling supplements
for pediatric use have been submitted and whether new studies in the
pediatric population to support appropriate labeling for the pediatric
population have been initiated. Where possible, an estimate of patient
exposure to the drug product, with special reference to the pediatric
population (neonates, infants, children, and adolescents) shall be
provided, including dosage form.
    (b) Clinical data. Analysis of available safety and efficacy data
in the pediatric population and changes proposed in the labeling based
on this information. An assessment of data needed to ensure appropriate
labeling for the pediatric population shall be included.
    (c) Status reports. A statement on the current status of any
postmarketing studies in the pediatric population performed by, or on
behalf of, the applicant. The statement shall include whether
postmarketing clinical studies in pediatric populations were required
or agreed to, and if so, the status of these studies, e.g., to be
initiated, ongoing (with projected completion date), completed
(including date), completed and results submitted to the BLA (including
date).

    Dated: November 24, 1998.
Michael A. Friedman,
Acting Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-31902 Filed 11-27-98; 8:45 am]
BILLING CODE 4160-01-P