[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.

-----------------------------------------------------------------------

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

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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.

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    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.

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G. Planning and Tracking Pediatric Studies

1. Sections 312.23(a)(3)(v), 312.47 (b)(