[Federal Register Volume 63, Number 231 (Wednesday, December 2, 1998)]
[Rules and Regulations]
[Pages 66632-66672]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-31902]



[[Page 66631]]

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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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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

  Federal Register / Vol. 63, No. 231 / Wednesday, December 2, 1998 / 
Rules and Regulations  

[[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\,\3
                                                                                    \ 10  \2\ 10      17      64
Pediatric labeling added after approval.................       1       0       2       4       2       2     11
----------------------------------------------------------------------------------------------------------------
\1\ In one case, pediatric use information provided for one of two approved indications.
\2\ In one case, pediatric data requested for second of two approved indications.
\3\ In one case, pediatric data requested for additional age groups.

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

[[Page 66639]]

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

[[Page 66640]]

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

B. Scope

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

[[Page 66641]]

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

C. Required Studies

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

[[Page 66642]]

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

D. Deferred Submission

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

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

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

[[Page 66643]]

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

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

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

[[Page 66644]]

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

E. Waivers

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

[[Page 66645]]

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

[[Page 66646]]

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

[[Page 66647]]

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

[[Page 66648]]

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

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

F. Pediatric Use Section of Application

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

[[Page 66649]]

G. Planning and Tracking Pediatric Studies

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

[[Page 66650]]

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

H. Studies in Different Pediatric Age Groups

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

[[Page 66651]]

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

I. Pediatric Formulations

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

[[Page 66652]]

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

[[Page 66653]]

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

J. Marketed Drug and Biological Products

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


[[Page 66654]]


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

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

K. Ethical Issues

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

[[Page 66655]]

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

L. Remedies

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

[[Page 66656]]

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

M. Pediatric Committee

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

N. Other Comments

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

[[Page 66657]]

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

IV. Legal Authority

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

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

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

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

[[Page 66658]]

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

V. Implementation Plan

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

[[Page 66659]]

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

VI. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the 
information collection requirements are shown below with an estimate of 
the annual reporting burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    With respect to the following collection of information, FDA 
invited comment on: (1) Whether the proposed collection of information 
is necessary for proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    OMB filed a Notice of Action, not approving the proposed collection 
of information. OMB requested that, as part of the final rule, FDA 
address all comments received on the information collection 
requirements contained in the rule, particularly with respect to the 
reporting burden imposed by the rule. FDA received one comment 
concerning the proposed burden estimates of this rulemaking under the 
PRA. The comment contended that FDA underestimated the time required to 
comply with the annual reporting requirements of the proposed 
rulemaking.
    The agency received several comments that questioned the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information as being too low and requested changes. For example, one 
comment requested changes in the burden estimate for manufacturers 
requesting deferrals of submission of pediatric data as well as the 
estimate for manufacturers to submit pediatric information in their 
annual report. In addition, the estimate for manufacturers to submit in 
their annual reports the analysis of available safety and efficacy data 
conducted or obtained in the pediatric population as well as proposed 
labeling was questioned. Based on these comments the agency increased 
the proposed burden estimates. These issues are discussed in more 
detail in the preamble to the final rule.
    Concerning Sec. 314.50(d)(7), the comment stated that in order to 
comply with this requirement, ``one company'' estimated that, for one 
pediatric reporting project, medical staff had spent at least 118 
hours, rather than the 8 hours that FDA had estimated, reviewing the 
medical literature and summarizing the findings. FDA does not believe 
that this comparison is fully appropriate because Sec. 314.50(d)(7) 
does not require an applicant to review the medical literature, or 
other studies, de novo. It simply requires an applicant to provide a 
brief summary of data that have already been fully reported and 
analyzed elsewhere in the same application. However, because the data 
to be summarized may be more extensive than originally estimated, FDA 
has, in response to the comment, increased its estimate of the 
reporting burden for this requirement from 8 hours to 50 hours.
    Concerning Sec. 314.55(a), the comment contended that FDA's 
estimate of 10 companies submitting NDA's annually for NME's is too 
low. The comment implied that, based on data for 1996, 50 companies 
would be a more realistic estimate. The comment also contended that 
FDA's estimate of 16 hours for a manufacturer to prepare the report of 
the data supporting the safety and effectiveness of the drug for the 
indication for the pediatric population is too low. In response to this 
comment, FDA has revised its burden estimate from 16 to 48 hours. FDA 
has also made a corresponding change in the estimate for 
Sec. 601.27(a). FDA has revised the estimate of the number of companies 
affected from 10 to 51 to reflect the broader scope of the rule.
    Concerning Sec. 314.55(b), the comment stated that FDA's estimate 
of 9 manufacturers requesting deferrals of the submission of pediatric 
study data and the estimate that this would take 8 hours to complete 
are too low. In response to this comment, FDA has revised its burden 
estimate from 8 hours to 24 hours. FDA has also made a corresponding 
change in the estimate for Sec. 601.27(b). FDA has revised the estimate 
of the number of companies affected from 8 to 51 to respond to the 
comment and to reflect the broader scope of the rule.
    Concerning Sec. 314.81(b)(2)(i), the comment contended that FDA's 
estimate of 1.5 hours for manufacturers to submit pediatric information 
in their annual reports is too low. In response to this comment, FDA 
has revised its burden estimate from 1.5 hours to 8 hours and has made 
a corresponding change in its estimate for Sec. 601.27(c).
    Concerning Sec. 314.81(b)(2)(vi)(c), the comment contended that 
FDA's estimate of 1.5 hours for manufacturers to submit in their annual 
reports the analysis of available safety and efficacy data conducted or 
obtained in the pediatric population as well as proposed labeling 
changes is too low. The comment stated that even an estimate of 15 
hours would be too low. Although the comment did not provide an 
estimate of the hours required to satisfy Sec. 314.81(b)(2)(i) and 
(b)(2)(vi)(c), FDA has increased its estimates to 8 and 24 hours, 
respectively.
    Based upon these comments, FDA has decided to increase the agency's 
proposed burden estimates. These revisions are reflected in the Table 2 
of this document. In addition, the burden estimates for 
Secs. 314.55(a), (b), and (c), and 601.27(a), (b), and (c), have 
increased because of the new requirements in the final rule to include, 
in addition to applications for new chemical entities and never-before-
approved biologics, applications for new active ingredients, new 
indications, new dosage forms, new dosing regimens, and new routes of 
administration. These estimates are based upon FDA's analysis of all 
marketing applications and efficacy

[[Page 66660]]

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

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

    The information collection provisions of this final rule have been 
submitted to OMB for review. Prior to the effective date of this final 
rule, FDA will publish a notice in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection provisions in this final rule. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

VII. Environmental Impact

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

VIII. Analysis of Impacts

A. Introduction and Summary

    FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act (Pub. L. 104-4). Executive Order 12866 
directs agencies to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, unless an agency certifies that a rule will not have a 
significant economic impact on a substantial number of small entities, 
the agency must analyze regulatory options that would minimize the 
impact of the rule on small entities. The Unfunded Mandates Reform Act 
(Pub. L. 104-4) (in section 202) requires that agencies prepare an 
assessment of anticipated costs and benefits before proposing any rule 
that may result in an expenditure by State, local, and tribal 
governments,

[[Page 66661]]

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

B. Number of Affected Products and Required Studies

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

[[Page 66662]]

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

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

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

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

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

[[Page 66663]]



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


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

C. Number of Pediatric Patients

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

D. Costs of Compliance

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

[[Page 66664]]

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

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

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

[[Page 66665]]

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

*COM041**COM041*E. Benefits

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

[[Page 66666]]

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

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

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

[[Page 66667]]

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

F. Small Entities

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

G. Regulatory Alternatives

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

IX. References

    The following references have been placed on display in the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852, and may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Pina, L.M., Drugs Widely Used off Label in Pediatrics, Report of 
the Pediatric Use Survey Working Group of the Pediatric Subcommittee, 
in News Along the Pike, January 1997.
    2. Food and Drug Administration, Guidance for Industry: Standards 
for the Prompt Review of Efficacy Supplements, Including Priority 
Efficacy Supplements, May 1998.
    3. Population Division, United States Bureau of the Census, PPL-91, 
Appendix a. Resident Population--Estimates by Age, Sex, Race, and 
Hispanic Origin, Washington, DC 20233, 1998.
    4. Powell, D.A. et al., ``Chloramphenicol: New Perspectives on an 
Old Drug,'' Drug Intelligences & Clinical Pharmacy, 16:295-300, 1982.
    5. Koren, G. et al., ``Unexpected Alterations in Fentanyl 
Pharmacokinetics in Pediatric Patients Undergoing Cardiac Surgery: Age 
Related or Disease Related?'' Developmental Pharmacology Therapeutics, 
9:183-191, 1986.
    6. Gauntlett, I.S. et al., ``Pharmacokinetics of Fentanyl in 
Neonatal Humans and Lambs: Effects of Age,'' Anesthesiology, 69:683-
687, 1988.
    7. Kauffman, R.E., ``Fentanyl, Fads, and Folly: Who Will Adopt the 
Therapeutic Orphans?'' Journal of Pediatrics, 119:588-589, 1991.
    8. McCloskey J.J. et al., ``Bupivacaine Toxicity Secondary to 
Continuous Caudal Epidural Infusion in Pediatric Patients,'' Anesthesia 
Analgesia, 75:287-290, 1992.
    9. Fisher, D.M. et al., ``Neuromuscular Effects of Vecuronium (ORG 
NC45) in Infants and Pediatric Patients During N2O Halothane 
Anesthesia,'' Anesthesiology, 58:519-523, 1983.
    10. Agarwal, R. et al., ``Seizures Occurring in Pediatric Patients 
Receiving Continuous Infusion of Bupivacaine,'' Anesthesia and 
Analgesia, 75:284-286, 1992.
    11. Mevorach, D.L. et al., ``Bupivacaine Toxicity Secondary to 
Continuous Caudal Epidural Infusion in Pediatric Patients,'' Anesthesia 
Analgesia, 77:13005-1306, 1993.
    12. Editorial: ``Cystic Fibrosis and Colonic Strictures,'' Journal 
of Clinical Gastroenterology, 21(1):2-5, 1995.
    13. Olkkola, K.T. et al., ``A Potentially Hazardous Interaction 
Between Erythromycin and Midazolam,'' Clinical Pharmacology Therapy, 
53:298-305, 1993.

[[Page 66668]]

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

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 312

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

21 CFR Part 314

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

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

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

PART 201--LABELING

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

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

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


Sec. 201.23  Required pediatric studies.

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

[[Page 66669]]

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

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

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

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

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


Sec. 312.23  IND content and format.

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


Sec. 312.47  Meetings.

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


Sec. 312.82  Early consultation.

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

[[Page 66670]]

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

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

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

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


Sec. 314.50  Content and format of an application.

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


Sec. 314.55  Pediatric use information.

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


Sec. 314.81  Other postmarketing reports.

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

[[Page 66671]]

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

PART 601--LICENSING

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

    Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 321, 351, 352, 353, 
355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 
241, 262, 263.

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


Sec. 601.27  Pediatric studies.

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

[[Page 66672]]

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


Sec. 601.37  Annual reports of postmarketing pediatric studies.

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

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