[Federal Register Volume 59, Number 238 (Tuesday, December 13, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-30238]


[[Page Unknown]]

[Federal Register: December 13, 1994]


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Part II





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Part 201




Specific Requirements on Content and Format of Labeling for Human 
Prescription Drugs; Revision of ``Pediatric Use'' Subsection in the 
Labeling; Final Rule
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 92N-0165]

 
Specific Requirements on Content and Format of Labeling for Human 
Prescription Drugs; Revision of ``Pediatric Use'' Subsection In the 
Labeling

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations governing the content and format on labeling for human 
prescription drug products. The final rule revises the current 
``Pediatric use'' subsection of the professional labeling requirements 
for prescription drugs to provide for the inclusion of more complete 
information about the use of a drug in the pediatric population (ages 
birth to 16 years). The final rule, which applies to prescription drug 
products (including biological prescription drug products), recognizes 
several methods of establishing substantial evidence to support 
pediatric labeling claims, including relying, in certain cases, on 
studies carried out in adults. This final rule also requires that if 
there is not substantial evidence to support any pediatric use or use 
in a particular pediatric population, the labeling shall state this. 
Sponsors must reexamine existing data to determine whether the 
``Pediatric use'' subsection of the labeling can be modified based on 
adequate and well-controlled studies in adults, and other information 
supporting pediatric use, and, if appropriate, submit a supplemental 
application to comply with new Sec. 201.57(f)(9)(iv) by December 13, 
1996. This action responds to concerns in FDA and elsewhere that 
current prescription drug labeling often does not contain adequate 
information about the use of drugs in the pediatric population. This 
action promotes safer and more effective use of prescription drugs in 
the pediatric population.

DATES: Effective January 12, 1995. The agency will accept ``pediatric 
use'' information based on revised Sec. 201.57(f)(9) (21 CFR 
201.57(f)(9)) after January 12, 1995. Sponsors must reexamine existing 
data, and, if appropriate, submit a supplemental application to comply 
with new Sec. 201.57(f)(9)(iv) by December 13, 1996.

FOR FURTHER INFORMATION CONTACT: Erica L. Keys, Center for Drug 
Evaluation and Research (HFD-362), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1046.

SUPPLEMENTARY INFORMATION: 

I. Background

    In the Federal Register of October 16, 1992 (57 FR 47423), FDA 
proposed to amend its regulations pertaining to the content and format 
of prescription drug labeling in Sec. 201.57 by revising the current 
``Pediatric use'' subsection (Sec. 201.57(f)(9)) to allow a broader 
basis for the inclusion of information about use of a drug in the 
pediatric population. The proposal would have allowed pediatric claims 
based not only on adequate and well-controlled studies in the pediatric 
population but also, in some cases, on such trials in adults. The 
proposed regulation described other data needed when pediatric claims 
are based on trials in adults and indicated specific labeling language 
and the location of various kinds of information.
    FDA issued the current pediatric labeling requirements in 1979 (44 
FR 37434, June 26, 1979). The current regulation, codified at 
Sec. 201.57(f)(9), requires that specific pediatric indications, if 
any, be described under the ``Indications and Usage'' section of the 
labeling, with appropriate pediatric dosage provided under the ``Dosage 
and Administration'' section. The current regulation also requires that 
recommendations for pediatric use be based on substantial evidence 
derived from adequate and well-controlled studies in the pediatric 
population, unless that requirement is waived. If a drug's safety and 
effectiveness in the pediatric population cannot be established or if 
the drug's use in the pediatric population is associated with a 
specific hazard, the current regulation requires appropriate statements 
or details.
    By establishing a ``Pediatric use'' subsection and describing its 
content and format, the 1979 regulation was intended to encourage drug 
labeling that would regularly provide adequate information about use of 
prescription drugs in pediatric patients. As stated in the preamble to 
the proposed rule on which this final rule is based, however, most 
prescription drug products still lack adequate information about their 
use in pediatric populations. For example, an informal survey done in 
1990 by the American Academy of Pediatrics examined labeling of all new 
molecular entities approved between 1984 and 1989 and found that 80 
percent had no information on pediatric use. Other surveys have shown 
that the labeling for many prescription drugs states that safety and 
effectiveness in children have not been established and contains no 
information on pediatric use, even for drugs that are commonly 
prescribed for pediatric patients.
    FDA continues to be concerned that, without adequate information, 
practitioners may be reluctant to prescribe certain drugs for their 
pediatric patients, or may prescribe them inappropriately, choosing 
dosages, for instance, that are arbitrarily based on the child's age, 
body weight, or body surface area without specific information as to 
whether this is appropriate. As a result, pediatric patients may be 
exposed to an increased risk of adverse reactions, or decreased 
effectiveness of the drugs prescribed, or may be denied access to 
valuable therapeutic agents.
    The continuing absence of pediatric use information in prescription 
drug labeling may be due in part to the impression, perhaps conveyed by 
the existing regulation, that pediatric claims must always be based on 
adequate and well-controlled studies conducted in the pediatric 
population. Given the many problems associated with the testing of 
drugs in the pediatric population (e.g., obtaining informed consent for 
tests not directly of benefit to the child, use of placebo controls in 
a vulnerable population), studies meeting this standard are often 
difficult to obtain. Existing FDA regulations do not, in fact, require 
that controlled trials always be conducted in the pediatric population 
to support a pediatric use. Under current Sec. 201.57(f)(9), the need 
for such studies may be waived where other data can satisfy the 
requirements of law. The basis for granting such a waiver is not, 
however, clear in the existing regulation. Section 201.57(f)(9)(iv) of 
this final rule clarifies how the agency will determine that data from 
adequate and well-controlled studies with adult subjects can provide 
substantial evidence of effectiveness in the pediatric population.
    In summary, this rule is intended to provide practitioners with 
more pediatric use information in the labeling of human prescription 
drug products so that practitioners will have more reliable information 
upon which to base a decision to prescribe a drug for use in their 
pediatric patients. The rule does this by encouraging manufacturers to 
provide more information on drug labels upon which practitioners can 
base their decisions. The rule does not, however, limit the manner in 
which a practitioner may prescribe an approved drug.

II. Highlights of the Final Rule

    The final rule revises the current ``Pediatric use'' subsection of 
the professional labeling requirements for prescription drugs to 
provide for the inclusion of more comprehensive information about use 
of a drug in the pediatric population. Under the final rule, products 
may be labeled for pediatric use based on adequate and well-controlled 
studies in adults together with other information supporting pediatric 
use (e.g., pharmacokinetic data, safety data, pharmacodynamic data). 
Such reliance on studies in adults was possible under the waiver 
provision in the existing rule, but the waiver provision was not often 
used. Of course, products may also be labeled for pediatric use based 
on adequate and well-controlled studies in the pediatric population. 
The pediatric age group, birth to 16 years, includes pediatric age 
groups often called neonates, infants, children, and adolescents. In 
the final rule, because the term ``children'' can be interpreted as 
referring only to a particular subset of the pediatric population (ages 
2 to 12 years), and to make clear that the provisions of this rule 
apply to the entire pediatric population, references to ``children'' in 
the proposed rule have been deleted and replaced by ``pediatric 
population'' or ``pediatric patients.''
    The major provisions of the final rule are summarized as follows:
    The final rule continues to permit a specific pediatric indication 
(i.e., an indication different from those approved in adults) supported 
by adequate and well-controlled studies in the appropriate pediatric 
population, to be described under the ``Indications and Usage'' section 
of the labeling, with the appropriate pediatric dosage given under the 
``Dosage and Administration'' section of the labeling. The ``Pediatric 
use'' subsection of the labeling must include any limitations on the 
pediatric indication, need for specific monitoring, specific hazards of 
the drug, differences between pediatric and adult responses to the 
drug, and other information related to the safe and effective use of 
the drug in pediatric patients.
    If there are specific statements on pediatric use of the drug for 
an indication also approved for adults that are based on adequate and 
well-controlled studies in the pediatric population, they must be 
summarized in the ``Pediatric use'' subsection of the labeling and 
discussed in more detail, if appropriate, under the ``Clinical 
Pharmacology'' and ``Clinical Studies'' sections. Appropriate pediatric 
dosage must be given under the ``Dosage and Administration'' section of 
the labeling. This subsection of the labeling must also cite any 
limitations on the pediatric use statement, need for specific 
monitoring, specific hazards associated with use of the drug in any 
subsets of the pediatric population (e.g., neonates), differences 
between pediatric and adult responses to the drug, and other 
information related to the safe and effective pediatric use of the 
drug.
    A pediatric use statement may also be based on adequate and well-
controlled studies in adults, provided that the agency concludes that 
the course of the disease and the drug's effects are sufficiently 
similar in the pediatric and adult populations to permit extrapolation 
from the adult efficacy data to pediatric patients. Where needed, 
pharmacokinetic data to allow determination of an appropriate pediatric 
dosage, and additional pediatric safety information must also be 
submitted.
    Where the requirements for a finding of substantial evidence to 
support a specific pediatric indication or a pediatric use statement 
have not been met for a particular pediatric subgroup, the ``Pediatric 
use'' subsection of the labeling must contain a statement that 
appropriately characterizes the limitation, such as ``Safety and 
effectiveness in pediatric patients [below the age of (--) (years/
months/weeks)] have not been established.'' If use of the drug is 
associated with a specific hazard in this pediatric subgroup, the 
``Pediatric use'' subsection must contain information about this 
hazard, or, where appropriate, refer to a more complete description of 
the hazard in the ``Contraindications'' or ``Warnings'' section of the 
labeling.
    Where the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for any pediatric population, the ``Pediatric use'' subsection 
of the labeling must contain the following statement: ``Safety and 
effectiveness in pediatric patients have not been established.'' If use 
of the drug in premature or neonatal infants, or other pediatric 
subgroups, is associated with a specific hazard, the ``Pediatric use'' 
subsection must contain information about this hazard, or, where 
appropriate, refer to a more complete description of the hazard in the 
``Contraindications'' or ``Warnings'' section of the labeling.
    Any sponsor who believes that no ``Pediatric use'' subsection is 
appropriate or relevant to the labeling of its particular drug product 
must provide FDA with reasons justifying its omission, and may propose 
alternative statement(s).
    Finally, recognizing the hazards that inactive ingredients can pose 
to the pediatric population, the final rule requires that prescription 
drug labeling contain statements about inactive ingredients that might 
be toxic to the neonate or other pediatric subgroup.

III. General Comments on the Proposed Rule

    FDA received 11 comments on the proposed rule from prescription 
drug manufacturers, prescribers, professional societies, organizations 
with special interests in the pediatric population, the lay public, and 
others. Most supported the proposed labeling change, calling it 
``timely and important,'' ``an important * * * step to facilitate the 
inclusion of information about use of drugs in children in the approved 
labeling,'' ``a significant step toward the goal of including infants 
and children in the drug approval process,'' and a way ``to fill the 
gap of information that currently exists in the area of appropriate 
drug usage in children.''
    One comment, for example, stated that providing pediatric use 
information in labeling will help health professionals reach rational 
drug therapy decisions for pediatric patients. The comment added ``any 
information that can be used by pharmacists to assure rational drug 
therapy in special populations will be a positive addition to drug 
information. * * * Such labeling will enhance the likelihood of 
positive outcomes in pediatric patients.''
    However, some comments were less supportive, including one that 
stated: ``While * * * [we] commend the FDA on its initiatives to 
improve information available to physicians and their pediatric 
patients regarding prescription drug use, we remain concerned that this 
approach will not measurably assist physicians.''
    Most comments also raised specific issues for consideration by the 
agency. These issues are described below.

A. Definition of ``Pediatric''

    1. Several comments suggested that age breakdowns within the 
pediatric population might be appropriate. The pediatric age range 
begins at birth, and may cover individuals as old as 18 years to 21 
years, encompassing the subspecialties of neonatology and adolescent 
medicine. One comment suggested that the rule define ``pediatric'' as 
children under 12 years, because ``it has been commonly accepted that 
ages 12 years to 18 years may be included without previous clinical 
work in that age group.'' The comment also suggested that the rule 
state the age group when pharmacokinetic studies should be done in 
order to extrapolate the results from infancy through adolescence, or 
state whether the age range will be broken into subgroups with testing 
required for each. Another comment said that a definition of 
``pediatric'' would have to consider drug metabolism, pharmacokinetics, 
and interaction with various organs and other body systems. The comment 
suggested that a system by which distinct classes of drugs are 
considered differently may be more logical and appropriate.
    Another comment noted that pediatric patients are not homogeneous, 
and that age groups show significant differences in functional and 
physiological functions. The comment suggested that information from 
clinical studies be subdivided by age groups and their respective 
responses to drugs, suggesting age categories of premature infant, 
newborn, children under 2 years of age, children 2 years to 13 years, 
and adolescents 13 years to 18 years.
    Another comment said that individuals 16 years to 18 years of age 
pose particular problems and suggested consultation with the American 
Academy of Pediatrics' Committee on Drugs to consider defining age 
categories or groups for pediatric labeling.
    The ``Pediatric use'' subsection of labeling is where information 
about use of a drug in pediatric patients is located, and 
Sec. 201.57(f)(9) describes in general terms the kind of information 
that should be included. The ``Pediatric use'' subsection does not 
attempt to resolve the many difficult issues related to use of drugs in 
this population. What appears in this subsection (e.g., age groups 
covered) will depend on the data available, and the ability to define 
results for specific subgroups. As a general matter, however, the 
agency offers the following guidance and useful breakdowns. The 
following age categories for the pediatric population are commonly 
distinguished, although the distinctions are inevitably arbitrary: (1) 
Birth up to 1 month (neonates), (2) 1 month up to 2 years of age 
(infants), (3) 2 years up to 12 years (children), and (4) 12 years up 
to 16 years (adolescents). Where possible, data should be analyzed by 
these groups, but it should not usually be necessary to establish a 
drug product's effectiveness in each group. It may, on the other hand, 
be important to have some pharmacokinetic information in each group, 
especially the younger age groups, to guide dosing and additional 
information, such as a specific study in neonates, to establish safety.
    Although the agency has determined that the term ``pediatric 
patients'' refers to individuals from birth to 16 years of age, the 
agency recognizes that for some drugs, adult studies may be applicable 
to pediatric patients under the age of 16 years who have passed 
puberty; indeed, a primary purpose of this rule is to allow pediatric 
labeling based on adult studies, when appropriate. Although in many 
cases, additional pharmacokinetic and safety data may be needed to 
support pediatric use statements, in other cases, particularly for 
pediatric patients in the 12-to 16-year age group, there may be less 
additional data needed.

B. Applicability of the Rule to Biological Drug Products

    2. One comment said that it was unclear whether the rule applies to 
biological drug products.
    The rule (as well as Sec. 201.57 in general) applies to biological 
drug products.

C. Pediatric Studies

    3. One comment noted that about 80 percent of drug labeling 
currently contains language excluding use of the drug in pediatric 
patients or limiting use only to specific age groups. The comment asked 
FDA to encourage sponsors to include pediatric patients in their 
clinical studies when the drug is likely to be effective for an 
indication in this population.
    As stated in the preamble to the proposed rule, FDA encourages 
sponsors to include pediatric patients in their clinical studies, and 
analyzes investigational new drug applications and new drug 
applications (NDA's) to determine whether studies in this population 
should be done before the drug is approved (57 FR 47423 at 47424). 
Under certain circumstances, the agency may require that clinical 
studies in the pediatric population be conducted before marketing 
approval (see response to comment number 4 in section III.C. of this 
document). If a drug is likely to be effective for pediatric use, the 
agency is making it clear that labeling for pediatric use may sometimes 
be based on adequate and well-controlled studies in adults, with 
additional pediatric data. FDA intends that this rule will call further 
attention to the need for creating and reviewing data on pediatric use.
    4. One comment asked whether FDA intended to require a sponsor to 
submit information for a specific pediatric indication or use if there 
are available data suggesting that such an indication or use would be 
permitted under the regulation. The comment said that there may be 
``good reasons'' why a sponsor might not wish to seek a pediatric 
indication or use for a drug even when available evidence would support 
such a use. For example, the drug's benefit/risk ratio in the pediatric 
population might be different from that in adults, or there might be 
sufficient and better alternative therapies available for the pediatric 
use. Additionally, the comment expressed concern that a drug that has 
been tested in adults may not provide a sufficient legal defense 
against a claim for injury of a child. The comment said that a sponsor 
should not be forced to assume or be placed in the position of having 
to defend such an action unless the sponsor believes the data in 
support of the pediatric use are sufficient, and that a sponsor should 
not be mandated or forced by the rule to seek a pediatric use if the 
sponsor, for whatever reason, does not wish to do so.
    Another comment expressed concern that FDA might delay approval of 
products that have good existing available data for safety and efficacy 
in adults while acceptable pediatric information is developed.
    This rule does not add a new requirement that sponsors carry out 
new pediatric studies, nor does it require that sponsors submit 
labeling with claims that are inadequately supported. New 
Sec. 201.57(f)(9)(iv) provides that a pediatric use statement may be 
based on adequate and well-controlled studies in adults, provided that 
the course of the disease and the drug effects are sufficiently similar 
in the pediatric and adult populations to permit extrapolation from the 
adult efficacy data to pediatric patients. Sponsors are required to 
reexamine existing data to determine whether the ``Pediatric use'' 
subsection of the labeling can be modified based on adequate and well-
controlled studies in adults, and other information supporting 
pediatric use, and, if safety and effectiveness for pediatric use have 
been demonstrated, submit a supplemental application to comply with new 
Sec. 201.57(f)(9)(iv) by December 13, 1996. A sponsor who does not 
believe that the disease and drug effects are similar in the pediatric 
and adult populations, or who believes that use in pediatric patients 
is otherwise not adequately supported by data, should not propose 
revised labeling under this provision. Under new Sec. 201.57(f)(9)(vi), 
the sponsor may propose labeling stating that safety and effectiveness 
in pediatric patients have not been established.
    Additionally, under new Sec. 201.57(f)(9)(vii), if the sponsor 
believes that none of the statements described in paragraphs (f)(9)(ii) 
through (f)(9)(vi) of that section is appropriate or relevant to the 
labeling of a particular drug, the sponsor must provide reasons for 
omission of the statements and may propose alternative statement(s). In 
response to such a proposal, FDA may permit use of an alternative 
statement if FDA determines that no statement described in those 
paragraphs is appropriate or relevant to the drug's labeling and that 
the alternative statement is accurate and appropriate. Section 
201.57(f)(9)(vii) has been modified to make this explicit.
    Although this rule does not add new requirements for conducting 
pediatric studies, various provisions of the Federal Food, Drug, and 
Cosmetic Act (the act), the Public Health Service Act (the PHS act), 
and existing regulations authorize FDA to require such studies under 
certain circumstances.
    Under section 505(k) of the act (21 U.S.C. 355(k)), FDA may require 
NDA holders to establish records and submit reports to the agency on 
data relating to clinical experience or other data or information in 
order to determine whether there may be grounds for revoking the NDA 
approval. Such a requirement may be established either through 
regulation or through an order regarding the NDA (21 U.S.C. 355(k)(1)).
    Existing regulations require application holders to report to the 
agency adverse experiences occurring in the course of use of the 
product in professional practice, as well as during clinical 
investigations (21 CFR 312.32, 314.80). In addition, approved 
application holders must submit as part of the annual report a summary 
of significant new information that might affect the safety, 
effectiveness, or labeling of the product, as well as copies of 
unpublished and published reports of studies of the drug (21 CFR 
314.81(b)(2)(i), (b)(2)(v), and (b)(2)(vi)). The report also must 
contain a description of the action the company has taken or intends to 
take because of the new information, such as submission of a 
supplement, addition of a warning, or initiation of a new study (21 CFR 
314.81(b)(2)(i)).
    Section 505(e) of the act specifies grounds on which the agency may 
withdraw or suspend approval of an NDA. If there is an imminent hazard 
to the public health, approval of the NDA may be suspended immediately 
by the Secretary of the Department of Health and Human Services. In 
addition to other circumstances, approval of an NDA is to be withdrawn 
if clinical experience or other data show that the product is unsafe or 
not shown to be safe under the conditions of use upon the basis of 
which the application was approved. Moreover, the approval may be 
withdrawn if the labeling is false or misleading and not corrected 
within a reasonable time after notice of the matter.
    Under section 502(a) of the act (21 U.S.C. 352(a)), a drug is 
considered misbranded if its labeling is false or misleading. Section 
201(n) of the act (21 U.S.C. 321(n)) makes it clear that the 
``misleading'' determination is to be based not only on representations 
made or suggested in the labeling, but also on failure to reveal 
material facts. Material facts include those which concern consequences 
which may result from use of the product under the labeled conditions 
of use or under customary or usual conditions of use. These conditions 
of use may include off-label uses prescribed by practitioners for their 
patients.
    In addition, drugs are considered misbranded under section 502(f) 
of the act if the labeling fails to bear adequate directions for use. 
FDA regulations define adequate directions for use as directions under 
which the lay person can use a drug safely and for the purposes for 
which it is intended (21 CFR 201.5). ``Intended uses'' are further 
defined in the regulations to include uses other than the ones on the 
labeling (21 CFR 201.128). If a manufacturer knows that a drug is used 
for an off-label use, the manufacturer may be required to provide 
adequate labeling for that use (21 CFR 201.128).
    Prescription drugs for human use are exempt from the requirement to 
carry adequate directions for lay use under certain circumstances, if 
labeled with the prescription legend (21 CFR 201.100). Among the 
exemption criteria is the requirement that the drug carry adequate 
labeling for the prescriber, as authorized by an approved application, 
for the intended use. In summary, the drug product is misbranded if the 
intended use is not approved in an NDA.
    Drug products are also misbranded, under section 502(f)(2) of the 
act, if the labeling does not carry adequate warnings against unsafe 
use. Such unsafe use may include use by pediatric patients where the 
use may be dangerous to their health, or unsafe dosage or methods or 
duration of administration in the pediatric population.
    Biological drug products are approved under authority of section 
351 of the PHS act (42 U.S.C. 262). This provision authorizes the 
promulgation of regulations designed to ensure the continued safety, 
purity, and potency of the products (42 U.S.C. 262(d)(1)). An approved 
product license application (PLA) may be revoked if the product does 
not conform to applicable requirements in the regulations or is not 
safe and effective for all of its intended uses or is misbranded with 
respect to any such use (21 CFR 601.5(b)(4) through (b)(6)). If there 
is a danger to health, the Commissioner may suspend the product license 
(21 CFR 601.6). Under section 351(b) of the PHS act, no one may falsely 
label a biological product. Biological drug products are also subject 
to the applicable drug provisions of the Federal Food, Drug, and 
Cosmetic Act, as previously discussed.
    Moreover, the agency has stated that an application for marketing 
approval should contain data on a reasonable sample of the patients 
likely to be given a drug once it is marketed (58 FR 39406 at 39409, 
July 22, 1993). This conclusion, stated explicitly in a guideline on 
the need for data in both genders, applies equally to age subgroups, 
including pediatric and geriatric populations. FDA may refuse to 
approve an application that fails to contain sufficient information to 
determine whether the product can be safely and effectively used in 
populations likely to receive it. In addition, for an approved drug, in 
certain cases (e.g., where the drug is widely used, represents a 
potential hazard, or is therapeutically important in pediatric 
patients), FDA may require further studies in pediatric populations and 
appropriate labeling changes. As previously discussed, an already 
approved drug may be considered illegally marketed if adequate 
information on safe and effective use in pediatric patients is not 
obtained and included in the labeling.
    The agency thus expects sponsors to seek supplemental claims for 
pediatric uses that are supported by adequate data. This does not 
imply, however, that a sponsor should seek a claim for a pediatric use 
if the benefits of that use do not outweigh its risks; the 
determination of whether to include a pediatric use statement must be 
based on clinical data, and other use information, not on a vague 
concern about liability.
    5. One comment said that although the desire to use potentially 
relevant data in the ``Pediatric use'' subsection of the labeling was 
``understandable,'' such data should not take the place of adequate and 
well-designed controlled studies in the pediatric population, and that 
FDA ultimately may have to require such studies. The comment stated 
that FDA should require manufacturers to fund research projects 
regarding drug safety and efficacy, including short-term and long-term 
side effects, in pediatric patients.
    FDA agrees that clinical studies regarding a drug's safety and 
effectiveness in pediatric patients are desirable, and the agency 
encourages such studies in appropriate cases. As discussed in comment 4 
in section III.C. of this document, the agency has the authority to 
require such studies under certain circumstances. In some cases, such 
studies may be required prior to approval where pediatric use is 
important and where the adult and pediatric diseases cannot be 
considered sufficiently similar. In other cases, the controlled trials 
in adults, with pharmacokinetic and other data as needed, may support 
valid pediatric labeling.
    6. One comment stated that FDA should consider other alternatives 
to the rule, including a formal review process that collects and 
analyzes available safety and efficacy data on a drug's use in the 
pediatric population both before and after marketing approval, which, 
through committee review, could recommend further testing of the drug 
after it is marketed if specific pediatric safety or efficacy concerns 
are found.
    FDA believes that the comment has misinterpreted the purpose of the 
rule. The rule describes the kind of data and information that can be 
included in labeling for the pediatric population. In general, it is 
the sponsor's responsibility to collect, on a continuing basis, 
available data on safety and efficacy, propose revised labeling, and 
carry out needed studies. In some circumstances, FDA has required 
pediatric studies prior to approval, elicited agreement by drug 
sponsors at the time of marketing approval to carry out additional 
pediatric studies after approval, or stimulated conduct of pediatric 
studies after approval. When appropriate, FDA makes use of its standing 
advisory committees to help decide whether and when pediatric studies 
are needed.
    7. One comment stated that FDA should revise the rule to specify 
what data must be provided by manufacturers. The comment asked what 
number of pediatric patients would be sufficient to determine if there 
is a difference in age-related response, and how FDA will determine 
that all available information about the pediatric use of all available 
drugs has been included, including epidemiologic studies.
    FDA declines to accept the comment's suggestion. The agency 
believes that specifying an exact number of pediatric patients to be 
studied would be impractical due to variations in the pediatric 
population and responses to different drugs. This is particularly true, 
given the various kinds of data that can be used under the rule to 
support pediatric labeling.

D. Drugs Currently Under Review

    8. One comment suggested that drugs currently under development or 
under review by FDA should be given special consideration to avoid 
delays in development and approval associated with implementation of 
the rule.
    FDA does not expect delays in review or approval as a result of 
this rule. FDA already examines available pediatric data under current 
labeling regulations. The principal change created by the revised 
regulation is the ability to rely on studies in adults to support 
pediatric efficacy in some situations.

E. Supplements for Drugs Already Approved

    9. One comment suggested that FDA work with manufacturers of 
approved drugs to develop a method that allows the manufacturers to 
update their labeling in a quick and cost-effective manner. The comment 
also said that package inserts do not generally reflect current 
scientific literature because of the problems with current methods of 
updating labeling. The comment said that this had created situations 
where prescribers are making decisions on treatment modalities without 
the benefit of timely information.
    FDA does not believe that changes in regulations are needed to 
allow timely updating of labeling. Under the current regulations, 
applicants can propose changes in their approved labeling. FDA normally 
reviews supplements subject to prior approval in the order received. 
Effectiveness supplements are rated as priority or standard and are 
subject to performance goals set in connection with the Prescription 
Drug User Fee Act of 1992.
    10. One comment said that the filing and approval of pediatric 
labeling supplements from different sponsors on different timetables 
could mean that some labels for products considered to be substantially 
similar might be silent with regard to pediatric usage, while others 
might be detailed. The comment suggested that FDA and the American 
Academy of Pediatrics' Committee on Drugs could identify therapeutic 
classes to be relabeled first, so that FDA could review and approve 
pediatric use labeling for products from different companies and 
coordinate implementation of labeling changes for similar agents.
    With respect to effectiveness claims, pharmacokinetics, and safety 
data, much information is drug specific and will be reviewed as it is 
submitted. Therefore, the agency is not adopting the comment's 
suggestions. The agency advises, however, that, in general, when a 
class of drug products is involved, FDA examines labeling as it applies 
to the class.

F. Impact on Industry

    11. One comment claimed that the rule places NDA holders at a 
competitive disadvantage relative to abbreviated new drug application 
(ANDA) holders. The comment stated that the rule would give NDA holders 
the burden and responsibility for pediatric studies and literature 
searches, but not impose a similar burden and responsibility on ANDA 
holders.
    FDA disagrees with the comment in part. The rule is directed to 
anyone marketing a prescription drug and is intended to encourage the 
inclusion of more complete information about use of a drug in the 
pediatric population and about hazards associated with this use. The 
rule permits a new basis for reference to pediatric uses, but it does 
not impose a new requirement to conduct studies in pediatric 
populations. To the extent that NDA holders have access to data not 
available to ANDA holders, they will have more data to examine and more 
likelihood of having a basis for proposing changes to the ``Pediatric 
use'' subsection of labeling. The agency believes this represents only 
a modest burden and, in any event, sees no other way to gain further 
pediatric information in labeling. ANDA holders cannot be required to 
examine data they do not possess. ANDA holders are not precluded from 
providing pediatric use data, and are expected to do so under this 
rule, if data are available. An ANDA applicant who believes new safety 
or effectiveness information should be added to a product's labeling 
should provide adequate supporting information to FDA, and FDA will 
determine whether the labeling for the generic and listed drugs should 
be revised.

G. Minor Editorial Changes

    12. One comment said that labeling revisions that are editorial in 
nature and are used to reformat existing pediatric use labeling 
information to conform to the rule should be made in accordance with 
Sec. 314.70(d) (21 CFR 314.70(d)) (changes described in the annual 
report). The comment said that this would also facilitate the agency's 
processing of minor changes.
    FDA agrees with the comment. As stated in the preamble to the 
proposed rule, ``[m]inor editorial changes may be made in accordance 
with Sec. 314.70(d)'' (57 FR 47423 at 47426). To comply with this rule, 
references to ``children'' in the ``Pediatric use'' subsection of the 
insert labeling of products already being marketed must be changed, 
where appropriate, to ``pediatric population'' or ``pediatric 
patients.'' For products other than biological products, such changes 
are considered minor editorial changes.
    As stated in the preamble to the proposed rule, for biological 
products, such changes are to be submitted in accordance with the 
procedures outlined in Sec. 601.12 (21 CFR 601.12) (57 FR 47423 at 
47426).

H. Format of Proposed Labeling

    13. One comment said that it is impractical and impossible to list 
on the labeling all dosages and hazards for the pediatric population. 
The comment suggested placement of a general label on all adult 
prescription drugs stating that the medication should not be given to 
pediatric patients without a physician's instructions. The comment said 
that requiring overly complicated and lengthy information on labeling 
would discourage the prescribing of needed medications.
    FDA believes that the comment misinterprets the proposed rule and 
the purpose of pediatric use labeling. The purpose of the rule is to 
encourage more pediatric use information in labeling and to provide 
practitioners with more information on pediatric use.
    14. One comment said that for certain products, e.g., 
corticosteroids, where class labeling has been in effect, the agency 
will have to decide and communicate how the pediatric wording will be 
addressed.
    In most cases, pediatric labeling will be drug specific. Where 
class labeling exists, FDA generally examines the labeling for those 
products as a whole.

IV. Specific Comments on the Proposed Rule

A. Section 201.57(f)(9)(i)

    FDA, on its own initiative, has added a definition in 
Sec. 201.57(f)(9)(i) to indicate that under paragraphs (f)(9)(ii) 
through (f)(9)(viii), the terms ``pediatric population(s)'' and 
``pediatric patient(s)'' are defined as the pediatric age group, from 
birth to 16 years, including age groups often called neonates, infants, 
children, and adolescents.

B. Proposed Sec. 201.57 (f)(9)(i) and (f)(9)(ii)

    FDA received no comments on these provisions (renumbered as 
Sec. 201.57(f)(9)(ii) and (f)(9)(iii)), and has finalized them without 
change.

C. Proposed Sec. 201.57(f)(9)(iii)

    Proposed Sec. 201.57(f)(9)(iii) (renumbered as 
Sec. 201.57(f)(9)(iv)) states, in part, that ``FDA may approve a drug 
for pediatric use based on adequate and well-controlled studies in 
adults, with other information supporting pediatric use. In such cases, 
the agency will have concluded that the course of the disease and the 
effects of the drugs are sufficiently similar in children and adults to 
permit extrapolation from the adult data to children. The additional 
information supporting pediatric use must include data on the 
pharmacokinetics of the drug in children for determination of pediatric 
dosage. Other information, such as data from pharmacodynamic studies of 
the drug in children, controlled or uncontrolled studies confirming the 
safety or effectiveness of the drug in children, pertinent premarketing 
or postmarketing studies or experience, may be necessary to establish 
the applicability of the adult data to children.''
    15. One comment said FDA should revise proposed 
Sec. 201.57(f)(9)(iii) to indicate that pharmacokinetic data are not 
mandatory in some situations. Another comment stated that 
pharmacokinetic data may not be the most appropriate way to determine 
pediatric dosing because the differences in metabolism or in 
distribution in pediatric patients may support dosing that will not 
necessarily be related to blood levels. Both comments stated that 
dosing for inhalation products should not be based on pharmacokinetics.
    Another comment said that difficulties in obtaining informed 
consent, use of placebo controls, and obtaining adequate blood samples 
for pharmacokinetic analysis in pediatric patients are not serious 
impediments to performing studies necessary for appropriate pediatric 
labeling. The comment said there is a well-established ethical 
structure within which informed consent may be obtained and placebo 
controls used in the pediatric population, and that current technology 
requires only very small blood samples for measurement of most 
compounds. According to the comment, the primary impediments to doing 
adequate clinical trials in the pediatric population are the absence of 
a regulatory mandate and the existence of economic disincentives.
    The agency recognizes that pharmacokinetic data are important 
sources of information, but may not always be the most appropriate 
method for determining pediatric dosing schedules and may be 
infeasible, unnecessary, or insufficient. Other types of data or 
experience may sometimes substitute for pharmacokinetic data, and other 
data or experience in the pediatric population may be needed in 
addition to pharmacokinetic data. The agency has modified the rule to 
state that the additional information supporting pediatric use must 
ordinarily include data on the pharmacokinetics of the drug in the 
pediatric population for determination of pediatric dosage.
    As discussed in response to comment 4 in section III.C. of this 
document, this rule does not create a new requirement for pediatric 
studies, but the authority for requiring pediatric studies already 
exists. There are situations in which data on safe and effective use in 
pediatric patients may be necessary for approval or for continued 
marketing of a drug. Revised Sec. 201.57(f)(9) does not create the 
requirement for pediatric studies, but is intended to encourage the 
inclusion of more comprehensive labeling about pediatric use by 
permitting use of adult data in establishing pediatric efficacy. 
Specifically, the rule allows the pediatric use statement to be based 
on adequate and well-controlled studies in adults when additional 
information exists to show that the course of the disease and the 
effects of the drug are sufficiently similar in adults and pediatric 
patients to permit extrapolation from the adult efficacy data to 
pediatric populations.
    FDA has, on its own initiative, amended proposed 
Sec. 201.57(f)(9)(iii) to indicate that FDA's determination whether the 
effects of a drug are sufficiently similar in adults and pediatric 
patients will include an examination of the drug's beneficial and 
adverse effects. FDA has also amended Sec. 201.57(f)(9)(iii) to make 
clear that other information besides pharmacokinetic data may be 
necessary not simply to ``establish the applicability of the adult data 
to pediatric patients,'' but, more generally, ``to show that the drug 
can be used safely and effectively in pediatric patients.'' Section 
201.57(f)(9)(iii) has also been modified to remove any potential 
misimpression that uncontrolled studies could demonstrate 
effectiveness.
    16. One comment questioned the rule's language about extrapolating 
adult data to pediatric patients. The comment said that the exact 
mechanism by which many psychiatric drugs work is not known, so that, 
for these drug products, extrapolation between adult and pediatric 
populations may be inaccurate and potentially hazardous. The comment 
noted that randomized controlled studies of tricyclic antidepressants 
in pediatric patients have raised questions regarding efficacy, while 
safety issues have been raised based on noncontrolled data indicating a 
potential risk, which might not have been clear based on adult data, of 
sudden cardiac death in pediatric patients using tricyclics.
    FDA agrees that extrapolation from adult experience is 
inappropriate, and thus unacceptable, in some cases. Extrapolation is 
not necessary under the rule, but is an alternative to the conduct of 
adequate and well-controlled studies in pediatric patients. In those 
cases where the pediatric use statement is based primarily on adequate 
and well-controlled studies in adults, additional information 
supporting pediatric use is usually needed, ordinarily including data 
on the pharmacokinetics of the drug in the pediatric population for 
determination of pediatric dosage. Other information, such as data from 
pharmacodynamic studies of the drug in pediatric patients, data from 
other studies supporting the safety or effectiveness of the drug in 
pediatric patients, pertinent premarketing or postmarketing studies or 
experience, may be necessary to show that the drug can be used safely 
and effectively in the pediatric population.
    17. One comment said that the preamble to the final regulation 
should clarify that ``other information'' supporting pediatric use in 
proposed Sec. 201.57(f)(9)(iii) need not be limited to data developed 
or sponsored by the NDA holder, but may include data such as reports of 
studies by academic researchers in peer-review journals that were 
prepared by persons who are not related to the NDA sponsor.
    The agency believes that no change is needed in revised 
Sec. 201.57(f)(9)(iv) because the section does not suggest that the 
data must have been developed or sponsored by the NDA holder.

D. Proposed Sec. 201.57(f)(9)(iv)

    FDA received no comments on this provision (renumbered as 
Sec. 201.57(f)(9)(v)), and has finalized it without change.

E. Proposed Sec. 201.57(f)(9)(v)

    Proposed Sec. 201.57(f)(9)(v) (renumbered as Sec. 201.57(f)(9)(vi)) 
provides, in part, that ``[i]f the requirements for a finding of 
substantial evidence to support a pediatric indication or a pediatric 
use statement have not been met for any pediatric population, this 
subsection of the labeling shall contain the following statement: 
`Safety and effectiveness in children have not been established.'''
    18. One comment expressed concern that this provision may create 
disincentives for sponsors to develop better information on pediatric 
use of their drugs. The comment suggested that FDA require mandatory 
phased-in safety testing and appropriate clinical studies of 
pharmaceuticals in the pediatric population. Alternatively, the comment 
recommended that FDA and manufacturers work to develop agreements 
whereby the manufacturer consents to carry out additional postapproval 
pediatric studies.
    FDA believes that the comment suggests actions beyond the scope of 
this rule. FDA encourages pediatric testing, and, as discussed in 
comment 4 in section III.C. of this document, has the authority to 
require pediatric studies. In some cases, FDA will require pediatric 
studies for approval or continued marketing. This rule, however, does 
not add new requirements for pediatric studies, but rather describes 
the kind of data that can be used to support labeling claims.

F. Proposed Sec. 201.57(f)(9)(vi)

    Proposed Sec. 201.57(f)(9)(vi) (renumbered as 
Sec. 201.57(f)(9)(vii)) provides ``[i]f the sponsor believes that none 
of the statements described in paragraphs (f)(9)(i) through (f)(9)(v) 
(renumbered as (f)(9)(ii) through (f)(9)(vi)) of this section is 
appropriate or relevant to the labeling of a particular drug, the 
sponsor shall provide reasons for omission of the statements and may 
propose alternative statement(s). FDA may permit use of an alternative 
statement.''
    19. One comment asserted that the proposal did not adequately 
address the problem of a large number of drugs that have been approved 
and marketed for years without pediatric usage information in their 
labeling, which are widely used in pediatric patients and for which 
there is substantial published literature regarding their pediatric 
use. The comment noted that proposed Sec. 201.57(f)(9)(vi) would impose 
on the sponsor the responsibility for providing information that would 
promote the safe and effective use of prescription drugs in pediatric 
patients and noted that the sponsor may have complex reasons for not 
necessarily wanting to include pediatric information in the labeling. 
The comment recommended that the final rule include a mechanism that 
would allow summary information from authoritative published literature 
to be added to the labeling of currently marketed drugs so this 
information would be available to the pediatric prescriber. It 
suggested that the rule should provide an option permitting 
``recognized authoritative medical experts or groups of experts'' to 
provide information to support pediatric information in the labeling in 
lieu of the sponsor.
    Another comment urged the agency to provide for the incorporation 
of supplemental indications into drug labeling based solely on 
information submitted by persons other than the sponsor. The comment 
said that changes should be made based on studies reported in peer-
reviewed medical literature, rather than relying on submissions by the 
sponsor. The comment stated that this was necessary to make the 
labeling of certain drugs, particularly anticancer agents, conform to 
the current state of medical knowledge. The comment noted that FDA 
restricts promotion of off-label uses, and third-party payers often 
take the position that agents that have no labeled indication for 
treatment of cancers in pediatric patients are experimental and 
therefore nonreimbursable, even though they may be safe and effective.
    The sponsor is primarily responsible for bringing forth evidence to 
support labeling changes. A third party could, however, provide 
evidence to persuade the agency to direct the sponsor to submit a 
labeling supplement. A study need not have been conducted by or on 
behalf of the sponsor in order to support a labeling change. The 
evidence to support labeling should continue to be of the type and 
quality that would ordinarily support labeling statements. Published 
literature on pediatric use may contribute to this evidence, and 
authoritative groups may suggest approaches, but the views of 
authoritative groups do not themselves represent sufficient evidence of 
effectiveness. With respect to the comment concerning reimbursements, 
the agency advises that reimbursements to patients are beyond the scope 
of the rule and FDA authority. However, FDA agrees with the underlying 
concern that appropriate indications be on the label so that 
practitioners understand how best to prescribe the drug for the 
patient's medical benefit.

G. Proposed Sec. 201.57(f)(9)(vii)

    Proposed Sec. 201.57(f)(9)(vii) (renumbered as 
Sec. 201.57(f)(9)(viii)) states ``[i]f the drug product contains one or 
more excipients that present an increased risk of toxic effects to 
neonates or other pediatric subgroups, a special note of this risk, 
generally in the `Contraindications,' `Warnings,' or `Precautions' 
section, shall be made.''
    20. Four comments expressed concern about this proposed 
requirement. One comment said that the data relating to the toxicity of 
excipients, including preservatives, are inconclusive, making the 
requirement inappropriate. The comment stated that FDA should encourage 
collection and analysis of data to enable specific determinations on 
the use of excipients and preservatives.
    Another comment asked FDA to clarify whether the proposed 
requirement that labeling contain statements about excipients that 
present an increased risk of adverse effects to the neonate or other 
pediatric subgroups was intended to reflect published literature or to 
be based on studies designed to show whether an increased risk exists. 
It added that it was not clear how or by whom a determination of 
increased risk would be established. The comment suggested that the 
final rule state that a sponsor can rely on existing information and is 
not required to conduct additional studies. The comment also suggested 
that, if additional studies were necessary, animal data be used rather 
than requiring clinical studies in neonates. It suggested that a 
standardized list could be developed jointly by industry and FDA.
    A third comment suggested that a requirement that any labeling 
identify any increased risk of toxic effects to neonates or other 
pediatric groups should not be interpreted as establishing a 
requirement that sponsors conduct toxicology or other studies to 
identify or quantify such risks. The comment also stated that the 
preamble to the final regulation should state whether the increased 
risk of toxic effects is limited to those established by human data or 
experience, or would also include those based on animal or in vitro 
models.
    A fourth comment noted that ANDA holders may use excipients 
different from those used by the reference listed drug. The comment 
suggested that ANDA holders should be required to provide specific 
information regarding excipients used.
    The final rule requires the labeling for a drug product containing 
one or more inactive ingredients that present an increased risk of 
toxic effects to neonates or other pediatric subgroups to note such 
risks in the ``Contraindications,'' ``Warnings,'' or ``Precautions'' 
section of the labeling. If toxicity data for the inactive 
ingredient(s) do not exist or are inconclusive, revised 
Sec. 201.57(f)(9)(viii) would not require the labeling to contain a 
statement about an increased risk to neonates or other pediatric 
subgroups. However, in such cases, FDA encourages applicants to collect 
and analyze data on inactive ingredients and preservatives that could 
represent a pediatric risk. These data may include human data, animal 
data, or data derived from in vitro models.
    FDA also notes that current regulations already require ANDA 
applicants whose inactive ingredients differ from those used in the 
reference listed drug to identify and characterize the inactive 
ingredients in a proposed drug product and to provide information 
demonstrating that such inactive ingredients do not affect the safety 
of the proposed drug product (see 21 CFR 314.94(a)(9)). Given these 
provisions, there is no reason to believe that the inactive ingredients 
used in a generic drug product are any less safe than those in the 
reference listed drug.
    The agency has determined that, for the purposes of this final 
rule, the terms ``excipient'' and ``inactive ingredient'' have the same 
meaning. However, because the agency generally uses the term ``inactive 
ingredient,'' the agency has, on its own initiative, amended proposed 
Sec. 201.57(f)(9)(vii) to refer to ``inactive ingredients'' instead of 
``excipients.''

V. Legal Authority

    FDA's revision to the ``Pediatric use'' subsection of prescription 
drug labeling is authorized by the Federal Food, Drug, and Cosmetic Act 
(the act) and by the Public Health Service Act (the PHS act). Section 
502(a) of the act prohibits false or misleading labeling of drugs, 
including, under section 201(n) of the act, failure to reveal material 
facts relating to potential consequences under customary conditions of 
use.
    Section 502(f) of the act requires drug labeling to have adequate 
directions for use and adequate warnings against use by the pediatric 
population where its use may be dangerous to health, as well as 
adequate warnings against unsafe dosage or methods or duration of 
administration, as are necessary to protect users.
    Section 502(j) of the act prohibits use of drugs that are dangerous 
to health when used in the manner suggested in their labeling. Drug 
products that do not meet the requirements of any paragraph of section 
502 of the act are deemed to be misbranded.
    In addition to the misbranding provisions, the premarket approval 
provisions of the act authorize FDA to require that prescription drug 
labeling provide the practitioner with adequate information to permit 
safe and effective use of the drug product. Under section 505 of the 
act, FDA will approve an NDA only if the drug is shown to be both safe 
and effective for its intended use under the conditions set forth in 
the drug's labeling. Section 701(a) of the act (21 U.S.C. 371(a)) 
authorizes FDA to issue regulations for the efficient enforcement of 
the act.
    Under Sec. 201.100(d) (21 CFR 201.100(d)) of FDA's labeling 
regulations, prescription drug products must bear labeling that 
contains adequate information under which licensed practitioners can 
use the drug safely for their intended uses. Section 201.57 describes 
specific categories of information, including information for drug use 
in selected subgroups of the general population, which must be present 
to meet the requirements of Sec. 201.100.
    In addition, under 21 CFR 314.125, FDA will not approve an NDA 
unless, among other things, there is adequate safety and effectiveness 
information for the labeled uses and the product labeling complies with 
the requirements of part 201 (21 CFR part 201).
    Section 351 of the PHS act provides legal authority for the agency 
to regulate the labeling and shipment of biological products. Licenses 
for biological products are to be issued only upon a showing that they 
meet standards ``designed to insure the continued safety, purity, and 
potency of such products'' prescribed in regulations (42 U.S.C. 
262(d)). The ``potency'' of a biological product includes its 
effectiveness (21 CFR 600.3(s)). Section 351(b) of the PHS act 
prohibits false labeling of a biological product. FDA's regulations in 
part 201 apply to all prescription drug products, including biological 
products.
    A drug product that is not in compliance with Sec. 201.57(f)(9) 
would be considered misbranded and an unapproved new drug under the 
act. A noncomplying product that is a biological product would, in 
addition, be considered falsely labeled and an unlicensed biological 
product under the PHS act.

VI. Implementation

    The primary purpose of the proposed rule was to revise the existing 
pediatric labeling requirements by expanding the basis on which 
information about use of a drug in the pediatric population may be 
included. The proposed rule would have required sponsors to comply with 
the pediatric use provisions 1 year after the date of publication of a 
final rule in the Federal Register.
    21. Several comments said that the proposed 1-year implementation 
period was too short. The comments claimed that extrapolating and 
reviewing data would be time consuming and that the agency would be 
unable to approve pediatric use labeling within 1 year. The comments 
suggested that the agency cooperate with industry to establish a 3-year 
implementation schedule, only require sponsors to submit revised 
labeling in 1 year, or make the rule effective in 2 years.
    The agency has carefully considered the comments and has revised 
the implementation schedule for the final rule. The agency will accept 
pediatric use information based on revised Sec. 201.57(f)(9) after 
January 12, 1995.
    Sponsors have a continuing obligation to maintain labeling that is 
truthful and comprehensive in accordance with Sec. 201.57, including 
Sec. 201.57(f)(9). Section 201.57(f)(9) requires labeling to contain at 
least one of the statements under Sec. 201.57(f)(9)(ii) through 
(f)(9)(vi), or to propose an alternative statement under 
Sec. 201.57(f)(9)(vii). The statement must accurately describe 
available data.
    Sponsors must, therefore, reexamine existing data to determine 
whether the ``Pediatric use'' subsection of the labeling can be 
modified based on adequate and well-controlled studies in adults and 
other information supporting pediatric use, and, if appropriate, submit 
a supplemental application to comply with new Sec. 201.57(f)(9)(iv) by 
December 13, 1996. A sponsor who does not believe that the disease and 
drug effects are similar in the pediatric and adult populations, or who 
believes that use in pediatric patients is otherwise not adequately 
supported by data, should not propose revised labeling under new 
Sec. 201.57(f)(9)(iv), and need not inform the agency of this 
conclusion.
    Therefore, FDA expects sponsors to examine available information 
and update pediatric labeling for their products, if appropriate. 
Sponsors should also examine data on the extent and nature of use of 
their products in pediatric patients. If FDA concludes that a 
particular drug is widely used, represents a safety hazard, or is 
therapeutically important in the pediatric population, 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 
well as an unapproved new drug or unlicensed biological product. (See 
21 U.S.C. 355 and 42 U.S.C. 262).
    Under the final rule, any new or revised pediatric indications, or 
statements on pediatric indications, or statements on pediatric use 
under the provisions of Sec. 201.57(f)(9)(ii) through (f)(9)(iv) would 
require FDA approval of a supplemental application in accordance with 
Sec. 314.70(b) or Sec. 601.12. Other changes to proposed 
Sec. 201.57(f)(9)(ii) through (f)(9)(iv) to add or strengthen 
precautions, contraindications, warnings, or adverse reactions or to 
add or strengthen dosage and administration instructions to increase a 
product's safety (for products other than biological products) could be 
put into effect at the time a supplement covering the change is 
submitted to FDA in accordance with Sec. 314.70(c). Minor editorial 
changes to products other than biological products may be made in 
accordance with Sec. 314.70(d).
    To comply with this rule, references to ``children'' in the 
``Pediatric use'' subsection of the insert labeling of products already 
being marketed must be changed, where appropriate, to ``Pediatric 
population'' or ``pediatric patients.'' The agency advises that after 
January 12, 1995, such changes must be made, no later than the first 
time that labeling is sent to the printers or ordered for reprinting to 
replenish old stocks of labeling. Such changes for products other than 
biological products are considered minor editorial changes and may be 
submitted in an annual report in accordance with Sec. 314.70(d).
    Any new or revised statement under Sec. 201.57(f)(9)(viii) 
regarding inactive ingredients that may be toxic to the neonate or 
other pediatric subgroup should be made in accordance with the 
provisions of Sec. 314.70(c) or Sec. 601.12 (21 CFR 601.12), as 
appropriate.
    All supplements containing pediatric use information and their 
mailing covers should be plainly marked ``Pediatric supplements.''
    For those products subject to section 351 of the PHS act, labeling 
changes should be made in accordance with Sec. 601.12. Persons who have 
questions regarding such changes and need guidance on whether a 
supplement is necessary should contact one of the following three 
divisions as appropriate: Office of Therapeutics Research and Review, 
Division of Application Review and Policy (HFM-585), 301-594-5109; 
Office of Vaccine Research and Review, Division of Vaccine and Related 
Product Applications (HFM-475), 301-594-2090; or Office of Blood 
Research and Review, Division of Blood Applications (HFM-370), 301-594-
2012; at the following address: Center for Biologics Evaluation and 
Research, Food and Drug Administration, 1401 Rockville Pike, suite 
200N, Rockville, MD 20852.
    22. One comment suggested that the rule would have a substantial 
economic impact, particularly if the agency adheres to the proposed 1-
year implementation period. The comment said that there are cost 
factors arising from the extensive resources required to reevaluate the 
available clinical study data and literature to extrapolate adult 
safety data to the pediatric age group or groups. The comment noted 
that drug studies in pediatric patients have additional costs not 
experienced with the adult population, and may, in some cases, require 
inpatient studies. The comment also claimed that encouraging pediatric 
studies prior to approval or as a Phase 4 commitment could lengthen the 
development process, slow drug approval, and thereby have an additional 
economic impact.
    The agency has considered the comment and has revised the 
implementation schedule for this final rule. The implementation 
schedule is discussed in section VI. of this document.
    The agency stresses that this rule does not require sponsors to 
conduct pediatric studies. The authority to require studies is found in 
the act and regulations already promulgated. Rather, this rule 
recognizes alternative methods of establishing substantial evidence to 
support pediatric labeling claims. Where a finding of substantial 
evidence to support a pediatric indication or a pediatric use statement 
has not been met for a specific subgroup or for any pediatric 
population, the sponsor must instead indicate that no data are 
available. If a sponsor believes that a pediatric use statement would 
be inappropriate or irrelevant to the labeling of a particular drug, it 
must provide a reason for omitting the statement. This rule does not 
affect any determination by the agency that pediatric studies are 
needed before or after approval for a new drug.

VII. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) 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

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
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). The agency believes that 
this final rule is consistent with the principles set out in the 
Executive Order. In addition, the final rule is not a significant 
regulatory action as defined by the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the final rule does not impose additional 
requirements for sponsors to conduct pediatric studies, the agency 
certifies that the final rule will not have a significant economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.
    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 part 201 is amended as follows:

PART 201--LABELING

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

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 508, 
510, 512, 530-542, 701, 704, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358, 
360, 360b, 360gg-360ss, 371, 374, 379e); secs. 215, 301, 351, 361 of 
the Public Health Service Act (42 U.S.C. 216, 241, 262, 264).

    2. Section 201.57 is amended by revising paragraph (f)(9) to read 
as follows:


Sec. 201.57  Specific requirements on content and format of labeling 
for human prescription drugs.

* * * * *
    (f) * * *
    (9) Pediatric use:
    (i) Pediatric population(s)/pediatric patient(s): For the purposes 
of paragraphs (f)(9)(ii) through (f)(9)(viii) of this setion, the terms 
``pediatric population(s)'' and ``pediatric patient(s)'' are defined as 
the pediatric age group, from birth to 16 years, including age groups 
often called neonates, infants, children, and adolescents.
    (ii) If there is a specific pediatric indication (i.e., an 
indication different from those approved for adults) that is supported 
by adequate and well-controlled studies in the pediatric population, it 
shall be described under the ``Indications and Usage'' section of the 
labeling, and appropriate pediatric dosage information shall be given 
under the ``Dosage and Administration'' section of the labeling. The 
``Pediatric use'' subsection shall cite any limitations on the 
pediatric indication, need for specific monitoring, specific hazards 
associated with use of the drug in any subsets of the pediatric 
population (e.g., neonates), differences between pediatric and adult 
responses to the drug, and other information related to the safe and 
effective pediatric use of the drug. Data summarized in this subsection 
of the labeling should be discussed in more detail, if appropriate, 
under the ``Clinical Pharmacology'' or ``Clinical Studies'' section. As 
appropriate, this information shall also be contained in the 
``Contraindications,'' ``Warnings,'' and elsewhere in the 
``Precautions'' sections.
    (iii) If there are specific statements on pediatric use of the drug 
for an indication also approved for adults that are based on adequate 
and well-controlled studies in the pediatric population, they shall be 
summarized in the ``Pediatric use'' subsection of the labeling and 
discussed in more detail, if appropriate, under the ``Clinical 
Pharmacology'' and ``Clinical Studies'' sections. Appropriate pediatric 
dosage shall be given under the ``Dosage and Administration'' section 
of the labeling. The ``Pediatric use'' subsection of the labeling shall 
also cite any limitations on the pediatric use statement, need for 
specific monitoring, specific hazards associated with use of the drug 
in any subsets of the pediatric population (e.g., neonates), 
differences between pediatric and adult responses to the drug, and 
other information related to the safe and effective pediatric use of 
the drug. As appropriate, this information shall also be contained in 
the ``Contraindications,'' ``Warnings,'' and elsewhere in the 
``Precautions'' sections.
    (iv) FDA may approve a drug for pediatric use based on adequate and 
well-controlled studies in adults, with other information supporting 
pediatric use. In such cases, the agency will have concluded that the 
course of the disease and the effects of the drug, both beneficial and 
adverse, are sufficiently similar in the pediatric and adult 
populations to permit extrapolation from the adult efficacy data to 
pediatric patients. The additional information supporting pediatric use 
must ordinarily include data on the pharmacokinetics of the drug in the 
pediatric population for determination of appropriate dosage. Other 
information, such as data from pharmacodynamic studies of the drug in 
the pediatric population, data from other studies supporting the safety 
or effectiveness of the drug in pediatric patients, pertinent 
premarketing or postmarketing studies or experience, may be necessary 
to show that the drug can be used safely and effectively in pediatric 
patients. When a drug is approved for pediatric use based on adequate 
and well-controlled studies in adults with other information supporting 
pediatric use, the ``Pediatric use'' subsection of the labeling shall 
contain either the following statement, or a reasonable alternative: 
``The safety and effectiveness of (drug name) have been established in 
the age groups -- to -- (note any limitations, e.g., no data for 
pediatric patients under 2, or only applicable to certain indications 
approved in adults). Use of (drug name) in these age groups is 
supported by evidence from adequate and well-controlled studies of 
(drug name) in adults with additional data (insert wording that 
accurately describes the data submitted to support a finding of 
substantial evidence of effectiveness in the pediatric population).'' 
Data summarized in the preceding prescribed statement in this 
subsection of the labeling shall be discussed in more detail, if 
appropriate, under the ``Clinical Pharmacology'' or the ``Clinical 
Studies'' section. For example, pediatric pharmacokinetic or 
pharmacodynamic studies and dose-response information should be 
described in the ``Clinical Pharmacology'' section. Pediatric dosing 
instructions shall be included in the ``Dosage and Administration'' 
section of the labeling. Any differences between pediatric and adult 
responses, need for specific monitoring, dosing adjustments, and any 
other information related to safe and effective use of the drug in 
pediatric patients shall be cited briefly in the ``Pediatric use'' 
subsection and, as appropriate, in the ``Contraindications,'' 
``Warnings,'' ``Precautions,'' and ``Dosage and Administration'' 
sections.
    (v) If the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for a particular pediatric population, the ``Pediatric use'' 
subsection of the labeling shall contain an appropriate statement such 
as ``Safety and effectiveness in pediatric patients below the age of 
(--) have not been established.'' If use of the drug in this pediatric 
population is associated with a specific hazard, the hazard shall be 
described in this subsection of the labeling, or, if appropriate, the 
hazard shall be stated in the ``Contraindications'' or ``Warnings'' 
section of the labeling and this subsection shall refer to it.
    (vi) If the requirements for a finding of substantial evidence to 
support a pediatric indication or a pediatric use statement have not 
been met for any pediatric population, this subsection of the labeling 
shall contain the following statement: ``Safety and effectiveness in 
pediatric patients have not been established.'' If use of the drug in 
premature or neonatal infants, or other pediatric subgroups, is 
associated with a specific hazard, the hazard shall be described in 
this subsection of the labeling, or, if appropriate, the hazard shall 
be stated in the ``Contraindications'' or ``Warnings'' section of the 
labeling and this subsection shall refer to it.
    (vii) If the sponsor believes that none of the statements described 
in paragraphs (f)(9)(ii) through (f)(9)(vi) of this section is 
appropriate or relevant to the labeling of a particular drug, the 
sponsor shall provide reasons for omission of the statements and may 
propose alternative statement(s). FDA may permit use of an alternative 
statement if FDA determines that no statement described in those 
paragraphs is appropriate or relevant to the drug's labeling and that 
the alternative statement is accurate and appropriate.
    (viii) If the drug product contains one or more inactive 
ingredients that present an increased risk of toxic effects to neonates 
or other pediatric subgroups, a special note of this risk shall be 
made, generally in the ``Contraindications,'' ``Warnings,'' or 
``Precautions'' section.
* * * * *

    Dated: November 15, 1994.
David A. Kessler,
Commissioner of Food and Drugs.
[FR Doc. 94-30238 Filed 12-12-94; 8:45 am]
BILLING CODE 4160-01-F