WAIS Document Retrieval[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