[Senate Report 108-84]
[From the U.S. Government Publishing Office]
Calendar No. 183
108th Congress Report
SENATE
1st Session 108-84
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PEDIATRIC RESEARCH EQUITY ACT OF 2003
_______
June 27 (legislative day, June 26), 2003.--Ordered to be printed
_______
Mr. Gregg, from the Committee on Health, Education, Labor, and
Pensions, submitted the following
R E P O R T
together with
ADDITIONAL VIEWS
[To accompany S. 650]
The Committee on Health, Education, Labor, and Pensions, to
which was referred the bill (S. 650) to authorize the Food and
Drug Administration to require certain research into drugs used
in pediatric patients, having considered the same, reports
favorably thereon with an amendment and recommends that the
bill (as amended) do pass.
CONTENTS
Page
I. Purpose and need for legislation.................................1
II. Summary..........................................................7
III. History of legislation and votes in committee....................9
IV. Explanation of bill and committee views..........................9
V. Regulatory Impact Statement.....................................12
VI. Application of law to the legislative branch....................12
VII. Cost estimate...................................................12
VIII.Section-by-section analysis.....................................13
IX. Additional views................................................17
X. Changes in existing law.........................................24
I. Purpose and Need for Legislation
As part of the Food and Drug Administration Modernization
Act (``FDAMA'') of 1997 (Pub. L. No. 105-115), Congress
established new incentives for drug manufacturers to conduct
pediatric research. These pediatric exclusivity provisions were
reauthorized and enhanced in 2002 by the Best Pharmaceuticals
for Children Act (``BPCA'') (Pub. L. No. 107-109). The
legislation works by providing an incentive of 6 months of
additional market exclusivity for sponsors in exchange for the
voluntary performance of clinical studies of drugs in the
pediatric population in response to a written request from FDA.
The BPCA also created programs administered by the NIH to issue
grants and contracts for researchers to conduct additional
pediatric studies with privately donated and publicly
appropriated funds. These laws have made headway in rectifying
the historical lack of clinical study data and labeling
information on the appropriate use of medicines in children.
Notwithstanding the progress that these prior pediatric
initiatives have produced, at least sixty-two percent of drugs
on the market remain unstudied and labeled for use in
children.\1\ However, that number reflects research in
accordance with the old Pediatric Rule. The authority for the
new Pediatric Research Authority is based on the percentage of
drugs projected to need pediatric labeling in light of ongoing
commitments and research. Further action is needed to ensure
that medications are adequately studied and labeled for use in
children. The committee has approved this legislation to
complement the existing voluntary pediatric exclusivity and NIH
study provisions by providing FDA with new, unprecedented
authority to require that drug manufacturers conduct pediatric
studies and submit pediatric assessments to FDA. On December 2,
1998, FDA published in the Federal Register (63 FR 66632-66672)
a final regulation known as the ``Pediatric Rule'' asserting
the authority to mandate pediatric testing in certain
circumstances. On October 17, 2002, a Federal court held that
FDA lacked the statutory authority to promulgate the Pediatric
Rule, and declared the Rule invalid. The legislation reported
by the committee now provides FDA with statutory authority to
require pediatric studies in certain defined circumstances.
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\1\ ``Testing Medications in Children,'' by Robert Steinbrook, M.D.
October 31, 2002. The New England Journal of Medicine.
---------------------------------------------------------------------------
There is a need to provide FDA legislative authority to
require pediatric testing because of the particular importance
of pediatric drug labeling. At the same time, the committee
recognizes that appropriate safeguards must accompany this
special grant of mandatory testing authority. The committee
intends that the new legislation, the pediatric exclusivity
incentive provisions, and the NIH study provisions of the BPCA
will work in a comprehensive and complementary fashion. This
legislation not only establishes provisions regarding new drugs
but also provides a default mechanism by which FDA can require
pediatric studies where the voluntary incentives and available
contracts and grants have not produced needed pediatric
treatment information.
Children suffer from many of the same diseases as adults
and are often treated with the same medicines. Yet certain
medicines have not been adequately studied and labeled for use
in children. Dosing children based merely on their lower weight
is often imprecise, since their bodies can metabolize medicines
differently than adults. Some drugs may have different adverse
side effects or toxicities in children than in adults, so
extrapolating safety or effectiveness for children for
medicines found to be safe and effective in adults may not be
appropriate. The lack of pediatric studies and labeling
information may lead to unintended medical errors and place
children at risk of being under-dosed or over-dosed with
medication. The lack of age-appropriate formulations (e.g.,
liquid form) can also make it difficult to give children and
infants prescribed amounts of a needed medication.
There are a variety of reasons why greater pediatric
testing has not been conducted historically despite its
importance as a matter of public health. Drug sponsors have
often lacked incentives to develop drugs for pediatric use
because of the comparatively small size of the pediatric market
for most products. Designing and completing pediatric research
trials can also present heightened scientific, ethical, and
logistical challenges, from recruiting sufficient study
participants to obtaining consent from parents or guardians to
developing formulations of a drug that can be administered to
younger patients. Pediatric research can also present greater
risks of legal liability for sponsors due, for example, to the
tolling of the statute of limitations as applied to children,
as well as other reasons. In the face of these obstacles,
before 1997, regulatory efforts to address the lack of
pediatric studies and insufficient labeling information had
been largely unsuccessful. In 1979, the FDA first issued a rule
requiring specific pediatric indications, if any, to be
described under the ``Indications and Usage'' section of the
label, with pediatric dose information included in the ``Dosage
and Administration'' section. The rule also required that
recommendations for pediatric use must be based on data from
adequate and well-controlled studies in the pediatric
population. The 1979 rule did not successfully encourage drug
sponsors to conduct pediatric studies and appropriately label
their products for children.
Accordingly, in 1994, the FDA published a final rule
requiring drug manufacturers to survey existing data and to
determine whether it would support pediatric labeling, and if
it did, to file a supplemental new drug application. FDA's
December 1994 Pediatric Plan sought to encourage manufacturers'
voluntary development of pediatric data both during the drug
development process and after marketing. Neither of these 1994
initiatives sufficiently increased the number of drugs with
adequate pediatric labeling.
In 1997, FDA proposed a Pediatric Rule by regulation
claiming authority to require manufacturers to submit needed
pediatric testing. Before FDA finalized the Pediatric Rule
Congress enacted the Better Pharmaceuticals for Children Act as
part of the Food and Drug Administration Modernization Act of
1997 (Pub. L. 105-115). This act created a new section 505A of
the FFDCA to provide a market incentive of 6 months of
additional exclusivity to drug sponsors for completing and
submitting studies of medicines in children in response to a
written request from FDA for the studies. The studies must
fairly respond to FDA's written request and be conducted in
accordance with a subsequent written agreement with the FDA, or
in the absence of such a written agreement in accordance with
commonly accepted scientific principles and protocols. The 6-
month pediatric exclusivity period is added to any patent or
exclusivity (such as orphan exclusivity or a 5- or 3-year
Hatch-Waxman exclusivity) on the drug.
The new incentives were intended to address the systemic
disincentives that had previously existed to conducting
pediatric studies. The results of the pediatric exclusivity
incentives to date are highly encouraging. As FDA reported to
Congress in 2001, the incentives have ``done more to generate
clinical studies and useful prescribing information for the
pediatric population than any other regulatory or legislative
process to date.''
Based in part on FDA's report, Congress reauthorized the
pediatric exclusivity provision in 2001 in the BPCA. In the
BPCA, Congress also provided an off-patent research fund at the
National Institutes of Health (NIH) for the study of off-patent
drugs and a process using first the Foundation of the National
Institutes of Health (Foundation) and then the research fund
for the study of drugs for which the manufacturers have
declined written requests to study the drug under the pediatric
exclusivity provision.
At the same time that the pediatric exclusivity provisions
were being put in place by legislation, FDA proceeded with
rulemaking proceedings for the Pediatric Rule, which the agency
finalized in 1998, and which became effective in 1999. The rule
remained in effect until October 17, 2002, when a Federal court
in the District of Columbia in the Association of American
Physicians and Surgeons, Inc. v. FDA case held that the rule
exceeded FDA's existing statutory authority, and declared the
rule invalid. In December 2002, the American Academy of
Pediatrics and the Elizabeth Glaser Pediatric AIDS Foundation,
which had participated as amici curiae in the district court,
were permitted to intervene and to appeal the case to the U.S.
Court of Appeals for the District of Columbia Circuit.
Prior to the court's decision, under FDA's Pediatric Rule,
each new drug application under section 505 of the FFDCA or
biologics license application under section 351 of the PHSA for
a new active ingredient, new indication (except indications for
which orphan designation has been granted), new dosage form,
new dosing regimen, or new route of administration was required
to contain certain data, unless there were grounds for a waiver
or deferral. Absent a waiver or deferral, the application was
required to contain data adequate to assess the safety and
effectiveness of the drug or biological product for its claimed
indications in all relevant pediatric subpopulations, and to
support dosing and administration for each pediatric
subpopulation for which the drug was safe and effective.
With respect to an already-marketed drug or biological
product that was used in a substantial number of pediatric
patients or that provided a meaningful therapeutic benefit over
existing treatments for pediatric patients and for which the
absence of adequate pediatric labeling could pose significant
risks to pediatric patients, the rule allowed FDA in these
compelling circumstances or ``high priority'' situations to
require the product's manufacturer or manufacturers to submit
an application containing data adequate to assess whether the
drug was safe and effective in pediatric populations for the
drug's approved indications, as well as adequate evidence to
support dosage and administration in some or all pediatric
populations, depending on the known or appropriate use of the
drug in those pediatric subpopulations. FDA was also able to
require the manufacturer or manufacturers to develop a
pediatric formulation for a drug product that represented a
meaningful therapeutic benefit over existing treatments for
pediatric populations for whom a pediatric formulation was
necessary, unless the manufacturer demonstrated that reasonable
attempts to produce a pediatric formulation necessary for that
age group had failed.
Full and partial waivers could also be obtained for both
new and already marketed products. A drug or biological product
for which a full or partial waiver was granted because there
was evidence that the product would be ineffective or unsafe in
pediatric populations was required to be labeled with that
information.
The Pediatric Rule was intended to work as a safety net to
(or as a backstop to) pediatric exclusivity. While the FDAMA
was intended to provide a substantial incentive for sponsors to
conduct some pediatric studies, the rule was intended to
increase the number of drug and biological products that have
adequate labeling. Because of the voluntary nature of the
incentive provided by the FDAMA the possibility arose that many
drugs may still have remained unstudied for pediatric uses.
The Pediatric Rule was both broader and narrower than the
pediatric exclusivity provision first enacted by Congress in
1997 and reauthorized by the BPCA in 2001. Most significantly,
the rule was broader than pediatric exclusivity because the
rule covered biological products approved under section 351 of
the Public Health Service Act while neither the pediatric
exclusivity provision nor the provisions for contracting for
pediatric studies at the Foundation and at NIH applies to
biological products.
In addition, the Pediatric Rule was broader than pediatric
exclusivity because it covered subsequent indications and
pediatric subpopulations that pediatric exclusivity, with its
associated contracting process at the Foundation and NIH, may
not. For example, if FDA did not include studies of newborns
and infants in a written request for a drug under the pediatric
exclusivity provision (because FDA believed it would not be
ethical or feasible to study these populations until older
populations had been studied), pediatric exclusivity was
generally not available to ensure that the drug would be
studied for these children if subsequent data made it apparent
the product was efficacious in the older population and
warranted studies in the younger populations. However, FDA
could have used the rule to require studies in those pediatric
subpopulations. Moreover, if the pediatric exclusivity
provision has been applied to a drug and subsequently the
drug's manufacturer seeks approval for a new indication;
pediatric exclusivity is generally not available to ensure that
the new indication will be studied in children. FDA, however,
could have invoked the rule to require that the new indication
be studied.
In some respects, the Pediatric Rule was narrower than
pediatric exclusivity and its associated contracting process at
the Foundation and NIH. For example, the rule could only have
been used for an indication for which the drug was approved or
approval was being sought in adults, whereas FDA may also use
pediatric exclusivity to request pediatric studies of an
indication not approved for adult use. In addition, the rule
applied only to drugs that would be used by a substantial
number of pediatric patients or that would provide a meaningful
therapeutic benefit for pediatric patients, whereas pediatric
exclusivity applies to drugs for which information relating to
the use of the drug in the pediatric population may produce
health benefits in that population.
Even given these differences in scope, the Pediatric Rule
and the pediatric exclusivity provision worked together to
ensure that a drug or biological product would be tested in and
labeled for children when appropriate. When their scopes
overlapped, Congress provided in section 505A(h) of the FFDCA
that any pediatric studies required by regulation also
satisfied the requirements for market exclusivity. There were
many drugs for which the rule and the incentive worked together
successfully to encourage a drug company to respond
affirmatively to FDA's request for pediatric studies.
But the rule and pediatric exclusivity did not always both
apply to a drug. FDA reports that, between April 1, 1999, when
the rule first became effective, and March 31, 2002, 404 new
drug applications and supplements fell within the scope of the
rule. For approximately 266 of these, manufacturers submitted,
or would have been required to submit, studies in one or more
pediatric age groups (the remaining received complete waivers,
typically as a result of safety concerns regarding the testing
of the drug in children or because the drug's approved
indication was not for a childhood disease). As of June 5,
2003, 129 submitted applications contained complete or partial
pediatric use information. Because pediatric exclusivity
incentives were not involved in these applications and these
were not drugs primarily developed for children, FDA attributes
67 of these submissions to the Pediatric Rule alone. By
comparison, FDA reports that as of June 2, 2003, 72 drugs have
been granted exclusivity and 9 have been denied exclusivity,
with 49 of these drugs currently labeled for use in the
pediatric population. It is therefore clear that the Pediatric
Rule and exclusivity have worked together to improve the
pediatric labeling of drugs and biological products that has
occurred since 1997, when Congress first provided for pediatric
exclusivity and FDA first proposed the Pediatric Rule.
At the same time, the court's decision in the Association
of American Physicians and Surgeons case invalidating the rule
highlights the tension between a mandatory study requirement
and the basic operation of the FFDCA, which leaves it to drug
sponsors to determine the claims they wish to make for a
product. In that case, the court held that FDA lacked authority
under the existing FFDCA to require that drug sponsors conduct
studies or develop formulations for claims or patient
populations that the sponsor is not seeking to include in
labeling for its product. In the court's words, FDA ``has
repeatedly stated that it may only regulate claimed uses of
drugs, not all foreseeable or actual uses.'' The court further
stated that it is a ``long-established foundation of federal
food and drug law'' that manufacturers determine the intended
uses of a product through the representations they make for the
product.
This legislation responds to the court's holding by
providing FDA new statutory authority to require pediatric
assessments. The authority granted by the legislation tracks
many elements of the former Pediatric Rule to ensure that the
progress produced by the incentive and the Pediatric Rule will
continue. There is a compelling basis for providing FDA such
authority because of the importance of ongoing pediatric
research. At the same time, the legislation establishes clear
limitations on the new authority to require pediatric
assessments to ensure that the unique needs of the pediatric
population continue to be met by the co-existence of the
incentive and the mandate.
II. Summary
1. The legislation gives FDA new statutory authority to require certain
pediatric tests
The legislation amends the Federal Food, Drug, and Cosmetic
Act (FFDCA) by adding a new section 505B, which provides FDA
with unprecedented statutory authority to require that sponsors
submit assessments regarding the use of drugs in pediatric
patients in certain specified circumstances. With respect to
drugs and biological products that are not yet approved, the
legislation provides that each new drug application under
section 505 of the FFDCA or biologics license application under
section 351 of the Public Health Service Act (PHSA) for a new
active ingredient, new indication (except for an orphan drug
indication, unless the Secretary requires otherwise by
rulemaking), new dosage form, new dosing regimen, or new route
of administration must contain data adequate to assess the
safety and effectiveness of the drug or biological product for
its claimed indications, and to support dosing and
administration for each pediatric subpopulation for which the
product is safe and effective. With respect to drugs and
biological products that are already marketed, the legislation
allows FDA in compelling circumstances, having made certain
findings and under certain conditions, to require that all
holders of approved applications for a product submit data on
safety and effectiveness and dosing and administration, after
having provided the holders with notice and an opportunity for
written response and a meeting.
Under the legislation, FDA is required to grant a full or
partial waiver of the pediatric data requirement for a drug or
biological product for certain reasons, including if the FDA
finds that necessary studies are impossible or highly
impractical (because, for example, the number of such pediatric
patients is so small or geographically dispersed); if there is
evidence strongly suggesting that the drug or biological
product would be ineffective or unsafe in the pediatric age
groups; or if the drug or biological product does not represent
a meaningful therapeutic benefit over existing therapies for
pediatric patients, the drug or biological product is not
likely to be used by a substantial number of pediatric
patients, and the absence of adequate labeling would not pose
significant risks to pediatric patients. Under the legislation,
when the Secretary grants a full or partial waiver because
there is evidence that the drug or biological product would be
ineffective or unsafe in pediatric populations, the information
must be included in the labeling for the drug or biological
product. Also, if the Secretary grants a partial waiver because
it is not possible to produce a pediatric formulation, the
waiver will only cover the pediatric age groups requiring that
formulation.
For new drugs, the Secretary, on his own initiative or by
request from the applicant, may defer the submission of some or
all of the assessments required under the amendment until a
specified date after the approval of the drug or after the
license for the biological product is granted if two
requirements are met. The first is met if the Secretary finds
that the drug is ready for approval for use in adults before
the pediatric studies are complete, or the pediatric studies
should be delayed until additional safety or effectiveness data
have been collected, or there is another appropriate reason for
deferral. The second is met if the applicant has submitted to
the Secretary certification for the grounds for deferring, a
description of the planned or ongoing studies, and evidence
that the studies are being conducted or will be conducted with
due diligence at the earliest possible time.
The legislation provides for meetings with a drug sponsor
during the investigational new drug process to discuss plans
and timelines of pediatric studies or requests for waiver or
deferral of pediatric studies.
2. The legislation clarifies the interaction of the new pediatric study
requirements with the pediatric exclusivity provisions when
applied to already-marketed drugs
The legislation provides that FDA may only impose pediatric
study requirements for already marketed drugs when the
pediatric exclusivity incentives provisions of section 505A of
the FFDCA and the NIH grant and contract programs of sections
409I and 499 of the PHSA have failed to yield necessary
pediatric information. FDA must first allow an opportunity for
these other BPCA mechanisms to work before invoking the new
pediatric study requirements for marketed drugs. The new
pediatric assessment requirement serves as a safety net to
ensure that certain critical studies are performed and labeling
adopted for marketed drugs if the other mechanisms from the
BPCA do not work. The pediatric assessment requirement is the
default, and not the first option. For already-marketed drugs,
the legislation requires that, before FDA may invoke the
Pediatric Research Authority (if it is applicable), FDA must
ask the manufacturer to conduct the study voluntarily under
section 505A of the FFDCA, which provides for 6 months of
market exclusivity for completing pediatric studies, or section
409I of the PHSA, and that the company does not agree or that
FDA does not receive a response. In addition, no later than 60
days after making such determination, FDA must certify that
there are insufficient funds to complete the study under
sections 409I and 499 and publish in the Federal Register that
no contract or grant has been awarded.
This requirement is not inconsistent with current FDA
practice.
3. The legislation provides for appropriate enforcement of the
requirement to submit timely pediatric assessments
The legislation provides that a drug or biological product
for which a pediatric assessment is not filed by the date
specified by FDA may be considered misbranded and subject to
relevant enforcement action. The Committee recognizes that the
agency has generally found seizure of a drug or biological
product to be an unsatisfactory remedy from a public health
perspective because it denies adequately studied populations
access to safe and effective medicines. As a result, the
Committee intends for seizure of a drug or biological product
to be used rarely, if at all, as a remedy for failure to
conduct required pediatric studies. This legislation makes
clear that the failure to submit required assessments shall not
be the basis for criminal proceedings, withdrawal of approval
as a new drug, or revocation of an approved biologics license.
Apart from those specifically exempted, however, all of the
Secretary's misbranding enforcement authorities are available.
The Secretary, as always, has discretion to choose the
appropriate enforcement action, as well as discretion to choose
whether to bring an enforcement action.
4. The legislation does not provide FDA with authority to require
studies or labeling for other populations or uses
The legislation states that section 505B does not provide
FDA with any authority to require pediatric assessments,
assessments regarding other populations, or assessments
regarding other uses of drugs or biological products except as
described in section 505B. As the Federal court stated in the
case challenging the legality of FDA's former Pediatric Rule
(Association of American Physicians and Surgeons, Inc. v. FDA),
it is the long-established foundation of our food and drug laws
that drug sponsors determine the ``intended uses'' of a
product, and that FDA does not regulate foreseeable or actual
uses of a product that the sponsor does not claim. The
legislation makes clear, however, that the new authority it
provides FDA does not go beyond the specified limits of section
505B.
III. History of Legislation and Votes in Committee
On March 18, 2003, Senator DeWine, for himself and Senators
Clinton, Gregg, Dodd and Kennedy introduced S.650, to amend the
Federal Food, Drug, and Cosmetic Act to authorize the FDA to
require certain research into drugs used in pediatric patients
if the voluntary mechanisms fail.
On March 19, 2003, the committee held an executive session
to consider S.650. Senator Gregg offered an amendment that the
committee passed by a vote of 11-10. The committee approved
S.650, as amended, by a unanimous vote of 21-0.
A. Amendment adopted
The Committee adopted 1 amendment by a vote of 11-10. This
amendment ensures the integration of the pediatric study
mechanisms under the BPCA and this new authority for the FDA.
The amendment further integrates the two programs by conforming
the dates on which the programs require reauthorization (see
for example section 505A(n) of the BPCA). By ensuring the co-
existence of both the incentive mechanisms and the mandate,
this amendment ensures FDA has every tool available to best
protect children.
IV. Explanation of Bill and Committee Views
New authority for FDA to require pediatric assessments
The legislation amends the FFDCA by adding a new section
505B.
The legislation assures that, when appropriate, new drugs
and biological products will be studied for safety and
effectiveness and dosing and administration in children before
new active ingredients, new indications, new dosage forms, new
dosing regimens, or new routes of administration are approved,
unless a deferral or waiver is obtained.
It also gives FDA the statutory authority to require that
already-marketed drugs and biological products be tested in
children for approved indications in compelling circumstances
if the agency finds, after certain conditions are met, that the
absence of adequate labeling could pose significant risks to
pediatric patients and that either (1) the drug or biological
product is used for a substantial number of pediatric patients
for the labeled indications, or (2) there is reason to believe
that the drug or biological product would represent a
meaningful therapeutic benefit over existing therapies for
pediatric patients for 1 or more of the claimed indications.
The legislation allows FDA to conclude that pediatric
effectiveness may be extrapolated from studies in adults,
usually supplemented with information about pediatric patients,
if the course of a disease and the effects of a drug are
sufficiently similar in adults and pediatric patients. The
legislation also allows FDA, on its own initiative or that of
an applicant, to defer submission of these data. Deferrals are
appropriate where either (1) the product is ready for use in
adults before pediatric studies are or will be complete, or (2)
there are ethical or clinical grounds to delay some or all of
the pediatric studies until additional safety or effectiveness
data are available.
Under the legislation, FDA may grant a full (or partial)
waiver of the pediatric assessment for a drug or biological
product under certain conditions, including if (1) necessary
studies are impossible or highly impractical, because, for
example, the number of patients (in that age group) is so small
or geographically dispersed (2) there is evidence strongly
suggesting that the drug or biological product would be
ineffective or unsafe in all pediatric age groups (or that
pediatric age group), (3) the drug or biological product does
not represent a meaningful therapeutic benefit over existing
therapies for pediatric patients (in that age group), the drug
or biological product is not likely to be used by a substantial
number of pediatric patients (in that age group), and the
absence of adequate labeling would not pose significant risks
to pediatric patients, or (4) attempts to develop a formulation
needed for certain age groups have failed. The legislation
requires that, when the Secretary grants a full or partial
waiver because there is evidence that the drug or biological
product would be ineffective or unsafe in pediatric
populations, the information must be included in the labeling
for the drug or biological product. If a partial waiver is
granted based on the ground that it is not possible to develop
a pediatric formulation, the waiver must cover only the
pediatric groups requiring that formulation.
Special provisions for already marketed drugs
The legislation states that FDA may not require pediatric
assessments for already marketed drugs unless FDA first issues
a written request under the pediatric exclusivity provisions of
section 505A and subsequently issues a request for contract or
grant proposals under the sections 409I or 499 of the Public
Health Service Act, as modified by the BPCA, before FDA may
invoke the Pediatric Research Authority (if it is applicable),
FDA must ask the manufacturer to conduct the study voluntarily
under section 505A of the FFDCA or section 409I of the PHSA and
that the company does not agree or that FDA does not receive a
response. Section 1 also clarifies that it does not change the
provisions in the BPCA that establish a process at NIH to
contract for studies to gather pediatric information. Section 1
further clarifies that use of the NIH contracting process does
not preclude FDA from using the Pediatric Research Authority
(``PRA'') to require that a manufacturer study an already-
marketed drug. Section 1 provides that the rule PRA may only be
invoked to study approved indications, even if the written
request is broader.
Section 505B does not affect whatever existing authority
FDA has to require studies, in addition to those required under
section 505B, of the safety and effectiveness of drugs and
biological products in pediatric populations. It also states
that FDA's authority, if any, to require studies for specific
populations other than the pediatric population shall be
exercised under the FFDCA as in effect on the day before the
date of enactment of the legislation.
The committee intends for FDA to continue to issue broad
written requests under section 505A of the FFDCA, section 409I
of the PHSA, and the authorities of this legislation to capture
the full scope of pediatric information desired, including for
all uses of the drug in the pediatric population for which
pediatric information may produce health benefits in that
population.
If the Secretary issues a written request for pediatric
studies of a drug under section 505A(d) of the FFDCA and the
recipient of the written request does not agree to conduct the
studies, under section 505A(d)(4)(B) the Secretary must refer
the drug for study to the Foundation for the National
Institutes of Health established under section 499 of the PHSA.
If the Secretary issues a written request for pediatric studies
under section 409I(c) of the PHSA and the recipient of the
written request does not agree to conduct the studies, section
409I(c)(2) requires the Secretary to issue a request for
contract proposals to conduct the pediatric studies. As
adequate funding is necessary for the contracting process to
work effectively, the committee does not intend for the
Secretary to issue requests for contract proposals without
regard to the availability of funding needed for those
proposals. At the same time, the committee also emphasizes that
the Secretary should issue written requests under section
505A(d) or section 409I without regard for whether there are
sufficient funds at the Foundation or NIH to fund the studies
should the recipient of the written request not agree to
conduct the studies. Therefore, insufficient funding to
contract for studies under section 409I will not preclude the
Secretary from requiring pediatric studies under the
legislation.
This amendment adds restrictions on the Secretary's
authority to invoke the PRA, including a restriction on use of
the authority before the Secretary has asked the company to
conduct the studies voluntarily and the company has either
declined or failed to respond.
This provision makes clear that before invoking section
505B, FDA must first ask a company to conduct the study of an
already-marketed drug voluntarily and these requests must fail
to yield the specified studies within the specified amount of
time when the company does not agree or FDA has not received a
response. FDA will then be able to invoke the new pediatric
research authority. For already marketed drugs, the committee
views section 505B as a provision that may apply only when the
other available voluntary mechanisms have been used but have
not resulted in the necessary studies.
Enforcement
The legislation provides that FDA has misbranding authority
with respect to a drug or biological product for which a
pediatric assessment is not filed by the date specified by FDA
may be considered misbranded and subject to relevant
enforcement action. The committee stresses that seizure is
generally an unsatisfactory remedy from a public health
perspective because it denies adequately studied populations
access to safe and effective medicines. As a result, the
committee intends for seizure to be used rarely, if at all, as
a remedy for failure to conduct required pediatric studies.
This legislation makes clear that the failure to submit
required assessments shall not be the basis for criminal
proceedings, withdrawal of approval as a new drug, or
revocation of an approved biologics license. The committee
intends for FDA to enforce the mandate by using its injunction
authority without affecting the availability of otherwise safe
and effective products for other patients.
No effect on current authority
The legislation states that section 505B does not provide
FDA with any authority to require pediatric assessments, or
assessments of other populations or uses, except as provided in
section 505B. The committee notes the court's holding in
Association of American Physicians and Surgeons, Inc. v. FDA
that FDA lacks the current authority to require pediatric
assessments. This legislation does not expand FDA's current
authority except as specifically enumerated in section 505B.
Integration with other pediatric provisions
The legislation is integrated with the pediatric
exclusivity provisions of section 505A of the FFDCA. The
committee views the two sections as working together in a
complementary fashion. The committee understands that section
505A is set to be reviewed for reauthorization in 2007, and
intends that the new section 505B be reviewed for
reauthorization at the same time.
V. Regulatory Impact Statement
The committee has determined that there will be minimal
increases in the regulatory burden imposed by this bill.
VI. Application of Law to the Legislative Branch
S. 650 adds section 505B to the Federal Food, Drug, and
Cosmetic Act to further improve the safety and efficacy of both
drugs and biological products for children. As such, it has no
application to the legislative branch.
VII. Cost Estimate
Due to time constraints the Congressional Budget Office
estimate was not included in the report. When received by the
committee, it will appear in the Congressional Record at a
later time.
VIII. Section-by-Section Analysis
Sec. 1. Short title
Section 1 entitles the Act the ``Pediatric Research Equity
Act of 2003.''
Sec. 2. Pediatric labeling of drugs and biological products
Section 2 amends the FFDCA by adding a new section 505B,
which grants FDA new authority to mandate pediatric data under
certain circumstances in order to reinforce the existing
provisions for generating pediatric information under the BPCA.
Section 505B(a): New Drugs and Biological Products
Section 505B(a)(1): With respect to new applications for
drugs and biological products, subsection (a)(1) provides that
each new drug application under section 505 of the FFDCA or
biologics license application under section 351 of the PHSA for
a new active ingredient, new indication (except for an orphan
drug indication--see section 505B(g)), new dosage form, new
dosing regimen, or new route of administration must include
assessments containing pediatric data.
Section 505B(a)(2): The assessments required by subsection
(a)(1) must contain data adequate to assess the safety and
effectiveness of the drug or biological product for its claimed
indications, and to support dosing and administration for each
pediatric subpopulation for which the product is safe and
effective. FDA may conclude, however, that pediatric
effectiveness can be extrapolated from studies in adults,
usually supplemented with information about pediatric patients,
if the course of a disease and the effects of a drug or
biological product are sufficiently similar in adults and
pediatric patients. FDA may also determine that studies are not
needed in each pediatric subpopulation if data from one
subpopulation can be extrapolated to another subpopulation.
Section 505B(a)(3): FDA may, on its own initiative or that
of an applicant, defer submission of pediatric data in certain
circumstances, provided the applicant submits certain
information to FDA. FDA may issue a deferral if it finds that
the product is ready for approval for use in adults before
pediatric studies are complete, pediatric studies should be
delayed until additional safety or effectiveness data have been
collected, or for other appropriate reasons. In order to secure
a deferral, the applicant must submit to FDA certification of
the grounds for deferring assessments, a description of planned
or ongoing studies, and evidence that the studies are being or
will be conducted diligently and as soon as possible.
Section 505B(a)(4): FDA shall grant, as appropriate, a full
waiver of the pediatric data requirement for a new drug or
biological product if: (1) necessary studies are impossible or
highly impracticable; (2) there is evidence strongly suggesting
that the drug or biological product would be ineffective or
unsafe in all pediatric age groups; or (3) the drug or
biological product does not represent a meaningful therapeutic
benefit over existing therapies for pediatric patients, and the
drug or biological product is not likely to be used by a
substantial number of pediatric patients. FDA shall grant, as
appropriate a partial waiver of the pediatric data requirement
for a new drug or biological product with respect to a
particular pediatric subpopulation if any of these 3 reasons
applies to that subpopulation, or if the applicant can
demonstrate that reasonable attempts to produce a pediatric
formulation necessary for that pediatric subpopulation have
failed. If a full or partial waiver is granted because of
evidence that the product would be ineffective or unsafe in the
pediatric population or a pediatric subpopulation, that
information shall be included in the product's labeling.
Section 505B(b): Marketed Drugs and Biological Products
Section 505B(b)(1): With respect to drugs and biological
products that are already marketed, FDA may, only after making
certain findings and under limited circumstances, require the
holder of an approved new drug application or biologics license
application to submit data on safety and effectiveness, dosing,
and administration as described in subsection (a)(2). Before
issuing such an order, FDA must find that the absence of
adequate labeling could pose significant risks to pediatric
patients and that either: (1) the drug or biological product is
used for a substantial number of pediatric patients for the
labeled indications; or (2) there is reason to believe that the
drug or biological product would represent a meaningful
therapeutic benefit over existing therapies for pediatric
patents for 1 or more of the claimed indications. FDA may
require this submission only after providing the holder with
notice and an opportunity for written response and a meeting,
which may include an advisory committee meeting.
Section 505B(b)(2): FDA shall grant, as appropriate a full
waiver of the pediatric data requirement for an already
marketed drug or biological product if: (1) necessary studies
are impossible or highly impracticable; or (2) there is
evidence strongly suggesting that the drug or biological
product would be ineffective or unsafe in all pediatric age
groups. FDA must grant a partial waiver of the pediatric data
requirement for specific pediatric subpopulations if the
applicant certifies and FDA finds that: (1) necessary studies
are impossible or highly impracticable for a specific
subpopulation; (2) there is evidence strongly suggesting that
the drug or biological product would be ineffective or unsafe
in that subpopulation; (3) the drug or biological product does
not represent a meaningful therapeutic benefit over existing
therapies for that subpopulation, the product is not likely to
be used by a substantial number of patients in that
subpopulation, and the lack of adequate labeling does not pose
significant risks to pediatric patients; or (4) the applicant
can demonstrate that reasonable attempts to produce a pediatric
formulation necessary for that pediatric subpopulation have
failed. If a waiver is granted because FDA finds it is not
possible to develop a pediatric formulation of the product, the
waiver will only over the pediatric groups requiring that
formulation. If a full or partial waiver is granted because the
product would be ineffective or unsafe in the pediatric
population or a pediatric subpopulation, that information shall
be included in the product's labeling.
Section 505B(b)(3): Subsection (b)(3) clarifies that FDA
may only impose the pediatric study requirements for already
marketed drugs when the provisions of section 505A in the
FFDCA, offering pediatric exclusivity incentives, and the NIH
grant and contract programs of sections 409I and 499 of the
PHSA, have both proven to be unsuccessful in producing the
necessary pediatric information. If requests are made on the
two provisions, and the secretary determines that there are
insufficient funds under sections 409I and 499 of the PHSA, the
assessment may be required. The assessment may also be required
if the Secretary certifies that no grant has been awarded and
not less than 270 days have passed since the certification
there are sufficient funds to conduct the study. This
precondition ensures that the existing provisions of the BPCA
will be utilized and establishes required pediatric studies as
a default. Before invoking the agency's new authority to
mandate pediatric studies under this Act, FDA must first have
made a written request for the manufacturer to conduct the
study voluntarily under section 505A of the FFDCA or section
409I of the PHSA, to which the manufacturer either did not
agree or that FDA did not receive a timely response. Subsection
(b)(3) also clarifies that the mandatory pediatric study
provisions of this Act do not alter the provisions in the BPCA
that establish a process at NIH to contract for studies to
gather pediatric information. Before requiring submission of
pediatric data of an already marketed drug product, subsection
(b)(3) requires FDA to certify either that insufficient funds
are available to contract for studies, or that sufficient funds
are available but no contract or grant has been awarded within
the specified time frame.
Section 505B(c): A product will be considered to offer a
``meaningful therapeutic benefit'' over existing therapies if
FDA determines that it would represent a significant
improvement in the treatment, diagnosis, or prevention of a
disease compared with already marketed products labeled for
that use in the relevant pediatric subpopulation, or that it is
in a class of products or is used for an indication for which
there is a need for additional options.
Section 505B(d): FDA has misbranding authority over a drug
or biological product for which a pediatric assessment is not
filed by the date specified by FDA but FDA does not have the
ability to bring criminal proceedings or to withdrawal of
approval as a new drug or revocation of an approved biologics
license.
Section 505B(e): FDA shall meet with the sponsor of a drug
or biological product at appropriate times during the
investigational process to discuss plans and timelines for
pediatric studies or requests for waivers or deferrals of
pediatric studies.
Section 505B(f): Subsection (f) clarifies that this Act
provides no authority for FDA to require pediatric studies of
any drug or biological product, or studies regarding any other
populations or uses of a drug or biological product, except
under the conditions provided for in this Act.
Section 505B(g): The pediatric data requirements of this
Act do not apply to any drug for an indication for which
``orphan'' drug designation has been granted under Section 526
of the FFDCA, unless FDA determines otherwise by regulation.
Section 505B(h): Subsection (h) ties the new authority
provided under this Act to the pediatric exclusivity provisions
codified at section 505A of the FFDCA. This Act provides, in
essence, that the new authority to require pediatric studies
shall only remain in effect so long as the pediatric
exclusivity provisions also remain in effect. The pediatric
exclusivity provisions currently have a sunset date of October
1, 2007.
Sec. 3. Technical corrections
Sec. 4. Effective date
Section 4 makes the Act effective on October 17, 2002.
IX. Additional Views
ADDITIONAL VIEWS OF SENATORS DeWINE, KENNEDY, DODD, CLINTON, MIKULSKI,
MURRAY, AND REED
Relationship between this legislation, the Pediatric Rule, and
pediatric exclusivity
The report asserts that the Pediatric Rule was intended to
work as a ``backstop'' to pediatric exclusivity. This assertion
is clearly incorrect, particularly in relation to new drugs and
biological products. The final rule states that it is
``designed to ensure that new drugs and biological products
contain adequate pediatric labeling for the approved
indications at the time of, or soon after, approval. The final
rule establishes a presumption that all new drugs and biologics
will be studied in pediatric patients.'' (Federal Register/Vol.
63, No. 231, December 2, 1998, p. 66634) Neither the intent
conveyed by FDA nor FDA's implementation of the rule supports
the report's contention that the rule was intended to work as a
``backstop'' to pediatric exclusivity or to be employed only to
fill the gaps in coverage left by the exclusivity.
The report also incorrectly asserts that the authors of
this legislation introduced S. 650 ``to authorize the FDA to
require certain research into drugs used in pediatric patients
if the voluntary mechanisms fail.'' While this assertion may
hold for already-marketed products, it is simply incorrect in
relation to new drugs and biological products. Nothing in the
bill requires FDA to wait until the voluntary mechanisms have
failed before invoking the pediatric studies requirement for
new drugs or biologics.
Ted Kennedy.
Chris Dodd.
Barbara A. Mikulski.
Jack Reed.
Hillary Rodham Clinton.
Patty Murray.
Mike DeWine.
ADDITIONAL VIEWS OF SENATORS KENNEDY, DODD, CLINTON, MIKULSKI, MURRAY,
AND REED
Enforcement
The report states that FDA has misbranding authority with
respect to a drug or biological product for which a pediatric
assessment is not filed by the date specified by FDA. While
this statement helps to clarify that the bill is intended to
give FDA the authority to deem a product misbranded solely on
the basis that an assessment was not submitted in accordance
with the requirements of the legislation, it is not a
substitute for, and must be accompanied by, a modification to
the legislation.
The legislation states that if a sponsor fails to submit an
assessment, the product may be considered misbranded. The use
of the word ``may'' in relation to the ability of FDA to
determine a product to be misbranded or adulterated is an
anomaly in the FFDCA. The use of ``may be considered
misbranded'' rather than ``shall be deemed misbranded'', as
occurs elsewhere in the FFDCA, may create uncertainty about the
Committee's intent to give FDA full and unambiguous authority
to enforce the requirements of S. 650.
The Committee clearly intends for a court to interpret this
language as giving FDA new misbranding authority, the use of
the word ``may'' creates a risk that a court will apply an
interpretation that would be contrary to the Committee's
intent. Given that the impetus for this legislation was to
unequivocally provide FDA with the exact statutory authority to
require pediatric studies that the federal district court ruled
in October 2002 it lacked, it is critical that the statutory
language be modified and that ``may'' be replaced with
``shall'' to comport with the term used elsewhere in the FFDCA.
In addition, the report incorrectly asserts that FDA has
misbranding authority when a pediatric assessment is not filed
by the date specified by FDA. In accordance with the plain
language of the legislation, any misbranding authority extends
to bringing an enforcement action for failure to comply with
any of the requirements of the legislation related to the
submission of assessments or requests for approval of a
pediatric formulation, not just timeliness.
Effective date
We are also concerned that the current effective date in S.
650 may allow significant numbers of pediatric studies to be
lost in the gap between the requirements of the Pediatric Rule
and the requirements of this legislation, despite the stated
intent of the Committee that the Rule and the legislation be
``seamless.'' Because the current language applies the testing
requirement to drug applications submitted on or after October
17, 2002, we are concerned that several categories of
applications will not be subject to the requirements of S. 650.
For example, the legislation may be incorrectly read as not
applying to applications submitted to FDA before October 17,
2002, and pending before FDA on October 17, 2002. Also, it is
not clear that sponsors with applications approved before
October 17, 2002, that made commitments under the Rule to
conduct pediatric studies at a later date would have to honor
those commitments. According to FDA, in just the category of
deferred studies alone, 192 studies may be lost. Also according
to FDA, in total, more than 300 pediatric studies will be lost
if the effective date of the legislation is not corrected to
ensure a seamless transition of the pediatric testing
requirement from the Pediatric Rule to this legislation.
We have raised the need to modify this provision, and the
enforcement provision discussed previously, to ensure that S.
650 fully and seamlessly restores the protections of the 1998
Pediatric Rule. Although we would have preferred that these two
issues had been resolved in the language of the bill reported
out of the Committee, we are amenable to addressing them in a
manager's amendment prior to full Senate consideration of this
legislation. We expect that we can address and resolve these
issues quickly so that this important legislation may be
considered by the full Senate without further delay.
Sunset
The bill was amended by a majority of the committee to
sunset the bill's requirements on October 1, 2007, the same
date the pediatric exclusivity authority is sunset. The report
asserts that this ``integration'' of the two programs ensures
their co-existence, which ``ensures FDA has every tool
available to best protect children.''
Some proponents of the amendment may believe that it
ensures that the pediatric exclusivity provision will be
reauthorized in 2007. They may also believe, as we do, that the
pediatric exclusivity provision has been extremely beneficial
to children's health and that it deserves serious consideration
for reauthorization in 2007.
But it is simply not the case that requiring the
reauthorization of the pediatric assessment authority in 2007
promotes children's health. Instead, it seriously undermines
the goal of the legislation, which is to address the
uncertainty surrounding pediatric drug testing and to eliminate
the threat that children's protections may lapse. In addition,
the requirement for reauthorization leaves open the possibility
that the pediatric assessment requirement will be weakened, or
will be eliminated altogether. This possibility shows the
amendment as an anathema to the purpose of the legislation and
the purpose of protecting children.
Adults can count on FDA to assure trials for drug safety
and efficacy without returning to Congress every 5 years for
that assurance. Because of the amendment, children will be
denied that same protection. Once again they will have to seek
legislation to assure what adults now take for granted, that
the drugs we use have been shown to be safe and effective for
us to use.
Intended use
FDA's Pediatric Rule to require the study in children of
drugs and biological products for their approved uses was held
to be invalid by a federal district judge. The report makes
several references to and quotations from this ill-considered
and obviously errant decision about how intended uses of FDA-
regulated products are made and about the scope of FDA's
authority under the FFDCA. We write to clarify these issues
because we believe that both the court and the report
fundamentally misconstrue the authority of FDA, and that FDA
already has the authority to require studies on subpopulations
that will use a drug. Although the district court concluded
that FDA did not have sufficient authority to require studies
on off-label uses, it ignored, without discussion, FDA's
determination that use in children is not an ``off-label'' use,
just as use in women is not an ``off-label'' use. It is a use
in an expected, major subpopulation, which may raise some
different questions than use in other populations. In choosing
to ignore the agency's central argument in support of its
authority, the decision fails to answer the question of the
agency's pre-existing authority to require pediatric studies,
or studies on other subpopulations.
The report also asserts, relying exclusively on the
district court opinion, that it is ``the long-established
foundation of our food and drug laws'' that drug sponsors
determine the ``intended uses'' of a product, and that FDA does
not regulate foreseeable or actual uses of a product that the
sponsor does not claim.'' Although this assertion is often
found in the arguments of the pharmaceutical industry in
attempts to weaken FDA's long-standing authority, it is
contradicted by decades of FDA practice and numerous judicial
opinions from higher courts.
When determining a product's intended use, it is well-
established that FDA may consider evidence other than express
claims that a product is intended to have a certain effect.
Indeed, the text of the FFDCA, longstanding FDA regulations,
the legislative history of the Medical Device Amendments of
1976, appeals court decisions, and FDA's regulatory practice
fully support this view.
For example, sections 201(g)(1)(C) and (h)(3) of the FFDCA
make ``intended'' effects, not ``market claims,'' the decisive
factor. Although market claims are one important way to
establish a product's intended effect, other circumstances can
establish a product's intended effect, and nothing in the text
of the operative definitions bars FDA from relying on such
evidence.
Longstanding FDA regulations provide that ``intended use''
refers to ``the objective intent of the persons legally
responsible for labeling,'' and may be determined not only by
``labeling claims'' and ``advertising matter,'' but also by
other ``oral or written statements'' made by persons legally
responsible for the labeling; ``the circumstances surrounding
the distribution of the article''; ``the circumstances that the
article is, with the knowledge of [the manufacturer], * * *
offered and used for a purpose for which it is neither labeled
nor advertised''; and (4) evidence that ``a manufacturer knows,
or has knowledge of facts that would give him notice'' that a
drug or device ``is to be used'' for purposes other than those
for which the manufacturer offered the product. 21 CFR 201.128
and 801.4.
A House report on the Medical Device Amendments of 1976,
Pub. L. No. 94-295, supports the view that ``intended'' effects
are not limited to manufacturer claims. That report
specifically rejected the proposition that a claim is
dispositive and explained that the Secretary ``may consider
actual use of a product in determining whether or not it is a
device.'' H.R. Rep. No. 853, 94th Cong., 2d Ses. 14 (1976).
Many appeals courts have agreed that a manufacturer's
intent with respect to effects or use may be determined on the
basis of all relevant circumstances, including consumer use,
not simply a manufacturer's market claims. National Nutritional
Foods Ass'n v. Mathews, 557 F.2d 325, 334 (2d Cir. 1977)
(intent may be determined from any relevant source, including
consumer use); United States v. An Article * * * Consisting of
* * * 216 Cartoned Bottles, 409 F.2d 734, 739, 742 (2d Cir.
1969) (the intended use of a product may be determined from its
label, accompanying labeling, promotional material, advertising
and any other relevant source, including consumer use); United
States v. Storage Spaces Designated Nos. ``8'' & ``49'', 777
F.2d 1363, 1366 (9th Cir. 1985), (manufacturer intent may be
derived from any relevant source), cert. denied, 479 U.S. 1086
(1987); Action on Smoking & Health v. Harris, 655 F.2d 236,
239-240 (D.C. Cir. 1980) (consumer use can be relevant in
determining manufacturer intent).
Finally, in its administration of the FFDCA, FDA has
treated products as drugs or devices, despite the absence of
explicit market claims. Among other products, FDA has treated
as drugs or devices: (1) cosmetics containing hormones based on
the absence of any legitimate cosmetic purpose for the
hormones; (2) toothpaste containing fluoride because fluoride
is widely accepted as an anti-cavity agent and affects the
structure of the tooth; (3) thyroid-containing food supplements
based on the recognized physiological effects of thyroid
products; (4) interferon based on media coverage touting it as
a possible miracle cure; (5) novelty condoms based on their
likely use as prophylactics; (6) sun screen products based on
consumer expectations that they will provide protection against
the harmful effects of the sun on the body; and (7) tanning
booths based on the known effects of ultraviolet rays on the
structure or function of the body. In each of these cases, FDA
found that the product was intended for use as a drug or a
device based on the inherent nature of the product, its
predominant use or effects, or both.
Some of these cases required FDA to determine whether a
product was under its jurisdiction at all, while others
required FDA to determine whether a product would be regulated
merely as a cosmetic or food or instead as a drug or device. It
is also the case that FDA may use its authority to regulate the
off-label use of a drug or a device. Indeed, when a particular
off-label use becomes widespread or endangers public health,
FDA must investigate it thoroughly and take appropriate action
to protect the public, including requiring a change in the
product's labeling to warn against or approve the unapproved
use, seeking substantial evidence to substantiate its use,
restricting the distribution of the drug, or even withdrawing
approval of the drug and removing it from the market.
Accordingly, some of the withdrawals of approved drugs in
the last several years, including fenfluramine hydrochloride,
dexfenfluramine hydrochloride, mibefradil dihydrochloride, and
bromfenac sodium, have followed after off-label use of the
drugs was associated with patient injuries and deaths. FDA has
required the relabeling of other drugs, such as the anti-
arrhythmic drugs, Encainide and Flecainide, because of wide-
spread off-label use that was shown to have caused hundreds if
not thousands of deaths. Indeed, numerous drugs carry FDA-
required warnings about dangerous or unsubstantiated off-label
uses. If FDA lacked authority over off-label uses, it would not
be able to require warnings about such uses.
These cases illustrate most dramatically the importance of
FDA determining a product's intended use by any available
evidence, and not only by marketing claims, because nothing
less than the public health and safety depends upon it.
It is therefore incorrect both as a matter of law and
practice that the report asserts that FDA may only consider a
manufacturer's claimed uses for its product when determining
intended use. This legislation is limited to addressing FDA's
authority to require pediatric testing of drugs. It does not
alter or affect the authority of FDA under the FFDCA with
respect to testing of drugs in other subpopulations, such as
women and minorities, or for other uses, including off-label
uses in appropriate circumstances. And it is outrageous that
the report has been used as an opportunity to promote an
unfounded and dangerous view of FDA's authority in these other
areas.
Seizures
The report also asserts that FDA's seizure authority is an
unsatisfactory remedy from a public health perspective because
it denies adequately studied populations access to a safe and
effective drug. It would be true that a mass seizure of all of
a manufacturer's drug or biological product would disrupt
patient access to a safe and effective product. It is not the
case, however, that seizure of the lots of a drug in one
warehouse, when there are other stores of the drug that are not
seized, would disrupt consumer access to a drug or biological
product.
In fact, such a seizure may be a particularly appropriate
way for FDA to seek enforcement of a statutory or regulatory
requirement, because it allows patients to have access to
products that the government has not seized and because the
manufacturer's interest in being able to distribute the seized
product can facilitate quicker resolution of the dispute. In
the instances under consideration here, that would mean quicker
completion of pediatric studies that a manufacturer has failed
to complete in a timely way.
The legislation clearly authorizes FDA to use the full
range of its enforcement authorities with the single exception
of criminal penalties. Under S. 650, the agency retains its
full discretion as to whether to use its seizure authority.
Ted Kennedy.
Chris Dodd.
Barbara A. Mikulski.
Hillary Rodham Clinton.
Patty Murray.
Jack Reed.
X. Changes in Existing Law
In compliance with rule XXVI paragraph 12 of the Standing
Rules of the Senate, the following provides a print of the
statute or the part or section thereof to be amended or
replaced (existing law proposed to be omitted is enclosed in
black brackets, new matter is printed in italic, existing law
in which no change is proposed is shown in roman):
PEDIATRIC RESEARCH EQUITY ACT OF 2003
* * * * * * *
FEDERAL FOOD, DRUG, AND COSMETIC ACT
Sec. 505. (a) No person shall introduce or deliver for
introduction into interstate commerce any new drug, unless an
approval of an application filed pursuant to subsection (b) or
(j) is effective with respect to such drug.
(b)(1) Any person may file with the Secretary an
application with respect to any drug subject to the provisions
of subsection (a). Such persons shall submit to the Secretary
as a part of the application (A) full reports of investigations
which have been made to show whether or not such drug is safe
for use and whether such drug is effective in use; (B) a full
list of the articles used as components of such drug; (C) a
full statement of the composition of such drug; (D) a full
description of the methods used in, and the facilities and
controls used for, the manufacture, processing, and packing of
such drug; (E) such samples of such drug and of the articles
used as components thereof as the Secretary may require; (F)
[and (F)] specimens of the labeling proposed to be used for
such drug. The applicant shall file with the application the
patent number and the expiration date of any patent which
claims the drug for which the applicant submitted the
application or which claims a method of using such drug and
with respect to which a claim of patent infringement could
reasonably be asserted if a person not licensed by the owner
engaged in the manufacture use, or sale of the drug. If a
application is filed under this subsection for a drug and a
patent which claims such drug or a method of using such drug is
issued after the filing date but before approval of the
application, the applicant shall amend the application to
include the information required by the preceding sentence.
Upon approval of the application, the Secretary shall publish
information submitted under the two preceding sentences. The
Secretary shall, in consultation with the Director of the
National Institutes of Health and with representatives of the
drug manufacturing industry, review and develop guidance, as
appropriate, on the inclusion of women and minorities in
clinical trials required by clause (A)[.] and (G) any
assessments required under section 505B.
SEC. 505A. [21 U.S.C. 355A] PEDIATRIC STUDIES OF DRUGS.
(a) Definitions.--* * *
* * * * * * *
(b) Market Exclusively for New Drugs.--* * *
* * * * * * *
(1)(A)(i) * * *
* * * * * * *
(2)(A) if the drug is the subject of--
(i) a listed patent for which a certification
has been submitted under subsection
(b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of section
505 and for which pediatric studies were
submitted prior to the expiration of the patent
(including any patent extensions); or
(ii) a listed patent for which a
certification has been submitted under
subsections (b)(2)(A)(iii) or
(j)(2)(A)(vii)(III) of section 505,
the period during which an application may not be approved
under section 505(c)(3) or section [505(j)(4)(B)] 505(j)(4)(B)
shall be extended by a period of six months after the date the
patent expires (including any patent extensions); or
(B) if the drug is the subject of a listed patent for which
a certification has been submitted under subsection
(b)(2)(A)(iv) or (j)(2)(A)(vii)(IV) of section 505, and in the
patent infringement litigation resulting from the certification
the court determines that the patent is valid and would be
infringed, the period during which an application may not be
approved under section 505(c)(3) or section [505(j)(4)(B)]
505(j)(4)(B) shall be extended by a period of six months after
the date the patent expires (including any patent extensions).
(c) Market Exclusively for Already-Marketed Drugs.--* * *
(1)(A)(i) * * *
(2)(A) if the drug is the subject of--
(i) a listed patent for which a certification
has been submitted under subsection
(b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of section
505 and for which pediatric studies were
submitted prior to the expiration of the patent
(including any patent extensions); or
(ii) a listed patent for which a
certification has been submitted under
subsection (b)(2)(A)(iii) or
(j)(2)(A)(vii)(III) of section 505,
the period during which an application may not be approved
under section 505(c)(3) or section [505(j)(4)(B)] 505(j)(4)(B)
shall be extended by a period of six months after the date the
patent expires (including any patent extensions); or
(B) if the drug is the subject of a listed patent for
which a certification has been submitted under
subsection (b)(2)(A)(iv) or (j)(2)(A)(vii)(IV) of
section 505, and in the patent infringement litigation
resulting from the certification the court determines
that the patent is valid and would be infringed, the
period during which an application may not be approved
under section 505(c)(3) or section [505(j)(4)(B)]
505(j)(4)(B) shall be extended by a period of six
months after the date the patent expires (including any
patent extensions).
* * * * * * *
(h) Relationship to [Regulations] Pediatric Research
Requirements.--Notwithstanding any other provision of law, if
any pediatric study is required [pursuant to regulations
promulgated by the Secretary] by a provision of law (including
a regulation) other than this section and such study meets the
completeness, timeliness, and other requirements of this
section, such study shall be deemed to satisfy the requirement
for market exclusivity pursuant to this section.
(i) Labeling Supplements.--* * *
* * * * * * *
(i) Labeling Supplements.--
(1) Priority status for pediatric supplements.--* * *
(A) * * *
(B) * * *
(2) Dispute resolution.--
(A) Request for labeling change and failure
to agree.--If the Commissioner determines that
an application with respect to which a
pediatric study is conducted under this section
is approvable and that the only open issue for
final action on the application is the reaching
of an agreement between the sponsor of the
application and the Commissioner on appropriate
changes to the labeling for the drug that is
the subject of the application, not later than
180 days after the date of submission of the
application--
(i) the Commissioner shall request
that the sponsor of the application
make any labeling change that the
Commissioner determines to be
appropriate; and
(ii) if the sponsor of the
application does not agree to make a
labeling change requested by the
Commissioner, the Commissioner shall
refer the matter to the Pediatric
[Advisory Subcommittee of the Anti-
Infective Drugs] Advisory Committee.
(B) Action by the pediatric [advisory
subcommittee of the anti-effective drugs]
advisory committee.--Not later than 90 days
after receiving a referral under subparagraph
(A)(ii), the Pediatric [Advisory Subcommittee
of the Anti-Infective Drugs] Advisory Committee
shall--
(i) review the pediatric study
reports; and
(ii) make a recommendation to the
Commissioner concerning appropriate
labeling changes, if any.
(C) Consideration of recommendations.--The
Commissioner shall consider the recommendations
of the Pediatric [Advisory Subcommittee of the
Anti-Infective Drugs] Advisory Committee and,
if appropriate, not later than 30 days after
receiving the recommendation, make a request to
the sponsor of the application to make any
labeling change that the Commissioner
determines to be appropriate.
(D) Misbranding.--If the sponsor of the
application, within 30 days after receiving a
request under subparagraph (C), dose not agree
to make a labeling change requested by the
Commissioner, the Commissioner may deem the
drug that is the subject of the application to
be misbranded.
(E) No effect on authority.--Nothing in this
subsection limits the authority of the United
States to bring an enforcement action under
this Act when a drug lacks appropriate
pediatric labeling. Neither course of action
(the Pediatric [Advisory Subcommittee of the
Anti-Infective Drugs] Advisory Committee
process or an enforcement action referred to in
the preceding sentence) shall preclude, delay,
or serve as the basis to stay the other course
of action.
* * * * * * *
Best Pharmaceuticals for Children Act
HISTORICAL AND STATUTORY NOTES
Pediatric [Pharmacology] Therapeutics Advisory Committee.
Pub. L. 117-109, Sec. 14, Jan. 4, 2002, 115 Stat. 1419,
provided that:
``(a) In general.--The Secretary of Health and Human
Services shall, under section 222 of the Public Health Service
Act [42 U.S.C. 217a),] (42 U.S.C. 217a) or other appropriate
authority, convene and consult an advisory committee on
pediatric [pharmacology] therapeutics (referred to in this
section as the ``advisory committee'').
``(b) Purpose.--
``(1) In general.--The advisory committee shall
advise and make recommendations to the Secretary,
through the Commissioner of Food and Drugs [and in
consultation with the Director of the National
Institutes of Health] on matters relating to pediatric
[pharmacology] therapeutics.
``(2) Matters included.--The matters referred to in
paragraph (1) include--
``(A) pediatric research conducted under
sections 351, 409I, and 499 of the Public
Health Service Act [42 U.S.C. A. Sec. Sec. 262,
284m, and 290b] and sections 501, 502, 505, and
[505A] 505B of the Federal Food, Drug, and
Cosmetic Act [21 U.S.C.A. Sec. Sec. 351, 352,
355, and 355a];
``(B) identification of research priorities
related to pediatric [pharmacology]
therapeutics and the need for additional
treatments of specific pediatric diseases or
conditions; and
``(C) the ethics, design, and analysis of
clinical trials related to pediatric
[pharmacology] therapeutics.
* * * * * * *
SEC. 15. PEDIATRIC SUBCOMMITTEE OF THE ONCOLOGIC DRUGS ADVISORY
COMMITTEE.
(a) Clarification of Authorities.--
(1) In general.--* * *
(A) * * *
(B) * * *
(C) * * *
(2) Membership.--
(A) In general.--The Secretary shall appoint
not more than 11 voting members to the
Pediatric Subcommittee from the membership of
the Pediatric [Pharmacology] Advisory Committee
and the Oncologic Drugs Advisory Committee.
* * * * * * *
SEC. 16. REPORT ON PEDIATRIC EXCLUSIVITY PROGRAM.
* * * * * * *
(1) The effectiveness of section 505A of the Federal Food,
Drug, and Cosmetic Act and section 409I of the Public Health
Service Act (as added by this Act) in ensuring that medicines
used by children are tested and properly labeled, including--
(A) * * *
(B) * * *
(C) the number of drugs for which testing is being
done, exclusivity granted, and labeling changes
required, including the date pediatric exclusivity is
granted and the date labeling changes are made and
which labeling changes required the use of the dispute
resolution process established pursuant to the
amendments made by this Act, together with a
description of the outcomes of such process, including
a description of the disputes and the recommendations
of the Pediatric [Advisory Subcommittee of the Anti-
Infective Drugs] Advisory Committee.
* * * * * * *
SEC. 17. ADVERSE-EVENT REPORTING.
(a) Toll-Free Number in Labeling.--* * *
(1) * * *
(2) * * *
(3) * * *
(b) Drugs With Pediatric Market Exclusivity.--
(1) In general.--During the one year beginning on the
date on which a drug receives a period of market
exclusivity under 505A of the Federal Food, Drug, and
Cosmetic Act, any report of an adverse event regarding
the drug that the Secretary of health and Human
Services receives shall be referred to the Office of
Pediatric Therapeutics established under section 6 of
this Act. In considering the report, the Director of
such Office shall provide for the review of the report
by the Pediatric [Advisory Subcommittee of the Anti-
Infective Drugs] Advisory Committee, including
obtaining any recommendations of such subcommittee
regarding whether the Secretary should take action
under the Federal Food, Drug, and Cosmetic Act in
response to the report.
* * * * * * *
SEC. 505B. RESEARCH INTO PEDIATRIC USES FOR DRUGS AND BIOLOGICAL
PRODUCTS.
(a) New Drugs and Biological Products.--
(1) In general.--A person that submits an application
(or supplement to an application)--
(A) under section 505 for a new active
ingredient, new indication, new dosage form,
new dosing regimen, or new route of
administration; or
(B) under section 351 of the Public Health
Service Act (42 U.S.C. 262) for a new active
ingredient, new indication, new dosage form,
new dosing regimen, or new route of
administration;
shall submit with the application the assessments
described in paragraph (2).
(2) Assessments.--
(A) In general.--The assessments referred to
in paragraph (1) shall contain data, gathered
using appropriate formulations for each age
group for which the assessment is required,
that are adequate--
(i) to assess the safety and
effectiveness of the drug or the
biological product for the claimed
indications in all relevant pediatric
subpopulations; and
(ii) to support dosing and
administration for each pediatric
subpopulation for which the drug or the
biological product is safe and
effective.
(B) Similar course of disease or similar
effect of drug or biological product.--
(i) In general.--If the course of the
disease and the effects of the drug are
sufficiently similar in adults and
pediatric patients, the Secretary may
conclude that pediatric effectiveness
can be extrapolated from adequate and
well-controlled studies in adults,
usually supplemented with other
information obtained in pediatric
patients, such as pharmacokinetic
studies.
(ii) Extrapolation between age
groups.--A study may not be needed in
such pediatric age group if data from 1
age group can be extrapolated to
another age group.
(3) Deferral.--On the initiative of the Secretary or
at the request of the applicant, the Secretary may
defer submission of some or all assessments required
under paragraph (1) until a specified date after
approval of the drug or issuance of the license for a
biological product if--
(A) the Secretary finds that--
(i) the drug or biological product is
ready for approval for use in adults
before pediatric studies are complete;
(ii) pediatric studies should be
delayed until additional safety or
effectiveness data have been collected;
or
(iii) there is another appropriate
reason for deferral; and
(B) the applicant submits to the Secretary--
(i) certification of the grounds for
deferring the assessments;
(ii) a description of the planned or
ongoing studies; and
(iii) evidence that the studies are
being conducted or will be conducted
with due diligence and at the earliest
possible time.
(4) Waivers.--
(A) Full Waiver.--On the initiative of the
Secretary or at the request of an applicant,
the Secretary shall grant a full waiver, as
appropriate, of the requirement to submit
assessments for a drug or biological product
under this subsection if the applicant
certifies and the Secretary finds that--
(i) necessary studies are impossible
or highly impracticable (because, for
example, the number of patients is so
small or the patients are
geographically dispersed);
(ii) there is evidence strongly
suggesting that the drug or biological
product would be ineffective or unsafe
in all pediatric age groups; or
(iii) the drug or biological
product--
(I) does not represent a
meaningful therapeutic benefit
over existing therapies for
pediatric patients; and
(II) is not likely to be used
in a substantial number of
pediatric patients.
(B) Partial waiver.--On the initiative of the
Secretary or at the request of an applicant,
the Secretary shall grant a partial waiver, as
appropriate, of the requirement to submit
assessments for a drug or biological product
under this subsection with respect to a
specific pediatric age group if the applicant
certifies and the Secretary finds that--
(i) necessary studies are impossible
or highly impracticable (because, for
example, the number of patients in that
age group is so small or patients in
that age group are geographically
dispersed);
(ii) there is evidence strongly
suggesting that the drug or biological
product would be ineffective or unsafe
in that age group;
(iii) the drug or biological
product--
(I) does not represent a
meaningful therapeutic benefit
over existing therapies for
pediatric patients in that age
group; and
(II) is not likely to be used
by a substantial number of
pediatric patients in that age
group; or
(iv) the applicant can demonstrate
that reasonable attempts to produce a
pediatric formulation necessary for
that age group have failed.
(C) Pediatric formulation not possible.--If a
waiver is granted on the ground that it is not
possible to develop a pediatric formulation,
the waiver shall cover only the pediatric
groups requiring that formulation.
(D) Labeling requirement.--If the Secretary
grants a full or partial waiver because there
is evidence that a drug or biological product
would be ineffective or unsafe inn pediatric
populations, the information shall be included
in the labeling for the drug or biological
product.
(b) Marketed Drugs and Biological Products.--
(1) In general.--After providing notice in the form
of a letter and an opportunity for written response and
a meeting, which may include an advisory committee
meeting, the Secretary may (by order in the form of a
letter) require the holder of an approved application
for a drug under section 505 or the holder of a license
for a biological product under section 351 of the
Public Health Service Act (42 U.S.C. 262) to submit by
a specified date the assessment described in subsection
(a)(2) if the Secretary finds that--
(A)(i) the drug or biological product is used
for a substantial number of pediatric patients
for the labeled indications; and
(ii) the absence of adequate labeling could
pose significant risks to pediatric patients;
or
(B)(i) there is reason to believe that the
drug or biological product would represent a
meaningful therapeutic benefit over existing
therapies for pediatric patients for 1 or more
of the claimed indications; and
(ii) the absence of adequate labeling could
pose significant risks to pediatric patients.
(2) Waivers.--
(A) Full waiver.--At the request of an
applicant, the Secretary shall grant a full
waiver, as appropriate, of the requirement to
submit assessments under this subsection if the
applicant certifies and the Secretary finds
that--
(i) necessary studies are impossible
or highly impracticable (because, for
example, the number of patients in that
age group is so small or patients in
that age group are geographically
dispersed); or
(ii) there is evidence strongly
suggesting that the drug or biological
product would be ineffective or unsafe
in all pediatric age groups.
(B) Partial waiver.--At the request of an
applicant, the Secretary shall grant a partial
waiver, as appropriate, of the requirement to
submit assessments under this subsection with
respect to a specific pediatric age group if
the applicant certifies and the Secretary finds
that--
(i) necessary studies are impossible
or highly impracticable (because, for
example, the number of patients in that
age group is so small or patients in
that age group are geographically
dispersed);
(ii) there is evidence strongly
suggesting that the drug or biological
product would be ineffective or unsafe
in that age group;
(iii)(I) the drug or biological
product--
(aa) does not represent a
meaningful therapeutic benefit
over existing therapies for
pediatric patients in that age
group; and
(bb) is not likely to be used
in a substantial number of
pediatric patients in that age
group; and
(II) the absence of adequate labeling
could not pose significant risks to
pediatric patients; or
(iv) the applicant can demonstrate
that reasonable attempts to produce a
pediatric formulation necessary for
that age group have failed.
(C) Pediatric formulation not possible.--If a
waiver is granted on the ground that it is not
possible to develop a pediatric formulation,
the waiver shall cover only the pediatric
groups requiring that formulation.
(D) Labeling requirement.--If the Secretary
grants a full or partial waiver because there
is evidence that a drug or biological product
would be ineffective or unsafe in pediatric
populations, the information shall be included
in the labeling for the drug or biological
product.
(3) Relationship to other pediatric provisions.--
(A) No assessment without written request.--
No assessment may be required under paragraph
(1) for a drug subject to an approved
application under section 505 unless--
(i) the Secretary has issued a
written request for a related
pediatrict study under section 505A(c)
of this Act or section 409I of the
Public Health Service Act (42 U.S.C.
284m);
(ii)(I) if the request was made under
section 505A(c)--
(aa) the recipient of the
written request does not agree
to the request; or
(bb) the Secretary does not
receive a response as specified
under section 505A(d)(4)(A); or
(II) if the request was made under
section 409I of the Public Health
Service Act (42 U.S.C. 284m)--
(aa) the recipient of the
written request does not agree
to the request; or
(bb) the Secretary does not
receive a response as specified
under section 409I(c)(2) of
that Act; and
(iii)(I) the Secretary certifies
under subparagraph (B) that there are
insufficient funds under sections 409I
and 499 of the Public Health Service
Act (42 U.S.C. 284m, 290b) to conduct
the study; or
(II) the Secretary publishes in the
Federal Register a certification that
certifies that--
(aa) no contract or grant has
been awarded under section 409I
or 499 of the Public Health
Service Act (42 U.S.C. 284m,
290b); and
(bb) not less than 270 days
have passed since the date of a
certification under
subparagraph (B) that there are
sufficient funds to conduct the
study.
(B) No agreement to request.--Not later than
60 days after determining that no holder will
agree to the written request (including a
determination that the Secretary has not
received a response specified under section
505A(d) of this Act or section 409I of the
Public Health Service Act (42 U.S.C. 284m), the
Secretary shall certify whether the Secretary
has sufficient funds to conduct the study under
section 409I or 499 of the Public Health
Service Act (42 U.S.C. 284m 290b), taking into
account the prioritization under section 409I.
(c) Meaningful Therapeutic Benefit.--For the purposes of
paragraph (4)(A)(iii)(I) and (4)(B)(iii)(I) of subsection (a)
and paragraphs (1)(B)(i) and (2)(B)(iii)(I)(aa) of subsection
(b), a drug or biological product shall be considered to
represent a meaningful therapeutic benefit over existing
therapies if the Secretary estimates that--
(1) if approved, the drug or biological product would
represent a significant improvement in the treatment,
diagnosis, or prevention of a disease, compared with
marketed products adequately labeled for that use in
the relevant pediatric population; or
(2) the drug or biological product is in a class of
products or for an indication for which there is a need
for additional options.
(d) Submission of Assessments.--If a person fails to submit
an assessment described in subsection (a)(2), or a request for
approval of a pediatric formulation described in subsection (a)
or (b), in accordance with applicable provisions of subsections
(a) and (b)--
(1) the drug or biological product that is the
subject of the assessment or request may be considered
misbranded and subject to relevant enforcement action
(except that the drug or biological product shall not
be subject to action under section 303); but
(2) the failure to submit the assessment or request
shall not be the basis for a proceeding--
(A) to withdraw approval for a drug under
section 505(e); or
(B) to revoke the license for a biological
product under section 351 of the Public Health
Service Act (42 U.S.C. 262).
(e) Meetings.--Before and during the investigational
process for a new drug or biological product, the Secretary
shall meet at appropriate times with the sponsor of the new
drug or biological product to discuss--
(1) information that the sponsor submits on plans and
timelines for pediatric studies; or
(2) any planned request by the sponsor for waiver or
deferral of pediatric studies.
(f) Scope of Authority.--Nothing in this section provides
to the Secretary any authority to require a pediatric
assessment of any drug or biological product, or any assessment
regarding other populations or uses of a drug or biological
product, other than the pediatric assessments described in this
section.
(g) Orphan Drugs.--Unless the Secretary requires otherwise
by regulation, this section does not apply to any drug for an
indication for which orphan designation has been granted under
section 526.
(h) Integration With Other Pediatric Studies.--The
authority under this section shall remain in effect so long as
an application subject to this section may be accepted for
filing by the Secretary on or before the date specified in
section 505A(n).
* * * * * * *
PUBLIC HEALTH SERVICE ACT
Part F--Licensing--Biological Products and Clinical Laboratories
Subpart 1--Biological Products
REGULATION OF BIOLOGICAL PRODUCTS
Sec. 351. (a)(1) * * *
(2)(A) The Secretary shall establish, by regulation,
requirements for the approval, suspension, and revocation of
biologics licenses.
(B) Pediatric Studies.--A person that submits an
application for a license under this paragraph shall submit to
the Secretary as part of the application any assessments
required under section 505B of the Federal Food, Drug, and
Cosmetic Act.
[(B)] (C) The Secretary shall approve a biologics license
application--
(i) on the basis of a demonstration that--
(I) the biological product that is the
subject of the application is safe, pure, and
potent; and
(II) the facility in which the biological
product is manufactured, processed, packed, or
held meets standards designed to assure that
the biological product continues to be safe,
pure, and potent; and
(ii) if the applicant (or other appropriate person)
consents to the inspection of the facility that is the
subject of the application, in accordance with
subsection (c).
* * * * * * *
SEC. 409I. [284M] PROGRAM FOR PEDIATRIC STUDIES OF DRUGS.
(a) List of Drugs for Which Pediatric Studies Are Needed.--
(1) In general.--* * *
* * * * * * *
(c) Process for Contracts and Labeling Changes.--
(1) Written request to holders of approved
application for drugs lacking exclusivity.--The
Commissioner of Food and Drugs, in consultation with
the Director of the National Institutes of Health, may
issue a written request (which shall include a
timeframe for negotiations for an agreement) for
pediatric studies concerning a drug identified in the
list described in subsection (a)(1)(A) (except clause
(iv)) to all holders of an approved application for the
drug under section 505 of the Federal Food, Drug and
Cosmetic Act. Such a written request shall be made in a
manner equivalent to the manner in which a written
request is made under subsection (a) or (b) of section
505A of the Federal Food, Drug and Cosmetic Act,
including with respect to information provided on the
pediatric studies to be conducted pursuant to the
request.
(2) Requests for contract proposals.--* * *
* * * * * * *
(7) Requests for labeling change.--During the 180-day
period after the date on which a report is submitted
under paragraph (6)(A), the Commissioner of Food and
Drugs shall--
(A) review the report and such other data as
are available concerning the safe and effective
use in the pediatric population of the drug
studied;
(B) negotiate with the holders of approved
applications for the drug studied for any
labeling changes that the Commissioner of Food
and Drugs determines to be appropriate and
requests the holders to make; and
(C)(i) place in the public docket file a copy
of the report and of any requested labeling
changes; and
(ii) publish in the Federal Register a
summary of the report and a copy of any
requested labeling changes.
(8) Dispute resolution.--
(A) Referral to pediatric [advisory
subcommittee of the anti-infective drugs]
advisory committee.--If, not later than the end
of the 180-day period specified in paragraph
(7), the holder of an approved application for
the drug involved does not agree to any
labeling change requested by the Commission of
Food and Drugs under that paragraph, the
Commissioner of Food and Drugs shall refer the
request to the Pediatric [Advisory Subcommittee
of the Anti-Infective Drugs] Advisory Committee
(B) Action by the pediatric [advisory
subcommittee of the anti-infective drugs]
advisory committee.--Not later than 90 days
after receiving a referral under subparagraph
(A), the Pediatric [Advisory Subcommittee of
the Anti-Infective Drugs] Advisory Committee
shall--
(i) review the available information
on the safe and effective use of the
drug in the pediatric population,
including study reports submitted under
this section; and
(ii) make a recommendation to the
Commissioner of Food and Drugs as to
appropriate labeling changes if any.
(9) FDA determination.--Not later than 30 days after
receiving a recommendation from the Pediatric [Advisory
Subcommittee of the Anti-Infective Drugs] Advisory
Committee under paragraph (8)(B)(ii) with respect to a
drug, the Commissioner of Food and Drugs shall consider
the recommendation and, if appropriate, make a request
to the holders of approved applications for the drug to
make any labeling change that the Commissioner of Food
and Drugs determines to be appropriate.
(10) Failure to agree.--If a holder of an approved
application for a drug, within 30 days after receiving
a request to make a labeling change under paragraph
(9), does not agree to make a requested labeling
change, the Commissioner may deem the drug to be
misbranded under the Federal Food, Drug, and Cosmetic
Art (21 U.S.C. 301 et seq.).
(11) No effect on authority.--Nothing in this
subsection limits the authority of the United States to
bring an enforcement action under the Federal Food,
Drug, and Cosmetic Act when a drug lacks appropriate
pediatric labeling. Neither course of action (the
Pediatric [Advisory Subcommittee of the Anti-Infective
Drugs] Advisory Committee process or an enforcement
action referred to in the preceding sentence) shall
preclude, delay, or serve as the basis to stay the
other course of action.
* * * * * * *