[Senate Report 108-84]
[From the U.S. Government Publishing Office]



                                                       Calendar No. 183
108th Congress                                                   Report
                                 SENATE
 1st Session                                                     108-84

======================================================================



 
                 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.
---------------------------------------------------------------------------
    \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.

           *       *       *       *       *       *       *


                                
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