[Senate Report 107-79]
[From the U.S. Government Publishing Office]
Calendar No. 184
107th Congress Report
SENATE
1st Session 107-79
======================================================================
BEST PHARMACEUTICALS FOR CHILDREN ACT
_______
October 4, 2001.--Ordered to be printed
_______
Mr. Kennedy, from the Committee on Health, Education, Labor, and
Pensions, submitted the following
R E P O R T
[To accompany S. 838]
The Committee on Health, Education, Labor, and Pensions, to
which was referred the bill (S. 838) to amend the Federal Food,
Drug, and Cosmetic Act to improve the safety and efficacy of
pharmaceuticals for children, having considered the same,
reports favorably thereon with an amendment and recommends that
the bill (as amended) do pass.
CONTENTS
Page
I. Purpose and summary of the bill..................................1
II. Background and need for the legislation..........................3
III. Legislative history and committee action.........................5
IV. Explanation of legislation and committee views...................7
V. Cost estimate...................................................11
VI. Application of law to the legislative branch....................11
VII. Regulatory impact statement.....................................11
VIII.Section-by-section analysis.....................................12
IX. Changes in existing law.........................................14
I. Purpose and Summary of the Bill
To address a longstanding concern that only 20 percent of
prescription medications on the market have been tested and
approved for use in children, Congress enacted a market
incentive law, commonly referred to as the ``pediatric
exclusivity'' or ``pediatric testing'' incentive, as part of
the Food and Drug Administration Modernization Act of 1997
(FDAMA Pub. L. 105-115). By providing 6 months of additional
market exclusivity on a drug for a holder of an approved
application under section 505(b)(1) of the Federal Food, Drug,
and Cosmetic Act (FFDCA) that has completed pediatric studies
of the drug when requested by the Food and Drug Administration
(FDA), Congress sought to find an approach that would be more
successful than previous efforts to have the pharmaceutical
industry study the safety and effectiveness in children of
drugs that, without such studies, would be prescribed ``off-
label'' to children.
The Best Pharmaceuticals for Children Act, S. 838, is
designed to continue the successes of and improve upon the
current pediatric exclusivity law in generating studies of
medicines for children. Drug companies have studied several
drugs in children and those drugs now carry appropriate
pediatric labeling because of the FDAMA pediatric exclusivity
provision. It remains the case, however, that drug
manufacturers have tested only 25 percent of medicines in
children, and so FDA has approved only that small percentage of
today's drugs for use in children. The FDA, the General
Accounting office (GAO), and others have issued reports
describing how highly effective the pediatric exclusivity law
has been in generating pediatric studies and useful new
labeling information. They have also, however, expressed
concerns about areas that need to be improved. This legislation
seeks to stimulate additional pediatric testing and to provide
for the testing of off-patent medicines for children, for
timely labeling changes, and for testing in neonates so that
they also benefit from additional studies and labeling
information.
1. the legislation authorizes the testing of drugs lacking patent or
other exclusivity protections
The current pediatric testing incentive was not designed to
stimulate pediatric studies for medicines that lack patent
terms or other market exclusivities because there is no patent
or other exclusivity on the drug to which to attach a 6-month
period of additional market exclusivity. An FDA analysis of
1994 data found that 6 of 10 drugs most commonly prescribed for
children were off-patent. This legislation creates an off-
patent research fund to provide for studies of such drugs by
pediatric pharmacology research units (PPRUs) or other
entities, after the manufacturers of the drug have declined a
right of first refusal to conduct the studies of the drug.
2. the legislation provides for timely labeling changes for drugs that
are granted exclusivity and that are studied through the off-patent
research fund
The Prescription Drug User Fee Act (PDUFA), as amended by
FDAMA, exempts supplements for a new indication for use in
pediatric populations from the user fee that must ordinarily
accompany filings with FDA. This provision has meant that
manufacturers have not paid user fees when they submit their
reports of studies in response to a request from FDA
forpediatric studies, as such reports are submitted in the form of
supplements to their new drug applications. This legislation removes
this exemption by requiring companies to pay PDUFA fees at the time
they submit pediatric supplements with reports of their completed
studies to the FDA. It thereby helps ensure that FDA will have
sufficient resources to review pediatric labeling supplements as
``priority supplements.''
The legislation also provides a procedure for timely
labeling of branded drugs granted pediatric exclusivity and for
drugs tested under the off-patent research fund. If a
manufacturer refuses to make labeling changes requested by FDA,
the agency must refer the issue to its Pediatric Advisory
subcommittee of the Anti-Infective Drugs Advisory Committee,
which then makes a recommendation to the agency about a
labeling change. After considering this recommendation, FDA may
request an appropriate labeling change and, if the company
refuses to make the requested change, the FDA may deem the
company's drug to be misbranded.
3. THE LEGISLATION CLARIFIES THAT WRITTEN REQUESTS FOR PEDIATRIC
STUDIES MAY INCLUDE NEONATES WHEN APPROPRIATE
The legislation clarifies that written requests for
pediatric testing my include neonates (newborns to 1 month old)
in all appropriate cases.
4. THE LEGISLATION PROVIDES FOR THE PUBLIC DISSEMINATION OF PEDIATRIC
TEST INFORMATION BEFORE LABELING CHANGES ARE MADE
The legislation requires the FDA to make public a summary
of the medical and clinical pharmacology reviews of the
pediatric studies, except that confidential commercial
information or trade secrets contained in the pediatric
supplement would not be disclosed.
5. THE LEGISLATION PROVIDES FOR THE INSTITUTE OF MEDICINE TO REVIEW
FEDERAL REGULATIONS, REPORTS AND RESEARCH INVOLVING CHILDREN
The legislation recognizes the need to review current legal
and ethical safeguards for children involved in clinical
research and provides for a study of this matter by the
Institute of Medicine (IOM). The IOM, with the involvement of
pediatric experts, must complete its review and report to
Congress with recommendations in 2 years.
II. Background and Need for the Legislation
Although children suffer from many of the same diseases as
adults and are often treated with the same medicines, the
pharmaceutical industry has studied and labeled for use in
children only about 25 percent of today's medicines. 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 estimating dosages
for children from dosages 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.
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 the
pharmaceutical industry 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 the pharmaceutical industry
to develop voluntarily pediatric data both during the drug
development process and after marketing. Neither of these 1994
initiatives increased substantially the number of drugs with
adequate pediatric labeling.
Senators Dodd and Kassebaum first introduced the Better
Pharmaceuticals for Children Act in the 102nd Congress, and it
was reintroduced in each subsequent Congress until it was
enacted in 1997 as part of FDAMA. In the 1997 report on the
legislation, the committee stated, ``there is little incentive
for drug sponsors to perform studies for medications which they
intend to market primarily for adults and whose use in children
is expected to generate little additional revenue. Pediatric
studies pose ethical and moral issues relating to using new
unapproved drugs in young patients. Second, there are
substantial produce liability and medical malpractice issues.
Third, pediatric patients are more difficult to attract into
studies. Fourth, the some drugs, pediatric use represents more
difficult issues of drug administration and patient compliance
than adult use.''
Accordingly, the pediatric exclusivity provision enacted by
congress in 1997 provides a market incentive of 6 months of
additional exclusive sales to drug companies for studies of
medicines in children. Also in 1997, FDA proposed its Pediatric
rule, which it finalized in 1998, and which became effective
only 1999. That rule requires the manufacturers of certain new
and marketed drugs and biological products to provide adequate
labeling for the use of the products in children. The rule is
both broader and narrower than the pediatric exclusivity
provision enacted by congress in 1997. When their scopes
overlap, Congress provided that pediatric studies required
under the rule could also satisfy the requirements for market
exclusivity.
The incentive provided by 6 months of market exclusivity
has successfully encouraged drug companies to respond
affirmatively to most of FDA's requests for pediatric studies.
Yet the incentive varies widely from drug to drug. For example,
nearly three quarters, or 27, of the first 37 drugs granted
exclusivity would have sales in 6 months of less than $150
million, based on 2000 sales data. The remaining 10 of those 37
drugs, by contrast, had sales in 6 months over $200 million,
and 1 of those had sales in 6 months exceeding $2 billion, a
second had sales exceeding $1.2 billion, and 2 had sales
exceeding $800 million.
Because of pediatric exclusivity, FDA had granted 37 drugs
pediatric exclusivity as of September 7, 2001. The results of
the pediatric studies have provided new and useful information
for use of these medicines in children, 19 of which have been
relabeled to include pediatric information. As of August 6,
2001, FDA had issued 196 written requests for more than 422
studies of drugs for anti-inflammatory, cardiovascular, anti-
viral, oncology, neurology, and endocrine, among other,
diseases and conditions.
In its January 2001 Status Report to Congress on the
pediatric exclusivity provision, the FDA wrote:
The pediatric exclusivity provision has done more to
generate clinical studies and useful prescribing
information for the pediatric population than any other
regulatory or legislative process to date. * * * As a
result of the pediatric exclusivity provision and FDA's
filing requirement that study reports be submitted in a
manner which will result in labeling information for
children, critical drugs used to treat a variety of
conditions (e.g., gastro intestinal reflux disease,
diabetes mellitus, pain, asthma, hypertension) have or
soon will have pediatric use information in their
labeling.
The GAO Director for Health Care, Janet Heinrich, testified
at the committee's May 8, 2001, hearing that, ``[s]ince
enactment of the pediatric exclusivity provision, both the
numbers of drugs studied in children and the therapeutic
classes they represent have substantially increased. Hundreds
of studies are being done on drugs that are important to
pediatric patients.'' The pediatric exclusivity law has
provided for pediatric research on different medicines in the
same therapeutic class because it is important that children
have a choice of medicines, as do adults, because some children
may only tolerate 1 drug in a therapeutic class.
At a time when the infrastructure is now in place to
accommodate the increasing pediatric studies, many pediatric
experts are concerned about the January 1, 2002, sunset date in
the current law. During the May 8, 2001, committee hearing, the
GAO stated that, ``Experts agree that, since FDAMA, there also
has been significant growth in the infrastructure necessary to
conduct pediatric studies. For example, NICHD [National
Institute of Child Health and Development] has expanded the
number of PPRUs from 7 to 13. * * * Prior to FDAMA, the PPRU
Network had conducted 17 studies for drug sponsors. By 2000,
the PPRUs were conducting 73 pediatric drug studies for drug
sponsors. The pharmaceutical industry also has increased its
capacity to conduct pediatric studies since enactment of
FDAMA.'' This strong infrastructure for conducting pediatric
studies will help to ensure the continuing success of this law,
which has seen the study of a wide range of drugs in many
therapeutic areas.
III. Legislative History and Committee Action
On May 7, 2001, Senators Dodd and DeWine introduced S. 838,
the ``Best Pharmaceuticals for Children Act.'' On May 8, 2001,
the committee held a hearing entitled ``Better Pharmaceuticals
for Children: Assessment and Opportunities.'' In the hearing,
the committee examined how the 1997 pediatric exclusivity law
has worked and how it could be improved, so as to determine
whether and how the provision should be reauthorized.
On August 1, 2001, the committee held an executive session
to consider S. 838. Senators Dodd and DeWine offered an
amendment in the nature of a substitute that the committee
considered as original text for purposes of further amendment.
Senators Dodd, Kennedy, and DeWine offered an amendment that
the committee accepted without objection. Also without
objection, the committee directed that technical and conforming
changes be made. The committee approved S. 838, as amended, by
voice vote.
A. Amendment Adopted Without Objection During Executive Session
The committee adopted 1 amendment without objection.
1. Senator Dodd offered an amendment for himself, Senators
Kennedy and DeWine that clarifies the interaction of pediatric
market exclusivity under this provision and the market
exclusivity awarded to an applicant for approval of a drug
under section 505(j) of the FFDCA. Under the 1997 pediatric
exclusivity law, Congress created a 6-month market incentive
for a holder of an approved application under section 505(b)(1)
of the FFDCA to conduct pediatric studies of a drug FDA's
request, thereby rewarding companies that invest resources to
test medicines for children. Under the 1984 Waxman-Hatch Act,
Congress created a 6-month period of market exclusivity (``ANDA
exclusivity'') for the first applicant for approval of a drug
under section 505(j) of the FFDCA to challenge a patent on that
drug, during which FDA may not approve subsequent abbreviated
applications for the drug; this incentive rewards the first
filer of an abbreviated application that pursues the risk and
expense of challenging a patent.
When Congress passed the pediatric exclusivity provision in
1997, it had not meant to change the incentives for challenging
patents under the Waxman-Hatch Act by reducing periods of ANDA
exclusivity. The committee has since learned, however, that in
some instances, pediatric exclusivity on a drug may run over
all or a portion of the 180 days of ANDA exclusivity for the
first applicant to challenge a patent on that drug.
The amendment clarifies how a period of ANDA exclusivity on
a drug is to be extended when a pediatric exclusivity period on
the drug overlaps with it. When there is overlap and the period
of ANDA exclusivity expires after the period of pediatric
exclusivity, the period of ANDA exclusivity is extended by the
length of the overlap. When there is overlap and the period of
ANDA exclusivity expires during the period of pediatric
exclusivity, the period of ANDA exclusivity is extended by six
months. The amendment gives the filer of an abbreviated drug
application who challenges a patent no more and no less time to
market his drug exclusively before subsequent abbreviated
applications for the drug may be approved then it would have
received but for the intervening period of pediatric
exclusivity.
For example, the committee understands there may be
instances in which 2 patents on a drug are challenged in an
abbreviated new drug application, and that, in subsequent
litigation, a court holds the first patent to expire to be
valid and infringed, and the second patent to expire tobe
invalid. If the section 505(b)(1) drug is granted a period of pediatric
exclusivity with respect to the first patent, and if the court
decision, which triggers the beginning of the ANDA exclusivity, falls
60 days before that period of pediatric exclusivity begins (that is, 60
days before the first patent will expire), the ANDA exclusivity will
overlap with the pediatric exclusivity for 120 days. In the absence of
pediatric exclusivity, the holder of the abbreviated drug application
would enjoy at most 120 days to market its drug before a subsequent
abbreviated application for the drug could be approved. But for the
amendment, because of pediatric exclusivity, the holder of the
abbreviated drug application would enjoy no ANDA exclusivity, because
the first 120 days of the pediatric exclusivity period would run over
the last 120 days of its ANDA exclusivity. The amendment adds 6 months
to the ANDA exclusivity period, so that the manufacturer of the section
505(j) drug would enjoy 120 days of ANDA exclusivity after the period
of pediatric exclusivity expires.
B. Five Amendments Offered and Subsequently Withdrawn
1. Senator Clinton offered and then withdrew an amendment
to establish a council on pediatric cancer therapeutics to
identify, evaluate, and prioritize new and promising oncology
drugs for use in children, and to require manufacturers to
include in an application for study of a new drug their intent
for pediatric studies of the drug and their procedures for
individual access to the drug.
2. Senator Bond offered and then withdrew an amendment to
provide an additional 3 months of exclusivity when a company
does studies of a drug in a pediatric population not studied
under the first request for pediatric studies.
3. Senator Clinton offered and then withdrew an amendment
to provide that, when a manufacturer does not accept a written
request from FDA to study a drug, the drug could be studied
under the process for studying off-patent drugs provided for in
S. 838.
4. Senator Clinton offered and then withdrew an amendment
to provide that drugs that have annual sales of $800 million or
more would receive 3 months rather than 6 months of pediatric
exclusivity.
5. Senator Kennedy offered and then withdrew an amendment
to require pediatric testing of new drugs for their approved
uses in adults.
IV. Explanation of the Legislation and Committee Views
Priority lists of drugs to be studied
The FDA recommended that the requirement that the Secretary
create and maintain a priority list of drugs to be studied for
their pediatric use in children be eliminated. Development of
the list was resource intensive, and diverted resources from
other needed work on pediatric drugs. The list also did little
to prioritize effectively which drugs should be studied in
children. Finally, the priority list created the mistaken
impression on the part of some drug manufacturers that only
those drugs on the list could qualify for the pediatric
incentive. Accordingly, the legislation has eliminated the
list.
At the same time, the legislation establishes a process and
standard by which the National Institutes of Health (NIH) and
FDA are to prioritize the study of drugs that lack patents or
other market exclusivity protections. The committee expects
that this process and standard for the prioritization of drugs
will produce a useful priority list for the study of such
drugs. These drugs will be studied using limited Federal funds,
and the committee believes that these funds can be used most
efficiently to study drugs that will provide significant
benefit to significant numbers of children. The committee
intends the standards in the legislation to guide the
prioritization process, so that a rational plan for the study
of off-patent drugs will emerge.
Fund and process for study of drugs lacking patents and other market
exclusivities
The 1997 pediatric exclusivity law makes no provision for
the study of drugs lacking patent and other market exclusivity
protections, as such drugs lack any market exclusivity to which
the 6-month period of pediatric exclusivity may attach. This
legislation therefore addresses concerns raised by the FDA,
GAO, and pediatric groups about the urgent need for pediatric
studies of such drugs. Data from 1994 showed that 6 of 10 drugs
most commonly prescribed for children lacked patent terms. By
creating an off-patent research fund, this legislation creates
a mechanism for the Secretary to contract with PPRUs and other
entities that have expertise to conduct pediatric clinical
trials (universities, hospitals, and, other public or private
institutions) for studies of an off-patent drug. Under this
provision, the companies that market the drug would be offered
the right of first refusal to conduct and fund the studies and,
if the companies do not respond within 30 days, they would not
be eligible to receive funds from the off-patent research fund
to conduct the study. Only the entity awarded a contract by the
Secretary to perform the study of the off-patent drug would
have access to public funds in the off-patent research fund.
Under sections 505(c)(3)(D)(iii) and (iv) and
505(j)(5)(D)(iii) and (iv) of the FFDCA, a company is eligible
for three-year Waxman-Hatch exclusivity only if it submits a
new drug application (NDA) to FDA containing reports of new
clinical investigations that are essential to approval of the
application and that are conducted or sponsored by the
applicant. By regulation, FDA has required that a study is
``conducted or sponsored by'' a company if (1) the company is
the sponsor named in the IND for the study submitted to FDA
(i.e., the company conducts the study), or (2) the company
provides 50 percent or more of the cost of conducting the
study. 21 CFR 314.50(j)(4)(iii). Accordingly, if a company
declines to conduct or sponsor studies of an off-patent drug
and another entity (such as a PPRU) conducts the studies, it is
the committee's understanding that the company would not be
able to benefit from an additional 3 years of Hatch-Waxman
exclusivity. If the Secretary agrees with an off-patent study
that shows that a formulation change is necessary, the
legislation requires that the Secretary send a nonbinding
letter recommending such formulation change to each holder of
an approved application for the drug.
Timely labeling of drugs granted exclusivity and of off-patent drugs
The committee understands that some drug companies have
been reluctant to relabel their products once pediatric studies
are complete when the information from the study is adverse.
The committee believes that all useful and appropriate
information on the safety and effectiveness of a drug in
children should appear in drug labeling, and that this
information should appear in the drug label as soon as
possible. Pediatricians and parents must have timely access to
all appropriate information when they are deciding whether and
how to give a drug to a child.
Accordingly, the legislation provides a process by which
FDA can seek labeling changes to drugs granted pediatric
exclusivity and to of off-patient drugs studied under the off-
patent research fund. The committee intends the process to be a
reasonably quick and open process, after which the government
could initiate an enforcement action to require relabeling of
the drug. The process requires referral to the Pediatric
Advisory Subcommittee of the Anti-Infective Drugs Advisory
Committee after a company has refused an FDA request to relabel
a product. The FDA then makes a second request for a labeling
change after considering the recommendation of the Pediatric
Advisory Subcommittee and, if the company refuses to relabel
its drug, the FDA can deem the drug to be misbranded.
The committee expects that, generally, the government would
rely on the injunction provisions of the FFDCA to seek an order
from the court for the company to label its product with
appropriate pediatric labeling, not seizure or criminal
provisions. The committee does not believe that the government
should routinely seek an order enjoining the company from
marketing what is a safe and effective drug for use in adults
merely because it may lack appropriate pediatric labeling.
The committee believes that the government would make its
case that a company's drug is misbranded before the court by
showing that FDA made an initial request for relabeling that
the company refuse, that FDA referred the issue of the
Pediatric Advisory Subcommittee, which reviewed the matter and
made a recommendation about a labeling change to FDA, that FDA
made a second request for a labeling change, which the company
refused, and that FDA's second requested labeling change was
appropriate because without the change the drug would lack
adequate directions for use in children.
The committee expects this Pediatric Advisory process to be
an open one, in that, in accordance with existing law and FDA
policies and procedures, materials provided to the Pediatric
Advisory Subcommittee will be made available to the public,
including by posting the material on the FDA's website. All
disclosures of information are subject to the Freedom of
Information Act and the Trade Secrets Act. The committee
understands that current FDA guidance on the disclosure of
information provided to an advisory committee can be found in
the following FDA Guidance Documents: ``Disclosure of Materials
Provided to Advisory Committee in Connection with Open Advisory
Committees Convened by the Center for Drug Evaluation and
Research Beginning on January 1, 2000'' (Nov. 1999), and
``Disclosing Information Provided to Advisory Committees in
Connection with Open Advisory Committee Meetings Related to the
Testing or Approval of New Drugs and Convened by the Center for
Drug Evaluation and Research, Beginning on January 1, 2000''
(Dec. 1999).
As an additional means to provide for timely pediatric
labeling changes on drugs, the legislation removes the
exemption for pediatric indication supplements in PDUFA that
excludes companies that perform pediatric drug studies at FDA's
request from paying a user fee. By requiring that drug
companies pay PDUFA fees when they submit their completed
studies as supplements to the FDA, the committee expects that
FDA will have sufficient resources to review pediatric labeling
supplements quickly as ``priority supplements,'' and that
pediatric labeling changes can be made as quickly as possible.
Pediatric expertise at FDA
The committee is aware that the incentives created by the
pediatric exclusivity provision have encouraged the drug
industry to develop and expand its infrastructure and expertise
in the study of drugs in pediatrics. The committee intends that
both the payment of user fees for the review of pediatric
labeling supplements and the establishment of an Office of
Pediatric Therapeutics at FDA will facilities similar gains in
coordinated expertise and infrastructure at FDA.
Pediatric studies in neonates
The committee understands that, at times, FDA has awarded
pediatric exclusivity without requesting studies in neonates
(newborns less than a month old), often because study in
neonates must follow studies in older children for scientific,
medical, or ethical reasons. This practice recognizes that
neonates are an especially vulnerable population and should be
tested only with the highest regard for their safe and ethical
treatment. For the same reasons, however, it is important that
drugs be studied in neonates whenever appropriate; otherwise,
any use in neonates will be unguided by the knowledge that
could be appropriately gained in high quality clinical trials
using neonates. The legislation therefore emphasizes that
neonate testing should be included in a written request by FDA
in appropriate cases.
The committee is not mandating that neonate studies be
done. Nor does the committee intend this change to mean that
neonate testing should be performed prematurely. However, it
does intend that FDA will have broad discretion to structure
its requests for pediatric trials so as to protect children and
enhance the value of the information obtained through pediatric
studies. For example, the committee intends that, if FDA
concludes that it would be appropriate to conduct neonatal
studies after it has had the opportunity to examine data from
studies in older children, FDA may, in 1 written request for
pediatric studies, request the submission of a report from
studies in older children, to be followed by studies in younger
children and neonates if the data from the earlier studies may
allow appropriate studies in the younger children.
Dissemination of pediatric information
The committee believes that public dissemination of
information about pediatric drugstudies will facilitate
improved understanding and use of drugs in children. The legislation
accomplishes this goal by requiring that, subject to the Freedom of
Information Act and the Trade Secrets Act, the FDA make public a
summary of the medical and clinical pharmacology reviews of the
pediatric studies, including by publication in the Federal Register.
Confidential commercial information or trade secrets contained in the
pediatric supplement could not be disclosed and would have to be
redacted from any information released to the public.
Study of research involving children
The pediatric exclusivity provision has increased
significantly the number of drug studies conducted in children.
This increase, coupled with reports of unrelated incidents that
have raised concern about human subject protection, has led
some to request a thorough examination of safety and ethical
controls on pediatric studies. The committee shares the concern
that the ethical conduct of pediatric research and the safety
of children be paramount. The legislation therefore requires
that the IOM conduct a 2-year study of Federal regulations and
reports to assess the adequacy of current legal and ethical
safeguards. The committee expects the IOM to conduct an
independent review and to consider a number of options to
improve current legal and ethical safeguards, including those
proposed in the May 2001 review by the Department of Health and
Human Services mandated in the Children's Health Act of 2000
(P.L. 106-310).
V. 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.
VI. Application of Law to the Legislative Branch
The Best Pharmaceuticals for Children Act reauthorizes and
amends the section 505A of the Federal Food, Drug, and Cosmetic
Act to further improve the safety and efficacy of
pharmaceuticals for children. It also provides for the study of
off-patent drugs by amending the Public Health Service Act. As
such, it has no application to the legislative branch.
VII. Regulatory Impact Statement
By granting drug manufacturers a 6-month extension of
market exclusivity for a drug upon satisfactory completion of
requested pediatric studies of the product and delaying the
availability of lower cost generic alternatives, the bill will
make those prescription drugs, when provided under Medicaid,
more expensive. This provision would not constitute a mandate
under the Unfunded Mandates Reform Act because prescription
drugs under Medicaid are provided at a State's option. In
addition, there would be cost savings to the Medicaid program
because, for example, safe and effective use of drugs in
children is expected to reduce the need to hospitalize many
children and to reduce errors in dosing and medicating
children. The private sector is affected by the bill because it
increases the nation's annual pharmaceutical bill by one half
of one percent. There would also be cost savings to the private
sector by, for example, the reduced need for hospitalization of
children and reduced errors in medicating children. FDA
calculated the aggregate increased cost of drugs from pediatric
exclusivity to be $695 million per year in undiscounted dollars
and it estimated the direct medical cost savings from reduced
hospitalizations of children for just 5 illnesses to be $228
million annually.
VIII. Section-by-Section Analysis
Sec. 1. Short title
Sec. 2. Pediatric studies of already-marketed drugs
Section 2 deletes the requirement that the Secretary
develop a priority list of on-patent drugs for which additional
pediatric information may be beneficial. It provides that a
drug may qualify for a written request for pediatric studies if
the Secretary determines that information relating to the use
of an approved drug in the pediatric population may produce
health benefits in that population.
Sec. 3. Research fund for the study of drugs lacking exclusivity
Section 3 creates a research fund for the pediatric studies
of off-patent drugs, authorized at $200 million for FY 2002
(and such sums for each of the next 5 years), to be
administered by the National Institutes of Health (NIH). The
Secretary, acting through the Director of NIH in consultation
with the Commissioner of Food ad Drugs, would establish a
prioritized list of off-patent drugs that need to be tested for
children. Drugs would be prioritized considering the
availability of information on safe and effective use of the
drug in children, whether additional information is needed,
whether new pediatric studies of the drug may produce health
benefits for children, and whether a reformulation of the drug
is necessary.
Section 3 specifies the process for contracts for the
studies and labeling of drugs lacking patent and other market
exclusivity protection. The Commissioner of Food and Drugs, in
consultation with the Director of NIH, would issue a written
request for pediatric studies of such a drug to all companies
that produce the drug. If a company accepts, then that company
would pay for the study and perform the study pursuant to the
requirements stated in the FDA's written request. If no company
responds within 30 days to the written request (or if companies
decline to perform the study), the Secretary must publish a
request for contract proposals to conduct the pediatric studies
described in the written request. If the Secretary is able to
enter into a satisfactory contract for the studies, and once
the contractor completes the study, the contractor must submit
a report, including all data generated by the study, to the
Director and the Commissioner, and the report must then be made
available to the public.
Within 180 days of submission of the report, the
Commissioner must review the data and negotiate labeling
changes with the drug's manufacturer indicating the labeling
change sought by the Commissioner. The Commissioner must place
a copy of the report and any requested labeling changes sought
in a public docket file, and must publish a summary of the
report and the requested labeling changes in the Federal
Register. If a company refuses to make the labeling changes
sought by the Commissioner with 180 days of submission of the
report, theCommissioner must immediately refer the report,
data, and labeling change request to the Pediatric Advisory
Subcommittee of the Anti-Infective Drug Advisory Committee. The
Pediatric Advisory Subcommittee then has 90 days to review the report,
data, and labeling change request and recommend to the Commissioner
appropriate labeling changes. The Commissioner would then have 30 days
to consider the Subcommittee's recommendation, and then make a final
request to the drug company regarding a labeling change. If the drug
company fails to agree to the labeling changes within 30 days, the
Commissioner may deem the drug to be misbranded under the FEDCA. If the
pediatric studies indicate that formulation change is necessary (from a
pill to a liquid form, for example), the Secretary must send a
nonbinding letter of recommendation for such a formulation change to
all drug companies that market the drug.
Sec. 4. Timely labeling changes for drugs granted exclusivity; drug
fees
Section 4 requires drug companies to pay user fees at the
time they submit their completed studies to the FDA. Payment of
user fees would then trigger the PDUFA ``priority supplement''
goal of 6 months for FDA to review pediatric labeling
supplements submitted by the company. Within 180 days of
submission of the report, the Commissioner of Food and Drugs
must request whatever labeling changes he deems appropriate. If
the drug company does not agree within that 180-day period to
make the changes sought by the FDA, then the Commissioner must
immediately refer the matter to the agency's Pediatric Advisory
Subcommittee. Within 90 days, the Pediatric Advisory
Subcommittee must review the pediatric study reports and make a
recommendation to the Commissioner as to appropriate labeling
changes. Within 30 days, the Commissioner must consider the
recommendations of the Subcommittee and make a final request to
the drug company for a labeling change. If the drug company
does not agree with 30 days to this labeling change request
from the Commissioner, the Commissioner may deem the drug
misbranded.
Sec. 5. Office of Pediatric Therapeutics
Section 5 requires the Secretary to establish an Office of
Pediatric Therapeutics within the FDA. This office would
oversee and coordinate RDA activities that could have an effect
on pediatrics. The office would include 1 or more people with
expertise in pediatric ethics and 1 or more people with
pediatric expertise to consult on FDA activities that might
have an effect on pediatrics.
Sec. 6. Neonates
Section 6 clarifies that the pediatric age groups in which
pediatric studies are to be performed in response to requests
for such studies by FDA should include neonates when their
inclusion is appropriate.
Sec. 7. Sunset
Section 7 sunsets the billion October 1, 2007, and provides
that a drug may receive pediatric exclusivity if, before that
date, the Secretary makes a written request for pediatric
studies of the drug and an approvable application for the drug
has been submitted, and all requirements of section 505A of the
FFDCA are met.
Sec. 8. Dissemination of pediatric information
Section 8 requires that, within 6 months after a drug
manufacturer has submitted a pediatric labeling change
supplement to the FDA, the FDA must make public a summary of
the medical and clinical pharmacology reviews of the pediatric
studies, including by publication in the Federal Register. All
disclosures of information are subject to the Freedom of
Information Act and the Trade Secrets Act.
Sec. 9. Clarification of interaction of market exclusivity under
section 505 of the Federal Food, Drug, and Cosmetic Act and
market exclusivity awarded to an applicant for approval of a
drug under section 505(j) of that act
Section 9 clarifies the interaction of pediatric
exclusivity provided under this legislation with ANDA
exclusivity awarded under the Waxman-Hatch Law. It specifies
that, when the pediatric exclusivity period for a drug overlaps
with a period of ANDA exclusivity for the drug, the period of
ANDA exclusivity is extended by an amount necessary to ensure
that the holder of ANDA exclusivity enjoys the same possibility
of exclusive commercial marketing that the holder would have
enjoyed in the absence of pediatric exclusivity, no more and no
less.
Sec. 10. Study concerning research involving children
Section 10 requires the Secretary to contract with the IOM
to conduct a 2-year study of Federal regulations involving
children in research; the written and oral processes for
obtaining ``assent, permission,and informed consent'' of
children in research from parents, guardians, and legal
representatives; the definition of ``minimal risk'' with
respect to children with illnesses or health children; the
appropriateness of regulations applicable to children of
differing ages and maturity; financial (or other) incentives
that are or may be offered; the monitoring and enforcement of
violations of existing regulations; the roles and
responsibilities of institutional review boards (IRBs) in
reviewing research involving children; and the composition of
membership of such IRBs.
Sec. 11. Technical and conforming amendments
IX. 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):
PUBLIC HEALTH SERVICE ACT
* * * * * * *
TITLE IV--NATIONAL RESEARCH INSTITUTES
Part A--National Institutes of Health
organization of the national institutes of health
Sec. 401. [281] (a) * * *
* * * * * * *
SEC. [409C.] 409G. CLINICAL RESEARCH.
(a) In General.--The director of National Institutes of
Health shall undertake activities to support and expand the
involvement of the National Institutes of Health in clinical
research.
(b) Requirements.--In carrying out subsection (a), the
Director of National Institutes of Health Shall--
(1) consider the recommendations of the Division of
Research Grants Clinical Research Study Group and other
recommendations for enhancing clinical research; and
(2) establish intramural and extramural clinical
research fellowship programs directed specifically at
medical and dental students and a continuing education
clinical research training program at the National
Institutes of Health.
(c) Support for the Diverse Needs of Clinical Research.--
The Director of National Institutes of health, in cooperation
with the Directors of the Institutes, Centers, and Divisions of
the National Institutes of Health, shall support and expand the
resources available for the diverse needs of the clinical
research community, including inpatient, outpatient, and
critical care clinical research.
(d) Peer Review.--The Director of National Institutes of
Health shall establish peer review mechanisms to evaluate
applications for the awards and fellowships provided for in
subsection (b)(2) and section 409D. Such review mechanisms
shall include individuals who are exceptionally qualified to
appraise the merits of potential clinical research training and
research grant proposals.
SEC. [409D.] 409H. ENHANCEMENT AWARDS.
(a) Mentored Patient-Oriented Research Career Development
Awards.--
(1) Grants.--
(A) In general.--The Director of the National
Institutes of Health shall make grants (to be
referred to as ``Mentored Patient-Oriented
Research Career Development Awards'') to
support individual careers in clinical research
at general clinical research centers or at
other institutions that have the infrastructure
and resources deemed appropriate for conducting
patient-oriented clinical research.
(B) Use.--Grants under subparagraph (A) shall
be used to support clinical investigators in
the early phases of their independent careers
by providing salary and such other support for
a period of supervised study.
(2) Applications.--An application for a grant under
this subsection shall be submitted by an individual
scientist at such time as the Director may require.
(3) Authorization of appropriations.--For the purpose
of carrying out this subsection, there are authorized
to be appropriated such sums as may be necessary for
each fiscal year.
(b) Mid-Career Investigator Awards in Patient-Oriented
Research.--
(1) Grants.--
(A) In general.--The Director of the National
Institutes of Health shall make grants (to be
referred to as ``Mid-Career Investigator Awards
in Patient-Oriented Research'') to support
individual clinical research projects at
general clinical research centers or at other
institutions that have the infrastructure and
resources deemed appropriate for conducting
patient-oriented clinical research.
(B) Use.--Grants under subparagraph (A) shall
be used to provide support for mid-career level
clinicians to allow such clinicians to devote
time to clinical research and to act as mentors
for beginning clinical investigators.
(2) Applications.--An application for a grant under
this subsection shall be submitted by an individual
scientists at such time as the Director requires.
(3) Authorization of appropriations.--For the purpose
of carrying out this subsection, there are authorized
to be appropriated such sums as may be necessary for
each fiscal year.
(c) Graduate Training in Clinical Investigation Award.--
(1) In general.--The Director of the National
Institutes of Health shall make grants (to be referred
to as ``Graduate Training in Clinical Investigation
Awards'') to support individuals pursuing master's or
doctoral degrees in clinical investigation.
(2) Applications.--An application for a grant under
this subsection shall be submitted by an individual
scientist at such time as the Director may require.
(3) Limitations.--Grants under this subsection shall
be for terms of 2 years or more and shall provide
stipend, tuition, and institutional support for
individual advanced degree programs in clinical
investigation.
(4) Definition.--As used in this subsection, the term
``advanced degree programs in clinical investigation''
means programs that award a master's or Ph.D degree in
clinical investigation after 2 years of training in
areas such as the following:
(A) Analytical methods, biostatistics, and
study design.
(B) Principles of clinical pharmacology and
pharmacokinetics.
(C) Clinical epidemiology.
(D) Computer data management and medical
informatics.
(E) Ethical and regulatory issues.
(F) Biomedical writing.
(5) Authorization of appropriations.--For the purpose
of carrying out this subsection, there are authorized
to be appropriated such sums as may be necessary for
each fiscal year.
(d) Clinical Research Curriculum Awards.--
(1) In general.--The Director of the National
Institutes of Health shall make grants (to be referred
to as ``Clinical Research Curriculum Awards'') to
institutions for the development and support of
programs of core curricula for training clinical
investigators, including medical students. Such core
curricula may include training in areas such as the
following:
(A) Analytical methods, biostatistics, and
study design.
(B) Principles of clinical pharmacology and
pharmacokinetics.
(C) Clinical epidemiology.
(D) Computer data management and medical
informatics.
(E) Ethical and regulatory issues.
(F) Biomedical writing.
(2) Applications.--An application for a grant under
this subsection shall be submitted by an individual
institution or a consortium of institutions at such
time as the Director may require. An institution may
submit only one such application.
(3) Limitations.--Grants under this subsection shall
be for terms of up to 5 years and may be renewable.
(4) Authorization of appropriations.--For the purpose
of carrying out this subsection, there are authorized
to be appropriated such sums as may be necessary for
each fiscal year.
SEC. 409I. PROGRAM FOR PEDIATRIC STUDIES OF DRUGS LACKING EXCLUSIVITY.
(a) List of Drugs Lacking Exclusivity for Which Pediatric
Studies Are Needed.--
(1) In general.--Not later than 1 year after the date
of enactment of this section, the Secretary, acting
through the Director of the National Institutes of
Health and in consultation with the Commissioner of
Food and Drugs and experts in pediatric research, shall
develop, prioritize, and publish an annual list of
approved drugs for which--
(A)(i) there is an approved application under
section 505(j) of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 355(j));
(ii) there is a submitted application that
could be approved under the criteria of section
505(j) of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 355(j)); or
(iii) there is no patent protection or market
exclusivity protection under the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 301 et seq.);
and
(B) additional studies are needed to assess
the safety and effectiveness of the use of the
drug in the pediatric population.
(2) Consideration of available information.--In
developing the list under paragraph (1), the Secretary
shall consider, for each drug on the list--
(A) the availability of information
concerning the safe and effective use of the
drug in the pediatric population;
(B) whether additional information is needed;
(C) whether new pediatric studies concerning
the drug may produce health benefits in the
pediatric population; and
(D) whether reformulation of the drug is
necessary;
(b) Contracts for Pediatric Studies.--The Secretary shall
award contracts to entities that have the expertise to conduct
pediatric clinical trials (including qualified universities,
hospitals, laboratories, contract research organizations,
federally funded programs such as pediatric pharmacology
research units, other public or private institutions, or
individuals) to enable the entities to conduct pediatric
studies concerning one or more drugs identified in the list
described in subsection (a).
(c) Process for Contracts and Labeling Changes.--
(1) Written request to holders of approved
applications for drugs lacking exclusivity.--
(A) In general.--The Commissioner of Food and
Drugs, in consultation with the Director of
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) to all holders of an approved application
for the drug under section 505 of the Federal
Food, Drug, and Cosmetic Act. Such a request
shall be made in accordance with section 505A
of the Federal Food, Drug, and Cosmetic Act.
(B) Publication of request.--If the
Commissioner of Food and Drugs does not receive
a response to a written request issued under
subparagraph (A) within 30 days of the date on
which a request was issued, the Secretary,
acting through the Director of National
Institutes of Health and in consultation with
the Commissioner of Food and Drugs, shall
publish a request for contract proposals to
conduct the pediatric studies described in the
written request.
(C) Disqualification.--A holder that receives
a first right of refusal shall not be entitled
to respond to a request for contract proposals
under subparagraph (B).
(D) Guidance.--Not later than 270 days after
the date of enactment of this section, the
Commissioner of Food and Drugs shall promulgate
guidance to establish the process for the
submission of responses to written requests
under subparagraph (A).
(2) Contracts.--A contract under this section may be
awarded only if a proposal for the contract is
submitted to the Secretary in such form and manner, and
containing such agreements, assurances, and information
as the Secretary determines to be necessary to carry
out this section.
(3) Reporting of studies.--
(A) Upon completion of a pediatric study in
accordance with a contract awarded under this
section, a report concerning the study shall be
submitted to the Director of National
Institutes of Health and the Commissioner of
Food and Drugs. The report shall include all
data generated in connection with the study.
(B) Availability of reports.--Each report
submitted under subparagraph (a) shall be
considered to be in the public domain, and
shall be assigned a docket number by the
Commissioner of Food and Drugs. An interested
person may submit written comments concerning
such pediatric studies to the Commissioner of Food
and Drugs, and the written comments shall become
part of the docket file with respect to each of
the drugs.
(C) Action by commissioner.--The Commissioner
of Food and Drugs shall take appropriate action
in response to the reports submitted under
subparagraph (A) in accordance with paragraph
(4).
(4) Request for labeling changes.--During the 180-day
period after the date on which a report is submitted
under paragraph (3)(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; and
(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.
(5) Dispute resolution.--If, not later than the end
of the 180-day period specified in paragraph (4), the
holder of an approved application for the drug involved
does not agree to any labeling change requested by the
Commissioner of Food and Drugs under that paragraph--
(A) the Commissioner of Food and Drugs shall
immediately refer the request to the Pediatric
Advisory Subcommittee of the Anti-Infective
Drugs Advisory Committee; and
(B) not later than 90 days after receiving
the referral, the Subcommittee 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.
(6) FDA determination.--Not later than 30 days after
receiving a recommendation from the Sub-committee under
paragraph (5)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.
(7) 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
(6), 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
Act.
(8) Recommendation for formulation changes.--If a
pediatric study completed under public contract
indicates that a formulation change is necessary and
the Secretary agrees, the Secretary shall send a
nonbinding letter of recommendation regarding that
change to each holder of an approved application.
(d) Authorization of Appropriations.--
(1) In general.--There are authorized to be
appropriated to carry out this section--
(A) $200,000,000 for fiscal year 2002; and
(B) such sums as are necessary for each of
the 5 succeeding fiscal years.
(2) Availability.--Any amount appropriated under
paragraph (1) shall remain available to carry out this
section until expended.
* * * * * * *
FEDERAL FOOD, DRUG, AND COSMETIC ACT
* * * * * * *
CHAPTER II--DEFINITIONS
Sec. 201 [21 U.S.C. 321] For the purposes of this Act--
(a)(1) * * *
* * * * * * *
(kk) Priority Supplement.--The term ``priority supplement''
means a drug application referred to in section 101(4) of the
Food and Drug Administration Modernization Act of 1997 (111
Stat. 2298).
* * * * * * *
SEC. 505A. [21 U.S.C. 355A] PEDIATRIC STUDIES OF DRUGS.
[(g)] (a) Definitions.--As used in this section, the term
``pediatric studies'' or ``studies'' means at least one
clinical investigation (that, at the Secretary's discretion,
may include pharmacokinetic studies) in pediatric age groups
(including neonates in appropriate cases) in which a drug is
anticipated to be used.
[(a)] (b) Market Exclusivity for New Drugs.--If, prior to
approval of an application that is submitted under section
505(b)(1), the Secretary determines that information relating
to the use of a new drug in the pediatric population may
produce health benefits in that population, the Secretary makes
a written request for pediatric studies (which shall include a
timeframe for completing such studies), and such studies are
completed within any such time-frame and the reports thereof
submitted in accordance with subsection (d)(2) or accepted in
accordance with subsection (d)(3)--
(1)(A)(i) the period referred to in subsection
(c)(3)(D)(ii) of section 505, and in subsection
[(j)(4)(D)(ii)] (j)(5)(D)(ii) of such section, is
deemed to be five years and six months rather than five
years, and the references in subsections (c)(3)(D)(ii)
and [(j)(4)(D)(ii)] (j)(5)(D)(ii) of such section to
four years, to forty-eight months, and to seven and
one-half years are deemed to be four and one-half
years, fifty-four months, and eight years,
respectively; or
(ii) the period referred to in clauses (iii) and (iv)
of subsection (c)(3)(D) of such section, and in clauses
(iii) and (iv) of subsection [(j)(4)(D)] (j)(5)(D) of
such section, is deemed to be three years and six
months rather than three years; and
(B) if the drug is designated under section 526 for a
rare disease or condition, the period referred to in
section 527(a) is deemed to be seven years and six
months rather than seven years; and
(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)] 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) shall
be extended by a period of six months after the date
the patent expires (including any patent extensions).
[(b) Secretary To Develop List of Drugs for Which
Additional Pediatric Information May Be Beneficial.--Not later
than 180 days after the date of enactment of the Food and Drug
Administration Modernization Act of 1997, the Secretary, after
consultation with experts in pediatric research shall develop,
prioritize, and publish an initial list of approved drugs for
which additional pediatric information may produce health
benefits in the pediatric population. The Secretary shall
annually update the list.]
(c) Market Exclusivity for Already-Marketed Drugs.--If the
Secretary determines that information relating to the use of an
approved drug in the pediatric population may produce health
benefits in that population and makes a written request to the
holder of an approved application under section 505(b)(1) for
pediatric studies (which shall include a timeframe for
completing such studies) [concerning a drug identified in the
list described in subsection (b)], the holder agrees to the
request, the studies are completed within any such timeframe,
and the reports thereof are submitted in accordance with
subsection (d)(2) or accepted in accordance with subsection
(d)(3)--
(1)(A)(i) the period referred to in the subsection
(c)(3)(D)(ii) of section 505, and in subsection
[(j)(4)(D)(ii)] (j)(5)(D)(ii) of such section, is
deemed to be five years and six months rather than five
years, and the references in subsections (c)(3)(D)(ii)
and [(j)(4)(D)(ii)] (j)(5)(D)(ii) of such section for
four years, to forty-eight months, and to seven and
one-half years are deemed to be four and one-half
years, fifty-four months, and eight years,
respectively; or
(ii) the period referred to the clauses (iii) and
(iv) of subsection (c)(3)(D) of such section, and in
clauses (iii) and (iv) of subsection [(j)(4)(D)]
(j)(5)(D) of such section, is deemed to be three years
and six months rather than three years; and
(B) if the drug is designated under section 526 for a
rare disease or condition, the period referred to in
section 527(a) is deemed to be seven years and six
months rather than seven years; and
(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) 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 an application may not be approved under
section 505(c)(3) or section 505(j)(4)(B) shall be
extended by a period of six months after the date the
patent expires (including any patent extensions).
(d) Conduct of Pediatric Studies.--
(1) Agreement for studies.--The Secretary may,
pursuant to a written request from the Secretary under
subsection [(a) or (c)] (b) or (c), after consultation
with--
(A) the sponsor of an application for an
investigational new drug under section 505(i);
(B) the sponsor of an application for a new
drug under section 505(b)(1); or
(C) the holder of an approved application for
a drug under section 505(b)(1),
agree with the sponsor or holder for the conduct of
pediatric studies for such drug. Such agreement shall
be in writing and shall include a timeframe for such
studies.
(2) Written protocols to meet the studies
requirement.--If the sponsor or holder and the
Secretary agree upon written protocols for the studies,
the studies requirement of subsection [(a) or (c)] (b)
or (c) is satisfied upon the completion of the studies
and submission of the reports thereof in accordance
with the original written request and the written
agreement referred to in paragraph (1). Not later than
60 days after the submission of the report of the
studies, the Secretary shall determine if such studies
were or were not conducted in accordance with the
original written request and the written agreement and
reported in accordance with the requirements of the
Secretary for filing and so notify the sponsor or
holder.
(3) Other methods to meet the studies requirement.--
If the sponsor or holder and the Secretary have not
agreed in writing on the protocols for the studies, the
studies requirement of subsection [(a) or (c)] (b) or
(c) is satisfied when such studies have been completed
and the reports accepted by the Secretary. Not later
than 90 days after the submission of the reports of the
studies, the Secretary shall accept or reject such
reports and so notify the sponsor or holder. The
Secretary's only responsibility in accepting or
rejecting the reports shall be to determine, within the
90 days, whether the studies fairly respond to the
written request, have been conducted in accordance with
commonly accepted scientific principles and protocols,
and have been reported in accordance with the
requirements of the Secretary for filing.
(e) Delay of Effective Date for Certain Application.--If
the Secretary determines that the acceptance or approval of an
application under section 505(b)(2) or 505(j) for a new drug
may occur after submission of reports of pediatric studies
under this section, which were submitted prior to the
expiration of the patent (including any patent extension) or
the applicable period under clauses (ii) through (iv) of
section 505(c)(3)(D) or clauses (ii) through (iv) of section,
[505(j)(4)(D)] 505(j)(5)(D), but before the Secretary has
determined whether the requirements of subsection (d) have been
satisfied, the Secretary shall delay the acceptance or approval
under section 505(b)(2) or 505(j) until the determination under
subsection (d) is made, but any such delay shall not exceed 90
days. In the event that requirements of this section are
satisfied, the applicable six-month period under subsection
[(a) or (c)] (b) or (c) shall be deemed to have been running
during the period of delay.
(f) Notice of Determinations on Studies Requirement.--The
Secretary shall publish a notice of any determination that the
requirements of subsection (d) have been met and that
submissions and approvals under subsection (b)(2) or (j) of
section 505 for a drug will be subject to the provisions of
this section.
[(h)] (g) Limitations.--A drug to which the six-month
period under subsection [(a) or (b)] (b) or (c) has already
been applied--
(1) may receive an additional six-month period under
subsection (c)(1)(A)(ii) for a supplemental application
if all other requirements under this section are
satisfied, except that such a drug may not receive any
additional such period under subsection (c)(2); and
(2) may not receive any additional such period under
subsection (c)(1)(B).
[(i)] (h) Relationship to Regulations.--Notwithstanding any
other provision of law, if any pediatric study is required
pursuant to regulations promulgated by the Secretary 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.
[(j) Sunset.--A drug may not receive any six-month period
under subsection [(a) or (c)] (b) or (c) unless the application
for the drug under section 505(b)(1) is submitted on or before
January 1, 2002. After January 1, 2002, a drug shall receive a
six-month period under subsection (c) if--
[(1) the drug was in commercial distribution as of
the date of enactment of the Food and Drug
Administration Modernization Act of 1997;
[(2) the drug was included by the Secretary on the
list under subsection (b) as of January 1, 2002;
[(3) the Secretary determines that there is a
continuing need for information relating to the use of
the drug in the pediatric population and that the drug
may provide health benefits in that population; and
[(4) All requirements of this section are met.]
[(l)] (i) Labeling Supplements._
(1) Priority status for pediatric supplements.--Any
supplement to an application under section 505
proposing a labeling change pursuant to a report on a
pediatric study under this section--
(A) shall be considered to be a priority
supplement; and
(B) shall be subject to the performance goals
established by the Commissioner for priority
drugs.
(2) Dispute resolution.--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--
(A) 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 by that date, the
Commissioner shall immediately refer
the matter to the Pediatric Advisory
Subcommittee of the Anti-Infective
Drugs Advisory Committee;
(B) not later than 90 days after receiving
the referral, 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) 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; and
(D) if the sponsor of the application, within
30 days after receiving a request under
subparagraph (C), does 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.
[(m)] (j) Dissemination of Pediatric Information._
(1) In general.--Not later than 180 days after the
date of submission of a report on a pediatric study
under this section, the Commissioner shall make
available to the public a summary of the medical and
clinical pharmacology reviews of pediatric studies
conducted for the supplement, including by publication
in the Federal Register.
(2) Effect of subsection.--Nothing in this subsection
alters or amends in any way section 552 of title 5 or
section 1905 of title 18, United States Code.
[(n)] (k) Clarification of Interaction of Market
Exclusivity Awarded to an Applicant for Approval of a Drug
Under Section 505(j)._
(1) In general.--If a 180-day period under section
505(j)(5)(B)(iv) overlaps with a 6-month extension
under this section, so that the applicant for approval
of a drug under section 505(j) entitled to the 180-day
period under that section loses a portion of the 180-
day period to which the applicant is entitled for the
drug, the 180-day period shall be extended--
(A) if the 180-day period would, but for this
subsection, expire after the 6-month extension,
by the number of days of the overlap; or
(B) if the 180-day period would, but for this
subsection, expire during the 6-month
extension, by 6 months.
(2) Effect of subsection.--Under no circumstances
shall application of this section result in enabling an
applicant for approval of a new drug under section
505(j) to commercially market the drug to the exclusion
of a subsequent applicant for approval of a new drug
under section 505(j) for more than 180 days.
[(k)] (l) Report.--The Secretary shall conduct a study and
report to Congress not later than January 1, 2001, based on the
experience under the program established under this section.
The study and report shall examine all relevant issues,
including--
(1) the effectiveness of the program in improving
information about important pediatric uses for approved
drugs;
(2) the adequacy of the inventive provided under this
section;
(3) the economic impact of the program on taxpayers
and consumers, including the impact of the lack of
lower cost generic drugs on patients, including on
lower income patients; and
(4) any suggestions for modification that the
Secretary determines to be appropriate.
[(j)] (m) Sunset.--A drug may not receive any 6-month
period under subsection (b) or (c) unless--
(1) on or before October 1, 2007, the Secretary makes
a written request for pediatric studies of the drug;
(2) on or before October 1, 2007, an approvable
application for the drug is submitted under section
505(b)(1); and
(3) all requirements of this section are met.
* * * * * * *
SEC. 736. [21 U.S.C. 379H] AUTHORITY TO ASSESS AND USE DRUG FEES.
(a) Types of Fees.--Beginning in fiscal year 1998, the
Secretary shall assess and collect fees in accordance with this
section as follows:
(1) Human drug application and supplement fee.--
(A) * * *
* * * * * * *
[(F) Exception for supplements for pediatric
indications.--A supplement to a human drug
application proposing to include a new
indication for use in pediatric populations
shall not be assessed a fee under subparagraph
(A).]
[(G)] (F) Refund of fee if application
withdrawn.--If an application or supplement is
withdrawn after the application or supplement
was filed, the Secretary may refund the fee or
a portion of the fee if no substantial work was
performed on the application or supplement
after the application or supplement was filed.
The Secretary shall have the sole discretion to
refund a fee or a portion of the fee under this
subparagraph. A determination by the Secretary
concerning a refund under this paragraph shall
not be reviewable.
* * * * * * *