Order Code RL33986
FDA’s Authority to Ensure That Drugs
Prescribed to Children Are Safe and Effective
May 1, 2007
Susan Thaul
Specialist in the Regulation of Prescription Drugs and Biologics
Domestic Social Policy Division

FDA’s Authority to Ensure That Drugs
Prescribed to Children Are Safe and Effective
Summary
The Best Pharmaceuticals for Children Act (BPCA, P.L. 107-109) and the
Pediatric Research Equity Act (PREA, P.L. 108-155) allow the Food and Drug
Administration (FDA) to offer financial and regulatory incentives to manufacturers
for testing their products for pediatric use. Unless Congress acts, both programs will
end on October 1, 2007. FDA has approved for adult use many products never tested
in children. Yet clinicians often prescribe them for children believing that the safety
and effectiveness demonstrated with adults would hold for younger patients.
However, this off-label prescribing results in children receiving ineffective drugs or
too much or too little of a potentially useful drug. Some side effects are unique to
children, or children of specific ages, including effects on growth and development.
Studies show that drugs vary in bioavailability in children, which depends on the
maturation and development of organs and other factors.
About 75% of drugs have not had pediatric studies. The market has not been
able to overcome the economic, ethical, legal, and mechanical obstacles that make
manufacturers reluctant to conduct these tests. FDA had tried to spur pediatric drug
research through administrative action. With the FDA Modernization Act of 1997
(FDAMA, P.L. 105-115), Congress provided an incentive: in exchange for a
manufacturer’s completion of pediatric studies according to an FDA written request,
FDA would extend its market exclusivity for that product for six months. BPCA
gave this program a five-year reauthorization in 2002. From 1997 through November
2006, FDA sent 338 written requests to patent-holding manufacturers; 44%
responded and 91% of those conducted the studies and were granted pediatric
exclusivity. This resulted in 118 labeling changes — for 87% of the drugs granted
exclusivity, but only 35% of the drugs for which FDA requested studies. BPCA also
set up study referral processes through the National Institutes of Health (NIH) for off-
patent drugs and on-patent drugs for which the manufacturer declined FDA’s request.
Those programs have yet to yield labeling changes.
To get pediatric use information on the drugs that manufacturers were not
studying, in 1998, FDA published the Pediatric Rule requiring that manufacturers
submit pediatric testing data at the time of all new drug applications. In 2002, a
federal court declared the rule invalid, holding that FDA lacked the statutory
authority to promulgate it. Congress gave FDA that authority with PREA. PREA
covers drugs and biological products and includes provisions for deferrals, waivers,
and the required pediatric assessment of an approved marketed product. From 2003
through 2006, FDA approved more than 372 drugs and biologics; there have been 63
PREA-related labeling changes.
The FDA Revitalization Act (S. 1082, as reported) contains pediatric research
provisions, including the continuing of BPCA and PREA. Updates of this report will
reflect legislative activity.

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Manufacturers Have Been Reluctant to Test Drugs in Children . . . . . . . . . . . . . . 4
The Current Laws Evolved from Earlier Attempts . . . . . . . . . . . . . . . . . . . . . . . . 4
1979: Rule on Drug Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1994: Revised Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Food and Drug Administration Modernization Act of 1997 . . . . . . . . . . . . . 6
1997: The Pediatric Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
BPCA and PREA: Laws to Encourage Pediatric Drug Research . . . . . . . . . . . . . 7
The Best Pharmaceuticals for Children Act . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Pediatric Exclusivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
FDA-NIH Collaboration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Other Provisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Pediatric Research Equity Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
New Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Products on the Market . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Other Provisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
BPCA and PREA Have Had Some Impact on Pediatric Drug Research . . . . . . . . 9
Best Pharmaceuticals for Children Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
On-Patent Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
NIH Route for Off-Patent Drugs and
On-Patent Drugs for Which Manufacturers
Declined FDA’s Requests for Study . . . . . . . . . . . . . . . . . . . . . . 10
GAO Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Pediatric Research Equity Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Comparison of BPCA and PREA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
FDA Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Exclusivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Whether Pediatric Information Is Required . . . . . . . . . . . . . . . . . . . . . 15
Content of Included Pediatric Information . . . . . . . . . . . . . . . . . . . . . 15
Enforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Sunset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Bills in the 110th Congress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

List of Tables
Table 1. Examples of Differences in Effectiveness, Dosing,
and Adverse Events for Children Administered Adult-Tested,
FDA-Approved Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Table 2. Administrative and Statutory Efforts to Encourage
Pediatric Drug Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Table 3. Two Ways to Describe the Effect of
Pediatric Exclusivity on Pediatric Labeling Changes . . . . . . . . . . . . . . . . . 10
Table 4. Research Status of Drugs That NIH Deemed
In Need of Pediatric Studies, by Patent Status . . . . . . . . . . . . . . . . . . . . . . . 10
Table 5. Content of PREA-Associated Labeling Changes . . . . . . . . . . . . . . . . . . 11
Table 6. Major Differences in the BPCA and PREA Approaches . . . . . . . . . . . . 12

FDA’s Authority to Ensure
That Drugs Prescribed to Children
Are Safe and Effective
Introduction
FDA has approved for adult use many drugs never tested in children. Yet
clinicians often prescribe them for children believing that the safety and effectiveness
demonstrated with adults probably reasonably transfers to younger patients. The data
show that this is not always true. To address this situation, earlier Congresses have
offered manufacturers incentives to test drugs in children. Two current statutory
programs offering such incentives will cease at the end of this fiscal year if the 110th
Congress does not act:
! the Best Pharmaceuticals for Children Act (BPCA, P.L. 107-109)
and
! the Pediatric Research Equity Act of 2003 (PREA, P.L. 108-155).
This report first provides a background to the development of these laws,
including:
! why research on a drug’s pharmacokinetics, safety, and effectiveness
in children is necessary;
! why the marketplace has not provided sufficient incentive to
manufacturers of drugs approved for adult use;
! how the current laws evolved;
! what the current laws — BPCA and PREA — are meant to do; and
! what impact the laws have had on pediatric drug research.
It then outlines some issues that Congress may consider as its discusses how (or
whether) to continue the programs beyond September 30, 2007.
Background
A drug cannot be marketed in the United States without Food and Drug
Administration (FDA) approval. A manufacturer’s application to FDA must include
an Indication for Use section that describes what the drug does and the clinical
condition and population for which drug use is intended. To approve a drug, FDA
must find that the manufacturer has sufficiently demonstrated the drug’s safety and
effectiveness for the specific intended indication (rationale for treatment and its

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context) and population specified in the application.1 The Federal Food, Drug, and
Cosmetic Act (FFDCA) prohibits a manufacturer from promoting or advertising a
drug for any use not listed in the FDA-approved labeling; only those claims for which
FDA has reviewed safety and effectiveness evidence can appear in the labeling.
However, the FFDCA does not give FDA authority to regulate the practice of
medicine; that responsibility rests with the states and medical professional
associations. Once a drug is approved, therefore, a licensed physician may — except
in highly regulated circumstances — prescribe it without restriction. A prescription
to an individual whose demographic or medical characteristics differ from those
indicated in a drug’s FDA-approved labeling is called off-label use, and is accepted
medical practice.
Most of the prescriptions that physicians write for children fall into the category
of off-label use. FDA has evaluated the drugs’ safety and effectiveness when used
to treat adults, but has not seen data relating to their use in children — and thus the
labeling does not address indications, dosage, or warnings related to use in children.
Faced with an ill child, clinicians must deduce/infer/guess whether the drug might
help and what amount of the drug (and frequency of administration) might best
balance the drug’s intended effect with its anticipated and unanticipated side effects.
Clinicians face an obstacle: children are not miniature adults.2 At different
ages, a body handles a given amount of an administered drug differently, resulting
in varying bioavailability. This occurs, in part, because the rate at which the body
eliminates a drug (after which the drug is no longer available) varies based on
changes in the maturation and development of organs and other factors. Clearance
can be quicker or slower in children depending on the age of child, the organs
involved, and body surface area.3
Errors in prescribing drugs to children, as outlined by the Director of FDA’s
Office of Pediatric Therapeutics, include unnecessary exposure to ineffective drugs;
ineffective dosing of an effective drug; overdosing of an effective drug; undefined
unique pediatric adverse events; and effects on growth and behavior.4 Table 1
1 For descriptions and discussions of the FDA procedure for approving new drugs, see CRS
Report RL32797, Drug Safety and Effectiveness: Issues and Action Options After FDA
Approval
, by Susan Thaul; and FDA, “Drug Approval Application Process,” at
[http://www.fda.gov/cder/regulatory/applications/default.htm].
2 David A. Williams, Haiming Xu, and Jose A. Cancelas, “Children are not little adults: just
ask their hematopoietic stem cells,” J Clin Invest., vol. 116, no. 10, October 2, 2006, pp.
2593-2596; and Stephen Ashwal (Editor), The Founders of Child Neurology (San Francisco:
Norman Publishing, 1990).
3 William Rodriguez, Office of New Drugs, FDA, “What We Learned from the Study of
Drugs Under the Pediatric Initiatives,” June 2006 presentation to the Institute of Medicine,
at [http://www.fda.gov/oc/opt/presentations/whatwelearned.ppt].
4 Dianne Murphy, Director, Office of Pediatric Therapeutics, Office of the Commissioner,
FDA, “Impact of Pediatric Legislative Initiatives: USA,” January 26, 2005 presentation to
the European Forum for Good Clinical Practice, at [http://www.fda.gov/oc/opt/
presentations/Brussels.ppt]; and Rodriguez, June 2006.

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includes some of the examples that FDA scientists have included in recent
presentations on pediatric drug development.
Table 1. Examples of Differences in Effectiveness, Dosing, and
Adverse Events for Children Administered Adult-Tested,
FDA-Approved Medications
Type of
Examples of the need for pediatric labeling
difference
Inability to
• some cancer drugs
demonstrate
• buspirone (Buspar) for general anxiety disorder
effectiveness
• some combination diabetes drugs
• gabapentin (Neurontin) for seizures:
Children require
in children less than 5 years old
higher doses
• fluvoxamine (Luvox) for obsessive compulsive disorder (OCD):
than adults
in adolescents (12-17 year olds)
• benazepril (Lotensin) for hypertension
Children require
• famotidine (Pepcid) for gastroesophageal reflux:
lower doses
in patients less than 3 months of age
than adults
• fluvoxamine (Luvox) for OCD: in 8-11 year old girls
Unique
• betamethasone (Diprolene AF, Lotrisone) for some dermatoses:
pediatric
not recommended in patients less than 12 years of age due to
adverse events
hypopituitary adrenal (HPA) axis suppression
• atomoxetine (Strattera) for attention deficit hyperactivity
Effects on
disorder
growth and
• fluoxetine (Prozac) for depression and OCD
development
• ribaviron/intron A (Rebetron) for chronic hepatitis C
Sources: Presentations by Drs. Dianne Murphy and William Rodriguez, FDA.
Such examples demonstrate the need for studies in children of each drug’s
pharmacokinetics — uptake, distribution, binding, elimination, and biotransformation
rates within the body. Those studies are particularly valuable because doses for some
drugs must be larger than the adult dose to be effective in children, and because there
is great pharmacokinetic variation among children of different ages.
Clinicians need pediatric-specific information in the FDA-approved labeling of
drugs to help them decide which, if any, drug to use, in what amount, and by what
route to administer the drug. They — and their patients’ parents or guardians — need
to know what range of adverse events have been noted. That information would
come from well-designed and well-conducted studies in children — studies that have
been slow to appear.

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Manufacturers Have Been Reluctant
to Test Drugs in Children
Depending on how one defines the denominator (e.g., all drugs, or all drugs used
by children), an estimated 65-80% of drugs have not been tested in children. Why
not? The market has not been able to overcome the obstacles — which could be
economic, ethical, legal, or mechanical — that make manufacturers reluctant to
conduct these tests.
The market for any individual drug’s pediatric indications is generally small,
providing an economic disincentive for manufacturers to commit resources to
pediatric testing. Because young children cannot swallow tablets, the manufacturer
might have a mechanical hurdle in developing different formulation (such as a
liquid). The ethical and legal difficulties encountered in recruiting adult participants
in clinical trials are even greater when seeking children: many parents do not want
their children in experiments and liability concerns include not only injury but
difficult-to-calculate lifetime compensation.
Congress has offered incentives to manufacturers for pediatric research for two
main reasons. First, it is clear that, in treating sick children, doctors will continue
prescribing drugs despite insufficient pediatric-use studies. Second, Congress has
generally believed that, despite the difficulty in conducting such studies, children
could be better served once the research was done.
The Current Laws Evolved from Earlier Attempts
Before the 2002 BPCA and the 2003 PREA, FDA attempted to spur pediatric
drug research through administrative action (see Table 2).
1979: Rule on Drug Labeling
In a 1979 rule on drug labeling, FDA established a “Pediatric use” subsection.
The rule required that labeling include pediatric dosage information for a drug with
a specific pediatric indication [approved use of the drug]. It also required that
statements regarding pediatric use for indications approved for adults be based on
“substantial evidence derived from adequate and well-controlled studies” or that the
labeling include the statement “Safety and effectiveness in children have not been
established.”5
Despite the 1979 rule, most prescription drug labels continued to lack adequate
pediatric use information. The requirement for adequate and well-controlled studies
deterred many manufacturers who, apparently, did not understand that the rule
included a waiver option. FDA, therefore, issued another rule in 1994.
5 FDA, “Labeling and Prescription Drug Advertising; Content and Format for Labeling for
Human Prescription Drugs; Final rule,” Federal Register, vol. 44, no. 124, June 26, 1979,
pp. 37434-37467.

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Table 2. Administrative and Statutory Efforts to Encourage
Pediatric Drug Research
Year
Action
FDA pediatric guidance on “General Considerations for the Clinical
1977
Evaluation of Drugs in Infants and Children”
FDA rule on Pediatric Use subsection of product package insert:
1979
Precautions section [21 CFR 201.57(f)(9)] (in 44 Fed. Reg. 37434)
1994
FDA rule revised
1996
FDA guidance on “Content and Format of Pediatric Use Section”
Food and Drug Administration Modernization Act (FDAMA,
1997
P.L. 105-115), included the Better Pharmaceuticals for Children Act
1998
FDA Pediatric Rule finalized (effective 1999; invalidated 2002)
Adaptation of HHS Subpart D (pediatric) regulations [45 CFR 36 Subpart D]
2001
to FDA-regulated research [21 CFR 50 Subpart D]
2002
Best Pharmaceuticals for Children Act (BPCA, P.L. 107-109)
2003
Pediatric Research Equity Act (PREA, P.L. 108-155)
Source: Adapted from Steven Hirschfeld, Division of Oncology Drug Products & Division of
Pediatric Drug Development, Center for Drug Evaluation and Research (CDER), FDA, “History of
Pediatric Labeling,” presentation to the Pediatric Oncology Subcommittee of the Oncologic Drugs
Advisory Committee, March 4, 2003, at [http://www.fda.gov/ohrms/dockets/ac/03/slides/3927S1_
01_Hirshfeld%20.ppt].
1994: Revised Rule
The purpose of the revised rule was to make clear that the “adequate and well-
controlled studies” language did not require that clinical trials be conducted in
children. The new rule described how FDA would determine whether the evidence
was substantial and adequate. A pediatric indication that did not match an approved
adult indication (for example, if clinicians would use the drug to treat a different
condition in children than its FDA-approved use in adults) would require trials in a
pediatric population. However, if the drug would be used in children for the same
condition for which FDA had approved its use in adults, the labeling statement
regarding effectiveness could be based on adult trials alone. In such instances, FDA
might also require pediatric study-based data on pharmacokinetics or relevant safety
measures. The 1994 rule continued the 1979 requirement that manufacturers include
statements regarding uses for which there is no substantial evidence of safety and
effectiveness. It added a requirement that labels include information about known
specific hazards from the active or inactive ingredients.6
6 FDA, “Specific Requirements on Content and Format of Labeling for Human Prescription
Drugs; Revision of “Pediatric Use” Subsection In the Labeling; Final rule,” Federal
Register
, vol. 59, no. 238, December 13, 1994, pp.64240-64250.

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Food and Drug Administration Modernization Act of 1997
FDAMA (P.L. 105-115), incorporating the provisions introduced as the Better
Pharmaceuticals for Children Act, created a Section 505A (21 U.S.C. 355a) in the
FFDCA: Pediatric studies of drugs. It provided drug manufacturers an incentive to
conduct pediatric use studies on their patented products. In exchange for a
manufacturer’s completing a pediatric study according to FDA’s written request,
which included design, size, and other specifications, FDA would extend its market
exclusivity for that product for six months.7 The law required that the Secretary each
year publish a list of FDA-approved drugs for which additional pediatric information
might produce health benefits. FDAMA also required a report from the Secretary
examining whether the new law enhanced pediatric use information, whether the
incentive was adequate, and what was the program’s economic impact on taxpayers
and consumers.
1997: The Pediatric Rule
Also in 1997, FDA issued a proposed regulation that came to be called the
Pediatric Rule.8 The Pediatric Rule mandated that manufacturers submit pediatric
testing data at the time of all new drug applications to FDA. [Note: This concept is
the basis of the Pediatric Research Equity Act, discussed in the next section of this
report.] The rule went into effect in 1999. The Competitive Enterprise Institute and
the Association of American Physicians and Surgeons filed a lawsuit against FDA,
claiming that the agency was acting outside its authority in considering off-label uses
of approved drugs. In October 2002, a federal court declared the Pediatric Rule
invalid, noting that its finding related not to the Rule’s policy value but to FDA’s
statutory authority in promulgating it:
The Pediatric Rule may well be a better policy tool than the one enacted by
Congress (which encourages testing for pediatric use, but does not require it) ...
It might reflect the most thoughtful, reasoned, balanced solution to a vexing
public health problem. The issue here is not the Rule’s wisdom ... The issue is
the Rule’s statutory authority, and it is this that the court finds wanting.9
7 Although market exclusivity is a characteristic of patent benefit, the FDA-granted
exclusivity is not a patent extension; rather, it means that, during the six-month period, FDA
would not grant marketing approval to another identical product (usually a generic). For
more discussion of pharmaceutical patents and marketing exclusivity, see, for example, CRS
Report RL33288, Proprietary Rights in Pharmaceutical Innovation: Issues at the
Intersection of Patents and Marketing Exclusivities
, by John R. Thomas.
8 FDA, “Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of
New Drugs and Biological Products in Pediatric Patients; Final rule,” Federal Register, vol.
63, no. 231, December 2, 1998, pp. 66632-66672.
9 U.S. District Judge Henry H. Kennedy Jr. quoted in Marc Kaufman, “Judge Rejects Drug
Testing on Children; Ruling Finds FDA Overstepped Authority in Forcing Pediatric
Studies,” Washington Post, October 19, 2002, p. A9.

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BPCA and PREA:
Laws to Encourage Pediatric Drug Research
Although other laws (such as those affecting drug development, safety and
effectiveness efforts, and general health care and consumer protection) serve to
promote or protect the health of children, the two laws that are scheduled to sunset
as FY2007 ends — the Best Pharmaceuticals for Children Act and the Pediatric
Research Equity Act — authorize the programs most focused on pediatric drug
research.
The Best Pharmaceuticals for Children Act
Pediatric Exclusivity. The Best Pharmaceuticals for Children Act (BPCA,
P.L. 107-109), in 2002, reauthorized FDAMA’s pediatric exclusivity provisions in
FFDCA Section 505A (21 U.S.C. 355a). BPCA renewed the agency’s authority to
give an additional six-month period of marketing exclusivity to a manufacturer in
return for FDA-requested pediatric use studies and reports.
FDA-NIH Collaboration. Pediatric exclusivity, however, is not relevant to
products that are no longer covered by patent or other marketing exclusivity
agreements. Also, a patent-holding manufacturer may decline to conduct the FDA-
requested study and, therefore, the exclusivity. BPCA, therefore, added provisions
to encourage pediatric research in those products.
Off-patent products. BPCA addressed the first group, which it described as
“off-patent,” by adding to the Public Health Service Act (PHSA) a new Section 409I
(42 U.S.C. 284m). It established an off-patent research fund at NIH for these studies
and authorized appropriations of $200 million for FY2002 and such sums as are
necessary for each of the five years until the provisions are set to sunset on October
1, 2007.
Sponsor-declined studies. For on-patent drugs whose manufacturers
declined FDA’s written requests for studies, BPCA amended the FFDCA Section
505A to allow their referral by FDA to the Foundation for the National Institutes of
Health for pediatric studies, creating a second program of FDA-NIH collaboration.
Other Provisions. Other BPCA provisions included giving priority status to
pediatric supplemental applications; the establishment of an FDA Office of Pediatric
Therapeutics; the definition of pediatric age groups to include neonates; and a
direction to the HHS Secretary to contract with the Institute of Medicine for a review
of regulations, federally prepared or supported reports, and federally supported
evidence-based research, all relating to research involving children.10 The IOM
report to Congress was to include recommendations on best practices relating to
research involving children.
10 See Institute of Medicine, Ethical Conduct of Clinical Research Involving Children,
Committee on Clinical Research Involving Children (Washington, DC: National Academies
Press, 2004), done with funding from NIH and FDA.

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Pediatric Research Equity Act
When a federal court ruled that FDA had overstepped its statutory authority in
promulgating the Pediatric Rule, Members of Congress moved to give FDA that
authority. The Pediatric Research Equity Act of 2003 (PREA, P.L. 108-155)
essentially codified the Pediatric Rule by adding to the FFDCA a new Section 505B
(21 U.S.C. 355c): Research into pediatric uses for drugs and biological products.
Unlike BPCA, which applies only to drugs, PREA applies both to drugs regulated
under the FFDCA and to biological products (e.g., vaccines) regulated under the
PHSA.
New Applications. With PREA, a manufacturer submitting an application
to market a new active ingredient, new indication, new dosage form, new dosing
regimen, or new route of administration must at the same time submit a pediatric
assessment. The submission must be adequate to assess the safety and effectiveness
of the product for the claimed indications in all relevant pediatric subpopulations;
and to support dosing and administration for each pediatric subpopulation for which
the product is safe and effective. If the disease course and drug effects are
sufficiently similar for adults and children, the HHS Secretary may allow
extrapolation from adult study data as evidence of pediatric effectiveness, usually
supplemented with other data from children, such as pharmacokinetic studies.
The law specifies situations in which the Secretary may defer or waive the
pediatric assessment requirement, such as when it is known that a drug should never
be used by children. In those cases, it directs that the product’s labeling include any
waiver that was based on evidence that pediatric use would be unsafe or ineffective.
Products on the Market. The Secretary may require the manufacturer11 of
an approved drug or licensed biologic to submit a pediatric assessment in situations
in which not having pediatric use information on the label could pose significant
risks. Those situations include a finding by the Secretary that a marketed product is
used by pediatric patients for indications labeled for adults, or that the product may
provide a meaningful therapeutic benefit over available alternatives for children.
Before requiring the assessment, the Secretary must have issued a written request
under FFDCA Section 505A (BPCA, pediatric exclusivity) or PHSA Section 409I
(NIH funding mechanisms). Further, the manufacturer must not have agreed to
conduct the assessment, and the Secretary must have stated that the NIH funding
programs either have or do not have sufficient funds to conduct that study.
If the manufacturer does not comply with the Secretary’s notice of a required
study, the Secretary may consider the product misbranded. Because the Congress
wanted to protect adult access to a product under these circumstances, the law sets
limits on FDA’s enforcement options, precluding, for example, the withdrawal of
approval or license to market.
11 The laws refer to the sponsor of an application or the holder of an approved application.
Because that entity is usually the product’s manufacturer, this report uses the term
manufacturer throughout.

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Other Provisions. Seeing PREA and BPCA as complementary approaches
to the same goal, Congress linked PREA to BPCA. [Note: A discussion of this
linkage appears later in this report.] Therefore, rather than specify a sunset date,
Congress authorized PREA to remain in effect only as long as BPCA has not sunset.
BPCA and PREA Have Had Some Impact on
Pediatric Drug Research
Best Pharmaceuticals for Children Act
On-Patent Drugs. As of February 28, 2007, FDA had issued 338 written
requests outlining 782 specific pediatric studies to manufacturers holding patent or
other exclusivity benefits.12 The requests also specify the study purpose: about half
of the studies addressed efficacy and safety, more than a third focused on aspects of
pharmacokinetics.13
The data in Table 3 illustrate where the pediatric exclusivity provisions in
FDAMA and BPCA have helped and where they have not. They show that when
FDA granted companies exclusivity for a drug, 87% of those drugs’ labeling changed
to reflect pediatric information. In other words, the incentive worked. However,
those drugs (with labeling changes) make up only 35% of the drugs that FDA asked
the manufacturers to study. BPCA did not give FDA any authority to address the
remaining 65%, those drugs whose manufacturers chose not to accept exclusivity and
the pediatric study requirements.
12 FDA, “Pediatric Exclusivity Statistics as of February 28, 2007,” updated March 9, 2007,
at [http://www.fda.gov/cder/pediatric/wrstats.htm]; and FDA, “Pediatric Exclusivity,”
updated January 9, 2007, at [http://www.fda.gov/cder/pediatric/breakdown.htm].
13 FDA, “Pediatric Exclusivity,” updated January 9, 2007, at [http://www.fda.gov/cder/
pediatric/breakdown.htm].

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Table 3. Two Ways to Describe the Effect of Pediatric
Exclusivity on Pediatric Labeling Changes
% of
% of
Number
previous category
written requests
a
FDA written requests
338

100

100
Exclusivity determinations
149
(149/338)
44
(149/338)
44
b
Drugs granted exclusivity
136
(136/149)
91
(136/338)
40
c
Labeling changed
118
(118/136)
87
(118/338)
35
Sources: FDA, “Approved Active Moieties to Which FDA has Granted Pediatric Exclusivity for
Pediatric Studies under Section 505A of the Federal Food, Drug, and Cosmetic Act,” updated March
19, 2007; and “Pediatric Exclusivity Labeling Changes as of November 22, 2006,” updated Dec. 18,
2006; both at [http://www.fda.gov/cder/pediatric].
a. These 338 written requests entailed 782 studies.
b. These 136 drugs reflect 129 active components.
c. Labeling data go through November 2006, whereas the other data go to mid-March 2007.
NIH Route for Off-Patent Drugs and On-Patent Drugs for Which
Manufacturers Declined FDA’s Requests for Study. Under BPCA, NIH has
put 51 drug-indication entries on its “List of Drugs for Which Pediatric Studies Are
Needed.”14 Of those, only nine (17.6%) have progressed to choice of clinical trial
sites, an indication that they are funded.
Table 4 shows how the 51 items recommended for pediatric study from 2003
through the first quarter of 2006, are distributed by patent status and whether a study
had begun.
Table 4. Research Status of Drugs That NIH Deemed In Need of
Pediatric Studies, by Patent Status
Clinical trial site chosen
Patent status
Yes
No
Total
On
2
(16.7%)
10
12
Off
7
(17.9%)
32
39
Total
9
(17.6%)
42
51
Source: Adapted from NIH, “List of Drugs for Which Pediatric Studies Are
Needed; Notice,” Federal Register, vol. 71, no. 79, April 25, 2006, pp. 23931-
23936.
14 NIH, “List of Drugs for Which Pediatric Studies Are Needed; Notice,” Federal Register,
vol. 71, no. 79, April 25, 2006, pp. 23931-23936.

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GAO Study. In March 2007, the Government Accountability Office (GAO)
issued a report that the BPCA legislation had required.15 Noting that most of the
exclusivity-associated studies resulted in labeling changes, GAO calculated the time
that elapsed before those changes were completed. The entire process — from initial
data submission, through FDA review and frequent requests for additional data, to
follow-up submissions and reviews — took an average of nine months. One-third
of the drugs’ labeling changing took less than three months, while labeling change
for one took almost three years. Most of the studies supported labeling changes to
inform of ineffective drugs, dosing that was too high or too low, and newly identified
adverse events. The GAO report juxtaposed those finding with the statement that
children take many of these drugs for common, serious, or life-threatening
conditions.
Pediatric Research Equity Act
FDA approved more than 372 new drug and biologics license applications from
the beginning of 2003 through 2006.16 For that same period, FDA attributes 63
labeling changes to PREA.17 Table 5 indicates the topics of those label changes.
Table 5. Content of PREA-Associated Labeling Changes
Topic of label change
Number of label changes
Extended indication
2
New active ingredient
11
New dosage form
17
New dosing regimen
8
New drug
4
New indication
19
New route of administration
2
Total number of label changes
63 a
Source: FDA, “PREA Labeling Changes,” page created March 23, 2007, at
[http://www.fda.gov/CDER/pediatric/PREA_label_post-mar_2_mtg.pdf].
a. Eight products had two label changes (e.g., Xopenex HFA Inhalation Aerosol
had both a new active ingredient and an extended indication).
15 Government Accountability Office (GAO), Pediatric Drug Research: Studies Conducted
under Best Pharmaceuticals for Children Act
, Report to Congressional Committees, GAO-
07-557, March 2007.
16 FDA, “CDER Approval Times for Priority and Standard NDAs and BLAs, Calendar
Years 1993-2006,” January 29, 2007, at [http://www.fda.gov/cder/rdmt/NDAapps93-
06.htm]. FDA’s Center for Drug Evaluation and Research has, since 2004, covered
Biologics License Applications (BLAs) for therapeutic biologics [e.g., monoclonal
antibodies for in vivo use; most proteins intended for therapeutic use, including cytokines
(e.g., interferons), enzymes (e.g. thrombolytics), and other novel proteins;
immunomodulators; and growth factors]; other BLAs [e.g., vaccines, blood products, and
coagulation factors], which are regulated within FDA’s Center for Biologics Evaluation and
Research, are not included in this tally.
17 FDA, “PREA Labeling Changes,” March 23, 2007, at [http://www.fda.gov/CDER/
pediatric/PREA_label_post-mar_2_mtg.pdf].

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Comparison of BPCA and PREA
When presenting material about the pediatric research provisions in law, more
than one FDA speaker has referred to “the carrot and the stick.” BPCA offers a
carrot — extended market exclusivity in return for specific studies on pediatric use;
PREA follows up with a stick — required studies of a drug’s safety and effectiveness
when used by children. Table 6, adapted from an FDA slide presentation,
summarizes the key differences between these two laws.
Table 6. Major Differences in the BPCA and PREA Approaches
BPCA
PREA
Added FFDCA Section 505A
Added FFDCA Section 505B
Pediatric research
Pediatric assessments
Pediatric studies are voluntary and in
Pediatric studies are mandatory
exchange for marketing exclusivity
Applies to drugs
Applies to drugs and biologics
Research and exclusivity to cover all uses of
Research to cover the indicated use, dose, and
the active drug component
route of administration under FDA review
Source: Adapted from Lisa Mathis, Associate Director, Pediatric and Maternal Health Team, Office
of New Drugs, CDER, “Growth and Development of Pediatric Drug Development at the FDA,” June
2006 presentation to the Institute of Medicine, the National Academies, at [http://www.fda.gov/oc/
opt/presentations/drugdevelopment.ppt].
FDA Activities
In its implementation of the pediatric research laws, FDA has published
numerous documents and provides electronic links to these documents on its
“Pediatric Drug Development” page, at [http://www.fda.gov/cder/pediatric/]. These
include:
! Rules and announcements, such as “Summaries of Medical and
Clinical Pharmacology Reviews of Pediatric Studies; Availability,”
Federal Register, vol. 71, no. 201, October 18, 2006, pp.
61484-61485;
! Final and draft guidances, such as Qualifying for Pediatric
Exclusivity Under Section 505A of the Federal Food, Drug, and
Cosmetic Act
, issued in 1999; and How to Comply with the Pediatric
Research Equity Act
, draft issued in 2005;
! Written request templates, such as “Sample Written Request For
Division of Oncology Drug Products”;
! Agenda and transcripts for the meetings of advisory committees,
such as “FDA Pediatric Ethics Working Group Consensus Statement
on the Pediatric Advisory Subcommittee’s April 24, 2001 Meeting”;
and
! Statistics, such as “Pediatric Exclusivity Labeling Changes as of
November 22, 2006,” and “PREA Labeling Changes,” March 30,
2007.

CRS-13
Congressional Options
Recent statements by Members of both the House and the Senate make it seem
likely that the 110th Congress will preserve the concept and structure of the Best
Pharmaceuticals for Children Act and the Pediatric Research Equity Act. There is
broad support for some version of these programs that encourage — with carrot and
stick — increased research to support accurate labeling information regarding
pediatric use of FDA-approved drugs.
But there is also support for change. What issues and options might Congress
consider in such an effort?
So far, most discussion in Congress has revolved around five issues: exclusivity,
cost, labeling, enforcement, and sunset policy.
Exclusivity
BPCA offers pharmaceutical companies a reward for agreeing to conduct studies
on drugs for pediatric populations. But PREA requires pediatric studies. Some may
ask why Congress must offer industry a reward for something it requires them to do.
After reviewing the history of pediatric exclusivity during the period when
Congress was considering reauthorizing the FDAMA exclusivity provisions in a
proposed BPCA, one legal analyst wrote:
The strongest argument in support of this incentive structure is that without it
pharmaceutical companies would not be willing to conduct pediatric tests. This
argument depends, however, on a voluntary system of pediatric testing. If
Congress had codified the FDA’s power to require testing in all new and already
marketed drugs, the notion of an incentive or reward for testing would appear
ludicrous.18
When considering the PREA bill in 2002, Members of Congress debated how the
two laws would relate. But the record provides no clear answer.19 Three years later,
in its draft guidance on “How to Comply with the Pediatric Research Equity Act,”
FDA wrote that “[t]he Pediatric Rule was designed to work in conjunction with the
pediatric exclusivity provisions of section 505A of the Act....”
18 Lauren Hammer Breslow, “The Best Pharmaceuticals for Children Act of 2002: The Rise
of the Voluntary Incentive Structure and Congressional Refusal to Require Pediatric
Testing,” Harvard Journal on Legislation, vol. 40, 2003, pp. 133-191.
19 S.Rept. 108-84, to accompany S. 650, the Pediatric Research Equity Act of 2003, June 27,
2003. Sen. Gregg, as committee chair, wrote: “The Pediatric Rule was intended to work as
a safety net to (or as a backstop to) pediatric exclusivity;” and Sen. Clinton and others wrote
in the report’s “Additional Views” section: “Neither the intent conveyed by FDA nor FDA’s
implementation of the [Pediatric] [R]ule 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.”

CRS-14
Cost
In assessing the value of BPCA and PREA, identification of the intended and
unintended effects — both positive and negative — of their implementation thus far
can be useful. One hypothetical product illustrates effects on manufacturers, patients,
and the government.
The manufacturer holding pediatric exclusivity incurs the research and
development expenses related to the FDA-requested pediatric studies. It then enjoys
six months of sales without a competitor product and a potentially lucrative head start
on future sales. The manufacturers that do not hold the exclusivity, must wait six
months during which they cannot launch competing products. After that, however,
they may be able to market generic versions of a drug that has been assessed for
pediatric use and has had six months’ experience in the public’s awareness.
Nonfinancial benefits to government include its progress in protecting children’s
health. Costs to the government include administrative and regulatory expenses.
Because the government also pays for drugs, both directly and indirectly, it must pay
the higher price that exclusivity allows for six months. The better pediatric
information, however, may yield future financial savings by avoiding ineffective and
unsafe uses. Private payers also face the same financial cost and benefit. Some
children may incur risks as study subjects; they and others might benefit from more
appropriate use of drugs, including accurate dosing.
Although assigning quantitative values to those effects is beyond the scope of
this report, some researchers have examined the financial costs and benefits faced by
manufacturers that receive pediatric exclusivity. One study appeared in February
2007, written by a team lead by Jennifer Li of Duke University’s Department of
Pediatrics, with co-authors from its Department of Economics and the Duke Clinical
Research Institute, as well as from the Office of the Commissioner at FDA.20 It
calculated the net economic benefit (costs minus benefits, after much estimating and
adjusting for other factors) to a manufacturer that, in 2002-2004, responded to an FDA
request for pediatric studies and received pediatric exclusivity. The median net
economic benefit of six-month exclusivity was $134.3 million. The study found a
large range, from a net loss to a net benefit of over half a billion dollars.
Are these effects — on manufacturers, pediatric patients and their families, adult
patients, others, and on government itself — in line with Congress’s intentions in
passing the legislation? Might this Congress want to modify the programs to modify
the distribution of benefits and costs?
20 Jennifer S. Li, Eric L. Eisenstein, Henry G. Grabowski, et al., “Economic Return of
Clinical Trials Performed Under the Pediatric Exclusivity Program,” Journal of the
American Medical Association
, vol. 297, no. 5, February 7, 2007, pp. 480-488.

CRS-15
Labeling
Whatever information researchers learn — about safety, effectiveness, dosing,
or side effects when a child takes a medication — must reach clinicians and others
who care for children (including parents) before a child can benefit. BPCA and
PREA, therefore, include labeling provisions. Have they been successful? Could they
be modified to be better?
Whether Pediatric Information Is Required. Currently, FDA requires, by
law or regulation, pediatric usage labeling in the following circumstances:
! manufacturer has successfully applied (via an original new drug
application [NDA] or a supplement) for approval to list a pediatric
indication; or
! manufacturer received pediatric exclusivity after conducting
appropriate studies.
In the first case, pediatric use information is included in the labeling only if FDA
approved the pediatric indication. If FDA turned down or the manufacturer withdrew
a request for a pediatric indication, not only does pediatric use information not appear
in the product’s labeling, the fact that the manufacturer had made an unsuccessful
attempt — and the research findings that blocked the approval — are neither noted in
the label nor made public in other ways.
The rules for labeling that come with pediatric exclusivity are different. If the
studies required for exclusivity support pediatric use or specific limits to pediatric use
(different dosing or subgroups), that information would go in the labeling. If the
studies did not find the drug to be effective in children or if FDA waived the
requirement to study because children should not or would not be given the drug, that
information, too, would go in the labeling.
Despite the requirements and the progress that has been made, not all drugs used
by children have labeling that addresses pediatric use. As previously noted, FDA
approved more than 372 new drug and biologics license applications from the
beginning of 2003 through 2006.21 Yet, the PREA statistics on labeling note 63
labeling changes over that period.
Also, BPCA (January 2002) required HHS to promulgate a rule within one year
of enactment (therefore, January 2003) regarding the placement on all drug labels of
a toll-free telephone number with which to report adverse events. FDA has not yet
issued that rule.
Content of Included Pediatric Information. While an improvement over
no mention at all, a statement such as “... effectiveness in pediatric patients has not
been established” still deprives a clinician of information that is available. The
statement does not distinguish between drugs studied and not studied in children. If
no studies were done, effectiveness could not have been established. If studies were
21 For more information, see [http://www.fda.gov/cder/rdmt/NDAapps93-06.htm].

CRS-16
conducted, were they appropriately designed to test safety and effectiveness? Among
drugs that were studied in children, adding “effectiveness in pediatric patients has not
been established” to the labeling does not distinguish among the following:
! studied in children, found to be ineffective;
! studied in children, found to be unsafe; or
! studied in children, not found to be effective ... inconclusive.
If studies suggest that safety, effectiveness, or dosage reactions vary by age,
condition to be treated, or patient circumstances, then detailed information could be
included in the labeling.
Enforcement
Congress has given FDA limited authority regarding pediatric drug use labeling,
similar to the FDA’s situation with direct-to-consumer (DTC) prescription drug
advertising. FDA is charged to regulate direct-to-consumer (DTC) prescription drug
advertising, but without the authority, except in egregious situations, to require that
a manufacturer change an ad’s content. For both situations — pediatric labeling and
DTC advertising, Congress has given FDA the authority to use its sledgehammer —
deeming a product to be “misbranded” and thereby gaining the authority to pull it
from the market — but has not given the agency authority to require less drastic
actions, such as labeling changes.
To pull from the market a drug on which many consumers rely would be,
according to some health care analysts, akin to throwing out the baby with the
bathwater. In its report accompanying the PREA bill, the Senate committee specifies
that the misbranding authority regarding pediatric use labeling should not be the basis
for criminal proceedings or withdrawal of approval, and could only rarely result in
seizure of the offending product.
Enforcement scenarios: What options should FDA have if a manufacturer that
has already received the six-month pediatric exclusivity then refuses or delays making
an appropriate labeling change? For studies that result in labeling changes, when
should FDA make study results available to the public?
In considering whether to strengthen FDA’s enforcement authority within the
context of pediatric research and labeling, Congress has the option to address
manufacturers’ actions at many points in the regulatory process, if and when, for
example,FDA notes: a manufacturer’s reluctance to accept the agency’s requested
study scope, design, and timetable; that a study’s completion is clearly lagging or
overdue; that a manufacturer does not complete such a study; or does not release its
results to FDA, peer-reviewed publications, or the public; or that procedures to
incorporate pediatric study results into a drug’s labeling have not proceeded
appropriately.

CRS-17
Sunset
Not every law contains a sunset provision. BPCA does, and PREA, although the
term is not used, essentially is set to cease if and when BPCA does. By including an
end date or another indication of a predetermined termination date, Congress provides
“an ‘action-forcing’ mechanism, carrying the ultimate threat of termination, and a
framework or guidelines for the systematic review and evaluation of past
performance.”22
Although the concept of a sunset is apparently accepted for BPCA (which offers
pediatric exclusivity as a financial incentive to manufacturers), whether it is
appropriate for PREA (which seeks to ensure that the labeling of all drugs that
clinicians prescribe for children’s use includes information about safety, effectiveness,
and dosing in relevant subsets of children) is again a topic of debate.23
If proponents of a PREA sunset intend it as a trigger for regular evaluation of the
law’s usefulness, there may be other legislative approaches that would more directly
achieve that. If, however, the intent is to use PREA to test the idea of requiring
pediatric assessments, that would likely engender a different focus of debate.
Bills in the 110th Congress
! S. 830, Pediatric Medical Device Safety and Improvement Act of
2007, introduced March 8, 2007, by Senator Dodd.
! H.R. 1494, Pediatric Medical Device Safety and Improvement Act of
2007, March 13, 2007, by Representative Markey. [This bill includes
all these provisions in S. 830 and would also require an annual review
by FDA’s Pediatric Advisory Committee.]
! S. 993, the Pediatric Research Improvement Act, introduced March
28, 2007, by Senator Clinton.
! S. 1082, the Food and Drug Administration Revitalization Act,
introduced April 10, 2007, by Senator Kennedy.24 The bill includes
22 CRS Report RS21210, Sunset Review: A Brief Introduction, by Virginia A. McMurtry.
23 See Senator Clinton’s comments at the Senate Committee on Health, Education, Labor,
and Pensions hearing, “Ensuring Safe Medicines and Medical Devices for Children,” March
27, 2007, at [http://www.cq.com/display.do?dockey=/cqonline/prod/data/docs/html/
transcripts/congressional/110/congressionaltranscripts110-000002481833.html@
committees&metapub=CQ-CONGTRANSCRIPTS&searchIndex=0&seqNum=13]; and
S.Rept. 108-84, Additional Views.
24 Other provisions in S. 1082, as reported, are prescription drug and medical device user fee
program reauthorizations, drug safety, clinical trial databases, and conflicts of interest. See
related CRS reports, including CRS Report RL33914, The Prescription Drug User Fee Act
(continued...)

CRS-18
three sets of related provisions in its Title IV: “Pediatric Medical
Products.”
S. 1082 includes, as Subsection A of Title IV, the Best Pharmaceuticals for
Children Amendments of 2007. Subsection B is the Pediatric Research Improvement
Act, which includes the provisions of S. 993, except for one. S. 993 would eliminate
the provision in the Pediatric Research Equity Act that linked authorization to the
sunset provision in the Best Pharmaceuticals for Children Act. As reported, S. 1082
allows for the sunset on October 1, 2012. Subsection C is the Pediatric Medical
Device Safety and Improvement Act of 2007. It includes many of the provisions of
S. 830.
The Senate Committee on Health, Education, Labor, and Pensions, on April 24,
2007, reported the Chairman’s April 16, 2007 mark of S. 1082, with amendments.
This FDA Revitalization Act is scheduled for Senate floor consideration.
The House Energy and Commerce Committee has held hearings on pediatric
drug safety, but has not yet considered any specific bill.
24 (...continued)
(PDUFA): Background and Issues for PDUFA IV Reauthorization, by Susan Thaul; CRS
Report RL33981, Medical Device User Fee and Modernization Act (MDUFMA)
Reauthorization
, by Erin D. Williams; CRS Report RL32797, Drug Safety and
Effectiveness: Issues and Action Options After FDA Approval
, by Susan Thaul; and CRS
Report RL32832, Clinical Trials Reporting and Publication, by Erin D. Williams.