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Pediatric Research Equity Act of 2003
Pediatric Research Equity Act of 2003
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DOC
21.1/5:108-84
Calendar No. 183
108TH CONGRESS REPORT
1st Session } SENATE
{ 108-84
Page
I. Purpose and need for legislation 1
II . Summary 7
III. History of legislation and votes in committee 9
IV . Explanation of bill and committee views 9
V. Regulatory Impact Statement 12
VI. Application of law to the legislative branch 12
VII. Cost estimate .... 12
VIII. Section -by -section analysis 13
IX . Additional views 17
X. Changes in existing law 24
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Act (“ BPCA ”) (Pub. L. No. 107–109) . The legislation works by pro
viding an incentive of 6 months of additional market exclusivity for
sponsors in exchange for the voluntary performance of clinical stud
ies of drugs in the pediatric populationin response to a written re
quest from FDA. The BPCA also created programs administered by
the NIH to issue grants and contracts for researchers to conduct
additional pediatric studies with privately donated and publicly ap
propriated funds. These laws have made headway in rectifying the
historical lack of clinical study data and labeling information on
the appropriate use of medicines in children .
Notwithstanding the progress that these prior pediatric initia
tives have produced, at least sixty -two percent of drugs onthe mar
ket remain unstudied and labeled for use in children.1 However,
that number reflects research in accordance with the old Pediatric
Rule. The authority for the new Pediatric Research Authority is
based on the percentage of drugs projected to need pediatric label
ing in light of ongoing commitments and research . Further action
is needed to ensure that medications are adequately studied and
labeled for use in children. The committee has approved this legis
lationto complement the existing voluntary pediatric exclusivity
and NIH study provisions by providing FDA with new , unprece
dented authorityto require that drug manufacturers conduct pedi
atric studies and submit pediatric assessments to FDA. On Decem
ber 2, 1998, FDA published in the Federal Register (63 FR 66632–
66672) a final regulation known as the “Pediatric Rule ” asserting
the authority to mandate pediatric testing in certain cir
cumstances . On October 17, 2002, a Federal court held that FDA
lacked the statutory authority to promulgate the Pediatric Rule,
and declared the Rule invalid . The legislation reported by the com
mittee now provides FDA with statutory authority to require pedi
atric studies in certain defined circumstances .
There is a need to provide FDA legislative authority to require
pediatric testing because of the particular importance of pediatric
drug labeling. At the same time, the committee recognizes that ap
propriate safeguards must accompany this special grant of manda
tory testing authority. The committee intends that the new legisla
tion, the pediatric exclusivity incentive provisions, and the NIH
study provisions of the BPCA will work in a comprehensive and
complementary fashion . This legislation not only establishes provi
sions regarding new drugs but also provides a default mechanism
by which FDA can require pediatric studies where the voluntary
incentives and available contracts and grants have not produced
needed pediatric treatment information.
Children suffer from many of the same diseases as adults and
are often treated with the same medicines. Yet certain medicines
have not been adequately studied and labeled for use in children .
Dosing children based merely on their lower weight is often impre
cise, since their bodies can metabolize medicines differently than
adults. Some drugs may have different adverse side effects or
toxicities in children than in adults, so extrapolating safety or ef
fectiveness for children for medicines found to be safe and effective
in adults may not be appropriate. The lack of pediatric studies and
1 “ Testing Medications in Children ,” by Robert Steinbrook , M.D. October 31 , 2002. The New
England Journal of Medicine.
0-800
Sellos
3
Even given these differences in scope, the Pediatric Rule and the
pediatric exclusivity provision worked together to ensure that a
drug or biological product would be tested in and labeled for chil
dren when appropriate. When their scopes overlapped, Congress
provided in section 505A (h ) of the FFDCA that any pediatric stud
ies required by regulation also satisfied the requirements for mar
ket exclusivity. There were many drugs for which the rule and the
incentive worked together successfully to encourage a drug com
pany to respond affirmatively to FDA's request for pediatric stud
ies .
But the rule and pediatric exclusivity did not always both apply
to a drug. FDA reports that, between April 1 , 1999, when the rule
first became effective, and March 31, 2002, 404 new drug applica
tions and supplements fell within the scope of the rule. For ap
proximately 266 of these, manufacturers submitted, or would have
been required to submit, studies in one or more pediatric age
groups (the remaining received complete waivers, typically as a re
sult of safety concerns regarding the testing of the drug in children
or because the drug's approvedindication was not fora childhood
disease). As of June 5, 2003, 129 submitted applications contained
complete or partial pediatric use information. Because pediatric ex
clusivity incentives were not involved in these applications and
these were not drugs primarily developed for children, FDA at
tributes 67 ofthese submissions to the Pediatric Rule alone. By
comparison , FDA reports that as of June 2, 2003 , 72 drugs have
been granted exclusivity and 9 have been denied exclusivity, with
49 of these drugs currently labeled for use in the pediatric popu
lation. It is therefore clear that the Pediatric Rule and exclusivity
have worked together to improve the pediatric labeling of drugs
and biological products that has occurred since 1997, when Con
gress first provided for pediatric exclusivity and FDA first proposed
the Pediatric Rule .
At the same time, the court's decision in the Association of Amer
ican Physicians and Surgeons case invalidating the rule highlights
the tension between a mandatory study requirement and the basic
operation of the FFDCA, which leaves it to drug sponsors to deter
mine the claims they wish to make for a product. In that case,the
court held that FDA lacked authority under the existing FFDCA to
require that drug sponsors conduct studies or develop formulations
forclaims or patient populations that the sponsor is not seeking to
include in labeling for its product. In the court's words, FDA “ has
repeatedly stated that it may only regulate claimed uses of drugs,
not all foreseeable or actual uses .” The court further stated that it
is a “ long-established foundation of federal food and drug law ” that
manufacturers determine the intended uses of a product through
the representations they make for the product.
This legislation responds to the court's holding by providing FDA
new statutory authority to require pediatric assessments. The au
thority granted by the legislation tracks many elements of the
former Pediatric Rule to ensure that the progress produced by the
incentive and the Pediatric Rule will continue. There is a compel
ling basis for providing FDA such authority because of the impor
tance of ongoing pediatric research. At the same time, the legisla
tion establishes clear limitations on the new authority to require
pediatric assessments to ensure that the unique needs of the pedi
7
Enforcement
The legislation provides that FDA has misbranding authority
with respect to a drug or biological product for which a pediatric
assessment is not filed by the date specified by FDA may be consid
ered misbranded and subject to relevant enforcement action. The
committee stresses that seizure is generally an unsatisfactory rem
edy from a public health perspective because it denies adequately
studied populations access to safe and effective medicines. As a re
sult, the committee intends for seizure to be used rarely, if at all,
as a remedy for failure to conduct required pediatric studies. This
legislation makes clear that the failure to submit required assess
ments shall not be the basis for criminal proceedings, withdrawal
of approval as a new drug, or revocation of an approved biologics
license . The committee intends for FDA to enforce the mandate by
using its injunction authority without affecting the availability of
otherwise safe and effective products for other patients.
No effect on current authority
The legislation states that section 505B does not provide FDA
with any authority to require pediatric assessments, or assess
ments of other populations or uses , except as provided in section
505B . The committee notes the court's holding in Association of
American Physicians and Surgeons, Inc. v. FDA that FDA lacks the
current authority to require pediatric assessments. This legislation
does not expand FDA's current authority except as specifically enu
merated in section 505B .
Integration with other pediatric provisions
The legislation is integrated with the pediatric exclusivity provi
sions of section 505A of the FFDCA. The committee views the two
sections as working together in a complementary fashion . The com
mittee understands that section 505A is set to be reviewed for re
authorization in 2007 , and intends that the new section 505B be
reviewed for reauthorization at the same time.
V. REGULATORY IMPACT STATEMENT
The committee has determined that there will be minimal in
creases in the regulatory burden imposed by this bill.
VI. APPLICATION OF LAW TO THE LEGISLATIVE BRANCH
S. 650 adds section 505B to the Federal Food, Drug, and Cos
metic Act to further improve the safety and efficacy of both drugs
and biological products for children. As such, it has no application
to the legislative branch .
VII. COST ESTIMATE
and 499 of the PHSA, the assessment may be required. The assess
ment may also be required if the Secretary certifies that no grant
has been awarded and not less than 270 days have passed since
the certification there are sufficient funds to conduct the study.
This precondition ensures that the existing provisions of the BPCA
will be utilized and establishes required pediatric studies as a de
fault. Before invoking the agency's new authority to mandate pedi
atric studies under this Act, FDA must first have made a written
request for the manufacturer to conduct the study voluntarily
under section 505A of the FFDCA or section 4091 of the PHSA , to
which the manufacturer either did not agree or that FDA did not
receive a timely response. Subsection (b ) (3 ) also clarifies that the
mandatory pediatric study provisions of this Act do not alter the
provisions in the BPCA that establish a process at NIH to contract
for studies to gather pediatric information . Before requiring sub
mission of pediatric data of an already marketed drug product, sub
section ( b )( 3) requires FDA to certify either that insufficient funds
are available to contract for studies, or that sufficient funds are
available but no contract or grant has been awarded within the
specified time frame.
Section 505B (c): A product will be considered to offer a “meaning
ful therapeutic benefit” over existing therapies if FDA determines
that it would represent a significant improvement in the treatment,
diagnosis, or prevention of a disease compared with already mar
keted products labeled for that use in the relevant pediatric sub
population, or that it is in a class of products or is used for an indi
cation for which there is a need for additional options.
Section 505B(d) : FDA has misbranding authority over a drug or
biological product for which a pediatric assessment is not filed by
the date specified by FDA but FDA does not have the ability to
bring criminal proceedings or to withdrawal of approval as a new
drug or revocation of an approved biologics license.
Section 505B(e): FDA shall meet with the sponsor of a drug or
biological product at appropriate times during the investigational
process to discuss plans and timelines for pediatric studies or re
quests for waivers or deferrals of pediatric studies.
Section 505B (f): Subsection ( f) clarifies that this Act provides no
authority for FDA to require pediatric studies of any drug or bio
logical product, or studies regarding any other populations or uses
of a drug or biological product, except under the conditions pro
vided for in this Act.
Section 505B(g): The pediatric data requirements of this Act do
not apply to any drug for an indication for which “ orphan ” drug
designation has been granted under Section 526 of the FFDCA, un
less FDA determines otherwise by regulation .
Section 505B(h) : Subsection (h) ties the new authority provided
under this Act to the pediatric exclusivityprovisions codified at sec
tion 505A of the FFDCA. This Act provides, in essence, that the
new authority to require pediatric studies shall only remain in ef
fect so long as the pediatric exclusivity provisions also remain in
effect. The pediatric exclusivity provisions currently have a sunset
date of October 1 , 2007 .
16
( 17 )
ADDITIONAL VIEWS OF SENATORS KENNEDY, DODD,
CLINTON , MIKULSKI, MURRAY, AND REED
Enforcement
The report states that FDA has misbranding authority with re
spect to a drug or biological product for which a pediatric assess
ment is not filed by the date specified by FDA. While this state
ment helps to clarify that the bill is intended to give FDA the au
thority to deem a product misbranded solely on the basis that an
assessment was not submitted in accordance with the requirements
of the legislation, it is not a substitute for, and must be accom
panied by, a modification to the legislation.
The legislation states that if a sponsor fails to submit an assess
ment, the product may be considered misbranded. The use ofthe
word “may ” in relation to the ability of FDA to determine a product
to be misbranded or adulterated is an anomaly in the FFDCA. The
use of “may be considered misbranded” rather than “ shall be
deemed misbranded ", as occurs elsewhere in the FFDCA, may cre
ate uncertainty about the Committee's intent to give FDA full and
unambiguous authority to enforce the requirements of S. 650.
The Committee clearly intends for a court to interpret this lan
guage as giving FDA new misbranding authority, the use of the
word “may” creates a risk that a court will apply an interpretation
that would be contrary to the Committee's intent. Given that the
impetus for this legislation was to unequivocally provide FDA with
the exact statutory authority to require pediatric studies that the
federal district court ruled in October 2002 it lacked, it is critical
that the statutory language be modified and that “may ” be replaced
with “ shall ” to comport with the term used elsewhere in the
FFDCA.
In addition, the report incorrectly asserts that FDA has mis
branding authority when a pediatric assessment is not filed by the
date specified by FDA. In accordance with the plain language of
the legislation, any misbranding authority extends to bringing an
enforcement action for failure to comply with any of the require
ments of the legislation related to the submission of assessments
or requests for approval of a pediatric formulation , not just timeli
ness .
Effective date
We are also concerned that the current effective date in S. 650
may allow significant numbers of pediatric studies to be lost in the
gap between the requirements of the Pediatric Rule and the re
quirements of this legislation , despite the stated intent of the Com
mittee that the Rule and the legislation be " seamless.” Because the
current language applies the testing requirement to drug applica
tions submitted on or after October 17, 2002, we are concerned that
several categories of applications will not be subject to the require
( 18)
19
Intended use
FDA's Pediatric Rule to require the study in children of drugs
and biological products for their approved uses was held to be in
valid by a federal district judge . The report makes several ref
erences to and quotations from this ill- considered and obviously er
rant decision about how intended uses of FDA -regulated products
are made and about the scope of FDA's authority under the
FFDCA. We write to clarify these issues because we believe that
both the court and the report fundamentally misconstrue the au
thority of FDA, and that FDA already has the authority to require
studies on subpopulations that will use a drug. Although the dis
trict court concluded that FDA did not have sufficient authority to
require studies on off-label uses , it ignored, without discussion ,
FDA's determination that use in children is not an “off-label” use,
just as use in women is not an “off-label” use . It is a use in an ex
pected, major subpopulation, which may raise some different ques
tions than use in other populations. In choosing to ignore the agen
cy's centralargument in support of its authority, the decision fails
to answer the question of the agency's pre-existing authority to re
quire pediatric studies, or studies on other subpopulations.
The report also asserts, relying exclusively on the district court
opinion, that it is " the long- established foundation of our food and
drug laws” that drug sponsors determine the “ intended uses” of a
product, and that FDA does not regulate foreseeable or actual uses
of a product that the sponsor does not claim .” Although this asser
tion is often found in the arguments of the pharmaceutical industry
in attempts to weakenFDA's long -standing authority, it is contra
dicted by decades of FDA practice and numerous judicial opinions
from higher courts .
When determining a product's intended use, it is well-established
that FDA may consider evidence other thanexpress claims that a
product is intended to have a certain effect. Indeed, the text of the
FFDCA, longstanding FDA regulations, the legislative history of
the Medical Device Amendments of 1976, appeals court decisions,
and FDA's regulatory practice fully support this view.
For example, sections 201(g)( 1)(C) and (h)(3 ) of the FFDCA make
“ intended” effects, not “market claims,” the decisive factor. Al
though market claims are one important way to establish a prod
uct's intended effect, other circumstances can establish a product's
intended effect, and nothing in the text of the operative definitions
bars FDA from relying on such evidence.
Longstanding FDA regulations provide that “intended use” refers
to “ the objective intent of the persons legally responsible for label
ing,” and may be determined not only by “ labeling claims” and “ ad
vertising matter,” but also by other " oral or written statements ”
made by persons legally responsible for the labeling; " the cir
cumstances surroundingthe distribution of the article”; “ the cir
cumstances that the article is, with the knowledge of [the manufac
turer ),* * * offered and used for a purpose for which it is neither
labeled nor advertised ”; and (4) evidence that “ a manufacturer
knows, or has knowledge of facts that would give him notice ” that
a drug or device “ is to be used” for purposes other than those for
which the manufacturer offered the product . 21 CFR 201.128 and
801.4 .
21
intent may be derived from any relevant source), cert. denied, 479
U.S. 1086 ( 1987 ); Action on Smoking & Health v. Harris, 655 F.2d
236, 239–240 (D.C. Cir. 1980) (consumer use can be relevant in de
termining manufacturer intent) .
Finally, in its administration of the FFDCA, FDA has treated
products as drugs or devices, despite the absence of explicit market
claims. Among other products, FDA has treated as drugs or de
vices: ( 1) cosmetics containing hormones based on the absence of
any legitimate cosmetic purpose for the hormones; (2 ) toothpaste
containing fluoride because fluoride is widely accepted as an anti
cavity agent and affects the structure of the tooth; (3) thyroid - con
taining food supplements based on the recognized physiological ef
fects of thyroid products; ( 4 ) interferon based on media coverage
touting it as a possible miracle cure; (5 ) novelty condoms based on
their likely use as prophylactics; (6 ) sun screen products based on
consumer expectations that they will provide protection against the
harmful effects of the sun on the body; and (7) tanning booths
based on the known effects of ultraviolet rays on the structure or
function of the body. In each of these cases, FDA found that the
product was intended for use as a drug or a device based on the
inherent nature of the product, its predominant use or effects, or
both.
Some of these cases required FDA to determine whether a prod
uct was under its jurisdiction at all, while others required FDA to
determine whether a product would be regulated merely as a cos
metic or food or instead as a drug or device. It is also the case that
FDA may use its authority to regulate the off-label use of a drug
or a device. Indeed, when a particular off-label use becomes wide
spread or endangers public health, FDA must investigate it thor
oughly and take appropriate action to protect the public, including
requiring a change in the product's labeling to warn against or ap
prove the unapproved use, seeking substantial evidence to substan
tiate its use, restricting the distribution of the drug, or even with
drawing approval of the drug and removing it from the market.
22
Seizures
The report also asserts that FDA's seizure authority is an unsat
isfactory remedy from a public health perspective because it denies
adequately studied populations access to a safe and effective drug.
It would be true that a mass seizure of all of a manufacturer's drug
or biological product would disrupt patient access to a safe and ef
fective product. It is not the case, however, that seizure of the lots
of a drug in one warehouse, when there are other stores of the drug
that are not seized, would disrupt consumer access to a drug or bio
logical product.
In fact, such a seizure may be a particularly appropriate way for
FDA to seek enforcement of a statutory or regulatory requirement,
because it allows patients to have access to products that the gov
ernment has not seized and because the manufacturer's interest in
being able to distribute the seized product can facilitate quicker
resolution of the dispute. In the instances under consideration
here, that would mean quicker completion of pediatric studies that
a manufacturer has failed to complete in a timely way.
23
The legislation clearly authorizes FDA to use the full range of its
enforcement authorities with the single exception of criminal pen
alties. Under S. 650, the agency retains its full discretion as to
whether to use its seizure authority.
TED KENNEDY.
CHRIS DODD .
BARBARA A. MIKULSKI.
HILLARY RODHAM CLINTON .
PATTY MURRAY.
JACK REED .
X. CHANGES IN EXISTING LAW
In compliance with rule XXVI paragraph 12 of the Standing
Rules of the Senate, the following provides a print of the statute
or the part or section thereof to be amended or replaced ( existing
law proposed to be omitted is enclosed in black brackets, new mat
ter is printed in italic, existing law in which no change is proposed
is shown in roman ):
*
*
IXAXCH)
( 1) ( A )(i) * * *
*
* * *
1
26
(i ) LABELING SUPPLEMENTS.
( 1 ) PRIORITY STATUS FOR PEDIATRIC SUPPLEMENTS .—* * *
(A ) * * *
(B) * * *
( 2 ) DISPUTE RESOLUTION.—
(A) REQUEST FOR LABELING CHANGE AND FAILURE TO
AGREE . If the Commissioner determines that an applica
tion with respect to which a pediatric study is conducted
under this section is approvable and that the only open
issue for final action on the application is the reaching of
an agreement between the sponsor of the application and
the Commissioner on appropriate changes to the labeling
for the drug that is the subject of the application , not later
than 180 days after the date of submission of the applica
tion
( 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 Commis
sioner, the Commissioner shall refer the matter to the
Pediatric [Advisory Subcommittee of the Anti- Infec
tive Drugs] Advisory Committee.
(B ) ACTION BY THE PEDIATRIC (ADVISORY SUBCOMMITTEE
OF THE ANTI -EFFECTIVE DRUGS] ADVISORY COMMITTEE.
Not later than 90 days after receiving a referral under
subparagraph ( A )(ii), the Pediatric (Advisory
[Advisory Sub
committee of the Anti -Infective Drugs ] Advisory Com
mittee shall
(i) review the pediatric study reports; and
( ii ) make a recommendation to the Commissioner
concerning appropriate labeling changes, if any.
( C ) CONSIDERATION OF RECOMMENDATIONS . — The Com
missioner shall consider the recommendations of the Pedi
atric [ 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 appro
priate.
27
* *
shall, under section 222 of the Public Health Service Act (42
U.S.Ć. 217a),] (42 U.S.C. 217a ) or other appropriate authority, con
vene and consult an advisory committee on pediatric (pharma
cology ) therapeutics (referred to in this section as the “ advisory
committee ” ).
“ (b ) PURPOSE . -
“ ( 1) IN GENERAL . — The advisory committee shall advise and
make recommendations to the Secretary, through the Commis
sioner of Food and Drugs (and in consultation with the Direc
tor of the National Institutes of Health ) on matters relating to
pediatric ( pharmacology ) therapeutics.
“ ( 2 ) MATTERS INCLUDED. — The matters referred to in para
graph ( 1 ) include
“ ( A ) pediatric research conducted under sections 351 ,
4091 , and 499 of the Public Health Service Act [42 U.S.C.
A. $$ 262, 284m , and 290b] and sections 501 , 502, 505, and
(505A) 505B of the Federal Food, Drug, and Cosmetic Act
[21 U.S.C.A. $$ 351 , 352 , 355, and 355a );
“ ( B ) identification of research priorities related to pedi
atric [ pharmacology ) therapeutics and the need for addi
tional treatments of specific pediatric diseases or condi
tions ; and
" (C ) the ethics, design, and analysis of clinical trials re
lated to pediatric ( pharmacology ) therapeutics.
* * * *
(B) * *
(C) * * *
(2 ) MEMBERSHIP.
(A) IN GENERAL . — The Secretary shall appoint not more
than 11 voting members to the Pediatric Subcommittee
from the membership of the Pediatric (Pharmacology ) Ad
visory Committee and the Oncologic Drugs Advisory Com
mittee .
*
SEC. 505B. RESEARCH INTO PEDIATRIC USES FOR DRUGS AND BIO
LOGICAL PRODUCTS .
( a ) New DRUGS AND BIOLOGICAL PRODUCTS.
29
* * * *
34
( 1 ) IN GENERAL._ * * *
* * * *
* *
35
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