19–010

Calendar No. 183

108TH CONGRESS REPORT " SENATE ! 1st Session 108–84

PEDIATRIC RESEARCH EQUITY ACT OF 2003

JUNE 27 (legislative day, JUNE 26), 2003.—Ordered to be printed 

Mr. GREGG, from the Committee on Health, Education, Labor, and 

Pensions, submitted the following 

R E P O R T 

together with 

ADDITIONAL VIEWS 

[To accompany S. 650]

The Committee on Health, Education, Labor, and Pensions, to 

which was referred the bill (S. 650) to authorize the Food and Drug 

Administration to require certain research into drugs used in pediatric patients, having considered the same, reports favorably thereon with an amendment and recommends that the bill (as amended) 

do pass.

CONTENTS 

Page 

I. Purpose and need for legislation .................................................................. 1

II. Summary ........................................................................................................ 7

III. History of legislation and votes in committee ............................................. 9

IV. Explanation of bill and committee views ..................................................... 9

V. Regulatory Impact Statement ....................................................................... 12

VI. Application of law to the legislative branch ................................................ 12

VII. Cost estimate .................................................................................................. 12

VIII. Section-by-section analysis ............................................................................ 13

IX. Additional views ............................................................................................. 17

X. Changes in existing law ................................................................................ 24

I. PURPOSE AND NEED FOR LEGISLATION

As part of the Food and Drug Administration Modernization Act 

(‘‘FDAMA’’) of 1997 (Pub. L. No. 105–115), Congress established 

new incentives for drug manufacturers to conduct pediatric research. These pediatric exclusivity provisions were reauthorized 

and enhanced in 2002 by the Best Pharmaceuticals for Children 

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1 ‘‘Testing Medications in Children,’’ by Robert Steinbrook, M.D. October 31, 2002. The New 

England Journal of Medicine. 

Act (‘‘BPCA’’) (Pub. L. No. 107–109). The legislation works by providing an incentive of 6 months of additional market exclusivity for 

sponsors in exchange for the voluntary performance of clinical studies of drugs in the pediatric population in response to a written request from FDA. The BPCA also created programs administered by 

the NIH to issue grants and contracts for researchers to conduct 

additional pediatric studies with privately donated and publicly appropriated funds. These laws have made headway in rectifying the 

historical lack of clinical study data and labeling information on 

the appropriate use of medicines in children. 

Notwithstanding the progress that these prior pediatric initiatives have produced, at least sixty-two percent of drugs on the market remain unstudied and labeled for use in children.1 However, 

that number reflects research in accordance with the old Pediatric 

Rule. The authority for the new Pediatric Research Authority is 

based on the percentage of drugs projected to need pediatric labeling in light of ongoing commitments and research. Further action 

is needed to ensure that medications are adequately studied and 

labeled for use in children. The committee has approved this legislation to complement the existing voluntary pediatric exclusivity 

and NIH study provisions by providing FDA with new, unprecedented authority to require that drug manufacturers conduct pediatric studies and submit pediatric assessments to FDA. On December 2, 1998, FDA published in the Federal Register (63 FR 66632–

66672) a final regulation known as the ‘‘Pediatric Rule’’ asserting 

the authority to mandate pediatric testing in certain circumstances. On October 17, 2002, a Federal court held that FDA 

lacked the statutory authority to promulgate the Pediatric Rule, 

and declared the Rule invalid. The legislation reported by the committee now provides FDA with statutory authority to require pediatric studies in certain defined circumstances. 

There is a need to provide FDA legislative authority to require 

pediatric testing because of the particular importance of pediatric 

drug labeling. At the same time, the committee recognizes that appropriate safeguards must accompany this special grant of mandatory testing authority. The committee intends that the new legislation, the pediatric exclusivity incentive provisions, and the NIH 

study provisions of the BPCA will work in a comprehensive and 

complementary fashion. This legislation not only establishes provisions regarding new drugs but also provides a default mechanism 

by which FDA can require pediatric studies where the voluntary 

incentives and available contracts and grants have not produced 

needed pediatric treatment information. 

Children suffer from many of the same diseases as adults and 

are often treated with the same medicines. Yet certain medicines 

have not been adequately studied and labeled for use in children. 

Dosing children based merely on their lower weight is often imprecise, since their bodies can metabolize medicines differently than 

adults. Some drugs may have different adverse side effects or 

toxicities in children than in adults, so extrapolating safety or effectiveness for children for medicines found to be safe and effective 

in adults may not be appropriate. The lack of pediatric studies and 

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labeling information may lead to unintended medical errors and 

place children at risk of being under-dosed or over-dosed with 

medication. The lack of age-appropriate formulations (e.g., liquid 

form) can also make it difficult to give children and infants prescribed amounts of a needed medication. 

There are a variety of reasons why greater pediatric testing has 

not been conducted historically despite its importance as a matter 

of public health. Drug sponsors have often lacked incentives to develop drugs for pediatric use because of the comparatively small 

size of the pediatric market for most products. Designing and completing pediatric research trials can also present heightened scientific, ethical, and logistical challenges, from recruiting sufficient 

study participants to obtaining consent from parents or guardians 

to developing formulations of a drug that can be administered to 

younger patients. Pediatric research can also present greater risks 

of legal liability for sponsors due, for example, to the tolling of the 

statute of limitations as applied to children, as well as other reasons. In the face of these obstacles, before 1997, regulatory efforts 

to address the lack of pediatric studies and insufficient labeling information had been largely unsuccessful. In 1979, the FDA first 

issued a rule requiring specific pediatric indications, if any, to be 

described under the ‘‘Indications and Usage’’ section of the label, 

with pediatric dose information included in the ‘‘Dosage and Administration’’ section. The rule also required that recommendations 

for pediatric use must be based on data from adequate and wellcontrolled studies in the pediatric population. The 1979 rule did not 

successfully encourage drug sponsors to conduct pediatric studies 

and appropriately label their products for children. 

Accordingly, in 1994, the FDA published a final rule requiring 

drug manufacturers to survey existing data and to determine 

whether it would support pediatric labeling, and if it did, to file a 

supplemental new drug application. FDA’s December 1994 Pediatric Plan sought to encourage manufacturers’ voluntary development of pediatric data both during the drug development process 

and after marketing. Neither of these 1994 initiatives sufficiently 

increased the number of drugs with adequate pediatric labeling. 

In 1997, FDA proposed a Pediatric Rule by regulation claiming 

authority to require manufacturers to submit needed pediatric testing. Before FDA finalized the Pediatric Rule Congress enacted the 

Better Pharmaceuticals for Children Act as part of the Food and 

Drug Administration Modernization Act of 1997 (Pub. L. 105–115). 

This act created a new section 505A of the FFDCA to provide a 

market incentive of 6 months of additional exclusivity to drug sponsors for completing and submitting studies of medicines in children 

in response to a written request from FDA for the studies. The 

studies must fairly respond to FDA’s written request and be conducted in accordance with a subsequent written agreement with 

the FDA, or in the absence of such a written agreement in accordance with commonly accepted scientific principles and protocols. 

The 6-month pediatric exclusivity period is added to any patent or 

exclusivity (such as orphan exclusivity or a 5- or 3-year HatchWaxman exclusivity) on the drug. 

The new incentives were intended to address the systemic disincentives that had previously existed to conducting pediatric studies. The results of the pediatric exclusivity incentives to date are 

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highly encouraging. As FDA reported to Congress in 2001, the incentives have ‘‘done more to generate clinical studies and useful 

prescribing information for the pediatric population than any other 

regulatory or legislative process to date.’’

Based in part on FDA’s report, Congress reauthorized the pediatric exclusivity provision in 2001 in the BPCA. In the BPCA, Congress also provided an off-patent research fund at the National Institutes of Health (NIH) for the study of off-patent drugs and a 

process using first the Foundation of the National Institutes of 

Health (Foundation) and then the research fund for the study of 

drugs for which the manufacturers have declined written requests 

to study the drug under the pediatric exclusivity provision. 

At the same time that the pediatric exclusivity provisions were 

being put in place by legislation, FDA proceeded with rulemaking 

proceedings for the Pediatric Rule, which the agency finalized in 

1998, and which became effective in 1999. The rule remained in effect until October 17, 2002, when a Federal court in the District 

of Columbia in the Association of American Physicians and Surgeons, Inc. v. FDA case held that the rule exceeded FDA’s existing 

statutory authority, and declared the rule invalid. In December 

2002, the American Academy of Pediatrics and the Elizabeth 

Glaser Pediatric AIDS Foundation, which had participated as amici 

curiae in the district court, were permitted to intervene and to appeal the case to the U.S. Court of Appeals for the District of Columbia Circuit. 

Prior to the court’s decision, under FDA’s Pediatric Rule, each 

new drug application under section 505 of the FFDCA or biologics 

license application under section 351 of the PHSA for a new active 

ingredient, new indication (except indications for which orphan designation has been granted), new dosage form, new dosing regimen, 

or new route of administration was required to contain certain 

data, unless there were grounds for a waiver or deferral. Absent a 

waiver or deferral, the application was required to contain data 

adequate to assess the safety and effectiveness of the drug or biological product for its claimed indications in all relevant pediatric 

subpopulations, and to support dosing and administration for each 

pediatric subpopulation for which the drug was safe and effective. 

With respect to an already-marketed drug or biological product 

that was used in a substantial number of pediatric patients or that 

provided a meaningful therapeutic benefit over existing treatments 

for pediatric patients and for which the absence of adequate pediatric labeling could pose significant risks to pediatric patients, the 

rule allowed FDA in these compelling circumstances or ‘‘high priority’’ situations to require the product’s manufacturer or manufacturers to submit an application containing data adequate to assess 

whether the drug was safe and effective in pediatric populations for 

the drug’s approved indications, as well as adequate evidence to 

support dosage and administration in some or all pediatric populations, depending on the known or appropriate use of the drug in 

those pediatric subpopulations. FDA was also able to require the 

manufacturer or manufacturers to develop a pediatric formulation 

for a drug product that represented a meaningful therapeutic benefit over existing treatments for pediatric populations for whom a 

pediatric formulation was necessary, unless the manufacturer demVerDate Jan 31 2003 13:21 Jul 01, 2003 Jkt 019010 PO 00000 Frm 00004 Fmt 6659 Sfmt 6602 E:\HR\OC\SR084.XXX SR084
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onstrated that reasonable attempts to produce a pediatric formulation necessary for that age group had failed. 

Full and partial waivers could also be obtained for both new and 

already marketed products. A drug or biological product for which 

a full or partial waiver was granted because there was evidence 

that the product would be ineffective or unsafe in pediatric populations was required to be labeled with that information. 

The Pediatric Rule was intended to work as a safety net to (or 

as a backstop to) pediatric exclusivity. While the FDAMA was intended to provide a substantial incentive for sponsors to conduct 

some pediatric studies, the rule was intended to increase the number of drug and biological products that have adequate labeling. 

Because of the voluntary nature of the incentive provided by the 

FDAMA the possibility arose that many drugs may still have remained unstudied for pediatric uses. 

The Pediatric Rule was both broader and narrower than the pediatric exclusivity provision first enacted by Congress in 1997 and 

reauthorized by the BPCA in 2001. Most significantly, the rule was 

broader than pediatric exclusivity because the rule covered biological products approved under section 351 of the Public Health Service Act while neither the pediatric exclusivity provision nor the provisions for contracting for pediatric studies at the Foundation and 

at NIH applies to biological products. 

In addition, the Pediatric Rule was broader than pediatric exclusivity because it covered subsequent indications and pediatric subpopulations that pediatric exclusivity, with its associated contracting process at the Foundation and NIH, may not. For example, 

if FDA did not include studies of newborns and infants in a written 

request for a drug under the pediatric exclusivity provision (because FDA believed it would not be ethical or feasible to study 

these populations until older populations had been studied), pediatric exclusivity was generally not available to ensure that the 

drug would be studied for these children if subsequent data made 

it apparent the product was efficacious in the older population and 

warranted studies in the younger populations. However, FDA could 

have used the rule to require studies in those pediatric subpopulations. Moreover, if the pediatric exclusivity provision has been applied to a drug and subsequently the drug’s manufacturer seeks approval for a new indication; pediatric exclusivity is generally not 

available to ensure that the new indication will be studied in children. FDA, however, could have invoked the rule to require that 

the new indication be studied. 

In some respects, the Pediatric Rule was narrower than pediatric 

exclusivity and its associated contracting process at the Foundation 

and NIH. For example, the rule could only have been used for an 

indication for which the drug was approved or approval was being 

sought in adults, whereas FDA may also use pediatric exclusivity 

to request pediatric studies of an indication not approved for adult 

use. In addition, the rule applied only to drugs that would be used 

by a substantial number of pediatric patients or that would provide 

a meaningful therapeutic benefit for pediatric patients, whereas pediatric exclusivity applies to drugs for which information relating 

to the use of the drug in the pediatric population may produce 

health benefits in that population. 

6

Even given these differences in scope, the Pediatric Rule and the 

pediatric exclusivity provision worked together to ensure that a 

drug or biological product would be tested in and labeled for children when appropriate. When their scopes overlapped, Congress 

provided in section 505A(h) of the FFDCA that any pediatric studies required by regulation also satisfied the requirements for market exclusivity. There were many drugs for which the rule and the 

incentive worked together successfully to encourage a drug company to respond affirmatively to FDA’s request for pediatric studies. 

But the rule and pediatric exclusivity did not always both apply 

to a drug. FDA reports that, between April 1, 1999, when the rule 

first became effective, and March 31, 2002, 404 new drug applications and supplements fell within the scope of the rule. For approximately 266 of these, manufacturers submitted, or would have 

been required to submit, studies in one or more pediatric age 

groups (the remaining received complete waivers, typically as a result of safety concerns regarding the testing of the drug in children 

or because the drug’s approved indication was not for a childhood 

disease). As of June 5, 2003, 129 submitted applications contained 

complete or partial pediatric use information. Because pediatric exclusivity incentives were not involved in these applications and 

these were not drugs primarily developed for children, FDA attributes 67 of these submissions to the Pediatric Rule alone. By 

comparison, FDA reports that as of June 2, 2003, 72 drugs have 

been granted exclusivity and 9 have been denied exclusivity, with 

49 of these drugs currently labeled for use in the pediatric population. It is therefore clear that the Pediatric Rule and exclusivity 

have worked together to improve the pediatric labeling of drugs 

and biological products that has occurred since 1997, when Congress first provided for pediatric exclusivity and FDA first proposed 

the Pediatric Rule. 

At the same time, the court’s decision in the Association of American Physicians and Surgeons case invalidating the rule highlights 

the tension between a mandatory study requirement and the basic 

operation of the FFDCA, which leaves it to drug sponsors to determine the claims they wish to make for a product. In that case, the 

court held that FDA lacked authority under the existing FFDCA to 

require that drug sponsors conduct studies or develop formulations 

for claims or patient populations that the sponsor is not seeking to 

include in labeling for its product. In the court’s words, FDA ‘‘has 

repeatedly stated that it may only regulate claimed uses of drugs, 

not all foreseeable or actual uses.’’ The court further stated that it 

is a ‘‘long-established foundation of federal food and drug law’’ that 

manufacturers determine the intended uses of a product through 

the representations they make for the product. 

This legislation responds to the court’s holding by providing FDA 

new statutory authority to require pediatric assessments. The authority granted by the legislation tracks many elements of the 

former Pediatric Rule to ensure that the progress produced by the 

incentive and the Pediatric Rule will continue. There is a compelling basis for providing FDA such authority because of the importance of ongoing pediatric research. At the same time, the legislation establishes clear limitations on the new authority to require 

pediatric assessments to ensure that the unique needs of the pediVerDate Jan 31 2003 13:21 Jul 01, 2003 Jkt 019010 PO 00000 Frm 00006 Fmt 6659 Sfmt 6602 E:\HR\OC\SR084.XXX SR084
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atric population continue to be met by the co-existence of the incentive and the mandate.

II. SUMMARY

1. The legislation gives FDA new statutory authority to require certain pediatric tests 

The legislation amends the Federal Food, Drug, and Cosmetic 

Act (FFDCA) by adding a new section 505B, which provides FDA 

with unprecedented statutory authority to require that sponsors 

submit assessments regarding the use of drugs in pediatric patients in certain specified circumstances. With respect to drugs and 

biological products that are not yet approved, the legislation provides that each new drug application under section 505 of the 

FFDCA or biologics license application under section 351 of the 

Public Health Service Act (PHSA) for a new active ingredient, new 

indication (except for an orphan drug indication, unless the Secretary requires otherwise by rulemaking), new dosage form, new 

dosing regimen, or new route of administration must contain data 

adequate to assess the safety and effectiveness of the drug or biological product for its claimed indications, and to support dosing 

and administration for each pediatric subpopulation for which the 

product is safe and effective. With respect to drugs and biological 

products that are already marketed, the legislation allows FDA in 

compelling circumstances, having made certain findings and under 

certain conditions, to require that all holders of approved applications for a product submit data on safety and effectiveness and dosing and administration, after having provided the holders with notice and an opportunity for written response and a meeting. 

Under the legislation, FDA is required to grant a full or partial 

waiver of the pediatric data requirement for a drug or biological 

product for certain reasons, including if the FDA finds that necessary studies are impossible or highly impractical (because, for example, the number of such pediatric patients is so small or geographically dispersed); if there is evidence strongly suggesting that 

the drug or biological product would be ineffective or unsafe in the 

pediatric age groups; or if the drug or biological product does not 

represent a meaningful therapeutic benefit over existing therapies 

for pediatric patients, the drug or biological product is not likely to 

be used by a substantial number of pediatric patients, and the absence of adequate labeling would not pose significant risks to pediatric patients. Under the legislation, when the Secretary grants a 

full or partial waiver because there is evidence that the drug or biological product would be ineffective or unsafe in pediatric populations, the information must be included in the labeling for the 

drug or biological product. Also, if the Secretary grants a partial 

waiver because it is not possible to produce a pediatric formulation, 

the waiver will only cover the pediatric age groups requiring that 

formulation. 

For new drugs, the Secretary, on his own initiative or by request 

from the applicant, may defer the submission of some or all of the 

assessments required under the amendment until a specified date 

after the approval of the drug or after the license for the biological 

product is granted if two requirements are met. The first is met if 

the Secretary finds that the drug is ready for approval for use in 

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adults before the pediatric studies are complete, or the pediatric 

studies should be delayed until additional safety or effectiveness 

data have been collected, or there is another appropriate reason for 

deferral. The second is met if the applicant has submitted to the 

Secretary certification for the grounds for deferring, a description 

of the planned or ongoing studies, and evidence that the studies 

are being conducted or will be conducted with due diligence at the 

earliest possible time. 

The legislation provides for meetings with a drug sponsor during 

the investigational new drug process to discuss plans and timelines 

of pediatric studies or requests for waiver or deferral of pediatric 

studies. 

2. The legislation clarifies the interaction of the new pediatric study 

requirements with the pediatric exclusivity provisions when applied to already-marketed drugs 

The legislation provides that FDA may only impose pediatric 

study requirements for already marketed drugs when the pediatric 

exclusivity incentives provisions of section 505A of the FFDCA and 

the NIH grant and contract programs of sections 409I and 499 of 

the PHSA have failed to yield necessary pediatric information. FDA 

must first allow an opportunity for these other BPCA mechanisms 

to work before invoking the new pediatric study requirements for 

marketed drugs. The new pediatric assessment requirement serves 

as a safety net to ensure that certain critical studies are performed 

and labeling adopted for marketed drugs if the other mechanisms 

from the BPCA do not work. The pediatric assessment requirement 

is the default, and not the first option. For already-marketed drugs, 

the legislation requires that, before FDA may invoke the Pediatric 

Research Authority (if it is applicable), FDA must ask the manufacturer to conduct the study voluntarily under section 505A of the 

FFDCA, which provides for 6 months of market exclusivity for completing pediatric studies, or section 409I of the PHSA, and that the 

company does not agree or that FDA does not receive a response. 

In addition, no later than 60 days after making such determination, FDA must certify that there are insufficient funds to complete 

the study under sections 409I and 499 and publish in the Federal 

Register that no contract or grant has been awarded. 

This requirement is not inconsistent with current FDA practice. 

3. The legislation provides for appropriate enforcement of the requirement to submit timely pediatric assessments 

The legislation provides that a drug or biological product for 

which a pediatric assessment is not filed by the date specified by 

FDA may be considered misbranded and subject to relevant enforcement action. The Committee recognizes that the agency has 

generally found seizure of a drug or biological product to be an unsatisfactory remedy from a public health perspective because it denies adequately studied populations access to safe and effective 

medicines. As a result, the Committee intends for seizure of a drug 

or biological product to be used rarely, if at all, as a remedy for 

failure to conduct required pediatric studies. This legislation makes 

clear that the failure to submit required assessments shall not be 

the basis for criminal proceedings, withdrawal of approval as a new 

drug, or revocation of an approved biologics license. Apart from 

9

those specifically exempted, however, all of the Secretary’s misbranding enforcement authorities are available. The Secretary, as 

always, has discretion to choose the appropriate enforcement action, as well as discretion to choose whether to bring an enforcement action.

4. The legislation does not provide FDA with authority to require 

studies or labeling for other populations or uses 

The legislation states that section 505B does not provide FDA 

with any authority to require pediatric assessments, assessments 

regarding other populations, or assessments regarding other uses 

of drugs or biological products except as described in section 505B. 

As the Federal court stated in the case challenging the legality of 

FDA’s former Pediatric Rule (Association of American Physicians 

and Surgeons, Inc. v. FDA), it is the long-established foundation of 

our food and drug laws that drug sponsors determine the ‘‘intended 

uses’’ of a product, and that FDA does not regulate foreseeable or 

actual uses of a product that the sponsor does not claim. The legislation makes clear, however, that the new authority it provides 

FDA does not go beyond the specified limits of section 505B. 

III. HISTORY OF LEGISLATION AND VOTES IN COMMITTEE

On March 18, 2003, Senator DeWine, for himself and Senators 

Clinton, Gregg, Dodd and Kennedy introduced S.650, to amend the 

Federal Food, Drug, and Cosmetic Act to authorize the FDA to require certain research into drugs used in pediatric patients if the 

voluntary mechanisms fail. 

On March 19, 2003, the committee held an executive session to 

consider S.650. Senator Gregg offered an amendment that the committee passed by a vote of 11–10. The committee approved S.650, 

as amended, by a unanimous vote of 21–0. 

A. Amendment adopted 

The Committee adopted 1 amendment by a vote of 11–10. This 

amendment ensures the integration of the pediatric study mechanisms under the BPCA and this new authority for the FDA. The 

amendment further integrates the two programs by conforming the 

dates on which the programs require reauthorization (see for example section 505A(n) of the BPCA). By ensuring the co-existence of 

both the incentive mechanisms and the mandate, this amendment 

ensures FDA has every tool available to best protect children. 

IV. EXPLANATION OF BILL AND COMMITTEE VIEWS

New authority for FDA to require pediatric assessments 

The legislation amends the FFDCA by adding a new section 

505B. 

The legislation assures that, when appropriate, new drugs and 

biological products will be studied for safety and effectiveness and 

dosing and administration in children before new active ingredients, new indications, new dosage forms, new dosing regimens, or 

new routes of administration are approved, unless a deferral or 

waiver is obtained. 

It also gives FDA the statutory authority to require that alreadymarketed drugs and biological products be tested in children for 

10

approved indications in compelling circumstances if the agency 

finds, after certain conditions are met, that the absence of adequate 

labeling could pose significant risks to pediatric patients and that 

either (1) the drug or biological product is used for a substantial 

number of pediatric patients for the labeled indications, or (2) there 

is reason to believe that the drug or biological product would represent a meaningful therapeutic benefit over existing therapies for 

pediatric patients for 1 or more of the claimed indications. 

The legislation allows FDA to conclude that pediatric effectiveness may be extrapolated from studies in adults, usually supplemented with information about pediatric patients, if the course of 

a disease and the effects of a drug are sufficiently similar in adults 

and pediatric patients. The legislation also allows FDA, on its own 

initiative or that of an applicant, to defer submission of these data. 

Deferrals are appropriate where either (1) the product is ready for 

use in adults before pediatric studies are or will be complete, or (2) 

there are ethical or clinical grounds to delay some or all of the pediatric studies until additional safety or effectiveness data are 

available. 

Under the legislation, FDA may grant a full (or partial) waiver 

of the pediatric assessment for a drug or biological product under 

certain conditions, including if (1) necessary studies are impossible 

or highly impractical, because, for example, the number of patients 

(in that age group) is so small or geographically dispersed (2) there 

is evidence strongly suggesting that the drug or biological product 

would be ineffective or unsafe in all pediatric age groups (or that 

pediatric age group), (3) the drug or biological product does not represent a meaningful therapeutic benefit over existing therapies for 

pediatric patients (in that age group), the drug or biological product 

is not likely to be used by a substantial number of pediatric patients (in that age group), and the absence of adequate labeling 

would not pose significant risks to pediatric patients, or (4) attempts to develop a formulation needed for certain age groups have 

failed. The legislation requires that, when the Secretary grants a 

full or partial waiver because there is evidence that the drug or biological product would be ineffective or unsafe in pediatric populations, the information must be included in the labeling for the 

drug or biological product. If a partial waiver is granted based on 

the ground that it is not possible to develop a pediatric formulation, the waiver must cover only the pediatric groups requiring that 

formulation. 

Special provisions for already marketed drugs 

The legislation states that FDA may not require pediatric assessments for already marketed drugs unless FDA first issues a written request under the pediatric exclusivity provisions of section 

505A and subsequently issues a request for contract or grant proposals under the sections 409I or 499 of the Public Health Service 

Act, as modified by the BPCA, before FDA may invoke the Pediatric Research Authority (if it is applicable), FDA must ask the 

manufacturer to conduct the study voluntarily under section 505A 

of the FFDCA or section 409I of the PHSA and that the company 

does not agree or that FDA does not receive a response. Section 1 

also clarifies that it does not change the provisions in the BPCA 

that establish a process at NIH to contract for studies to gather peVerDate Jan 31 2003 13:21 Jul 01, 2003 Jkt 019010 PO 00000 Frm 00010 Fmt 6659 Sfmt 6602 E:\HR\OC\SR084.XXX SR084
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diatric information. Section 1 further clarifies that use of the NIH 

contracting process does not preclude FDA from using the Pediatric 

Research Authority (‘‘PRA’’) to require that a manufacturer study 

an already-marketed drug. Section 1 provides that the rule PRA 

may only be invoked to study approved indications, even if the 

written request is broader. 

Section 505B does not affect whatever existing authority FDA 

has to require studies, in addition to those required under section 

505B, of the safety and effectiveness of drugs and biological products in pediatric populations. It also states that FDA’s authority, 

if any, to require studies for specific populations other than the pediatric population shall be exercised under the FFDCA as in effect 

on the day before the date of enactment of the legislation. 

The committee intends for FDA to continue to issue broad written requests under section 505A of the FFDCA, section 409I of the 

PHSA, and the authorities of this legislation to capture the full 

scope of pediatric information desired, including for all uses of the 

drug in the pediatric population for which pediatric information 

may produce health benefits in that population. 

If the Secretary issues a written request for pediatric studies of 

a drug under section 505A(d) of the FFDCA and the recipient of 

the written request does not agree to conduct the studies, under 

section 505A(d)(4)(B) the Secretary must refer the drug for study 

to the Foundation for the National Institutes of Health established 

under section 499 of the PHSA. If the Secretary issues a written 

request for pediatric studies under section 409I(c) of the PHSA and 

the recipient of the written request does not agree to conduct the 

studies, section 409I(c)(2) requires the Secretary to issue a request 

for contract proposals to conduct the pediatric studies. As adequate 

funding is necessary for the contracting process to work effectively, 

the committee does not intend for the Secretary to issue requests 

for contract proposals without regard to the availability of funding 

needed for those proposals. At the same time, the committee also 

emphasizes that the Secretary should issue written requests under 

section 505A(d) or section 409I without regard for whether there 

are sufficient funds at the Foundation or NIH to fund the studies 

should the recipient of the written request not agree to conduct the 

studies. Therefore, insufficient funding to contract for studies 

under section 409I will not preclude the Secretary from requiring 

pediatric studies under the legislation. 

This amendment adds restrictions on the Secretary’s authority to 

invoke the PRA, including a restriction on use of the authority before the Secretary has asked the company to conduct the studies 

voluntarily and the company has either declined or failed to respond. 

This provision makes clear that before invoking section 505B, 

FDA must first ask a company to conduct the study of an alreadymarketed drug voluntarily and these requests must fail to yield the 

specified studies within the specified amount of time when the 

company does not agree or FDA has not received a response. FDA 

will then be able to invoke the new pediatric research authority. 

For already marketed drugs, the committee views section 505B as 

a provision that may apply only when the other available voluntary 

mechanisms have been used but have not resulted in the necessary 

studies. 

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Enforcement 

The legislation provides that FDA has misbranding authority 

with respect to a drug or biological product for which a pediatric 

assessment is not filed by the date specified by FDA may be considered misbranded and subject to relevant enforcement action. The 

committee stresses that seizure is generally an unsatisfactory remedy from a public health perspective because it denies adequately 

studied populations access to safe and effective medicines. As a result, the committee intends for seizure to be used rarely, if at all, 

as a remedy for failure to conduct required pediatric studies. This 

legislation makes clear that the failure to submit required assessments shall not be the basis for criminal proceedings, withdrawal 

of approval as a new drug, or revocation of an approved biologics 

license. The committee intends for FDA to enforce the mandate by 

using its injunction authority without affecting the availability of 

otherwise safe and effective products for other patients. 

No effect on current authority 

The legislation states that section 505B does not provide FDA 

with any authority to require pediatric assessments, or assessments of other populations or uses, except as provided in section 

505B. The committee notes the court’s holding in Association of 

American Physicians and Surgeons, Inc. v. FDA that FDA lacks the 

current authority to require pediatric assessments. This legislation 

does not expand FDA’s current authority except as specifically enumerated in section 505B. 

Integration with other pediatric provisions 

The legislation is integrated with the pediatric exclusivity provisions of section 505A of the FFDCA. The committee views the two 

sections as working together in a complementary fashion. The committee understands that section 505A is set to be reviewed for reauthorization in 2007, and intends that the new section 505B be 

reviewed for reauthorization at the same time. 

V. REGULATORY IMPACT STATEMENT

The committee has determined that there will be minimal increases in the regulatory burden imposed by this bill. 

VI. APPLICATION OF LAW TO THE LEGISLATIVE BRANCH

S. 650 adds section 505B to the Federal Food, Drug, and Cosmetic Act to further improve the safety and efficacy of both drugs 

and biological products for children. As such, it has no application 

to the legislative branch. 

VII. COST ESTIMATE

Due to time constraints the Congressional Budget Office estimate 

was not included in the report. When received by the committee, 

it will appear in the Congressional Record at a later time. 

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VIII. SECTION-BY-SECTION ANALYSIS

Sec. 1. Short title 

Section 1 entitles the Act the ‘‘Pediatric Research Equity Act of 

2003.’’

Sec. 2. Pediatric labeling of drugs and biological products 

Section 2 amends the FFDCA by adding a new section 505B, 

which grants FDA new authority to mandate pediatric data under 

certain circumstances in order to reinforce the existing provisions 

for generating pediatric information under the BPCA. 

Section 505B(a): New Drugs and Biological Products 

Section 505B(a)(1): With respect to new applications for drugs 

and biological products, subsection (a)(1) provides that each new 

drug application under section 505 of the FFDCA or biologics license application under section 351 of the PHSA for a new active 

ingredient, new indication (except for an orphan drug indication— see section 505B(g)), new dosage form, new dosing regimen, or new 

route of administration must include assessments containing pediatric data. 

Section 505B(a)(2): The assessments required by subsection (a)(1) 

must contain data adequate to assess the safety and effectiveness 

of the drug or biological product for its claimed indications, and to 

support dosing and administration for each pediatric subpopulation 

for which the product is safe and effective. FDA may conclude, 

however, that pediatric effectiveness can be extrapolated from studies in adults, usually supplemented with information about pediatric patients, if the course of a disease and the effects of a drug 

or biological product are sufficiently similar in adults and pediatric 

patients. FDA may also determine that studies are not needed in 

each pediatric subpopulation if data from one subpopulation can be 

extrapolated to another subpopulation. 

Section 505B(a)(3): FDA may, on its own initiative or that of an 

applicant, defer submission of pediatric data in certain circumstances, provided the applicant submits certain information to 

FDA. FDA may issue a deferral if it finds that the product is ready 

for approval for use in adults before pediatric studies are complete, 

pediatric studies should be delayed until additional safety or effectiveness data have been collected, or for other appropriate reasons. 

In order to secure a deferral, the applicant must submit to FDA 

certification of the grounds for deferring assessments, a description 

of planned or ongoing studies, and evidence that the studies are 

being or will be conducted diligently and as soon as possible. 

Section 505B(a)(4): FDA shall grant, as appropriate, a full waiver 

of the pediatric data requirement for a new drug or biological product if: (1) necessary studies are impossible or highly impracticable; 

(2) there is evidence strongly suggesting that the drug or biological 

product would be ineffective or unsafe in all pediatric age groups; 

or (3) the drug or biological product does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients, and the drug or biological product is not likely to be used 

by a substantial number of pediatric patients. FDA shall grant, as 

appropriate a partial waiver of the pediatric data requirement for 

a new drug or biological product with respect to a particular pediatric subpopulation if any of these 3 reasons applies to that subVerDate Jan 31 2003 13:21 Jul 01, 2003 Jkt 019010 PO 00000 Frm 00013 Fmt 6659 Sfmt 6602 E:\HR\OC\SR084.XXX SR084
14

population, or if the applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that pediatric subpopulation have failed. If a full or partial waiver is granted because of evidence that the product would be ineffective or unsafe in the pediatric population or a pediatric subpopulation, that 

information shall be included in the product’s labeling. 

Section 505B(b): Marketed Drugs and Biological Products 

Section 505B(b)(1): With respect to drugs and biological products 

that are already marketed, FDA may, only after making certain 

findings and under limited circumstances, require the holder of an 

approved new drug application or biologics license application to 

submit data on safety and effectiveness, dosing, and administration 

as described in subsection (a)(2). Before issuing such an order, FDA 

must find that the absence of adequate labeling could pose significant risks to pediatric patients and that either: (1) the drug or biological product is used for a substantial number of pediatric patients for the labeled indications; or (2) there is reason to believe 

that the drug or biological product would represent a meaningful 

therapeutic benefit over existing therapies for pediatric patents for 

1 or more of the claimed indications. FDA may require this submission only after providing the holder with notice and an opportunity 

for written response and a meeting, which may include an advisory 

committee meeting. 

Section 505B(b)(2): FDA shall grant, as appropriate a full waiver 

of the pediatric data requirement for an already marketed drug or 

biological product if: (1) necessary studies are impossible or highly 

impracticable; or (2) there is evidence strongly suggesting that the 

drug or biological product would be ineffective or unsafe in all pediatric age groups. FDA must grant a partial waiver of the pediatric 

data requirement for specific pediatric subpopulations if the applicant certifies and FDA finds that: (1) necessary studies are impossible or highly impracticable for a specific subpopulation; (2) there 

is evidence strongly suggesting that the drug or biological product 

would be ineffective or unsafe in that subpopulation; (3) the drug 

or biological product does not represent a meaningful therapeutic 

benefit over existing therapies for that subpopulation, the product 

is not likely to be used by a substantial number of patients in that 

subpopulation, and the lack of adequate labeling does not pose significant risks to pediatric patients; or (4) the applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that pediatric subpopulation have failed. If a 

waiver is granted because FDA finds it is not possible to develop 

a pediatric formulation of the product, the waiver will only over the 

pediatric groups requiring that formulation. If a full or partial 

waiver is granted because the product would be ineffective or unsafe in the pediatric population or a pediatric subpopulation, that 

information shall be included in the product’s labeling. 

Section 505B(b)(3): Subsection (b)(3) clarifies that FDA may only 

impose the pediatric study requirements for already marketed 

drugs when the provisions of section 505A in the FFDCA, offering 

pediatric exclusivity incentives, and the NIH grant and contract 

programs of sections 409I and 499 of the PHSA, have both proven 

to be unsuccessful in producing the necessary pediatric information. If requests are made on the two provisions, and the secretary 

determines that there are insufficient funds under sections 409I 

15

and 499 of the PHSA, the assessment may be required. The assessment may also be required if the Secretary certifies that no grant 

has been awarded and not less than 270 days have passed since 

the certification there are sufficient funds to conduct the study. 

This precondition ensures that the existing provisions of the BPCA 

will be utilized and establishes required pediatric studies as a default. Before invoking the agency’s new authority to mandate pediatric studies under this Act, FDA must first have made a written 

request for the manufacturer to conduct the study voluntarily 

under section 505A of the FFDCA or section 409I of the PHSA, to 

which the manufacturer either did not agree or that FDA did not 

receive a timely response. Subsection (b)(3) also clarifies that the 

mandatory pediatric study provisions of this Act do not alter the 

provisions in the BPCA that establish a process at NIH to contract 

for studies to gather pediatric information. Before requiring submission of pediatric data of an already marketed drug product, subsection (b)(3) requires FDA to certify either that insufficient funds 

are available to contract for studies, or that sufficient funds are 

available but no contract or grant has been awarded within the 

specified time frame. 

Section 505B(c): A product will be considered to offer a ‘‘meaningful therapeutic benefit’’ over existing therapies if FDA determines 

that it would represent a significant improvement in the treatment, 

diagnosis, or prevention of a disease compared with already marketed products labeled for that use in the relevant pediatric subpopulation, or that it is in a class of products or is used for an indication for which there is a need for additional options. 

Section 505B(d): FDA has misbranding authority over a drug or 

biological product for which a pediatric assessment is not filed by 

the date specified by FDA but FDA does not have the ability to 

bring criminal proceedings or to withdrawal of approval as a new 

drug or revocation of an approved biologics license. 

Section 505B(e): FDA shall meet with the sponsor of a drug or 

biological product at appropriate times during the investigational 

process to discuss plans and timelines for pediatric studies or requests for waivers or deferrals of pediatric studies. 

Section 505B(f): Subsection (f) clarifies that this Act provides no 

authority for FDA to require pediatric studies of any drug or biological product, or studies regarding any other populations or uses 

of a drug or biological product, except under the conditions provided for in this Act. 

Section 505B(g): The pediatric data requirements of this Act do 

not apply to any drug for an indication for which ‘‘orphan’’ drug 

designation has been granted under Section 526 of the FFDCA, unless FDA determines otherwise by regulation. 

Section 505B(h): Subsection (h) ties the new authority provided 

under this Act to the pediatric exclusivity provisions codified at section 505A of the FFDCA. This Act provides, in essence, that the 

new authority to require pediatric studies shall only remain in effect so long as the pediatric exclusivity provisions also remain in 

effect. The pediatric exclusivity provisions currently have a sunset 

date of October 1, 2007. 

16

Sec. 3. Technical corrections 

Sec. 4. Effective date 

Section 4 makes the Act effective on October 17, 2002. 

(17)

IX. ADDITIONAL VIEWS

ADDITIONAL VIEWS OF SENATORS DEWINE, KENNEDY, 

DODD, CLINTON, MIKULSKI, MURRAY, AND REED 

Relationship between this legislation, the Pediatric Rule, and pediatric exclusivity 

The report asserts that the Pediatric Rule was intended to work 

as a ‘‘backstop’’ to pediatric exclusivity. This assertion is clearly incorrect, particularly in relation to new drugs and biological products. The final rule states that it is ‘‘designed to ensure that new 

drugs and biological products contain adequate pediatric labeling 

for the approved indications at the time of, or soon after, approval. 

The final rule establishes a presumption that all new drugs and 

biologics will be studied in pediatric patients.’’ (Federal Register/

Vol. 63, No. 231, December 2, 1998, p. 66634) Neither the intent 

conveyed by FDA nor FDA’s implementation of the rule supports 

the report’s contention that the rule was intended to work as a ‘‘backstop’’ to pediatric exclusivity or to be employed only to fill the 

gaps in coverage left by the exclusivity. 

The report also incorrectly asserts that the authors of this legislation introduced S. 650 ‘‘to authorize the FDA to require certain 

research into drugs used in pediatric patients if the voluntary 

mechanisms fail.’’ While this assertion may hold for already-marketed products, it is simply incorrect in relation to new drugs and 

biological products. Nothing in the bill requires FDA to wait until 

the voluntary mechanisms have failed before invoking the pediatric 

studies requirement for new drugs or biologics.

TED KENNEDY. 

CHRIS DODD. 

BARBARA A. MIKULSKI. 

JACK REED. 

HILLARY RODHAM CLINTON. 

PATTY MURRAY. 

MIKE DEWINE. 

(18)

ADDITIONAL VIEWS OF SENATORS KENNEDY, DODD, 

CLINTON, MIKULSKI, MURRAY, AND REED 

Enforcement 

The report states that FDA has misbranding authority with respect to a drug or biological product for which a pediatric assessment is not filed by the date specified by FDA. While this statement helps to clarify that the bill is intended to give FDA the authority to deem a product misbranded solely on the basis that an 

assessment was not submitted in accordance with the requirements 

of the legislation, it is not a substitute for, and must be accompanied by, a modification to the legislation. 

The legislation states that if a sponsor fails to submit an assessment, the product may be considered misbranded. The use of the 

word ‘‘may’’ in relation to the ability of FDA to determine a product 

to be misbranded or adulterated is an anomaly in the FFDCA. The 

use of ‘‘may be considered misbranded’’ rather than ‘‘shall be 

deemed misbranded’’, as occurs elsewhere in the FFDCA, may create uncertainty about the Committee’s intent to give FDA full and 

unambiguous authority to enforce the requirements of S. 650. 

The Committee clearly intends for a court to interpret this language as giving FDA new misbranding authority, the use of the 

word ‘‘may’’ creates a risk that a court will apply an interpretation 

that would be contrary to the Committee’s intent. Given that the 

impetus for this legislation was to unequivocally provide FDA with 

the exact statutory authority to require pediatric studies that the 

federal district court ruled in October 2002 it lacked, it is critical 

that the statutory language be modified and that ‘‘may’’ be replaced 

with ‘‘shall’’ to comport with the term used elsewhere in the 

FFDCA. 

In addition, the report incorrectly asserts that FDA has misbranding authority when a pediatric assessment is not filed by the 

date specified by FDA. In accordance with the plain language of 

the legislation, any misbranding authority extends to bringing an 

enforcement action for failure to comply with any of the requirements of the legislation related to the submission of assessments 

or requests for approval of a pediatric formulation, not just timeliness. 

Effective date 

We are also concerned that the current effective date in S. 650 

may allow significant numbers of pediatric studies to be lost in the 

gap between the requirements of the Pediatric Rule and the requirements of this legislation, despite the stated intent of the Committee that the Rule and the legislation be ‘‘seamless.’’ Because the 

current language applies the testing requirement to drug applications submitted on or after October 17, 2002, we are concerned that 

several categories of applications will not be subject to the requireVerDate Jan 31 2003 13:21 Jul 01, 2003 Jkt 019010 PO 00000 Frm 00018 Fmt 6604 Sfmt 6604 E:\HR\OC\SR084.XXX SR084
19

ments of S. 650. For example, the legislation may be incorrectly 

read as not applying to applications submitted to FDA before October 17, 2002, and pending before FDA on October 17, 2002. Also, 

it is not clear that sponsors with applications approved before October 17, 2002, that made commitments under the Rule to conduct 

pediatric studies at a later date would have to honor those commitments. According to FDA, in just the category of deferred studies 

alone, 192 studies may be lost. Also according to FDA, in total, 

more than 300 pediatric studies will be lost if the effective date of 

the legislation is not corrected to ensure a seamless transition of 

the pediatric testing requirement from the Pediatric Rule to this 

legislation. 

We have raised the need to modify this provision, and the enforcement provision discussed previously, to ensure that S. 650 

fully and seamlessly restores the protections of the 1998 Pediatric 

Rule. Although we would have preferred that these two issues had 

been resolved in the language of the bill reported out of the Committee, we are amenable to addressing them in a manager’s 

amendment prior to full Senate consideration of this legislation. 

We expect that we can address and resolve these issues quickly so 

that this important legislation may be considered by the full Senate without further delay. 

Sunset 

The bill was amended by a majority of the committee to sunset 

the bill’s requirements on October 1, 2007, the same date the pediatric exclusivity authority is sunset. The report asserts that this 

‘‘integration’’ of the two programs ensures their co-existence, which 

‘‘ensures FDA has every tool available to best protect children.’’

Some proponents of the amendment may believe that it ensures 

that the pediatric exclusivity provision will be reauthorized in 

2007. They may also believe, as we do, that the pediatric exclusivity provision has been extremely beneficial to children’s health 

and that it deserves serious consideration for reauthorization in 

2007. 

But it is simply not the case that requiring the reauthorization 

of the pediatric assessment authority in 2007 promotes children’s 

health. Instead, it seriously undermines the goal of the legislation, 

which is to address the uncertainty surrounding pediatric drug 

testing and to eliminate the threat that children’s protections may 

lapse. In addition, the requirement for reauthorization leaves open 

the possibility that the pediatric assessment requirement will be 

weakened, or will be eliminated altogether. This possibility shows 

the amendment as an anathema to the purpose of the legislation 

and the purpose of protecting children. 

Adults can count on FDA to assure trials for drug safety and efficacy without returning to Congress every 5 years for that assurance. Because of the amendment, children will be denied that same 

protection. Once again they will have to seek legislation to assure 

what adults now take for granted, that the drugs we use have been 

shown to be safe and effective for us to use. 

20

Intended use 

FDA’s Pediatric Rule to require the study in children of drugs 

and biological products for their approved uses was held to be invalid by a federal district judge. The report makes several references to and quotations from this ill-considered and obviously errant decision about how intended uses of FDA-regulated products 

are made and about the scope of FDA’s authority under the 

FFDCA. We write to clarify these issues because we believe that 

both the court and the report fundamentally misconstrue the authority of FDA, and that FDA already has the authority to require 

studies on subpopulations that will use a drug. Although the district court concluded that FDA did not have sufficient authority to 

require studies on off-label uses, it ignored, without discussion, 

FDA’s determination that use in children is not an ‘‘off-label’’ use, 

just as use in women is not an ‘‘off-label’’ use. It is a use in an expected, major subpopulation, which may raise some different questions than use in other populations. In choosing to ignore the agency’s central argument in support of its authority, the decision fails 

to answer the question of the agency’s pre-existing authority to require pediatric studies, or studies on other subpopulations. 

The report also asserts, relying exclusively on the district court 

opinion, that it is ‘‘the long-established foundation of our food and 

drug laws’’ that drug sponsors determine the ‘‘intended uses’’ of a 

product, and that FDA does not regulate foreseeable or actual uses 

of a product that the sponsor does not claim.’’ Although this assertion is often found in the arguments of the pharmaceutical industry 

in attempts to weaken FDA’s long-standing authority, it is contradicted by decades of FDA practice and numerous judicial opinions 

from higher courts. 

When determining a product’s intended use, it is well-established 

that FDA may consider evidence other than express claims that a 

product is intended to have a certain effect. Indeed, the text of the 

FFDCA, longstanding FDA regulations, the legislative history of 

the Medical Device Amendments of 1976, appeals court decisions, 

and FDA’s regulatory practice fully support this view. 

For example, sections 201(g)(1)(C) and (h)(3) of the FFDCA make ‘‘intended’’ effects, not ‘‘market claims,’’ the decisive factor. Although market claims are one important way to establish a product’s intended effect, other circumstances can establish a product’s 

intended effect, and nothing in the text of the operative definitions 

bars FDA from relying on such evidence. 

Longstanding FDA regulations provide that ‘‘intended use’’ refers 

to ‘‘the objective intent of the persons legally responsible for labeling,’’ and may be determined not only by ‘‘labeling claims’’ and ‘‘advertising matter,’’ but also by other ‘‘oral or written statements’’ made by persons legally responsible for the labeling; ‘‘the circumstances surrounding the distribution of the article’’; ‘‘the circumstances that the article is, with the knowledge of [the manufacturer], * * * offered and used for a purpose for which it is neither 

labeled nor advertised’’; and (4) evidence that ‘‘a manufacturer 

knows, or has knowledge of facts that would give him notice’’ that 

a drug or device ‘‘is to be used’’ for purposes other than those for 

which the manufacturer offered the product. 21 CFR 201.128 and 

801.4. 

21

A House report on the Medical Device Amendments of 1976, Pub. 

L. No. 94–295, supports the view that ‘‘intended’’ effects are not 

limited to manufacturer claims. That report specifically rejected the 

proposition that a claim is dispositive and explained that the Secretary ‘‘may consider actual use of a product in determining whether or not it is a device.’’ H.R. Rep. No. 853, 94th Cong., 2d Ses. 14 

(1976). 

Many appeals courts have agreed that a manufacturer’s intent 

with respect to effects or use may be determined on the basis of 

all relevant circumstances, including consumer use, not simply a 

manufacturer’s market claims. National Nutritional Foods Ass’n v. 

Mathews, 557 F.2d 325, 334 (2d Cir. 1977) (intent may be determined from any relevant source, including consumer use); United 

States v. An Article * * * Consisting of * * * 216 Cartoned Bottles, 

409 F.2d 734, 739, 742 (2d Cir. 1969) (the intended use of a product 

may be determined from its label, accompanying labeling, promotional material, advertising and any other relevant source, including consumer use); United States v. Storage Spaces Designated 

Nos. ‘‘8’’ & ‘‘49’’, 777 F.2d 1363, 1366 (9th Cir. 1985), (manufacturer 

intent may be derived from any relevant source), cert. denied, 479 

U.S. 1086 (1987); Action on Smoking & Health v. Harris, 655 F.2d 

236, 239–240 (D.C. Cir. 1980) (consumer use can be relevant in determining manufacturer intent). 

Finally, in its administration of the FFDCA, FDA has treated 

products as drugs or devices, despite the absence of explicit market 

claims. Among other products, FDA has treated as drugs or devices: (1) cosmetics containing hormones based on the absence of 

any legitimate cosmetic purpose for the hormones; (2) toothpaste 

containing fluoride because fluoride is widely accepted as an anticavity agent and affects the structure of the tooth; (3) thyroid-containing food supplements based on the recognized physiological effects of thyroid products; (4) interferon based on media coverage 

touting it as a possible miracle cure; (5) novelty condoms based on 

their likely use as prophylactics; (6) sun screen products based on 

consumer expectations that they will provide protection against the 

harmful effects of the sun on the body; and (7) tanning booths 

based on the known effects of ultraviolet rays on the structure or 

function of the body. In each of these cases, FDA found that the 

product was intended for use as a drug or a device based on the 

inherent nature of the product, its predominant use or effects, or 

both. 

Some of these cases required FDA to determine whether a product was under its jurisdiction at all, while others required FDA to 

determine whether a product would be regulated merely as a cosmetic or food or instead as a drug or device. It is also the case that 

FDA may use its authority to regulate the off-label use of a drug 

or a device. Indeed, when a particular off-label use becomes widespread or endangers public health, FDA must investigate it thoroughly and take appropriate action to protect the public, including 

requiring a change in the product’s labeling to warn against or approve the unapproved use, seeking substantial evidence to substantiate its use, restricting the distribution of the drug, or even withdrawing approval of the drug and removing it from the market. 

22

Accordingly, some of the withdrawals of approved drugs in the 

last several years, including fenfluramine hydrochloride, 

dexfenfluramine hydrochloride, mibefradil dihydrochloride, and 

bromfenac sodium, have followed after off-label use of the drugs 

was associated with patient injuries and deaths. FDA has required 

the relabeling of other drugs, such as the anti-arrhythmic drugs, 

Encainide and Flecainide, because of wide-spread off-label use that 

was shown to have caused hundreds if not thousands of deaths. Indeed, numerous drugs carry FDA-required warnings about dangerous or unsubstantiated off-label uses. If FDA lacked authority 

over off-label uses, it would not be able to require warnings about 

such uses. 

These cases illustrate most dramatically the importance of FDA 

determining a product’s intended use by any available evidence, 

and not only by marketing claims, because nothing less than the 

public health and safety depends upon it.

It is therefore incorrect both as a matter of law and practice that 

the report asserts that FDA may only consider a manufacturer’s 

claimed uses for its product when determining intended use. This 

legislation is limited to addressing FDA’s authority to require pediatric testing of drugs. It does not alter or affect the authority of 

FDA under the FFDCA with respect to testing of drugs in other 

subpopulations, such as women and minorities, or for other uses, 

including off-label uses in appropriate circumstances. And it is outrageous that the report has been used as an opportunity to promote 

an unfounded and dangerous view of FDA’s authority in these 

other areas. 

Seizures 

The report also asserts that FDA’s seizure authority is an unsatisfactory remedy from a public health perspective because it denies 

adequately studied populations access to a safe and effective drug. 

It would be true that a mass seizure of all of a manufacturer’s drug 

or biological product would disrupt patient access to a safe and effective product. It is not the case, however, that seizure of the lots 

of a drug in one warehouse, when there are other stores of the drug 

that are not seized, would disrupt consumer access to a drug or biological product. 

In fact, such a seizure may be a particularly appropriate way for 

FDA to seek enforcement of a statutory or regulatory requirement, 

because it allows patients to have access to products that the government has not seized and because the manufacturer’s interest in 

being able to distribute the seized product can facilitate quicker 

resolution of the dispute. In the instances under consideration 

here, that would mean quicker completion of pediatric studies that 

a manufacturer has failed to complete in a timely way.

23

The legislation clearly authorizes FDA to use the full range of its 

enforcement authorities with the single exception of criminal penalties. Under S. 650, the agency retains its full discretion as to 

whether to use its seizure authority.

TED KENNEDY. 

CHRIS DODD. 

BARBARA A. MIKULSKI. 

HILLARY RODHAM CLINTON. 

PATTY MURRAY. 

JACK REED. 

(24)

X. CHANGES IN EXISTING LAW

In compliance with rule XXVI paragraph 12 of the Standing 

Rules of the Senate, the following provides a print of the statute 

or the part or section thereof to be amended or replaced (existing 

law proposed to be omitted is enclosed in black brackets, new matter is printed in italic, existing law in which no change is proposed 

is shown in roman): 

PEDIATRIC RESEARCH EQUITY ACT OF 2003

* * * * * * *

FEDERAL FOOD, DRUG, AND COSMETIC ACT 

SEC. 505. (a) No person shall introduce or deliver for introduction 

into interstate commerce any new drug, unless an approval of an 

application filed pursuant to subsection (b) or (j) is effective with 

respect to such drug. 

(b)(1) Any person may file with the Secretary an application with 

respect to any drug subject to the provisions of subsection (a). Such 

persons shall submit to the Secretary as a part of the application 

(A) full reports of investigations which have been made to show 

whether or not such drug is safe for use and whether such drug 

is effective in use; (B) a full list of the articles used as components 

of such drug; (C) a full statement of the composition of such drug; 

(D) a full description of the methods used in, and the facilities and 

controls used for, the manufacture, processing, and packing of such 

drug; (E) such samples of such drug and of the articles used as 

components thereof as the Secretary may require; (F) øand (F)¿

specimens of the labeling proposed to be used for such drug. The 

applicant shall file with the application the patent number and the 

expiration date of any patent which claims the drug for which the 

applicant submitted the application or which claims a method of 

using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by 

the owner engaged in the manufacture use, or sale of the drug. If 

a application is filed under this subsection for a drug and a patent 

which claims such drug or a method of using such drug is issued 

after the filing date but before approval of the application, the applicant shall amend the application to include the information required by the preceding sentence. Upon approval of the application, 

the Secretary shall publish information submitted under the two 

preceding sentences. The Secretary shall, in consultation with the 

Director of the National Institutes of Health and with representatives of the drug manufacturing industry, review and develop guidance, as appropriate, on the inclusion of women and minorities in 

clinical trials required by clause (A)ø.¿ and (G) any assessments required under section 505B.

25

SEC. 505A. [21 U.S.C. 355A] PEDIATRIC STUDIES OF DRUGS. 

(a) DEFINITIONS.—***

* * * * * * *

(b) MARKET EXCLUSIVELY FOR NEW DRUGS.—***

* * * * * * *

(1)(A)(i) * * *

* * * * * * *

(2)(A) if the drug is the subject of— (i) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of 

section 505 and for which pediatric studies were submitted 

prior to the expiration of the patent (including any patent 

extensions); or 

(ii) a listed patent for which a certification has been submitted under subsections (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of 

section 505, 

the period during which an application may not be approved under 

section 505(c)(3) or section ø505(j)(4)(B)¿ 505(j)(4)(B) shall be extended by a period of six months after the date the patent expires 

(including any patent extensions); or 

(B) if the drug is the subject of a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iv) or 

(j)(2)(A)(vii)(IV) of section 505, and in the patent infringement litigation resulting from the certification the court determines that the 

patent is valid and would be infringed, the period during which an 

application may not be approved under section 505(c)(3) or section 

ø505(j)(4)(B)¿ 505(j)(4)(B) shall be extended by a period of six 

months after the date the patent expires (including any patent extensions). 

(c) MARKET EXCLUSIVELY FOR ALREADY-MARKETED DRUGS.—

***

(1)(A)(i) * * *

(2)(A) if the drug is the subject of—

(i) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of 

section 505 and for which pediatric studies were submitted 

prior to the expiration of the patent (including any patent 

extensions); or 

(ii) a listed patent for which a certification has been submitted under subsection (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of 

section 505, 

the period during which an application may not be approved under 

section 505(c)(3) or section ø505(j)(4)(B)¿ 505(j)(4)(B) shall be extended by a period of six months after the date the patent expires 

(including any patent extensions); or 

(B) if the drug is the subject of a listed patent for which a 

certification has been submitted under subsection (b)(2)(A)(iv) 

or (j)(2)(A)(vii)(IV) of section 505, and in the patent infringement litigation resulting from the certification the court determines that the patent is valid and would be infringed, the period during which an application may not be approved under 

section 505(c)(3) or section ø505(j)(4)(B)¿ 505(j)(4)(B) shall be 

26

extended by a period of six months after the date the patent 

expires (including any patent extensions). 

* * * * * * *

(h) RELATIONSHIP TO øREGULATIONS¿ PEDIATRIC RESEARCH RE- QUIREMENTS.—Notwithstanding any other provision of law, if any 

pediatric study is required øpursuant to regulations promulgated 

by the Secretary¿ by a provision of law (including a regulation) 

other than this section and such study meets the completeness, 

timeliness, and other requirements of this section, such study shall 

be deemed to satisfy the requirement for market exclusivity pursuant to this section. 

(i) LABELING SUPPLEMENTS.—***

* * * * * * *

(i) LABELING SUPPLEMENTS.— (1) PRIORITY STATUS FOR PEDIATRIC SUPPLEMENTS.—*** (A) * * *

(B) * * *

(2) DISPUTE RESOLUTION.— (A) REQUEST FOR LABELING CHANGE AND FAILURE TO

AGREE.—If the Commissioner determines that an application with respect to which a pediatric study is conducted 

under this section is approvable and that the only open 

issue for final action on the application is the reaching of 

an agreement between the sponsor of the application and 

the Commissioner on appropriate changes to the labeling 

for the drug that is the subject of the application, not later 

than 180 days after the date of submission of the application— (i) the Commissioner shall request that the sponsor 

of the application make any labeling change that the 

Commissioner determines to be appropriate; and 

(ii) if the sponsor of the application does not agree 

to make a labeling change requested by the Commissioner, the Commissioner shall refer the matter to the 

Pediatric øAdvisory Subcommittee of the Anti-Infective Drugs¿ Advisory Committee. 

(B) ACTION BY THE PEDIATRIC øADVISORY SUBCOMMITTEE

OF THE ANTI-EFFECTIVE DRUGS¿ ADVISORY COMMITTEE.—

Not later than 90 days after receiving a referral under 

subparagraph (A)(ii), the Pediatric øAdvisory Subcommittee of the Anti-Infective Drugs¿ Advisory Committee shall—

(i) review the pediatric study reports; and 

(ii) make a recommendation to the Commissioner 

concerning appropriate labeling changes, if any. 

(C) CONSIDERATION OF RECOMMENDATIONS.—The Commissioner shall consider the recommendations of the Pediatric øAdvisory 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. 

27

(D) MISBRANDING.—If the sponsor of the application, 

within 30 days after receiving a request under subparagraph (C), dose not agree to make a labeling change requested by the Commissioner, the Commissioner may 

deem the drug that is the subject of the application to be 

misbranded. 

(E) NO EFFECT ON AUTHORITY.—Nothing in this subsection limits the authority of the United States to bring 

an enforcement action under this Act when a drug lacks 

appropriate pediatric labeling. Neither course of action 

(the Pediatric øAdvisory Subcommittee of the Anti-Infective Drugs¿ Advisory Committee process or an enforcement action referred to in the preceding sentence) shall 

preclude, delay, or serve as the basis to stay the other 

course of action. 

* * * * * * *

Best Pharmaceuticals for Children Act 

HISTORICAL AND STATUTORY NOTES

Pediatric øPharmacology¿ Therapeutics Advisory Committee. 

Pub. L. 117–109, § 14, Jan. 4, 2002, 115 Stat. 1419, provided that: ‘‘(a) IN GENERAL.—The Secretary of Health and Human Services 

shall, under section 222 of the Public Health Service Act ø42 

U.S.C. 217a),¿ (42 U.S.C. 217a) or other appropriate authority, convene and consult an advisory committee on pediatric øpharmacology¿ therapeutics (referred to in this section as the ‘‘advisory 

committee’’). ‘‘(b) PURPOSE.— ‘‘(1) IN GENERAL.—The advisory committee shall advise and 

make recommendations to the Secretary, through the Commissioner of Food and Drugs øand in consultation with the Director of the National Institutes of Health¿ on matters relating to 

pediatric øpharmacology¿ therapeutics. ‘‘(2) MATTERS INCLUDED.—The matters referred to in paragraph (1) include— ‘‘(A) pediatric research conducted under sections 351, 

409I, and 499 of the Public Health Service Act [42 U.S.C. 

A. §§ 262, 284m, and 290b] and sections 501, 502, 505, and 

ø505A¿ 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 pediatric øpharmacology¿ therapeutics and the need for additional treatments of specific pediatric diseases or conditions; and 

‘‘(C) the ethics, design, and analysis of clinical trials related to pediatric øpharmacology¿ therapeutics. 

* * * * * * *

SEC. 15. PEDIATRIC SUBCOMMITTEE OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE. 

(a) CLARIFICATION OF AUTHORITIES.—

(1) IN GENERAL.—***

(A) * * *

28

(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 øPharmacology¿ Advisory Committee and the Oncologic Drugs Advisory Committee. 

* * * * * * *

SEC. 16. REPORT ON PEDIATRIC EXCLUSIVITY PROGRAM. 

* * * * * * *

(1) The effectiveness of section 505A of the Federal Food, Drug, 

and Cosmetic Act and section 409I of the Public Health Service Act 

(as added by this Act) in ensuring that medicines used by children 

are tested and properly labeled, including—

(A) * * *

(B) * * *

(C) the number of drugs for which testing is being done, exclusivity granted, and labeling changes required, including the 

date pediatric exclusivity is granted and the date labeling 

changes are made and which labeling changes required the use 

of the dispute resolution process established pursuant to the 

amendments made by this Act, together with a description of 

the outcomes of such process, including a description of the disputes and the recommendations of the Pediatric øAdvisory 

Subcommittee of the Anti-Infective Drugs¿ Advisory Committee. 

* * * * * * *

SEC. 17. ADVERSE-EVENT REPORTING. 

(a) TOLL-FREE NUMBER IN LABELING.—***

(1) * * *

(2) * * *

(3) * * *

(b) DRUGS WITH PEDIATRIC MARKET EXCLUSIVITY.—

(1) IN GENERAL.—During the one year beginning on the date 

on which a drug receives a period of market exclusivity under 

505A of the Federal Food, Drug, and Cosmetic Act, any report 

of an adverse event regarding the drug that the Secretary of 

health and Human Services receives shall be referred to the 

Office of Pediatric Therapeutics established under section 6 of 

this Act. In considering the report, the Director of such Office 

shall provide for the review of the report by the Pediatric øAdvisory Subcommittee of the Anti-Infective Drugs¿ Advisory 

Committee, including obtaining any recommendations of such 

subcommittee regarding whether the Secretary should take action under the Federal Food, Drug, and Cosmetic Act in response to the report. 

* * * * * * *

SEC. 505B. RESEARCH INTO PEDIATRIC USES FOR DRUGS AND BIOLOGICAL PRODUCTS. 

(a) NEW DRUGS AND BIOLOGICAL PRODUCTS.—

29

(1) IN GENERAL.—A person that submits an application (or 

supplement to an application)— (A) under section 505 for a new active ingredient, new indication, new dosage form, new dosing regimen, or new 

route of administration; or 

(B) under section 351 of the Public Health Service Act (42 

U.S.C. 262) for a new active ingredient, new indication, 

new dosage form, new dosing regimen, or new route of administration; 

shall submit with the application the assessments described in 

paragraph (2). 

(2) ASSESSMENTS.— (A) IN GENERAL.—The assessments referred to in paragraph (1) shall contain data, gathered using appropriate 

formulations for each age group for which the assessment 

is required, that are adequate— (i) to assess the safety and effectiveness of the drug 

or the biological product for the claimed indications in 

all relevant pediatric subpopulations; and 

(ii) to support dosing and administration for each 

pediatric subpopulation for which the drug or the biological product is safe and effective. 

(B) SIMILAR COURSE OF DISEASE OR SIMILAR EFFECT OF

DRUG OR BIOLOGICAL PRODUCT.— (i) IN GENERAL.—If the course of the disease and the 

effects of the drug are sufficiently similar in adults and 

pediatric patients, the Secretary may conclude that pediatric effectiveness can be extrapolated from adequate 

and well-controlled studies in adults, usually supplemented with other information obtained in pediatric 

patients, such as pharmacokinetic studies. 

(ii) EXTRAPOLATION BETWEEN AGE GROUPS.—A study 

may not be needed in such pediatric age group if data 

from 1 age group can be extrapolated to another age 

group. 

(3) DEFERRAL.—On the initiative of the Secretary or at the request of the applicant, the Secretary may defer submission of 

some or all assessments required under paragraph (1) until a 

specified date after approval of the drug or issuance of the license for a biological product if— (A) the Secretary finds that— (i) the drug or biological product is ready for approval for use in adults before pediatric studies are 

complete; 

(ii) pediatric studies should be delayed until additional safety or effectiveness data have been collected; 

or 

(iii) there is another appropriate reason for deferral; 

and 

(B) the applicant submits to the Secretary—

(i) certification of the grounds for deferring the assessments; 

(ii) a description of the planned or ongoing studies; 

and 

30

(iii) evidence that the studies are being conducted or 

will be conducted with due diligence and at the earliest 

possible time. 

(4) WAIVERS.— (A) FULL WAIVER.—On the initiative of the Secretary or 

at the request of an applicant, the Secretary shall grant a 

full waiver, as appropriate, of the requirement to submit 

assessments for a drug or biological product under this 

subsection if the applicant certifies and the Secretary finds 

that—(i) necessary studies are impossible or highly impracticable (because, for example, the number of patients is 

so small or the patients are geographically dispersed); 

(ii) there is evidence strongly suggesting that the 

drug or biological product would be ineffective or unsafe in all pediatric age groups; or 

(iii) the drug or biological product— (I) does not represent a meaningful therapeutic 

benefit over existing therapies for pediatric patients; and 

(II) is not likely to be used in a substantial number of pediatric patients.

(B) PARTIAL WAIVER.—On the initiative of the Secretary 

or at the request of an applicant, the Secretary shall grant 

a partial waiver, as appropriate, of the requirement to submit assessments for a drug or biological product under this 

subsection with respect to a specific pediatric age group if 

the applicant certifies and the Secretary finds that— (i) necessary studies are impossible or highly impracticable (because, for example, the number of patients in 

that age group is so small or patients in that age group 

are geographically dispersed); 

(ii) there is evidence strongly suggesting that the 

drug or biological product would be ineffective or unsafe in that age group; 

(iii) the drug or biological product—

(I) does not represent a meaningful therapeutic 

benefit over existing therapies for pediatric patients 

in that age group; and 

(II) is not likely to be used by a substantial number of pediatric patients in that age group; or 

(iv) the applicant can demonstrate that reasonable 

attempts to produce a pediatric formulation necessary 

for that age group have failed. 

(C) PEDIATRIC FORMULATION NOT POSSIBLE.—If a waiver 

is granted on the ground that it is not possible to develop 

a pediatric formulation, the waiver shall cover only the pediatric groups requiring that formulation. 

(D) LABELING REQUIREMENT.—If the Secretary grants a 

full or partial waiver because there is evidence that a drug 

or biological product would be ineffective or unsafe inn pediatric populations, the information shall be included in 

the labeling for the drug or biological product. 

(b) MARKETED DRUGS AND BIOLOGICAL PRODUCTS.—

31

(1) IN GENERAL.—After providing notice in the form of a letter 

and an opportunity for written response and a meeting, which 

may include an advisory committee meeting, the Secretary may 

(by order in the form of a letter) require the holder of an approved application for a drug under section 505 or the holder 

of a license for a biological product under section 351 of the 

Public Health Service Act (42 U.S.C. 262) to submit by a specified date the assessment described in subsection (a)(2) if the 

Secretary finds that—

(A)(i) the drug or biological product is used for a substantial number of pediatric patients for the labeled indications; and 

(ii) the absence of adequate labeling could pose significant risks to pediatric patients; or 

(B)(i) there is reason to believe that the drug or biological 

product would represent a meaningful therapeutic benefit 

over existing therapies for pediatric patients for 1 or more 

of the claimed indications; and 

(ii) the absence of adequate labeling could pose significant risks to pediatric patients. 

(2) WAIVERS.—

(A) FULL WAIVER.—At the request of an applicant, the 

Secretary shall grant a full waiver, as appropriate, of the 

requirement to submit assessments under this subsection if 

the applicant certifies and the Secretary finds that—

(i) necessary studies are impossible or highly impracticable (because, for example, the number of patients in 

that age group is so small or patients in that age group 

are geographically dispersed); or 

(ii) there is evidence strongly suggesting that the 

drug or biological product would be ineffective or unsafe in all pediatric age groups. 

(B) PARTIAL WAIVER.—At the request of an applicant, the 

Secretary shall grant a partial waiver, as appropriate, of 

the requirement to submit assessments under this subsection with respect to a specific pediatric age group if the 

applicant certifies and the Secretary finds that—

(i) necessary studies are impossible or highly impracticable (because, for example, the number of patients in 

that age group is so small or patients in that age group 

are geographically dispersed); 

(ii) there is evidence strongly suggesting that the 

drug or biological product would be ineffective or unsafe in that age group; 

(iii)(I) the drug or biological product—

(aa) does not represent a meaningful therapeutic 

benefit over existing therapies for pediatric patients 

in that age group; and 

(bb) is not likely to be used in a substantial 

number of pediatric patients in that age group; 

and 

(II) the absence of adequate labeling could not pose 

significant risks to pediatric patients; or 

32

(iv) the applicant can demonstrate that reasonable 

attempts to produce a pediatric formulation necessary 

for that age group have failed. 

(C) PEDIATRIC FORMULATION NOT POSSIBLE.—If a waiver 

is granted on the ground that it is not possible to develop 

a pediatric formulation, the waiver shall cover only the pediatric groups requiring that formulation. 

(D) LABELING REQUIREMENT.—If the Secretary grants a 

full or partial waiver because there is evidence that a drug 

or biological product would be ineffective or unsafe in pediatric populations, the information shall be included in the 

labeling for the drug or biological product. 

(3) RELATIONSHIP TO OTHER PEDIATRIC PROVISIONS.—

(A) NO ASSESSMENT WITHOUT WRITTEN REQUEST.—No assessment may be required under paragraph (1) for a drug 

subject to an approved application under section 505 unless—

(i) the Secretary has issued a written request for a related pediatrict study under section 505A(c) of this Act 

or section 409I of the Public Health Service Act (42 

U.S.C. 284m); 

(ii)(I) if the request was made under section 

505A(c)—

(aa) the recipient of the written request does not 

agree to the request; or 

(bb) the Secretary does not receive a response as 

specified under section 505A(d)(4)(A); or 

(II) if the request was made under section 409I of the 

Public Health Service Act (42 U.S.C. 284m)—

(aa) the recipient of the written request does not 

agree to the request; or 

(bb) the Secretary does not receive a response as 

specified under section 409I(c)(2) of that Act; and 

(iii)(I) the Secretary certifies under subparagraph (B) 

that there are insufficient funds under sections 409I 

and 499 of the Public Health Service Act (42 U.S.C. 

284m, 290b) to conduct the study; or 

(II) the Secretary publishes in the FEDERAL REGISTER a certification that certifies that—

(aa) no contract or grant has been awarded 

under section 409I or 499 of the Public Health 

Service Act (42 U.S.C. 284m, 290b); and 

(bb) not less than 270 days have passed since the 

date of a certification under subparagraph (B) that 

there are sufficient funds to conduct the study. 

(B) NO AGREEMENT TO REQUEST.—Not later than 60 days 

after determining that no holder will agree to the written 

request (including a determination that the Secretary has 

not received a response specified under section 505A(d) of 

this Act or section 409I of the Public Health Service Act (42 

U.S.C. 284m), the Secretary shall certify whether the Secretary has sufficient funds to conduct the study under section 409I or 499 of the Public Health Service Act (42 U.S.C. 

33

284m 290b), taking into account the prioritization under 

section 409I. 

(c) MEANINGFUL THERAPEUTIC BENEFIT.—For the purposes of 

paragraph (4)(A)(iii)(I) and (4)(B)(iii)(I) of subsection (a) and paragraphs (1)(B)(i) and (2)(B)(iii)(I)(aa) of subsection (b), a drug or biological product shall be considered to represent a meaningful therapeutic benefit over existing therapies if the Secretary estimates 

that—

(1) if approved, the drug or biological product would represent a significant improvement in the treatment, diagnosis, or 

prevention of a disease, compared with marketed products adequately labeled for that use in the relevant pediatric population; 

or 

(2) the drug or biological product is in a class of products or 

for an indication for which there is a need for additional options.

(d) SUBMISSION OF ASSESSMENTS.—If a person fails to submit an 

assessment described in subsection (a)(2), or a request for approval 

of a pediatric formulation described in subsection (a) or (b), in accordance with applicable provisions of subsections (a) and (b)—

(1) the drug or biological product that is the subject of the assessment or request may be considered misbranded and subject 

to relevant enforcement action (except that the drug or biological product shall not be subject to action under section 303); but 

(2) the failure to submit the assessment or request shall not 

be the basis for a proceeding—

(A) to withdraw approval for a drug under section 505(e); 

or 

(B) to revoke the license for a biological product under 

section 351 of the Public Health Service Act (42 U.S.C. 

262). 

(e) MEETINGS.—Before and during the investigational process for 

a new drug or biological product, the Secretary shall meet at appropriate times with the sponsor of the new drug or biological product 

to discuss—

(1) information that the sponsor submits on plans and 

timelines for pediatric studies; or 

(2) any planned request by the sponsor for waiver or deferral 

of pediatric studies. 

(f) SCOPE OF AUTHORITY.—Nothing in this section provides to the 

Secretary any authority to require a pediatric assessment of any 

drug or biological product, or any assessment regarding other populations or uses of a drug or biological product, other than the pediatric assessments described in this section. 

(g) ORPHAN DRUGS.—Unless the Secretary requires otherwise by 

regulation, this section does not apply to any drug for an indication 

for which orphan designation has been granted under section 526. 

(h) INTEGRATION WITH OTHER PEDIATRIC STUDIES.—The authority under this section shall remain in effect so long as an application subject to this section may be accepted for filing by the Secretary on or before the date specified in section 505A(n). 

* * * * * * *

34

PUBLIC HEALTH SERVICE ACT 

PART F—LICENSING—BIOLOGICAL PRODUCTS AND CLINICAL

LABORATORIES

Subpart 1—Biological Products 

REGULATION OF BIOLOGICAL PRODUCTS

SEC. 351. (a)(1) * * *

(2)(A) The Secretary shall establish, by regulation, requirements 

for the approval, suspension, and revocation of biologics licenses.

(B) PEDIATRIC STUDIES.—A person that submits an application 

for a license under this paragraph shall submit to the Secretary as 

part of the application any assessments required under section 505B 

of the Federal Food, Drug, and Cosmetic Act.

ø(B)¿ (C) The Secretary shall approve a biologics license application—

(i) on the basis of a demonstration that—

(I) the biological product that is the subject of the application is safe, pure, and potent; and 

(II) the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be 

safe, pure, and potent; and 

(ii) if the applicant (or other appropriate person) consents to 

the inspection of the facility that is the subject of the application, in accordance with subsection (c). 

* * * * * * *

SEC. 409I. ø284m¿ PROGRAM FOR PEDIATRIC STUDIES OF DRUGS. 

(a) LIST OF DRUGS FOR WHICH PEDIATRIC STUDIES ARE NEEDED.—

(1) IN GENERAL.—***

* * * * * * *

(c) PROCESS FOR CONTRACTS AND LABELING CHANGES.—

(1) WRITTEN REQUEST TO HOLDERS OF APPROVED APPLICATION

FOR DRUGS LACKING EXCLUSIVITY.—The Commissioner of Food 

and Drugs, in consultation with the Director of the National 

Institutes of Health, may issue a written request (which shall 

include a timeframe for negotiations for an agreement) for pediatric studies concerning a drug identified in the list described 

in subsection (a)(1)(A) (except clause (iv)) to all holders of an 

approved application for the drug under section 505 of the Federal Food, Drug and Cosmetic Act. Such a written request shall 

be made in a manner equivalent to the manner in which a 

written request is made under subsection (a) or (b) of section 

505A of the Federal Food, Drug and Cosmetic Act, including 

with respect to information provided on the pediatric studies to 

be conducted pursuant to the request. 

(2) REQUESTS FOR CONTRACT PROPOSALS.—***

* * * * * * *

35

(7) REQUESTS FOR LABELING CHANGE.—During the 180-day 

period after the date on which a report is submitted under 

paragraph (6)(A), the Commissioner of Food and Drugs shall— (A) review the report and such other data as are available concerning the safe and effective use in the pediatric 

population of the drug studied; 

(B) negotiate with the holders of approved applications 

for the drug studied for any labeling changes that the 

Commissioner of Food and Drugs determines to be appropriate and requests the holders to make; and 

(C)(i) place in the public docket file a copy of the report 

and of any requested labeling changes; and 

(ii) publish in the Federal Register a summary of the report and a copy of any requested labeling changes. 

(8) DISPUTE RESOLUTION.— (A) REFERRAL TO PEDIATRIC øADVISORY SUBCOMMITTEE

OF THE ANTI-INFECTIVE DRUGS¿ ADVISORY COMMITTEE.—If, 

not later than the end of the 180-day period specified in 

paragraph (7), the holder of an approved application for 

the drug involved does not agree to any labeling change requested by the Commission of Food and Drugs under that 

paragraph, the Commissioner of Food and Drugs shall 

refer the request to the Pediatric øAdvisory Subcommittee 

of the Anti-Infective Drugs¿ Advisory Committee 

(B) ACTION BY THE PEDIATRIC øADVISORY SUBCOMMITTEE

OF THE ANTI-INFECTIVE DRUGS¿ ADVISORY COMMITTEE.— Not later than 90 days after receiving a referral under 

subparagraph (A), the Pediatric øAdvisory Subcommittee 

of the Anti-Infective Drugs¿ Advisory Committee shall— (i) review the available information on the safe and 

effective use of the drug in the pediatric population, 

including study reports submitted under this section; 

and 

(ii) make a recommendation to the Commissioner of 

Food and Drugs as to appropriate labeling changes if 

any. 

(9) FDA DETERMINATION.—Not later than 30 days after receiving a recommendation from the Pediatric øAdvisory Subcommittee of the Anti-Infective Drugs¿ Advisory Committee 

under paragraph (8)(B)(ii) with respect to a drug, the Commissioner of Food and Drugs shall consider the recommendation 

and, if appropriate, make a request to the holders of approved 

applications for the drug to make any labeling change that the 

Commissioner of Food and Drugs determines to be appropriate. 

(10) FAILURE TO AGREE.—If a holder of an approved application for a drug, within 30 days after receiving a request to 

make a labeling change under paragraph (9), does not agree to 

make a requested labeling change, the Commissioner may 

deem the drug to be misbranded under the Federal Food, 

Drug, and Cosmetic Art (21 U.S.C. 301 et seq.). 

(11) NO EFFECT ON AUTHORITY.—Nothing in this subsection 

limits the authority of the United States to bring an enforcement action under the Federal Food, Drug, and Cosmetic Act 

when a drug lacks appropriate pediatric labeling. Neither 

36

course of action (the Pediatric øAdvisory Subcommittee of the 

Anti-Infective Drugs¿ Advisory Committee process or an enforcement action referred to in the preceding sentence) shall 

preclude, delay, or serve as the basis to stay the other course 

of action. 

* * * * * * *

Æ