United States Government Accountability Office

GAO Report to Congressional Committees

PEDIATRIC DRUG 

RESEARCH 

Studies Conducted 

under Best 

Pharmaceuticals for 

Children Act 

March 2007 

 

GAO-07-557 
What GAO Found

United States Government Accountability Office

Why GAO Did This Study

Highlights

Accountability Integrity Reliability

March 2007

PEDIATRIC DRUG RESEARCH 

Studies Conducted under Best 

Highlights of GAO-07-557, a report to Pharmaceuticals for Children Act 

congressional committees 

About two-thirds of drugs that are 

prescribed for children have not 

been studied and labeled for

pediatric use, which places 

children at risk of being exposed to 

ineffective treatment or incorrect 

dosing. The Best Pharmaceuticals 

for Children Act (BPCA), enacted

in 2002, encourages the

manufacturers, or sponsors, of 

drugs that still have marketing

exclusivity—that is, are onpatent—to conduct pediatric drug

studies, as requested by the Food

and Drug Administration (FDA). If 

they do so, FDA may extend for 6 

months the period during which no

equivalent generic drugs can be 

marketed. This is referred to as

pediatric exclusivity. 

BPCA required that GAO assess the

effect of BPCA on pediatric drug

studies and labeling. As discussed 

with the committees of jurisdiction, 

GAO (1) assessed the extent to 

which pediatric drug studies were 

being conducted under BPCA for 

on-patent drugs, including when 

drug sponsors declined to conduct 

the studies; (2) evaluated the 

impact of BPCA on labeling drugs 

for pediatric use and the process by 

which the labeling was changed; 

and (3) illustrated the range of 

diseases treated by the drugs 

studied under BPCA. GAO 

examined data about the drugs for

which FDA requested studies under

BPCA from 2002 through 2005. 

GAO also interviewed officials 

from relevant federal agencies, 

pharmaceutical industry 

representatives, and health

advocates. 

Drug sponsors have initiated pediatric drug studies for most of the on-patent 

drugs for which FDA has requested studies, but no drugs were being studied 

when drug sponsors declined these requests. Sponsors agreed to 173 of the 

214 written requests for pediatric studies of on-patent drugs. In cases where 

drug sponsors decline to study the drugs, BPCA provides for FDA to refer 

the study of these drugs to the Foundation for the National Institutes of 

Health (FNIH), a nonprofit corporation. FNIH had not funded studies for any 

of the nine drugs that FDA referred as of December 2005. 

Written Requests Issued under BPCA for the Study of On-Patent Drugs (2002-2005) 

Source: GAO. 

Number of applications that pass through decision point

On-patent drugs

denied pediatric 

exclusivity

3

On-patent drugs

granted pediatric 

exclusivity

52

4

Exclusivity determination 

made by FDA through 

December 2005

55

Studies ongoing

through 

December 2005

114

Studies completed and results

submitted to FDA for review 

through December 2005

Written requests

not referred to 

FNIH for funding

32

Written requests

referred to 

FNIH for funding

Studies

not funded 

by FNIH

9

Studies

funded 

by FNIH

0

Written requests

declined by drug 

sponsors

214

On-patent written requests

issued by FDA from January 

2002 through December 2005

173

Written requests

accepted by drug 

sponsors

59

41

9

Exclusivity determination 

pending 

through 2005

X

Most drugs (about 87 percent) granted pediatric exclusivity under BPCA had 

labeling changes—often because the pediatric drug studies found that 

children may have been exposed to ineffective drugs, ineffective dosing, 

overdosing, or previously unknown side effects. However the process for 

approving labeling changes was often lengthy. It took from 238 to 1,055 days 

for information to be reviewed and labeling changes to be approved for 18

drugs (about 40 percent), and 7 of those took more than 1 year. Drugs were 

studied under BPCA for the treatment of a wide range of diseases, including 

those that are common, serious, or life threatening to children. These drugs

represented more than 17 broad categories of disease, such as cancer. 

The Department of Health and Human Services stated that the report 

provides a significant amount of data and analysis and generally explains the 

BPCA process, but expressed concern that it did not sufficiently 

acknowledge the success of BPCA or clearly describe some elements of 

FDA’s process. GAO incorporated comments as appropriate. 

www.gao.gov/cgi-bin/getrpt?GAO-07-557.

To view the full product, including the scope 

and methodology, click on the link above. 

For more information, contact Marcia Crosse 

at (202) 512-7119 or crossem@gao.gov. 
Contents 

Letter 1

Results in Brief 4

Background 5

Drug Sponsors Agreed to Study the Majority of On-Patent Drugs 

with Written Requests under BPCA, but No Studies Were 

Conducted When Drug Sponsors Declined the Written Requests 12 

Most Drugs Granted Pediatric Exclusivity under BPCA Had 

Labeling Changes, but the Process for Making Changes Was 

Sometimes Lengthy 16 

Drugs Studied under BPCA Address a Wide Range of Diseases, 

Including Some That Are Common, Serious, or Life Threatening 

to Children 21 

Agency Comments and Our Evaluation 23 

Appendix I Scope and Methodology 26 

Appendix II FDA and NIH Efforts to Encourage the Study 

of Drugs in Neonates since Passage of BPCA 28 

Appendix III NIH Efforts to Support Pediatric Drug Studies 30 

Appendix IV Studies of Off-Patent Drugs under BPCA 33 

Appendix V Status of Pediatric Drug Studies Requested by FDA 37 

Appendix VI Complexity of Completed Pediatric Drug Studies 41 

Appendix VII Strengths of and Suggested Changes for BPCA 42 

Page i GAO-07-557 Pediatric Drug Research
Appendix VIII Comments from the Department of Health and 

Human Services 45 

Appendix IX GAO Contact and Staff Acknowledgments 48 

 

Tables 

Table 1: Estimated Costs of Funding the Study of On-Patent Drugs 

Referred to FNIH under BPCA 16 

Table 2: Examples of Labeling Changes 18 

Table 3: Examples of Drugs Approved for Use by Younger Children 

or for Which New Formulations Are Available 19 

Table 4: Examples of Diseases to Be Treated by Drugs Studied 

under BPCA 22 

Table 5: NIH-Sponsored Activities, through 2005, Related to 

Children in Clinical Trials 31 

Table 6: Anticipated NIH Spending for Off-Patent Drug Studies 

Committed to through 2005 35 

Table 7: Complexity of Pediatric Drug Studies Conducted under 

BPCA, According to Study Reports from July 2002 through 

December 2005 41 

Figures 

Figure 1: BPCA Process 8 

Figure 2: Status of Written Requests Issued under BPCA for the 

Study of On-Patent Drugs, from January 2002 through 

December 2005 14 

Figure 3: Status of Written Requests Issued under FDAMA and 

BPCA through December 2005 38 

Page ii GAO-07-557 Pediatric Drug Research
Abbreviations 

BPCA Best Pharmaceuticals for Children Act 

FDA Food and Drug Administration 

FDAMA Food and Drug Administration Modernization Act of 1997 

FNIH Foundation for the National Institutes of Health 

HHS Department of Health and Human Services 

HIV Human Immunodeficiency Virus 

NDDI Newborn Drug Development Initiative 

NIH National Institutes of Health 

This is a work of the U.S. government and is not subject to copyright protection in the 

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permission from GAO. However, because this work may contain copyrighted images or 

other material, permission from the copyright holder may be necessary if you wish to 

reproduce this material separately. 

Page iii GAO-07-557 Pediatric Drug Research
United States Government Accountability Office

Washington, DC 20548 

March 22, 2007 

The Honorable Edward M. Kennedy 

Chairman 

The Honorable Michael B. Enzi 

Ranking Minority Member 

Committee on Health, Education, Labor, and Pensions 

United States Senate 

The Honorable John D. Dingell 

Chairman 

The Honorable Joe L. Barton 

Ranking Minority Member 

Committee on Energy and Commerce 

House of Representatives 

Although children suffer from many of the same diseases as adults and are 

often treated with the same drugs, only about one-third of the drugs that 

are prescribed for children have been studied and labeled for pediatric 

use.1

 This has placed children taking drugs for which there have not been 

adequate pediatric drug studies at risk of being exposed to ineffective 

treatment or receiving incorrect dosing. In order to encourage the study of 

more drugs for pediatric use, Congress passed the Best Pharmaceuticals 

for Children Act (BPCA)2

 in 2002 to provide marketing incentives to drug 

sponsors for conducting pediatric drug studies.3 Drug sponsors (typically 

drug manufacturers) may obtain 6 months of additional market exclusivity 

for drugs on which they have conducted pediatric studies in accordance 

 1

The drug “label” refers to written, printed, or graphic material placed on the drug 

container, while drug “labeling” is much broader and includes all labels and other written, 

printed, or graphic materials on any container, wrapper, or materials accompanying the 

drug. 21 U.S.C. § 321(k), (m).

2

Provisions regarding pediatric studies of drug are generally codified at 21 U.S.C. § 355a. 

Pub. L. No. 107-109, 115 Stat. 1408. The market exclusivity provisions of BPCA will sunset 

on October 1, 2007. 21 U.S.C. § 355a(n). 

3

BPCA reauthorized and enhanced incentives for conducting pediatric drug studies that 

were first established in the Food and Drug Administration Modernization Act of 1997, 

Pub. L. No. 105-115, 111 Stat. 2296. 

Page 1 GAO-07-557 Pediatric Drug Research
with pertinent law and regulations.4

 This market exclusivity is known as 

pediatric exclusivity. When a drug has market exclusivity, it is protected

from competition for a limited period, for example by prohibition on Food

and Drug Administration (FDA)5

 approval of a generic copy for marketing.6

Generally, pediatric exclusivity can only be granted to those drugs that are 

on-patent—that is, those that still have market exclusivity7

—and for which 

FDA has issued a written request for pediatric drug studies.8 Once a drug’s

patent or market exclusivity has expired, however, FDA can still request 

pediatric drug studies for off-patent drugs. BPCA also included provisions 

designed to provide for the study of both on-patent and off-patent drugs 

that drug sponsors have declined to study. 

When FDA determines that a drug may provide health benefits to children, 

it may issue a written request to the drug sponsor to conduct pediatric 

drug studies. Under BPCA, drug sponsors of on-patent drugs must accept 

or decline a written request. Drug sponsors of off-patent drugs are not 

required to respond to a written request. However, if FDA does not receive 

a response within 30 days, the written request is assumed to be declined. 

When a drug sponsor accepts a written request for an on-patent drug and 

subsequently submits a study report in response, FDA generally has 

90 days to complete its review of the reports to determine whether to 

grant pediatric exclusivity to the drug. If FDA is satisfied that the studies 

have been conducted and the report submitted as required, the drug in 

 4

The value of 6 months additional marketing exclusivity is difficult to assess and depends 

on a number of factors for which data are not available. However, a recent study estimated 

that for some drugs the benefit of 6 months of marketing exclusivity was quite large, while 

for others the return the drug sponsor received for pediatric exclusivity was less than the

cost of the studies. See Jennifer S. Li, et al., “Economic Return of Clinical Trials Performed 

Under the Pediatric Exclusivity Program,” JAMA, vol. 297, no. 5 (2007). 

5

FDA is an agency within the Department of Health and Human Services. 

6

Drug sponsors can obtain market exclusivity for drugs protected by patents, as well as for

drugs designed to treat rare diseases, drugs consisting of new chemical entities, and 

already-marketed drugs approved for new uses. See for example, 21 U.S.C. §§ 

355(j)(5)(F)(ii), (iii); 21 C.F.R. § 314.108 (2006). Pediatric exclusivity under BPCA attaches 

to an existing listed patent or any existing market exclusivity held by the drug sponsor. 

7

For purposes of this report, we refer to drugs that have patent protection or market 

exclusivity as on-patent and those whose patent protection or market exclusivity has ended 

as off-patent. This is the same terminology typically used by government agencies to 

describe the exclusivity status of a drug under BPCA. 

8

FDA is responsible for issuing written requests for pediatric studies, determining whether

a drug merits pediatric exclusivity as a result of those studies, and all steps in between. 

Page 2 GAO-07-557 Pediatric Drug Research
question may receive additional market exclusivity. FDA also reviews 

these pediatric drug study reports to see if the drug requires labeling 

changes. The agency refers to this review as its scientific review, which it 

has a goal of completing within 180 days. 

BPCA provides for pediatric drug studies even if the drug sponsor declined 

the written request. First, if a drug sponsor declines a written request by 

FDA to study an on-patent drug, BPCA provides for FDA to refer the drug

to the Foundation for the National Institutes of Health (FNIH), which can 

fund the study if funds are available.9

 When a sponsor declines a written 

request for an on-patent drug, the sponsor cannot receive pediatric 

exclusivity in response to that written request. Second, BPCA provides for 

the funding of the study of off-patent drugs by the Department of Health 

and Human Services’ (HHS) National Institutes of Health (NIH). 

BPCA required that we assess, among other things, the effect of provisions 

regarding pediatric drug studies on the study and proper labeling of drugs 

for pediatric use. As discussed with the committees of jurisdiction, we 

(1) assessed the extent to which pediatric drug studies were being 

conducted under BPCA for on-patent drugs, including when drug sponsors 

declined to conduct the studies; (2) evaluated the impact of BPCA on 

labeling of drugs for pediatric use and the process by which the labeling 

was changed; and (3) illustrated the range of diseases treated by the drugs 

studied under BPCA. 

To assess the extent to which pediatric drug studies were being conducted 

under BPCA for on-patent drugs, including when drug sponsors declined

to do the studies, we examined data about the drugs for which FDA issued

written requests from January 2002 through December 2005. Our work 

focused on actions regarding these drugs prior to 2006. Specifically, we 

examined data on the numbers of written requests, drugs studied, written 

requests that were declined, and drugs granted pediatric exclusivity during 

this 4-year period. We reviewed data from FNIH on the funding status of 

on-patent drugs that drug sponsors declined to study. To evaluate the 

impact of BPCA on the labeling of drugs for pediatric use and the process 

by which labeling was changed, we reviewed summaries of the labeling 

changes for drugs studied from the enactment of BPCA through 2005. We

 9

FNIH is an independent, nonprofit corporation. The majority of funds that FNIH receives

are from the private sector. Only a portion of these funds are available for FNIH to award 

to researchers to conduct studies related to BPCA. 

Page 3 GAO-07-557 Pediatric Drug Research
reviewed the dates the labeling changes were agreed to and the reasons 

why some drugs did not have labeling changes. To illustrate the range of 

diseases treated by the drugs studied under BPCA, we identified the 

diseases the drugs were studied to treat, as well as the therapeutic areas 

addressed by the drugs. We also examined data from national surveys on 

the extent to which these drugs are prescribed for children. In addition, to 

assist with our review in general, we interviewed officials from FDA, NIH, 

and FNIH as well as representatives of the pharmaceutical industry and 

health advocates—such as the American Academy of Pediatrics, the 

Pharmaceutical Research and Manufacturers of America, the Generic 

Pharmaceutical Association, the National Organization for Rare Disorders, 

Public Citizen, the Elizabeth Glaser Pediatric AIDS Foundation, and the 

Tufts Center for the Study of Drug Development. (See app. I for a detailed 

description of our methodology.) 

We conducted our work from September 2005 through March 2007 in 

accordance with generally accepted government auditing standards. 

Most of the on-patent drugs for which FDA requested pediatric drug 

studies under BPCA were being studied, but no studies resulted when the 

requests were declined by drug sponsors. Drug sponsors agreed to 

conduct studies in response to 173 of the 214 written requests for onpatent drugs (81 percent) issued by FDA from January 2002 through 

December 2005. Drug sponsors completed pediatric drug studies for 59 of

the 173 accepted written requests—studies for the remaining 114 written 

requests for on-patent drugs were ongoing—and FDA made a pediatric 

exclusivity determination for 55 of those through December 2005. Of those 

55 written requests, 52 (95 percent) resulted in FDA granting pediatric 

exclusivity. BPCA provides for FDA to refer the study of on-patent drugs 

to FNIH when drug sponsors have declined written requests. However, of 

the 41 written requests for on-patent drugs that drug sponsors declined to

study, FDA referred 9 to FNIH, which had not funded the study of any as 

of December 2005. 

Results in Brief 

Almost all the drugs—about 87 percent—that have been granted pediatric 

exclusivity under BPCA have had important labeling changes as a result of

pediatric drug studies conducted under BPCA, but the process for 

obtaining all the necessary information, reviewing the study results, and 

approving these changes can be lengthy. The labeling of drugs was often 

changed because the pediatric drug studies revealed that children may 

have been exposed to ineffective drugs, ineffective dosing, overdosing, or 

previously unknown side effects. The review and approval process, 

Page 4 GAO-07-557 Pediatric Drug Research
including time for sponsors to provide needed information, took from 238 

to 1,055 days when FDA required additional information to support the 

proposed labeling changes. 

Drugs studied under BPCA were for the treatment of a wide range of 

diseases, including some that are common, serious, or life threatening to

children. FDA identified 17 broad categories of disease that were treated 

by the drugs studied under BPCA. The most frequently studied drugs were 

those used to treat cancer, neurological and psychiatric disorders, 

metabolic diseases, cardiovascular disease, and viral infections. In 

addition, nearly half of the 10 drugs most frequently prescribed for 

children have been studied under BPCA. 

In written comments on a draft of this report, HHS stated that the draft 

report provided a significant amount of data and analysis and generally

explains the BPCA process, but expressed concern that it did not 

sufficiently acknowledge the success of BPCA or clearly describe some 

elements of its implementation. While assessing the overall success of 

BPCA was beyond the scope of this report, much of the information we 

present speaks to the impact BPCA has had on the studying and labeling of 

drugs for pediatric use. Further, we believe that we accurately presented

the implementation of BPCA. We incorporated HHS’s comments as 

appropriate.

Prior to enactment of the Food and Drug Administration Modernization 

Act of 1997 (FDAMA), which first established incentives for conducting 

pediatric drug studies in the form of additional market exclusivity, few 

drugs were studied for pediatric use.10 As a result, there was a lack of 

information on optimal dosage, possible side effects, and the effectiveness 

of drugs for pediatric use. For example, while physicians typically had 

determined drug dosing for children based on their weight, pediatric drug 

studies conducted under FDAMA showed that in many cases this was not 

the best approach. To continue to encourage pediatric drug studies,11

Background 

 10We previously described how FDAMA was responsible for an increase in pediatric drug 

studies. GAO, Pediatric Drug Research: Substantial Increase in Studies of Drugs for 

Children, But Some Challenges Remain, GAO-01-705T (Washington, D.C.: May 8, 2001). 

11FDA generally defines the pediatric population covered under BPCA as children from

birth to 16 years old, though studies have included children as old as 18. BPCA provides 

that neonates be included in pediatric drug studies, as appropriate. See app. II for 

information about federal efforts to encourage the study of drugs in neonates. 

Page 5 GAO-07-557 Pediatric Drug Research
BPCA was enacted on January 4, 2002, just after the pediatric exclusivity 

provisions of FDAMA expired on January 1, 2002. BPCA reauthorized and 

enhanced the pediatric exclusivity provisions of FDAMA. Like FDAMA, 

BPCA allows FDA to grant drug sponsors pediatric exclusivity—6 months 

of additional market exclusivity—in exchange for conducting and 

submitting reports on pediatric drug studies. The goal of the program is to 

develop additional health information on the use of such drugs in pediatric 

populations so they can be administered safely and effectively to children.

This incentive is similar to that provided by FDAMA; however, BPCA 

provides additional mechanisms to provide for pediatric studies of drugs 

that drug sponsors decline to study.

BPCA Process The process for initiating pediatric studies under BPCA formally begins 

when FDA issues a written request to a drug sponsor to conduct pediatric 

drug studies for a particular drug. FDA may issue a written request after it 

has reviewed a proposed pediatric study request from a drug sponsor, in 

which the drug sponsor describes the pediatric drug study or studies it 

proposes doing in return for pediatric exclusivity. In deciding whether to 

approve the proposed pediatric study request and issue a written request, 

FDA must determine if the proposed studies will produce information that 

may result in health benefits for children.12 Alternatively, FDA may 

determine on its own that there is a need for more research on a drug for 

pediatric use and issue a written request without having received a 

proposed pediatric study request from the drug sponsor. A written request 

outlines, among other things, the nature of the pediatric drug studies that 

the drug sponsor must conduct in order to qualify for pediatric exclusivity 

and a time frame by which those studies should be completed. When a 

drug sponsor accepts the written request and completes the pediatric drug 

studies, it submits reports to FDA describing the studies and the study 

results. BPCA specifies that FDA generally has 90 days to review the study 

 12FDA officials report that 51 of 134 proposed pediatric study requests submitted by drug 

sponsors from 2002 to 2005 did not result in written requests. Drug sponsors sometimes 

later submitted revised proposed pediatric study requests, which resulted in written 

requests. 

Page 6 GAO-07-557 Pediatric Drug Research
reports to determine whether the pediatric drug studies met the conditions 

outlined in the written request.13 If FDA determines that the pediatric drug 

studies conducted by the drug sponsor were responsive to the written 

request, it will grant a drug pediatric exclusivity regardless of the study 

findings.14 Figure 1 illustrates the process under BPCA. 

 13Under certain circumstances, FDA could have only 60 days to review the study report to

determine pediatric exclusivity. However, FDA officials told us that under BPCA, this has 

never happened. Otherwise, FDA has 90 days to determine if the studies fairly respond to

the written request, were conducted in accordance with commonly accepted scientific 

principles and protocols, and were properly submitted. 

14Pediatric exclusivity applies to all approved uses of the drug, not just those studied in

children. Therefore, if the studies find that the drug is not safe for use by children, the drug 

will still receive pediatric exclusivity and therefore extended market exclusivity for the 

adult uses of the drug. 

Page 7 GAO-07-557 Pediatric Drug Research
Figure 1: BPCA Process 

Source: GAO.

FDA decides whether to Sponsor conducts studies of drug.

further refer the drug for study.

Drug sponsor receives written request and determines

whether to accept or decline the written request.

Process ends.

FDA determines whether to issue a written request. The written request may be in response 

to a drug sponsor’s proposed pediatric study request or may be FDA initiated.

Process ends.

Drug sponsor may submit a proposed 

pediatric study request.

No written 

request is 

issued.

Written 

request is 

issued.

Written 

request is 

declined. a

Written 

request is 

accepted.

Written 

request is 

not referred.

Written request 

is referred.

Studies of 

drug are 

finished.

Sponsor submits study reports to FDA 

for pediatric exclusivity determination.

FDA grants

pediatric 

exclusivity.b

Process ends.

Pediatric 

exclusivity 

is denied.

Pediatric 

exclusivity 

is granted.

NIH develops and publishes

a list of drugs in need of 

study in children.

FNIH 

receives

referral 

for study 

of an onpatent 

drug.

NIH 

receives

referral 

for study 

of an offpatent 

drug.

a

If a drug sponsor of an off-patent drug does not respond to FDA’s written request within 30 days, the

written request is considered declined. Pediatric exclusivity is not granted to drugs where the drug 

sponsor declined the written request. 

b

FDA has granted pediatric exclusivity in response to written requests for on-patent drugs only. Under 

certain circumstances FDA could grant pediatric exclusivity in response to a written request for an offpatent drug. 

Page 8 GAO-07-557 Pediatric Drug Research
To further the study of drugs when drug sponsors decline a written 

request, BPCA includes two provisions that did not exist under FDAMA. 

First, if a drug sponsor declines to conduct the pediatric drug studies 

requested by FDA for an on-patent drug, BPCA provides for FDA to refer 

the study of that drug to FNIH, which might then agree to fund the studies. 

Second, if a drug sponsor declines a request to study an off-patent drug, 

BPCA provides for referral of the study to NIH for funding. FDA cannot 

extend pediatric exclusivity in response to written requests for any drugs

for which the drug sponsor declined to conduct the requested pediatric 

drug studies. 

BPCA Provisions for 

Pediatric Drug Studies 

Declined by Drug Sponsors 

When drug sponsors decline written requests for studies of on-patent 

drugs, BPCA provides for FDA to refer the study of those drugs to FNIH 

for funding, when FDA believes that the pediatric drug studies are still 

warranted. FNIH, which was authorized by Congress to be established in 

1990, is guided by a board of directors and began formal operations in 

1996 to support the mission of NIH and advance research by linking 

private sector donors and partners to NIH programs. Although FNIH is a 

nonprofit corporation that is independent of NIH, FNIH and NIH 

collaborate to fund certain projects. FNIH has raised approximately 

$300 million from the private sector over the past 10 years to support four 

general types of projects: (1) research partnerships; (2) educational 

programs and projects for fellows, interns, and postdoctoral students; 

(3) events, lectures, conferences, and communication initiatives; and 

(4) special projects. Included in these funds is $4.13 million that FNIH 

raised as of December 2005 to fund pediatric drug studies under BPCA. 

The majority of FNIH’s funds are restricted by donors for specific projects 

and cannot be reallocated.15 In recent years, appropriations of $500,000

were authorized to FNIH annually.16

To further the study of off-patent drugs, NIH—in consultation with FDA 

and other experts—develops a list of drugs, including off-patent drugs, 

which the agency believes are in need of study in children. NIH lists these 

drugs annually in the Federal Register. FDA may issue written requests for 

those drugs on the list that it determines to be most in need of study. If the 

 15FNIH can certify that it has insufficient funds to fund the study of a drug and refer the

funding to NIH.

16As of fiscal year 2007, NIH is required to transfer from its appropriations at least $500,000 

but no more than $1.25 million to FNIH annually. This requirement was established with 

the enactment of the NIH Reform Act of 2006 (Pub. L. No. 109-482, 120 Stat. 3675 (2007)). 

Page 9 GAO-07-557 Pediatric Drug Research
drug sponsor declines or fails to respond to the written request, NIH can 

contract for, and fund the conduct of, the pediatric drug studies. These 

pediatric drug studies could then be conducted by qualified universities, 

hospitals, laboratories, contract research organizations, federally funded

programs such as pediatric pharmacology research units, other public or 

private institutions or individuals. Drug sponsors generally decline written 

requests for off-patent drugs because the financial incentives are 

considerably limited. (See app. II for a description of federal efforts to 

encourage research on drugs for children less than 1 month of age and 

app. III for NIH efforts to support pediatric drug studies.) 

Making Labeling Changes 

under BPCA for On-Patent 

Drugs 

Pediatric drug studies often reveal new information about the safety or 

effectiveness of a drug, which could indicate the need for a change to its 

labeling. Generally, the labeling includes important information for health

care providers, including proper uses of the drug, proper dosing, and 

possible adverse effects that could result from taking the drug. FDA may 

determine that the drug is not approved for use by children, which would 

be reflected in any labeling changes.17

According to FDA officials, in order to be considered for pediatric 

exclusivity, a drug sponsor typically submits results from pediatric drug 

studies in the form of a “supplemental new drug application.”

18 BPCA 

specifies that study results, when submitted as part of a supplemental new 

drug application, are subject to FDA’s performance goals for a scientific 

review, which in this case is 180 days.

19 FDA’s processes for reviewing 

study results submitted under BPCA for consideration of labeling changes 

are not unique to BPCA. These are the same processes the agency would 

use to review any drug study results in consideration of labeling changes. 

FDA’s action on the application can include approving the application, 

determining that the application is approvable (pending the submission of 

 17The granting of pediatric exclusivity does not depend on finding that the drug is safe and

effective for pediatric use. 

18Most drugs studied under BPCA have previously been approved for marketing in the

United States, so a supplement to the original “new drug application” is submitted. If the 

drug studied under BPCA was not previously approved for marketing in the United States, 

the application would be submitted as a new drug application. FDA has a performance goal 

to review non-priority new drug applications in 10 months. 

19BPCA requires that supplemental new drug applications submitted by drug sponsors be 

treated as “priority supplements.” FDA’s goal is to take action on priority supplements 

within 180 days. 

Page 10 GAO-07-557 Pediatric Drug Research
additional information from the sponsor), or determining that the 

application is not approvable. If studies demonstrate that an approved 

drug is not safe or effective for pediatric use, this information would be 

reflected in the drug’s labeling. 

With a determination that the application is approvable, FDA 

communicates to the drug sponsor that some issues need to be resolved 

before the application can be approved and describes what additional 

work is necessary to resolve the issues. This might require that drug 

sponsors conduct additional analyses. However, this communication 

would complete the scientific review cycle. When a drug sponsor 

resubmits the application with the additional analyses, a new scientific 

review cycle begins. As a result, multiple scientific review cycles might be 

necessary, increasing the time between initial submission of the 

application, which includes the pediatric study reports, and approval of a 

labeling change. 

If, during FDA’s review of the study report submitted as part of the 

application, the agency determines that the application is approvable and 

the only unresolved issue is labeling, FDA and the drug sponsor must 

attempt to reach agreement on labeling changes within 180 days after the

application is submitted to FDA. If FDA and the drug sponsor cannot 

reach agreement, FDA must refer the matter to its Pediatric Advisory 

Committee,20 which would convene and provide recommendations to the 

Commissioner on the appropriate changes to the drug’s labeling. The 

Commissioner would then consider the committee’s recommendations in 

making the final determination on the proper labeling. 

 20The Pediatric Advisory Committee is also responsible for reviewing reports of adverse 

effects related to drugs granted pediatric exclusivity after the period of exclusivity begins, 

among other things. The committee consists of 13 voting members, appointed by the

Commissioner of FDA, who are knowledgeable in pediatric research, pediatric 

subspecialties, statistics, and biomedical ethics. The committee includes one

representative from a pediatric health organization and one from a relevant patient or 

patient-family organization. 

Page 11 GAO-07-557 Pediatric Drug Research
Most of the on-patent drugs for which FDA requested pediatric drug 

studies under BPCA were being studied, but no studies resulted when the 

requests were declined by drug sponsors. Of the 214 on-patent drugs for 

which FDA requested pediatric drug studies from January 2002 through 

December 2005, drug sponsors agreed to study 173 (81 percent). Of the 41 

on-patent drugs that drug sponsors declined to study, FDA referred 9 to 

FNIH for funding and the foundation had not funded any of those studies 

as of December 2005. 

From January 2002 through December 2005, FDA issued 214 written 

requests for on-patent drugs to be studied under BPCA, and drug sponsors 

agreed to conduct pediatric drug studies for 173 (81 percent) of those.21

The remaining 41 written requests were declined.

22 (See app. IV for details 

about the study of off-patent drugs under BPCA and app. V for a detailed

description of the status of all written requests issued by FDA.) Drug 

sponsors completed pediatric drug studies for 59 of the 173 accepted 

written requests—studies for the remaining 114 written requests were 

ongoing—and FDA made a pediatric exclusivity determination for 55 of 

those through December 2005.

23 Of those 55 written requests, 

Drug Sponsors 

Agreed to Study the 

Majority of On-Patent 

Drugs with Written 

Requests under 

BPCA, but No Studies 

Were Conducted 

When Drug Sponsors 

Declined the Written 

Requests 

Drug Sponsors Agreed to 

Conduct Pediatric Drug 

Studies for Most On-Patent 

Drugs with Written 

Requests Issued under 

BPCA 

 21Some drugs have two written requests for a variety of reasons. In some cases, FDA may

have requested that the drug sponsor study the effects of the drug on different diseases. In

other cases, there could be two written requests for the same drug, issued to different drug 

sponsors for different dosage forms of the drug. In addition, FDA told us that the specified

period for studies to be completed elapsed for some written requests before the completion 

of studies, and the agency issued new written requests. In all of these situations, we

counted each of these written requests separately. Therefore, there are more written 

requests than there are unique drugs with written requests. 

22Of the 214 written requests issued by FDA, 68 were written requests first issued under 

BPCA. The remaining 146 written requests were originally issued under FDAMA and

reissued under BPCA because drug sponsors had not responded to the written requests or 

completed the requested pediatric drug studies at the time that BPCA went into effect. 

23FDA had not completed its review of the study results to determine exclusivity prior to 

December 2005 for the remaining four drugs. 

Page 12 GAO-07-557 Pediatric Drug Research
52 (95 percent) resulted in FDA granting pediatric exclusivity.

24 Figure 2 

shows the status of written requests issued under BPCA for the study of 

on-patent drugs, from January 2002 through December 2005. (See app. VI

for a description of the complexity of pediatric drug studies conducted 

under BPCA.) 

 24The other three drugs were denied pediatric exclusivity. The dates that drugs are granted

exclusivity and also had labeling changes are available at 

http://www.fda.gov/cder/pediatric/labelchange.htm. The dates of exclusivity for other drugs

are not available on FDA’s Web site. Most of these pediatric drug studies began under

FDAMA but were continued under BPCA. Most of the pediatric drug studies begun in

response to written requests initially issued under BPCA have not yet been completed. 

Page 13 GAO-07-557 Pediatric Drug Research
Figure 2: Status of Written Requests Issued under BPCA for the Study of On-Patent Drugs, from January 2002 through 

December 2005

Source: GAO.

X Number of applications that pass through decision point

On-patent drugs

denied pediatric 

exclusivity

3

On-patent drugs

granted pediatric 

exclusivity

52

4

Exclusivity determination 

made by FDA through 

December 2005

55

Studies ongoing

through 

December 2005

114

Studies completed and results

submitted to FDA for review 

through December 2005

Written requests

not referred to 

FNIH for funding

32

Written requests

referred to 

FNIH for funding

Studies

not funded 

by FNIH

9

Studies

funded 

by FNIH

0

Written requests

declined by drug 

sponsors

214

On-patent written requests

issued by FDA from January 

2002 through December 2005

173

Written requests

accepted by drug 

sponsors

59

41

9

Exclusivity determination 

pending 

through 2005

Note: Written requests issued from January 2002 through December 2005 include new written 

requests issued under BPCA combined with written requests originally issued under FDAMA but 

reissued under BPCA. 

Page 14 GAO-07-557 Pediatric Drug Research
Under BPCA, when a written request to study an on-patent drug is 

declined, the study of the drug may be referred to FNIH. However, FNIH is 

limited in its ability to fund drug studies by its available funds. Through 

December 2005, drug sponsors declined written requests issued under 

BPCA for 41 on-patent drugs. FDA referred 9 of these 41 written requests 

(22 percent) to FNIH for funding.25 FNIH had not funded the study of any 

of these drugs.26 NIH has estimated that the cost of studying the drugs that 

were referred to FNIH for study would exceed $43 million (see table 1). 

FNIH has been raising funds for the study of drugs referred under BCPA at 

a rate of approximately $1 million per year. 

FNIH Had Not Funded the 

Study of Any On-Patent 

Drugs in Children 

 25When a drug sponsor of an on-patent drug declines a written request, the agency must

determine if there is a continuing need for information relating to the use of the drug in

children. Reasons that FDA has concluded that there is not a continuing need include the

drug was not yet approved, some part of the study was being performed by the drug

sponsor or another party, the drug’s patent ended, the risk-benefit assessment shifted, safe 

alternative therapies were already on the market even though the agency had issued the

written request in hope of obtaining additional valuable information, another drug may

have been approved or may soon be approved with a better safety record, or there is 

minimal use of the drug by children.

26In April 2006, FNIH agreed to allocate all $4.13 million it had raised for pediatric drug 

studies under BPCA to fund half the cost to study one on-patent drug—baclofen. Baclofen

was identified by NIH and FNIH as the highest priority on-patent drug that a drug sponsor

had declined to study. NIH is responsible for developing requests for proposals for the 

study of on-patent drugs for pediatric use. The requests for proposals outline the need for 

studies of specific drugs and include the specific details of the studies to be conducted.

NIH requested proposals for the study of baclofen and has selected a contractor to perform 

the studies. NIH expects the cost of the study of baclofen to be about $7.8 million over 

3 years, and NIH agreed to cover the costs of the study that exceed the contribution from

FNIH. Because FNIH has committed all of its BPCA funds to the study of baclofen, there

are no resources left for FNIH to fund the study of any other drugs. 

Page 15 GAO-07-557 Pediatric Drug Research
Table 1: Estimated Costs of Funding the Study of On-Patent Drugs Referred to FNIH 

under BPCA 

On-patent drug Disease or condition to be studied Estimated cost

Baclofen Spasticity in children with cerebral palsy $7.8 million

Bupropion Depression $7.4 million

Dexrazoxane Used to block the cardiac effects of the 

anticancer drug adriamycin 

Not provideda

Eletriptan Migraine headaches Not provideda

HydroxyureabSickle cell disease $8 million to 

$10 millionc

Metoclopramide Gastroesophageal reflux disease Not provideda

Morphine Analgesia $8.7 million

Sevelamer Renal failure $2.7 million

Zonisamide Refractory partial seizures $8.4 million

Total $43 million to 

$45 milliond

Source: NIH. 

a

Cost estimates have not been provided by NIH. 

b

Hydroxyurea is available in on-patent and generic (or off-patent) formulations. According to NIH 

officials, after the written request was referred to FNIH for funding, NIH determined that a study 

funded by its National Heart, Lung, and Blood Institute would provide much of the needed information

for appropriate pediatric use. In 2005, NIH’s National Institute of Child Health and Human 

Development agreed to cofund the study. 

c

A formal cost estimate has not been made by NIH, but an initial estimate ranged from $8 million to 

$10 million. 

d

Total estimated cost is for the six drugs for which an estimated cost is available. 

Most drugs—about 87 percent—that have been granted pediatric 

exclusivity under BPCA have had labeling changes as a result of the 

pediatric drug studies conducted under BPCA. Pediatric drug studies 

conducted under BPCA showed that children may have been exposed to 

ineffective drugs, ineffective dosing, overdosing, or side effects that were 

previously unknown. However, the process for reviewing study results and 

completing labeling changes was sometimes lengthy, particularly when 

FDA required additional information to support the changes.

Most Drugs Granted 

Pediatric Exclusivity 

under BPCA Had 

Labeling Changes, but 

the Process for 

Making Changes Was 

Sometimes Lengthy 

Page 16 GAO-07-557 Pediatric Drug Research
Of the 52 drugs studied and granted pediatric exclusivity under BPCA from 

January 2002 through December 2005, 45 (about 87 percent) had labeling 

changes as a result of the pediatric drug studies. FDA officials told us that 

labeling changes were not made for the remaining 7 (about 13 percent) 

drugs granted pediatric exclusivity, generally because data provided by the 

pediatric drug studies did not support labeling changes. In addition, 3 

other drugs had labeling changes prior to FDA making a decision on 

granting pediatric exclusivity.27 FDA officials said these labeling changes 

were made prior to determining whether pediatric exclusivity should be 

granted because the pediatric drug studies provided important safety 

information that should be reflected in the labeling without waiting until 

the full study results were submitted or pediatric exclusivity was 

determined. 

Pediatric drug studies conducted under BPCA have shown that the way 

that some drugs were being administered to children potentially exposed 

them to an ineffective therapy, ineffective dosing, overdosing, or 

previously unknown side effects—including some that affect growth and 

development. The labeling for these drugs was changed to reflect these 

study results. Table 2 shows some of these drugs and illustrates these 

types of labeling changes. FDA officials said that the agency has been 

working to increase the amount of information included in drug labeling, 

particularly when pediatric drug studies indicate that an approved drug 

may not be safe or effective for pediatric use. 

Most Drugs Granted 

Pediatric Exclusivity Had 

Labeling Changes 

Labeling Changes for 

Drugs Studied under BPCA 

Had Important 

Implications for Pediatric 

Use 

 27These drugs had labeling changes made after the drug sponsors submitted partial results 

of their studies to FDA. Because some studies were ongoing, the drug sponsors had not 

submitted the final study results to FDA for consideration of pediatric exclusivity. 

Page 17 GAO-07-557 Pediatric Drug Research
Table 2: Examples of Labeling Changes

Potential risks 

or hazards Drug name

Disease or 

condition treated 

Summary of new information contained

in drug labeling 

Unnecessary exposure to 

ineffective therapies 

Sumatriptan Migraines Five studies did not establish safety and 

effectiveness, and postmarketing experience

showed children were having serious adverse

effects, such as stroke and vision loss. The product 

is not recommended for children under 18 years old. 

Tolterodine Overactive bladder and urge

incontinence 

The drug was not shown to be effective for children 

and appeared to show a possible increase in 

aggressive, hyperactive, and abnormal behavior. 

Irinotecan Tumors Children had more rapid disease progression and 

died more quickly. The labeling states that the drug 

should not be used to treat children with a particular 

kind of tumor. 

Ineffective dosing Oxcarbazepine Partial seizures Dose for children aged 2 to 4 and weighing less than 

44 pounds is twice the dose per body weight

compared to adults. 

Methylphenidate Attention-deficit hyperactivity

disorder 

Children aged 13 to 17 eliminated the drug from 

their bodies faster than the comparison age group. 

Therefore the dosing regimen may be increased to 

prevent ineffective dosing. 

Overdosing Leflunomide Juvenile rheumatoid arthritis Children weighing less than 88 pounds require a 

lower-than-expected dose. Overdosing leflunomide, 

which has significant toxicity, could make the drug’s 

risks to children outweigh its benefits. 

Venlafaxine Depression; generalized

anxiety disorder

This drug is associated with an increased risk of 

suicidal thinking and behavior. 

Previously unlabeled side

effects, including effect on 

growth and development Ciprofloxacin Complicated urinary tract

infection or kidney infection 

This drug is associated with increased adverse 

effects to joints or surrounding tissues for children. 

Fentanyl Chronic pain This drug should be used only by children who are 

2 years of age or older and are opioid-tolerant. Use 

by others can lead to life-threatening respiratory 

depression and death. 

Budesonide Asthma Budesonide can cause growth suppression. 

Source: GAO analysis of FDA data. 

Other drugs have had labeling changes indicating that the drug may be 

used safely and effectively by children in certain dosages or forms. 

Typically, this resulted in the drug labeling being changed to indicate that 

the drug was approved for use by children younger than those for whom it 

had previously been approved. In other cases, the changes reflected a new 

formulation of a drug, such as a syrup that was developed for pediatric 

Page 18 GAO-07-557 Pediatric Drug Research
use, or new directions for preparing the drug for pediatric use were 

identified during the pediatric drug studies conducted under BPCA.28 (See 

table 3 for examples of drugs with this new type of information.) 

Table 3: Examples of Drugs Approved for Use by Younger Children or for Which 

New Formulations Are Available

Uses and

formulations Drug 

Disease or

condition treated 

or prevented

Summary of new 

information

New age groups Moxifloxacin 

Ophthalmic 

Bacterial 

conjunctivitis 

Found to be safe and 

effective for children over 

1 year old. 

Ondansetron Nausea and

vomiting after 

chemotherapy

Established dosing for 

surgical patients down to 

1 month from 2 years of age; 

established dosing for cancer

patients down to 6 months 

from 4 years of age. 

New formulations 

or preparations

Benazepril Hypertension Labeled with directions for 

how to prepare a suspension 

for administering the drug to 

children. 

Desloratadine Seasonal and

perennial allergic 

rhinitis and hives 

Newly available in a syrup, 

labeled specifically for 

children. 

Source: GAO analysis.

 28There were no off-patent drugs for which the pediatric drug studies indicated that a 

formulation change was necessary. 

Page 19 GAO-07-557 Pediatric Drug Research
Although FDA generally completed its first scientific review of study 

results submitted as a supplemental new drug application—including 

consideration of labeling changes—within its 180-day goal, the process for 

completing the review, including obtaining sufficient information to 

support and approve labeling changes, sometimes took longer. For the 45 

drugs granted pediatric exclusivity that had labeling changes, it took an 

average of almost 9 months after study results were first submitted to FDA 

for the sponsor to submit and the agency to review all of the information it 

required and agree with the drug sponsor to approve the labeling 

changes.29 For 13 drugs (about 29 percent), FDA completed this scientific 

review process and FDA approved labeling changes within 180 days. It 

took from 181 to 187 days to complete the scientific review process and to 

approve labeling changes for 14 drugs (about 31 percent). For the 

remaining 18 drugs (about 40 percent), it took from 238 to 1,055 days for 

FDA to complete the scientific review process and approve labeling 

changes. For 7 of those drugs, it took more than a year to complete the 

scientific review process and approve labeling changes. 

The Process for Reviewing 

Study Results and 

Approving Labeling 

Changes Was Sometimes 

Lengthy, Particularly When 

FDA Required Additional 

Information from Drug 

Sponsors 

To determine whether and how drug labeling should be changed, FDA 

conducts a scientific review of the study results that are submitted to the 

agency by the drug sponsor. Included with the study results is the drug 

sponsor’s proposal for how the labeling should be changed. FDA can 

either accept the proposed wording or propose alternative wording. For 

some drugs, however, the process does not end with FDA’s first scientific 

review. While the first scientific reviews were generally completed within 

180 days, for the 18 drugs that took 238 days or more, FDA determined 

that it needed additional information from the drug sponsors in order to be

able to approve the applications. This often required that the drug 

sponsors conduct additional analyses or pediatric drug studies. FDA 

officials said they could not approve any changes to drug labeling until the

drug sponsors provided this information. When FDA completed its review 

of the information that was originally submitted and requested additional 

information from the drug sponsors, the initial 180-day scientific review 

ended. A new 180-day scientific review began when the drug sponsors 

 29These data are based on the dates on which FDA approved the labeling changes. FDA 

officials said that manufacturers might not immediately make approved labeling changes 

on the printed material associated with a marketed product. However, this information is

posted on FDA’s Web site, generally within 48 hours. Sponsors often update labeling on a

quarterly basis or several times a year, rather than each time a labeling change is approved. 

FDA does not track the actual date that revised labeling enters the market. The dates that 

FDA agreed to these labeling changes are reported at 

http://www.fda.gov/cder/pediatric/labelchange.htm. 

Page 20 GAO-07-557 Pediatric Drug Research
submitted the additional information to FDA. Drug sponsors sometimes 

took as long as 1 year to gather the additional necessary data and respond 

to FDA’s requests. This time did not count against FDA’s 180-day goal to 

complete its scientific review and approve labeling changes because a new 

180-day scientific review begins after the required information is 

submitted. However, we counted the total number of days between 

submission of study reports and approval of labeling changes. FDA 

considers itself in conformance with its review goals even though the 

entire process may take longer than 180 days. 

BPCA provides a dispute resolution process to be used if FDA and the 

drug sponsor cannot reach agreement on labeling changes within 180 days 

of when FDA received the application and the only issue holding up FDA 

approval is the wording of the drug labeling. However, FDA officials said

they have never used this process because labeling has never been the

only unresolved issue for those applications whose review period 

exceeded 180 days. Agency officials told us that the possibility of referral 

to the Pediatric Advisory Committee facilitates its negotiations with drug 

sponsors on labeling changes because it is something that drug sponsors 

want to avoid. Reminding the drug sponsors that such a process exists has 

motivated drug sponsors to complete labeling change negotiations by 

reaching agreement with FDA. (See app. VII for a discussion of strengths 

of BPCA identified by FDA and NIH, as well as suggestions for ways to 

improve BPCA.) 

Drugs were studied under BPCA for their safety and effectiveness in 

treating children for a wide range of diseases, including some that are 

common, serious, or life threatening. We found that the drugs studied 

under BPCA represented more than 17 broad categories of disease. The 

category that had the most drugs studied under BPCA was cancer, with 28 

drugs. In addition, there were 26 drugs studied for neurological and 

psychiatric disorders, 19 for endocrine and metabolic disorders, 18 related 

to cardiovascular disease—including drugs related to hypertension, and 17 

related to viral infections. Written requests for some types of drugs were 

more frequently declined by the drug sponsor than others. For example, 

36 percent of written requests for pulmonary drugs and 41 percent of 

written requests for drugs that treat nonviral infection were declined. In 

contrast, 19 percent of written requests were declined overall.

Drugs Studied under 

BPCA Address a Wide 

Range of Diseases, 

Including Some That 

Are Common, 

Serious, or Life 

Threatening to 

Children 

Some of the drugs studied under BPCA were for the treatment of diseases 

that are common, including those for the treatment of asthma and 

allergies. Analysis of two national databases shows that about half of the 

Page 21 GAO-07-557 Pediatric Drug Research
10 most frequently prescribed drugs for children were studied under 

BPCA. Based on a survey of prescriptions written by physicians in 2004, 4 

of the 10 drugs most frequently prescribed for children were studied under 

BPCA.30 A survey of families and their medical providers in 2003 found that 

5 of the 10 drugs most frequently prescribed for children were studied 

under BPCA.31 In addition, several of the drugs studied under BPCA were 

for the treatment of diseases that are serious or life threatening to 

children, such as hypertension, cancer, HIV, and influenza. Table 4 

provides information on some of the drugs studied for pediatric use and 

what is known about the diseases that are relevant to children. 

Table 4: Examples of Diseases to Be Treated by Drugs Studied under BPCA 

Specific disease 

treated by drug Information about the disease 

Allergies Allergies affect up to 40 percent of, or about 29 million, children in

the United States. 

Asthma Asthma affects 6.2 million or 9 percent of children in the United 

States. Further, asthma is the most common chronic illness among 

children. 

Cancer Cancer is the leading cause of death by disease for children aged 

1 to 14 in the United States. 

HIV About 20 percent of HIV-infected children worldwide develop

serious disease before they turn 1, and most of those die before 

age 4. Through the end of 2002, 9,300 children under age 13 in 

the United States were living with HIV. 

Hypertension An estimated 3.25 million (4.5 percent ) children in the United

States have high blood pressure. Untreated, high blood pressure 

can lead to damage to the heart, brain, kidneys, and eyes.

Influenza Population-based studies show that 15 to 42 percent of preschool 

and school-aged children contract the flu. Influenza can have

serious complications for children, including pneumonia and 

dehydration, and can lead to death. In the 2003-2004 flu season, 

more United States children died from the flu than chicken pox, 

whooping cough, and measles combined, and nearly two-thirds 

were under the age of 5. 

Source: GAO analysis.

Note: Based on data published from 2000 through 2006. 

 30National Center for Health Statistics, 2004 National Ambulatory Medical Care Survey

Data File (Hyattsville, Md.: February 2004). 

31Medical Expenditure Panel Survey (Agency for Health Care Policy and Research, 2003 

Medical Expenditure Panel Survey Household Data File (Rockville, Md.: November 

2005)). 

Page 22 GAO-07-557 Pediatric Drug Research
Some of the drugs were studied under BPCA to treat complicating 

conditions in children who had other diseases, while others treated rare 

diseases. For example a drug was studied for the treatment of painful 

bladder spasms in children who have spina bifida. Other drugs were 

studied to treat overactive bladder symptoms in children with spina bifida

and cerebral palsy, to treat children who require chronic pain management 

because of severe illnesses such as cancer, and to treat partial seizures 

and epilepsy in children who require more than one drug to control 

seizures. About 12 percent of the 52 drugs that were granted pediatric 

exclusivity under BPCA were studied for the treatment of rare diseases, 

including certain types of leukemia, juvenile rheumatoid arthritis, and 

narcolepsy.

HHS provided written comments on a draft of this report, which we have 

reprinted in appendix VIII. HHS stated that the draft report provided a 

significant amount of data and analysis and generally explains the BPCA 

process. HHS also made four general comments. First, HHS commented 

that the report does not sufficiently acknowledge the success of BPCA. 

HHS noted that BPCA provides additional incentives for the study of onpatent drugs, a process for the study of off-patent drugs, a safety review of 

all drugs granted pediatric exclusivity, and the public dissemination of 

information from pediatric studies conducted. HHS concluded that BPCA 

has generated more clinical information for the pediatric population than 

any other legislative or regulatory effort to date. Second, HHS commented 

that the report confuses FDA’s process for reviewing reports of drug 

studies conducted under BPCA with time frames for the labeling dispute 

resolution process outlined in BPCA. HHS suggested that we did not 

sufficiently acknowledge that some of the time it takes for FDA to approve 

labeling changes includes time spent by sponsors collecting and 

submitting additional information. Third, in commenting on our finding 

that few written requests included neonates, HHS pointed out that written 

requests for 9 drugs required the inclusion of “newborns” and written 

requests for 13 drugs required the inclusion of infants (children under 4 

months of age). Fourth, HHS commented that we failed to mention that 

exclusivity attaches to patents as well as existing market exclusivity. 

Agency Comments 

and Our Evaluation 

We believe that the draft report sent to HHS for comment accurately and

adequately addressed each of the four issues upon which HHS 

commented. An explicit discussion of the overall success of BPCA was 

outside the scope of this report, as directed by the BPCA mandate and as 

discussed with the committees of jurisdiction. Nevertheless, the draft 

report extensively discussed HHS accomplishments such as the number of 

Page 23 GAO-07-557 Pediatric Drug Research
studies conducted, the number and importance of labeling changes that 

FDA approved, and the wide range of diseases, including some that are 

common, serious, or life threatening to children, for which drugs were 

studied. 

In drafting our report we believe we clearly distinguished between FDA’s 

goals for completing its review and approval of drug applications and the 

time frames mandated for using the labeling dispute resolution process as 

outlined in BPCA. In finding that the process for approving labeling 

changes is lengthy, we clearly stated that the process included time spent 

during FDA’s initial review as well as time drug sponsors took to respond 

to FDA’s requests for additional information, which was as long as 1 year.

We also acknowledged that FDA completed its initial review of 

applications within its 180-day goal. We stated in the draft that FDA has 

never used the dispute resolution process because labeling has never been

the only issue preventing FDA’s approval of a label for more than 180 days. 

Nevertheless, we have included additional language in this report to 

further clarify the distinction between FDA’s review process for pediatric 

applications and labeling dispute resolution. 

Our draft clearly stated that while written requests issued under BPCA 

required the inclusion of neonates, the majority of those on-patent written 

requests—32 of 36—had been first issued under FDAMA. It is therefore 

not appropriate to attribute the inclusion of neonates in these written 

requests to BPCA. Further, we included in our count of written requests 

requiring the inclusion of neonates the 9 written requests that HHS 

referred to in its comments as requiring the inclusion of newborns. We did 

not specifically include in our counts the other 13 written requests 

mentioned in HHS’s comments. According to data provided by FDA, 1 of

these written requests was not issued under BPCA, and 2 others were 

counted among the 9 mentioned above. The remaining 10 written requests 

were not specifically included in our counts, because the written requests 

were first issued prior to BPCA and do not specifically require the 

inclusion of neonates. The written requests to which HHS referred in its 

comments required the inclusion of very young children, age 0-4 months. 

Our draft report had indicated that written requests requiring the inclusion 

of young children might produce data about neonates. 

Our draft report included language that indicated the conditions under 

which pediatric exclusivity applies. We added language to the report to 

further clarify the conditions under which pediatric exclusivity can be

granted. 

Page 24 GAO-07-557 Pediatric Drug Research
HHS provided technical comments which we incorporated as appropriate.

HHS also stated that many of the oral comments provided by FDA were 

not reflected in the draft report sent to HHS for formal comment. Some of

FDA’s suggested revisions and comments were outside the scope of the 

report and in some instances we chose to use alternative wording to that 

suggested by FDA for readability and consistency. As we did with HHS’s 

general and technical comments on this report, we previously 

incorporated FDA’s oral comments as appropriate. 

We are sending copies of this report to the Secretary of Health and Human 

Services, appropriate congressional committees, and other interested 

parties. We will also make copies available to others upon request. In 

addition, the report will be available at no charge on GAO’s Web site at 

http://www.gao.gov. If you have any questions about this report, please 

contact me at (202) 512-7119 or crossem@gao.gov. Contact points for our 

Offices of Congressional Relations and Public Affairs may be found on the 

last page of this report. GAO staff who made major contributions to this 

report are listed in appendix IX. 

Marcia Crosse 

Director, Health Care 

Page 25 GAO-07-557 Pediatric Drug Research
Appendix I: Scope and Methodology Appendix I: Scope and Methodology 

In this report, we (1) assessed the extent to which pediatric drug studies 

were being conducted for on-patent drugs under the Best Pharmaceuticals 

for Children Act (BPCA), including when drug sponsors declined to 

conduct the studies; (2) evaluated the impact of BPCA on labeling of drugs 

for pediatric use and the process by which the labeling was changed; and 

(3) illustrated the range of diseases treated by the drugs studied under 

BPCA. 

Our review focused primarily on those on-patent drugs for which written 

requests were issued or reissued by the Department of Health and Human 

Services’ (HHS) Food and Drug Administration (FDA) from January 2002, 

when BPCA was enacted, through December 2005. Actions taken on these 

drugs after December 2005 (such as a determination of pediatric 

exclusivity or a labeling change) were not included in our review. In 

addition, we reviewed some summary data available about the number of 

written requests issued under the Food and Drug Administration 

Modernization Act of 1997 (FDAMA) from January 1998 through 

December 2001. We also reviewed pertinent laws, regulations, and 

legislative histories. 

To assess the extent to which pediatric drug studies were being conducted 

for on-patent drugs under BPCA, including when the drug sponsors 

declined to conduct the studies, we identified written requests issued for 

on-patent drugs from January 2002 through December 2005, and 

determined which of those were declined by drug sponsors. We also 

reviewed data provided by FDA on the nature of the pediatric drug studies 

that were conducted in response to the written requests issued under 

BPCA. We also examined notices published in the Federal Register, 

identifying the drugs designated by HHS’s National Institutes of Health 

(NIH) as most in need of study in children. We reviewed data provided to 

us by the Foundation for the National Institutes of Health (FNIH)—a 

nonprofit corporation independent of NIH—about funding for pediatric 

drug studies of on-patent drugs. We interviewed officials from FDA, NIH,

and FNIH to understand the processes by which pediatric drug studies are 

prioritized by the agencies, written requests are issued, drug sponsors 

respond to written requests, study results are submitted to FDA, and 

pediatric exclusivity determinations are made. We also reviewed 

background material describing the role of FNIH in supporting research 

on children and the funding available for such research. 

To evaluate the impact of BPCA on the labeling of drugs for pediatric use 

and the process by which the labeling was changed, we reviewed data 

provided to us by FDA summarizing the changes made from January 2002

Page 26 GAO-07-557 Pediatric Drug Research
Appendix I: Scope and Methodology 

through December 2005 for drugs studied under BPCA. We also used the 

dates that the changes were approved in order to calculate how long it 

took for FDA to approve labeling changes. We interviewed officials from 

FDA about the process by which FDA approves labeling changes as well 

as the reasons why some drugs did not have labeling changes. 

To illustrate the range of diseases treated by the drugs studied under 

BPCA, we reviewed data provided by FDA about the disease each drug 

was proposed to treat. We also examined data from the Medical 

Expenditure Panel Survey—administered by the Agency for Healthcare 

Research and Quality—and the National Ambulatory Medical Care 

Survey—administered by the National Center for Health Statistics—to 

assess the extent to which the drugs studied under BPCA were prescribed 

to children. 

To obtain other information that is provided in appendixes to this report, 

we collected and analyzed a variety of data from FDA, NIH, and FNIH 

about written requests and pediatric studies for both on- and off-patent 

drugs. To obtain a broad perspective on the many issues addressed in our 

report, we also interviewed representatives of the pharmaceutical industry 

and health advocates—such as representatives of the American Academy 

of Pediatrics, the Pharmaceutical Research and Manufacturers of America, 

the Generic Pharmaceutical Association, the National Organization of Rare

Disorders, Public Citizen, the Elizabeth Glaser Pediatric AIDS Foundation,

and the Tufts Center for the Study of Drug Development. 

We evaluated the data used in this report and determined that they were 

sufficiently reliable for our purposes. We conducted our work from 

September 2005 through March 2007 in accordance with generally 

accepted government auditing standards. 

Page 27 GAO-07-557 Pediatric Drug Research
Appendix II: F

Enco

sin

DA and NIH Efforts to 

urage the Study of Drugs in Neonates 

ce Passage of BPCA 

Page 28 GAO-07-557 

Appendix II: FDA and NIH Efforts to 

Encourage the Study of Drugs in Neonates 

since Passage of BPCA 

FDA and NIH have engaged in efforts to increase the inclusion of 

neonates—children under the age of 1 month—in pediatric drug studies. 

As part of its encouragement of pediatric studies in general, BPCA 

identified neonates as a specific group to be included in studies, as 

appropriate. An examination of the written requests revealed that only 4 of

36 written requests for on-patent drugs first issued under BPCA required 

the inclusion of neonates. Further, no written requests for on-patent drugs 

and only two written requests for off-patent drugs have required the 

inclusion of neonates since FDA and NIH held a workshop that began their 

major initiative in this regard in 2004.

In 2003, NIH conducted three workshops focused on increasing the 

inclusion of neonates in pediatric drug studies and discussing diseases 

that affect neonates. In September 2003, NIH staff met to discuss drug 

studies in neonatology and pediatrics with special emphasis placed on

ways to better apply current knowledge in future pediatric drug studies. 

Two months later, NIH met with a group of experts to discuss the use of 

the drug dobutamine—used to treat low blood pressure—in neonates. NIH 

ended 2003 with a 1-day seminar designed to address parental attitudes 

toward neonatal clinical trials. 

FDA and NIH have collaborated to develop the Newborn Drug 

Development Initiative (NDDI), a multiphase program intended to identify

gaps in knowledge concerning neonatal pharmacology and pediatric drug

study design and to explore novel designs for studies of drugs for use by 

neonates. The NDDI is intended to consist of a series of meetings that will 

help frame state-of-the-art approaches and research needs. After forming 

various discussion groups in February 2003, the agencies held a workshop 

in March 2004 to help frame issues and challenges associated with 

designing and conducting drug studies with neonates. The workshop 

addressed ethical issues and drug prioritization in four specialty areas: 

pain control, pulmonology (the study of conditions affecting the lungs and

breathing), cardiology (the study of conditions affecting the heart), and 

neurology (the study of disorders of the brain and central nervous 

system). For example, participants in the pain control group reviewed data 

demonstrating that neonates who undergo multiple painful procedures 

and receive medication to treat pain may differ in their development of 

pain receptors compared to those who do not undergo such procedures 

and treatment. FDA officials said that FDA would apply the findings from 

the NDDI workshop to written requests for pediatric drug studies in the 

four specialty areas. 

NIH Workshops 

NIH Initiatives 

Pediatric Drug Research
Appendix II: FDA and NIH Efforts to 

Encourage the Study of Drugs in Neonates 

since Passage of BPCA 

NIH officials said that the Pediatric Formulations Initiative is a related 

effort. They said that both initiatives are long-standing activities that 

engage in various efforts to enhance information dissemination to improve 

all pediatric drug studies. According to NIH officials, these initiatives have

resulted in numerous publications. 

Pediatric Drug Studies 

Requiring the Study of 

Neonates

FDA and NIH efforts to increase the inclusion of neonates in pediatric 

drug studies conducted under BPCA have been limited. Through 2005, 9 of 

16 (56 percent) written requests for off-patent drugs required the inclusion 

of neonates in the pediatric drug studies. NIH is currently funding 

pediatric drug studies for four of these written requests. Similarly, 36 of 

214 (17 percent) written requests for the study of on-patent drugs issued 

from January 2002 through December 2005 included a requirement to 

study neonates, but only 4 of those 36 (11 percent) were first issued under 

BPCA. The remaining 32 (89 percent) written requests were originally 

issued under FDAMA, which did not place an emphasis on the inclusion of

neonates in pediatric drug studies. Further, all of the written requests 

requiring the inclusion of neonates were issued in 2003, prior to the NDDI. 

Further, only two of the written requests for off-patent drugs were issued 

after the NDDI, and studies for neither of those have been funded. 

According to information provided by FDA, no written requests for 

on-patent drugs issued from January 2004 through December 2005

required the inclusion of neonates. FDA officials indicated, however, that

they receive information about neonates in response to written requests 

that do not specifically target them. According to these officials, many 

written requests require that children from birth through 2 years of age be

studied. These pediatric drug studies therefore may include neonates. In 

addition, inclusion of neonates in some studies may not be appropriate for 

medical or ethical reasons. 

Page 29 GAO-07-557 Pediatric Drug Research
Appendix III: N

Pediatri

IH Efforts to Support 

c Drug Studies 

Page 30 GAO-07-557 

Appendix III: NIH Efforts to Support 

Pediatric Drug Studies 

BPCA was designed in part to increase pediatric drug studies through 

federal efforts. NIH has engaged in several efforts to support pediatric 

drug studies since the passage of BPCA. 

While NIH plays an important role in providing funding for research for 

children, the amount provided by NIH to support such activities has not 

increased significantly under BPCA. Since the enactment of BPCA, NIH 

funding for children’s research has increased from $3.1 billion in fiscal 

year 2003 to $3.2 billion in fiscal year 2005. These figures represent about 

11 percent of NIH’s total budget each year from 2003 through 2005. The 

research funds for children were distributed by most of NIH’s 28 institutes,

centers, and offices.1

 For example, in 2005, 24 of these institutes, centers, 

and offices funded research on children. One institute, the National 

Institute of Child Health and Human Development, was responsible for 

about 26 percent of funding for pediatric research—the largest proportion 

of NIH’s research funding for children. This institute organizes study 

design teams with FDA and other relevant NIH institutes, conducts 

contracting activities, and modifies drug labeling for specific ages and 

diseases. 

The number of pediatric pharmacology research units—initiated by NIH—

devoted to studies for children has remained the same under BPCA.2

 NIH 

provides about $500,000 annually to each of these research units to 

provide the infrastructure for independent investigators to initiate and 

collaborate on studies and clinical trials with private industry and NIH. 

The number of such research units grew from 7 in 1994 to 13 in 1999 to 

support the infrastructure for collaborative efforts of pharmacologists to 

conduct clinical trials that include children. While the number has not 

changed since the passage of BPCA in 2002, NIH officials said that staff 

from these units often move on to hospitals throughout the country and 

enhance the pediatric research capacity nationwide. In addition, they said 

that an overall increase in pediatric research capacity nationwide in recent 

years has made it possible to conduct pediatric clinical trials at a number 

of other sites. They said that, on average, these pediatric pharmacology 

NIH Funding 

Pediatric Pharmacology 

Research Units 

 1

NIH is made up of 28 institutes, centers, and offices that focus on different health 

concerns. The mission of NIH overall is to conduct and support medical research. 

2

Pediatric pharmacology research units are primarily located in children’s hospitals and 

academic research centers specializing in research with children. 

Pediatric Drug Research
Appendix III: NIH Efforts to Support 

Pediatric Drug Studies 

research units conduct more than 50 pediatric drug studies annually. Of 

these, as many as 20 pediatric drug studies are funded by drug sponsors. 

NIH officials told us that of the seven off-patent drugs being studied under 

BPCA with NIH funding through 2005, two were being conducted by these 

research units. NIH officials said that since on-patent written requests are 

not published, the full contribution of the research units under BPCA 

cannot be ascertained. 

Meetings and Forums NIH has sponsored a number of forums designed to increase the number 

of children included in drug studies. As shown in table 5, these forums 

generated advice and suggestions for NIH concerning drug testing from 

health experts, process improvements on drug studies and medication use 

with the pediatric community, and explanations of models and data 

related to research for children. 

Table 5: NIH-Sponsored Activities, through 2005, Related to Children in Clinical Trials 

Year(s) Activity focus 

2002, 2003, 2004, 2005 Pediatric experts offered advice to NIH concerning drugs that should be studied for use by children, 

leading to the published list of off-patent drugs in the Federal Register. 

2003 Discussed ways to improve access to information on the frequency of medication use by children and 

improve the list development process surrounding the measurement of this frequency. 

2003 Discussed ways to use current knowledge to better inform future studies of drugs in children. 

2003 Discussed the use of two drugs, dobutamine and dopamine, in neonates.

2003 Discussed parent attitudes toward studies of neonates and other issues related to the consent for 

studies in children. 

2004 Explored diverse models useful in understanding efficacy and toxicity of drugs across the course of 

development. 

2005 Discussed the development of treatment strategies and recommendations for drugs to be studied in

managing pediatric hypertension. 

2005 Reviewed and analyzed databases used to describe the frequency of health conditions leading families 

to seek care for their children in different outpatient health care delivery settings, such as pediatric 

clinics and offices, and inpatient hospital settings. Those conditions leading to death were also part of 

the review. 

2005 Reviewed and analyzed databases available to describe the frequency of use of medications by 

children in outpatient delivery settings. 

2005 Discussed challenges from lack of appropriate pediatric formulations and improvements of pediatric 

therapeutics. 

Source: NIH. 

Page 31 GAO-07-557 Pediatric Drug Research
Appendix III: NIH Efforts to Support 

Pediatric Drug Studies 

NIH has also conducted meetings and entered numerous intra-agency and 

FDA agreements to strengthen its relationship with FDA and establish a 

firm commitment to study medical issues relevant to children. For 

example, NIH conducted a series of internal meetings in fiscal year 2004 to

identify ongoing pediatric drug studies by the National Institute of Mental 

Health. As an outcome of these meetings, NIH identified and utilized data 

sets related to the study of lithium as it is used for the treatment of bipolar 

disorder in children. NIH will use this information to enhance its current 

understanding of the drug’s therapeutic benefit.

Page 32 GAO-07-557 Pediatric Drug Research
A

under BPC

ppendix IV: Studies of Off-Patent Drugs 

A

Page 33 GAO-07-557 

Appendix IV: Studies of Off-Patent Drugs 

under BPCA 

In addition to providing a mechanism to study on-patent drugs, BPCA also 

contains provisions for the study of off-patent drugs. FDA initiates its 

process by issuing a written request to the drug sponsor to study an offpatent drug. If the sponsor declines to study the drug, FDA can refer the 

study of the drug to NIH for funding. NIH initiates the BPCA process for 

off-patent drugs by prioritizing the list of drugs that need to be studied. 

Written Requests for 

Studies of Off-Patent 

Drugs under BPCA 

BPCA includes a provision that provides for the funding of the study of offpatent drugs by NIH. BPCA requires that NIH—in consultation with FDA 

and other experts—publish an annual list of drugs for which additional 

studies are needed to assess their safety and effectiveness in children.1

FDA can then issue a written request for pediatric studies of the off-patent

drugs on the list. If the written request is declined by the drug sponsor, 

NIH can fund the studies. 

Few off-patent drugs identified by NIH as in need of study for pediatric use 

have been studied. From 2003 through 2006, NIH has listed off-patent 

drugs that were recommended for study by experts in pediatric research 

and clinical practice.2

 By 2005, NIH had identified 40 off-patent drugs that 

it believed should be studied for pediatric use.3

 Through 2005, FDA issued 

written requests for 16 of these drugs.4

 All but one of these written 

requests were declined by drug sponsors. NIH funded pediatric drug 

studies for 7 of the remaining 15 written requests declined by drug 

sponsors through December 2005. 

 1

The list, published in the Federal Register, can include on-patent and off-patent drugs. NIH

did not include on-patent drugs on this list until 2005. 

2

See 71 Fed. Reg. 23931-36 (Apr. 25, 2006), 70 Fed. Reg. 3937 (Jan. 27, 2005), 69 Fed. Reg. 

7243-7244 (Feb. 13, 2004), 68 Fed. Reg. 48402 (Aug. 13, 2003), and 68 Fed. Reg. 2789-2790 

(Jan. 21, 2003). 

3

Some drugs have two written requests; in such cases, each written request is designed to

study either the effects of the drug on a different disease or dosage form, or the drug has 

two sponsors. In these cases, we counted each of these written requests separately. For 

example, Beclomethasone had written requests issued to two sponsors for different dosage 

forms of the drug. An additional 3 off-patent drugs were identified in 2006. From 2003 

through 2006, 12 on-patent drugs have also been listed as important for study. See 71 

Fed. Reg. 23931-23936 (2006). 

4

Two of these drugs changed patent status after the off-patent written request was issued 

because a new formulation of each drug was approved, resulting in new patents or 

exclusivities. They have had new written requests issued and are now considered on-patent 

drugs. Both drug sponsors also declined the on-patent written requests. 

Pediatric Drug Research
Appendix IV: Studies of Off-Patent Drugs 

under BPCA

NIH provided several reasons why it has not pursued the study of some 

off-patent drugs that drug sponsors declined to study. Concerns about the 

incidence of the diseases that the drugs were developed to treat, the 

feasibility of study design, drug safety, and changes in the drugs’ patent 

status have caused the agency to reconsider the merit of studying some of 

the drugs it identified as important for study in children.5

 For example, in 

one case NIH issued a request for proposals to study a drug but received 

no response. In other cases, NIH is awaiting consultation with pediatric 

experts to determine the potential for study. 

Further, NIH has not received appropriations specifically for funding 

pediatric drug studies under BPCA. Rather, according to agency officials, 

NIH uses lump sum appropriations made to various institutes to fund 

pediatric drug studies under BPCA. In fiscal year 2005, NIH spent 

approximately $25 million for these pediatric drug studies. 

Funding for Studies of OffPatent Drugs under BPCA 

NIH anticipates spending an estimated $52.5 million for pediatric drug 

studies following seven written requests to drug sponsors issued by FDA 

from January 2002 through December 2005.6

 These pediatric drug studies 

were designed to take from 3 to 4 years and will be completed in 2007 at 

the earliest. Where possible, NIH identifies another government agency or

institute within NIH that might be able to meet the requirements of the 

written requests and conduct the pediatric drug studies. In cases where a 

government agency will conduct the pediatric drug studies, NIH institutes 

enter into intra- or interagency agreements for the studies. If those efforts 

fail, the agency develops and publishes requests for proposals for others to 

conduct the pediatric studies. NIH anticipates spending approximately 

$16.0 million for the funding of pediatric drug studies of four additional 

off-patent drugs for which FDA did not issue written requests—and 

therefore are not covered by the requirements of BPCA—but three of 

these drugs have since been listed by NIH in the Federal Register as 

needing study in children.7

 (See table 6.) 

 5

Since its inception, no drug has been removed from the list published in the Federal 

Register, regardless of the feasibility or likelihood of being studied. 

6

The costs reported by NIH are estimates, which may change during the course of the

studies. 

7

NIH determined that these drugs were a priority for study in children and certain 

conditions made it appropriate to initiate studies prior to FDA being able to issue a written 

request. 

Page 34 GAO-07-557 Pediatric Drug Research
Appendix IV: Studies of Off-Patent Drugs 

under BPCA

Table 6: Anticipated NIH Spending for Off-Patent Drug Studies Committed to through 2005 

Drug Total cost

a

Disease or

condition Funded agency or organization 

Anticipated 

completion

Studies for drugs with a written request

Dactinomycinb$1,800,000c Cancer Children’s Oncology Group through 

the National Cancer Institute

2007

Hydroxyurea $7,000,000cSickle cell National Heart Lung and Blood 

Institute 

2008

Lithium $17,400,000cMania in bipolar

disorder 

Case Western University 2008

Status epilepticus 

(seizures) 

Lorazepam (two National Institutes of Health 2008

diseases/conditions) 

$15,100,000d

Sedation National Institutes of Health 2008

Sodium nitroprusside $9,400,000cControl of blood

pressure 

Stanford University and Duke

University 

2007

Vincristineb$1,800,000cMalignancies Children’s Oncology Group through 

the National Cancer Institute

2007

Subtotal $52,500,000

Studies initiated prior to a written request

e

Daunomycin (Daunorubicin) $1,400,000cCancer Children’s Oncology Group through 

the National Cancer Institute

2008

Ketamine $1,000,000dSedation FDA’s National Center for 

Toxicological Research

2008

Methotrexate $8,900,000dCancer Children’s Oncology Group through 

the National Cancer Institute

2009

Methylphenidate $4,700,000fAttention deficit

hyperactivity 

disorder 

National Institute of Environmental 

Health Sciences

2007

Subtotal $16,000,000

Total $68,500,000

Source: GAO analysis of NIH data. 

a

Total costs proposed for most studies are estimates and may vary over time because of 

modifications of initial projects, rounded to the nearest $100,000. 

b

Dactinomycin and Vincristine are commonly used together and the cost to study both is $3,600,000. 

c

Studies to be completed over 3 years. 

d

Studies to be completed over 4 years. 

Page 35 GAO-07-557 Pediatric Drug Research
Appendix IV: Studies of Off-Patent Drugs 

under BPCA

e

No written request was issued by FDA for the specific studies prior to being funded by NIH. Ketamine 

is listed in the Federal Register as a drug in need of study in children (69 Fed. Reg. 7243-44, Feb. 13, 

2004). Because of data demonstrating that ketamine enhances cell death in the brain in animals, it is 

not possible to design an ethical study using children. Ketamine has since been listed in the Federal 

Register as having preclinical toxicology studies under way, with clinical studies awaiting their 

completion (71 Fed. Reg. 23931-36, Apr. 25, 2006). Methylphenidate was selected, though it is not 

included on the list published in the Federal Register, because of a potentially serious public health 

concern that arose unexpectedly. HHS officials reported that studies on ketamine and 

methylphenidate are not the type that typically would be requested under BPCA, nor was a written 

request issued for these specific studies. Daunomycin and methotrexate were selected prior to being 

listed in the Federal Register because the National Cancer Institute had access to the appropriate 

children for study and was developing studies that would produce data for both drugs. 

f

Studies to be completed over 2 years. 

The drugs whose study NIH is funding without written requests were 

selected because of special circumstances that raised their priority for 

funding. NIH funded the study of daunomycin and methotrexate—both

cancer drugs—before placing them on its 2006 list of drugs for study in 

children. NIH officials told us that the Children’s Oncology Group of the 

National Cancer Institute was already working with an appropriate group

of patients and was at a critical stage in developing the pediatric drug 

studies that would produce data for both drugs, so pediatric drug studies 

were funded before the drugs were placed on the priority list. NIH officials 

also told us that ketamine is administered to more than 30,000 children for 

sedation each year. Studies done in animals, however, have suggested that 

the drug may lead to cell death in the brain. As a result, the drug cannot be

ethically tested in children. NIH is therefore collaborating with FDA to 

conduct studies in nonhuman primates. NIH officials report that 

methylphenidate is used by an estimated 2.5 million school-aged children 

to treat attention deficit hyperactivity disorder. However, a recent study

suggested some potential genetic toxicity of the drug. Because of these 

findings, the drug was targeted as a priority and NIH was able to fund 

some of the planned studies related to this drug. 

Page 36 GAO-07-557 Pediatric Drug Research
Appendix V: St

Requested b

atus of Pediatric Drug Studies 

y FDA 

Page 37 GAO-07-557 

Appendix V: Status of Pediatric Drug Studies 

Requested by FDA 

From January 2002 through December 2005, FDA issued 214 written 

requests for the study of on-patent drugs. The agency also issued 16 

written requests for the study of off-patent drugs. Fewer written requests 

were issued and more were declined by drug sponsors under BPCA than 

under FDAMA. 

Written Requests Issued 

under BPCA Compared to 

FDAMA 

From January 2002, when BPCA was enacted, through December 2005, 

FDA issued or reissued 214 written requests for on-patent drugs, and drug

sponsors declined 41 of those. FDA issued 68 written requests under BPCA 

for the study of on-patent drugs,1

 20 (29 percent) of which were declined 

by the drug sponsors. FDA reissued 146 written requests for on-patent 

drugs that were originally issued under FDAMA because the pediatric drug

studies had not been completed at the time BPCA went into effect. 

Included in the 146 were 21 (14 percent) written requests that were 

subsequently declined by the drug sponsors. Therefore, drug sponsors 

accepted 173 written requests for the study of on-patent drugs under 

BPCA during this period. Under FDAMA, FDA issued 227 written requests.

Drug sponsors did not conduct pediatric drug studies or submit study 

results for 30 of the 227 (13 percent) written requests issued under 

FDAMA (see fig. 3).2

 1

We counted all written requests individually. In some cases, FDA issued more than one 

written request for a drug, such as when there was more than one sponsor, when the first 

written request was declined by the drug sponsor and a new written request was issued 

when FDA became aware of new information, or when the drug was being studied for more

than one disease (though these studies may also be in the same written request). 

2

Since FDAMA did not require that drug sponsors accept or decline a written request, as 

required by BPCA for on-patent drugs, we could not determine the exact number of written 

requests that were declined. Instead, we were able to determine the number of written 

requests for which study results were not submitted under FDAMA and the number of

written requests declined when reissued under BPCA. This is the most conservative 

equivalent measure. FDA officials report that it is possible that studies were conducted

under FDAMA and the drug sponsors decided not to submit them to FDA for exclusivity 

consideration. 

Pediatric Drug Research
Appendix V: Status of Pediatric Drug Studies 

Requested by FDA 

Figure 3: Status of Written Requests Issued under FDAMA and BPCA through December 2005 

Source: GAO.

 Number of applications that pass through decision point

Compilation of number of applications

X

214

173 41

Written requests for on-patent drugs

issued under FDAMA

9

Finished 

under FDAMA 

72 146

Not finished 

under FDAMA 

Not started or not continued

under BPCA (“Declined”)

227

Written requests for on-patent 

drugs reissued under BPCA

New written requests for onpatent drugs issued under BPCANew written requests for offpatent drugs issued under BPCA

Accepted Declined 

146

125 21

Accepted Declined 

68

48 20

Accepted Declined 

16

1 15 

X

Note: If a drug sponsor of an off-patent drug does not respond to FDA’s written request within 30 

days, the written request is considered declined. 

Page 38 GAO-07-557 Pediatric Drug Research
Appendix V: Status of Pediatric Drug Studies 

Requested by FDA 

FDA officials offered two primary reasons why fewer written requests 

were issued under BPCA than under FDAMA. First, according to FDA 

officials, when FDAMA was enacted, FDA and some drug sponsors had 

already identified a large number of drugs that they believed needed to be

studied for pediatric use. By the time BPCA was enacted, written requests 

for the study of these drugs had already been issued. Second, FDA officials 

said there was a surge of written requests prior to the sunset of FDAMA. 

Agency officials expect the same surge to occur prior to the sunset of the 

pediatric exclusivity provisions of BPCA in 2007.

Reasons for Decline in 

Written Requests Issued 

and Accepted under BPCA 

Compared to FDAMA 

FDA officials also offered a number of reasons that the proportion of 

written requests issued under BPCA that were declined was greater than 

that for those issued under FDAMA. While FDA does not track the reasons 

that drug sponsors decline specific written requests, FDA officials expect

that a major reason that the written requests were declined is that the 

agency sometimes requests more extensive pediatric drug studies, and 

therefore more costly studies, than the sponsors would like to do. This 

may be the case even when the drug sponsors initiated the written request

process. FDA officials said that upon consideration of FDA’s written 

requests, drug sponsors may make a business decision not to conduct the 

requested pediatric drug studies because they may be too costly for the 

expected return associated with pediatric exclusivity. Agency officials 

reported that since the drugs studied under FDAMA were more likely to be

those with the greatest expected financial return or the easiest to study, 

they are not surprised at the higher proportion of pediatric drug studies 

declined under BPCA. Further, under BPCA drug sponsors are required to

pay user fees—as high as $767,400 in fiscal year 2006—when study results 

are submitted for pediatric exclusivity consideration. As a result, the 

process of gaining pediatric exclusivity has become more expensive than

it was under FDAMA when drug sponsors were exempt from such fees for 

pediatric drug studies. 

FDA officials said they are not discouraged by the increase in the number 

of written requests that have been declined. In 2001, FDA reported to 

Congress that the agency expected drug sponsors to conduct pediatric 

drug studies for 80 percent of written requests. The rate at which written 

requests for studies of on-patent drugs were accepted under BPCA— 

71 percent—is close to the target of 80 percent, and it is substantially 

larger than the 15 to 30 percent of drugs that FDA officials have reported

Page 39 GAO-07-557 Pediatric Drug Research
Appendix V: Status of Pediatric Drug Studies 

Requested by FDA 

were labeled for pediatric use prior to the authorization of pediatric 

exclusivity under FDAMA and BPCA.3

 3

Prior to FDAMA, over a 6-year period from 1991 to 1996, only 11 of 71 requested studies 

were completed without such an incentive.

Page 40 GAO-07-557 Pediatric Drug Research
Appendix VI: Complexity of Completed Appendix VI: Complexity of Completed Pediatric Drug Studies 

Pediatric Drug Studies 

The pediatric drug studies conducted under BPCA were complex and 

sizable, involving a large number of study sites and children. From July 

2002 through December 2005,

1

 drug sponsors submitted study reports to 

FDA in response to 59 written requests. FDA made pediatric exclusivity 

determinations for 55 of those written requests by December 2005, and 

most—51, or 93 percent—were made in 90 days or less. 

For the 59 written requests for which study results were submitted to 

FDA, a total of 143 pediatric drug studies were conducted at 2,860 

different study sites with more than 25,000 children participating (see 

table 7). In December 2005, FDA projected that for the drugs for which 

studies had not yet been submitted for review, there would be nearly 

20,000 more children participating in the studies. 

Table 7: Complexity of Pediatric Drug Studies Conducted under BPCA, According 

to Study Reports from July 2002 through December 2005

Number of 

individual studies

Number of study

sites for all studies 

Number of 

participants in all 

studies

Count 143 2,860 25,397

Average 2 68 430

Median 2 48 255

Mode 2 83 192

Minimum 1 3 11

Maximum 7 232 2,517

Number of written 

requests data are 

based on 59 42 59

Source: GAO analysis of FDA data. 

 1

For these analyses, we looked at study reports submitted after July 2002 because those 

submitted from January 2002 through June 2002 were in response to written requests 

issued under FDAMA, not BPCA. 

Page 41 GAO-07-557 Pediatric Drug Research
Appendix VII: S

Chan

trengths of and Suggested 

ges for BPCA 

Page 42 GAO-07-557 

Appendix VII: Strengths of and Suggested 

Changes for BPCA 

Officials from FDA and NIH discussed a number of important strengths of 

BPCA. In our interviews with industry group representatives and in a 

public forum, a number of suggestions have also been made for ways that 

BPCA could be improved. 

Pediatric Drug Research

FDA officials identified a number of important strengths of BCPA. 

Specifically, they commented on the following: 

• Economic incentives to conduct pediatric drug studies. Because of the 

economic incentives in BPCA, FDA officials argue that many logistical 

issues inherent in conducting pediatric drug studies have been overcome.

FDA may also issue a written request for pediatric drug studies for rare 

conditions, offering an additional incentive to develop medications for 

rare diseases that occur only in children. 

Strengths of BPCA 

Identified by FDA and NIH 

Officials 

• Availability of summaries of pediatric drug studies. FDA officials 

reported that the public dissemination of study summaries has ensured 

that study information is available to the health care community and has 

been useful to prescribers to know what has been learned about drugs’ use 

in children. 

• Broad scope of pediatric drug studies. BPCA allows FDA to issue written 

requests for pediatric drug studies for the treatment of any disease, 

regardless of whether the drug in question is currently indicated to treat 

that disease in adults. For example, FDA issued a written request for the 

study of a drug currently indicated to treat prostate cancer. The drug is 

being tested in children to see if it is effective in treating early puberty in 

boys. 

• Use of dispute resolution as a negotiating tool in ensuring labeling 

changes. Although FDA has never invoked its authority under BPCA to use 

the dispute resolution process for making labeling changes, it has been an

important negotiating tool. FDA officials indicated that when the agency

has expressed its intention to use the process, the issues that had been 

raised in labeling negotiations were effectively resolved. 

• Improved safety through focused pediatric safety reviews. BPCA’s 

requirement that FDA conduct additional monitoring of adverse event 

reports for 1 year after a drug is granted pediatric exclusivity has been 

useful to FDA in prioritizing safety issues for children. For example, an 

analysis of a drug 1 year after pediatric exclusivity was granted showed 

that there were deaths among children as a result of overuse or misuse of 
Appendix VII: Strengths of and Suggested 

Changes for BPCA 

the drug. This led the agency to amend the labeling regarding the 

appropriate population for the drug.

NIH officials said they have found the process of developing the list of 

drugs important for study in children to be extremely helpful. NIH officials 

told us that since the inception of BPCA, they have learned a great deal 

about existing gaps in the drug development process for children, 

including a lack of data about which drugs are used by children and how 

frequently. To gather additional information, NIH has contracted for 

literature reviews to decrease the possibility that unnecessary pediatric 

drug studies are conducted. These officials also stated that BPCA and the 

development of the priority list have helped to solidify an alliance between 

NIH and FDA, which has led to discussions and resolutions of scientific 

and ethical issues relating to pediatric drug studies. 

The Institute of Medicine convened a forum on pediatric research in June 

2006 where forum participants made suggestions for how BPCA could be

improved.1

 In addition, we discussed suggestions for improving BPCA with 

interest group representatives. Forum participants suggested that the 

timing of the determination of pediatric exclusivity should parallel the 

scientific review of a drug application and that both should be within 

180 days of FDA receiving the results from the pediatric drug studies. 

FDA’s ability to assess the overall quality of the pediatric drug studies in 

the 90 days currently allotted for the review was questioned. Some forum 

participants also stated that a longer review period could result in 

different determinations in some cases. For example, FDA’s scientific 

review of data related to the study of one drug showed that the children 

participating in the pediatric drug studies had not received the treatments 

as the drug sponsors had suggested in their description of the study 

results. While the agency had granted the drug sponsor pediatric 

exclusivity based on its 90-day review to determine pediatric exclusivity, it

might not have done so based on what was learned during the longer, 

180-day scientific review. 

In addition, it was suggested that drug sponsors be required to submit 

their study results for pediatric exclusivity determination at least 1 year 

prior to patent expiration. This would allow the generic drug industry time 

Suggestions for Changes to 

BPCA 

 1

Forum on Drug Discovery, Development, and Translation: Addressing the Barriers to

Development in Pediatrics (conference sponsored by the Institute of Medicine of the 

National Academies, Washington, D.C., June 2006). The program can be accessed at 

www.iom.edu/CMS/3740/24155/34241.aspx. 

Page 43 GAO-07-557 Pediatric Drug Research
Appendix VII: Strengths of and Suggested 

Changes for BPCA 

to better plan its release of drugs. We were told that sometimes generic 

drugs have had to be destroyed because pediatric exclusivity

determinations were made after the generic version of the drug had been 

manufactured and the drug’s expiration date would not allow the product 

to be sold. 

Representatives from interest groups would like the written requests to be

public information and would also like FDA to publicly announce when it

receives study results that have been submitted in response to a written 

request. This would allow the generic drug industry to better schedule the 

introduction of generic drugs into the market. 

Other suggestions for how the study of off-patent drugs could be more 

effectively encouraged were offered at the forum. A forum participant 

suggested that methods similar to those being adopted by the European 

Union be implemented. According to forum participants, under new 

legislation in Europe, companies that study off-patent drugs will be offered 

a variety of incentives, such as 10 years of data protection (meaning that 

the data generated to support the marketing of the drug cannot be used to 

support another drug, in an effort to delay competition), the right to use 

the existing brand name (to enable the drug sponsor to capitalize on 

existing brand recognition), and the ability to add a symbol to the drug 

labeling indicating the drug has been studied in children. 

Another suggestion was that current fees paid by drug sponsors for review 

of their drug applications could be used to fund the study of off-patent 

drugs (as well as on-patent drugs that drug sponsors decline to study). 

These fees—$767,400 for a new drug application and $383,700 for a 

supplemental drug application in fiscal year 2006—are collected from drug 

sponsors when study results are submitted to FDA for review and 

consideration of pediatric exclusivity.

Page 44 GAO-07-557 Pediatric Drug Research
Appendix VIII: Comments from the Department Appendix VIII: Comments from the of Health and Human Services 

Department of Health and Human Services 

Page 45 GAO-07-557 Pediatric Drug Research
Appendix VIII: Comments from the Department 

of Health and Human Services 

Page 46 GAO-07-557 Pediatric Drug Research
Appendix VIII: Comments from the Department 

of Health and Human Services 

Page 47 GAO-07-557 Pediatric Drug Research
Appendix IX: 

A

GAO Contact and Staff 

cknowledgments 

Page 48 GAO-07-557 

Appendix IX: GAO Contact and Staff 

Acknowledgments 

Marcia Crosse, (202) 512-7119 or crossem@gao.gov

In addition to the contact named above, Thomas Conahan, Assistant 

Director; Shaunessye Curry; Cathleen Hamann; Martha Kelly; Julian 

Klazkin; Carolyn Feis Korman; Gloria Taylor; and Suzanne Worth made 

key contributions to this report. 

Pediatric Drug Research

GAO Contact 

Acknowledgments 

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