This is the accessible text file for GAO report number GAO-07-557 
entitled 'Pediatric Drug Research: Studies Conducted under Best 
Pharmaceuticals for Children Act' which was released on March 22, 2007. 

This text file was formatted by the U.S. Government Accountability 
Office (GAO) to be accessible to users with visual impairments, as part 
of a longer term project to improve GAO products' accessibility. Every 
attempt has been made to maintain the structural and data integrity of 
the original printed product. Accessibility features, such as text 
descriptions of tables, consecutively numbered footnotes placed at the 
end of the file, and the text of agency comment letters, are provided 
but may not exactly duplicate the presentation or format of the printed 
version. The portable document format (PDF) file is an exact electronic 
replica of the printed version. We welcome your feedback. Please E-mail 
your comments regarding the contents or accessibility features of this 
document to Webmaster@gao.gov. 

This is a work of the U.S. government and is not subject to copyright 
protection in the United States. It may be reproduced and distributed 
in its entirety without further permission from GAO. 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. 

Report to Congressional Committees: 

United States Government Accountability Office: 

GAO: 

March 2007: 

Pediatric Drug Research: 

Studies Conducted under Best Pharmaceuticals for Children Act: 

GAO-07-557: 

GAO Highlights: 

Highlights of GAO-07-557, a report to congressional committees 

Why GAO Did This Study: 

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 on-patent—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. 

What GAO Found: 

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 

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

[See PDF for Image] 

Source: GAO. 

[End of figure] 

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. 

[Hyperlink, http://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. 

[End of section] 

Contents: 

Letter: 

Results in Brief: 

Background: 

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: 

Most Drugs Granted Pediatric Exclusivity under BPCA Had Labeling 
Changes, but the Process for Making Changes Was Sometimes Lengthy: 

Drugs Studied under BPCA Address a Wide Range of Diseases, Including 
Some That Are Common, Serious, or Life Threatening to Children: 

Agency Comments and Our Evaluation: 

Appendix I: Scope and Methodology: 

Appendix II: FDA and NIH Efforts to Encourage the Study of Drugs in 
Neonates since Passage of BPCA: 

Appendix III: NIH Efforts to Support Pediatric Drug Studies: 

Appendix IV: Studies of Off-Patent Drugs under BPCA: 

Appendix V: Status of Pediatric Drug Studies Requested by FDA: 

Appendix VI: Complexity of Completed Pediatric Drug Studies: 

Appendix VII: Strengths of and Suggested Changes for BPCA: 

Appendix VIII: Comments from the Department of Health and Human 
Services: 

Appendix IX: GAO Contact and Staff Acknowledgments: 

Tables: 

Table 1: Estimated Costs of Funding the Study of On-Patent Drugs 
Referred to FNIH under BPCA: 

Table 2: Examples of Labeling Changes: 

Table 3: Examples of Drugs Approved for Use by Younger Children or for 
Which New Formulations Are Available: 

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

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

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

Table 7: Complexity of Pediatric Drug Studies Conducted under BPCA, 
According to Study Reports from July 2002 through December 2005: 

Figures: 

Figure 1: BPCA Process: 

Figure 2: Status of Written Requests Issued under BPCA for the Study of 
On-Patent Drugs, from January 2002 through December 2005: 

Figure 3: Status of Written Requests Issued under FDAMA and BPCA 
through December 2005: 

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: 

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.[Footnote 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)[Footnote 2] in 2002 to provide marketing incentives to drug 
sponsors for conducting pediatric drug studies.[Footnote 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 with pertinent law and 
regulations.[Footnote 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)[Footnote 5] approval of a generic copy 
for marketing.[Footnote 6] Generally, pediatric exclusivity can only be 
granted to those drugs that are on-patent--that is, those that still 
have market exclusivity[Footnote 7]--and for which FDA has issued a 
written request for pediatric drug studies.[Footnote 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 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.[Footnote 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 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. 

Results in Brief: 

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 on- 
patent 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. 

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, 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. 

Background: 

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.[Footnote 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,[Footnote 11] 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.[Footnote 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 
reports to determine whether the pediatric drug studies met the 
conditions outlined in the written request.[Footnote 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.[Footnote 14] 
Figure 1 illustrates the process under BPCA. 

Figure 1: BPCA Process: 

[See PDF for image] 

Source: GAO. 

[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 off-patent drug. 

[End of figure] 

BPCA Provisions for Pediatric Drug Studies Declined by Drug Sponsors: 

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. 

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.[Footnote 15] In recent years, appropriations of $500,000 
were authorized to FNIH annually.[Footnote 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 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.[Footnote 
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."[Footnote 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.[Footnote 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 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,[Footnote 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. 

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: 

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. 

Drug Sponsors Agreed to Conduct Pediatric Drug Studies for Most On- 
Patent Drugs with Written Requests Issued under BPCA: 

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.[Footnote 21] The remaining 41 written requests were 
declined.[Footnote 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.[Footnote 23] Of those 55 written requests, 52 (95 
percent) resulted in FDA granting pediatric exclusivity.[Footnote 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.) 

Figure 2: Status of Written Requests Issued under BPCA for the Study of 
On-Patent Drugs, from January 2002 through December 2005: 

[See PDF for image] 

Source: GAO. 

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. 

[End of figure] 

FNIH Had Not Funded the Study of Any On-Patent Drugs in Children: 

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.[Footnote 25] FNIH had not 
funded the study of any of these drugs.[Footnote 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. 

Table 1: Estimated Costs of Funding the Study of On-Patent Drugs 
Referred to FNIH under BPCA: 

On-patent drug: Baclofen; 
Disease or condition to be studied: Spasticity in children with 
cerebral palsy; 
Estimated cost: $7.8 million. 

On-patent drug: Bupropion; 
Disease or condition to be studied: Depression; 
Estimated cost: $7.4 million. 

On-patent drug: Dexrazoxane; 
Disease or condition to be studied: Used to block the cardiac effects 
of the anticancer drug adriamycin; 
Estimated cost: Not provided[A]. 

On-patent drug: Eletriptan; 
Disease or condition to be studied: Migraine headaches; 
Estimated cost: Not provided[A]. 

On-patent drug: Hydroxyurea[B]; 
Disease or condition to be studied: Sickle cell disease; 
Estimated cost: $8 million to $10 million[C]. 

On-patent drug: Metoclopramide; 
Disease or condition to be studied: Gastroesophageal reflux disease; 
Estimated cost: Not provided[A]. 

On-patent drug: Morphine; 
Disease or condition to be studied: Analgesia; 
Estimated cost: $8.7 million. 

On-patent drug: Sevelamer; 
Disease or condition to be studied: Renal failure; 
Estimated cost: $2.7 million. 

On-patent drug: Zonisamide; 
Disease or condition to be studied: Refractory partial seizures; 
Estimated cost: $8.4 million. 

On-patent drug: Total; 
Disease or condition to be studied: [Empty]; 
Estimated cost: $43 million to $45 million[D]. 

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. 

[End of table] 

Most Drugs Granted Pediatric Exclusivity under BPCA Had Labeling 
Changes, but the Process for Making Changes Was Sometimes Lengthy: 

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 Had Labeling Changes: 

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.[Footnote 
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. 

Labeling Changes for Drugs Studied under BPCA Had Important 
Implications for Pediatric Use: 

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. 

Table 2: Examples of Labeling Changes: 

Potential risks or hazards: Unnecessary exposure to ineffective 
therapies; 
Drug name: Sumatriptan; 
Disease or condition treated: Migraines; 
Summary of new information contained in drug labeling: 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. 

Potential risks or hazards: Unnecessary exposure to ineffective 
therapies; 
Drug name: Tolterodine; 
Disease or condition treated: Overactive bladder and urge incontinence; 
Summary of new information contained in drug labeling: The drug was not 
shown to be effective for children and appeared to show a possible 
increase in aggressive, hyperactive, and abnormal behavior. 

Potential risks or hazards: Unnecessary exposure to ineffective 
therapies; 
Drug name: Irinotecan; 
Disease or condition treated: Tumors; 
Summary of new information contained in drug labeling: 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. 

Potential risks or hazards: Ineffective dosing; 
Drug name: Oxcarbazepine; 
Disease or condition treated: Partial seizures; 
Summary of new information contained in drug labeling: Dose for 
children aged 2 to 4 and weighing less than 44 pounds is twice the dose 
per body weight compared to adults. 

Potential risks or hazards: Ineffective dosing; 
Drug name: Methylphenidate; 
Disease or condition treated: Attention-deficit hyperactivity disorder; 
Summary of new information contained in drug labeling: 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. 

Potential risks or hazards: Overdosing; 
Drug name: Leflunomide; 
Disease or condition treated: Juvenile rheumatoid arthritis; 
Summary of new information contained in drug labeling: 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. 

Potential risks or hazards: Previously unlabeled side effects, 
including effect on growth and development; 
Drug name: Venlafaxine; 
Disease or condition treated: Depression; generalized anxiety disorder; 
Summary of new information contained in drug labeling: This drug is 
associated with an increased risk of suicidal thinking and behavior. 

Potential risks or hazards: Previously unlabeled side effects, 
including effect on growth and development; 
Drug name: Ciprofloxacin; 
Disease or condition treated: Complicated urinary tract infection or 
kidney infection; 
Summary of new information contained in drug labeling: This drug is 
associated with increased adverse effects to joints or surrounding 
tissues for children. 

Potential risks or hazards: Previously unlabeled side effects, 
including effect on growth and development; 
Drug name: Fentanyl; 
Disease or condition treated: Chronic pain; 
Summary of new information contained in drug labeling: 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. 

Potential risks or hazards: Previously unlabeled side effects, 
including effect on growth and development; 
Drug name: Budesonide; 
Disease or condition treated: Asthma; 
Summary of new information contained in drug labeling: Budesonide can 
cause growth suppression. 

Source: GAO analysis of FDA data. 

[End of table] 

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 use, or new directions for preparing the drug 
for pediatric use were identified during the pediatric drug studies 
conducted under BPCA.[Footnote 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: New age groups; 
Drug: Moxifloxacin Ophthalmic; 
Disease or condition treated or prevented: Bacterial conjunctivitis; 
Summary of new information: Found to be safe and effective for children 
over 1 year old. 

Uses and formulations: New age groups; 
Drug: Ondansetron; 
Disease or condition treated or prevented: Nausea and vomiting after 
chemotherapy; 
Summary of new information: 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. 

Uses and formulations: New formulations or preparations; 
Drug: Benazepril; 
Disease or condition treated or prevented: Hypertension; 
Summary of new information: Labeled with directions for how to prepare 
a suspension for administering the drug to children. 

Uses and formulations: New formulations or preparations; 
Drug: Desloratadine; 
Disease or condition treated or prevented: Seasonal and perennial 
allergic rhinitis and hives; 
Summary of new information: Newly available in a syrup, labeled 
specifically for children. 

Source: GAO analysis. 

[End of table] 

The Process for Reviewing Study Results and Approving Labeling Changes 
Was Sometimes Lengthy, Particularly When FDA Required Additional 
Information from Drug Sponsors: 

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.[Footnote 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. 

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 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 Studied under BPCA Address a Wide Range of Diseases, Including 
Some That Are Common, Serious, or Life Threatening to Children: 

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. 

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 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.[Footnote 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.[Footnote 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: Allergies; 
Information about the disease: Allergies affect up to 40 percent of, or 
about 29 million, children in the United States. 

Specific disease treated by drug: Asthma; 
Information about the disease: Asthma affects 6.2 million or 9 percent 
of children in the United States. Further, asthma is the most common 
chronic illness among children. 

Specific disease treated by drug: Cancer; 
Information about the disease: Cancer is the leading cause of death by 
disease for children aged 1 to 14 in the United States. 

Specific disease treated by drug: HIV; 
Information about the disease: 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. 

Specific disease treated by drug: Hypertension; 
Information about the disease: 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. 

Specific disease treated by drug: Influenza; 
Information about the disease: 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. 

[End of table] 

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. 

Agency Comments and Our Evaluation: 

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 on- 
patent 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. 

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 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. 

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. 

Signed by: 

Marcia Crosse: 
Director, Health Care: 

[End of section] 

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 
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. 

[End of section] 

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. 

NIH Workshops: 

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. 

NIH Initiatives: 

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 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. 

[End of section] 

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. 

NIH Funding: 

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.[Footnote 32] 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. 

Pediatric Pharmacology Research Units: 

The number of pediatric pharmacology research units--initiated by NIH-
-devoted to studies for children has remained the same under 
BPCA.[Footnote 33] 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 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): 2002, 2003, 2004, 2005; 
Activity focus: 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. 

Year(s): 2003; 
Activity focus: 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. 

Year(s): 2003; 
Activity focus: Discussed ways to use current knowledge to better 
inform future studies of drugs in children. 

Year(s): 2003; 
Activity focus: Discussed the use of two drugs, dobutamine and 
dopamine, in neonates. 

Year(s): 2003; 
Activity focus: Discussed parent attitudes toward studies of neonates 
and other issues related to the consent for studies in children. 

Year(s): 2004; 
Activity focus: Explored diverse models useful in understanding 
efficacy and toxicity of drugs across the course of development. 

Year(s): 2005; 
Activity focus: Discussed the development of treatment strategies and 
recommendations for drugs to be studied in managing pediatric 
hypertension. 

Year(s): 2005; 
Activity focus: 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. 

Year(s): 2005; 
Activity focus: Reviewed and analyzed databases available to describe 
the frequency of use of medications by children in outpatient delivery 
settings. 

Year(s): 2005; 
Activity focus: Discussed challenges from lack of appropriate pediatric 
formulations and improvements of pediatric therapeutics. 

Source: NIH. 

[End of table] 

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. 

[End of section] 

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 off-patent 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 
off-patent 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.[Footnote 34] 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.[Footnote 35] By 2005, NIH had 
identified 40 off-patent drugs that it believed should be studied for 
pediatric use.[Footnote 36] Through 2005, FDA issued written requests 
for 16 of these drugs.[Footnote 37] 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. 

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.[Footnote 38] 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 Off-Patent 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.[Footnote 39] 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.[Footnote 40] (See table 6.) 

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

Studies for drugs with a written request. 

Drug: Dactinomycin[B]; 
Total cost[A]: Studies for drugs with a written request: $1,800,000[C]; 
Disease or condition: Cancer; 
Funded agency or organization: Children's Oncology Group through the 
National Cancer Institute; 
Anticipated completion: 2007. 

Drug: Hydroxyurea; 
Total cost[A]: Studies for drugs with a written request: $7,000,000[C]; 
Disease or condition: Sickle cell; 
Funded agency or organization: National Heart Lung and Blood Institute; 
Anticipated completion: 2008. 

Drug: Lithium; 
Total cost[A]: Studies for drugs with a written request: 
$17,400,000[C]; 
Disease or condition: Mania in bipolar disorder; 
Funded agency or organization: Case Western University; 
Anticipated completion: 2008. 

Drug: Lorazepam (two diseases/conditions); 
Total cost[A]: Studies for drugs with a written request: 
$15,100,000[D]; 
Disease or condition: Status epilepticus (seizures); 
Funded agency or organization: National Institutes of Health; 
Anticipated completion: 2008. 

Drug: Lorazepam (two diseases/conditions); 
Total cost[A]: Studies for drugs with a written request: 
$15,100,000[D]; 
Disease or condition: Sedation; 
Funded agency or organization: National Institutes of Health; 
Anticipated completion: 2008. 

Drug: Sodium nitroprusside; 
Total cost[A]: Studies for drugs with a written request: $9,400,000[C]; 
Disease or condition: Control of blood pressure; 
Funded agency or organization: Stanford University and Duke University; 
Anticipated completion: 2007. 

Drug: Vincristine[B]; 
Total cost[A]: Studies for drugs with a written request: $1,800,000[C]; 
Disease or condition: Malignancies; 
Funded agency or organization: Children's Oncology Group through the 
National Cancer Institute; 
Anticipated completion: 2007. 

Drug: Subtotal; 
Total cost[A]: Studies for drugs with a written request: $52,500,000; 
Disease or condition: [Empty]; 
Funded agency or organization: [Empty]; 
Anticipated completion: [Empty]. 

Studies initiated prior to a written request[E]. 

Drug: Daunomycin (Daunorubicin); 
Total cost[A]: Studies for drugs with a written request: $1,400,000[C]; 
Disease or condition: Cancer; 
Funded agency or organization: Children's Oncology Group through the 
National Cancer Institute; 
Anticipated completion: 2008. 

Drug: Ketamine; 
Total cost[A]: Studies for drugs with a written request: $1,000,000[D]; 
Disease or condition: Sedation; 
Funded agency or organization: FDA's National Center for Toxicological 
Research; 
Anticipated completion: 2008. 

Drug: Methotrexate; 
Total cost[A]: Studies for drugs with a written request: $8,900,000[D]; 
Disease or condition: Cancer; 
Funded agency or organization: Children's Oncology Group through the 
National Cancer Institute; 
Anticipated completion: 2009. 

Drug: Methylphenidate; 
Total cost[A]: Studies for drugs with a written request: $4,700,000[F]; 
Disease or condition: Attention deficit hyperactivity disorder; 
Funded agency or organization: National Institute of Environmental 
Health Sciences; 
Anticipated completion: 2007. 

Drug: Subtotal; 
Total cost[A]: Studies for drugs with a written request: $16,000,000; 
Disease or condition: [Empty]; 
Funded agency or organization: [Empty]; 
Anticipated completion: [Empty]. 

Drug: Total; 
Total cost[A]: Studies for drugs with a written request: $68,500,000; 
Disease or condition: [Empty]; 
Funded agency or organization: [Empty]; 
Anticipated completion: [Empty]. 

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. 

[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. 

[End of table] 

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. 

[End of section] 

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,[Footnote 41] 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).[Footnote 42] 

Figure 3: Status of Written Requests Issued under FDAMA and BPCA 
through December 2005: 

[See PDF for image] 

Source: GAO. 

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. 

[End of figure] 

Reasons for Decline in Written Requests Issued and Accepted under BPCA 
Compared to FDAMA: 

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. 

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 were labeled for pediatric use prior to the 
authorization of pediatric exclusivity under FDAMA and BPCA.[Footnote 
43] 

[End of section] 

Appendix VI: Complexity of Completed 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,[Footnote 44] 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: 

Count; 
Number of individual studies: 143; 
Number of study sites for all studies: 2,860; 
Number of participants in all studies: 25,397. 

Average; 
Number of individual studies: 2; 
Number of study sites for all studies: 68; 
Number of participants in all studies: 430. 

Median; 
Number of individual studies: 2; 
Number of study sites for all studies: 48; 
Number of participants in all studies: 255. 

Mode; 
Number of individual studies: 2; 
Number of study sites for all studies: 83; 
Number of participants in all studies: 192. 

Minimum; 
Number of individual studies: 1; 
Number of study sites for all studies: 3; 
Number of participants in all studies: 11. 

Maximum; 
Number of individual studies: 7; 
Number of study sites for all studies: 232; 
Number of participants in all studies: 2,517. 

Number of written requests data are based on; 
Number of individual studies: 59; 
Number of study sites for all studies: 42; 
Number of participants in all studies: 59. 

Source: GAO analysis of FDA data. 

[End of table] 

[End of section] 

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. 

Strengths of BPCA Identified by FDA and NIH Officials: 

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. 

* 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 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. 

Suggestions for Changes to BPCA: 

The Institute of Medicine convened a forum on pediatric research in 
June 2006 where forum participants made suggestions for how BPCA could 
be improved.[Footnote 45] 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 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. 

[End of section] 

Appendix VIII: Comments from the Department of Health and Human 
Services: 

Department Of Health & Human Services: 
Office of the Assistant Secretary for Legislation: 
Washington, D.C. 20201: 

Ms. Marcia Crosse: 
Director, Health Care: 
U.S. Government Accountability Office: 
Washington, DC 20548: 

Dear Ms. Crosse: 

Enclosed are the Department's comments on the U.S. Government 
Accountability Office's (GAO) draft report entitled, "Pediatric Drug 
Research: Studies Conducted Under Best Pharmaceuticals for Children 
Act" (GAO-07-557), before its publication. 

We appreciate the effort that went into the analysis of Best 
Pharmaceuticals for Children Act statistics and information provided by 
FDA to GAO. We are providing General and Technical Comments on the 
draft report on the primary substantive issues and factual corrections. 
Although we had a telephone conference call with members of the GAO 
team on March 7, 2007, to identify factual and technical errors in the 
Statement of Facts provided to FDA, many of the corrections we 
explained to GAO on March 7 are not reflected in the draft report. To 
ensure the data and analysis are not subject to misinterpretation, we 
identify the technical corrections that should be made to the draft 
report. 

Sincerely, 

Signed by: 

Vincent J. Ventimiglia: 
Assistant Secretary for Legislation: 

General Comments On The Department Of Health And Human Services On The 
Government Accountability Office Draft Report Entitled: "Pediatric Drug 
Research studies Conducted Under Best Pharmaceuticals For Children Act 
(GAO-07-557): 

The HHS Food and Drug Administration (FDA) and the National Institutes 
of Health (NIH) are responsible for implementation of the BPCA. FDA has 
the primary responsibility for the BPCA exclusivity process. Although 
there are no recommendations on BPCA contained in the draft report for 
HHS (FDA) comment, we are providing General Comments on several key 
substantive issues. 

While the GAO draft report has provided a significant amount of data 
and analysis and generally explains the BPCA process, the draft report 
contains several statements and characterizations, which may provide a 
misleading impression to Congress and other readers of the final 
report. We believe the general comments provided below are critical to 
understanding the public health benefits of BPCA and the full scope of 
the program as currently implemented. 

* Success of BPCA. The GAO draft report does not acknowledge that BPCA 
is a successful program. Although the draft report includes statistics 
on how many drugs have been studied in pediatric populations and how 
many drugs have been labeled, it fails to state that the pediatric 
studies were conducted and drugs were labeled as a result of the BPCA 
process. Approximately a quarter of the products studies resulted in 
either new safety or dosing labeling information or information 
suggesting that the product was ineffective at the dose and manner in 
which it was studied. In addition to the important use information now 
in labels, BPCA has improved the infrastructure for pediatric drug 
development by providing additional incentives for the study of on-
patent drugs, a process for the study of off-patent drugs, a vigorous 
and public safety review of all products granted pediatric exclusivity, 
and the public dissemination of information in pediatric studies 
conducted. As a result, BPCA has generated more clinical information 
for the pediatric population than any other legislative or regulatory 
effort to date. 

Although there have been no finished studies on certain products, such 
as those off-patent drugs or drugs for which the sponsor declined to 
conduct studies, which have gone through the NIH contracting process, 
these are often the most complex studies to conduct and we are 
confident that these efforts will show results in the next several 
years. 

* Label changes under BPCA. The GAO draft report confuses FDA's review 
process for pediatric supplements with timeframes described in the BPCA 
for labeling dispute resolution. As written, the draft report states 
that it often takes a long time to make labeling changes. However, the 
time as reported in the draft report includes the review of the 
scientific data, requests for additional information, and the sponsor's 
submission of additional information that support any labeling changes. 
FDA was not negotiating labeling changes for the entire time period as 
reported in the draft report. 

- Pediatric studies submitted as supplements to a new drug application 
by sponsors in response to written requests must be treated as 
"priority supplements." FDA's performance goals are to review priority 
supplements in 180 days. 

- This goal is not a BPCA mandate (although BPCA requires that 
pediatric supplements under BPCA receive a priority review). If FDA 
determines that the supplement is deficient and requests additional 
information from the sponsor, the first scientific review cycle is 
completed. A new cycle does not begin until the sponsor submits the 
requested information. A supplement cannot be approved and labeling 
negotiations generally do not begin until all of the required 
information from all of the review cycles is submitted and reviewed. 
The multiple review cycles increase the time between the initial 
submission and the ultimate approval of labeling change. 

- If pediatric studies are submitted as a new drug application and not 
a supplement, then it is not required to be reviewed as a priority. FDA 
has a performance goal to review new drug applications in 10 months. 

- If the application or supplement is otherwise ready for approval and 
the only outstanding issue is the need to reach agreement on labeling 
changes, the BPCA's dispute resolution process can be utilized. In that 
case, in not later than 180 days after submission of the application, 
the Commissioner would request that the sponsor make any labeling 
changes that the Commissioner deems appropriate. If the sponsor does 
not agree to them, the labeling issue should be referred to the 
Pediatric Advisory Committee. The Pediatric Advisory Committee is given 
90 days after receiving such a referral to review the pediatric study 
reports and make a recommendation regarding appropriate labeling 
changes. The Commissioner then has 30 days to review the Advisory 
Committee recommendations and, if appropriate, make a request that the 
sponsor make a labeling change. If the sponsor does not agree, the 
Commissioner may deem the drug to be misbranded. 

* Study of neonates under BPCA. The GAO draft report, in Appendix II, 
states that despite FDA and NIH efforts to increase inclusion of 
neonates, defined as children under 1 month of age, in written 
requests, few written requests under BPCA include neonates. BPCA 
requires the inclusion of neonates in pediatric studies as appropriate, 
but in some cases inclusion of neonates may not be appropriate for 
medical or ethical reasons. In addition, although no written requests 
have specifically required the inclusion of "neonates" as a specific 
group, 14 studies of 9 drugs required the inclusion of "newborns" (also 
defined as children under 1 month of age and which includes neonates) 
and 24 studies of 13 drugs required the inclusion of infants (defined 
as children under 4 months of age). 

* Pediatric exclusivity attaches to an existing patent or market 
exclusivity. The GAO draft report does not mention that pediatric 
exclusivity under BPCA attaches to an existing listed patent or any 
existing marketing exclusivities held by the drug sponsor. The 
exclusivity is not limited to extending market exclusivity, but also 
attaches to existing patents even if there is no market exclusivity 
left on the drug in question. Like marketing exclusivity, the existence 
of a listed patent affects the timing of generic drug application 
submission and approval. 

[End of section] 

Appendix IX: GAO Contact and Staff Acknowledgments: 

GAO Contact: 

Marcia Crosse, (202) 512-7119 or crossem@gao.gov: 

Acknowledgments: 

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. 

FOOTNOTES 

[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. 

[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. 

[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. 

[10] We 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). 

[11] FDA 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. 

[12] FDA 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. 

[13] Under 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. 

[14] Pediatric 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. 

[15] FNIH can certify that it has insufficient funds to fund the study 
of a drug and refer the funding to NIH. 

[16] As 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)). 

[17] The granting of pediatric exclusivity does not depend on finding 
that the drug is safe and effective for pediatric use. 

[18] Most 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. 

[19] BPCA 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. 

[20] The 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. 

[21] Some 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. 

[22] Of 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. 

[23] FDA had not completed its review of the study results to determine 
exclusivity prior to December 2005 for the remaining four drugs. 

[24] The other three drugs were denied pediatric exclusivity. The dates 
that drugs are granted exclusivity and also had labeling changes are 
available at [Hyperlink, 
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. 

[25] When 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. 

[26] In 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. 

[27] These 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. 

[28] There were no off-patent drugs for which the pediatric drug 
studies indicated that a formulation change was necessary. 

[29] These 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 [Hyperlink, 
http://www.fda.gov/cder/pediatric/labelchange.htm]. 

[30] National Center for Health Statistics, 2004 National Ambulatory 
Medical Care Survey Data File (Hyattsville, Md.: February 2004). 

[31] Medical Expenditure Panel Survey (Agency for Health Care Policy 
and Research, 2003 Medical Expenditure Panel Survey Household Data File 
(Rockville, Md.: November 2005)). 

[32] 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. 

[33] Pediatric pharmacology research units are primarily located in 
children's hospitals and academic research centers specializing in 
research with children. 

[34] 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. 

[35] 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). 

[36] 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). 

[37] 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. 

[38] 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. 

[39] The costs reported by NIH are estimates, which may change during 
the course of the studies. 

[40] 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. 

[41] 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). 

[42] 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. 

[43] Prior to FDAMA, over a 6-year period from 1991 to 1996, only 11 of 
71 requested studies were completed without such an incentive. 

[44] 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. 

[45] 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 [Hyperlink, 
http://www.iom.edu/CMS/3740/24155/34241.aspx]. 

GAO's Mission: 

The Government Accountability Office, the audit, evaluation and 
investigative arm of Congress, exists to support Congress in meeting 
its constitutional responsibilities and to help improve the performance 
and accountability of the federal government for the American people. 
GAO examines the use of public funds; evaluates federal programs and 
policies; and provides analyses, recommendations, and other assistance 
to help Congress make informed oversight, policy, and funding 
decisions. GAO's commitment to good government is reflected in its core 
values of accountability, integrity, and reliability. 

Obtaining Copies of GAO Reports and Testimony: 

The fastest and easiest way to obtain copies of GAO documents at no 
cost is through GAO's Web site (www.gao.gov). Each weekday, GAO posts 
newly released reports, testimony, and correspondence on its Web site. 
To have GAO e-mail you a list of newly posted products every afternoon, 
go to www.gao.gov and select "Subscribe to Updates." 

Order by Mail or Phone: 

The first copy of each printed report is free. Additional copies are $2 
each. A check or money order should be made out to the Superintendent 
of Documents. GAO also accepts VISA and Mastercard. Orders for 100 or 
more copies mailed to a single address are discounted 25 percent. 
Orders should be sent to: 

U.S. Government Accountability Office 441 G Street NW, Room LM 
Washington, D.C. 20548: 

To order by Phone: Voice: (202) 512-6000 TDD: (202) 512-2537 Fax: (202) 
512-6061: 

To Report Fraud, Waste, and Abuse in Federal Programs: 

Contact: 

Web site: www.gao.gov/fraudnet/fraudnet.htm E-mail: fraudnet@gao.gov 
Automated answering system: (800) 424-5454 or (202) 512-7470: 

Congressional Relations: 

Gloria Jarmon, Managing Director, JarmonG@gao.gov (202) 512-4400 U.S. 
Government Accountability Office, 441 G Street NW, Room 7125 
Washington, D.C. 20548: 

Public Affairs: 

Paul Anderson, Managing Director, AndersonP1@gao.gov (202) 512-4800 
U.S. Government Accountability Office, 441 G Street NW, Room 7149 
Washington, D.C. 20548: