Pediatric Drug Research: Studies Conducted under Best		 
Pharmaceuticals for Children Act (22-MAR-07, GAO-07-557).	 
                                                                 
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.	 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-07-557 					        
    ACCNO:   A67124						        
  TITLE:     Pediatric Drug Research: Studies Conducted under Best    
Pharmaceuticals for Children Act				 
     DATE:   03/22/2007 
  SUBJECT:   Children						 
	     Diseases						 
	     Drug testing					 
	     Drug treatment					 
	     Drugs						 
	     Food and drug law					 
	     Labeling law					 
	     Patents						 
	     Pediatrics 					 
	     Pharmacological research				 
	     Policy evaluation					 
	     Research programs					 

******************************************************************
** This file contains an ASCII representation of the text of a  **
** GAO Product.                                                 **
**                                                              **
** No attempt has been made to display graphic images, although **
** figure captions are reproduced.  Tables are included, but    **
** may not resemble those in the printed version.               **
**                                                              **
** Please see the PDF (Portable Document Format) file, when     **
** available, for a complete electronic file of the printed     **
** document's contents.                                         **
**                                                              **
******************************************************************
GAO-07-557

   

     * [1]Results in Brief
     * [2]Background

          * [3]BPCA Process
          * [4]BPCA Provisions for Pediatric Drug Studies Declined by Drug
          * [5]Making Labeling Changes under BPCA for On-Patent Drugs

     * [6]Drug Sponsors Agreed to Study the Majority of On-Patent Drug

          * [7]Drug Sponsors Agreed to Conduct Pediatric Drug Studies for M
          * [8]FNIH Had Not Funded the Study of Any On-Patent Drugs in Chil

     * [9]Most Drugs Granted Pediatric Exclusivity under BPCA Had Labe

          * [10]Most Drugs Granted Pediatric Exclusivity Had Labeling Change
          * [11]Labeling Changes for Drugs Studied under BPCA Had Important
          * [12]The Process for Reviewing Study Results and Approving Labeli

     * [13]Drugs Studied under BPCA Address a Wide Range of Diseases, I
     * [14]Agency Comments and Our Evaluation
     * [15]Appendix I: Scope and Methodology
     * [16]Appendix II: FDA and NIH Efforts to Encourage the Study of D

          * [17]NIH Workshops

               * [18]NIH Initiatives
               * [19]Pediatric Drug Studies Requiring the Study of Neonates

     * [20]Appendix III: NIH Efforts to Support Pediatric Drug Studies

          * [21]NIH Funding

               * [22]Pediatric Pharmacology Research Units
               * [23]Meetings and Forums

     * [24]Appendix IV: Studies of Off-Patent Drugs under BPCA

          * [25]Written Requests for Studies of Off-Patent Drugs under BPCA

               * [26]Funding for Studies of Off-Patent Drugs under BPCA

     * [27]Appendix V: Status of Pediatric Drug Studies Requested by FD

          * [28]Written Requests Issued under BPCA Compared to FDAMA

               * [29]Reasons for Decline in Written Requests Issued and
                 Accepted

     * [30]Appendix VI: Complexity of Completed Pediatric Drug Studies
     * [31]Appendix VII: Strengths of and Suggested Changes for BPCA

          * [32]Strengths of BPCA Identified by FDA and NIH Officials

               * [33]Suggestions for Changes to BPCA

     * [34]Appendix VIII: Comments from the Department of Health and Hu
     * [35]Appendix IX: GAO Contact and Staff Acknowledgments

          * [36]GAO Contact
          * [37]Acknowledgments

               * [38]Order by Mail or Phone

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

Contents

Letter 1

Results in Brief 4
Background 5
Drug Sponsors Agreed to Study the Majority of On-Patent Drugs with Written
Requests under BPCA, but No Studies Were Conducted When Drug Sponsors
Declined the Written Requests 12
Most Drugs Granted Pediatric Exclusivity under BPCA Had Labeling Changes,
but the Process for Making Changes Was Sometimes Lengthy 16
Drugs Studied under BPCA Address a Wide Range of Diseases, Including Some
That Are Common, Serious, or Life Threatening to Children 21
Agency Comments and Our Evaluation 23
Appendix I Scope and Methodology 26
Appendix II FDA and NIH Efforts to Encourage the Study of Drugs in
Neonates since Passage of BPCA 28
Appendix III NIH Efforts to Support Pediatric Drug Studies 30
Appendix IV Studies of Off-Patent Drugs under BPCA 33
Appendix V Status of Pediatric Drug Studies Requested by FDA 37
Appendix VI Complexity of Completed Pediatric Drug Studies 41
Appendix VII Strengths of and Suggested Changes for BPCA 42
Appendix VIII Comments from the Department of Health and Human Services 45
Appendix IX GAO Contact and Staff Acknowledgments 48

Tables

Table 1: Estimated Costs of Funding the Study of On-Patent Drugs Referred
to FNIH under BPCA 16
Table 2: Examples of Labeling Changes 18
Table 3: Examples of Drugs Approved for Use by Younger Children or for
Which New Formulations Are Available 19
Table 4: Examples of Diseases to Be Treated by Drugs Studied under BPCA 22
Table 5: NIH-Sponsored Activities, through 2005, Related to Children in
Clinical Trials 31
Table 6: Anticipated NIH Spending for Off-Patent Drug Studies Committed to
through 2005 35
Table 7: Complexity of Pediatric Drug Studies Conducted under BPCA,
According to Study Reports from July 2002 through December 2005 41

Figures

Figure 1: BPCA Process 8
Figure 2: Status of Written Requests Issued under BPCA for the Study of
On-Patent Drugs, from January 2002 through December 2005 14
Figure 3: Status of Written Requests Issued under FDAMA and BPCA through
December 2005 38

Abbreviations

BPCA Best Pharmaceuticals for Children Act
FDA Food and Drug Administration
FDAMA Food and Drug Administration Modernization Act of 1997
FNIH Foundation for the National Institutes of Health
HHS Department of Health and Human Services
HIV Human Immunodeficiency Virus
NDDI Newborn Drug Development Initiative
NIH National Institutes of Health

This is a work of the U.S. government and is not subject to copyright
protection in the United States. It may be reproduced and distributed in
its entirety without further permission from GAO. However, because this
work may contain copyrighted images or other material, permission from the
copyright holder may be necessary if you wish to reproduce this material
separately.

United States Government Accountability Office

Washington, DC 20548

March 22, 2007

The Honorable Edward M. Kennedy
Chairman
The Honorable Michael B. Enzi
Ranking Minority Member
Committee on Health, Education, Labor, and Pensions
United States Senate

The Honorable John D. Dingell
Chairman
The Honorable Joe L. Barton
Ranking Minority Member
Committee on Energy and Commerce
House of Representatives

Although children suffer from many of the same diseases as adults and are
often treated with the same drugs, only about one-third of the drugs that
are prescribed for children have been studied and labeled for pediatric
use.^1 This has placed children taking drugs for which there have not been
adequate pediatric drug studies at risk of being exposed to ineffective
treatment or receiving incorrect dosing. In order to encourage the study
of more drugs for pediatric use, Congress passed the Best Pharmaceuticals
for Children Act (BPCA)^2 in 2002 to provide marketing incentives to drug
sponsors for conducting pediatric drug studies.^3 Drug sponsors (typically
drug manufacturers) may obtain 6 months of additional market exclusivity
for drugs on which they have conducted pediatric studies in accordance
with pertinent law and regulations.^4 This market exclusivity is known as
pediatric exclusivity. When a drug has market exclusivity, it is protected
from competition for a limited period, for example by prohibition on Food
and Drug Administration (FDA)^5 approval of a generic copy for
marketing.^6 Generally, pediatric exclusivity can only be granted to those
drugs that are on-patent--that is, those that still have market
exclusivity^7--and for which FDA has issued a written request for
pediatric drug studies.^8 Once a drug's patent or market exclusivity has
expired, however, FDA can still request pediatric drug studies for
off-patent drugs. BPCA also included provisions designed to provide for
the study of both on-patent and off-patent drugs that drug sponsors have
declined to study.

^1The 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. S
321(k), (m).

^2Provisions regarding pediatric studies of drug are generally codified at
21 U.S.C. S 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. S
355a(n).

^3BPCA 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.

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.

^4The 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).

^5FDA is an agency within the Department of Health and Human Services.

^6Drug 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. SS 355(j)(5)(F)(ii), (iii); 21
C.F.R. S 314.108 (2006). Pediatric exclusivity under BPCA attaches to an
existing listed patent or any existing market exclusivity held by the drug
sponsor.

^7For 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.

^8FDA 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.

BPCA provides for pediatric drug studies even if the drug sponsor declined
the written request. First, if a drug sponsor declines a written request
by FDA to study an on-patent drug, BPCA provides for FDA to refer the drug
to the Foundation for the National Institutes of Health (FNIH), which can
fund the study if funds are available.^9 When a sponsor declines a written
request for an on-patent drug, the sponsor cannot receive pediatric
exclusivity in response to that written request. Second, BPCA provides for
the funding of the study of off-patent drugs by the Department of Health
and Human Services' (HHS) National Institutes of Health (NIH).

BPCA required that we assess, among other things, the effect of provisions
regarding pediatric drug studies on the study and proper labeling of drugs
for pediatric use. As discussed with the committees of jurisdiction, we
(1) assessed the extent to which pediatric drug studies were being
conducted under BPCA for on-patent drugs, including when drug sponsors
declined to conduct the studies; (2) evaluated the impact of BPCA on
labeling of drugs for pediatric use and the process by which the labeling
was changed; and (3) illustrated the range of diseases treated by the
drugs studied under BPCA.

To assess the extent to which pediatric drug studies were being conducted
under BPCA for on-patent drugs, including when drug sponsors declined to
do the studies, we examined data about the drugs for which FDA issued
written requests from January 2002 through December 2005. Our work focused
on actions regarding these drugs prior to 2006. Specifically, we examined
data on the numbers of written requests, drugs studied, written requests
that were declined, and drugs granted pediatric exclusivity during this
4-year period. We reviewed data from FNIH on the funding status of
on-patent drugs that drug sponsors declined to study. To evaluate the
impact of BPCA on the labeling of drugs for pediatric use and the process
by which labeling was changed, we reviewed summaries of the labeling
changes for drugs studied from the enactment of BPCA through 2005. We
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.)

^9FNIH 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.

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.^10 As a result, there was a lack of
information on optimal dosage, possible side effects, and the
effectiveness of drugs for pediatric use. For example, while physicians
typically had determined drug dosing for children based on their weight,
pediatric drug studies conducted under FDAMA showed that in many cases
this was not the best approach. To continue to encourage pediatric drug
studies,^11 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.

^10We previously described how FDAMA was responsible for an increase in
pediatric drug studies. GAO, Pediatric Drug Research: Substantial Increase
in Studies of Drugs for Children, But Some Challenges Remain,
[39]GAO-01-705T (Washington, D.C.: May 8, 2001).

^11FDA generally defines the pediatric population covered under BPCA as
children from birth to 16 years old, though studies have included children
as old as 18. BPCA provides that neonates be included in pediatric drug
studies, as appropriate. See app. II for information about federal efforts
to encourage the study of drugs in neonates.

BPCA Process

The process for initiating pediatric studies under BPCA formally begins
when FDA issues a written request to a drug sponsor to conduct pediatric
drug studies for a particular drug. FDA may issue a written request after
it has reviewed a proposed pediatric study request from a drug sponsor, in
which the drug sponsor describes the pediatric drug study or studies it
proposes doing in return for pediatric exclusivity. In deciding whether to
approve the proposed pediatric study request and issue a written request,
FDA must determine if the proposed studies will produce information that
may result in health benefits for children.^12 Alternatively, FDA may
determine on its own that there is a need for more research on a drug for
pediatric use and issue a written request without having received a
proposed pediatric study request from the drug sponsor. A written request
outlines, among other things, the nature of the pediatric drug studies
that the drug sponsor must conduct in order to qualify for pediatric
exclusivity and a time frame by which those studies should be completed.
When a drug sponsor accepts the written request and completes the
pediatric drug studies, it submits reports to FDA describing the studies
and the study results. BPCA specifies that FDA generally has 90 days to
review the study
reports to determine whether the pediatric drug studies met the conditions
outlined in the written request.^13 If FDA determines that the pediatric
drug studies conducted by the drug sponsor were responsive to the written
request, it will grant a drug pediatric exclusivity regardless of the
study findings.^14 Figure 1 illustrates the process under BPCA.

^12FDA officials report that 51 of 134 proposed pediatric study requests
submitted by drug sponsors from 2002 to 2005 did not result in written
requests. Drug sponsors sometimes later submitted revised proposed
pediatric study requests, which resulted in written requests.

^13Under certain circumstances, FDA could have only 60 days to review the
study report to determine pediatric exclusivity. However, FDA officials
told us that under BPCA, this has never happened. Otherwise, FDA has 90
days to determine if the studies fairly respond to the written request,
were conducted in accordance with commonly accepted scientific principles
and protocols, and were properly submitted.

^14Pediatric exclusivity applies to all approved uses of the drug, not
just those studied in children. Therefore, if the studies find that the
drug is not safe for use by children, the drug will still receive
pediatric exclusivity and therefore extended market exclusivity for the
adult uses of the drug.

Figure 1: BPCA Process

aIf 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.

bFDA 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.

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.^15 In recent years, appropriations of $500,000 were
authorized to FNIH annually.^16

To further the study of off-patent drugs, NIH--in consultation with FDA
and other experts--develops a list of drugs, including off-patent drugs,
which the agency believes are in need of study in children. NIH lists
these drugs annually in the Federal Register. FDA may issue written
requests for those drugs on the list that it determines to be most in need
of study. If the 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.)

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

^16As of fiscal year 2007, NIH is required to transfer from its
appropriations at least $500,000 but no more than $1.25 million to FNIH
annually. This requirement was established with the enactment of the NIH
Reform Act of 2006 (Pub. L. No. 109-482, 120 Stat. 3675 (2007)).

Making Labeling Changes under BPCA for On-Patent Drugs

Pediatric drug studies often reveal new information about the safety or
effectiveness of a drug, which could indicate the need for a change to its
labeling. Generally, the labeling includes important information for
health care providers, including proper uses of the drug, proper dosing,
and possible adverse effects that could result from taking the drug. FDA
may determine that the drug is not approved for use by children, which
would be reflected in any labeling changes.^17

According to FDA officials, in order to be considered for pediatric
exclusivity, a drug sponsor typically submits results from pediatric drug
studies in the form of a "supplemental new drug application."^18 BPCA
specifies that study results, when submitted as part of a supplemental new
drug application, are subject to FDA's performance goals for a scientific
review, which in this case is 180 days.^19 FDA's processes for reviewing
study results submitted under BPCA for consideration of labeling changes
are not unique to BPCA. These are the same processes the agency would use
to review any drug study results in consideration of labeling changes.
FDA's action on the application can include approving the application,
determining that the application is approvable (pending the submission of
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.

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

^18Most drugs studied under BPCA have previously been approved for
marketing in the United States, so a supplement to the original "new drug
application" is submitted. If the drug studied under BPCA was not
previously approved for marketing in the United States, the application
would be submitted as a new drug application. FDA has a performance goal
to review non-priority new drug applications in 10 months.

^19BPCA requires that supplemental new drug applications submitted by drug
sponsors be treated as "priority supplements." FDA's goal is to take
action on priority supplements within 180 days.

With a determination that the application is approvable, FDA communicates
to the drug sponsor that some issues need to be resolved before the
application can be approved and describes what additional work is
necessary to resolve the issues. This might require that drug sponsors
conduct additional analyses. However, this communication would complete
the scientific review cycle. When a drug sponsor resubmits the application
with the additional analyses, a new scientific review cycle begins. As a
result, multiple scientific review cycles might be necessary, increasing
the time between initial submission of the application, which includes the
pediatric study reports, and approval of a labeling change.

If, during FDA's review of the study report submitted as part of the
application, the agency determines that the application is approvable and
the only unresolved issue is labeling, FDA and the drug sponsor must
attempt to reach agreement on labeling changes within 180 days after the
application is submitted to FDA. If FDA and the drug sponsor cannot reach
agreement, FDA must refer the matter to its Pediatric Advisory
Committee,^20 which would convene and provide recommendations to the
Commissioner on the appropriate changes to the drug's labeling. The
Commissioner would then consider the committee's recommendations in making
the final determination on the proper labeling.

^20The Pediatric Advisory Committee is also responsible for reviewing
reports of adverse effects related to drugs granted pediatric exclusivity
after the period of exclusivity begins, among other things. The committee
consists of 13 voting members, appointed by the Commissioner of FDA, who
are knowledgeable in pediatric research, pediatric subspecialties,
statistics, and biomedical ethics. The committee includes one
representative from a pediatric health organization and one from a
relevant patient or patient-family organization.

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.^21 The
remaining 41 written requests were declined.^22 (See app. IV for details
about the study of off-patent drugs under BPCA and app. V for a detailed
description of the status of all written requests issued by FDA.) Drug
sponsors completed pediatric drug studies for 59 of the 173 accepted
written requests--studies for the remaining 114 written requests were
ongoing--and FDA made a pediatric exclusivity determination for 55 of
those through December 2005.^23 Of those 55 written requests, 52 (95
percent) resulted in FDA granting pediatric exclusivity.^24 Figure 2 shows
the status of written requests issued under BPCA for the study of
on-patent drugs, from January 2002 through December 2005. (See app. VI for
a description of the complexity of pediatric drug studies conducted under
BPCA.)

^21Some drugs have two written requests for a variety of reasons. In some
cases, FDA may have requested that the drug sponsor study the effects of
the drug on different diseases. In other cases, there could be two written
requests for the same drug, issued to different drug sponsors for
different dosage forms of the drug. In addition, FDA told us that the
specified period for studies to be completed elapsed for some written
requests before the completion of studies, and the agency issued new
written requests. In all of these situations, we counted each of these
written requests separately. Therefore, there are more written requests
than there are unique drugs with written requests.

^22Of the 214 written requests issued by FDA, 68 were written requests
first issued under BPCA. The remaining 146 written requests were
originally issued under FDAMA and reissued under BPCA because drug
sponsors had not responded to the written requests or completed the
requested pediatric drug studies at the time that BPCA went into effect.

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

^24The other three drugs were denied pediatric exclusivity. The dates that
drugs are granted exclusivity and also had labeling changes are available
at http://www.fda.gov/cder/pediatric/labelchange.htm . The dates of
exclusivity for other drugs are not available on FDA's Web site. Most of
these pediatric drug studies began under FDAMA but were continued under
BPCA. Most of the pediatric drug studies begun in response to written
requests initially issued under BPCA have not yet been completed.

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

Note: Written requests issued from January 2002 through December 2005
include new written requests issued under BPCA combined with written
requests originally issued under FDAMA but reissued under BPCA.

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.^25 FNIH had not funded the study of any of these
drugs.^26 NIH has estimated that the cost of studying the drugs that were
referred to FNIH for study would exceed $43 million (see table 1). FNIH
has been raising funds for the study of drugs referred under BCPA at a
rate of approximately $1 million per year.

^25When a drug sponsor of an on-patent drug declines a written request,
the agency must determine if there is a continuing need for information
relating to the use of the drug in children. Reasons that FDA has
concluded that there is not a continuing need include the drug was not yet
approved, some part of the study was being performed by the drug sponsor
or another party, the drug's patent ended, the risk-benefit assessment
shifted, safe alternative therapies were already on the market even though
the agency had issued the written request in hope of obtaining additional
valuable information, another drug may have been approved or may soon be
approved with a better safety record, or there is minimal use of the drug
by children.

^26In April 2006, FNIH agreed to allocate all $4.13 million it had raised
for pediatric drug studies under BPCA to fund half the cost to study one
on-patent drug--baclofen. Baclofen was identified by NIH and FNIH as the
highest priority on-patent drug that a drug sponsor had declined to study.
NIH is responsible for developing requests for proposals for the study of
on-patent drugs for pediatric use. The requests for proposals outline the
need for studies of specific drugs and include the specific details of the
studies to be conducted. NIH requested proposals for the study of baclofen
and has selected a contractor to perform the studies. NIH expects the cost
of the study of baclofen to be about $7.8 million over 3 years, and NIH
agreed to cover the costs of the study that exceed the contribution from
FNIH. Because FNIH has committed all of its BPCA funds to the study of
baclofen, there are no resources left for FNIH to fund the study of any
other drugs.

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

On-patent drug Disease or condition to be studied           Estimated cost 
Baclofen       Spasticity in children with cerebral           $7.8 million 
                  palsy                                                       
Bupropion      Depression                                     $7.4 million 
Dexrazoxane    Used to block the cardiac effects of the     Not provided^a 
                  anticancer drug adriamycin                                  
Eletriptan     Migraine headaches                           Not provided^a 
Hydroxyurea^b  Sickle cell disease                       $8 million to $10 
                                                                    million^c 
Metoclopramide Gastroesophageal reflux disease              Not provided^a 
Morphine       Analgesia                                      $8.7 million 
Sevelamer      Renal failure                                  $2.7 million 
Zonisamide     Refractory partial seizures                    $8.4 million 
Total                                                   $43 million to $45 
                                                                    million^d 

Source: NIH.

aCost estimates have not been provided by NIH.

bHydroxyurea 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.

cA formal cost estimate has not been made by NIH, but an initial estimate
ranged from $8 million to $10 million.

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

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.^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.

^27These drugs had labeling changes made after the drug sponsors submitted
partial results of their studies to FDA. Because some studies were
ongoing, the drug sponsors had not submitted the final study results to
FDA for consideration of pediatric exclusivity.

Table 2: Examples of Labeling Changes

Potential                                         Summary of new
risks or                      Disease or          information contained
hazards       Drug name       condition treated   in drug labeling
Unnecessary   Sumatriptan     Migraines           Five studies did not
exposure to                                       establish safety and
ineffective                                       effectiveness, and
therapies                                         postmarketing
                                                     experience showed
                                                     children were having
                                                     serious adverse
                                                     effects, such as stroke
                                                     and vision loss. The
                                                     product is not
                                                     recommended for
                                                     children under 18 years
                                                     old.        
                 Tolterodine     Overactive bladder  The drug was not shown
                                 and urge            to be effective for
                                 incontinence        children and appeared
                                                     to show a possible
                                                     increase in aggressive,
                                                     hyperactive, and
                                                     abnormal behavior.
                 Irinotecan      Tumors              Children had more rapid
                                                     disease progression and
                                                     died more quickly. The
                                                     labeling states that
                                                     the drug should not be
                                                     used to treat children
                                                     with a particular kind
                                                     of tumor.   
Ineffective   Oxcarbazepine   Partial seizures    Dose for children aged
dosing                                            2 to 4 and weighing
                                                     less than 44 pounds is
                                                     twice the dose per body
                                                     weight compared to
                                                     adults.     
                 Methylphenidate Attention-deficit   Children aged 13 to 17
                                 hyperactivity       eliminated the drug
                                 disorder            from their bodies
                                                     faster than the
                                                     comparison age group.
                                                     Therefore the dosing
                                                     regimen may be
                                                     increased to prevent
                                                     ineffective dosing.
Overdosing    Leflunomide     Juvenile rheumatoid Children weighing less
                                 arthritis           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.
Previously    Venlafaxine     Depression;         This drug is associated
unlabeled                     generalized anxiety with an increased risk
side effects,                 disorder            of suicidal thinking
including                                         and behavior.
effect on     Ciprofloxacin   Complicated urinary tract       This drug is
growth and                    infection or kidney infection   associated  
development                                                   with        
                                                                 increased   
                                                                 adverse     
                                                                 effects to  
                                                                 joints or   
                                                                 surrounding 
                                                                 tissues for 
                                                                 children.   
                 Fentanyl        Chronic pain        This drug should be
                                                     used only by children
                                                     who are 2 years of age
                                                     or older and are
                                                     opioid-tolerant. Use by
                                                     others can lead to
                                                     life-threatening
                                                     respiratory depression
                                                     and death.  
                 Budesonide      Asthma              Budesonide can cause
                                                     growth suppression.

Source: GAO analysis of FDA data.

Other drugs have had labeling changes indicating that the drug may be used
safely and effectively by children in certain dosages or forms. Typically,
this resulted in the drug labeling being changed to indicate that the drug
was approved for use by children younger than those for whom it had
previously been approved. In other cases, the changes reflected a new
formulation of a drug, such as a syrup that was developed for pediatric
use, or new directions for preparing the drug for pediatric use were
identified during the pediatric drug studies conducted under BPCA.^28 (See
table 3 for examples of drugs with this new type of information.)

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

                                  Disease or                                  
Uses and                       condition treated  Summary of new           
formulations     Drug          or prevented       information              
New age groups   Moxifloxacin  Bacterial          Found to be safe and     
                    Ophthalmic    conjunctivitis     effective for children   
                                                     over 1 year old.         
                    Ondansetron   Nausea and         Established dosing for   
                                  vomiting after     surgical patients down   
                                  chemotherapy       to 1 month from 2 years  
                                                     of age; established      
                                                     dosing for cancer        
                                                     patients down to 6       
                                                     months from 4 years of   
                                                     age.                     
New formulations Benazepril    Hypertension       Labeled with directions  
or preparations                                   for how to prepare a     
                                                     suspension for           
                                                     administering the drug   
                                                     to children.             
                    Desloratadine Seasonal and       Newly available in a     
                                  perennial allergic syrup, labeled           
                                  rhinitis and hives specifically for         
                                                     children.                

Source: GAO analysis.

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

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.^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.

^29These data are based on the dates on which FDA approved the labeling
changes. FDA officials said that manufacturers might not immediately make
approved labeling changes on the printed material associated with a
marketed product. However, this information is posted on FDA's Web site,
generally within 48 hours. Sponsors often update labeling on a quarterly
basis or several times a year, rather than each time a labeling change is
approved. FDA does not track the actual date that revised labeling enters
the market. The dates that FDA agreed to these labeling changes are
reported at http://www.fda.gov/cder/pediatric/labelchange.htm .

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.^30 A survey of families and their medical providers in 2003 found
that 5 of the 10 drugs most frequently prescribed for children were
studied under BPCA.^31 In addition, several of the drugs studied under
BPCA were for the treatment of diseases that are serious or life
threatening to children, such as hypertension, cancer, HIV, and influenza.
Table 4 provides information on some of the drugs studied for pediatric
use and what is known about the diseases that are relevant to children.

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

Specific disease treated                                                   
by drug                  Information about the disease                     
Allergies                Allergies affect up to 40 percent of, or about 29 
                            million, children in the United States.           
Asthma                   Asthma affects 6.2 million or 9 percent of        
                            children in the United States. Further, asthma is 
                            the most common chronic illness among children.   
Cancer                   Cancer is the leading cause of death by disease   
                            for children aged 1 to 14 in the United States.   
HIV                      About 20 percent of HIV-infected children         
                            worldwide develop serious disease before they     
                            turn 1, and most of those die before age 4.       
                            Through the end of 2002, 9,300 children under age 
                            13 in the United States were living with HIV.     
Hypertension             An estimated 3.25 million (4.5 percent ) children 
                            in the United States have high blood pressure.    
                            Untreated, high blood pressure can lead to damage 
                            to the heart, brain, kidneys, and eyes.           
Influenza                Population-based studies show that 15 to 42       
                            percent of preschool and school-aged children     
                            contract the flu. Influenza can have serious      
                            complications for children, including pneumonia   
                            and dehydration, and can lead to death. In the    
                            2003-2004 flu season, more United States children 
                            died from the flu than chicken pox, whooping      
                            cough, and measles combined, and nearly           
                            two-thirds were under the age of 5.               

Source: GAO analysis.

Note: Based on data published from 2000 through 2006.

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

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

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 [email protected] . Contact
points for our Offices of Congressional Relations and Public Affairs may
be found on the last page of this report. GAO staff who made major
contributions to this report are listed in appendix IX.

Marcia Crosse Director, Health Care

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.

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.

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.^1 For example, in 2005, 24 of these
institutes, centers, and offices funded research on children. One
institute, the National Institute of Child Health and Human Development,
was responsible for about 26 percent of funding for pediatric
research--the largest proportion of NIH's research funding for children.
This institute organizes study design teams with FDA and other relevant
NIH institutes, conducts contracting activities, and modifies drug
labeling for specific ages and diseases.

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.^2
NIH provides about $500,000 annually to each of these research units to
provide the infrastructure for independent investigators to initiate and
collaborate on studies and clinical trials with private industry and NIH.
The number of such research units grew from 7 in 1994 to 13 in 1999 to
support the infrastructure for collaborative efforts of pharmacologists to
conduct clinical trials that include children. While the number has not
changed since the passage of BPCA in 2002, NIH officials said that staff
from these units often move on to hospitals throughout the country and
enhance the pediatric research capacity nationwide. In addition, they said
that an overall increase in pediatric research capacity nationwide in
recent years has made it possible to conduct pediatric clinical trials at
a number of other sites. They said that, on average, these pediatric
pharmacology 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.

^1NIH 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.

^2Pediatric pharmacology research units are primarily located in
children's hospitals and academic research centers specializing in
research with children.

Meetings and Forums

NIH has sponsored a number of forums designed to increase the number of
children included in drug studies. As shown in table 5, these forums
generated advice and suggestions for NIH concerning drug testing from
health experts, process improvements on drug studies and medication use
with the pediatric community, and explanations of models and data related
to research for children.

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

Year(s)           Activity focus                                           
2002, 2003, 2004, Pediatric experts offered advice to NIH concerning drugs 
2005              that should be studied for use by children, leading to   
                     the published list of off-patent drugs in the Federal    
                     Register.                                                
2003              Discussed ways to improve access to information on the   
                     frequency of medication use by children and improve the  
                     list development process surrounding the measurement of  
                     this frequency.                                          
2003              Discussed ways to use current knowledge to better inform 
                     future studies of drugs in children.                     
2003              Discussed the use of two drugs, dobutamine and dopamine, 
                     in neonates.                                             
2003              Discussed parent attitudes toward studies of neonates    
                     and other issues related to the consent for studies in   
                     children.                                                
2004              Explored diverse models useful in understanding efficacy 
                     and toxicity of drugs across the course of development.  
2005              Discussed the development of treatment strategies and    
                     recommendations for drugs to be studied in managing      
                     pediatric hypertension.                                  
2005              Reviewed and analyzed databases used to describe the     
                     frequency of health conditions leading families to seek  
                     care for their children in different outpatient health   
                     care delivery settings, such as pediatric clinics and    
                     offices, and inpatient hospital settings. Those          
                     conditions leading to death were also part of the        
                     review.                                                  
2005              Reviewed and analyzed databases available to describe    
                     the frequency of use of medications by children in       
                     outpatient delivery settings.                            
2005              Discussed challenges from lack of appropriate pediatric  
                     formulations and improvements of pediatric therapeutics. 

Source: NIH.

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.

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.^1
FDA can then issue a written request for pediatric studies of the
off-patent drugs on the list. If the written request is declined by the
drug sponsor, NIH can fund the studies.

Few off-patent drugs identified by NIH as in need of study for pediatric
use have been studied. From 2003 through 2006, NIH has listed off-patent
drugs that were recommended for study by experts in pediatric research and
clinical practice.^2 By 2005, NIH had identified 40 off-patent drugs that
it believed should be studied for pediatric use.^3 Through 2005, FDA
issued written requests for 16 of these drugs.^4 All but one of these
written requests were declined by drug sponsors. NIH funded pediatric drug
studies for 7 of the remaining 15 written requests declined by drug
sponsors through December 2005.

^1The 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.

^2See 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).

^3Some 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).

^4Two 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.

NIH provided several reasons why it has not pursued the study of some
off-patent drugs that drug sponsors declined to study. Concerns about the
incidence of the diseases that the drugs were developed to treat, the
feasibility of study design, drug safety, and changes in the drugs' patent
status have caused the agency to reconsider the merit of studying some of
the drugs it identified as important for study in children.^5 For example,
in one case NIH issued a request for proposals to study a drug but
received no response. In other cases, NIH is awaiting consultation with
pediatric experts to determine the potential for study.

Further, NIH has not received appropriations specifically for funding
pediatric drug studies under BPCA. Rather, according to agency officials,
NIH uses lump sum appropriations made to various institutes to fund
pediatric drug studies under BPCA. In fiscal year 2005, NIH spent
approximately $25 million for these pediatric drug studies.

Funding for Studies of 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.^6 These pediatric drug studies
were designed to take from 3 to 4 years and will be completed in 2007 at
the earliest. Where possible, NIH identifies another government agency or
institute within NIH that might be able to meet the requirements of the
written requests and conduct the pediatric drug studies. In cases where a
government agency will conduct the pediatric drug studies, NIH institutes
enter into intra- or interagency agreements for the studies. If those
efforts fail, the agency develops and publishes requests for proposals for
others to conduct the pediatric studies. NIH anticipates spending
approximately $16.0 million for the funding of pediatric drug studies of
four additional off-patent drugs for which FDA did not issue written
requests--and therefore are not covered by the requirements of BPCA--but
three of these drugs have since been listed by NIH in the Federal Register
as needing study in children.^7 (See table 6.)

^5Since its inception, no drug has been removed from the list published in
the Federal Register, regardless of the feasibility or likelihood of being
studied.

^6The costs reported by NIH are estimates, which may change during the
course of the studies.

^7NIH 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.

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

                                                     Funded agency             
                                       Disease or    or            Anticipated 
Drug                  Total cost^a  condition     organization   completion 
Studies for drugs                                               
with a written                                                  
request                                                         
Dactinomycin^b        $1,800,000^c  Cancer        Children's           2007 
                                                     Oncology                  
                                                     Group through             
                                                     the National              
                                                     Cancer                    
                                                     Institute                 
Hydroxyurea           $7,000,000^c  Sickle cell   National             2008 
                                                     Heart Lung                
                                                     and Blood                 
                                                     Institute                 
Lithium              $17,400,000^c  Mania in      Case Western         2008 
                                       bipolar       University                
                                       disorder                                
Lorazepam (two       $15,100,000^d  Status        National             2008 
diseases/conditions)                epilepticus   Institutes of             
                                       (seizures)    Health                    
                                       Sedation      National             2008 
                                                     Institutes of             
                                                     Health                    
Sodium nitroprusside  $9,400,000^c  Control of    Stanford             2007 
                                       blood         University                
                                       pressure      and Duke                  
                                                     University                
Vincristine^b         $1,800,000^c  Malignancies  Children's           2007 
                                                     Oncology                  
                                                     Group through             
                                                     the National              
                                                     Cancer                    
                                                     Institute                 
Subtotal               $52,500,000                                          
Studies initiated                                               
prior to a written                                              
request^e                                                       
Daunomycin            $1,400,000^c  Cancer        Children's           2008 
(Daunorubicin)                                    Oncology                  
                                                     Group through             
                                                     the National              
                                                     Cancer                    
                                                     Institute                 
Ketamine              $1,000,000^d  Sedation      FDA's                2008 
                                                     National                  
                                                     Center for                
                                                     Toxicological             
                                                     Research                  
Methotrexate          $8,900,000^d  Cancer        Children's           2009 
                                                     Oncology                  
                                                     Group through             
                                                     the National              
                                                     Cancer                    
                                                     Institute                 
Methylphenidate       $4,700,000^f  Attention     National             2007 
                                       deficit       Institute of              
                                       hyperactivity Environmental             
                                       disorder      Health                    
                                                     Sciences                  
Subtotal               $16,000,000                                          
Total                  $68,500,000                                          

Source: GAO analysis of NIH data.

aTotal costs proposed for most studies are estimates and may vary over
time because of modifications of initial projects, rounded to the nearest
$100,000.

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

cStudies to be completed over 3 years.

dStudies to be completed over 4 years.

eNo 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.

fStudies to be completed over 2 years.

The drugs whose study NIH is funding without written requests were
selected because of special circumstances that raised their priority for
funding. NIH funded the study of daunomycin and methotrexate--both cancer
drugs--before placing them on its 2006 list of drugs for study in
children. NIH officials told us that the Children's Oncology Group of the
National Cancer Institute was already working with an appropriate group of
patients and was at a critical stage in developing the pediatric drug
studies that would produce data for both drugs, so pediatric drug studies
were funded before the drugs were placed on the priority list. NIH
officials also told us that ketamine is administered to more than 30,000
children for sedation each year. Studies done in animals, however, have
suggested that the drug may lead to cell death in the brain. As a result,
the drug cannot be ethically tested in children. NIH is therefore
collaborating with FDA to conduct studies in nonhuman primates. NIH
officials report that methylphenidate is used by an estimated 2.5 million
school-aged children to treat attention deficit hyperactivity disorder.
However, a recent study suggested some potential genetic toxicity of the
drug. Because of these findings, the drug was targeted as a priority and
NIH was able to fund some of the planned studies related to this drug.

Appendix V: Status of Pediatric Drug Studies Requested by FDA

From January 2002 through December 2005, FDA issued 214 written requests
for the study of on-patent drugs. The agency also issued 16 written
requests for the study of off-patent drugs. Fewer written requests were
issued and more were declined by drug sponsors under BPCA than under
FDAMA.

Written Requests Issued under BPCA Compared to FDAMA

From January 2002, when BPCA was enacted, through December 2005, FDA
issued or reissued 214 written requests for on-patent drugs, and drug
sponsors declined 41 of those. FDA issued 68 written requests under BPCA
for the study of on-patent drugs,^1 20 (29 percent) of which were declined
by the drug sponsors. FDA reissued 146 written requests for on-patent
drugs that were originally issued under FDAMA because the pediatric drug
studies had not been completed at the time BPCA went into effect. Included
in the 146 were 21 (14 percent) written requests that were subsequently
declined by the drug sponsors. Therefore, drug sponsors accepted 173
written requests for the study of on-patent drugs under BPCA during this
period. Under FDAMA, FDA issued 227 written requests. Drug sponsors did
not conduct pediatric drug studies or submit study results for 30 of the
227 (13 percent) written requests issued under FDAMA (see fig. 3).^2

1We 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).

^2Since 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.

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

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.

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.^3

3Prior to FDAMA, over a 6-year period from 1991 to 1996, only 11 of 71
requested studies were completed without such an incentive.

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,^1 drug sponsors submitted study reports to FDA in
response to 59 written requests. FDA made pediatric exclusivity
determinations for 55 of those written requests by December 2005, and
most--51, or 93 percent--were made in 90 days or less.

For the 59 written requests for which study results were submitted to FDA,
a total of 143 pediatric drug studies were conducted at 2,860 different
study sites with more than 25,000 children participating (see table 7). In
December 2005, FDA projected that for the drugs for which studies had not
yet been submitted for review, there would be nearly 20,000 more children
participating in the studies.

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

                                          Number of study           Number of 
                                Number of   sites for all participants in all 
                       individual studies         studies             studies 
Count                              143           2,860              25,397 
Average                              2              68                 430 
Median                               2              48                 255 
Mode                                 2              83                 192 
Minimum                              1               3                  11 
Maximum                              7             232               2,517 
Number of written                                                          
requests data are                                                          
based on                            59              42                  59 

Source: GAO analysis of FDA data.

^1For 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.

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:

           o 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.

           o 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.

           o 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.

           o 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.

           o 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.^1 In addition, we discussed suggestions
           for improving BPCA with interest group representatives. Forum
           participants suggested that the timing of the determination of
           pediatric exclusivity should parallel the scientific review of a
           drug application and that both should be within 180 days of FDA
           receiving the results from the pediatric drug studies. FDA's
           ability to assess the overall quality of the pediatric drug
           studies in the 90 days currently allotted for the review was
           questioned. Some forum participants also stated that a longer
           review period could result in different determinations in some
           cases. For example, FDA's scientific review of data related to the
           study of one drug showed that the children participating in the
           pediatric drug studies had not received the treatments as the drug
           sponsors had suggested in their description of the study results.
           While the agency had granted the drug sponsor pediatric
           exclusivity based on its 90-day review to determine pediatric
           exclusivity, it might not have done so based on what was learned
           during the longer, 180-day scientific review.

           In addition, it was suggested that drug sponsors be required to
           submit their study results for pediatric exclusivity determination
           at least 1 year prior to patent expiration. This would allow the
           generic drug industry time 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.
			  
^1Forum 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
[51]www.iom.edu/CMS/3740/24155/34241.aspx .
			  
			  Appendix VIII: Comments from the Department of Health and Human
			  Services
			  
			  Appendix IX: GAO Contact and Staff Acknowledgments
			  
			  GAO Contact

           Marcia Crosse, (202) 512-7119 or [email protected]
			  
			  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.
			  
			  GAOï¿½s 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:
           [email protected] Automated answering system: (800) 424-5454 or
           (202) 512-7470
			  
			  Congressional Relations

           Gloria Jarmon, Managing Director, [email protected] (202)
           512-4400 U.S. Government Accountability Office, 441 G Street NW,
           Room 7125 Washington, D.C. 20548
			  
			  Public Affairs

           Paul Anderson, Managing Director, [email protected] (202)
           512-4800 U.S. Government Accountability Office, 441 G Street NW,
           Room 7149 Washington, D.C. 20548

(290501)

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
[email protected].

Highlights of [53]GAO-07-557 , a report to congressional committees

March 2007

PEDIATRIC DRUG RESEARCH

Studies Conducted under Best Pharmaceuticals for Children Act

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.

Drug sponsors have initiated pediatric drug studies for most of the
on-patent drugs for which FDA has requested studies, but no drugs were
being studied when drug sponsors declined these requests.  Sponsors agreed
to 173 of the 214 written requests for pediatric studies of on-patent
drugs. In cases where drug sponsors decline to study the drugs, BPCA
provides for FDA to refer the study of these drugs to the Foundation for
the National Institutes of Health  (FNIH), a nonprofit corporation. FNIH
had not funded studies for any of the nine drugs that FDA referred as of
December 2005.

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

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.

References

Visible links
  39. http://www.gao.gov/cgi-bin/getrpt?GAO-01-705T
  51. http://www.iom.edu/CMS/3740/24155534241.aspx
  53. http://www.gao.gov/cgi-bin/getrpt?GAO-07-557
*** End of document. ***