Pediatric Drug Research
The Study and Labeling of Drugs for Pediatric Use under the Best Pharmaceuticals for Children Act Gao ID: GAO-07-898T May 22, 2007About two-thirds of drugs that are prescribed for children have not been studied and labeled for pediatric use, placing 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 also provides for the study of off-patent drugs. GAO was asked to testify on the study and labeling of drugs for pediatric use under BPCA. This testimony is based on Pediatric Drug Research: Studies Conducted under Best Pharmaceuticals for Children Act, GAO-07-557 (Mar. 22, 2007). GAO assessed (1) the extent to which pediatric drug studies were being conducted under BPCA for on-patent drugs, (2) the extent to which pediatric drug studies were being conducted under BPCA for off-patent drugs, and (3) the impact of BPCA on the labeling of drugs for pediatric use and the process by which the labeling was changed. GAO examined data about the drugs for which FDA requested studies under BPCA from 2002 through 2005 and interviewed relevant federal officials.
Drug sponsors have initiated pediatric drug studies for most of the on-patent drugs for which FDA has requested such studies under BPCA, but no drugs were studied when 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. Few off-patent drugs identified by the National Institutes of Health (NIH) that need to be studied for pediatric use have been studied. BPCA provides for NIH to fund studies when drug sponsors decline written requests for off-patent drugs. While 40 such off-patent drugs were identified by 2005, FDA had issued written requests for 16. One written request was accepted by the drug sponsor. Of the remaining 15, NIH funded studies for 7 through December 2005. Most drugs granted pediatric exclusivity under BPCA (about 87 percent) 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. For 18 drugs that required labeling changes (about 40 percent), it took from 238 to 1,055 days for information to be reviewed and labeling changes to be approved.
GAO-07-898T, Pediatric Drug Research: The Study and Labeling of Drugs for Pediatric Use under the Best Pharmaceuticals for Children Act
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Testimony:
Before the Subcommittee on Health, Committee on Energy and Commerce,
House of Representatives:
United States Government Accountability Office:
GAO:
For Release on Delivery Expected at 10:00 a.m. EDT:
Tuesday, May 22, 2007:
Pediatric Drug Research:
The Study and Labeling of Drugs for Pediatric Use under the Best
Pharmaceuticals for Children Act:
Statement of Marcia Crosse:
Director, Health Care:
GAO-07-898T:
GAO Highlights:
Highlights of GAO-07-898T, a testimony before the Subcommittee on
Health, Committee on Energy and Commerce, House of Representatives
Why GAO Did This Study:
About two-thirds of drugs that are prescribed for children have not
been studied and labeled for pediatric use, placing 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 also provides for the study of off-patent drugs.
GAO was asked to testify on the study and labeling of drugs for
pediatric use under BPCA. This testimony is based on Pediatric Drug
Research: Studies Conducted under Best Pharmaceuticals for Children
Act, GAO-07-557 (Mar. 22, 2007). GAO assessed (1) the extent to which
pediatric drug studies were being conducted under BPCA for on-patent
drugs, (2) the extent to which pediatric drug studies were being
conducted under BPCA for off-patent drugs, and (3) the impact of BPCA
on the labeling of drugs for pediatric use and the process by which the
labeling was changed. GAO examined data about the drugs for which FDA
requested studies under BPCA from 2002 through 2005 and interviewed
relevant federal officials.
What GAO Found:
Drug sponsors have initiated pediatric drug studies for most of the on-
patent drugs for which FDA has requested such studies under BPCA, but
no drugs were studied when sponsors declined these requests. Sponsors
agreed to 173 of the 214 written requests for pediatric studies of on-
patent drugs. In cases where drug sponsors decline to study the drugs,
BPCA provides for FDA to refer the study of these drugs to the
Foundation for the National Institutes of Health (FNIH), a nonprofit
corporation. FNIH had not funded studies for any of the nine drugs that
FDA referred as of December 2005.
Figure: Written Requests Issued under BPCA for the Study of On-Patent
drugs (2002-2005):
[See PDF for Image]
Source: GAO.
[End of figure]
Few off-patent drugs identified by the National Institutes of Health
(NIH) that need to be studied for pediatric use have been studied. BPCA
provides for NIH to fund studies when drug sponsors decline written
requests for off-patent drugs. While 40 such off-patent drugs were
identified by 2005, FDA had issued written requests for 16. One written
request was accepted by the drug sponsor. Of the remaining 15, NIH
funded studies for 7 through December 2005.
Most drugs granted pediatric exclusivity under BPCA (about 87 percent)
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. For 18 drugs
that required labeling changes (about 40 percent), it took from 238 to
1,055 days for information to be reviewed and labeling changes to be
approved.
[Hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-07-898T.
To view the full product, including the scope and methodology, click on
the link above. For more information, contact Marcia Crosse at (202)
512-7119 or crossem@gao.gov.
[End of section]
Mr. Chairman and Members of the Subcommittee:
Although children suffer from many of the same diseases as adults and
are often treated with the same drugs, only about one-third of the
drugs that are prescribed for children have been studied and labeled
for pediatric use.[Footnote 1] This has placed children taking drugs
for which there have not been adequate pediatric drug studies at risk
of being exposed to ineffective treatment or receiving incorrect
dosing. In order to encourage the study of more drugs for pediatric
use,[Footnote 2] Congress passed the Best Pharmaceuticals for Children
Act (BPCA) in 2002 to provide marketing incentives to drug sponsors for
conducting pediatric drug studies.[Footnote 3] Drug sponsors (typically
drug manufacturers) may obtain 6 months of additional market
exclusivity for drugs on which they have conducted pediatric studies in
accordance with pertinent law and regulations.[Footnote 4] This market
exclusivity is known as pediatric exclusivity. When a drug has market
exclusivity, it is protected from competition for a limited period; for
example, the Food and Drug Administration (FDA) is prohibited from
approving a generic copy for marketing.[Footnote 5] Generally,
pediatric exclusivity can only be granted to those drugs that are on-
patent--that is, those that still have market exclusivity[Footnote 6]-
-and for which FDA has issued a written request for pediatric drug
studies.[Footnote 7] However, FDA can also request pediatric drug
studies for off-patent drugs--drugs for which the patent or market
exclusivity has expired. BPCA also included provisions designed to
provide for the study of both on-patent and off-patent drugs that drug
sponsors have declined to study.
When FDA determines that a drug may provide health benefits to
children, it may issue a written request to the drug sponsor to conduct
pediatric drug studies on that drug. When a drug sponsor accepts a
written request and conducts studies, FDA reviews the report from the
pediatric drug studies to determine whether to grant pediatric
exclusivity to the drug. If FDA is satisfied that the studies have been
conducted and reported properly, 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.
BPCA provides for pediatric drug studies when the drug sponsor declines
the written request. First, if a drug sponsor declines a written
request from FDA to study an on-patent drug, BPCA provides for FDA to
refer the drug to the Foundation for the National Institutes of Health
(FNIH), which can fund the study if funds are available.[Footnote 8]
Sponsors cannot receive pediatric exclusivity for on-patent drugs that
drug sponsors decline to study. Second, BPCA provides for the funding
of the study of off-patent drugs by the National Institutes of Health
(NIH), which, in consultation with FDA and experts in pediatric
research, identifies off-patent drugs that need to be studied for
pediatric use.
My remarks today provide an overview of the study and proper labeling
of drugs for pediatric use under BPCA. I will focus on (1) the extent
to which pediatric drug studies were being conducted under BPCA for on-
patent drugs, (2) the extent to which pediatric drug studies were being
conducted under BPCA for off-patent drugs, and (3) the impact of BPCA
on the labeling of drugs for pediatric use and the process by which the
labeling was changed. My remarks are based upon our report assessing
the effect of BPCA on pediatric drug studies and labeling.[Footnote 9]
In carrying out the work for our 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 from January 2002
through December 2005. Our work focused on actions regarding these
drugs prior to 2006. 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. In addition, to assist with our
review in general, we interviewed officials from FDA, NIH, and FNIH.
The work done for this statement was performed from September 2005
through March 2007 in accordance with generally accepted government
auditing standards.
In summary, 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 study 173 of the 214 on-patent drugs (81 percent)
for which FDA issued written requests for pediatric drug studies 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 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. In addition, of the 41 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.
Few of the off-patent drugs identified by NIH as in need of study for
pediatric use have been studied. By 2005, NIH had identified 40 off-
patent drugs it recommended be studied for pediatric use. Through 2005,
FDA issued written requests for 16 of these drugs, and all but one of
these written requests were declined by drug sponsors. NIH funded
pediatric drugs studies for 7 of the remaining 15 written requests
declined by drug sponsors through December 2005.
Almost all the drugs that have been granted pediatric exclusivity under
BPCA--about 87 percent--have had important labeling changes as a result
of pediatric drug studies conducted under BPCA, but the process for
reviewing the study results and making 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 process took from 238 to 1,055 days when FDA
required additional information to support changes in the drug
labeling.
Background:
BPCA was enacted on January 4, 2002, to encourage drug sponsors to
conduct pediatric drug studies.[Footnote 10] BPCA allows FDA to grant
drug sponsors pediatric exclusivity--6 months of additional market
exclusivity--in exchange for conducting and reporting on pediatric drug
studies. BPCA also provides mechanisms for pediatric drug studies that
drug sponsors decline to conduct.
BPCA Process:
The process for initiating pediatric drug studies under BPCA formally
begins when FDA issues a written request to a drug sponsor to conduct
pediatric drug studies for a particular drug. When a drug sponsor
accepts the written request and completes the pediatric drug studies,
it submits to FDA reports describing the studies and the study results.
BPCA specifies that FDA generally has 90 days to review the study
reports to determine whether the pediatric drug studies met the
conditions outlined in the written request.[Footnote 11] If FDA
determines that the pediatric drug studies conducted by the drug
sponsor were responsive to the written request, it will grant a drug
pediatric exclusivity regardless of the study findings.[Footnote 12]
Figure 1 illustrates the process under BPCA.
Figure 1: BPCA Process:
[See PDF for image]
Source: GAO>
[A] If a drug sponsor of an off-patent drug does not respond to FDA's
written request within 30 days, the written request is considered
declined. Pediatric exclusivity is not granted to drugs where the drug
sponsor declined the written request.
[B] FDA has granted pediatric exclusivity in response to written
requests for on-patent drugs only. Under certain circumstances FDA
could grant pediatric exclusivity in response to a written request for
an off-patent drug.
[End of figure]
BPCA Provisions for Pediatric Drug Studies Declined by Drug Sponsors:
BPCA includes two provisions to further the study of drugs when drug
sponsors decline written requests. FDA cannot extend pediatric
exclusivity in response to written requests for any drugs for which the
drug sponsors declined to conduct the requested pediatric drug studies.
First, 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. FNIH, which is a nonprofit corporation and
independent of NIH, supports the mission of NIH and advances research
by linking private sector donors and partners to NIH programs. FNIH and
NIH collaborate to fund certain projects. As of December 2005, FNIH had
raised $4.13 million to fund pediatric drug studies under BPCA.
Second, to further the study of off-patent drugs, NIH--in consultation
with FDA and experts in pediatric research--develops a list of drugs,
including off-patent drugs, which the agency believes need to be
studied 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 pediatric drug studies. Drug sponsors generally
decline written requests for off-patent drugs because the financial
incentives are considerably limited.
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 events that could result from taking the
drug. FDA may determine that the drug is not approved for use by
children, which would then be reflected in any labeling changes.
The agency refers to its review to determine the need for labeling
changes as its scientific review. BPCA specifies that study results
submitted as a supplemental new drug application--which, according to
FDA officials, most are--are subject to FDA's general performance goals
for a scientific review, which in this case is 180 days.[Footnote 13]
FDA's process for reviewing study results submitted under BPCA for
consideration of labeling changes is not unique to BPCA. FDA's action
can include approving the application, determining that the application
is approvable, or determining that the application is not approvable. A
determination that an application is approvable may require that drug
sponsors conduct additional analyses. Each time FDA takes action on the
application, a review cycle is ended.
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 have resulted
when the requests were declined by drug sponsors. From January 2002
through December 2005, FDA issued 214 written requests for on-patent
drugs to be studied under BPCA, and drug sponsors agreed to conduct
pediatric drug studies for 173 (81 percent) of those.[Footnote 14] The
remaining 41 written requests were declined. Of these 41, FDA referred
9 written requests to FNIH for funding and FNIH had not funded any of
those studies as of December 2005.
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 pediatric exclusivity
determinations for 55 of those through December 2005.[Footnote 15] Of
those 55 written requests, 52 (95 percent) resulted in FDA granting
pediatric exclusivity. Figure 2 shows the status of written requests
issued under BPCA for the study of on-patent drugs, from January 2002
through December 2005.
Figure 2: Status of Written Requests Issued under BPCA for the Study of
On-Patent Drugs, from January 2002 through December 2005:
[See PDF for image]
Source: GAO.
Note: Written requests issued from January 2002 through December 2005
include new written requests issued under BPCA combined with written
requests originally issued under FDAMA but reissued under BPCA.
[End of figure]
Drugs were studied under BPCA for their safety and effectiveness in
treating children for a wide range of diseases, including some that are
common--such as asthma and allergies--and serious or life threatening
in children--such as cancer, HIV, and hypertension. 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. Analyses
of two national databases shows that about half of the 10 most
frequently prescribed drugs for children were studied under BPCA.
Through December 2005, drug sponsors declined written requests issued
under BPCA for 41 on-patent drugs. FDA referred 9 of these 41 written
requests (22 percent) to FNIH for funding,[Footnote 16] but as of
December 2005, FNIH had not funded the study of any of these
drugs.[Footnote 17] NIH has estimated that the cost of studying these 9
drugs would exceed $43 million, but FNIH had raised only $4.13 million
for pediatric drug studies under BPCA.
Few Off-Patent Drugs Have Been Studied under BPCA:
Few off-patent drugs identified by NIH as in need of study for
pediatric use have been studied. By 2005, NIH had identified 40 off-
patent drugs that it believed should be studied for pediatric use.
Through 2005, FDA issued written requests for 16 of these drugs. All
but 1 of these written requests were declined by drug sponsors. NIH
funded pediatric drug studies for 7 of the remaining 15 written
requests declined by drug sponsors through December 2005.
NIH provided several reasons why it has not pursued the study of some
off-patent drugs that drug sponsors declined to study. Concerns about
the incidence of the disease that the drugs were developed to treat,
the feasibility of study design, drug safety, and changes in the drugs'
patent status have caused the agency to reconsider the merit of
studying some of the drugs it identified as important for study in
children.[Footnote 18] For example, in one case NIH issued a request
for proposals to study a drug but received no responses. 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. NIH anticipates spending an
estimated $52.5 million for pediatric drug studies associated with 7
written requests issued by FDA from January 2002 through December
2005.[Footnote 19]
Most Drugs Granted Pediatric Exclusivity under BPCA Had Labeling
Changes, but the Process for Making Changes Was Sometimes Lengthy:
Most drugs that have been granted pediatric exclusivity under BPCA--
about 87 percent--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 from drug
sponsors to support the 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. In
addition, 3 other drugs had labeling changes prior to FDA making a
decision on granting pediatric exclusivity. FDA officials said that the
pediatric drug studies conducted up to that time provided important
safety information that should be reflected in the labeling without
waiting until the full study results were submitted or pediatric
exclusivity determined.
Pediatric drug studies conducted under BPCA have shown that the way
that some drugs were being administered to children potentially exposed
them to an ineffective therapy, ineffective dosing, overdosing, or
previously unknown side effects--including some that affect growth and
development. The labeling for these drugs was changed to reflect these
study results. For example, studies of the drug Sumatriptan, which is
used to treat migraines, showed that there was no benefit derived from
this drug when it was used in children. There were also certain serious
adverse events associated with its use in children, such as vision loss
and stroke, so the labeling was changed to reflect that the drug is not
recommended for children under 18 years old.
Other drugs have had labeling changes indicating that the drugs 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 in the pediatric drug studies
conducted under BPCA.
Although FDA generally completed its first scientific review of study
results--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 approve
labeling changes. For 13 drugs (about 29 percent), FDA completed this
scientific review process and approved labeling changes within 180
days. It took from 181 to 187 days for the scientific review process to
be completed and labeling changes to be approved for 14 drugs (about 31
percent). For the remaining 18 drugs (about 40 percent), FDA took from
238 to 1,055 days 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.
While the first scientific reviews were generally completed within 180
days, it took 238 days or more for 18 drugs.[Footnote 20] For those 18
drugs, FDA determined that it needed additional information from the
drug sponsors in order to be able to approve the drugs for pediatric
use. This often required that the drug sponsor conduct additional
analyses or pediatric drug studies. FDA officials said they could not
approve any changes to drug labeling until the drug sponsor provided
this information. Drug sponsors sometimes took as long as 1 year to
gather the additional necessary data and respond to FDA's
request.[Footnote 21]
Mr. Chairman, this concludes my prepared remarks. I would be pleased to
respond to any questions that you or other members of the Subcommittee
may have.
For further information regarding this testimony, please contact Marcia
Crosse at (202) 512-7119 or crossem@gao.gov. Contact points for our
Offices of Congressional Relations and Public Affairs may be found on
the last page of this testimony. Thomas Conahan, Assistant Director;
Carolyn Feis Korman; and Cathleen Hamann made key contributions to this
statement.
(290642):
FOOTNOTES
[1] The drug "label" refers to written, printed, or graphic material
placed on the drug container while drug "labeling" is much broader and
includes all labels and other written, printed, or graphic materials on
any container, wrapper, or materials accompanying the drug. 21 U.S.C. §
321(k), (m).
[2] FDA generally defines the pediatric population covered under BPCA
as children from birth to 16 years old, though studies have included
children as old as 18.
[3] Provisions regarding pediatric studies of drugs are generally
codified at 21 U.S.C. § 355a. Pub. L. No. 107-109, 115 Stat. 1408. The
market exclusivity provisions of BPCA will sunset on October 1, 2007.
[4] The value of 6 months additional marketing exclusivity is difficult
to assess and depends on a number of factors for which data are not
available. However, a recent study estimated that for some drugs, the
benefit of 6 months of marketing exclusivity was quite large, while for
others the return the drug sponsor received for pediatric exclusivity
was less than the cost of the studies. See Jennifer S. Li, et al.,
"Economic Return of Clinical Trials Performed Under the Pediatric
Exclusivity Program," JAMA, vol. 297, no. 5 (2007).
[5] Drug sponsors can obtain additional market exclusivity or patent
protection for drugs protected by patents, drugs designed to treat rare
diseases, drugs consisting of new chemical entities, and already-
marketed drugs approved for new uses. See, for example, 21 U.S.C. §§
355(j)(5)(F)(ii), (iii); 21 C.F.R. § 314.108 (2006). Pediatric
exclusivity under BPCA attaches to an existing listed patent or any
existing market exclusivity held by the drug sponsor.
[6] For purposes of this statement, we refer to drugs that have patent
protection or market exclusivity as on-patent and those whose patent
protection or marketing 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.
[7] FDA is responsible for issuing written requests for pediatric
studies, determining whether a drug merits pediatric exclusivity as a
result of those studies, and all steps in between.
[8] FNIH is an independent, nonprofit corporation. The majority of
funds that FNIH receives are from the private sector. Only a portion of
these funds are available for FNIH to award to researchers to conduct
studies related to BPCA.
[9] GAO, Pediatric Drug Research: Studies Conducted under Best
Pharmaceuticals for Children Act, GAO-07-557 (Washington, D.C.: Mar.
22, 2007).
[10] BPCA reauthorized and enhanced the pediatric exclusivity
provisions of the Food and Drug Administration Modernization Act of
1997 (FDAMA), Pub. L. No. 105-115, 111 Stat. 2296, which first
established incentives for conducting pediatric drug studies--in the
form of additional market exclusivity--and whose pediatric exclusivity
provisions expired on January 1, 2002. We previously described how
FDAMA was responsible for an increase in pediatric drug studies. GAO,
Pediatric Drug Research: Substantial Increase in Studies of Drug for
Children, But Some Challenges Remain, GAO-01-705T (Washington, D.C.:
May 8, 2001).
[11] Under certain circumstances, FDA could have only 60 days to review
the study report to determine pediatric exclusivity. However, FDA
officials told us that under BPCA, this has never happened. Otherwise,
FDA has 90 days to determine if the studies fairly respond to the
written request, were conducted in accordance with commonly accepted
scientific principles and protocols, and were properly submitted.
[12] Pediatric exclusivity applies to all approved uses of the drug,
not just those studied in children. Therefore, if the studies find that
the drug is not safe for use by children, the drug will still receive
pediatric exclusivity and therefore extended market exclusivity for the
adult uses of the drug.
[13] Most drugs studied under BPCA have previously been approved for
marketing in the United States, so a supplement to the original "new
drug application" is submitted. BPCA requires that supplemental new
drug applications submitted by drug sponsors be treated as "priority
supplements." FDA's goal is to take action on priority supplements
within 180 days. 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 nonpriority new drug applications in 10 months.
[14] Some drugs have two written requests for a variety of reasons. In
some cases, FDA may have requested that the drug sponsor study the
effects of the drug on different diseases. In other cases, there could
be two written requests for the same drug, issued to different drug
sponsors for different dosage forms of the drug. In addition, FDA told
us that the specified time 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. Of the 214 written requests issued by FDA, 68 were written
requests first issued under BPCA. The remaining 146 written requests
were originally issued under FDAMA and reissued under BPCA because drug
sponsors had not responded to the written requests or completed the
requested pediatric drug studies at the time that BPCA went into
effect.
[15] FDA had not completed its review of the study results to determine
exclusivity prior to December 2005 for the remaining four drugs.
[16] When a drug sponsor of an on-patent drug declines a written
request, the agency must determine if there is a continuing need for
information relating to the use of the drug in children. Reasons that
FDA has concluded that there is not a continuing need include the drug
was not yet approved, some part of the study was being performed by the
drug sponsor or another party, the drug's patent ended, the risk-
benefit assessment shifted, safe alternative therapies were already on
the market even though the agency had issued the written request in
hope of obtaining additional valuable information, another drug may
have been approved or may soon be approved with a better safety record,
or there is minimal use of the drug by children.
[17] In April 2006, FNIH agreed to allocate all $4.13 million it had
raised for pediatric drug studies under BPCA to fund half of the cost
to study one on-patent day--baclofen. NIH expects the cost of the study
of baclofen to be about $7.8 million over three 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.
[18] Since its inception, no drug has been removed from the list
published in the Federal Register, regardless of the feasibility or
likelihood of it being studied.
[19] The costs reported by NIH are estimates, which may change during
the course of the studies.
[20] FDA considers itself in conformance with its review goals even
though the entire process often took longer than 180 days.
[21] BPCA provides a dispute resolution process that FDA can use to
resolve disagreements with drug sponsors regarding labeling of on-
patent drugs where the only remaining issue concerns the labeling. FDA
officials said they have never used this process because labeling has
never been the only unresolved issue for those drugs for which the
review period exceeded 180 days. Agency officials told us that
reminding the drug sponsors that such a process exists has motivated
drug sponsors to complete labeling change negotiations by reaching
agreement with FDA.
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