Pediatric Drug Research
Studies Conducted under Best Pharmaceuticals for Children Act Gao ID: GAO-07-557 March 22, 2007About 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. 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.
GAO-07-557, Pediatric Drug Research: Studies Conducted under Best Pharmaceuticals for Children Act
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Report to Congressional Committees:
United States Government Accountability Office:
GAO:
March 2007:
Pediatric Drug Research:
Studies Conducted under Best Pharmaceuticals for Children Act:
GAO-07-557:
GAO Highlights:
Highlights of GAO-07-557, a report to congressional committees
Why GAO Did This Study:
About two-thirds of drugs that are prescribed for children have not
been studied and labeled for pediatric use, which places children at
risk of being exposed to ineffective treatment or incorrect dosing. The
Best Pharmaceuticals for Children Act (BPCA), enacted in 2002,
encourages the manufacturers, or sponsors, of drugs that still have
marketing exclusivity”that is, are on-patent”to conduct pediatric drug
studies, as requested by the Food and Drug Administration (FDA). If
they do so, FDA may extend for 6 months the period during which no
equivalent generic drugs can be marketed. This is referred to as
pediatric exclusivity.
BPCA required that GAO assess the effect of BPCA on pediatric drug
studies and labeling. As discussed with the committees of jurisdiction,
GAO (1) assessed the extent to which pediatric drug studies were being
conducted under BPCA for on-patent drugs, including when drug sponsors
declined to conduct the studies; (2) evaluated the impact of BPCA on
labeling drugs for pediatric use and the process by which the labeling
was changed; and (3) illustrated the range of diseases treated by the
drugs studied under BPCA. GAO examined data about the drugs for which
FDA requested studies under BPCA from 2002 through 2005. GAO also
interviewed officials from relevant federal agencies, pharmaceutical
industry representatives, and health advocates.
What GAO Found:
Drug sponsors have initiated pediatric drug studies for most of the on-
patent drugs for which FDA has requested studies, but no drugs were
being studied when drug sponsors declined these requests. Sponsors
agreed to 173 of the 214 written requests for pediatric studies of on-
patent drugs. In cases where drug sponsors decline to study the drugs,
BPCA provides for FDA to refer the study of these drugs to the
Foundation for the National Institutes of Health (FNIH), a nonprofit
corporation. FNIH had not funded studies for any of the nine drugs that
FDA referred as of December 2005
Figure: Written Requests Issued under BPCA for the Study of On-Patent
Drug (2002-2005):
[See PDF for Image]
Source: GAO.
[End of figure]
Most drugs (about 87 percent) granted pediatric exclusivity under BPCA
had labeling changes”often because the pediatric drug studies found
that children may have been exposed to ineffective drugs, ineffective
dosing, overdosing, or previously unknown side effects. However the
process for approving labeling changes was often lengthy. It took from
238 to 1,055 days for information to be reviewed and labeling changes
to be approved for 18 drugs (about 40 percent), and 7 of those took
more than 1 year. Drugs were studied under BPCA for the treatment of a
wide range of diseases, including those that are common, serious, or
life threatening to children. These drugs represented more than 17
broad categories of disease, such as cancer.
The Department of Health and Human Services stated that the report
provides a significant amount of data and analysis and generally
explains the BPCA process, but expressed concern that it did not
sufficiently acknowledge the success of BPCA or clearly describe some
elements of FDA‘s process. GAO incorporated comments as appropriate.
[Hyperlink, http://www.gao.gov/cgi-bin/getrpt?GAO-07-557].
To view the full product, including the scope and methodology, click on
the link above. For more information, contact Marcia Crosse at (202)
512-7119 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Results in Brief:
Background:
Drug Sponsors Agreed to Study the Majority of On-Patent Drugs with
Written Requests under BPCA, but No Studies Were Conducted When Drug
Sponsors Declined the Written Requests:
Most Drugs Granted Pediatric Exclusivity under BPCA Had Labeling
Changes, but the Process for Making Changes Was Sometimes Lengthy:
Drugs Studied under BPCA Address a Wide Range of Diseases, Including
Some That Are Common, Serious, or Life Threatening to Children:
Agency Comments and Our Evaluation:
Appendix I: Scope and Methodology:
Appendix II: FDA and NIH Efforts to Encourage the Study of Drugs in
Neonates since Passage of BPCA:
Appendix III: NIH Efforts to Support Pediatric Drug Studies:
Appendix IV: Studies of Off-Patent Drugs under BPCA:
Appendix V: Status of Pediatric Drug Studies Requested by FDA:
Appendix VI: Complexity of Completed Pediatric Drug Studies:
Appendix VII: Strengths of and Suggested Changes for BPCA:
Appendix VIII: Comments from the Department of Health and Human
Services:
Appendix IX: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: Estimated Costs of Funding the Study of On-Patent Drugs
Referred to FNIH under BPCA:
Table 2: Examples of Labeling Changes:
Table 3: Examples of Drugs Approved for Use by Younger Children or for
Which New Formulations Are Available:
Table 4: Examples of Diseases to Be Treated by Drugs Studied under
BPCA:
Table 5: NIH-Sponsored Activities, through 2005, Related to Children in
Clinical Trials:
Table 6: Anticipated NIH Spending for Off-Patent Drug Studies Committed
to through 2005:
Table 7: Complexity of Pediatric Drug Studies Conducted under BPCA,
According to Study Reports from July 2002 through December 2005:
Figures:
Figure 1: BPCA Process:
Figure 2: Status of Written Requests Issued under BPCA for the Study of
On-Patent Drugs, from January 2002 through December 2005:
Figure 3: Status of Written Requests Issued under FDAMA and BPCA
through December 2005:
Abbreviations:
BPCA: Best Pharmaceuticals for Children Act:
FDA: Food and Drug Administration:
FDAMA: Food and Drug Administration Modernization Act of 1997:
FNIH: Foundation for the National Institutes of Health:
HHS: Department of Health and Human Services:
HIV: Human Immunodeficiency Virus:
NDDI: Newborn Drug Development Initiative:
NIH: National Institutes of Health:
United States Government Accountability Office:
Washington, DC 20548:
March 22, 2007:
The Honorable Edward M. Kennedy:
Chairman:
The Honorable Michael B. Enzi:
Ranking Minority Member:
Committee on Health, Education, Labor, and Pensions:
United States Senate:
The Honorable John D. Dingell:
Chairman:
The Honorable Joe L. Barton:
Ranking Minority Member:
Committee on Energy and Commerce:
House of Representatives:
Although children suffer from many of the same diseases as adults and
are often treated with the same drugs, only about one-third of the
drugs that are prescribed for children have been studied and labeled
for pediatric use.[Footnote 1] This has placed children taking drugs
for which there have not been adequate pediatric drug studies at risk
of being exposed to ineffective treatment or receiving incorrect
dosing. In order to encourage the study of more drugs for pediatric
use, Congress passed the Best Pharmaceuticals for Children Act
(BPCA)[Footnote 2] in 2002 to provide marketing incentives to drug
sponsors for conducting pediatric drug studies.[Footnote 3] Drug
sponsors (typically drug manufacturers) may obtain 6 months of
additional market exclusivity for drugs on which they have conducted
pediatric studies in accordance with pertinent law and
regulations.[Footnote 4] This market exclusivity is known as pediatric
exclusivity. When a drug has market exclusivity, it is protected from
competition for a limited period, for example by prohibition on Food
and Drug Administration (FDA)[Footnote 5] approval of a generic copy
for marketing.[Footnote 6] Generally, pediatric exclusivity can only be
granted to those drugs that are on-patent--that is, those that still
have market exclusivity[Footnote 7]--and for which FDA has issued a
written request for pediatric drug studies.[Footnote 8] Once a drug's
patent or market exclusivity has expired, however, FDA can still
request pediatric drug studies for off-patent drugs. BPCA also included
provisions designed to provide for the study of both on-patent and off-
patent drugs that drug sponsors have declined to study.
When FDA determines that a drug may provide health benefits to
children, it may issue a written request to the drug sponsor to conduct
pediatric drug studies. Under BPCA, drug sponsors of on-patent drugs
must accept or decline a written request. Drug sponsors of off-patent
drugs are not required to respond to a written request. However, if FDA
does not receive a response within 30 days, the written request is
assumed to be declined. When a drug sponsor accepts a written request
for an on-patent drug and subsequently submits a study report in
response, FDA generally has 90 days to complete its review of the
reports to determine whether to grant pediatric exclusivity to the
drug. If FDA is satisfied that the studies have been conducted and the
report submitted as required, the drug in question may receive
additional market exclusivity. FDA also reviews these pediatric drug
study reports to see if the drug requires labeling changes. The agency
refers to this review as its scientific review, which it has a goal of
completing within 180 days.
BPCA provides for pediatric drug studies even if the drug sponsor
declined the written request. First, if a drug sponsor declines a
written request by FDA to study an on-patent drug, BPCA provides for
FDA to refer the drug to the Foundation for the National Institutes of
Health (FNIH), which can fund the study if funds are
available.[Footnote 9] When a sponsor declines a written request for an
on-patent drug, the sponsor cannot receive pediatric exclusivity in
response to that written request. Second, BPCA provides for the funding
of the study of off-patent drugs by the Department of Health and Human
Services' (HHS) National Institutes of Health (NIH).
BPCA required that we assess, among other things, the effect of
provisions regarding pediatric drug studies on the study and proper
labeling of drugs for pediatric use. As discussed with the committees
of jurisdiction, we (1) assessed the extent to which pediatric drug
studies were being conducted under BPCA for on-patent drugs, including
when drug sponsors declined to conduct the studies; (2) evaluated the
impact of BPCA on labeling of drugs for pediatric use and the process
by which the labeling was changed; and (3) illustrated the range of
diseases treated by the drugs studied under BPCA.
To assess the extent to which pediatric drug studies were being
conducted under BPCA for on-patent drugs, including when drug sponsors
declined to do the studies, we examined data about the drugs for which
FDA issued written requests from January 2002 through December 2005.
Our work focused on actions regarding these drugs prior to 2006.
Specifically, we examined data on the numbers of written requests,
drugs studied, written requests that were declined, and drugs granted
pediatric exclusivity during this 4-year period. We reviewed data from
FNIH on the funding status of on-patent drugs that drug sponsors
declined to study. To evaluate the impact of BPCA on the labeling of
drugs for pediatric use and the process by which labeling was changed,
we reviewed summaries of the labeling changes for drugs studied from
the enactment of BPCA through 2005. We reviewed the dates the labeling
changes were agreed to and the reasons why some drugs did not have
labeling changes. To illustrate the range of diseases treated by the
drugs studied under BPCA, we identified the diseases the drugs were
studied to treat, as well as the therapeutic areas addressed by the
drugs. We also examined data from national surveys on the extent to
which these drugs are prescribed for children. In addition, to assist
with our review in general, we interviewed officials from FDA, NIH, and
FNIH as well as representatives of the pharmaceutical industry and
health advocates--such as the American Academy of Pediatrics, the
Pharmaceutical Research and Manufacturers of America, the Generic
Pharmaceutical Association, the National Organization for Rare
Disorders, Public Citizen, the Elizabeth Glaser Pediatric AIDS
Foundation, and the Tufts Center for the Study of Drug Development.
(See app. I for a detailed description of our methodology.)
We conducted our work from September 2005 through March 2007 in
accordance with generally accepted government auditing standards.
Results in Brief:
Most of the on-patent drugs for which FDA requested pediatric drug
studies under BPCA were being studied, but no studies resulted when the
requests were declined by drug sponsors. Drug sponsors agreed to
conduct studies in response to 173 of the 214 written requests for on-
patent drugs (81 percent) issued by FDA from January 2002 through
December 2005. Drug sponsors completed pediatric drug studies for 59 of
the 173 accepted written requests--studies for the remaining 114
written requests for on-patent drugs were ongoing--and FDA made a
pediatric exclusivity determination for 55 of those through December
2005. Of those 55 written requests, 52 (95 percent) resulted in FDA
granting pediatric exclusivity. BPCA provides for FDA to refer the
study of on-patent drugs to FNIH when drug sponsors have declined
written requests. However, of the 41 written requests for on-patent
drugs that drug sponsors declined to study, FDA referred 9 to FNIH,
which had not funded the study of any as of December 2005.
Almost all the drugs--about 87 percent--that have been granted
pediatric exclusivity under BPCA have had important labeling changes as
a result of pediatric drug studies conducted under BPCA, but the
process for obtaining all the necessary information, reviewing the
study results, and approving these changes can be lengthy. The labeling
of drugs was often changed because the pediatric drug studies revealed
that children may have been exposed to ineffective drugs, ineffective
dosing, overdosing, or previously unknown side effects. The review and
approval process, including time for sponsors to provide needed
information, took from 238 to 1,055 days when FDA required additional
information to support the proposed labeling changes.
Drugs studied under BPCA were for the treatment of a wide range of
diseases, including some that are common, serious, or life threatening
to children. FDA identified 17 broad categories of disease that were
treated by the drugs studied under BPCA. The most frequently studied
drugs were those used to treat cancer, neurological and psychiatric
disorders, metabolic diseases, cardiovascular disease, and viral
infections. In addition, nearly half of the 10 drugs most frequently
prescribed for children have been studied under BPCA.
In written comments on a draft of this report, HHS stated that the
draft report provided a significant amount of data and analysis and
generally explains the BPCA process, but expressed concern that it did
not sufficiently acknowledge the success of BPCA or clearly describe
some elements of its implementation. While assessing the overall
success of BPCA was beyond the scope of this report, much of the
information we present speaks to the impact BPCA has had on the
studying and labeling of drugs for pediatric use. Further, we believe
that we accurately presented the implementation of BPCA. We
incorporated HHS's comments as appropriate.
Background:
Prior to enactment of the Food and Drug Administration Modernization
Act of 1997 (FDAMA), which first established incentives for conducting
pediatric drug studies in the form of additional market exclusivity,
few drugs were studied for pediatric use.[Footnote 10] As a result,
there was a lack of information on optimal dosage, possible side
effects, and the effectiveness of drugs for pediatric use. For example,
while physicians typically had determined drug dosing for children
based on their weight, pediatric drug studies conducted under FDAMA
showed that in many cases this was not the best approach. To continue
to encourage pediatric drug studies,[Footnote 11] BPCA was enacted on
January 4, 2002, just after the pediatric exclusivity provisions of
FDAMA expired on January 1, 2002. BPCA reauthorized and enhanced the
pediatric exclusivity provisions of FDAMA. Like FDAMA, BPCA allows FDA
to grant drug sponsors pediatric exclusivity--6 months of additional
market exclusivity--in exchange for conducting and submitting reports
on pediatric drug studies. The goal of the program is to develop
additional health information on the use of such drugs in pediatric
populations so they can be administered safely and effectively to
children. This incentive is similar to that provided by FDAMA; however,
BPCA provides additional mechanisms to provide for pediatric studies of
drugs that drug sponsors decline to study.
BPCA Process:
The process for initiating pediatric studies under BPCA formally begins
when FDA issues a written request to a drug sponsor to conduct
pediatric drug studies for a particular drug. FDA may issue a written
request after it has reviewed a proposed pediatric study request from a
drug sponsor, in which the drug sponsor describes the pediatric drug
study or studies it proposes doing in return for pediatric exclusivity.
In deciding whether to approve the proposed pediatric study request and
issue a written request, FDA must determine if the proposed studies
will produce information that may result in health benefits for
children.[Footnote 12] Alternatively, FDA may determine on its own that
there is a need for more research on a drug for pediatric use and issue
a written request without having received a proposed pediatric study
request from the drug sponsor. A written request outlines, among other
things, the nature of the pediatric drug studies that the drug sponsor
must conduct in order to qualify for pediatric exclusivity and a time
frame by which those studies should be completed. When a drug sponsor
accepts the written request and completes the pediatric drug studies,
it submits reports to FDA describing the studies and the study results.
BPCA specifies that FDA generally has 90 days to review the study
reports to determine whether the pediatric drug studies met the
conditions outlined in the written request.[Footnote 13] If FDA
determines that the pediatric drug studies conducted by the drug
sponsor were responsive to the written request, it will grant a drug
pediatric exclusivity regardless of the study findings.[Footnote 14]
Figure 1 illustrates the process under BPCA.
Figure 1: BPCA Process:
[See PDF for image]
Source: GAO.
[A] If a drug sponsor of an off-patent drug does not respond to FDA's
written request within 30 days, the written request is considered
declined. Pediatric exclusivity is not granted to drugs where the drug
sponsor declined the written request.
[B] FDA has granted pediatric exclusivity in response to written
requests for on-patent drugs only. Under certain circumstances FDA
could grant pediatric exclusivity in response to a written request for
an off-patent drug.
[End of figure]
BPCA Provisions for Pediatric Drug Studies Declined by Drug Sponsors:
To further the study of drugs when drug sponsors decline a written
request, BPCA includes two provisions that did not exist under FDAMA.
First, if a drug sponsor declines to conduct the pediatric drug studies
requested by FDA for an on-patent drug, BPCA provides for FDA to refer
the study of that drug to FNIH, which might then agree to fund the
studies. Second, if a drug sponsor declines a request to study an off-
patent drug, BPCA provides for referral of the study to NIH for
funding. FDA cannot extend pediatric exclusivity in response to written
requests for any drugs for which the drug sponsor declined to conduct
the requested pediatric drug studies.
When drug sponsors decline written requests for studies of on-patent
drugs, BPCA provides for FDA to refer the study of those drugs to FNIH
for funding, when FDA believes that the pediatric drug studies are
still warranted. FNIH, which was authorized by Congress to be
established in 1990, is guided by a board of directors and began formal
operations in 1996 to support the mission of NIH and advance research
by linking private sector donors and partners to NIH programs. Although
FNIH is a nonprofit corporation that is independent of NIH, FNIH and
NIH collaborate to fund certain projects. FNIH has raised approximately
$300 million from the private sector over the past 10 years to support
four general types of projects: (1) research partnerships; (2)
educational programs and projects for fellows, interns, and
postdoctoral students; (3) events, lectures, conferences, and
communication initiatives; and (4) special projects. Included in these
funds is $4.13 million that FNIH raised as of December 2005 to fund
pediatric drug studies under BPCA. The majority of FNIH's funds are
restricted by donors for specific projects and cannot be
reallocated.[Footnote 15] In recent years, appropriations of $500,000
were authorized to FNIH annually.[Footnote 16]
To further the study of off-patent drugs, NIH--in consultation with FDA
and other experts--develops a list of drugs, including off-patent
drugs, which the agency believes are in need of study in children. NIH
lists these drugs annually in the Federal Register. FDA may issue
written requests for those drugs on the list that it determines to be
most in need of study. If the drug sponsor declines or fails to respond
to the written request, NIH can contract for, and fund the conduct of,
the pediatric drug studies. These pediatric drug studies could then be
conducted by qualified universities, hospitals, laboratories, contract
research organizations, federally funded programs such as pediatric
pharmacology research units, other public or private institutions or
individuals. Drug sponsors generally decline written requests for off-
patent drugs because the financial incentives are considerably limited.
(See app. II for a description of federal efforts to encourage research
on drugs for children less than 1 month of age and app. III for NIH
efforts to support pediatric drug studies.)
Making Labeling Changes under BPCA for On-Patent Drugs:
Pediatric drug studies often reveal new information about the safety or
effectiveness of a drug, which could indicate the need for a change to
its labeling. Generally, the labeling includes important information
for health care providers, including proper uses of the drug, proper
dosing, and possible adverse effects that could result from taking the
drug. FDA may determine that the drug is not approved for use by
children, which would be reflected in any labeling changes.[Footnote
17]
According to FDA officials, in order to be considered for pediatric
exclusivity, a drug sponsor typically submits results from pediatric
drug studies in the form of a "supplemental new drug
application."[Footnote 18] BPCA specifies that study results, when
submitted as part of a supplemental new drug application, are subject
to FDA's performance goals for a scientific review, which in this case
is 180 days.[Footnote 19] FDA's processes for reviewing study results
submitted under BPCA for consideration of labeling changes are not
unique to BPCA. These are the same processes the agency would use to
review any drug study results in consideration of labeling changes.
FDA's action on the application can include approving the application,
determining that the application is approvable (pending the submission
of additional information from the sponsor), or determining that the
application is not approvable. If studies demonstrate that an approved
drug is not safe or effective for pediatric use, this information would
be reflected in the drug's labeling.
With a determination that the application is approvable, FDA
communicates to the drug sponsor that some issues need to be resolved
before the application can be approved and describes what additional
work is necessary to resolve the issues. This might require that drug
sponsors conduct additional analyses. However, this communication would
complete the scientific review cycle. When a drug sponsor resubmits the
application with the additional analyses, a new scientific review cycle
begins. As a result, multiple scientific review cycles might be
necessary, increasing the time between initial submission of the
application, which includes the pediatric study reports, and approval
of a labeling change.
If, during FDA's review of the study report submitted as part of the
application, the agency determines that the application is approvable
and the only unresolved issue is labeling, FDA and the drug sponsor
must attempt to reach agreement on labeling changes within 180 days
after the application is submitted to FDA. If FDA and the drug sponsor
cannot reach agreement, FDA must refer the matter to its Pediatric
Advisory Committee,[Footnote 20] which would convene and provide
recommendations to the Commissioner on the appropriate changes to the
drug's labeling. The Commissioner would then consider the committee's
recommendations in making the final determination on the proper
labeling.
Drug Sponsors Agreed to Study the Majority of On-Patent Drugs with
Written Requests under BPCA, but No Studies Were Conducted When Drug
Sponsors Declined the Written Requests:
Most of the on-patent drugs for which FDA requested pediatric drug
studies under BPCA were being studied, but no studies resulted when the
requests were declined by drug sponsors. Of the 214 on-patent drugs for
which FDA requested pediatric drug studies from January 2002 through
December 2005, drug sponsors agreed to study 173 (81 percent). Of the
41 on-patent drugs that drug sponsors declined to study, FDA referred 9
to FNIH for funding and the foundation had not funded any of those
studies as of December 2005.
Drug Sponsors Agreed to Conduct Pediatric Drug Studies for Most On-
Patent Drugs with Written Requests Issued under BPCA:
From January 2002 through December 2005, FDA issued 214 written
requests for on-patent drugs to be studied under BPCA, and drug
sponsors agreed to conduct pediatric drug studies for 173 (81 percent)
of those.[Footnote 21] The remaining 41 written requests were
declined.[Footnote 22] (See app. IV for details about the study of off-
patent drugs under BPCA and app. V for a detailed description of the
status of all written requests issued by FDA.) Drug sponsors completed
pediatric drug studies for 59 of the 173 accepted written requests--
studies for the remaining 114 written requests were ongoing--and FDA
made a pediatric exclusivity determination for 55 of those through
December 2005.[Footnote 23] Of those 55 written requests, 52 (95
percent) resulted in FDA granting pediatric exclusivity.[Footnote 24]
Figure 2 shows the status of written requests issued under BPCA for the
study of on-patent drugs, from January 2002 through December 2005. (See
app. VI for a description of the complexity of pediatric drug studies
conducted under BPCA.)
Figure 2: Status of Written Requests Issued under BPCA for the Study of
On-Patent Drugs, from January 2002 through December 2005:
[See PDF for image]
Source: GAO.
Note: Written requests issued from January 2002 through December 2005
include new written requests issued under BPCA combined with written
requests originally issued under FDAMA but reissued under BPCA.
[End of figure]
FNIH Had Not Funded the Study of Any On-Patent Drugs in Children:
Under BPCA, when a written request to study an on-patent drug is
declined, the study of the drug may be referred to FNIH. However, FNIH
is limited in its ability to fund drug studies by its available funds.
Through December 2005, drug sponsors declined written requests issued
under BPCA for 41 on-patent drugs. FDA referred 9 of these 41 written
requests (22 percent) to FNIH for funding.[Footnote 25] FNIH had not
funded the study of any of these drugs.[Footnote 26] NIH has estimated
that the cost of studying the drugs that were referred to FNIH for
study would exceed $43 million (see table 1). FNIH has been raising
funds for the study of drugs referred under BCPA at a rate of
approximately $1 million per year.
Table 1: Estimated Costs of Funding the Study of On-Patent Drugs
Referred to FNIH under BPCA:
On-patent drug: Baclofen;
Disease or condition to be studied: Spasticity in children with
cerebral palsy;
Estimated cost: $7.8 million.
On-patent drug: Bupropion;
Disease or condition to be studied: Depression;
Estimated cost: $7.4 million.
On-patent drug: Dexrazoxane;
Disease or condition to be studied: Used to block the cardiac effects
of the anticancer drug adriamycin;
Estimated cost: Not provided[A].
On-patent drug: Eletriptan;
Disease or condition to be studied: Migraine headaches;
Estimated cost: Not provided[A].
On-patent drug: Hydroxyurea[B];
Disease or condition to be studied: Sickle cell disease;
Estimated cost: $8 million to $10 million[C].
On-patent drug: Metoclopramide;
Disease or condition to be studied: Gastroesophageal reflux disease;
Estimated cost: Not provided[A].
On-patent drug: Morphine;
Disease or condition to be studied: Analgesia;
Estimated cost: $8.7 million.
On-patent drug: Sevelamer;
Disease or condition to be studied: Renal failure;
Estimated cost: $2.7 million.
On-patent drug: Zonisamide;
Disease or condition to be studied: Refractory partial seizures;
Estimated cost: $8.4 million.
On-patent drug: Total;
Disease or condition to be studied: [Empty];
Estimated cost: $43 million to $45 million[D].
Source: NIH.
[A] Cost estimates have not been provided by NIH.
[B] Hydroxyurea is available in on-patent and generic (or off-patent)
formulations. According to NIH officials, after the written request was
referred to FNIH for funding, NIH determined that a study funded by its
National Heart, Lung, and Blood Institute would provide much of the
needed information for appropriate pediatric use. In 2005, NIH's
National Institute of Child Health and Human Development agreed to
cofund the study.
[C] A formal cost estimate has not been made by NIH, but an initial
estimate ranged from $8 million to $10 million.
[D] Total estimated cost is for the six drugs for which an estimated
cost is available.
[End of table]
Most Drugs Granted Pediatric Exclusivity under BPCA Had Labeling
Changes, but the Process for Making Changes Was Sometimes Lengthy:
Most drugs--about 87 percent--that have been granted pediatric
exclusivity under BPCA have had labeling changes as a result of the
pediatric drug studies conducted under BPCA. Pediatric drug studies
conducted under BPCA showed that children may have been exposed to
ineffective drugs, ineffective dosing, overdosing, or side effects that
were previously unknown. However, the process for reviewing study
results and completing labeling changes was sometimes lengthy,
particularly when FDA required additional information to support the
changes.
Most Drugs Granted Pediatric Exclusivity Had Labeling Changes:
Of the 52 drugs studied and granted pediatric exclusivity under BPCA
from January 2002 through December 2005, 45 (about 87 percent) had
labeling changes as a result of the pediatric drug studies. FDA
officials told us that labeling changes were not made for the remaining
7 (about 13 percent) drugs granted pediatric exclusivity, generally
because data provided by the pediatric drug studies did not support
labeling changes. In addition, 3 other drugs had labeling changes prior
to FDA making a decision on granting pediatric exclusivity.[Footnote
27] FDA officials said these labeling changes were made prior to
determining whether pediatric exclusivity should be granted because the
pediatric drug studies provided important safety information that
should be reflected in the labeling without waiting until the full
study results were submitted or pediatric exclusivity was determined.
Labeling Changes for Drugs Studied under BPCA Had Important
Implications for Pediatric Use:
Pediatric drug studies conducted under BPCA have shown that the way
that some drugs were being administered to children potentially exposed
them to an ineffective therapy, ineffective dosing, overdosing, or
previously unknown side effects--including some that affect growth and
development. The labeling for these drugs was changed to reflect these
study results. Table 2 shows some of these drugs and illustrates these
types of labeling changes. FDA officials said that the agency has been
working to increase the amount of information included in drug
labeling, particularly when pediatric drug studies indicate that an
approved drug may not be safe or effective for pediatric use.
Table 2: Examples of Labeling Changes:
Potential risks or hazards: Unnecessary exposure to ineffective
therapies;
Drug name: Sumatriptan;
Disease or condition treated: Migraines;
Summary of new information contained in drug labeling: Five studies did
not establish safety and effectiveness, and postmarketing experience
showed children were having serious adverse effects, such as stroke and
vision loss. The product is not recommended for children under 18 years
old.
Potential risks or hazards: Unnecessary exposure to ineffective
therapies;
Drug name: Tolterodine;
Disease or condition treated: Overactive bladder and urge incontinence;
Summary of new information contained in drug labeling: The drug was not
shown to be effective for children and appeared to show a possible
increase in aggressive, hyperactive, and abnormal behavior.
Potential risks or hazards: Unnecessary exposure to ineffective
therapies;
Drug name: Irinotecan;
Disease or condition treated: Tumors;
Summary of new information contained in drug labeling: Children had
more rapid disease progression and died more quickly. The labeling
states that the drug should not be used to treat children with a
particular kind of tumor.
Potential risks or hazards: Ineffective dosing;
Drug name: Oxcarbazepine;
Disease or condition treated: Partial seizures;
Summary of new information contained in drug labeling: Dose for
children aged 2 to 4 and weighing less than 44 pounds is twice the dose
per body weight compared to adults.
Potential risks or hazards: Ineffective dosing;
Drug name: Methylphenidate;
Disease or condition treated: Attention-deficit hyperactivity disorder;
Summary of new information contained in drug labeling: Children aged 13
to 17 eliminated the drug from their bodies faster than the comparison
age group. Therefore the dosing regimen may be increased to prevent
ineffective dosing.
Potential risks or hazards: Overdosing;
Drug name: Leflunomide;
Disease or condition treated: Juvenile rheumatoid arthritis;
Summary of new information contained in drug labeling: Children
weighing less than 88 pounds require a lower-than-expected dose.
Overdosing leflunomide, which has significant toxicity, could make the
drug's risks to children outweigh its benefits.
Potential risks or hazards: Previously unlabeled side effects,
including effect on growth and development;
Drug name: Venlafaxine;
Disease or condition treated: Depression; generalized anxiety disorder;
Summary of new information contained in drug labeling: This drug is
associated with an increased risk of suicidal thinking and behavior.
Potential risks or hazards: Previously unlabeled side effects,
including effect on growth and development;
Drug name: Ciprofloxacin;
Disease or condition treated: Complicated urinary tract infection or
kidney infection;
Summary of new information contained in drug labeling: This drug is
associated with increased adverse effects to joints or surrounding
tissues for children.
Potential risks or hazards: Previously unlabeled side effects,
including effect on growth and development;
Drug name: Fentanyl;
Disease or condition treated: Chronic pain;
Summary of new information contained in drug labeling: This drug should
be used only by children who are 2 years of age or older and are opioid-
tolerant. Use by others can lead to life- threatening respiratory
depression and death.
Potential risks or hazards: Previously unlabeled side effects,
including effect on growth and development;
Drug name: Budesonide;
Disease or condition treated: Asthma;
Summary of new information contained in drug labeling: Budesonide can
cause growth suppression.
Source: GAO analysis of FDA data.
[End of table]
Other drugs have had labeling changes indicating that the drug may be
used safely and effectively by children in certain dosages or forms.
Typically, this resulted in the drug labeling being changed to indicate
that the drug was approved for use by children younger than those for
whom it had previously been approved. In other cases, the changes
reflected a new formulation of a drug, such as a syrup that was
developed for pediatric use, or new directions for preparing the drug
for pediatric use were identified during the pediatric drug studies
conducted under BPCA.[Footnote 28] (See table 3 for examples of drugs
with this new type of information.)
Table 3: Examples of Drugs Approved for Use by Younger Children or for
Which New Formulations Are Available:
Uses and formulations: New age groups;
Drug: Moxifloxacin Ophthalmic;
Disease or condition treated or prevented: Bacterial conjunctivitis;
Summary of new information: Found to be safe and effective for children
over 1 year old.
Uses and formulations: New age groups;
Drug: Ondansetron;
Disease or condition treated or prevented: Nausea and vomiting after
chemotherapy;
Summary of new information: Established dosing for surgical patients
down to 1 month from 2 years of age; established dosing for cancer
patients down to 6 months from 4 years of age.
Uses and formulations: New formulations or preparations;
Drug: Benazepril;
Disease or condition treated or prevented: Hypertension;
Summary of new information: Labeled with directions for how to prepare
a suspension for administering the drug to children.
Uses and formulations: New formulations or preparations;
Drug: Desloratadine;
Disease or condition treated or prevented: Seasonal and perennial
allergic rhinitis and hives;
Summary of new information: Newly available in a syrup, labeled
specifically for children.
Source: GAO analysis.
[End of table]
The Process for Reviewing Study Results and Approving Labeling Changes
Was Sometimes Lengthy, Particularly When FDA Required Additional
Information from Drug Sponsors:
Although FDA generally completed its first scientific review of study
results submitted as a supplemental new drug application--including
consideration of labeling changes--within its 180-day goal, the process
for completing the review, including obtaining sufficient information
to support and approve labeling changes, sometimes took longer. For the
45 drugs granted pediatric exclusivity that had labeling changes, it
took an average of almost 9 months after study results were first
submitted to FDA for the sponsor to submit and the agency to review all
of the information it required and agree with the drug sponsor to
approve the labeling changes.[Footnote 29] For 13 drugs (about 29
percent), FDA completed this scientific review process and FDA approved
labeling changes within 180 days. It took from 181 to 187 days to
complete the scientific review process and to approve labeling changes
for 14 drugs (about 31 percent). For the remaining 18 drugs (about 40
percent), it took from 238 to 1,055 days for FDA to complete the
scientific review process and approve labeling changes. For 7 of those
drugs, it took more than a year to complete the scientific review
process and approve labeling changes.
To determine whether and how drug labeling should be changed, FDA
conducts a scientific review of the study results that are submitted to
the agency by the drug sponsor. Included with the study results is the
drug sponsor's proposal for how the labeling should be changed. FDA can
either accept the proposed wording or propose alternative wording. For
some drugs, however, the process does not end with FDA's first
scientific review. While the first scientific reviews were generally
completed within 180 days, for the 18 drugs that took 238 days or more,
FDA determined that it needed additional information from the drug
sponsors in order to be able to approve the applications. This often
required that the drug sponsors conduct additional analyses or
pediatric drug studies. FDA officials said they could not approve any
changes to drug labeling until the drug sponsors provided this
information. When FDA completed its review of the information that was
originally submitted and requested additional information from the drug
sponsors, the initial 180-day scientific review ended. A new 180-day
scientific review began when the drug sponsors submitted the additional
information to FDA. Drug sponsors sometimes took as long as 1 year to
gather the additional necessary data and respond to FDA's requests.
This time did not count against FDA's 180-day goal to complete its
scientific review and approve labeling changes because a new 180-day
scientific review begins after the required information is submitted.
However, we counted the total number of days between submission of
study reports and approval of labeling changes. FDA considers itself in
conformance with its review goals even though the entire process may
take longer than 180 days.
BPCA provides a dispute resolution process to be used if FDA and the
drug sponsor cannot reach agreement on labeling changes within 180 days
of when FDA received the application and the only issue holding up FDA
approval is the wording of the drug labeling. However, FDA officials
said they have never used this process because labeling has never been
the only unresolved issue for those applications whose review period
exceeded 180 days. Agency officials told us that the possibility of
referral to the Pediatric Advisory Committee facilitates its
negotiations with drug sponsors on labeling changes because it is
something that drug sponsors want to avoid. Reminding the drug sponsors
that such a process exists has motivated drug sponsors to complete
labeling change negotiations by reaching agreement with FDA. (See app.
VII for a discussion of strengths of BPCA identified by FDA and NIH, as
well as suggestions for ways to improve BPCA.)
Drugs Studied under BPCA Address a Wide Range of Diseases, Including
Some That Are Common, Serious, or Life Threatening to Children:
Drugs were studied under BPCA for their safety and effectiveness in
treating children for a wide range of diseases, including some that are
common, serious, or life threatening. We found that the drugs studied
under BPCA represented more than 17 broad categories of disease. The
category that had the most drugs studied under BPCA was cancer, with 28
drugs. In addition, there were 26 drugs studied for neurological and
psychiatric disorders, 19 for endocrine and metabolic disorders, 18
related to cardiovascular disease--including drugs related to
hypertension, and 17 related to viral infections. Written requests for
some types of drugs were more frequently declined by the drug sponsor
than others. For example, 36 percent of written requests for pulmonary
drugs and 41 percent of written requests for drugs that treat nonviral
infection were declined. In contrast, 19 percent of written requests
were declined overall.
Some of the drugs studied under BPCA were for the treatment of diseases
that are common, including those for the treatment of asthma and
allergies. Analysis of two national databases shows that about half of
the 10 most frequently prescribed drugs for children were studied under
BPCA. Based on a survey of prescriptions written by physicians in 2004,
4 of the 10 drugs most frequently prescribed for children were studied
under BPCA.[Footnote 30] A survey of families and their medical
providers in 2003 found that 5 of the 10 drugs most frequently
prescribed for children were studied under BPCA.[Footnote 31] In
addition, several of the drugs studied under BPCA were for the
treatment of diseases that are serious or life threatening to children,
such as hypertension, cancer, HIV, and influenza. Table 4 provides
information on some of the drugs studied for pediatric use and what is
known about the diseases that are relevant to children.
Table 4: Examples of Diseases to Be Treated by Drugs Studied under
BPCA:
Specific disease treated by drug: Allergies;
Information about the disease: Allergies affect up to 40 percent of, or
about 29 million, children in the United States.
Specific disease treated by drug: Asthma;
Information about the disease: Asthma affects 6.2 million or 9 percent
of children in the United States. Further, asthma is the most common
chronic illness among children.
Specific disease treated by drug: Cancer;
Information about the disease: Cancer is the leading cause of death by
disease for children aged 1 to 14 in the United States.
Specific disease treated by drug: HIV;
Information about the disease: About 20 percent of HIV-infected
children worldwide develop serious disease before they turn 1, and most
of those die before age 4. Through the end of 2002, 9,300 children
under age 13 in the United States were living with HIV.
Specific disease treated by drug: Hypertension;
Information about the disease: An estimated 3.25 million (4.5 percent )
children in the United States have high blood pressure. Untreated, high
blood pressure can lead to damage to the heart, brain, kidneys, and
eyes.
Specific disease treated by drug: Influenza;
Information about the disease: Population-based studies show that 15 to
42 percent of preschool and school-aged children contract the flu.
Influenza can have serious complications for children, including
pneumonia and dehydration, and can lead to death. In the 2003-2004 flu
season, more United States children died from the flu than chicken pox,
whooping cough, and measles combined, and nearly two-thirds were under
the age of 5.
Source: GAO analysis.
Note: Based on data published from 2000 through 2006.
[End of table]
Some of the drugs were studied under BPCA to treat complicating
conditions in children who had other diseases, while others treated
rare diseases. For example a drug was studied for the treatment of
painful bladder spasms in children who have spina bifida. Other drugs
were studied to treat overactive bladder symptoms in children with
spina bifida and cerebral palsy, to treat children who require chronic
pain management because of severe illnesses such as cancer, and to
treat partial seizures and epilepsy in children who require more than
one drug to control seizures. About 12 percent of the 52 drugs that
were granted pediatric exclusivity under BPCA were studied for the
treatment of rare diseases, including certain types of leukemia,
juvenile rheumatoid arthritis, and narcolepsy.
Agency Comments and Our Evaluation:
HHS provided written comments on a draft of this report, which we have
reprinted in appendix VIII. HHS stated that the draft report provided a
significant amount of data and analysis and generally explains the BPCA
process. HHS also made four general comments. First, HHS commented that
the report does not sufficiently acknowledge the success of BPCA. HHS
noted that BPCA provides additional incentives for the study of on-
patent drugs, a process for the study of off-patent drugs, a safety
review of all drugs granted pediatric exclusivity, and the public
dissemination of information from pediatric studies conducted. HHS
concluded that BPCA has generated more clinical information for the
pediatric population than any other legislative or regulatory effort to
date. Second, HHS commented that the report confuses FDA's process for
reviewing reports of drug studies conducted under BPCA with time frames
for the labeling dispute resolution process outlined in BPCA. HHS
suggested that we did not sufficiently acknowledge that some of the
time it takes for FDA to approve labeling changes includes time spent
by sponsors collecting and submitting additional information. Third, in
commenting on our finding that few written requests included neonates,
HHS pointed out that written requests for 9 drugs required the
inclusion of "newborns" and written requests for 13 drugs required the
inclusion of infants (children under 4 months of age). Fourth, HHS
commented that we failed to mention that exclusivity attaches to
patents as well as existing market exclusivity.
We believe that the draft report sent to HHS for comment accurately and
adequately addressed each of the four issues upon which HHS commented.
An explicit discussion of the overall success of BPCA was outside the
scope of this report, as directed by the BPCA mandate and as discussed
with the committees of jurisdiction. Nevertheless, the draft report
extensively discussed HHS accomplishments such as the number of studies
conducted, the number and importance of labeling changes that FDA
approved, and the wide range of diseases, including some that are
common, serious, or life threatening to children, for which drugs were
studied.
In drafting our report we believe we clearly distinguished between
FDA's goals for completing its review and approval of drug applications
and the time frames mandated for using the labeling dispute resolution
process as outlined in BPCA. In finding that the process for approving
labeling changes is lengthy, we clearly stated that the process
included time spent during FDA's initial review as well as time drug
sponsors took to respond to FDA's requests for additional information,
which was as long as 1 year. We also acknowledged that FDA completed
its initial review of applications within its 180-day goal. We stated
in the draft that FDA has never used the dispute resolution process
because labeling has never been the only issue preventing FDA's
approval of a label for more than 180 days. Nevertheless, we have
included additional language in this report to further clarify the
distinction between FDA's review process for pediatric applications and
labeling dispute resolution.
Our draft clearly stated that while written requests issued under BPCA
required the inclusion of neonates, the majority of those on-patent
written requests--32 of 36--had been first issued under FDAMA. It is
therefore not appropriate to attribute the inclusion of neonates in
these written requests to BPCA. Further, we included in our count of
written requests requiring the inclusion of neonates the 9 written
requests that HHS referred to in its comments as requiring the
inclusion of newborns. We did not specifically include in our counts
the other 13 written requests mentioned in HHS's comments. According to
data provided by FDA, 1 of these written requests was not issued under
BPCA, and 2 others were counted among the 9 mentioned above. The
remaining 10 written requests were not specifically included in our
counts, because the written requests were first issued prior to BPCA
and do not specifically require the inclusion of neonates. The written
requests to which HHS referred in its comments required the inclusion
of very young children, age 0-4 months. Our draft report had indicated
that written requests requiring the inclusion of young children might
produce data about neonates.
Our draft report included language that indicated the conditions under
which pediatric exclusivity applies. We added language to the report to
further clarify the conditions under which pediatric exclusivity can be
granted.
HHS provided technical comments which we incorporated as appropriate.
HHS also stated that many of the oral comments provided by FDA were not
reflected in the draft report sent to HHS for formal comment. Some of
FDA's suggested revisions and comments were outside the scope of the
report and in some instances we chose to use alternative wording to
that suggested by FDA for readability and consistency. As we did with
HHS's general and technical comments on this report, we previously
incorporated FDA's oral comments as appropriate.
We are sending copies of this report to the Secretary of Health and
Human Services, appropriate congressional committees, and other
interested parties. We will also make copies available to others upon
request. In addition, the report will be available at no charge on
GAO's Web site at http://www.gao.gov. If you have any questions about
this report, please contact me at (202) 512-7119 or crossem@gao.gov.
Contact points for our Offices of Congressional Relations and Public
Affairs may be found on the last page of this report. GAO staff who
made major contributions to this report are listed in appendix IX.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Scope and Methodology:
In this report, we (1) assessed the extent to which pediatric drug
studies were being conducted for on-patent drugs under the Best
Pharmaceuticals for Children Act (BPCA), including when drug sponsors
declined to conduct the studies; (2) evaluated the impact of BPCA on
labeling of drugs for pediatric use and the process by which the
labeling was changed; and (3) illustrated the range of diseases treated
by the drugs studied under BPCA.
Our review focused primarily on those on-patent drugs for which written
requests were issued or reissued by the Department of Health and Human
Services' (HHS) Food and Drug Administration (FDA) from January 2002,
when BPCA was enacted, through December 2005. Actions taken on these
drugs after December 2005 (such as a determination of pediatric
exclusivity or a labeling change) were not included in our review. In
addition, we reviewed some summary data available about the number of
written requests issued under the Food and Drug Administration
Modernization Act of 1997 (FDAMA) from January 1998 through December
2001. We also reviewed pertinent laws, regulations, and legislative
histories.
To assess the extent to which pediatric drug studies were being
conducted for on-patent drugs under BPCA, including when the drug
sponsors declined to conduct the studies, we identified written
requests issued for on-patent drugs from January 2002 through December
2005, and determined which of those were declined by drug sponsors. We
also reviewed data provided by FDA on the nature of the pediatric drug
studies that were conducted in response to the written requests issued
under BPCA. We also examined notices published in the Federal Register,
identifying the drugs designated by HHS's National Institutes of Health
(NIH) as most in need of study in children. We reviewed data provided
to us by the Foundation for the National Institutes of Health (FNIH)--
a nonprofit corporation independent of NIH--about funding for pediatric
drug studies of on-patent drugs. We interviewed officials from FDA,
NIH, and FNIH to understand the processes by which pediatric drug
studies are prioritized by the agencies, written requests are issued,
drug sponsors respond to written requests, study results are submitted
to FDA, and pediatric exclusivity determinations are made. We also
reviewed background material describing the role of FNIH in supporting
research on children and the funding available for such research.
To evaluate the impact of BPCA on the labeling of drugs for pediatric
use and the process by which the labeling was changed, we reviewed data
provided to us by FDA summarizing the changes made from January 2002
through December 2005 for drugs studied under BPCA. We also used the
dates that the changes were approved in order to calculate how long it
took for FDA to approve labeling changes. We interviewed officials from
FDA about the process by which FDA approves labeling changes as well as
the reasons why some drugs did not have labeling changes.
To illustrate the range of diseases treated by the drugs studied under
BPCA, we reviewed data provided by FDA about the disease each drug was
proposed to treat. We also examined data from the Medical Expenditure
Panel Survey--administered by the Agency for Healthcare Research and
Quality--and the National Ambulatory Medical Care Survey--administered
by the National Center for Health Statistics--to assess the extent to
which the drugs studied under BPCA were prescribed to children.
To obtain other information that is provided in appendixes to this
report, we collected and analyzed a variety of data from FDA, NIH, and
FNIH about written requests and pediatric studies for both on-and off-
patent drugs. To obtain a broad perspective on the many issues
addressed in our report, we also interviewed representatives of the
pharmaceutical industry and health advocates--such as representatives
of the American Academy of Pediatrics, the Pharmaceutical Research and
Manufacturers of America, the Generic Pharmaceutical Association, the
National Organization of Rare Disorders, Public Citizen, the Elizabeth
Glaser Pediatric AIDS Foundation, and the Tufts Center for the Study of
Drug Development.
We evaluated the data used in this report and determined that they were
sufficiently reliable for our purposes. We conducted our work from
September 2005 through March 2007 in accordance with generally accepted
government auditing standards.
[End of section]
Appendix II: FDA and NIH Efforts to Encourage the Study of Drugs in
Neonates since Passage of BPCA:
FDA and NIH have engaged in efforts to increase the inclusion of
neonates--children under the age of 1 month--in pediatric drug studies.
As part of its encouragement of pediatric studies in general, BPCA
identified neonates as a specific group to be included in studies, as
appropriate. An examination of the written requests revealed that only
4 of 36 written requests for on-patent drugs first issued under BPCA
required the inclusion of neonates. Further, no written requests for on-
patent drugs and only two written requests for off-patent drugs have
required the inclusion of neonates since FDA and NIH held a workshop
that began their major initiative in this regard in 2004.
NIH Workshops:
In 2003, NIH conducted three workshops focused on increasing the
inclusion of neonates in pediatric drug studies and discussing diseases
that affect neonates. In September 2003, NIH staff met to discuss drug
studies in neonatology and pediatrics with special emphasis placed on
ways to better apply current knowledge in future pediatric drug
studies. Two months later, NIH met with a group of experts to discuss
the use of the drug dobutamine--used to treat low blood pressure--in
neonates. NIH ended 2003 with a 1-day seminar designed to address
parental attitudes toward neonatal clinical trials.
NIH Initiatives:
FDA and NIH have collaborated to develop the Newborn Drug Development
Initiative (NDDI), a multiphase program intended to identify gaps in
knowledge concerning neonatal pharmacology and pediatric drug study
design and to explore novel designs for studies of drugs for use by
neonates. The NDDI is intended to consist of a series of meetings that
will help frame state-of-the-art approaches and research needs. After
forming various discussion groups in February 2003, the agencies held a
workshop in March 2004 to help frame issues and challenges associated
with designing and conducting drug studies with neonates. The workshop
addressed ethical issues and drug prioritization in four specialty
areas: pain control, pulmonology (the study of conditions affecting the
lungs and breathing), cardiology (the study of conditions affecting the
heart), and neurology (the study of disorders of the brain and central
nervous system). For example, participants in the pain control group
reviewed data demonstrating that neonates who undergo multiple painful
procedures and receive medication to treat pain may differ in their
development of pain receptors compared to those who do not undergo such
procedures and treatment. FDA officials said that FDA would apply the
findings from the NDDI workshop to written requests for pediatric drug
studies in the four specialty areas.
NIH officials said that the Pediatric Formulations Initiative is a
related effort. They said that both initiatives are long-standing
activities that engage in various efforts to enhance information
dissemination to improve all pediatric drug studies. According to NIH
officials, these initiatives have resulted in numerous publications.
Pediatric Drug Studies Requiring the Study of Neonates:
FDA and NIH efforts to increase the inclusion of neonates in pediatric
drug studies conducted under BPCA have been limited. Through 2005, 9 of
16 (56 percent) written requests for off-patent drugs required the
inclusion of neonates in the pediatric drug studies. NIH is currently
funding pediatric drug studies for four of these written requests.
Similarly, 36 of 214 (17 percent) written requests for the study of on-
patent drugs issued from January 2002 through December 2005 included a
requirement to study neonates, but only 4 of those 36 (11 percent) were
first issued under BPCA. The remaining 32 (89 percent) written requests
were originally issued under FDAMA, which did not place an emphasis on
the inclusion of neonates in pediatric drug studies. Further, all of
the written requests requiring the inclusion of neonates were issued in
2003, prior to the NDDI. Further, only two of the written requests for
off-patent drugs were issued after the NDDI, and studies for neither of
those have been funded. According to information provided by FDA, no
written requests for on-patent drugs issued from January 2004 through
December 2005 required the inclusion of neonates. FDA officials
indicated, however, that they receive information about neonates in
response to written requests that do not specifically target them.
According to these officials, many written requests require that
children from birth through 2 years of age be studied. These pediatric
drug studies therefore may include neonates. In addition, inclusion of
neonates in some studies may not be appropriate for medical or ethical
reasons.
[End of section]
Appendix III: NIH Efforts to Support Pediatric Drug Studies:
BPCA was designed in part to increase pediatric drug studies through
federal efforts. NIH has engaged in several efforts to support
pediatric drug studies since the passage of BPCA.
NIH Funding:
While NIH plays an important role in providing funding for research for
children, the amount provided by NIH to support such activities has not
increased significantly under BPCA. Since the enactment of BPCA, NIH
funding for children's research has increased from $3.1 billion in
fiscal year 2003 to $3.2 billion in fiscal year 2005. These figures
represent about 11 percent of NIH's total budget each year from 2003
through 2005. The research funds for children were distributed by most
of NIH's 28 institutes, centers, and offices.[Footnote 32] For example,
in 2005, 24 of these institutes, centers, and offices funded research
on children. One institute, the National Institute of Child Health and
Human Development, was responsible for about 26 percent of funding for
pediatric research--the largest proportion of NIH's research funding
for children. This institute organizes study design teams with FDA and
other relevant NIH institutes, conducts contracting activities, and
modifies drug labeling for specific ages and diseases.
Pediatric Pharmacology Research Units:
The number of pediatric pharmacology research units--initiated by NIH-
-devoted to studies for children has remained the same under
BPCA.[Footnote 33] NIH provides about $500,000 annually to each of
these research units to provide the infrastructure for independent
investigators to initiate and collaborate on studies and clinical
trials with private industry and NIH. The number of such research units
grew from 7 in 1994 to 13 in 1999 to support the infrastructure for
collaborative efforts of pharmacologists to conduct clinical trials
that include children. While the number has not changed since the
passage of BPCA in 2002, NIH officials said that staff from these units
often move on to hospitals throughout the country and enhance the
pediatric research capacity nationwide. In addition, they said that an
overall increase in pediatric research capacity nationwide in recent
years has made it possible to conduct pediatric clinical trials at a
number of other sites. They said that, on average, these pediatric
pharmacology research units conduct more than 50 pediatric drug studies
annually. Of these, as many as 20 pediatric drug studies are funded by
drug sponsors. NIH officials told us that of the seven off-patent drugs
being studied under BPCA with NIH funding through 2005, two were being
conducted by these research units. NIH officials said that since on-
patent written requests are not published, the full contribution of the
research units under BPCA cannot be ascertained.
Meetings and Forums:
NIH has sponsored a number of forums designed to increase the number of
children included in drug studies. As shown in table 5, these forums
generated advice and suggestions for NIH concerning drug testing from
health experts, process improvements on drug studies and medication use
with the pediatric community, and explanations of models and data
related to research for children.
Table 5: NIH-Sponsored Activities, through 2005, Related to Children in
Clinical Trials:
Year(s): 2002, 2003, 2004, 2005;
Activity focus: Pediatric experts offered advice to NIH concerning
drugs that should be studied for use by children, leading to the
published list of off-patent drugs in the Federal Register.
Year(s): 2003;
Activity focus: Discussed ways to improve access to information on the
frequency of medication use by children and improve the list
development process surrounding the measurement of this frequency.
Year(s): 2003;
Activity focus: Discussed ways to use current knowledge to better
inform future studies of drugs in children.
Year(s): 2003;
Activity focus: Discussed the use of two drugs, dobutamine and
dopamine, in neonates.
Year(s): 2003;
Activity focus: Discussed parent attitudes toward studies of neonates
and other issues related to the consent for studies in children.
Year(s): 2004;
Activity focus: Explored diverse models useful in understanding
efficacy and toxicity of drugs across the course of development.
Year(s): 2005;
Activity focus: Discussed the development of treatment strategies and
recommendations for drugs to be studied in managing pediatric
hypertension.
Year(s): 2005;
Activity focus: Reviewed and analyzed databases used to describe the
frequency of health conditions leading families to seek care for their
children in different outpatient health care delivery settings, such as
pediatric clinics and offices, and inpatient hospital settings. Those
conditions leading to death were also part of the review.
Year(s): 2005;
Activity focus: Reviewed and analyzed databases available to describe
the frequency of use of medications by children in outpatient delivery
settings.
Year(s): 2005;
Activity focus: Discussed challenges from lack of appropriate pediatric
formulations and improvements of pediatric therapeutics.
Source: NIH.
[End of table]
NIH has also conducted meetings and entered numerous intra-agency and
FDA agreements to strengthen its relationship with FDA and establish a
firm commitment to study medical issues relevant to children. For
example, NIH conducted a series of internal meetings in fiscal year
2004 to identify ongoing pediatric drug studies by the National
Institute of Mental Health. As an outcome of these meetings, NIH
identified and utilized data sets related to the study of lithium as it
is used for the treatment of bipolar disorder in children. NIH will use
this information to enhance its current understanding of the drug's
therapeutic benefit.
[End of section]
Appendix IV: Studies of Off-Patent Drugs under BPCA:
In addition to providing a mechanism to study on-patent drugs, BPCA
also contains provisions for the study of off-patent drugs. FDA
initiates its process by issuing a written request to the drug sponsor
to study an off-patent drug. If the sponsor declines to study the drug,
FDA can refer the study of the drug to NIH for funding. NIH initiates
the BPCA process for off-patent drugs by prioritizing the list of drugs
that need to be studied.
Written Requests for Studies of Off-Patent Drugs under BPCA:
BPCA includes a provision that provides for the funding of the study of
off-patent drugs by NIH. BPCA requires that NIH--in consultation with
FDA and other experts--publish an annual list of drugs for which
additional studies are needed to assess their safety and effectiveness
in children.[Footnote 34] FDA can then issue a written request for
pediatric studies of the off-patent drugs on the list. If the written
request is declined by the drug sponsor, NIH can fund the studies.
Few off-patent drugs identified by NIH as in need of study for
pediatric use have been studied. From 2003 through 2006, NIH has listed
off-patent drugs that were recommended for study by experts in
pediatric research and clinical practice.[Footnote 35] By 2005, NIH had
identified 40 off-patent drugs that it believed should be studied for
pediatric use.[Footnote 36] Through 2005, FDA issued written requests
for 16 of these drugs.[Footnote 37] All but one of these written
requests were declined by drug sponsors. NIH funded pediatric drug
studies for 7 of the remaining 15 written requests declined by drug
sponsors through December 2005.
NIH provided several reasons why it has not pursued the study of some
off-patent drugs that drug sponsors declined to study. Concerns about
the incidence of the diseases that the drugs were developed to treat,
the feasibility of study design, drug safety, and changes in the drugs'
patent status have caused the agency to reconsider the merit of
studying some of the drugs it identified as important for study in
children.[Footnote 38] For example, in one case NIH issued a request
for proposals to study a drug but received no response. In other cases,
NIH is awaiting consultation with pediatric experts to determine the
potential for study.
Further, NIH has not received appropriations specifically for funding
pediatric drug studies under BPCA. Rather, according to agency
officials, NIH uses lump sum appropriations made to various institutes
to fund pediatric drug studies under BPCA. In fiscal year 2005, NIH
spent approximately $25 million for these pediatric drug studies.
Funding for Studies of Off-Patent Drugs under BPCA:
NIH anticipates spending an estimated $52.5 million for pediatric drug
studies following seven written requests to drug sponsors issued by FDA
from January 2002 through December 2005.[Footnote 39] These pediatric
drug studies were designed to take from 3 to 4 years and will be
completed in 2007 at the earliest. Where possible, NIH identifies
another government agency or institute within NIH that might be able to
meet the requirements of the written requests and conduct the pediatric
drug studies. In cases where a government agency will conduct the
pediatric drug studies, NIH institutes enter into intra-or interagency
agreements for the studies. If those efforts fail, the agency develops
and publishes requests for proposals for others to conduct the
pediatric studies. NIH anticipates spending approximately $16.0 million
for the funding of pediatric drug studies of four additional off-patent
drugs for which FDA did not issue written requests--and therefore are
not covered by the requirements of BPCA--but three of these drugs have
since been listed by NIH in the Federal Register as needing study in
children.[Footnote 40] (See table 6.)
Table 6: Anticipated NIH Spending for Off-Patent Drug Studies Committed
to through 2005:
Studies for drugs with a written request.
Drug: Dactinomycin[B];
Total cost[A]: Studies for drugs with a written request: $1,800,000[C];
Disease or condition: Cancer;
Funded agency or organization: Children's Oncology Group through the
National Cancer Institute;
Anticipated completion: 2007.
Drug: Hydroxyurea;
Total cost[A]: Studies for drugs with a written request: $7,000,000[C];
Disease or condition: Sickle cell;
Funded agency or organization: National Heart Lung and Blood Institute;
Anticipated completion: 2008.
Drug: Lithium;
Total cost[A]: Studies for drugs with a written request:
$17,400,000[C];
Disease or condition: Mania in bipolar disorder;
Funded agency or organization: Case Western University;
Anticipated completion: 2008.
Drug: Lorazepam (two diseases/conditions);
Total cost[A]: Studies for drugs with a written request:
$15,100,000[D];
Disease or condition: Status epilepticus (seizures);
Funded agency or organization: National Institutes of Health;
Anticipated completion: 2008.
Drug: Lorazepam (two diseases/conditions);
Total cost[A]: Studies for drugs with a written request:
$15,100,000[D];
Disease or condition: Sedation;
Funded agency or organization: National Institutes of Health;
Anticipated completion: 2008.
Drug: Sodium nitroprusside;
Total cost[A]: Studies for drugs with a written request: $9,400,000[C];
Disease or condition: Control of blood pressure;
Funded agency or organization: Stanford University and Duke University;
Anticipated completion: 2007.
Drug: Vincristine[B];
Total cost[A]: Studies for drugs with a written request: $1,800,000[C];
Disease or condition: Malignancies;
Funded agency or organization: Children's Oncology Group through the
National Cancer Institute;
Anticipated completion: 2007.
Drug: Subtotal;
Total cost[A]: Studies for drugs with a written request: $52,500,000;
Disease or condition: [Empty];
Funded agency or organization: [Empty];
Anticipated completion: [Empty].
Studies initiated prior to a written request[E].
Drug: Daunomycin (Daunorubicin);
Total cost[A]: Studies for drugs with a written request: $1,400,000[C];
Disease or condition: Cancer;
Funded agency or organization: Children's Oncology Group through the
National Cancer Institute;
Anticipated completion: 2008.
Drug: Ketamine;
Total cost[A]: Studies for drugs with a written request: $1,000,000[D];
Disease or condition: Sedation;
Funded agency or organization: FDA's National Center for Toxicological
Research;
Anticipated completion: 2008.
Drug: Methotrexate;
Total cost[A]: Studies for drugs with a written request: $8,900,000[D];
Disease or condition: Cancer;
Funded agency or organization: Children's Oncology Group through the
National Cancer Institute;
Anticipated completion: 2009.
Drug: Methylphenidate;
Total cost[A]: Studies for drugs with a written request: $4,700,000[F];
Disease or condition: Attention deficit hyperactivity disorder;
Funded agency or organization: National Institute of Environmental
Health Sciences;
Anticipated completion: 2007.
Drug: Subtotal;
Total cost[A]: Studies for drugs with a written request: $16,000,000;
Disease or condition: [Empty];
Funded agency or organization: [Empty];
Anticipated completion: [Empty].
Drug: Total;
Total cost[A]: Studies for drugs with a written request: $68,500,000;
Disease or condition: [Empty];
Funded agency or organization: [Empty];
Anticipated completion: [Empty].
Source: GAO analysis of NIH data.
[A] Total costs proposed for most studies are estimates and may vary
over time because of modifications of initial projects, rounded to the
nearest $100,000.
[B] Dactinomycin and Vincristine are commonly used together and the
cost to study both is $3,600,000.
[C] Studies to be completed over 3 years.
[D] Studies to be completed over 4 years.
[E] No written request was issued by FDA for the specific studies prior
to being funded by NIH. Ketamine is listed in the Federal Register as a
drug in need of study in children (69 Fed. Reg. 7243-44, Feb. 13,
2004). Because of data demonstrating that ketamine enhances cell death
in the brain in animals, it is not possible to design an ethical study
using children. Ketamine has since been listed in the Federal Register
as having preclinical toxicology studies under way, with clinical
studies awaiting their completion (71 Fed. Reg. 23931-36, Apr. 25,
2006). Methylphenidate was selected, though it is not included on the
list published in the Federal Register, because of a potentially
serious public health concern that arose unexpectedly. HHS officials
reported that studies on ketamine and methylphenidate are not the type
that typically would be requested under BPCA, nor was a written request
issued for these specific studies. Daunomycin and methotrexate were
selected prior to being listed in the Federal Register because the
National Cancer Institute had access to the appropriate children for
study and was developing studies that would produce data for both
drugs.
[F] Studies to be completed over 2 years.
[End of table]
The drugs whose study NIH is funding without written requests were
selected because of special circumstances that raised their priority
for funding. NIH funded the study of daunomycin and methotrexate--both
cancer drugs--before placing them on its 2006 list of drugs for study
in children. NIH officials told us that the Children's Oncology Group
of the National Cancer Institute was already working with an
appropriate group of patients and was at a critical stage in developing
the pediatric drug studies that would produce data for both drugs, so
pediatric drug studies were funded before the drugs were placed on the
priority list. NIH officials also told us that ketamine is administered
to more than 30,000 children for sedation each year. Studies done in
animals, however, have suggested that the drug may lead to cell death
in the brain. As a result, the drug cannot be ethically tested in
children. NIH is therefore collaborating with FDA to conduct studies in
nonhuman primates. NIH officials report that methylphenidate is used by
an estimated 2.5 million school-aged children to treat attention
deficit hyperactivity disorder. However, a recent study suggested some
potential genetic toxicity of the drug. Because of these findings, the
drug was targeted as a priority and NIH was able to fund some of the
planned studies related to this drug.
[End of section]
Appendix V: Status of Pediatric Drug Studies Requested by FDA:
From January 2002 through December 2005, FDA issued 214 written
requests for the study of on-patent drugs. The agency also issued 16
written requests for the study of off-patent drugs. Fewer written
requests were issued and more were declined by drug sponsors under BPCA
than under FDAMA.
Written Requests Issued under BPCA Compared to FDAMA:
From January 2002, when BPCA was enacted, through December 2005, FDA
issued or reissued 214 written requests for on-patent drugs, and drug
sponsors declined 41 of those. FDA issued 68 written requests under
BPCA for the study of on-patent drugs,[Footnote 41] 20 (29 percent) of
which were declined by the drug sponsors. FDA reissued 146 written
requests for on-patent drugs that were originally issued under FDAMA
because the pediatric drug studies had not been completed at the time
BPCA went into effect. Included in the 146 were 21 (14 percent) written
requests that were subsequently declined by the drug sponsors.
Therefore, drug sponsors accepted 173 written requests for the study of
on-patent drugs under BPCA during this period. Under FDAMA, FDA issued
227 written requests. Drug sponsors did not conduct pediatric drug
studies or submit study results for 30 of the 227 (13 percent) written
requests issued under FDAMA (see fig. 3).[Footnote 42]
Figure 3: Status of Written Requests Issued under FDAMA and BPCA
through December 2005:
[See PDF for image]
Source: GAO.
Note: If a drug sponsor of an off-patent drug does not respond to FDA's
written request within 30 days, the written request is considered
declined.
[End of figure]
Reasons for Decline in Written Requests Issued and Accepted under BPCA
Compared to FDAMA:
FDA officials offered two primary reasons why fewer written requests
were issued under BPCA than under FDAMA. First, according to FDA
officials, when FDAMA was enacted, FDA and some drug sponsors had
already identified a large number of drugs that they believed needed to
be studied for pediatric use. By the time BPCA was enacted, written
requests for the study of these drugs had already been issued. Second,
FDA officials said there was a surge of written requests prior to the
sunset of FDAMA. Agency officials expect the same surge to occur prior
to the sunset of the pediatric exclusivity provisions of BPCA in 2007.
FDA officials also offered a number of reasons that the proportion of
written requests issued under BPCA that were declined was greater than
that for those issued under FDAMA. While FDA does not track the reasons
that drug sponsors decline specific written requests, FDA officials
expect that a major reason that the written requests were declined is
that the agency sometimes requests more extensive pediatric drug
studies, and therefore more costly studies, than the sponsors would
like to do. This may be the case even when the drug sponsors initiated
the written request process. FDA officials said that upon consideration
of FDA's written requests, drug sponsors may make a business decision
not to conduct the requested pediatric drug studies because they may be
too costly for the expected return associated with pediatric
exclusivity. Agency officials reported that since the drugs studied
under FDAMA were more likely to be those with the greatest expected
financial return or the easiest to study, they are not surprised at the
higher proportion of pediatric drug studies declined under BPCA.
Further, under BPCA drug sponsors are required to pay user fees--as
high as $767,400 in fiscal year 2006--when study results are submitted
for pediatric exclusivity consideration. As a result, the process of
gaining pediatric exclusivity has become more expensive than it was
under FDAMA when drug sponsors were exempt from such fees for pediatric
drug studies.
FDA officials said they are not discouraged by the increase in the
number of written requests that have been declined. In 2001, FDA
reported to Congress that the agency expected drug sponsors to conduct
pediatric drug studies for 80 percent of written requests. The rate at
which written requests for studies of on-patent drugs were accepted
under BPCA--71 percent--is close to the target of 80 percent, and it is
substantially larger than the 15 to 30 percent of drugs that FDA
officials have reported were labeled for pediatric use prior to the
authorization of pediatric exclusivity under FDAMA and BPCA.[Footnote
43]
[End of section]
Appendix VI: Complexity of Completed Pediatric Drug Studies:
The pediatric drug studies conducted under BPCA were complex and
sizable, involving a large number of study sites and children. From
July 2002 through December 2005,[Footnote 44] drug sponsors submitted
study reports to FDA in response to 59 written requests. FDA made
pediatric exclusivity determinations for 55 of those written requests
by December 2005, and most--51, or 93 percent--were made in 90 days or
less.
For the 59 written requests for which study results were submitted to
FDA, a total of 143 pediatric drug studies were conducted at 2,860
different study sites with more than 25,000 children participating (see
table 7). In December 2005, FDA projected that for the drugs for which
studies had not yet been submitted for review, there would be nearly
20,000 more children participating in the studies.
Table 7: Complexity of Pediatric Drug Studies Conducted under BPCA,
According to Study Reports from July 2002 through December 2005:
Count;
Number of individual studies: 143;
Number of study sites for all studies: 2,860;
Number of participants in all studies: 25,397.
Average;
Number of individual studies: 2;
Number of study sites for all studies: 68;
Number of participants in all studies: 430.
Median;
Number of individual studies: 2;
Number of study sites for all studies: 48;
Number of participants in all studies: 255.
Mode;
Number of individual studies: 2;
Number of study sites for all studies: 83;
Number of participants in all studies: 192.
Minimum;
Number of individual studies: 1;
Number of study sites for all studies: 3;
Number of participants in all studies: 11.
Maximum;
Number of individual studies: 7;
Number of study sites for all studies: 232;
Number of participants in all studies: 2,517.
Number of written requests data are based on;
Number of individual studies: 59;
Number of study sites for all studies: 42;
Number of participants in all studies: 59.
Source: GAO analysis of FDA data.
[End of table]
[End of section]
Appendix VII: Strengths of and Suggested Changes for BPCA:
Officials from FDA and NIH discussed a number of important strengths of
BPCA. In our interviews with industry group representatives and in a
public forum, a number of suggestions have also been made for ways that
BPCA could be improved.
Strengths of BPCA Identified by FDA and NIH Officials:
FDA officials identified a number of important strengths of BCPA.
Specifically, they commented on the following:
* Economic incentives to conduct pediatric drug studies. Because of the
economic incentives in BPCA, FDA officials argue that many logistical
issues inherent in conducting pediatric drug studies have been
overcome. FDA may also issue a written request for pediatric drug
studies for rare conditions, offering an additional incentive to
develop medications for rare diseases that occur only in children.
* Availability of summaries of pediatric drug studies. FDA officials
reported that the public dissemination of study summaries has ensured
that study information is available to the health care community and
has been useful to prescribers to know what has been learned about
drugs' use in children.
* Broad scope of pediatric drug studies. BPCA allows FDA to issue
written requests for pediatric drug studies for the treatment of any
disease, regardless of whether the drug in question is currently
indicated to treat that disease in adults. For example, FDA issued a
written request for the study of a drug currently indicated to treat
prostate cancer. The drug is being tested in children to see if it is
effective in treating early puberty in boys.
* Use of dispute resolution as a negotiating tool in ensuring labeling
changes. Although FDA has never invoked its authority under BPCA to use
the dispute resolution process for making labeling changes, it has been
an important negotiating tool. FDA officials indicated that when the
agency has expressed its intention to use the process, the issues that
had been raised in labeling negotiations were effectively resolved.
* Improved safety through focused pediatric safety reviews. BPCA's
requirement that FDA conduct additional monitoring of adverse event
reports for 1 year after a drug is granted pediatric exclusivity has
been useful to FDA in prioritizing safety issues for children. For
example, an analysis of a drug 1 year after pediatric exclusivity was
granted showed that there were deaths among children as a result of
overuse or misuse of the drug. This led the agency to amend the
labeling regarding the appropriate population for the drug.
NIH officials said they have found the process of developing the list
of drugs important for study in children to be extremely helpful. NIH
officials told us that since the inception of BPCA, they have learned a
great deal about existing gaps in the drug development process for
children, including a lack of data about which drugs are used by
children and how frequently. To gather additional information, NIH has
contracted for literature reviews to decrease the possibility that
unnecessary pediatric drug studies are conducted. These officials also
stated that BPCA and the development of the priority list have helped
to solidify an alliance between NIH and FDA, which has led to
discussions and resolutions of scientific and ethical issues relating
to pediatric drug studies.
Suggestions for Changes to BPCA:
The Institute of Medicine convened a forum on pediatric research in
June 2006 where forum participants made suggestions for how BPCA could
be improved.[Footnote 45] In addition, we discussed suggestions for
improving BPCA with interest group representatives. Forum participants
suggested that the timing of the determination of pediatric exclusivity
should parallel the scientific review of a drug application and that
both should be within 180 days of FDA receiving the results from the
pediatric drug studies. FDA's ability to assess the overall quality of
the pediatric drug studies in the 90 days currently allotted for the
review was questioned. Some forum participants also stated that a
longer review period could result in different determinations in some
cases. For example, FDA's scientific review of data related to the
study of one drug showed that the children participating in the
pediatric drug studies had not received the treatments as the drug
sponsors had suggested in their description of the study results. While
the agency had granted the drug sponsor pediatric exclusivity based on
its 90-day review to determine pediatric exclusivity, it might not have
done so based on what was learned during the longer, 180-day scientific
review.
In addition, it was suggested that drug sponsors be required to submit
their study results for pediatric exclusivity determination at least 1
year prior to patent expiration. This would allow the generic drug
industry time to better plan its release of drugs. We were told that
sometimes generic drugs have had to be destroyed because pediatric
exclusivity determinations were made after the generic version of the
drug had been manufactured and the drug's expiration date would not
allow the product to be sold.
Representatives from interest groups would like the written requests to
be public information and would also like FDA to publicly announce when
it receives study results that have been submitted in response to a
written request. This would allow the generic drug industry to better
schedule the introduction of generic drugs into the market.
Other suggestions for how the study of off-patent drugs could be more
effectively encouraged were offered at the forum. A forum participant
suggested that methods similar to those being adopted by the European
Union be implemented. According to forum participants, under new
legislation in Europe, companies that study off-patent drugs will be
offered a variety of incentives, such as 10 years of data protection
(meaning that the data generated to support the marketing of the drug
cannot be used to support another drug, in an effort to delay
competition), the right to use the existing brand name (to enable the
drug sponsor to capitalize on existing brand recognition), and the
ability to add a symbol to the drug labeling indicating the drug has
been studied in children.
Another suggestion was that current fees paid by drug sponsors for
review of their drug applications could be used to fund the study of
off-patent drugs (as well as on-patent drugs that drug sponsors decline
to study). These fees--$767,400 for a new drug application and $383,700
for a supplemental drug application in fiscal year 2006--are collected
from drug sponsors when study results are submitted to FDA for review
and consideration of pediatric exclusivity.
[End of section]
Appendix VIII: Comments from the Department of Health and Human
Services:
Department Of Health & Human Services:
Office of the Assistant Secretary for Legislation:
Washington, D.C. 20201:
Ms. Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
Washington, DC 20548:
Dear Ms. Crosse:
Enclosed are the Department's comments on the U.S. Government
Accountability Office's (GAO) draft report entitled, "Pediatric Drug
Research: Studies Conducted Under Best Pharmaceuticals for Children
Act" (GAO-07-557), before its publication.
We appreciate the effort that went into the analysis of Best
Pharmaceuticals for Children Act statistics and information provided by
FDA to GAO. We are providing General and Technical Comments on the
draft report on the primary substantive issues and factual corrections.
Although we had a telephone conference call with members of the GAO
team on March 7, 2007, to identify factual and technical errors in the
Statement of Facts provided to FDA, many of the corrections we
explained to GAO on March 7 are not reflected in the draft report. To
ensure the data and analysis are not subject to misinterpretation, we
identify the technical corrections that should be made to the draft
report.
Sincerely,
Signed by:
Vincent J. Ventimiglia:
Assistant Secretary for Legislation:
General Comments On The Department Of Health And Human Services On The
Government Accountability Office Draft Report Entitled: "Pediatric Drug
Research studies Conducted Under Best Pharmaceuticals For Children Act
(GAO-07-557):
The HHS Food and Drug Administration (FDA) and the National Institutes
of Health (NIH) are responsible for implementation of the BPCA. FDA has
the primary responsibility for the BPCA exclusivity process. Although
there are no recommendations on BPCA contained in the draft report for
HHS (FDA) comment, we are providing General Comments on several key
substantive issues.
While the GAO draft report has provided a significant amount of data
and analysis and generally explains the BPCA process, the draft report
contains several statements and characterizations, which may provide a
misleading impression to Congress and other readers of the final
report. We believe the general comments provided below are critical to
understanding the public health benefits of BPCA and the full scope of
the program as currently implemented.
* Success of BPCA. The GAO draft report does not acknowledge that BPCA
is a successful program. Although the draft report includes statistics
on how many drugs have been studied in pediatric populations and how
many drugs have been labeled, it fails to state that the pediatric
studies were conducted and drugs were labeled as a result of the BPCA
process. Approximately a quarter of the products studies resulted in
either new safety or dosing labeling information or information
suggesting that the product was ineffective at the dose and manner in
which it was studied. In addition to the important use information now
in labels, BPCA has improved the infrastructure for pediatric drug
development by providing additional incentives for the study of on-
patent drugs, a process for the study of off-patent drugs, a vigorous
and public safety review of all products granted pediatric exclusivity,
and the public dissemination of information in pediatric studies
conducted. As a result, BPCA has generated more clinical information
for the pediatric population than any other legislative or regulatory
effort to date.
Although there have been no finished studies on certain products, such
as those off-patent drugs or drugs for which the sponsor declined to
conduct studies, which have gone through the NIH contracting process,
these are often the most complex studies to conduct and we are
confident that these efforts will show results in the next several
years.
* Label changes under BPCA. The GAO draft report confuses FDA's review
process for pediatric supplements with timeframes described in the BPCA
for labeling dispute resolution. As written, the draft report states
that it often takes a long time to make labeling changes. However, the
time as reported in the draft report includes the review of the
scientific data, requests for additional information, and the sponsor's
submission of additional information that support any labeling changes.
FDA was not negotiating labeling changes for the entire time period as
reported in the draft report.
- Pediatric studies submitted as supplements to a new drug application
by sponsors in response to written requests must be treated as
"priority supplements." FDA's performance goals are to review priority
supplements in 180 days.
- This goal is not a BPCA mandate (although BPCA requires that
pediatric supplements under BPCA receive a priority review). If FDA
determines that the supplement is deficient and requests additional
information from the sponsor, the first scientific review cycle is
completed. A new cycle does not begin until the sponsor submits the
requested information. A supplement cannot be approved and labeling
negotiations generally do not begin until all of the required
information from all of the review cycles is submitted and reviewed.
The multiple review cycles increase the time between the initial
submission and the ultimate approval of labeling change.
- If pediatric studies are submitted as a new drug application and not
a supplement, then it is not required to be reviewed as a priority. FDA
has a performance goal to review new drug applications in 10 months.
- If the application or supplement is otherwise ready for approval and
the only outstanding issue is the need to reach agreement on labeling
changes, the BPCA's dispute resolution process can be utilized. In that
case, in not later than 180 days after submission of the application,
the Commissioner would request that the sponsor make any labeling
changes that the Commissioner deems appropriate. If the sponsor does
not agree to them, the labeling issue should be referred to the
Pediatric Advisory Committee. The Pediatric Advisory Committee is given
90 days after receiving such a referral to review the pediatric study
reports and make a recommendation regarding appropriate labeling
changes. The Commissioner then has 30 days to review the Advisory
Committee recommendations and, if appropriate, make a request that the
sponsor make a labeling change. If the sponsor does not agree, the
Commissioner may deem the drug to be misbranded.
* Study of neonates under BPCA. The GAO draft report, in Appendix II,
states that despite FDA and NIH efforts to increase inclusion of
neonates, defined as children under 1 month of age, in written
requests, few written requests under BPCA include neonates. BPCA
requires the inclusion of neonates in pediatric studies as appropriate,
but in some cases inclusion of neonates may not be appropriate for
medical or ethical reasons. In addition, although no written requests
have specifically required the inclusion of "neonates" as a specific
group, 14 studies of 9 drugs required the inclusion of "newborns" (also
defined as children under 1 month of age and which includes neonates)
and 24 studies of 13 drugs required the inclusion of infants (defined
as children under 4 months of age).
* Pediatric exclusivity attaches to an existing patent or market
exclusivity. The GAO draft report does not mention that pediatric
exclusivity under BPCA attaches to an existing listed patent or any
existing marketing exclusivities held by the drug sponsor. The
exclusivity is not limited to extending market exclusivity, but also
attaches to existing patents even if there is no market exclusivity
left on the drug in question. Like marketing exclusivity, the existence
of a listed patent affects the timing of generic drug application
submission and approval.
[End of section]
Appendix IX: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7119 or crossem@gao.gov:
Acknowledgments:
In addition to the contact named above, Thomas Conahan, Assistant
Director; Shaunessye Curry; Cathleen Hamann; Martha Kelly; Julian
Klazkin; Carolyn Feis Korman; Gloria Taylor; and Suzanne Worth made key
contributions to this report.
FOOTNOTES
[1] The drug "label" refers to written, printed, or graphic material
placed on the drug container, while drug "labeling" is much broader and
includes all labels and other written, printed, or graphic materials on
any container, wrapper, or materials accompanying the drug. 21 U.S.C. §
321(k), (m).
[2] Provisions regarding pediatric studies of drug are generally
codified at 21 U.S.C. § 355a. Pub. L. No. 107-109, 115 Stat. 1408. The
market exclusivity provisions of BPCA will sunset on October 1, 2007.
21 U.S.C. § 355a(n).
[3] BPCA reauthorized and enhanced incentives for conducting pediatric
drug studies that were first established in the Food and Drug
Administration Modernization Act of 1997, Pub. L. No. 105-115, 111
Stat. 2296.
[4] The value of 6 months additional marketing exclusivity is difficult
to assess and depends on a number of factors for which data are not
available. However, a recent study estimated that for some drugs the
benefit of 6 months of marketing exclusivity was quite large, while for
others the return the drug sponsor received for pediatric exclusivity
was less than the cost of the studies. See Jennifer S. Li, et al.,
"Economic Return of Clinical Trials Performed Under the Pediatric
Exclusivity Program," JAMA, vol. 297, no. 5 (2007).
[5] FDA is an agency within the Department of Health and Human
Services.
[6] Drug sponsors can obtain market exclusivity for drugs protected by
patents, as well as for drugs designed to treat rare diseases, drugs
consisting of new chemical entities, and already-marketed drugs
approved for new uses. See for example, 21 U.S.C. §§ 355(j)(5)(F)(ii),
(iii); 21 C.F.R. § 314.108 (2006). Pediatric exclusivity under BPCA
attaches to an existing listed patent or any existing market
exclusivity held by the drug sponsor.
[7] For purposes of this report, we refer to drugs that have patent
protection or market exclusivity as on-patent and those whose patent
protection or market exclusivity has ended as off-patent. This is the
same terminology typically used by government agencies to describe the
exclusivity status of a drug under BPCA.
[8] FDA is responsible for issuing written requests for pediatric
studies, determining whether a drug merits pediatric exclusivity as a
result of those studies, and all steps in between.
[9] FNIH is an independent, nonprofit corporation. The majority of
funds that FNIH receives are from the private sector. Only a portion of
these funds are available for FNIH to award to researchers to conduct
studies related to BPCA.
[10] We previously described how FDAMA was responsible for an increase
in pediatric drug studies. GAO, Pediatric Drug Research: Substantial
Increase in Studies of Drugs for Children, But Some Challenges Remain,
GAO-01-705T (Washington, D.C.: May 8, 2001).
[11] FDA generally defines the pediatric population covered under BPCA
as children from birth to 16 years old, though studies have included
children as old as 18. BPCA provides that neonates be included in
pediatric drug studies, as appropriate. See app. II for information
about federal efforts to encourage the study of drugs in neonates.
[12] FDA officials report that 51 of 134 proposed pediatric study
requests submitted by drug sponsors from 2002 to 2005 did not result in
written requests. Drug sponsors sometimes later submitted revised
proposed pediatric study requests, which resulted in written requests.
[13] Under certain circumstances, FDA could have only 60 days to review
the study report to determine pediatric exclusivity. However, FDA
officials told us that under BPCA, this has never happened. Otherwise,
FDA has 90 days to determine if the studies fairly respond to the
written request, were conducted in accordance with commonly accepted
scientific principles and protocols, and were properly submitted.
[14] Pediatric exclusivity applies to all approved uses of the drug,
not just those studied in children. Therefore, if the studies find that
the drug is not safe for use by children, the drug will still receive
pediatric exclusivity and therefore extended market exclusivity for the
adult uses of the drug.
[15] FNIH can certify that it has insufficient funds to fund the study
of a drug and refer the funding to NIH.
[16] As of fiscal year 2007, NIH is required to transfer from its
appropriations at least $500,000 but no more than $1.25 million to FNIH
annually. This requirement was established with the enactment of the
NIH Reform Act of 2006 (Pub. L. No. 109-482, 120 Stat. 3675 (2007)).
[17] The granting of pediatric exclusivity does not depend on finding
that the drug is safe and effective for pediatric use.
[18] Most drugs studied under BPCA have previously been approved for
marketing in the United States, so a supplement to the original "new
drug application" is submitted. If the drug studied under BPCA was not
previously approved for marketing in the United States, the application
would be submitted as a new drug application. FDA has a performance
goal to review non-priority new drug applications in 10 months.
[19] BPCA requires that supplemental new drug applications submitted by
drug sponsors be treated as "priority supplements." FDA's goal is to
take action on priority supplements within 180 days.
[20] The Pediatric Advisory Committee is also responsible for reviewing
reports of adverse effects related to drugs granted pediatric
exclusivity after the period of exclusivity begins, among other things.
The committee consists of 13 voting members, appointed by the
Commissioner of FDA, who are knowledgeable in pediatric research,
pediatric subspecialties, statistics, and biomedical ethics. The
committee includes one representative from a pediatric health
organization and one from a relevant patient or patient-family
organization.
[21] Some drugs have two written requests for a variety of reasons. In
some cases, FDA may have requested that the drug sponsor study the
effects of the drug on different diseases. In other cases, there could
be two written requests for the same drug, issued to different drug
sponsors for different dosage forms of the drug. In addition, FDA told
us that the specified period for studies to be completed elapsed for
some written requests before the completion of studies, and the agency
issued new written requests. In all of these situations, we counted
each of these written requests separately. Therefore, there are more
written requests than there are unique drugs with written requests.
[22] Of the 214 written requests issued by FDA, 68 were written
requests first issued under BPCA. The remaining 146 written requests
were originally issued under FDAMA and reissued under BPCA because drug
sponsors had not responded to the written requests or completed the
requested pediatric drug studies at the time that BPCA went into
effect.
[23] FDA had not completed its review of the study results to determine
exclusivity prior to December 2005 for the remaining four drugs.
[24] The other three drugs were denied pediatric exclusivity. The dates
that drugs are granted exclusivity and also had labeling changes are
available at [Hyperlink,
http://www.fda.gov/cder/pediatric/labelchange.htm]. The dates of
exclusivity for other drugs are not available on FDA's Web site. Most
of these pediatric drug studies began under FDAMA but were continued
under BPCA. Most of the pediatric drug studies begun in response to
written requests initially issued under BPCA have not yet been
completed.
[25] When a drug sponsor of an on-patent drug declines a written
request, the agency must determine if there is a continuing need for
information relating to the use of the drug in children. Reasons that
FDA has concluded that there is not a continuing need include the drug
was not yet approved, some part of the study was being performed by the
drug sponsor or another party, the drug's patent ended, the risk-
benefit assessment shifted, safe alternative therapies were already on
the market even though the agency had issued the written request in
hope of obtaining additional valuable information, another drug may
have been approved or may soon be approved with a better safety record,
or there is minimal use of the drug by children.
[26] In April 2006, FNIH agreed to allocate all $4.13 million it had
raised for pediatric drug studies under BPCA to fund half the cost to
study one on-patent drug--baclofen. Baclofen was identified by NIH and
FNIH as the highest priority on-patent drug that a drug sponsor had
declined to study. NIH is responsible for developing requests for
proposals for the study of on-patent drugs for pediatric use. The
requests for proposals outline the need for studies of specific drugs
and include the specific details of the studies to be conducted. NIH
requested proposals for the study of baclofen and has selected a
contractor to perform the studies. NIH expects the cost of the study of
baclofen to be about $7.8 million over 3 years, and NIH agreed to cover
the costs of the study that exceed the contribution from FNIH. Because
FNIH has committed all of its BPCA funds to the study of baclofen,
there are no resources left for FNIH to fund the study of any other
drugs.
[27] These drugs had labeling changes made after the drug sponsors
submitted partial results of their studies to FDA. Because some studies
were ongoing, the drug sponsors had not submitted the final study
results to FDA for consideration of pediatric exclusivity.
[28] There were no off-patent drugs for which the pediatric drug
studies indicated that a formulation change was necessary.
[29] These data are based on the dates on which FDA approved the
labeling changes. FDA officials said that manufacturers might not
immediately make approved labeling changes on the printed material
associated with a marketed product. However, this information is posted
on FDA's Web site, generally within 48 hours. Sponsors often update
labeling on a quarterly basis or several times a year, rather than each
time a labeling change is approved. FDA does not track the actual date
that revised labeling enters the market. The dates that FDA agreed to
these labeling changes are reported at [Hyperlink,
http://www.fda.gov/cder/pediatric/labelchange.htm].
[30] National Center for Health Statistics, 2004 National Ambulatory
Medical Care Survey Data File (Hyattsville, Md.: February 2004).
[31] Medical Expenditure Panel Survey (Agency for Health Care Policy
and Research, 2003 Medical Expenditure Panel Survey Household Data File
(Rockville, Md.: November 2005)).
[32] NIH is made up of 28 institutes, centers, and offices that focus
on different health concerns. The mission of NIH overall is to conduct
and support medical research.
[33] Pediatric pharmacology research units are primarily located in
children's hospitals and academic research centers specializing in
research with children.
[34] The list, published in the Federal Register, can include on-patent
and off-patent drugs. NIH did not include on-patent drugs on this list
until 2005.
[35] See 71 Fed. Reg. 23931-36 (Apr. 25, 2006), 70 Fed. Reg. 3937 (Jan.
27, 2005), 69 Fed. Reg. 7243-7244 (Feb. 13, 2004), 68 Fed. Reg. 48402
(Aug. 13, 2003), and 68 Fed. Reg. 2789-2790 (Jan. 21, 2003).
[36] Some drugs have two written requests; in such cases, each written
request is designed to study either the effects of the drug on a
different disease or dosage form, or the drug has two sponsors. In
these cases, we counted each of these written requests separately. For
example, Beclomethasone had written requests issued to two sponsors for
different dosage forms of the drug. An additional 3 off-patent drugs
were identified in 2006. From 2003 through 2006, 12 on-patent drugs
have also been listed as important for study. See 71 Fed. Reg. 23931-
23936 (2006).
[37] Two of these drugs changed patent status after the off-patent
written request was issued because a new formulation of each drug was
approved, resulting in new patents or exclusivities. They have had new
written requests issued and are now considered on-patent drugs. Both
drug sponsors also declined the on-patent written requests.
[38] Since its inception, no drug has been removed from the list
published in the Federal Register, regardless of the feasibility or
likelihood of being studied.
[39] The costs reported by NIH are estimates, which may change during
the course of the studies.
[40] NIH determined that these drugs were a priority for study in
children and certain conditions made it appropriate to initiate studies
prior to FDA being able to issue a written request.
[41] We counted all written requests individually. In some cases, FDA
issued more than one written request for a drug, such as when there was
more than one sponsor, when the first written request was declined by
the drug sponsor and a new written request was issued when FDA became
aware of new information, or when the drug was being studied for more
than one disease (though these studies may also be in the same written
request).
[42] Since FDAMA did not require that drug sponsors accept or decline a
written request, as required by BPCA for on-patent drugs, we could not
determine the exact number of written requests that were declined.
Instead, we were able to determine the number of written requests for
which study results were not submitted under FDAMA and the number of
written requests declined when reissued under BPCA. This is the most
conservative equivalent measure. FDA officials report that it is
possible that studies were conducted under FDAMA and the drug sponsors
decided not to submit them to FDA for exclusivity consideration.
[43] Prior to FDAMA, over a 6-year period from 1991 to 1996, only 11 of
71 requested studies were completed without such an incentive.
[44] For these analyses, we looked at study reports submitted after
July 2002 because those submitted from January 2002 through June 2002
were in response to written requests issued under FDAMA, not BPCA.
[45] Forum on Drug Discovery, Development, and Translation: Addressing
the Barriers to Development in Pediatrics (conference sponsored by the
Institute of Medicine of the National Academies, Washington, D.C., June
2006). The program can be accessed at [Hyperlink,
http://www.iom.edu/CMS/3740/24155/34241.aspx].
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