Pediatric Research
Products Studied under Two Related Laws, but Improved Tracking Needed by FDA Gao ID: GAO-11-457 May 31, 2011In 2007, Congress reauthorized two laws, the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA). PREA requires that sponsors conduct pediatric studies for certain products unless the Department of Health and Human Services' (HHS) Food and Drug Administration (FDA) grants a waiver or deferral. Sponsors submit studies to FDA in applications for review. BPCA is voluntary for sponsors. The FDA Amendments Act of 2007 required that GAO describe the effect of these laws since the 2007 reauthorization. GAO (1) examined how many and what types of products have been studied; (2) described the number and type of labeling changes and FDA's review periods; and (3) described challenges identified by stakeholders to conducting studies. GAO examined data on the studies from the 2007 reauthorization through June 2010, reviewed statutory requirements, and interviewed stakeholders and agency officials.
At least 130 products--80 products under PREA and 50 under BPCA--have been studied for use in children since the 2007 reauthorization. However, FDA cannot be certain how many additional products may have been studied because FDA does not track and aggregate data about applications submitted under PREA that would allow it to manage the review process. FDA was unable to provide information about some applications that had been submitted to the agency that were subject to PREA. Recent improvements to FDA's data system might assist the agency in tracking future applications. Under PREA, FDA has granted most of the study waivers and deferrals requested by sponsors since the 2007 reauthorization. Under BPCA, FDA granted pediatric exclusivity--an additional 6 months of market exclusivity, which generally delays marketing of generic forms of the product--to the sponsors of 44 of the 50 drugs in exchange for conducting pediatric studies. Because BPCA is voluntary, sponsors may decline FDA's request for pediatric studies. Although BPCA includes provisions to encourage the study of drugs when sponsors have declined FDA's request, few drugs have been studied under these provisions. Since the 2007 reauthorization, all of the 130 products with pediatric studies completed and applications reviewed under PREA and BPCA had labeling changes that included important pediatric information. The most commonly implemented labeling change expanded the pediatric age groups for which a product was indicated. The next most common type of labeling change indicated that safety and effectiveness had not been established in pediatric populations and provided a description of the study conducted. Additional labeling changes were recommended for products as a result of FDA's monitoring of adverse events associated with products after they had been approved for marketing. FDA officials said they need to complete their review of the application, including all studies, before they can reach agreement with the sponsor on labeling changes. Stakeholders, including sponsors, pediatricians, and health advocacy organizations, described challenges faced by sponsors that could limit the success of PREA and BPCA. Those challenges included confusion about how to comply with PREA and BPCA due to a lack of guidance from FDA for changes to the laws from the 2007 reauthorization of PREA or BPCA. FDA officials explained that they mitigate this lack of guidance by discussing questions or concerns that sponsors have regarding their pediatric studies with sponsors throughout the process. An additional challenge sponsors described was a lack of economic incentives to study products with no remaining market exclusivity. GAO recommends that the Commissioner of FDA track applications during its review process and maintain aggregate data on applications subject to PREA. HHS agreed that better tracking of information is needed but disagreed with GAO's finding that it does not track applications. While FDA is able to identify the status of individual applications during its review, it has not maintained data that would allow it to better manage its review process.
RecommendationsOur recommendations from this work are listed below with a Contact for more information. Status will change from "In process" to "Open," "Closed - implemented," or "Closed - not implemented" based on our follow up work.
Director: Marcia G. Crosse Team: Government Accountability Office: Health Care Phone: (202) 512-3407GAO-11-457, Pediatric Research: Products Studied under Two Related Laws, but Improved Tracking Needed by FDA
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United States Government Accountability Office:
GAO:
Report to Congressional Committees:
May 2011:
Pediatric Research:
Products Studied under Two Related Laws, but Improved Tracking Needed
by FDA:
GAO-11-457:
GAO Highlights:
Highlights of GAO-11-457, a report to congressional committees.
Why GAO Did This Study:
In 2007, Congress reauthorized two laws, the Pediatric Research Equity
Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA). PREA
requires that sponsors conduct pediatric studies for certain products
unless the Department of Health and Human Services‘ (HHS) Food and
Drug Administration (FDA) grants a waiver or deferral. Sponsors submit
studies to FDA in applications for review. BPCA is voluntary for
sponsors. The FDA Amendments Act of 2007 required that GAO describe
the effect of these laws since the 2007 reauthorization. GAO (1)
examined how many and what types of products have been studied;
(2) described the number and type of labeling changes and FDA‘s review
periods; and (3) described challenges identified by stakeholders to
conducting studies. GAO examined data on the studies from the 2007
reauthorization through June 2010, reviewed statutory requirements,
and interviewed stakeholders and agency officials.
What GAO Found:
At least 130 products”-80 products under PREA and 50 under BPCA-”have
been studied for use in children since the 2007 reauthorization.
However, FDA cannot be certain how many additional products may have
been studied because FDA does not track and aggregate data about
applications submitted under PREA that would allow it to manage the
review process. FDA was unable to provide information about some
applications that had been submitted to the agency that were subject
to PREA. Recent improvements to FDA‘s data system might assist the
agency in tracking future applications. Under PREA, FDA has granted
most of the study waivers and deferrals requested by sponsors since
the 2007 reauthorization. Under BPCA, FDA granted pediatric
exclusivity”an additional 6 months of market exclusivity, which
generally delays marketing of generic forms of the product”to the
sponsors of 44 of the 50 drugs in exchange for conducting pediatric
studies. Because BPCA is voluntary, sponsors may decline FDA‘s request
for pediatric studies. Although BPCA includes provisions to encourage
the study of drugs when sponsors have declined FDA‘s request, few
drugs have been studied under these provisions.
Since the 2007 reauthorization, all of the 130 products with pediatric
studies completed and applications reviewed under PREA and BPCA had
labeling changes that included important pediatric information. The
most commonly implemented labeling change expanded the pediatric age
groups for which a product was indicated. The next most common type of
labeling change indicated that safety and effectiveness had not been
established in pediatric populations and provided a description of the
study conducted. Additional labeling changes were recommended for
products as a result of FDA‘s monitoring of adverse events associated
with products after they had been approved for marketing. FDA
officials said they need to complete their review of the application,
including all studies, before they can reach agreement with the
sponsor on labeling changes.
Stakeholders, including sponsors, pediatricians, and health advocacy
organizations, described challenges faced by sponsors that could limit
the success of PREA and BPCA. Those challenges included confusion
about how to comply with PREA and BPCA due to a lack of guidance from
FDA for changes to the laws from the 2007 reauthorization of PREA or
BPCA. FDA officials explained that they mitigate this lack of guidance
by discussing questions or concerns that sponsors have regarding their
pediatric studies with sponsors throughout the process. An additional
challenge sponsors described was a lack of economic incentives to
study products with no remaining market exclusivity.
What GAO Recommends:
GAO recommends that the Commissioner of FDA track applications during
its review process and maintain aggregate data on applications subject
to PREA. HHS agreed that better tracking of information is needed but
disagreed with GAO‘s finding that it does not track applications.
While FDA is able to identify the status of individual applications
during its review, it has not maintained data that would allow it to
better manage its review process.
View [hyperlink, http://www.gao.gov/products/GAO-11-457] or key
components. For more information, contact Marcia Crosse, (202) 512-
7114 or crossem@gao.gov.
[End of section]
Contents:
Letter:
Background:
At Least 130 Products Have Been Studied in Numerous Therapeutic Areas
under PREA and BPCA, but FDA Does Not Know If Additional Products Have
Been Studied:
All Products with Completed Pediatric Studies Had Labeling Changes,
and FDA's Goals Often Differ from the PREA Requirement for Reaching
Agreement on Labeling Changes:
Stakeholders Identified Agency Guidance, Uncertainty Associated with
Reauthorization, and Lack of Economic Incentives as Potential
Challenges to Conducting Pediatric Studies:
Conclusions:
Recommendation for Executive Action:
Agency Comments and our Evaluation:
Appendix I: Inclusion of Neonates in Drug and Biological Product
Studies:
Appendix II: Inclusion of Ethnic and Racial Minority Participants in
Pediatric Drug Studies:
Appendix III: Pediatric Drug and Biological Product Studies in the
European Union and the United States:
Appendix IV: Comments from the Department of Health and Human Services:
Appendix V: GAO Contact and Staff Acknowledgments:
Tables:
Table 1: Products with Completed or Ongoing Pediatric Studies,
Categorized by Therapeutic Area:
Table 2: Number of Drug and Biological Products That Had Pediatric
Labeling Changes as a Result of Studies Conducted under PREA or BPCA:
Table 3: Number of Labeling Changes for Drug or Biological Products by
Category of Change, September 27, 2007, through June 30, 2010:
Figures:
Figure 1: PREA Process:
Figure 2: BPCA Process for On-Patent Drug or Biological Products:
Figure 3: BPCA Process for Off-Patent Drug or Biological Products:
Figure 4: Reasons Applications Were Granted a Waiver or Deferral,
September 27, 2007, through June 30, 2010:
Figure 5: Written Requests Issued for On-Patent Drug and Biological
Products, September 27, 2007, through June 30, 2010:
Figure 6: Pediatric Advisory Committee (PAC) Recommendations for Drug
and Biological Product Adverse Events, September 27, 2007, through
June 30, 2010:
Abbreviations:
BPCA: Best Pharmaceuticals for Children Act:
DARRTS: Document Archiving, Reporting and Regulatory Tracking System:
EU: European Union:
FDA: Food and Drug Administration:
FDAAA: Food and Drug Administration Amendments Act of 2007:
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:
NIH: National Institutes of Health:
PAC: Pediatric Advisory Committee:
PeRC: Pediatric Review Committee:
PIP: paediatric investigation plan:
PREA: Pediatric Research Equity Act:
PPSR: Proposed Pediatric Study Request:
[End of section]
United States Government Accountability Office:
Washington, DC 20548:
May 31, 2011:
[End of section]
The Honorable Tom Harkin:
Chairman:
The Honorable Michael B. Enzi:
Ranking Member:
Committee on Health, Education, Labor, and Pensions:
United States Senate:
[End of section]
The Honorable Fred Upton:
Chairman:
The Honorable Henry A. Waxman:
Ranking Member:
Committee on Energy and Commerce:
House of Representatives:
Congress and the Department of Health and Human Services' (HHS) Food
and Drug Administration (FDA) have worked to increase the number of
drug and biological products studied for use in children.[Footnote 1]
According to an article by FDA officials, researchers reported in 1999
that 81 percent of products used by children lacked sufficient
information or labeling regarding pediatric use.[Footnote 2],[Footnote
3] Products not labeled for pediatric use place children at risk of
being exposed to ineffective or harmful treatment or receiving
incorrect dosing. Since the late 1990s, Congress has passed laws to
encourage or require product sponsors, typically the product's
manufacturer, to conduct pediatric studies,[Footnote 4] including the
Pediatric Research Equity Act (PREA)[Footnote 5] and the Best
Pharmaceuticals for Children Act (BPCA).[Footnote 6] As a result of
these efforts, prior to the most recent reauthorizations of PREA and
BPCA, pediatric studies resulted in approximately 250 labeling changes
that added or clarified information on pediatric use of the product.
In 2007, as a part of the FDA Amendments Act of 2007 (FDAAA),[Footnote
7] Congress reauthorized PREA and BPCA in order to increase the number
of products studied for use in children. PREA requires that sponsors
conduct pediatric studies for certain drug and biological products
before they are marketed unless FDA grants a waiver or deferral for
some or all pediatric studies. A waiver removes the requirement that
some or all studies be completed, and a deferral allows the sponsor to
conduct a study by a specified date after the product has been
approved for marketing. BPCA, however, is voluntary for the sponsor;
it authorizes FDA to provide an incentive of an additional 6 months of
market exclusivity to product sponsors that conduct pediatric studies
requested by FDA. This market exclusivity generally delays marketing
of generic forms of the product and is known as pediatric exclusivity.
Pediatric exclusivity can only be granted to those products that are
"on-patent"--that is, those that have patent protection or market
exclusivity.[Footnote 8] BPCA also includes provisions (1) to allow
for the funding of pediatric studies of on-patent drugs that the
sponsor declined to study by the Foundation for the National
Institutes of Health (FNIH)[Footnote 9] and (2) to allow for the
conduct of studies of "off-patent" products, which no longer have
market exclusivity, through the National Institutes of Health (NIH).
[Footnote 10]
The results of pediatric studies conducted under PREA and BPCA are
submitted to FDA in an application. The application includes pediatric
study results and suggested labeling changes, among other things.
[Footnote 11] FDA reviews the application and works to come to
agreement with the sponsor on labeling changes, which FDA then
approves as part of its approval of the application.[Footnote 12] PREA
and BPCA require that one year after a product's labeling change is
implemented, any adverse events reported for that product be reviewed.
FDA may require additional labeling changes based on the adverse
events.[Footnote 13]
FDAAA required that we describe the effect PREA and BPCA have had on
the study and labeling of drug and biological products for pediatric
use.[Footnote 14] To respond to the requirement in FDAAA that we
report our findings to you no later than January 1, 2011, we briefed
you on our findings on December 15, 2010. This report contains
information we provided during that briefing as well as additional
information in which you expressed interest. As discussed with the
committees of jurisdiction, we (1) examine how many and what types of
drug and biological products have been studied under PREA and BPCA
since their 2007 reauthorization; (2) describe the number and type of
labeling changes and FDA's review periods for reaching agreement on
these changes for the drug and biological products for which studies
have been completed since the 2007 reauthorization; and (3) describe
challenges identified by stakeholders, including sponsors and other
interested parties, to conducting pediatric studies. FDAAA also
required that we describe efforts by FDA and NIH to encourage studies
in neonates, which are children under the age of one month. We discuss
these efforts in appendix I.
To examine how many and what type of drug and biological products have
been studied under PREA and BPCA since their 2007 reauthorization, we
reviewed FDA and NIH data on products studied in pediatric populations
from the date of the 2007 reauthorization of PREA and BPCA through
June 30, 2010, the most recent date for which data were available at
the time of our analysis.[Footnote 15] Specifically, we examined data
on the number of products for which studies have been completed since
the 2007 reauthorization. These studies were generally initiated prior
to the reauthorization. We also examined data on the number of
products for which studies were initiated since the 2007
reauthorization.[Footnote 16] These studies are generally still
ongoing. We compared FDA's procedures for tracking applications
submitted under PREA to the standards described in the Standards for
Internal Control in the Federal Government.[Footnote 17] In examining
FDA's procedures for tracking data, we examined the agency's ability
to locate individual applications and its ability to track aggregate
data about applications that would allow FDA to manage the review
process, including the total number of applications subject to PREA,
whether those applications were complete, and whether PREA
applications included pediatric studies or requests for waivers or
deferrals at the time of submission. We reviewed FDA data in order to
determine the extent to which FDA waived or deferred the requirement
for sponsors to submit studies under PREA. We also reviewed FDA data
on the therapeutic areas, or conditions treated, for the products
studied under PREA and BPCA. In addition, we interviewed officials
from FDA, NIH, and FNIH.
To describe the number and type of labeling changes and FDA's review
periods for reaching agreement on these changes for drug and
biological products for which studies have been completed since the
2007 reauthorization, we analyzed FDA data on all pediatric labeling
changes from the date of the 2007 reauthorization of PREA and BPCA
through June 30, 2010, the most recent date for which the data were
available at the time of our analysis.[Footnote 18] Specifically, we
determined the number and types of labeling changes that have been
approved both as a result of pediatric studies and reported adverse
events. In addition, we reviewed requirements in PREA and BPCA for
reaching agreement on labeling changes and FDA documents on
performance goals. We also interviewed FDA officials.
To describe challenges identified by stakeholders to conducting
pediatric studies, we interviewed various stakeholders and reviewed
articles written by some of these stakeholders. These stakeholders
included representatives from five drug and biological product
sponsors; three trade groups: the Pharmaceutical Research and
Manufacturers of America, the Biotechnology Industry
Organization,[Footnote 19] and the Generic Pharmaceutical Association;
and several health advocacy organizations, including the American
Academy of Pediatrics, the National Organization for Rare Disorders,
the Elizabeth Glaser Pediatric AIDS Foundation, the Tufts Center for
the Study of Drug Development, the Institute for Pediatric Innovation,
and the Pediatric Pharmacy Advocacy Group. In addition, we interviewed
officials from FDA, NIH, and FNIH.
To assess the reliability of data that FDA and NIH provided, we
interviewed agency officials. FDA and NIH officials described how they
maintained data on pediatric studies conducted under PREA and BPCA,
the resulting labeling changes, and pediatric adverse events. FDA
generally maintained the information in separate files rather than
centralized databases. To the extent possible, we looked for other
sources of information to corroborate or provide perspective on the
data FDA supplied. For example, we looked to data that is posted on
FDA's Web site and compared it, when possible, to data provided
directly by FDA. Although we found that FDA does not maintain certain
data on the programs, we generally found the data that FDA maintains
to be reliable for our purposes.
We conducted this performance audit from December 2009 through May
2011 in accordance with generally accepted government auditing
standards. Those standards require that we plan and perform the audit
to obtain sufficient, appropriate evidence to provide a reasonable
basis for our findings and conclusions based on our audit objectives.
We believe that the evidence obtained provides a reasonable basis for
our findings and conclusions based on our audit objectives.
Background:
The FDA Modernization Act of 1997 (FDAMA) established pediatric
exclusivity for sponsors that conducted pediatric studies for
drugs.[Footnote 20] In 1999, FDA implemented the Pediatric Rule, which
required that sponsors include the results of pediatric studies when
submitting certain new drug or biological product applications.
[Footnote 21] However, in 2002, the Pediatric Rule was declared
invalid by a federal court.[Footnote 22] In 2002, Congress
reauthorized FDAMA's pediatric exclusivity provisions in BPCA, and in
2003, Congress codified much of the Pediatric Rule in PREA, requiring
that pediatric studies be conducted and that the results of those
studies be included in certain new drug or biological product
applications. In September 2007, Congress reauthorized both PREA and
BPCA as a part of FDAAA, and in March 2010, Congress extended
pediatric exclusivity and applicable BPCA provisions to biological
products as a part of the Patient Protection and Affordable Care Act.
[Footnote 23] PREA and BPCA are both set to expire on October 1, 2012.
[Footnote 24]
PREA:
PREA requires that sponsors submit the results of pediatric studies in
certain drug and biological product applications to FDA. Specifically,
PREA applies to drug and biological product applications for any of
the following: a new active ingredient, a new indication, a new dosage
form, a new dosing regimen, or a new route of administration. In
addition, PREA requires that pediatric studies be conducted for the
indications described in the application--that is, the indications for
which the sponsor plans to market the product--but not for any
additional indications.
The 2007 reauthorization of PREA established the Pediatric Review
Committee (PeRC), an internal FDA committee responsible for providing
assistance in the review of pediatric study results and increasing the
consistency and quality of such reviews across the agency.[Footnote
25] The PeRC consists of approximately 40 FDA employees with a range
of expertise, including pediatrics, biopharmacology, statistics,
chemistry, legal issues, pediatric ethics, and others as pertinent to
the pediatric product under review. FDA officials explained that the
PeRC is divided into separate subcommittees for PREA and BPCA.
When a sponsor completes all of the required studies for a drug or
biological product, it submits an application to FDA.[Footnote 26] The
application includes these study results and suggested labeling
changes based on the pediatric studies' findings, among other things.
If the pediatric studies have not been completed, the application must
include a request for a waiver or deferral of the pediatric studies.
PREA established certain criteria under which, at the sponsors'
request, some or all of the required pediatric studies may either be
deferred until a specified date after approval of the product's
application or waived altogether by FDA.[Footnote 27] FDA may also
grant a deferral or waiver on its own initiative, under specified
circumstances. For example, a study required under PREA may be
deferred when additional data on the safety and effectiveness of the
product in adults is needed before the product can be studied for use
in children. If the sponsor requests a deferral, the product's
application must include, among other things, a description of the
planned pediatric studies and a time frame for completion. The study
may be waived when it is determined to be impossible or highly
impracticable, such as when the number of pediatric patients with a
disease that may be treated with that product is too small to study.
Sponsors may conduct multiple studies per product, such as separate
studies for subsets of pediatric populations like infants, children,
and adolescents. FDA may grant waivers or deferrals for only one type
of study, such as in one pediatric age group, or FDA may grant waivers
or deferrals for all pediatric studies of the product.
FDA's review of an application under PREA is part of the agency's
broader review of the entire application. Once the sponsor submits its
application, FDA directs the application to the agency's appropriate
division to review the entire application, including all adult study
results, the pediatric study results, and requests for a waiver or
deferral. FDA may determine that the application is incomplete and
more information is necessary from the sponsor. Generally, when this
happens, FDA notifies the sponsor and waits to finish reviewing the
application until the information is received. According to FDA
officials, toward the end of FDA's review, the division provides
requests for a waiver or a deferral and a summary of the relevant
pediatric data to the PeRC for review. The PeRC provides
recommendations on whether or not the pediatric portion of the
application satisfies PREA requirements and whether to grant or deny a
waiver or deferral. FDA then determines whether or not to approve the
application. As a part of the review process, FDA is required by PREA
to negotiate and reach an agreement with the sponsor on labeling
changes based on pediatric studies within 180 days of the
application's submission.[Footnote 28] If FDA and the sponsor are
unable to reach an agreement on labeling changes within 180 days, they
are required by PREA to proceed to a formal dispute resolution
process. The 2007 reauthorization of PREA provided FDA with authority
to make labeling changes on its own initiative when a product has been
studied for use in children, including when a study does not determine
that the product is safe or effective in pediatric populations.
Therefore, FDA can impose a labeling change unilaterally to describe
FDA's determination about the study results in the event that the
agency cannot reach agreement with the sponsor.
A sponsor can request that a drug or biological product that is
required to be studied under PREA be studied under BPCA as well, to
allow the sponsor of the product to be eligible to receive pediatric
exclusivity.[Footnote 29] According to FDA officials, the sponsor can
make this request through a proposed pediatric study request (PPSR).
If FDA agrees, it issues a formal written request to the sponsor that
outlines, among other things, the nature of the pediatric studies that
the sponsor must conduct in order to qualify for pediatric
exclusivity. (See figure 1.) According to FDA officials, the pediatric
studies requested under BPCA would generally also fulfill the PREA
requirement; however, even if the sponsor does not complete the
studies outlined in the BPCA written request, it is still required to
complete any studies required under PREA. FDA officials said that
pediatric studies conducted under BPCA are generally more extensive
than those required under PREA. For example, the written request could
include studies for indications in addition to those described by the
sponsor in its application, such as those that are relevant to
children.[Footnote 30]
Figure 1: PREA Process:
[Refer to PDF for image: process map]
1) Certain drug or biological products are required to be studied in
pediatric populations unless FDA grants a waiver[A].
2) Sponsor requests that the studies be conducted under BPCA as well:
* FDA grants BPCA study request. Sponsor conducts study under both
PREA and BPCA (See figure 2 for the BPCA process).
* FDA denies BPCA study request.
3) Sponsor conducts pediatric studies of drug or biological products.
* Studies of product are completed and submitted as part of application.
Study deferrals and waivers may also be requested as part of
application.
4) Application:
* Deferral requests:
- Deferral denied: return to #2;
- Deferral approved: deferral period ends: return to #2.
* Waiver requests:
- Waiver denied: return to #2;
- Wavier granted[B]: Process ends: return to #2.
* Study results;
* Suggested labeling changes.
Pediatric Review Committee reviews information from application and
provides recommendations to FDA.[C]
FDA determines whether to approve application.
FDA approves application and reaches agreement with sponsor on
labeling changes;[D] process ends.
Source: GAO analysis of PREA requirements.
[A] PREA applies to drug and biological product applications for any
of the following: a new active ingredient, a new indication, a new
dosage form, a new dosing regimen, or a new route of administration.
[B] If a waiver is granted because the product would be ineffective
and/or unsafe in children, such information must be included in the
product's labeling.
[C] FDA provides requests for a waiver or a deferral and a summary of
the relevant pediatric data to the Pediatric Review Committee for
review.
[D] PREA requires that FDA and the sponsor enter dispute resolution if
the labeling change is not agreed upon within 180 days of the
application's submission.
[End of figure]
BPCA:
Under BPCA, sponsors receive pediatric exclusivity as an incentive to
conduct studies of drug and biological products for use in children.
[Footnote 31] The BPCA process formally begins when FDA determines
that information related to the use of the product in a pediatric
population may produce health benefits and issues a written request
for pediatric studies to the sponsor of a product. Written requests
may be issued for new, not previously marketed, drug or biological
products or to products that are already on the market but still on-
patent. FDA may issue a written request on its own initiative or after
it has received and agreed to a PPSR from a sponsor to conduct a study
under BPCA. The PeRC reviews all written requests and provides
recommendations prior to their issuance to sponsors. According to FDA
officials, in the written request, FDA may ask for more than one study
of a single drug or biological product, such as studies for multiple
indications or separate studies for different age groups, such as
infants, children, and adolescents. BPCA requires that FDA take into
account adequate representation of children of ethnic and racial
minorities when developing written requests.[Footnote 32] (See
appendix II for information on FDA's efforts to ensure the inclusion
of racial and ethnic minorities in pediatric studies.) The sponsor
must respond to FDA within 180 days of receiving the written request
indicating whether the sponsor agrees to the request and, if so, when
the pediatric study will be initiated. If the sponsor does not agree
to the request, the sponsor must state the reasons for declining the
request.
When the pediatric studies are complete, the sponsor submits the
results to FDA in an application, which must include any suggested
labeling changes resulting from the studies' findings. FDA recommends
that the application be submitted 15 months prior to the end of the
sponsor's market exclusivity for the product in order to be considered
for pediatric exclusivity.[Footnote 33] Once the sponsor submits its
application, FDA is to review the sponsor's application in order to
(1) determine whether or not to approve the application, (2) negotiate
and reach an agreement with the sponsor on pediatric labeling changes,
and (3) grant or deny pediatric exclusivity. FDA is to grant pediatric
exclusivity if the study meets the conditions outlined in the written
request, regardless of the study's findings. Specifically, in
determining whether to grant or deny pediatric exclusivity, BPCA
requires that FDA assess whether the studies fairly responded to the
written request, were conducted in accordance with commonly accepted
scientific principles and protocols, and were properly submitted.
[Footnote 34]
During FDA's review of the application, the PeRC may review a summary
of relevant pediatric data from the application and provide
recommendations to FDA on whether or not to grant pediatric
exclusivity. FDA then determines whether or not to approve the
application. In addition, if FDA and the sponsor are unable to reach
an agreement on the labeling changes within 180 days, they are
required by BPCA to proceed to the same formal dispute resolution
process that exists for PREA.[Footnote 35] The 2007 reauthorization of
BPCA provided FDA with authority to make labeling changes on its own
initiative when a product has been studied for use in children,
including when a study does not determine that the product is safe or
effective in pediatric populations. Therefore, FDA can impose a
labeling change unilaterally to describe FDA's determination about the
study results in the event that the agency cannot reach agreement with
the sponsor.
BPCA includes provisions for the conduct of pediatric studies even if
the sponsor declines the written request. If a sponsor declines a
written request by FDA to study an on-patent drug or if a sponsor does
not complete studies outlined in an accepted written request, FDA may
refer the written request to FNIH if it determines that there is a
continuing need for information relating to the use of the drug in the
pediatric population. (See figure 2.) If FNIH is not able to fund all
studies, BPCA requires that FDA consider whether to require the
studies described in the written request under PREA.[Footnote 36]
Figure 2: BPCA Process for On-Patent Drug or Biological Products:
[Refer to PDF for image: process map]
1) FDA determines whether to issue a written request and what should
be included in the request. The written request may be in response to
a sponsor‘s proposed pediatric study request.
(Pediatric Review Committee reviews written requests)
2) No written request is issued: process ends; or:
3) Written request is issued.
4) Sponsor receives written request and determines whether to accept
or decline the written request.
5) Written request is declined:
* FDA decides whether to refer the written request to FNIH:
- Written request is not referred: process ends; or:
- Written request is referred: If sufficient funds are available to
conduct the studies, FNIH receives referral to fund the product
study.[A]
6) Written request (from #4) is accepted.
7) Sponsor conducts pediatric studies of drug or biological product.
Studies of product are completed and submitted as part of application.
8) Application:
Study results;
Suggest labeling changes.
Pediatric Review Committee may review information from application and
provide recommendations to FDA.[B]
FDA determines whether to approve application.
FDA determines whether to grant pediatric exclusivity.[C] and:
FDA approves application and reaches agreement with sponsor on
labeling changes;[D] process ends.
Source: GAO analysis of BPCA requirements.
[A] If FNIH does not have sufficient funds, BPCA requires that FDA
consider whether to require the studies described in the written
request under PREA.
[B] FDA may provide a summary of relevant pediatric data to the
Pediatric Review Committee for review.
[C] According to agency officials, FDA can deny a sponsor pediatric
exclusivity, but still approve labeling changes based on the studies
conducted.
[D] BPCA requires that FDA and the sponsor enter dispute resolution if
the labeling change is not agreed upon within 180 days of the
application's submission.
[End of figure]
The process under BPCA for off-patent products differs from the
process for on-patent products. To further the study of off-patent
products, NIH--in consultation with FDA and experts in pediatric
research--is required to develop and publish a list of priority needs
in pediatric therapeutics, including products or indications that
require study, every 3 years. NIH publishes this list on its Web site
and in the Federal Register.[Footnote 37] NIH may submit a PPSR to FDA
for the study under BPCA of an indication of an off-patent product
that is used for one of the pediatric therapeutic areas described on
the NIH list of priority needs. FDA is then to determine whether to
issue a written request in response to NIH's PPSR to all sponsors of
the drug or biological product, including the product's original
sponsor as well as any manufacturers of the generic product.[Footnote
38] The PeRC reviews all written requests and provides recommendations
prior to their issuance to sponsors. If a sponsor were to accept the
written request, it would conduct the studies outlined in the request
and then submit the study results and any suggested labeling changes
to FDA for review. However, according to FDA officials, a sponsor has
not accepted a written request to study an off-patent product since
the 2007 reauthorization. Off-patent products do not qualify for
pediatric exclusivity, so there are few financial incentives to
conduct the studies.
Under the 2007 reauthorization of BPCA, if the sponsors were to
decline or fail to respond to the written request for an off-patent
product within 30 days, FDA can refer the written request to NIH to
publish a request for proposals to conduct the studies. The sponsors
of off-patent products are not required to respond to a written
request. If within 30 days of FDA's issuance of the written request
the sponsors do not accept or decline the request, FDA considers the
request declined. NIH can then award funds--for example, through
grants or contracts--to entities that have the expertise and ability
to conduct the studies described in the written request. When these
studies are complete, the entity that completed the studies is to
submit the study results to NIH and FDA for review. For off-patent
studies conducted by a sponsor or funded by NIH, FDA is to negotiate
and reach an agreement with the product's sponsors on appropriate
labeling changes resulting from the study findings within 180 days.
(See figure 3.) As is the case with on-patent products studied under
PREA and BPCA, if FDA is unable to reach an agreement on the labeling
changes for an off-patent product within that time, FDA is required by
BPCA to proceed to the formal dispute resolution process.
Figure 3: BPCA Process for Off-Patent Drug or Biological Products:
[Refer to PDF for image: process map]
NIH may submit a proposed pediatric study request.
NIH develops and publishes a list of priority needs in pediatric
therapeutics.
1) FDA determines whether to issue a written request and what should
be included in the request.
(Pediatric Review Committee reviews written requests)
No written request is issued: process ends;
Written request is issued.
2) Sponsor receives Process written request and determines whether to
accept or decline the written request.
Written request is declined[A]: go to #3.
Written request is accepted: go to #6.
3) FDA can refer the written request to NIH.
4) NIH can award funds to entities that have the expertise and ability
to conduct the studies described in the written request: Studies of
product are completed.
5) The entity submits study results, including suggested labeling
changes, to NIH and FDA for review. go to #8.
6) Sponsor conducts studies outlined in the request: Studies of
product are completed.
7) Sponsor submits study results, including suggested labeling
changes, to FDA for review.
8) FDA reviews study results and reaches agreement with sponsors on
labeling changes;[B] process ends.
Source: GAO analysis of BPCA requirements.
[A] FDA also considers the written request to be declined if the
sponsor does not respond to FDA within 30 days.
[B] BPCA requires that FDA and the sponsor enter dispute resolution if
the labeling change is not agreed upon within 180 days of the
submission of study results.
[End of figure]
The Pediatric Advisory Committee:
The Pediatric Advisory Committee (PAC) is an FDA advisory committee
consisting of 14 voting members, who are appointed by the Commissioner
of FDA and are knowledgeable in pediatric research, pediatric
subspecialties, statistics, and/or biomedical ethics. The committee
includes a representative from a pediatric health organization and a
representative from a relevant patient advocacy organization. The PAC
is responsible for reviewing reports of all adverse events reported
for drug and biological products during a one-year period after a
labeling change is made under PREA or BPCA and may review reports of
pediatric adverse events in subsequent years. The committee makes
recommendations to FDA on how to respond to the adverse events. PAC
recommendations can include suggested labeling changes based on the
adverse events, continued heightened monitoring of the product, the
production or revision of a medication guide for consumers, or a
return to routine monitoring of adverse events.
In addition, as required by PREA and BPCA, the PAC is to assist in
FDA's dispute resolution if a proposed labeling change is not agreed
upon by FDA and the sponsor within 180 days of submission of the
application. If a labeling change enters dispute resolution, FDA is to
first request that the sponsor make any labeling changes that FDA has
determined to be appropriate. If the sponsor does not agree, FDA is to
refer the matter to the PAC. The PAC is then to convene to review the
results of the pediatric studies and provide recommendations to FDA on
appropriate changes to the product's labeling, if any. FDA is then to
consider the committee's recommendations and request that the sponsor
make any labeling changes recommended by the PAC that FDA has
determined to be appropriate. If the sponsor does not make the
labeling change, FDA may deem the product misbranded.
Internal Control:
The Standards for Internal Control in the Federal Government provides
the overall framework for establishing guidelines for internal control
that help government managers achieve desired objectives.[Footnote 39]
Internal control, which is synonymous with management control,
comprises the plans, methods, and procedures used to meet missions,
goals, and objectives. Internal control is not one event, but a series
of actions and activities that occur throughout an entity's operations
on an ongoing basis. The responsibility of good internal control rests
with managers; they set the objectives, put the control mechanisms and
activities in place, and monitor and evaluate these mechanisms and
activities. Internal control includes a variety of activities such as
ensuring effective information sharing throughout the organization and
conducting ongoing monitoring of agency activities.
At Least 130 Products Have Been Studied in Numerous Therapeutic Areas
under PREA and BPCA, but FDA Does Not Know If Additional Products Have
Been Studied:
At least 130 products--80 products under PREA and 50 under BPCA--have
been studied for use in children since the 2007 reauthorization.
However, FDA does not know if additional products with pediatric
studies are included in applications for which FDA reviews under PREA
are incomplete. The products studied under PREA and BPCA represent a
wide range of therapeutic areas. In addition, few drugs have been
studied when sponsors have declined written requests.
FDA Cannot be Certain How Many Additional Products Have Been Studied
under PREA; Most Requests for Waivers and Deferrals Have Been Granted:
Since the 2007 reauthorization, at least 80 products have been studied
under PREA, but FDA cannot be certain how many additional products may
have been studied. FDA does not track and aggregate data about
applications submitted under PREA until the PeRC has completed its
review of information from the application. This generally occurs late
in FDA's overall review of the application. Therefore, FDA was unable
to provide information about some applications that had been submitted
to the agency that were subject to PREA. For example, FDA officials
could not provide aggregate data about the total number of
applications, whether the applications were complete or incomplete, or
whether the application included pediatric studies or requests for
waivers or deferrals. Therefore, FDA could not be certain how many
additional applications for which it has not yet completed its review
under PREA include pediatric studies or requests for waivers or
deferrals. This lack of data during the review process about
applications subject to PREA, hampers FDA's ability to manage the
review process, including whether FDA is meeting statutory
requirements and whether the sponsor has complied with PREA's
requirements for pediatric studies.
FDA officials said that approximately 830 applications submitted to
FDA from September 27, 2007, through June 30, 2010, were subject to
PREA, but could not provide a precise number. The PeRC has completed
its review of information from 449 of these applications, 80 of which
contained the results of pediatric studies. Fifty-nine were drugs and
21 were biological products. FDA could not provide information about
the remaining 381 of the approximately 830 applications. Standards for
internal control in the federal government provide that managers need
certain data to determine whether they are meeting their agencies'
missions, goals, and objectives.[Footnote 40] This could include
whether FDA is meeting PREA requirements and whether the sponsor has
complied with PREA's requirements for pediatric studies. FDA officials
explained that these 381 applications were submitted to FDA, and were
under consideration in the relevant FDA division, but had not yet been
reviewed by the PeRC, which advises FDA in its review of pediatric
studies or requests for waivers or deferrals. FDA officials said that
they could not provide any details about these applications without
locating each application individually within the agency and reviewing
it to determine whether it included pediatric studies or requests for
waivers or deferrals, but stated that it is likely that most of the
approximately 381 applications are for products that sponsors plan to
market in adult indications and, therefore, would include a request
for a deferral of the pediatric studies rather than completed
pediatric studies. Although FDA officials could not say how many, they
said that some of the approximately 381 applications may be incomplete
and awaiting further review upon the sponsor's submission of
additional materials, and that some of the applications may have been
withdrawn by the sponsor. However, some of the applications could
include the results of completed pediatric studies. Therefore, the
total number of products with studies completed under PREA may be
greater than 80.
HHS officials stated in its comments on a draft of this report that an
update to the Document Archiving Reporting and Regulatory Tracking
System (DARRTS), completed in May 2011, will provide them with the
capability to include a code to indicate whether an application is
subject to PREA.[Footnote 41] However, the HHS comments do not state
that this data system update would provide the internal controls
necessary to track and aggregate data about applications that are
currently under review, which would allow FDA to readily retrieve
information to manage this program. In addition, HHS states that FDA
does not currently plan to code applications retrospectively until
they have ensured that there are available resources for such a
project. Therefore, unless they do these things, FDA still will not
know the status of the 381 applications, including whether the
applications were complete or incomplete, or whether the applications
included pediatric studies or requests for waivers or deferrals, until
the review of those applications is compete.
FDA has granted a full or partial waiver or deferral to more than half
of the applications that it has reviewed under PREA. According to FDA
officials, of the 449 applications for which FDA has completed its
review, FDA granted sponsors 237 waivers and 131 deferrals. FDA
officials noted that, generally, most sponsors request deferrals of
pediatric studies in the product's application rather than conduct the
pediatric studies prior to submitting the product's application. FDA
sometimes granted a full or partial waiver and a deferral to a single
application, therefore a single application could be included in both
totals. FDA officials could not provide additional information about
the remaining 381 applications submitted to FDA during this period but
not reviewed by the PeRC.
Waivers and deferrals were granted for multiple reasons. The reason
most frequently cited for granting a waiver was that the drug or
biological product studies were found to be impossible or highly
impracticable. Waivers may be granted for this reason because, for
example, the number of patients in that age group is too small. Most
deferrals were granted because the product was ready to be approved
for use in adults before pediatric studies had been completed. (See
figure 4).
Figure 4: Reasons Applications Were Granted a Waiver or Deferral,
September 27, 2007, through June 30, 2010:
[Refer to PDF for image: 2 pie-charts]
Reasons studies were granted a waiver:
Necessary studies impossible or highly impracticable in pediatric
populations: 75%;
Product does not represent a meaningful therapeutic benefit over
existing therapies for pediatric patients and product is not likely to
be used by a substantial number of pediatric patients: 15%;
Evidence strongly suggests product would be unsafe in pediatric
populations: 7%;
Evidence strongly suggests product would be ineffective in pediatric
populations: 2%;
Evidence strongly suggests product would be ineffective and unsafe in
pediatric populations: 1%.
Reasons studies were granted a deferral:
Ready for approval for use in one age group: 85%;
Need additional adult safety or effectiveness data: 10%;
Development of an age appropriate formulation needed: 1%;
Additional studies required in specific pediatric age group: 4%.
Source: GAO analysis of FDA data.
Note: PREA contains categories of reasons for FDA to use when granting
waivers and deferrals and the figure above reflects all of these
reasons. However, FDA has never granted a waiver for the reason,
"applicant can demonstrate that reasonable attempts to produce a
pediatric formulation necessary for that age group have failed."
[End of figure]
FDA officials also could not say how many studies are ongoing under
PREA because the agency does not maintain a count of those studies.
According to FDA, sponsors inform FDA of their plans for studies
currently being conducted under PREA, but FDA does not aggregate data
for these products until the sponsor completes the studies and the
results are submitted to FDA for review.
50 Products Have Been Studied under BPCA since Its 2007
Reauthorization:
Fifty products have been studied under BPCA from the 2007
reauthorization through June 30, 2010; FDA has reviewed applications
for 50 of these products, none of which were biological products.
[Footnote 42] As noted earlier, sponsors submit studies to FDA as part
of an application. According to FDA officials, FDA granted pediatric
exclusivity to the sponsors of 44 of the 50 drugs.[Footnote 43]
Sponsors of five of the six drugs that did not receive exclusivity
submitted only partial responses to the written request. FDA officials
explained that FDA reviews study results as they are submitted, but
does not make a pediatric exclusivity determination until it receives
a full response to the written request. Therefore, although FDA
completed its review of the applications, the pediatric exclusivity
determination is pending the completion of the remainder of the
studies FDA requested. FDA officials stated that FDA denied pediatric
exclusivity for one of the products prior to the 2007 reauthorization
because the studies completed by the sponsor did not meet the
conditions of the written request.[Footnote 44] Additionally, FDA
officials told us that two additional drugs were studied between
September 27, 2007, and June 30, 2010, but those studies were still
undergoing FDA review.
Since the 2007 reauthorization, according to FDA officials, FDA has
issued 37 written requests for on-patent drug and biological products
to sponsors under BPCA, 25 of which originated from a PPSR submitted
to FDA by the sponsor since the 2007 reauthorization of BPCA.[Footnote
45] Sponsors agreed to 35 of the written requests. (See figure 5.) FDA
officials stated that the sponsors completed studies for two of the
written requests; studies for the remaining 33 written requests are
ongoing.[Footnote 46] The two other written requests were declined
because the sponsors stated they would be unable to finish the studies
by the completion date outlined in the written request.[Footnote 47]
FDA officials stated that FDA is in the process of determining whether
there is a continuing need for the studies described in the two
declined written requests. If so, FDA will refer these studies to FNIH
pending the availability of sufficient funding at FNIH. We previously
reported that about 19 percent of on-patent written requests were
declined from 2002 though 2005.[Footnote 48] Since the 2007
reauthorization, about 5 percent of written requests have been
declined.
Figure 5: Written Requests Issued for On-Patent Drug and Biological
Products, September 27, 2007, through June 30, 2010:
[Refer to PDF for image: illustration]
Written requests issued by FDA to sponsors: 37.
Written requests declined by sponsors[A]: 2.
Written requests accepted by sponsors: 35.
Products with studies ongoing as of June 2010: 33;
Products with studies completed and results submitted to FDA as of
June 2010: 2.
Source: GAO analysis of FDA data.
[End of figure]
Drug and Biological Products Were Studied in a Wide Range of
Therapeutic Areas:
Drug and biological products were studied under PREA and BPCA for
their use in the treatment of a wide range of diseases in children,
including those that are common or life threatening. FDA categorized
the products studied under PREA and BPCA into 16 broad categories of
disease, which include endocrinology, infectious diseases, and
oncology; at our request, FDA also categorized the products studied
under PREA.[Footnote 49] Some of the products studied were for the
treatment of diseases that are common, including those for the
treatment of asthma and allergies, while other products studied treat
more life threatening diseases such as cancer or human
immunodeficiency virus (HIV) infection. Additionally, some products
studied were preventive vaccines. The largest numbers of products were
studied for the treatment of neurological diseases and viral
infectious diseases, with 23 products studied in each therapeutic area
since the 2007 reauthorization. (See table 1.) This number includes
both ongoing and completed studies that have been reviewed by FDA.
Table 1: Products with Completed or Ongoing Pediatric Studies,
Categorized by Therapeutic Area:
Therapeutic areas: Addiction;
Examples of diseases associated with each therapeutic area: Smoking
cessation, maintenance of abstinence from alcohol in patients with
alcohol dependency;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 0;
Completed: PREA: 0;
Completed: BPCA: 0.
Therapeutic areas: Analgesia/anesthesiology/anti-inflammatory;
Examples of diseases associated with each therapeutic area: Anesthesia;
pain;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 4;
Completed: PREA: 3;
Completed: BPCA: 1.
Therapeutic areas: Cardiovascular disease;
Examples of diseases associated with each therapeutic area: Congestive
heart failure; hypertension;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 2;
Completed: PREA: 1;
Completed: BPCA: 4.
Therapeutic areas: Dermatology;
Examples of diseases associated with each therapeutic area: Dermatitis;
skin and skin structure infections;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 0;
Completed: PREA: 6;
Completed: BPCA: 1.
Therapeutic areas: Endocrinology/metabolism;
Examples of diseases associated with each therapeutic area: Diabetes
Mellitus; obesity;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 1;
Completed: PREA: 5;
Completed: BPCA: 8.
Therapeutic areas: Gastroenterology;
Examples of diseases associated with each therapeutic area: Crohn's
Disease; ulcers;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 1;
Completed: PREA: 2;
Completed: BPCA: 6.
Therapeutic areas: Hematology/coagulation;
Examples of diseases associated with each therapeutic area: Deep vein
thrombosis (thromboembolism);
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 1;
Completed: PREA: 4;
Completed: BPCA: 1.
Therapeutic areas: Infectious disease (viral);
Examples of diseases associated with each therapeutic area: Hepatitis
B virus, human immunodeficiency virus (HIV) infection and/or
prophylaxis of HIV infection in exposed neonates;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 5;
Completed: PREA: 7;
Completed: BPCA: 11.
Therapeutic areas: Infectious disease (non viral);
Examples of diseases associated with each therapeutic area: Malaria;
pneumonia (bacteremic);
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 2;
Completed: PREA: 4;
Completed: BPCA: 1.
Therapeutic areas: Medical Imaging;
Examples of diseases associated with each therapeutic area: Myocardial
perfusion imaging; Cardiac imaging;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 1;
Completed: PREA: 1;
Completed: BPCA: 1.
Therapeutic areas: Neurology;
Examples of diseases associated with each therapeutic area: Adolescent
schizophrenia; depression/major depressive disorder;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 5;
Completed: PREA: 7;
Completed: BPCA: 11.
Therapeutic areas: Oncology;
Examples of diseases associated with each therapeutic area: Brain
tumors and other solid tumors; hematologic tumors;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 8;
Completed: PREA: 1;
Completed: BPCA: 1.
Therapeutic areas: Ophthalmology;
Examples of diseases associated with each therapeutic area:
Conjunctivitis; intraocular pressure;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 1;
Completed: PREA: 10;
Completed: BPCA: 0.
Therapeutic areas: Other therapeutic areas;
Examples of diseases associated with each therapeutic area: Symptoms
associated with common cold and influenza;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 0;
Completed: PREA: 5;
Completed: BPCA: 1.
Therapeutic areas: Pulmonary;
Examples of diseases associated with each therapeutic area: Allergic
Rhinitis; asthma;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 2;
Completed: PREA: 12;
Completed: BPCA: 3.
Therapeutic areas: Preventive vaccine[A];
Examples of diseases associated with each therapeutic area: Vaccines;
Number of products with completed or ongoing studies since the 2007
Reauthorizations of PREA and BPCA - September 27, 2007, through June
30, 2010:
Ongoing (BPCA only): 0;
Completed: PREA: 12;
Completed: BPCA: 0.
Source: FDA.
Note: A product may be used to treat more than one therapeutic area.
For the purposes of this table, a product is counted once for each
therapeutic area it is used to treat. Therefore, the number of
products with completed or ongoing studies by therapeutic area is
greater than the total number of products with completed or ongoing
studies.
[A] Preventive vaccines are not considered by FDA to be therapeutic
products but rather, are considered to be vaccines to prevent disease
caused by specific bacteria or viruses. We included them for the
purpose of providing a full outline of the types of products studied
under PREA.
[End of table]
Few Drugs Have Been Studied When Sponsors Have Declined Written
Requests:
Since the 2007 reauthorization, none of the on-patent products for
which written requests were declined or not completed by sponsors have
been funded for study by FNIH. A provision under BPCA allows FDA to
refer declined written requests for on-patent products to FNIH pending
the availability of sufficient funding. However, according to FNIH
representatives, FNIH does not have sufficient funding because it is
no longer raising funds for the study of on-patent drugs under BPCA.
Since the 2007 reauthorization, FNIH has partially funded the study of
two on-patent drugs for which written requests were declined by
sponsors or not completed, but NIH initiated and also partially funded
those studies prior to the 2007 reauthorization. FDA has not referred
any on-patent drugs to FNIH since the 2007 reauthorization of BPCA.
Since the 2007 reauthorization of BPCA, FDA has referred written
requests for the study of two off-patent drugs that have been declined
or not responded to by sponsors to NIH for funding. As of June 30,
2010, NIH initiated funding for the study of one of these two
products, but NIH has not submitted any study results for this product
to FDA. NIH has also funded 12 studies that are not product specific
since the 2007 reauthorization of BPCA.
Prior to the reauthorization of BPCA, FDA referred 15 written requests
for the study of off-patent drugs that were declined, or not responded
to, by sponsors to NIH for funding. Of these 15 drugs, NIH funded the
study of 10 of these drugs. As of June 30, 2010, NIH has submitted
study results for two of these off-patent drugs to FDA; however, NIH
has not yet completely satisfied the requirements of any written
request for the study of an off-patent drug under BPCA.
NIH does not receive appropriations specifically to fund studies for
products under BPCA. NIH officials said that NIH institutes and
centers spend a total of $25 million annually on BPCA activities,
which are coordinated by the Eunice Kennedy Shriver National Institute
of Child Health and Human Development. NIH officials have said that
when FDA refers a written request for the study of a product under
BPCA to NIH, NIH must determine if it is feasible to initiate funding
for the product's studies. This determination depends on the
availability of funding and the feasibility of conducting the
necessary pediatric studies.[Footnote 50] NIH officials stated that
funding a clinical trial with approximately 200 patients costs an
average of almost $10 million over 5 years. In addition, NIH annually
spends $4.5 million of this $25 million it spends on BPCA activities
on the contract for NIH's BPCA data coordinating center.
All Products with Completed Pediatric Studies Had Labeling Changes,
and FDA's Goals Often Differ from the PREA Requirement for Reaching
Agreement on Labeling Changes:
All of the drug and biological products with pediatric studies
completed and applications reviewed since the 2007 reauthorization had
labeling changes that included important pediatric information. FDA's
goals for the time it takes to review applications often differ from
the requirement in PREA for reaching agreement on labeling changes
with the sponsor.
All Products with Completed Pediatric Studies Since the 2007
Reauthorization Had Labeling Changes That Included Important Pediatric
Information:
All of the 130 drug and biological products with studies completed and
applications reviewed by FDA since the 2007 reauthorization had
labeling changes.[Footnote 51] As a point of comparison, in the 9
years prior to the 2007 reauthorization, 256 products had pediatric
study-related labeling changes agreed upon by FDA and the product's
sponsor. (See table 2.) In addition, we previously reported that not
all products studied under BPCA had labeling changes.[Footnote 52]
According to FDA officials, instances in which there were no labeling
changes for products studied prior to the 2007 reauthorization were
generally due to study results that did not establish that the
products were safe and/or effective in children. The 2007
reauthorizations of PREA and BPCA provided FDA with authority to make
labeling changes on its own initiative when a product has been studied
in children, including when a study does not determine that the
product is safe or effective in pediatric populations.
Table 2: Number of Drug and Biological Products That Had Pediatric
Labeling Changes as a Result of Studies Conducted under PREA or BPCA:
Pre 2007 Reauthorization (Oct. 1998 - Sept. 26, 2007);
PREA labeling changes: Drugs: 72;
PREA labeling changes: Biological products: 0;
BPCA labeling changes: Drugs: 136;
BPCA labeling changes: Biological products[B]: 0;
Pediatric Rule labeling changes[A]: Drugs: 48;
Pediatric Rule labeling changes[A]: Biological products: 0;
Total: 256.
Post 2007 Reauthorization (Sept. 27, 2007 - June 30, 2010);
PREA labeling changes: Drugs: 59;
PREA labeling changes: Biological products: 21;
BPCA labeling changes: Drugs: 50;
BPCA labeling changes: Biological products[B]: 0;
Pediatric Rule labeling changes[A]: Drugs: 0;
Pediatric Rule labeling changes[A]: Biological products: 0;
Total: 130.
Total;
PREA labeling changes: Drugs: [Empty];
PREA labeling changes: Biological products: [Empty];
BPCA labeling changes: Drugs: [Empty];
BPCA labeling changes: Biological products[B]: [Empty];
Pediatric Rule labeling changes[A]: Drugs: [Empty];
Pediatric Rule labeling changes[A]: Biological products: [Empty];
Total: 386.
Source: GAO analysis of FDA data.
[A] The Pediatric Rule went into effect in 1999, but a federal court
declared the Pediatric Rule invalid in October 2002. In 2003 Congress
codified much of the Pediatric Rule in PREA.
[B] BPCA did not apply to biological products until the Patient
Protection and Affordable Care Act extended pediatric exclusivity to
biological products.
[End of table]
The labeling changes for drug and biological products studied under
PREA and BPCA reflected important pediatric information. FDA
categorizes labeling changes into one or more of nine categories, and
each drug or biological product can have more than one category of
labeling change. These categories illustrate the important pediatric
information provided in labeling changes, ranging from providing new
or enhanced safety information to inserting a boxed warning for
pediatric populations. Since the 2007 reauthorization, the most
commonly implemented labeling change expanded the pediatric age groups
for which a product was indicated. There were 99 instances of this
type of labeling change. (See table 3.) For example, a labeling change
for a drug treating gastroesophageal reflux disease extended the
approved indication from adults only to pediatric patients 5 years of
age and older. In addition, 28 labeling changes indicated that, though
a study was conducted, safety and effectiveness had not been
established in pediatric populations. For example, pediatric studies
on a drug meant to treat osteogenesis imperfecta, a genetic disorder
commonly known as brittle bone disease, did not show a reduction in
the risk of bone fracture in children. Therefore, the drug's labeling
was changed to describe the study conducted and indicate that safety
and effectiveness were not established in pediatric populations.
Table 3: Number of Labeling Changes for Drug or Biological Products by
Category of Change, September 27, 2007, through June 30, 2010:
Categories of labeling changes for drug or biological products[A]:
Expanded pediatric age groups approved in the label, including the
addition of new pediatric indications;
PREA: Drugs: 50;
PREA: Biological products: 19;
BPCA: Drugs: 30;
BPCA: Biological products[B]: 0;
Total: 99.
Categories of labeling changes for drug or biological products[A]:
Provided new or enhanced pediatric safety information;
PREA: Drugs: 10;
PREA: Biological products: 4;
BPCA: Drugs: 8;
BPCA: Biological products[B]: 0;
Total: 22.
Categories of labeling changes for drug or biological products[A]:
Determined that safety and effectiveness was not established in
pediatric populations and added a description of the study conducted;
PREA: Drugs: 3;
PREA: Biological products: 2;
BPCA: Drugs: 23;
BPCA: Biological products[B]: 0;
Total: 28.
Categories of labeling changes for drug or biological products[A]:
Provided information on a specific change or adjustment to the
pediatric dosing;
PREA: Drugs: 3;
PREA: Biological products: 0;
BPCA: Drugs: 2;
BPCA: Biological products[B]: 0;
Total: 5.
Categories of labeling changes for drug or biological products[A]:
Provided label for a new pediatric formulation of an existing drug or
biological product;
PREA: Drugs: 2;
PREA: Biological products: 0;
BPCA: Drugs: 6;
BPCA: Biological products[B]: 0;
Total: 8.
Categories of labeling changes for drug or biological products[A]:
Provided original labeling, including pediatric information, for a new
active ingredient that was never before marketed in the United States;
PREA: Drugs: 3;
PREA: Biological products: 0;
BPCA: Drugs: 0;
BPCA: Biological products[B]: 0;
Total: 3.
Categories of labeling changes for drug or biological products[A]:
Inserted a boxed warning for pediatric populations;
PREA: Drugs: 0;
PREA: Biological products: 0;
BPCA: Drugs: 1;
BPCA: Biological products[B]: 0;
Total: 1.
Categories of labeling changes for drug or biological products[A]:
Provided pharmacists with detailed step-by-step instructions on how to
prepare formulations for pediatric populations;
PREA: Drugs: 0;
PREA: Biological products: 0;
BPCA: Drugs: 4;
BPCA: Biological products[B]: 0;
Total: 4.
Categories of labeling changes for drug or biological products[A]:
Provided details on dosing differences between pediatric and adult
populations due to pharmacokinetic differences;
PREA: Drugs: 0;
PREA: Biological products: 0;
BPCA: Drugs: 1;
BPCA: Biological products[B]: 0;
Total: 1.
Source: GAO analysis of FDA data.
[A] Each labeling change can be categorized as more than one category
of change.
[B] BPCA did not apply to biological products until the Patient
Protection and Affordable Care Act extended pediatric exclusivity to
biological products.
[End of table]
Since the 2007 reauthorization, the PAC reviewed the adverse events
reported for 74 drug and biological products and recommended
additional labeling changes for 17 of those 74 products.[Footnote 53]
(See figure 6.) As of June, 30, 2010, FDA reported that it had
approved 7 of the 17 PAC-recommended labeling changes. Of the
remaining 10 PAC-recommended labeling changes, FDA was still
considering whether to approve 5 labeling changes and had decided not
to approve 5 labeling changes. According to FDA, these five PAC-
recommended labeling changes were not approved because, after further
review of the adverse events, FDA determined that labeling changes
were not necessary. Reasons underlying these determinations include an
insufficient link between the reported adverse events and the product
and the presence of confounding factors, such as other preexisting
conditions that may have contributed to the adverse event.
Figure 6: Pediatric Advisory Committee (PAC) Recommendations for Drug
and Biological Product Adverse Events, September 27, 2007, through
June 30, 2010:
[Refer to PDF for image: illustration]
74 drug and biological products Adverse events reviewed by PAC:
50 drug and biological products: PAC recommended products return
to routine monitoring.
24 drug and biological products: PAC recommended labeling change
or other action:
* 7 drug and biological products: PAC recommended other action, such
as additional research;
* 17 drug and biological products: PAC recommended labeling change:
- 7 drug and biological products: FDA approved and sponsor implemented
labeling change;
- 5 drug and biological products: FDA is still considering whether to
approve labeling change;
- 5 drug and biological products: FDA determined not to approve
labeling change.
Source: GAO analysis of FDA data.
[End of figure]
FDA's Goals Often Differ from the PREA Requirement for Reaching
Agreement on Labeling Changes:
FDA's performance goal for the time it takes for FDA to review most
PREA applications often differs from PREA's requirement for the time
FDA is to take to reach agreement with the sponsor on labeling
changes.[Footnote 54] According to FDA officials, the agency cannot
adequately consider and agree upon a labeling change until it
completes its review of an application. FDA is required by both PREA
and BPCA to negotiate and reach agreement with the sponsor on labeling
changes based on pediatric study results within 180 days of submission
of the application. If FDA is unable to reach agreement with the
sponsor, it is required to enter the labeling change dispute
resolution process. FDA's review of suggested labeling changes is part
of a broader review--FDA's review to determine whether or not to
approve the application--for which it has specific performance goals
that include time periods within which it seeks to review
applications.[Footnote 55] Under these performance goals, applications
are classified as either priority or standard, depending on the
characteristics of the application, and FDA has committed to
completing its review of 90 percent of priority applications within
180 days of submission and 90 percent of standard applications within
300 days of submission. BPCA requires that applications submitted
under BPCA that propose a labeling change, which are all BPCA
applications, receive priority status. Therefore, all BPCA
applications have been subject to 180-day review. However, according
to FDA officials, only a subset of applications subject to PREA
requirements--those that provide major advances in therapy or new
therapies--receive priority status. All other applications submitted
under PREA are to be reviewed within the standard 300 days of
submission.
For priority applications, FDA's goal to complete its review of the
application within 180 days is consistent with the labeling change
requirements of PREA and BPCA since the two review periods--the
application review goal and the labeling change review period--are
both 180 days. However, for PREA applications subject to standard
review, which includes most PREA applications, the goal and required
review period are different. FDA's goal to complete its review of the
application within 300 days differs from PREA's requirement to reach
agreement on labeling changes within 180 days. FDA officials
acknowledged that the agency has generally not agreed upon labeling
changes within the required 180 days for PREA applications subject to
standard review. However, as noted previously, FDA could not account
for 381 applications submitted to the agency under PREA, making it
difficult for FDA to determine whether it is meeting either the
requirements of PREA or the agency's goals for these applications. FDA
has never initiated the labeling change dispute resolution process.
According to FDA officials, the agency has been able to reach
agreement with sponsors on labeling changes without needing to
initiate this process.
Stakeholders Identified Agency Guidance, Uncertainty Associated with
Reauthorization, and Lack of Economic Incentives as Potential
Challenges to Conducting Pediatric Studies:
Stakeholders whom we interviewed described several challenges to
conducting pediatric studies. One challenge stakeholders, including
sponsors, identified was confusion about how to comply with PREA and
BPCA due to a lack of current guidance from FDA. FDA officials
acknowledged that the most recent PREA guidance is draft guidance from
2005 and that the most recent BPCA guidance was revised in 1999. FDA
has not provided guidance for changes to the laws from the 2007
reauthorization for PREA or BPCA. FDA officials stated that they plan
to publish updated guidance on PREA and BPCA. However, they have no
timeline for when they plan to do so. FDA explained that officials can
discuss study timelines and questions or concerns sponsors may have
regarding their study submissions throughout the process.
Stakeholders said another challenge is that reauthorizations of PREA
and BPCA have led to uncertainty given the time required to conduct
studies. They said that since PREA and BPCA are subject to
reauthorization every 5 years, some of the statutory requirements for
studies could change while studies are under way or as they are being
planned; therefore, there is uncertainty as to the requirements that
will apply when they conduct studies.[Footnote 56] Two sponsors stated
this uncertainty makes it difficult to know what will be involved in
developing products for use in children over the long term, which
makes it difficult to plan studies. For the 50 drugs for which FDA has
completed its review since the 2007 reauthorization of BPCA, the
average amount of time from when FDA issued a written request through
when it completed its review of a drug's study results was 6 years.
Based on this experience, PREA and BPCA would be reauthorized during
the course of a drug or biological product study, possibly changing
the requirements with which the sponsors must comply. For example, the
2007 BPCA reauthorization added the requirement that sponsors submit
applications at least 9 months before the end of the product's market
exclusivity.[Footnote 57]
Another challenge identified by stakeholders is complying
simultaneously with the U.S. laws, PREA and BPCA, and the European
Union's (EU) Paediatric Regulation.[Footnote 58] (See appendix III for
a description of the Paediatric Regulation.) Stakeholders stated that
it is common for a sponsor to seek approval of a drug or biological
product in both the EU and the United States simultaneously, making it
necessary for the study to comply with PREA or BPCA and the Paediatric
Regulation if the sponsor wants to market the drug in the United
States and in the EU. For example, in the EU, the sponsor submits a
plan for the study of a product in pediatric populations that must be
approved by the European Medicines Agency before studies are
conducted. Stakeholders stated, in the United States, sponsors do not
have formal contact with FDA regarding their pediatric study design
for studies submitted under PREA until they submit completed study
results to FDA. Therefore, sponsors cannot be certain that studies
done to comply with the Paediatric Regulation will meet FDA
requirements.
Finally, stakeholders told us that the lack of economic incentives
presents a challenge to sponsors' willingness to conduct pediatric
studies voluntarily, as under BPCA. Stakeholders, including industry
representatives, told us that sponsors are reluctant to conduct
studies for drug and biological products that are nearing the end of
their market exclusivity or are off-patent because there is no
economic benefit associated with conducting these studies. Once a drug
or biological product is off-patent, the sponsor cannot receive
pediatric exclusivity for conducting pediatric studies. Stakeholders
told us that these drug and biological products are among the least
likely to be studied in pediatric populations. Given the lack of
economic incentive, a provision in BPCA gives NIH the responsibility
of awarding funds to entities that have the expertise and ability to
conduct studies of off-patent drug and biological products. However,
stakeholders reported that NIH's ability to conduct these studies is
limited due to a lack of resources devoted to this type of research.
Conclusions:
At least 130 drug and biological products have been studied in
pediatric populations under PREA and BPCA in a variety of therapeutic
areas since the laws' 2007 reauthorization, resulting in important
labeling changes. While this illustrates the laws' success in
facilitating pediatric studies, we found that FDA did not have
procedures in place to track and aggregate data about applications
subject to PREA until the PeRC completed its review of the pediatric
information included in the applications. Even though an application
subject to PREA cannot be considered complete unless it contains
pediatric study results or a request for a waiver or deferral, FDA has
not been tracking whether these are included until information from
the application is reviewed by the PeRC. According to FDA officials,
the PeRC generally reviews information about pediatric studies
submitted as part of the application near the end of FDA's application
review process. Because of the timing of this review, FDA staff
managing the review process cannot be certain how many applications
that have been submitted to the agency are subject to PREA, how many
of those applications include pediatric studies, or how many
applications include requests for waivers or deferrals, until FDA has
almost completed its review of the entire application. FDA's review of
applications can last 300 days or more in some cases, depending on the
specific attributes of the application.
FDA lacks an important internal control that would allow it to manage
its review process to ensure that the agency and sponsors are meeting
the law's requirements and that FDA is meeting its own mission, goals,
and objectives during the period of its review of the application.
Because several of the requirements of PREA and internal FDA goals
focus on the amount of time FDA takes to conduct a review or make a
decision and because some products studied under PREA may already be
on the market for adult use, it is imperative that FDA have this
information available to it throughout the review process. FDA's
inability to track how long it has had an application or whether or
not an application includes pediatric study results until after the
PeRC has completed its review could delay the dissemination of
important pediatric study results.
Recommendation for Executive Action:
We recommend that the Commissioner of FDA move expeditiously to track
applications upon their submission and throughout its review process
and maintain aggregate data, including the total number of
applications that are subject to PREA and whether those applications
include pediatric studies.
Agency Comments and our Evaluation:
We provided a draft of this report to the Secretary of HHS for
comment. In its comments, HHS noted that PREA and BPCA have been very
successful in generating important pediatric labeling of drugs and
biological products. HHS also agreed that better tracking of pediatric
labeling and other information is needed and expressed the hope that
future improvements in its databases will allow the agency to easily
identify all pediatric studies contained in all applications. HHS
acknowledged that such improvements could permit health care
providers, the public, and other stakeholders to conduct more
interactive and thorough searches for pediatric studies, indications,
and other information relevant to pediatric patients.
In its comments, HHS disagreed with our finding that FDA does not have
a system to track data about applications under PREA. The comments
note that the FDA Center for Biologics Evaluation and Research has a
specific code in its Regulatory Management System for Biologics
Licensing Application that allows it to track PREA-filed applications
for biological products. HHS describes the FDA Center for Drug
Evaluation and Research's process for tracking applications using
DARRTS and suggests that DARRTS allows FDA to track the status of any
application at any given time.
However, our recommendation is not based on FDA's ability to determine
the status of individual applications, but rather its lack of
aggregate data on applications that are subject to PREA during its
review of the applications so as to be able to better manage its
review process. We clarified our discussion of our findings in this
area and the wording of our recommendation. As discussed in this
report, FDA was unable to determine how many of the applications that
had been filed with the agency since PREA's 2007 reauthorization were
subject to PREA. We had initially requested this information in an
effort to provide context to some of the other information that we
reported about FDA's implementation of PREA. FDA was able to report
that approximately 830 applications were subject to PREA, but was
unable to provide a precise number. Since this was considerably more
than the 449 applications that had been reviewed by the PeRC, we
sought additional information about the status of these applications.
In response to our request, FDA officials explained that the agency
did not maintain this information and that determining the status of
these applications would require that they engage in a labor intensive
manual process that would require an extensive investment of FDA
resources and would take months to complete. We believe that FDA's
lack of aggregate data about an important program designed to enhance
the safety of drug and biological products for use in children is
inconsistent with sound internal controls because it does not provide
FDA officials with the information they need to effectively manage the
program to ensure that the review process is being implemented in
accordance with statutory and other requirements until the process is
almost complete.
In its comments, HHS states that in May 2011, FDA made an improvement
to DARRTS that was not in place during the time of our review. HHS
states that the improvement will allow FDA to better track future
applications that are subject to PREA. However, the comments do not
state whether the improvement will allow FDA to determine during its
review process whether applications include studies or requests for
waivers or deferrals. While it remains unclear what data will be
readily available to FDA officials as they manage this program, FDA's
efforts to improve its tracking of applications are consistent with
the goal of our recommendation and should enable it to better track
future applications. HHS's comments state that FDA hopes to include
enhanced information about applications in DARRTS retrospectively, but
notes that the agency will have to ensure that there are available
resources for such a project. Therefore, DARRTS will not include this
improved data for applications that are currently undergoing review.
HHS states that FDA maintains data about completed studies under PREA
on its Web site. However, this data is compiled and placed on FDA's
Web site after FDA's review of the applications is complete. Our
finding and recommendation address the lack of data that FDA has
available about PREA applications during the review process, which can
last 300 days or more.
We incorporated changes to the report to address HHS's comments about
FDA's ability to track applications and incorporated technical
comments as appropriate. HHS's comments are reprinted in appendix IV.
If you or your staff have any questions about this report, please
contact me at (202) 512-7114 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 V.
Signed by:
Marcia Crosse:
Director, Health Care:
[End of section]
Appendix I: Inclusion of Neonates in Drug and Biological Product
Studies:
The Food and Drug Administration (FDA) Amendments Act of 2007 required
that we describe the efforts made by FDA and the National Institutes
of Health (NIH) to encourage that studies be conducted in children 4
weeks old or less, also known as neonates. This appendix describes the
efforts of FDA and NIH to encourage studies in neonates and their
efforts to ensure that those studies are safe. We also describe the
number of products with completed and ongoing studies in neonates
since the 2007 reauthorization of the Pediatric Research Equity Act
(PREA) and the Best Pharmaceuticals for Children Act (BPCA).[Footnote
59] In addition, we describe the challenges to increasing the
inclusion of neonates in pediatric drug studies identified by
physicians.
To describe the efforts of FDA and NIH to encourage studies in
neonates, we interviewed FDA and NIH officials and examined FDA and
NIH data to summarize the number of pediatric drug studies being
conducted in neonates under PREA and BPCA. To assess the reliability
of the data FDA and NIH provided, we interviewed agency officials. FDA
and NIH officials described how they maintained data on pediatric
studies, and the resulting labeling changes conducted under PREA and
BPCA. We found the data reliable for our purposes. We also reviewed
literature on studies conducted in neonates and barriers to these
studies. We interviewed stakeholders including representatives from
three trade groups, the Pharmaceutical Research and Manufacturers of
America, the Biotechnology Industry Organization[Footnote 60] and the
Generic Pharmaceutical Association. We also interviewed health
advocacy organizations, including the American Academy of Pediatrics,
the National Organization for Rare Disorders, the Elizabeth Glaser
Pediatric AIDS Foundation, the Tufts Center for the Study of Drug
Development, the Institute for Pediatric Innovation, and the Pediatric
Pharmacy Advocacy Group.
To describe the challenges to increasing the inclusion of neonates in
pediatric drug studies identified by physicians, we convened two panel
discussions; we were assisted in convening one of the panels by the
American Association of Pediatrics and another by a director of
neonatology at a large research hospital. The panelists in both
instances were physicians who conducted pediatric drug studies in
neonates. We also interviewed FDA and NIH officials.
FDA's efforts to encourage the inclusion of neonates in pediatric drug
studies and its efforts to ensure that those studies are safe and
effective have been focused on including neonates in its written
requests. However, in some instances FDA has requested neonates'
inclusion but not required it. Since the 2007 reauthorization of BPCA,
FDA has issued four written requests to drug sponsors that have
mentioned neonates specifically.[Footnote 61] FDA required the
inclusion of neonates in the written request for the study of one of
the four drugs. FDA's written requests for three other drugs asked for
the inclusion of neonates in the study; however, the sponsors of these
products had the option of not including neonates in the studies. The
sponsors will inform FDA as to whether they included neonates in the
studies when they submit completed study results to FDA for review.
Sponsors have submitted completed studies to FDA that have included
neonates for nine products--eight drugs and one biological product--
since the 2007 reauthorization; FDA has reviewed all study results and
labeling changes have been made reflecting neonate information for all
of the products.[Footnote 62] Seven of these studies were submitted
under BPCA; two were submitted under PREA.
NIH has funded studies under BPCA for five drugs that have included
neonates. These studies were initiated before the 2007
reauthorization, but are ongoing. Additionally, NIH has conducted
several activities under BPCA to ensure the safety and effectiveness
of drugs in neonates, including neonates that are premature. These
activities include the 2009 co-funding of a large scale study of the
diagnosis and treatment of hypotension in premature infants, funding
of a study to determine outcome measures for chronic lung disease in
premature infants, and the development of a small volume sampling
technique for neonates with congenital heart disease.
FDA officials explained that a limited number of the studies conducted
under PREA have included neonates because PREA only requires that
pediatric studies be conducted for the indication described on the
drug application, which is typically applicable to adults and older
pediatric populations that would not apply to neonates.[Footnote 63]
Additionally, PREA provides sponsors with the option to request that
required pediatric studies be waived by FDA when there is a valid
reason. For some applications, FDA has agreed to waive studies after
it has determined that including neonates in a drug study may be
impossible or highly impracticable due to safety or ethical concerns.
FDA and NIH officials explained that they face challenges in
increasing the inclusion of neonates in pediatric studies under BPCA.
BPCA authorizes FDA to provide an incentive of an additional 6 months
of market exclusivity, known as pediatric exclusivity, to product
sponsors that conduct pediatric studies requested by FDA. FDA
officials explained that they have been granting pediatric exclusivity
for the study of products in children older than one month, so it is
difficult to have manufacturers go back and do the study in neonates
because it may be difficult for them to receive additional pediatric
exclusivity.[Footnote 64] FDA officials told us that the neonate
population has diseases that are very different from other pediatric
populations and that there are limited tools that can be used to study
these diseases. FDA and NIH officials told us that there are also
ethical issues that arise when working with this population that
create a barrier. Based on our review of the literature, we found
there is an ethical issue concerning whether neonates are a vulnerable
population that should not be enrolled in trials where there may be
increased risk to their health.
The physicians that we spoke with as a part of our two panels
explained that they encounter numerous challenges to conducting
studies in neonates. One challenge the panelists described is
obtaining informed consent from the parents, which is required for the
neonate to be enrolled in a study. For example, one panelist stated
that because the mother may be medicated from her delivery it may be
difficult to obtain consent from her. One panelist stated that he
encounters families for which English is their second language and he
may need them to review and understand a complex 10-to 12-page study
outline that is written in English. The panelist explained that while
his hospital provides doctors who speak another language and may
communicate in that language for families for which English is a
second language, they may encounter another challenge if the family is
not able to read in their native language.
The panel explained that there are also scientific challenges to
conducting studies in neonates. One scientific challenge is that the
amount of blood in neonates is extremely limited. However, blood must
be drawn to determine proper dosing of the products being tested,
requiring doctors to do needle pricks to obtain blood from the
neonate. These pricks are in addition to the pricks that must be done
to monitor the health of the neonate and there may not be enough blood
to test for both proper dosing and to monitor the neonate's health.
The panel went on to explain that the outcomes of the study must be
observed in the neonate between 3 to 5 years after the study. This
level of monitoring is costly to the sponsor and can be an economic
disincentive to conducting studies in neonates. The panel also
explained that neonates are heterogeneous--there can be a significant
difference in a neonate born at 23 weeks than a neonate that is 40
weeks--and any study designed to include them must account for this,
making it difficult to generalize the study results.
Panelists said that another challenge to increasing the inclusion of
neonates in studies involves FDA, stating that FDA sometimes seems to
be creating barriers rather than working to include neonates in
studies. For example, they said that FDA has required that a product
be proven safe and effective for adults before it can be studied in
neonates; however the panelists stated that because neonates often
have illnesses that are specific to their age and condition, this
requirement does not make sense. Furthermore, one panelist stated that
she believed that FDA did not have enough neonatologists on staff to
assist in preparing written requests. She also stated that it is
important that study designs that include neonates be reviewed by
neonatologists and not general pediatricians because neonatologists
understand the issues that must be confronted in the neonatal
intensive care unit. FDA's Pediatric Review Committee, which reviews
written requests and determines whether waivers and deferrals should
be granted, has about 40 members. However, FDA officials we
interviewed said that there is only one neonatologist on the
Committee.[Footnote 65] Additionally, the FDA officials stated that
there are three neonatologists in the two FDA divisions that review
pediatric studies. FDA officials said that they do not have the
resources to hire additional neonatologists.
[End of section]
Appendix II: Inclusion of Ethnic and Racial Minority Participants in
Pediatric Drug Studies:
The Food and Drug Administration Amendments Act of 2007 (FDAAA)
requires that FDA consider the adequate representation of children of
ethnic and racial minorities when issuing written requests to sponsors
to conduct pediatric studies for a product under the Best
Pharmaceuticals for Children Act (BPCA).[Footnote 66],[Footnote 67] It
is important to include minorities in pediatric studies because
proteins, metabolizing enzymes, and genetic traits can differ among
races and ethnicities. We previously reported that these differences
may result in a product having adverse or unexpected side effects for
users depending on their race or ethnicity.[Footnote 68] To examine
how FDA considered the representation of ethnic and racial minority
participants in product studies conducted under BPCA, we reviewed the
37 written requests that FDA issued to sponsors from the time of the
2007 reauthorization of BPCA on September 27, 2007 through June 30,
2010.
FDA issued guidance in 2005 on the collection of race and ethnicity
data in clinical trials recommending that sponsors use a standardized
approach developed by the Office of Management and Budget to report
the race and ethnicity of study participants.[Footnote 69] FDA's 2005
guidance recommends, rather than requires, that sponsors use the
specified categories because participants' racial and ethnic data may
not be able to be collected in some instances and because the
specified categories may not be sufficient or appropriate for some
studies. For example, when studies are conducted outside of the United
States, the recommended categories may not adequately describe the
racial and ethnic groups in foreign countries.
FDA has issued 37 written requests to sponsors for the study of on-
patent products under BPCA, since the 2007 reauthorization. In these
37 written requests, FDA asked that sponsors include information on
the representation of ethnic and racial minorities for all
participants using the standardized categories specified in agency
guidance when responding to written requests.[Footnote 70] In all but
two of the 37 written requests, FDA also requested that if the sponsor
chose to use other categories, the sponsor obtain FDA's agreement on
the use of alternate categories.
[End of section]
Appendix III: Pediatric Drug and Biological Product Studies in the
European Union and the United States:
The European Union's Paediatric Regulation for the development of drug
and biological products in pediatric populations was implemented in
January of 2007 in order to facilitate the development of, and improve
the availability of information on, products for use in children.
[Footnote 71] The European Union's Paediatric Regulation is similar to
laws on pediatric studies in the United States, some form of which has
been in existence since 1997.[Footnote 72] To describe the European
Union's Paediatric Regulation for drugs and biological products, we
examined European Medicines Agency literature, the Paediatric
Regulation, United States laws, and additional sources regarding
United States and European Union pediatric laws and regulations. We
also interviewed FDA officials.
The European Union's Paediatric Regulation:
The Paediatric Regulation requires sponsors to submit a plan for the
study of a product in pediatric populations, known as a paediatric
investigation plan (PIP), early in the development of a new product.
PIPs are required to include the sponsor's proposed timing and methods
for conducting pediatric studies in all age groups. Sponsors must
submit PIPs to the Paediatric Committee, which was created by the
Paediatric Regulation. Sponsors submit to the Paediatric Committee
through the European Medicines Agency. The Paediatric Committee
reviews the PIP and determines whether to agree or refuse the study
plan. The PIP is a binding agreement between the sponsor and the
European Medicines Agency, but can be modified as necessary. The
Paediatric Regulation allows for the agency to either defer pediatric
studies until the product has been studied in adults or waive the
studies altogether in certain circumstances.[Footnote 73] The
Paediatric Committee is responsible for granting or denying deferrals
and waivers. When studies are deferred, the sponsor must still submit
a PIP that includes details on the pediatric studies that will be
conducted and when those studies will begin, but when studies are
waived, the requirement to submit a PIP is also waived.
Once a new product is ready to be marketed, the sponsor submits a
marketing authorization application to the European Medicines Agency
that must include, among other things, the results of pediatric
studies conducted in accordance with the PIP or proof that a waiver or
deferral of the pediatric studies was granted.[Footnote 74] If the
sponsor has conducted studies in compliance with the PIP, it is
entitled to a six-month extension of the product's market exclusivity.
Additional information on the Paediatric Regulation can be found on
the European Medicines Agency website.[Footnote 75]
European Union and United States Collaboration:
The European Union and the United States collaborate by exchanging
information in order to ensure that pediatric studies are conducted in
a scientifically rigorous and ethical manner and that pediatric
patients are not exposed to duplicative studies. Stakeholders stated
that it is common for a sponsor to seek approval of a drug or
biological product in both the EU and the United States, making it
necessary for a sponsor to comply with both the EU and United States'
pediatric study processes if it wants to market the drug in both
locations. In addition, the European Medicines Agency and the FDA
communicate and collaborate to share information such as the status of
current studies, written requests, PIPs, waivers and deferrals, study
results, safety concerns, and other topics. According to FDA's Web
site, from August 2007 to March 2009, the European Medicines Agency
and the FDA discussed 144 products.[Footnote 76] This communication
and information sharing between the European Medicines Agency and the
FDA takes place through monthly teleconferences and by using a secure
electronic system.
[End of section]
Appendix IV: Comments from the Department of Health and Human Services:
Department Of Health And Human Services:
Office Of The Secretary:
Assistant Secretary for Legislation:
Washington, DC 20201:
May 9, 2011:
Marcia Crosse, Director:
Health Care:
U.S. Government Accountability Office:
441 G Street N.W.
Washington, DC 20548:
Dear Ms. Crosse:
Attached are comments on the U.S. Government Accountability Office's
(GAO) draft report entitled: "Pediatric Research: Products Studied
Under PREA and BPCA, But Improved Tracking Needed by FDA" (GAO 11-457).
The Department appreciates the opportunity to review this draft report
prior to publication.
Sincerely,
Signed by:
Jim R. Esquea:
Assistant Secretary for Legislation:
Attachment:
[End of letter]
General Comments Of The Department Of Health And Human Services (HHS)
On The Government Accountability Office's (GAO) Draft Report Entitled,
"Pediatric Research: Products Studied Under PREA And BPCA, But
Improved Tracking Needed By FDA (GAO-11-457)"
The Department appreciates the opportunity to review and comment on
this draft report.
Both PREA and BPCA have been very successful at generating important
pediatric labeling of drugs and biological products, and we appreciate
GAO's recognition of that fact. We agree that better tracking of
pediatric labeling and other information is needed, and we hope that
future improvements in our databases will allow us to easily identify
all pediatric studies contained in all applications, and not just
those required under PREA or conducted under BPCA. Such improvements
could permit health care providers, the public, and other stakeholders
to conduct more interactive and thorough searches for pediatric
studies, indications, and other information relevant to pediatric
patients.
That said, the GAO report suggests that the Food and Drug
Administration (FDA) does not track applications adequately to ensure
timely agency action, potentially delaying dissemination of important
pediatric study results (page 35), that FDA does not maintain data on
the products studied under PREA (the recommendation), and that FDA
does not have adequate internal controls because it does not know
whether certain applications have complied with PREA (page 21). For
the following reasons, we disagree:
* First, the Center for Drug Evaluation and Research (CDER) tracks its
applications through the Document Archiving, Reporting, and Regulatory
Tracking System (DARRTS). Given the requirements of various programs
and the timelines they impose, DARRTS was, and is, able to track all
CDER applications and identify the status of any application at any
given time. DARRTS contains numerous coded fields that identify
various types of information from which internal reports can be run
for different purposes. What was not available in DARRTS until a
recent update was a code that can be used to indicate whether or not a
particular filed application triggers PREA. The Center for Biologic
Evaluation and Research (CBER) uses the Regulatory Management System
for Biologics Licensing Application (RMS-BLA) to track CBER
applications, and RMS-BLA has a field code for PREA that CBER uses to
track PREA filed applications.
For all applications moving forward, CDER will enter the PREA code
into DARRTS by the time CDER files the application or within one week
after filing. "Filing" is the term used by FDA to indicate the
application has been accepted by FDA for review. As of May 2011, FDA
will be able to use this code to run various reports that we could not
run before regarding pending applications, even though the individual
information for any particular pending application has always been
available. Reports will more easily identify the total number of filed
applications that trigger PREA as well as provide a line listing of
all applications that trigger PREA. FDA will be able to generate these
reports for a specific time period. We hope to eventually code
applications retrospectively, but will have to ensure that there are
available resources for such a project.
Before this change to DARRTS, FDA used a number of checks and balances
to help ensure that the agency identified all applications that
triggered PREA and timely fulfilled our obligations under the
statutory requirements. These activities will continue and will be
supplemented by the new coded data to help ensure better tracking of
applications subject to PREA.
* Second, FDA has tracked data on "the total number of products
studied under PREA" since the Food and Drug Administration Amendments
Act of 2007; indeed, these data are readily retrievable on our
website. There are products such as new drug application submissions
for a new strength that may have been studied in children but were not
required to be studied under PREA, or were not studied under BPCA, and
these data are not as easily identified and retrieved from our
databases. The agency is currently involved in a project to index all
labeled indications by subpopulations, which would assist in
identifying all products that have labeling related to pediatrics, and
may help in identifying a greater number of products for which
children were studied.
* Third, although CDER and CBER determine that an application triggers
PREA when, or shortly after, it is filed (and, because of the recent
change, CDER will be able to track such determinations with DARRTS),
under the statute FDA only makes its determination that a sponsor has
or has not complied with PREA requirements when the Pediatric Review
Committee (PeRC) has reviewed the application. To assess compliance,
several experts in the relevant review divisions review the
application, and then the PeRC reviews the data from the review
divisions on these studies to ensure that all relevant experts have
been consulted to determine whether the PREA requirement has been
fulfilled. Simply put, under the statute, FDA will not know whether a
sponsor has complied with PREA until the PeRC has conducted its review
and assessment.
* Finally, it is contemplated that there will be products studied
under PREA that may already be on the market. Indeed, Congress drafted
PREA to apply not only to original applications but also to
supplemental applications for products already on the market where the
sponsor seeks approval for a new indication, new dosage form, new
dosing regime, or new route of administration. The pediatric
information cannot be disseminated until the application review is
complete, and that review is governed by the required timelines.
DARRTS, RMS-BLA and the Centers' application review SOPs have
consistently provided the necessary safeguards and tracking to ensure
that the PeRC review is conducted in parallel with the review of the
application and in time for the agency's action on an application, and
so there has never been a delay in dissemination of important
pediatric study results.
[End of section]
Appendix V: GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
Acknowledgments:
In addition to the contact named above, key contributors to this
report were Tom Conahan, Assistant Director; Rachel E. Batkins;
Romonda McKinney Bumpus; Kathleen Diamond; Cathleen Hamann; Lisa
Motley; Kathryn Richter; and Jessica C. Smith.
[End of section]
Footnotes:
[1] Biological products are derived from living sources (such as
humans, animals, and microorganisms), unlike drugs, which are
chemically synthesized. Biological products include blood, vaccines,
allergenic products, certain tissues, and cellular and gene therapies.
See 42 U.S.C. § 262(i).
[2] See D. K. Benjamin Jr., et al, "Safety and Transparency of
Pediatric Drug Trials," Archives of Pediatrics & Adolescent Medicine,
vol. 163, no. 12 (2009).
[3] Drug or biological product "labeling" includes all labels and
other written, printed, or graphic materials on any container,
wrapper, or materials accompanying the product. 21 U.S.C. § 321(k),
(m).
[4] A drug or biological product sponsor is the person or entity who
assumes responsibility for the marketing of a new product, including
responsibility for complying with applicable laws and regulations.
[5] 21 U.S.C. §§ 355c, 355d.
[6] 21 U.S.C. § 355a; 42 U.S.C. § 284m.
[7] Pub. L. No. 110-85, §§ 401-404, 501-503, 121 Stat. 823, 866-90
(2007).
[8] See 21 U.S.C § 355a(n)(1)(B); 42 U.S.C. § 284m. For purposes of
this report, we refer to drug and biological products 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 product under BPCA.
[9] FNIH is an independent, nonprofit corporation. The majority of
funds that FNIH receives are from the private sector. FNIH funds are
used for a variety of purposes, including awards to researchers to
conduct studies related to BPCA. See 42 U.S.C. § 290b.
[10] NIH is an agency within HHS and is comprised of 27 institutes and
centers, each with a specific research agenda.
[11] For products studied under PREA or BPCA, sponsors generally
submit new drug applications, supplemental new drug applications,
biologics license applications, or supplemental biologics license
applications to FDA. Before a drug or biological product can be
marketed in the United States, the sponsor must submit a new drug
application or a biologics license application to FDA containing data
demonstrating the safety and efficacy of the product. After a product
is marketed, sponsors submit supplemental new drug applications or
supplemental biologics license applications to support proposed
changes to a product's labeling, a new dosage form or strength of the
product, a new patient population or intended use, or changes to the
way the product is manufactured. See 21 U.S.C. § 355 (drugs); 42
U.S.C. § 262 (biological products).
[12] Although the product studied might be new to the market and,
therefore, its labeling would be new and not a change, FDA
characterizes the agreement on labeling as a "labeling change" under
PREA and BPCA.
[13] FDA uses the term "adverse event" to refer to any untoward
medical event associated with the use of a drug or biological product
in humans.
[14] Pub. L. No. 110-85, § 404, 121 Stat. 823, 875-76.
[15] The 2007 reauthorization of PREA and BPCA was enacted and went
into effect on September 27, 2007.
[16] FDA generally reports data to the public on the number of studies
conducted under PREA and BPCA, but for the purposes of this report we
report on the number of products studied. Since sponsors can conduct
multiple studies per product, the number of products studied will be
less than the total number of studies conducted. We counted each
application submitted by the sponsor to FDA as one product. We counted
the following types of applications: new drug applications,
supplemental new drug applications, biologics license applications,
and supplemental biologics license applications. For studies conducted
under BPCA, FDA reports studies by active moiety, or molecule
responsible for the physiological or pharmacological action of the
drug substance, rather than product. A single moiety could be active
in multiple products, such as different strengths of the same dosage
form, or a moiety could be present in different dosage forms such as a
lotion form and a tablet form. Therefore, because we analyzed the
number of products studied, not moieties studied, we may report a
different number of products studied than the moieties reported by
FDA. For the purposes of our report when we refer to products studied,
we are referring to products whose studies have been completed and for
whom FDA has completed the application review for the product. In
addition, for the purposes of our analyses, we considered all products
with biologics license applications as biological products.
[17] See GAO, Standards for Internal Control in the Federal
Government, [hyperlink,
http://www.gao.gov/products/GAO/AIMD-00-21.3.1] (Washington, D.C.:
November 1999). Internal control comprises the plans, methods, and
procedures used to meet missions, goals, and objectives.
[18] We also reviewed data on labeling changes that occurred prior to
the 2007 reauthorization in order to provide context to the total
number of labeling changes that have occurred as a result of laws
providing for pediatric studies, some form of which has been in
existence since 1997.
[19] The Biotechnology Industry Organization assisted us in convening
a panel discussion that included representatives from four drug and
biological product sponsors.
[20] Pub. L. No. 105-115, § 111, 111 Stat. 2296, 2305-09.
[21] 63 Fed. Reg. 66,632-66,672 (Dec. 2, 1998).
[22] Implementation of the Pediatric Rule prompted a lawsuit against
FDA by the Association of American Physicians and Surgeons, the
Competitive Enterprise Institute, and Consumer Alert, which claimed
that FDA acted outside of its authority in issuing the Pediatric Rule.
In 2002, the court ruled that FDA exceeded its authority in issuing
the rule and declared the rule invalid. Association of American
Physicians & Surgeons v. FDA, 226 F. Supp.2d 204 (D.D.C. 2002).
[23] Pub. L. No. 111-148, § 7002(g)(1), 124 Stat. 119, 819-20 (to be
codified at 42 U.S.C. § 262(m)).
[24] 21 U.S.C. §§ 355a(q), 355c(m).
[25] See 21 U.S.C. § 355d.
[26] Applications that are subject to PREA are submitted to FDA for
approval and undergo a broad application review process that, in
addition to reviewing pediatric studies, reviews the results of adult
studies and determines whether the application demonstrates that the
product is safe and effective for the indicated population.
[27] 21 U.S.C. § 355c(a)(3), (4). If a waiver is granted because the
product would be ineffective and/or unsafe in children, such
information must be included in the product's labeling.
[28] 21 U.S.C. § 355c(g)(1). FDA's review of proposed labeling changes
is part of its review of the application. Application review is
subject to its own specified time frames. Under the 2007
reauthorization of the prescription drug user fee program as a part of
FDAAA, FDA committed to performance goals related to the review of
drug applications and biologics license applications, including time
frames within which it seeks to review applications. See Pub. L. No.
110-85, § 101(c), 121 Stat. 823, 825 (2007). The performance goals are
identified in letters sent by the Secretary of Health and Human
Services to the Chairman of the Senate Committee on Health, Education,
Labor, and Pensions and the Chairman of the House Committee on Energy
and Commerce and are published on FDA's Web site. Each fiscal year,
FDA is required to submit a report on its progress in achieving those
goals and future plans for meeting them. See 21 U.S.C. § 379h-2(a).
Under these performance goals, drug and biological product
applications are classified as either priority or standard, and FDA
committed to completing its review of 90 percent of priority
applications within 180 days of submission and 90 percent of standard
applications within 300 days of submission. Applications submitted
under PREA may be either priority or standard, depending on the
characteristics of the applications.
[29] For the purposes of this report, we report data on products
studied in this manner under BPCA. FDA reports data on these products
in a separate category of products studied under both PREA and BPCA.
[30] These additional indications are often referred to as "off-label"
indications.
[31] In March 2010, the Patient Protection and Affordable Care Act
extended pediatric exclusivity and applicable BPCA provisions to
biological products. See Pub. L. No. 111-148, § 7002(g)(l), 124 Stat.
119, 819-20 (codified at 42 U.S.C. § 262(m)).
[32] In a 2003 report, we recommended FDA specify in its written
requests that sponsors use the standard racial and ethnic categories
described in FDA's January 2003 draft guidance. See GAO, Pediatric
Drug Research: Food and Drug Administration Should More Efficiently
Monitor Inclusion of Minority Children, [hyperlink,
http://www.gao.gov/products/GAO-03-950] (Washington, D.C.: Sept. 26,
2003), p. 18.
[33] BPCA requires that FDA make the determination that the sponsor
has met the study requirements outlined in the written request 9
months prior to the end of the drug or biological product's market
exclusivity. 21 U.S.C. § 355a(b)(2), (c)(2). FDA officials explained
that because BPCA provides the agency with 180 days to review the
study results, FDA recommends that the sponsor submit its results 15
months prior to the end of its market exclusivity. See 21 U.S.C. §
355a(d)(3).
[34] 21 U.S.C. § 355a(d)(3). Pediatric exclusivity applies to all
approved uses of the drug or biological product, not just those
studied in children. Therefore, if the studies find that the product
is not safe for use by children, the product will still receive
pediatric exclusivity--that is, extended market exclusivity--for the
adult uses of the product.
[35] 21 U.S.C. § 355a(i)(2). FDA's review of proposed labeling changes
is part of its review of the application. BPCA requires that all
applications submitted under BPCA that propose a labeling change
receive priority status and be subject to FDA's performance goals for
priority products, under which FDA seeks to complete its review of 90
percent of priority applications within 180 days of submission. See 21
U.S.C. § 355a(i)(l). PREA does not contain this requirement.
[36] Under a provision in BPCA added by the 2007 reauthorization, if
FNIH does not have sufficient funds, FDA is required to consider
whether to require a sponsor of an on-patent drug already on the
market to conduct pediatric studies under PREA. FDA may require
studies in this manner if FDA finds that the product is used for a
substantial number of pediatric patients for the labeled indication
and adequate pediatric labeling could confer a benefit on pediatric
patients, the product would represent a meaningful therapeutic benefit
over existing therapies for pediatric patients for a labeled
indication, or the absence of adequate pediatric labeling could pose a
risk to pediatric patients. 21 U.S.C. § 355a(n), § 355c(b). FDA has
never invoked this provision to require studies of on-patent products
for which sponsors have declined written requests.
[37] Prior to the 2007 reauthorization, instead of a list of
therapeutic areas, BPCA required NIH to develop an annual list of
specific drugs that the agency determined were in need of study in
children.
[38] See 42 U.S.C. § 284m(c).
[39] [hyperlink, http://www.gao.gov/products/GAO/AIMD-00-21.3.1].
[40] [hyperlink, http://www.gao.gov/products/GAO/AIMD-00-21.3.1].
[41] According to FDA, DARRTS is intended to be a flexible,
integrated, fully electronic workflow tracking and information
management system to receive, log, track, assign, process, and manage
official submissions with internal and external stakeholders. FDA is
releasing DARRTS in stages. The first version was released in January
2006. Updates to the system, which incorporate additional types of FDA
data into DARRTS, have been periodically implemented.
[42] Studies for all but two of these products were initiated prior to
the 2007 reauthorization.
[43] Thirty-one of the 50 drugs with completed and reviewed studies
were required to be studied under PREA, but sponsors requested and
received written requests for the products to be studied under BPCA,
as well.
[44] FDA officials explained that one product was denied pediatric
exclusivity prior to the 2007 reauthorization because the sponsor did
not enroll the number of participants in the study that was required
by the written request. We included this product in our group of
products studied since the 2007 reauthorization because FDA conducted
further analysis of the product using the submitted results to try to
determine the safety and effectiveness of the product's use in
children. This additional information was used for a labeling change
after the 2007 reauthorization.
[45] According to FDA officials, sponsors have submitted 64 PPSRs to
FDA since the 2007 reauthorization. Twenty-five of these PPSRs
resulted in a written request. FDA officials said that some of the
written requests issued after the 2007 reauthorization were issued in
response to PPSRs submitted to FDA before the 2007 reauthorization.
However, FDA officials noted that there was a flaw in the system that
tracks PPSRs and, therefore, they could not state with certainty the
exact number of PPSRs that the agency had received.
[46] The two completed studies are also counted as two of the 50
products with completed and reviewed studies under BPCA. The written
requests that prompted the studies were issued and the studies have
been completed since the 2007 reauthorization.
[47] According to FDA officials, the timelines outlined in the written
request are based on the statutory requirements outlined in BPCA.
[48] See GAO, Pediatric Drug Research: Studies Conducted under Best
Pharmaceuticals for Children Act, GAO-07-557 (Washington, D.C.: March
22, 2007), p.12.
[49] FDA does not generally categorize the drug and biological
products studied under PREA. FDA provided the therapeutic areas for
products with completed studies under PREA in response to our request.
[50] When determining the feasibility of conducting the necessary
pediatric studies, NIH considers the frequency and severity of the
condition, the availability of a patient population, and the
capability of researchers to conduct the studies.
[51] PREA requires that if a product is granted a waiver due to strong
evidence that the product would be ineffective and/or unsafe in
children, such information must be included in the labeling. 21 U.S.C.
§ 355c(a)(4)(D). Since the 2007 reauthorization, an additional 17
products received waivers that resulted in a labeling change on this
basis.
[52] See [hyperlink, http://www.gao.gov/products/GAO-07-557].
[53] PREA and BPCA require that one year after a product's labeling
change is implemented, the PAC review any adverse events reported for
that product. In subsequent years, FDA will determine whether to refer
any additional pediatric adverse events reported for that product to
the PAC for review.
[54] An application includes, among other things, suggested labeling
changes based on study findings.
[55] Under the 2007 reauthorization of the prescription drug user fee
program as part of FDAAA, FDA committed to performance goals related
to the review of drug applications and biologics license applications,
including time frames within which it seeks to review applications.
See Pub. L. No. 110-85, § 101(c), 121 Stat. 823, 825 (2007). The
performance goals are identified in letters sent by the Secretary of
Health and Human Services to the Chairman of the Senate Committee on
Health, Education, Labor, and Pensions and the Chairman of the House
Committee on Energy and Commerce and are published on FDA's website.
Each fiscal year FDA is required to submit a report on its progress in
achieving those goals and future plans for meeting them. See 21 U.S.C.
§ 379h-2(a).
[56] However, the 2007 reauthorization of PREA and BPCA provides that
certain studies pending before the date of the 2007 reauthorization
are subject to prior versions of PREA and BPCA. See Pub. L. No. 110-
85, §§ 402(b), 502(a)(2), 121 Stat. 823, 875, 885 (2007).
[57] BPCA requires that FDA make the determination that the sponsor
has met the study requirements outlined in the written request 9
months prior to the end of the drug or biological product's market
exclusivity. 21 U.S.C. § 355a(b)(2), (c)(2). FDA officials explained
that because BPCA provides the agency with 180 days to review the
study results, FDA recommends that the sponsor submit its results a
minimum of 15 months prior to the end of its market exclusivity. See
21 U.S.C. § 355a(d)(3).
[58] The Paediatric Regulation is a single law that both requires
sponsors to conduct studies as well as provides a 6-month exclusivity
extension.
[59] See 21 U.S.C. §§ 355a (BPCA), 355c (PREA), 355d (PREA); 42 U.S.C.
§ 284m (BPCA).
[60] The Biotechnology Industry Organization assisted us in convening
a discussion that included representatives from four of the drug
sponsors.
[61] Since the 2007 reauthorization, FDA has issued 37 written
requests for on-patent drug and biological products to sponsors under
BPCA.
[62] Sponsors submitted incomplete study results to FDA for studies
that included neonates for two other products. FDA has informed each
sponsor that it will discontinue its review until the sponsor has
completed the studies and resubmitted them.
[63] From September 27, 2007, through June 30, 2010, sponsors have
submitted completed studies to FDA that have included neonates for two
products under PREA.
[64] Under very narrow circumstances specified in BPCA, a drug may be
eligible for additional pediatric exclusivity for a supplemental
application. See 21 U.S.C. § 355a(g)(1).
[65] Our review of the Pediatric Review Committee roster found that
there are two neonatologists on the committee as of April 15, 2010.
[66] See Pub. L. No. 110-85, § 502(d)(1)(A), 121 Stat. 823, 879 (2007)
(codified at 21 U.S.C. § 355a(d)(1)(A)).
[67] BPCA encourages sponsors to conduct pediatric studies requested
by the Food and Drug Administration in drug and biological products
that are new or already on the market but still under patent
protection by offering the sponsors 6 months of additional market
exclusivity, known as pediatric exclusivity. See 21 U.S.C. § 355a; 42
U.S.C. § 284m. In March 2010, Congress extended pediatric exclusivity
and applicable BPCA provisions to biological products as part of the
Patient Protection and Affordable Care Act. Pub. L. No. 111-148, §
7002(g)(1), 124 Stat. 119, 819-20 (to be codified at 42 U.S.C. §
262(m)).
[68] See GAO, Pediatric Drug Research: Food and Drug Administration
Should More Efficiently Monitor Inclusion of Minority Children, GAO-03-
950 (Washington, D.C.: Sept. 26, 2003.
[69] See FDA, Guidance for Industry: Collection of Race and Ethnicity
Data in Clinical Trials (Rockville, MD: Sept. 2005).
[70] FDA's 2005 guidance recommends that sponsors use the United
States Office of Management and Budget's categories for data on race
which are: American Indian or Alaska Native, Asian, Black or African
American, Native Hawaiian or other Pacific Islander, and White. Office
of Management and Budget's categories for data on ethnicity are:
Hispanic or Latino, and Not Hispanic or Latino.
[71] Regulation (EC) 1901/2006 of 12 December 2006 on Medicinal
Products for Paediatric Use, 2006 O.J. (L 378) 1; Regulation (EC)
1902/2006 of 20 December 2006 amending Regulation 1901/2006 on
Medicinal Products for Paediatric Use, 2006 O.J. (L 378) 20.
[72] See 21 U.S.C. §§ 355a (Best Pharmaceuticals for Children Act),
355c (Pediatric Research Equity Act), 355d (Pediatric Research Equity
Act); 42 U.S.C. § 284m (Best Pharmaceuticals for Children Act).
[73] Waivers of pediatric studies may be granted to sponsors when
products: (1) are likely to be ineffective or unsafe in part or all of
the pediatric population; (2) are intended for conditions that occur
only in adult populations; or (3) do not represent a significant
therapeutic benefit over existing treatments for pediatric patients.
[74] The requirement also applies to applications for a new
indication, new pharmaceutical form, or new route of administration.
[75] [hyperlink, http://www.ema.europa.eu/].
[76] This is the most recent data available from FDA's Web site. See
[hyperlink,
http://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsRe
search/ucm106621.htm].
[End of section]
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