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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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