Pediatric Research: Products Studied under Two Related Laws, but Improved Tracking Needed by FDA
Published: 2011-05-31T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.
section_title: What GAO Recommends
paragraphs: 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.

section_title: Letter
paragraphs: 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. 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. 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, including the Pediatric  Research Equity Act (PREA) and the Best Pharmaceuticals for Children  Act (BPCA). 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),  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. 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) 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).
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. 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. 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.
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.  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. 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. 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. 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. 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, 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.
subsections: section_title: Background
paragraphs: The FDA Modernization Act of 1997 (FDAMA) established pediatric  exclusivity for sponsors that conducted pediatric studies for drugs.  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. However, in 2002, the Pediatric Rule  was declared invalid by a federal court. 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. PREA and BPCA are both set to expire on   October 1, 2012.
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. 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. 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. 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. 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.  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 fig. 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.
Under BPCA, sponsors receive pediatric exclusivity as an incentive to  conduct studies of drug and biological products for use in children. 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. (See app. 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. 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.
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. 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 fig. 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.
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. 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. 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 fig. 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.
subsections: section_title: The Pediatric Advisory Committee
paragraphs: 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.
section_title: Internal Control
paragraphs: 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. 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.
section_title: 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
paragraphs: 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.
subsections: section_title: FDA Cannot be Certain How Many Additional Products Have Been Studied under PREA; Most Requests for Waivers and Deferrals Have Been Granted
paragraphs: 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. 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. 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 fig. 4).
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.
section_title: 50 Products Have Been Studied under BPCA since Its 2007 Reauthorization
paragraphs: 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. 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. 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. 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. Sponsors agreed to 35 of  the written requests. (See fig. 5.) FDA officials stated that the sponsors  completed studies for two of the written requests; studies for the  remaining 33 written requests are ongoing. 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. 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. Since the 2007 reauthorization, about 5 percent of  written requests have been declined.
section_title: Drug and Biological Products Were Studied in a Wide Range of Therapeutic Areas
paragraphs: 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. 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.
section_title: Few Drugs Have Been Studied When Sponsors Have Declined Written Requests
paragraphs: 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. 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.
section_title: 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
paragraphs: 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.
subsections: section_title: All Products with Completed Pediatric Studies Since the 2007 Reauthorization Had Labeling Changes That Included Important Pediatric Information
paragraphs: All of the 130 drug and biological products with studies completed and  applications reviewed by FDA since the 2007 reauthorization had labeling  changes. 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. 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.
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.
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. (See fig. 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.
section_title: FDA’s Goals Often Differ from the PREA Requirement for Reaching Agreement on Labeling Changes
paragraphs: 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.  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. 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.
section_title: Stakeholders Identified Agency Guidance, Uncertainty Associated with Reauthorization, and Lack of Economic Incentives as Potential Challenges to Conducting Pediatric Studies
paragraphs: 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. 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.
Another challenge identified by stakeholders is complying simultaneously  with the U.S. laws, PREA and BPCA, and the European Union’s (EU)  Paediatric Regulation. (See app. 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.
section_title: Conclusions
paragraphs: 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.
section_title: Recommendation for Executive Action
paragraphs: 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.
section_title: Agency Comments and our Evaluation
paragraphs: 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.
section_title: Appendix I: Inclusion of Neonates in Drug and Biological Product Studies
paragraphs: 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). 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 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. 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. 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. 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. 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.  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.
section_title: Appendix II: Inclusion of Ethnic and Racial Minority Participants in Pediatric Drug Studies
paragraphs: 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). 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. 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. 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. 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.
section_title: Appendix III: Pediatric Drug and Biological Product Studies in the European Union and the United States
paragraphs: 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. 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. 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.
subsections: section_title: The European Union’s Paediatric Regulation
paragraphs: 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. 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. 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.
section_title: European Union and United States Collaboration
paragraphs: 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. 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.
section_title: Appendix IV: Comments from the Department of Health and Human Services
section_title: Appendix V: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Acknowledgments
paragraphs: 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.