Pediatric Drug Research: Studies Conducted under Best Pharmaceuticals for Children Act
Published: 2007-03-22T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: About two-thirds of drugs that are prescribed for children have not been studied and labeled for pediatric use, which places children at risk of being exposed to ineffective treatment or incorrect dosing. The Best Pharmaceuticals for Children Act (BPCA), enacted in 2002, encourages the manufacturers, or sponsors, of drugs that still have marketing exclusivity--that is, are on-patent--to conduct pediatric drug studies, as requested by the Food and Drug Administration (FDA). If they do so, FDA may extend for 6 months the period during which no equivalent generic drugs can be marketed. This is referred to as pediatric exclusivity. BPCA required that GAO assess the effect of BPCA on pediatric drug studies and labeling. As discussed with the committees of jurisdiction, GAO (1) assessed the extent to which pediatric drug studies were being conducted under BPCA for on-patent drugs, including when drug sponsors declined to conduct the studies; (2) evaluated the impact of BPCA on labeling drugs for pediatric use and the process by which the labeling was changed; and (3) illustrated the range of diseases treated by the drugs studied under BPCA. GAO examined data about the drugs for which FDA requested studies under BPCA from 2002 through 2005. GAO also interviewed officials from relevant federal agencies, pharmaceutical industry representatives, and health advocates.
section_title: What GAO Found
paragraphs: Drug sponsors have initiated pediatric drug studies for most of the on-patent drugs for which FDA has requested studies, but no drugs were being studied when drug sponsors declined these requests. Sponsors agreed to 173 of the 214 written requests for pediatric studies of on-patent drugs. In cases where drug sponsors decline to study the drugs, BPCA provides for FDA to refer the study of these drugs to the Foundation for the National Institutes of Health (FNIH), a nonprofit corporation. FNIH had not funded studies for any of the nine drugs that FDA referred as of December 2005. Most drugs (about 87 percent) granted pediatric exclusivity under BPCA had labeling changes--often because the pediatric drug studies found that children may have been exposed to ineffective drugs, ineffective dosing, overdosing, or previously unknown side effects. However the process for approving labeling changes was often lengthy. It took from 238 to 1,055 days for information to be reviewed and labeling changes to be approved for 18 drugs (about 40 percent), and 7 of those took more than 1 year. Drugs were studied under BPCA for the treatment of a wide range of diseases, including those that are common, serious, or life threatening to children. These drugs represented more than 17 broad categories of disease, such as cancer. The Department of Health and Human Services stated that the report provides a significant amount of data and analysis and generally explains the BPCA process, but expressed concern that it did not sufficiently acknowledge the success of BPCA or clearly describe some elements of FDA's process. GAO incorporated comments as appropriate.

section_title: Letter
paragraphs: Although children suffer from many of the same diseases as adults and are  often treated with the same drugs, only about one-third of the drugs that  are prescribed for children have been studied and labeled for pediatric  use. This has placed children taking drugs for which there have not been  adequate pediatric drug studies at risk of being exposed to ineffective  treatment or receiving incorrect dosing. In order to encourage the study of  more drugs for pediatric use, Congress passed the Best Pharmaceuticals  for Children Act (BPCA) in 2002 to provide marketing incentives to drug  sponsors for conducting pediatric drug studies. Drug sponsors (typically  drug manufacturers) may obtain 6 months of additional market exclusivity  for drugs on which they have conducted pediatric studies in accordance  with pertinent law and regulations. This market exclusivity is known as  pediatric exclusivity. When a drug has market exclusivity, it is protected  from competition for a limited period, for example by prohibition on Food  and Drug Administration (FDA) approval of a generic copy for marketing.  Generally, pediatric exclusivity can only be granted to those drugs that are  on-patent—that is, those that still have market exclusivity—and for which  FDA has issued a written request for pediatric drug studies. Once a drug’s  patent or market exclusivity has expired, however, FDA can still request  pediatric drug studies for off-patent drugs. BPCA also included provisions  designed to provide for the study of both on-patent and off-patent drugs  that drug sponsors have declined to study.
When FDA determines that a drug may provide health benefits to children,  it may issue a written request to the drug sponsor to conduct pediatric  drug studies. Under BPCA, drug sponsors of on-patent drugs must accept  or decline a written request. Drug sponsors of off-patent drugs are not  required to respond to a written request. However, if FDA does not receive  a response within 30 days, the written request is assumed to be declined.  When a drug sponsor accepts a written request for an on-patent drug and  subsequently submits a study report in response, FDA generally has   90 days to complete its review of the reports to determine whether to  grant pediatric exclusivity to the drug. If FDA is satisfied that the studies  have been conducted and the report submitted as required, the drug in  question may receive additional market exclusivity. FDA also reviews  these pediatric drug study reports to see if the drug requires labeling  changes. The agency refers to this review as its scientific review, which it  has a goal of completing within 180 days.
BPCA provides for pediatric drug studies even if the drug sponsor declined  the written request. First, if a drug sponsor declines a written request by  FDA to study an on-patent drug, BPCA provides for FDA to refer the drug  to the Foundation for the National Institutes of Health (FNIH), which can  fund the study if funds are available. When a sponsor declines a written  request for an on-patent drug, the sponsor cannot receive pediatric  exclusivity in response to that written request. Second, BPCA provides for  the funding of the study of off-patent drugs by the Department of Health  and Human Services’ (HHS) National Institutes of Health (NIH).
BPCA required that we assess, among other things, the effect of provisions  regarding pediatric drug studies on the study and proper labeling of drugs  for pediatric use. As discussed with the committees of jurisdiction, we   (1) assessed the extent to which pediatric drug studies were being  conducted under BPCA for on-patent drugs, including when drug sponsors  declined to conduct the studies; (2) evaluated the impact of BPCA on  labeling of drugs for pediatric use and the process by which the labeling  was changed; and (3) illustrated the range of diseases treated by the drugs  studied under BPCA.
To assess the extent to which pediatric drug studies were being conducted  under BPCA for on-patent drugs, including when drug sponsors declined  to do the studies, we examined data about the drugs for which FDA issued  written requests from January 2002 through December 2005. Our work  focused on actions regarding these drugs prior to 2006. Specifically, we  examined data on the numbers of written requests, drugs studied, written  requests that were declined, and drugs granted pediatric exclusivity during  this 4-year period. We reviewed data from FNIH on the funding status of  on-patent drugs that drug sponsors declined to study. To evaluate the  impact of BPCA on the labeling of drugs for pediatric use and the process  by which labeling was changed, we reviewed summaries of the labeling  changes for drugs studied from the enactment of BPCA through 2005. We  reviewed the dates the labeling changes were agreed to and the reasons  why some drugs did not have labeling changes. To illustrate the range of  diseases treated by the drugs studied under BPCA, we identified the  diseases the drugs were studied to treat, as well as the therapeutic areas  addressed by the drugs. We also examined data from national surveys on  the extent to which these drugs are prescribed for children. In addition, to  assist with our review in general, we interviewed officials from FDA, NIH,  and FNIH as well as representatives of the pharmaceutical industry and  health advocates—such as the American Academy of Pediatrics, the  Pharmaceutical Research and Manufacturers of America, the Generic  Pharmaceutical Association, the National Organization for Rare Disorders,  Public Citizen, the Elizabeth Glaser Pediatric AIDS Foundation, and the  Tufts Center for the Study of Drug Development. (See app. I for a detailed  description of our methodology.)
We conducted our work from September 2005 through March 2007 in  accordance with generally accepted government auditing standards.
subsections: section_title: Background
paragraphs: Prior to enactment of the Food and Drug Administration Modernization  Act of 1997 (FDAMA), which first established incentives for conducting  pediatric drug studies in the form of additional market exclusivity, few  drugs were studied for pediatric use. As a result, there was a lack of  information on optimal dosage, possible side effects, and the effectiveness  of drugs for pediatric use. For example, while physicians typically had  determined drug dosing for children based on their weight, pediatric drug  studies conducted under FDAMA showed that in many cases this was not  the best approach. To continue to encourage pediatric drug studies,  BPCA was enacted on January 4, 2002, just after the pediatric exclusivity  provisions of FDAMA expired on January 1, 2002. BPCA reauthorized and  enhanced the pediatric exclusivity provisions of FDAMA. Like FDAMA,  BPCA allows FDA to grant drug sponsors pediatric exclusivity—6 months  of additional market exclusivity—in exchange for conducting and  submitting reports on pediatric drug studies. The goal of the program is to  develop additional health information on the use of such drugs in pediatric  populations so they can be administered safely and effectively to children.  This incentive is similar to that provided by FDAMA; however, BPCA  provides additional mechanisms to provide for pediatric studies of drugs  that drug sponsors decline to study.
subsections: section_title: BPCA Process
paragraphs: The process for initiating pediatric studies under BPCA formally begins  when FDA issues a written request to a drug sponsor to conduct pediatric  drug studies for a particular drug. FDA may issue a written request after it  has reviewed a proposed pediatric study request from a drug sponsor, in  which the drug sponsor describes the pediatric drug study or studies it  proposes doing in return for pediatric exclusivity. In deciding whether to  approve the proposed pediatric study request and issue a written request,  FDA must determine if the proposed studies will produce information that  may result in health benefits for children. Alternatively, FDA may  determine on its own that there is a need for more research on a drug for  pediatric use and issue a written request without having received a  proposed pediatric study request from the drug sponsor. A written request  outlines, among other things, the nature of the pediatric drug studies that  the drug sponsor must conduct in order to qualify for pediatric exclusivity  and a time frame by which those studies should be completed. When a  drug sponsor accepts the written request and completes the pediatric drug  studies, it submits reports to FDA describing the studies and the study  results. BPCA specifies that FDA generally has 90 days to review the study   reports to determine whether the pediatric drug studies met the conditions  outlined in the written request. If FDA determines that the pediatric drug  studies conducted by the drug sponsor were responsive to the written  request, it will grant a drug pediatric exclusivity regardless of the study  findings. Figure 1 illustrates the process under BPCA.
section_title: BPCA Provisions for Pediatric Drug Studies Declined by Drug Sponsors
paragraphs: To further the study of drugs when drug sponsors decline a written  request, BPCA includes two provisions that did not exist under FDAMA.  First, if a drug sponsor declines to conduct the pediatric drug studies  requested by FDA for an on-patent drug, BPCA provides for FDA to refer  the study of that drug to FNIH, which might then agree to fund the studies.  Second, if a drug sponsor declines a request to study an off-patent drug,  BPCA provides for referral of the study to NIH for funding. FDA cannot  extend pediatric exclusivity in response to written requests for any drugs  for which the drug sponsor declined to conduct the requested pediatric  drug studies.
When drug sponsors decline written requests for studies of on-patent  drugs, BPCA provides for FDA to refer the study of those drugs to FNIH  for funding, when FDA believes that the pediatric drug studies are still  warranted. FNIH, which was authorized by Congress to be established in  1990, is guided by a board of directors and began formal operations in  1996 to support the mission of NIH and advance research by linking  private sector donors and partners to NIH programs. Although FNIH is a  nonprofit corporation that is independent of NIH, FNIH and NIH  collaborate to fund certain projects. FNIH has raised approximately   $300 million from the private sector over the past 10 years to support four  general types of projects: (1) research partnerships; (2) educational  programs and projects for fellows, interns, and postdoctoral students;   (3) events, lectures, conferences, and communication initiatives; and   (4) special projects. Included in these funds is $4.13 million that FNIH  raised as of December 2005 to fund pediatric drug studies under BPCA.  The majority of FNIH’s funds are restricted by donors for specific projects  and cannot be reallocated. In recent years, appropriations of $500,000  were authorized to FNIH annually.
To further the study of off-patent drugs, NIH—in consultation with FDA  and other experts—develops a list of drugs, including off-patent drugs,  which the agency believes are in need of study in children. NIH lists these  drugs annually in the Federal Register. FDA may issue written requests for  those drugs on the list that it determines to be most in need of study. If the  drug sponsor declines or fails to respond to the written request, NIH can  contract for, and fund the conduct of, the pediatric drug studies. These  pediatric drug studies could then be conducted by qualified universities,  hospitals, laboratories, contract research organizations, federally funded  programs such as pediatric pharmacology research units, other public or  private institutions or individuals. Drug sponsors generally decline written  requests for off-patent drugs because the financial incentives are  considerably limited. (See app. II for a description of federal efforts to  encourage research on drugs for children less than 1 month of age and  app. III for NIH efforts to support pediatric drug studies.)
section_title: Making Labeling Changes under BPCA for On-Patent Drugs
paragraphs: Pediatric drug studies often reveal new information about the safety or  effectiveness of a drug, which could indicate the need for a change to its  labeling. Generally, the labeling includes important information for health  care providers, including proper uses of the drug, proper dosing, and  possible adverse effects that could result from taking the drug. FDA may  determine that the drug is not approved for use by children, which would  be reflected in any labeling changes.
According to FDA officials, in order to be considered for pediatric  exclusivity, a drug sponsor typically submits results from pediatric drug  studies in the form of a “supplemental new drug application.” BPCA  specifies that study results, when submitted as part of a supplemental new  drug application, are subject to FDA’s performance goals for a scientific  review, which in this case is 180 days. FDA’s processes for reviewing  study results submitted under BPCA for consideration of labeling changes  are not unique to BPCA. These are the same processes the agency would  use to review any drug study results in consideration of labeling changes.  FDA’s action on the application can include approving the application,  determining that the application is approvable (pending the submission of  additional information from the sponsor), or determining that the  application is not approvable. If studies demonstrate that an approved  drug is not safe or effective for pediatric use, this information would be  reflected in the drug’s labeling.
With a determination that the application is approvable, FDA  communicates to the drug sponsor that some issues need to be resolved  before the application can be approved and describes what additional  work is necessary to resolve the issues. This might require that drug  sponsors conduct additional analyses. However, this communication  would complete the scientific review cycle. When a drug sponsor  resubmits the application with the additional analyses, a new scientific  review cycle begins. As a result, multiple scientific review cycles might be  necessary, increasing the time between initial submission of the  application, which includes the pediatric study reports, and approval of a  labeling change.
If, during FDA’s review of the study report submitted as part of the  application, the agency determines that the application is approvable and  the only unresolved issue is labeling, FDA and the drug sponsor must  attempt to reach agreement on labeling changes within 180 days after the  application is submitted to FDA. If FDA and the drug sponsor cannot  reach agreement, FDA must refer the matter to its Pediatric Advisory  Committee, which would convene and provide recommendations to the  Commissioner on the appropriate changes to the drug’s labeling. The  Commissioner would then consider the committee’s recommendations in  making the final determination on the proper labeling.
section_title: Drug Sponsors Agreed to Study the Majority of On-Patent Drugs with Written Requests under BPCA, but No Studies Were Conducted When Drug Sponsors Declined the Written Requests
paragraphs: Most of the on-patent drugs for which FDA requested pediatric drug  studies under BPCA were being studied, but no studies resulted when the  requests were declined by drug sponsors. Of the 214 on-patent drugs for  which FDA requested pediatric drug studies from January 2002 through  December 2005, drug sponsors agreed to study 173 (81 percent). Of the 41  on-patent drugs that drug sponsors declined to study, FDA referred 9 to  FNIH for funding and the foundation had not funded any of those studies  as of December 2005.
subsections: section_title: Drug Sponsors Agreed to Conduct Pediatric Drug Studies for Most On-Patent Drugs with Written Requests Issued under BPCA
paragraphs: From January 2002 through December 2005, FDA issued 214 written  requests for on-patent drugs to be studied under BPCA, and drug sponsors  agreed to conduct pediatric drug studies for 173 (81 percent) of those.  The remaining 41 written requests were declined. (See app. IV for details  about the study of off-patent drugs under BPCA and app. V for a detailed  description of the status of all written requests issued by FDA.) Drug  sponsors completed pediatric drug studies for 59 of the 173 accepted  written requests—studies for the remaining 114 written requests were  ongoing—and FDA made a pediatric exclusivity determination for 55 of  those through December 2005. Of those 55 written requests,   52 (95 percent) resulted in FDA granting pediatric exclusivity. Figure 2  shows the status of written requests issued under BPCA for the study of  on-patent drugs, from January 2002 through December 2005. (See app. VI  for a description of the complexity of pediatric drug studies conducted  under BPCA.)
section_title: FNIH Had Not Funded the Study of Any On-Patent Drugs in Children
paragraphs: Under BPCA, when a written request to study an on-patent drug is  declined, the study of the drug may be referred to FNIH. However, FNIH is  limited in its ability to fund drug studies by its available funds. Through  December 2005, drug sponsors declined written requests issued under  BPCA for 41 on-patent drugs. FDA referred 9 of these 41 written requests  (22 percent) to FNIH for funding. FNIH had not funded the study of any  of these drugs. NIH has estimated that the cost of studying the drugs that  were referred to FNIH for study would exceed $43 million (see table 1).  FNIH has been raising funds for the study of drugs referred under BCPA at  a rate of approximately $1 million per year.
section_title: Most Drugs Granted Pediatric Exclusivity under BPCA Had Labeling Changes, but the Process for Making Changes Was Sometimes Lengthy
paragraphs: Most drugs—about 87 percent—that have been granted pediatric  exclusivity under BPCA have had labeling changes as a result of the  pediatric drug studies conducted under BPCA. Pediatric drug studies  conducted under BPCA showed that children may have been exposed to  ineffective drugs, ineffective dosing, overdosing, or side effects that were  previously unknown. However, the process for reviewing study results and  completing labeling changes was sometimes lengthy, particularly when  FDA required additional information to support the changes.
subsections: section_title: Most Drugs Granted Pediatric Exclusivity Had Labeling Changes
paragraphs: Of the 52 drugs studied and granted pediatric exclusivity under BPCA from  January 2002 through December 2005, 45 (about 87 percent) had labeling  changes as a result of the pediatric drug studies. FDA officials told us that  labeling changes were not made for the remaining 7 (about 13 percent)  drugs granted pediatric exclusivity, generally because data provided by the  pediatric drug studies did not support labeling changes. In addition, 3  other drugs had labeling changes prior to FDA making a decision on  granting pediatric exclusivity. FDA officials said these labeling changes  were made prior to determining whether pediatric exclusivity should be  granted because the pediatric drug studies provided important safety  information that should be reflected in the labeling without waiting until  the full study results were submitted or pediatric exclusivity was  determined.
section_title: Labeling Changes for Drugs Studied under BPCA Had Important Implications for Pediatric Use
paragraphs: Pediatric drug studies conducted under BPCA have shown that the way  that some drugs were being administered to children potentially exposed  them to an ineffective therapy, ineffective dosing, overdosing, or  previously unknown side effects—including some that affect growth and  development. The labeling for these drugs was changed to reflect these  study results. Table 2 shows some of these drugs and illustrates these  types of labeling changes. FDA officials said that the agency has been  working to increase the amount of information included in drug labeling,  particularly when pediatric drug studies indicate that an approved drug  may not be safe or effective for pediatric use.
Other drugs have had labeling changes indicating that the drug may be  used safely and effectively by children in certain dosages or forms.  Typically, this resulted in the drug labeling being changed to indicate that  the drug was approved for use by children younger than those for whom it  had previously been approved. In other cases, the changes reflected a new  formulation of a drug, such as a syrup that was developed for pediatric  use, or new directions for preparing the drug for pediatric use were  identified during the pediatric drug studies conducted under BPCA. (See  table 3 for examples of drugs with this new type of information.)
section_title: The Process for Reviewing Study Results and Approving Labeling Changes Was Sometimes Lengthy, Particularly When FDA Required Additional Information from Drug Sponsors
paragraphs: Although FDA generally completed its first scientific review of study  results submitted as a supplemental new drug application—including  consideration of labeling changes—within its 180-day goal, the process for  completing the review, including obtaining sufficient information to  support and approve labeling changes, sometimes took longer. For the 45  drugs granted pediatric exclusivity that had labeling changes, it took an  average of almost 9 months after study results were first submitted to FDA  for the sponsor to submit and the agency to review all of the information it  required and agree with the drug sponsor to approve the labeling  changes. For 13 drugs (about 29 percent), FDA completed this scientific  review process and FDA approved labeling changes within 180 days. It  took from 181 to 187 days to complete the scientific review process and to  approve labeling changes for 14 drugs (about 31 percent). For the  remaining 18 drugs (about 40 percent), it took from 238 to 1,055 days for  FDA to complete the scientific review process and approve labeling  changes. For 7 of those drugs, it took more than a year to complete the  scientific review process and approve labeling changes.
To determine whether and how drug labeling should be changed, FDA  conducts a scientific review of the study results that are submitted to the  agency by the drug sponsor. Included with the study results is the drug  sponsor’s proposal for how the labeling should be changed. FDA can  either accept the proposed wording or propose alternative wording. For  some drugs, however, the process does not end with FDA’s first scientific  review. While the first scientific reviews were generally completed within  180 days, for the 18 drugs that took 238 days or more, FDA determined  that it needed additional information from the drug sponsors in order to be  able to approve the applications. This often required that the drug  sponsors conduct additional analyses or pediatric drug studies. FDA  officials said they could not approve any changes to drug labeling until the  drug sponsors provided this information. When FDA completed its review  of the information that was originally submitted and requested additional  information from the drug sponsors, the initial 180-day scientific review  ended. A new 180-day scientific review began when the drug sponsors  submitted the additional information to FDA. Drug sponsors sometimes  took as long as 1 year to gather the additional necessary data and respond  to FDA’s requests. This time did not count against FDA’s 180-day goal to  complete its scientific review and approve labeling changes because a new  180-day scientific review begins after the required information is  submitted. However, we counted the total number of days between  submission of study reports and approval of labeling changes. FDA  considers itself in conformance with its review goals even though the  entire process may take longer than 180 days.
BPCA provides a dispute resolution process to be used if FDA and the  drug sponsor cannot reach agreement on labeling changes within 180 days  of when FDA received the application and the only issue holding up FDA  approval is the wording of the drug labeling. However, FDA officials said  they have never used this process because labeling has never been the  only unresolved issue for those applications whose review period  exceeded 180 days. Agency officials told us that the possibility of referral  to the Pediatric Advisory Committee facilitates its negotiations with drug  sponsors on labeling changes because it is something that drug sponsors  want to avoid. Reminding the drug sponsors that such a process exists has  motivated drug sponsors to complete labeling change negotiations by  reaching agreement with FDA. (See app. VII for a discussion of strengths  of BPCA identified by FDA and NIH, as well as suggestions for ways to  improve BPCA.)
section_title: Drugs Studied under BPCA Address a Wide Range of Diseases, Including Some That Are Common, Serious, or Life Threatening to Children
paragraphs: Drugs were studied under BPCA for their safety and effectiveness in  treating children for a wide range of diseases, including some that are  common, serious, or life threatening. We found that the drugs studied  under BPCA represented more than 17 broad categories of disease. The  category that had the most drugs studied under BPCA was cancer, with 28  drugs. In addition, there were 26 drugs studied for neurological and  psychiatric disorders, 19 for endocrine and metabolic disorders, 18 related  to cardiovascular disease—including drugs related to hypertension, and 17  related to viral infections. Written requests for some types of drugs were  more frequently declined by the drug sponsor than others. For example,   36 percent of written requests for pulmonary drugs and 41 percent of  written requests for drugs that treat nonviral infection were declined. In  contrast, 19 percent of written requests were declined overall.
Some of the drugs studied under BPCA were for the treatment of diseases  that are common, including those for the treatment of asthma and  allergies. Analysis of two national databases shows that about half of the  10 most frequently prescribed drugs for children were studied under  BPCA. Based on a survey of prescriptions written by physicians in 2004, 4  of the 10 drugs most frequently prescribed for children were studied under  BPCA. A survey of families and their medical providers in 2003 found that  5 of the 10 drugs most frequently prescribed for children were studied  under BPCA. In addition, several of the drugs studied under BPCA were  for the treatment of diseases that are serious or life threatening to  children, such as hypertension, cancer, HIV, and influenza. Table 4  provides information on some of the drugs studied for pediatric use and  what is known about the diseases that are relevant to children.
Some of the drugs were studied under BPCA to treat complicating  conditions in children who had other diseases, while others treated rare  diseases. For example a drug was studied for the treatment of painful  bladder spasms in children who have spina bifida. Other drugs were  studied to treat overactive bladder symptoms in children with spina bifida  and cerebral palsy, to treat children who require chronic pain management  because of severe illnesses such as cancer, and to treat partial seizures  and epilepsy in children who require more than one drug to control  seizures. About 12 percent of the 52 drugs that were granted pediatric  exclusivity under BPCA were studied for the treatment of rare diseases,  including certain types of leukemia, juvenile rheumatoid arthritis, and  narcolepsy.
section_title: Agency Comments and Our Evaluation
paragraphs: HHS provided written comments on a draft of this report, which we have  reprinted in appendix VIII. HHS stated that the draft report provided a  significant amount of data and analysis and generally explains the BPCA  process. HHS also made four general comments. First, HHS commented  that the report does not sufficiently acknowledge the success of BPCA.  HHS noted that BPCA provides additional incentives for the study of on- patent drugs, a process for the study of off-patent drugs, a safety review of  all drugs granted pediatric exclusivity, and the public dissemination of  information from pediatric studies conducted. HHS concluded that BPCA  has generated more clinical information for the pediatric population than  any other legislative or regulatory effort to date. Second, HHS commented  that the report confuses FDA’s process for reviewing reports of drug  studies conducted under BPCA with time frames for the labeling dispute  resolution process outlined in BPCA. HHS suggested that we did not  sufficiently acknowledge that some of the time it takes for FDA to approve  labeling changes includes time spent by sponsors collecting and  submitting additional information. Third, in commenting on our finding  that few written requests included neonates, HHS pointed out that written  requests for 9 drugs required the inclusion of “newborns” and written  requests for 13 drugs required the inclusion of infants (children under 4  months of age). Fourth, HHS commented that we failed to mention that  exclusivity attaches to patents as well as existing market exclusivity.
We believe that the draft report sent to HHS for comment accurately and  adequately addressed each of the four issues upon which HHS  commented. An explicit discussion of the overall success of BPCA was  outside the scope of this report, as directed by the BPCA mandate and as  discussed with the committees of jurisdiction. Nevertheless, the draft  report extensively discussed HHS accomplishments such as the number of  studies conducted, the number and importance of labeling changes that  FDA approved, and the wide range of diseases, including some that are  common, serious, or life threatening to children, for which drugs were  studied.
In drafting our report we believe we clearly distinguished between FDA’s  goals for completing its review and approval of drug applications and the  time frames mandated for using the labeling dispute resolution process as  outlined in BPCA. In finding that the process for approving labeling  changes is lengthy, we clearly stated that the process included time spent  during FDA’s initial review as well as time drug sponsors took to respond  to FDA’s requests for additional information, which was as long as 1 year.  We also acknowledged that FDA completed its initial review of  applications within its 180-day goal. We stated in the draft that FDA has  never used the dispute resolution process because labeling has never been  the only issue preventing FDA’s approval of a label for more than 180 days.  Nevertheless, we have included additional language in this report to  further clarify the distinction between FDA’s review process for pediatric  applications and labeling dispute resolution.
Our draft clearly stated that while written requests issued under BPCA  required the inclusion of neonates, the majority of those on-patent written  requests—32 of 36—had been first issued under FDAMA. It is therefore  not appropriate to attribute the inclusion of neonates in these written  requests to BPCA. Further, we included in our count of written requests  requiring the inclusion of neonates the 9 written requests that HHS  referred to in its comments as requiring the inclusion of newborns. We did  not specifically include in our counts the other 13 written requests  mentioned in HHS’s comments. According to data provided by FDA, 1 of  these written requests was not issued under BPCA, and 2 others were  counted among the 9 mentioned above. The remaining 10 written requests  were not specifically included in our counts, because the written requests  were first issued prior to BPCA and do not specifically require the  inclusion of neonates. The written requests to which HHS referred in its  comments required the inclusion of very young children, age 0-4 months.  Our draft report had indicated that written requests requiring the inclusion  of young children might produce data about neonates.
Our draft report included language that indicated the conditions under  which pediatric exclusivity applies. We added language to the report to  further clarify the conditions under which pediatric exclusivity can be  granted.
HHS provided technical comments which we incorporated as appropriate.  HHS also stated that many of the oral comments provided by FDA were  not reflected in the draft report sent to HHS for formal comment. Some of  FDA’s suggested revisions and comments were outside the scope of the  report and in some instances we chose to use alternative wording to that  suggested by FDA for readability and consistency. As we did with HHS’s  general and technical comments on this report, we previously  incorporated FDA’s oral comments as appropriate.
We are sending copies of this report to the Secretary of Health and Human  Services, appropriate congressional committees, and other interested  parties. We will also make copies available to others upon request. In  addition, the report will be available at no charge on GAO’s Web site at  http://www.gao.gov. If you have any questions about this report, please  contact me at (202) 512-7119 or crossem@gao.gov. Contact points for our  Offices of Congressional Relations and Public Affairs may be found on the  last page of this report. GAO staff who made major contributions to this  report are listed in appendix IX.
section_title: Appendix I: Scope and Methodology
paragraphs: In this report, we (1) assessed the extent to which pediatric drug studies  were being conducted for on-patent drugs under the Best Pharmaceuticals  for Children Act (BPCA), including when drug sponsors declined to  conduct the studies; (2) evaluated the impact of BPCA on labeling of drugs  for pediatric use and the process by which the labeling was changed; and  (3) illustrated the range of diseases treated by the drugs studied under  BPCA.
Our review focused primarily on those on-patent drugs for which written  requests were issued or reissued by the Department of Health and Human  Services’ (HHS) Food and Drug Administration (FDA) from January 2002,  when BPCA was enacted, through December 2005. Actions taken on these  drugs after December 2005 (such as a determination of pediatric  exclusivity or a labeling change) were not included in our review. In  addition, we reviewed some summary data available about the number of  written requests issued under the Food and Drug Administration  Modernization Act of 1997 (FDAMA) from January 1998 through  December 2001. We also reviewed pertinent laws, regulations, and  legislative histories.
To assess the extent to which pediatric drug studies were being conducted  for on-patent drugs under BPCA, including when the drug sponsors  declined to conduct the studies, we identified written requests issued for  on-patent drugs from January 2002 through December 2005, and  determined which of those were declined by drug sponsors. We also  reviewed data provided by FDA on the nature of the pediatric drug studies  that were conducted in response to the written requests issued under  BPCA. We also examined notices published in the Federal Register,  identifying the drugs designated by HHS’s National Institutes of Health  (NIH) as most in need of study in children. We reviewed data provided to  us by the Foundation for the National Institutes of Health (FNIH)—a  nonprofit corporation independent of NIH—about funding for pediatric  drug studies of on-patent drugs. We interviewed officials from FDA, NIH,  and FNIH to understand the processes by which pediatric drug studies are  prioritized by the agencies, written requests are issued, drug sponsors  respond to written requests, study results are submitted to FDA, and  pediatric exclusivity determinations are made. We also reviewed  background material describing the role of FNIH in supporting research  on children and the funding available for such research.
To evaluate the impact of BPCA on the labeling of drugs for pediatric use  and the process by which the labeling was changed, we reviewed data  provided to us by FDA summarizing the changes made from January 2002  through December 2005 for drugs studied under BPCA. We also used the  dates that the changes were approved in order to calculate how long it  took for FDA to approve labeling changes. We interviewed officials from  FDA about the process by which FDA approves labeling changes as well  as the reasons why some drugs did not have labeling changes.
To illustrate the range of diseases treated by the drugs studied under  BPCA, we reviewed data provided by FDA about the disease each drug  was proposed to treat. We also examined data from the Medical  Expenditure Panel Survey—administered by the Agency for Healthcare  Research and Quality—and the National Ambulatory Medical Care  Survey—administered by the National Center for Health Statistics—to  assess the extent to which the drugs studied under BPCA were prescribed  to children.
To obtain other information that is provided in appendixes to this report,  we collected and analyzed a variety of data from FDA, NIH, and FNIH  about written requests and pediatric studies for both on- and off-patent  drugs. To obtain a broad perspective on the many issues addressed in our  report, we also interviewed representatives of the pharmaceutical industry  and health advocates—such as representatives of the American Academy  of Pediatrics, the Pharmaceutical Research and Manufacturers of America,  the Generic Pharmaceutical Association, the National Organization of Rare  Disorders, Public Citizen, the Elizabeth Glaser Pediatric AIDS Foundation,  and the Tufts Center for the Study of Drug Development.
We evaluated the data used in this report and determined that they were  sufficiently reliable for our purposes. We conducted our work from  September 2005 through March 2007 in accordance with generally  accepted government auditing standards.
section_title: Appendix II: FDA and NIH Efforts to Encourage the Study of Drugs in Neonates since Passage of BPCA
paragraphs: FDA and NIH have engaged in efforts to increase the inclusion of  neonates—children under the age of 1 month—in pediatric drug studies.  As part of its encouragement of pediatric studies in general, BPCA  identified neonates as a specific group to be included in studies, as  appropriate. An examination of the written requests revealed that only 4 of  36 written requests for on-patent drugs first issued under BPCA required  the inclusion of neonates. Further, no written requests for on-patent drugs  and only two written requests for off-patent drugs have required the  inclusion of neonates since FDA and NIH held a workshop that began their  major initiative in this regard in 2004.
subsections: section_title: NIH Workshops
paragraphs: In 2003, NIH conducted three workshops focused on increasing the  inclusion of neonates in pediatric drug studies and discussing diseases  that affect neonates. In September 2003, NIH staff met to discuss drug  studies in neonatology and pediatrics with special emphasis placed on  ways to better apply current knowledge in future pediatric drug studies.  Two months later, NIH met with a group of experts to discuss the use of  the drug dobutamine—used to treat low blood pressure—in neonates. NIH  ended 2003 with a 1-day seminar designed to address parental attitudes  toward neonatal clinical trials.
section_title: NIH Initiatives
paragraphs: FDA and NIH have collaborated to develop the Newborn Drug  Development Initiative (NDDI), a multiphase program intended to identify  gaps in knowledge concerning neonatal pharmacology and pediatric drug  study design and to explore novel designs for studies of drugs for use by  neonates. The NDDI is intended to consist of a series of meetings that will  help frame state-of-the-art approaches and research needs. After forming  various discussion groups in February 2003, the agencies held a workshop  in March 2004 to help frame issues and challenges associated with  designing and conducting drug studies with neonates. The workshop  addressed ethical issues and drug prioritization in four specialty areas:  pain control, pulmonology (the study of conditions affecting the lungs and  breathing), cardiology (the study of conditions affecting the heart), and  neurology (the study of disorders of the brain and central nervous  system). For example, participants in the pain control group reviewed data  demonstrating that neonates who undergo multiple painful procedures  and receive medication to treat pain may differ in their development of  pain receptors compared to those who do not undergo such procedures  and treatment. FDA officials said that FDA would apply the findings from  the NDDI workshop to written requests for pediatric drug studies in the  four specialty areas.
NIH officials said that the Pediatric Formulations Initiative is a related  effort. They said that both initiatives are long-standing activities that  engage in various efforts to enhance information dissemination to improve  all pediatric drug studies. According to NIH officials, these initiatives have  resulted in numerous publications.
section_title: Pediatric Drug Studies Requiring the Study of Neonates
paragraphs: FDA and NIH efforts to increase the inclusion of neonates in pediatric  drug studies conducted under BPCA have been limited. Through 2005, 9 of  16 (56 percent) written requests for off-patent drugs required the inclusion  of neonates in the pediatric drug studies. NIH is currently funding  pediatric drug studies for four of these written requests. Similarly, 36 of  214 (17 percent) written requests for the study of on-patent drugs issued  from January 2002 through December 2005 included a requirement to  study neonates, but only 4 of those 36 (11 percent) were first issued under  BPCA. The remaining 32 (89 percent) written requests were originally  issued under FDAMA, which did not place an emphasis on the inclusion of  neonates in pediatric drug studies. Further, all of the written requests  requiring the inclusion of neonates were issued in 2003, prior to the NDDI.  Further, only two of the written requests for off-patent drugs were issued  after the NDDI, and studies for neither of those have been funded.  According to information provided by FDA, no written requests for   on-patent drugs issued from January 2004 through December 2005  required the inclusion of neonates. FDA officials indicated, however, that  they receive information about neonates in response to written requests  that do not specifically target them. According to these officials, many  written requests require that children from birth through 2 years of age be  studied. These pediatric drug studies therefore may include neonates. In  addition, inclusion of neonates in some studies may not be appropriate for  medical or ethical reasons.
section_title: Appendix III: NIH Efforts to Support Pediatric Drug Studies
paragraphs: BPCA was designed in part to increase pediatric drug studies through  federal efforts. NIH has engaged in several efforts to support pediatric  drug studies since the passage of BPCA.
subsections: section_title: NIH Funding
paragraphs: While NIH plays an important role in providing funding for research for  children, the amount provided by NIH to support such activities has not  increased significantly under BPCA. Since the enactment of BPCA, NIH  funding for children’s research has increased from $3.1 billion in fiscal  year 2003 to $3.2 billion in fiscal year 2005. These figures represent about  11 percent of NIH’s total budget each year from 2003 through 2005. The  research funds for children were distributed by most of NIH’s 28 institutes,  centers, and offices. For example, in 2005, 24 of these institutes, centers,  and offices funded research on children. One institute, the National  Institute of Child Health and Human Development, was responsible for  about 26 percent of funding for pediatric research—the largest proportion  of NIH’s research funding for children. This institute organizes study  design teams with FDA and other relevant NIH institutes, conducts  contracting activities, and modifies drug labeling for specific ages and  diseases.
section_title: Pediatric Pharmacology Research Units
paragraphs: The number of pediatric pharmacology research units—initiated by NIH— devoted to studies for children has remained the same under BPCA. NIH  provides about $500,000 annually to each of these research units to  provide the infrastructure for independent investigators to initiate and  collaborate on studies and clinical trials with private industry and NIH.  The number of such research units grew from 7 in 1994 to 13 in 1999 to  support the infrastructure for collaborative efforts of pharmacologists to  conduct clinical trials that include children. While the number has not  changed since the passage of BPCA in 2002, NIH officials said that staff  from these units often move on to hospitals throughout the country and  enhance the pediatric research capacity nationwide. In addition, they said  that an overall increase in pediatric research capacity nationwide in recent  years has made it possible to conduct pediatric clinical trials at a number  of other sites. They said that, on average, these pediatric pharmacology  research units conduct more than 50 pediatric drug studies annually. Of  these, as many as 20 pediatric drug studies are funded by drug sponsors.  NIH officials told us that of the seven off-patent drugs being studied under  BPCA with NIH funding through 2005, two were being conducted by these  research units. NIH officials said that since on-patent written requests are  not published, the full contribution of the research units under BPCA  cannot be ascertained.
section_title: Meetings and Forums
paragraphs: NIH has sponsored a number of forums designed to increase the number  of children included in drug studies. As shown in table 5, these forums  generated advice and suggestions for NIH concerning drug testing from  health experts, process improvements on drug studies and medication use  with the pediatric community, and explanations of models and data  related to research for children.
NIH has also conducted meetings and entered numerous intra-agency and  FDA agreements to strengthen its relationship with FDA and establish a  firm commitment to study medical issues relevant to children. For  example, NIH conducted a series of internal meetings in fiscal year 2004 to  identify ongoing pediatric drug studies by the National Institute of Mental  Health. As an outcome of these meetings, NIH identified and utilized data  sets related to the study of lithium as it is used for the treatment of bipolar  disorder in children. NIH will use this information to enhance its current  understanding of the drug’s therapeutic benefit.
section_title: Appendix IV: Studies of Off-Patent Drugs under BPCA
paragraphs: In addition to providing a mechanism to study on-patent drugs, BPCA also  contains provisions for the study of off-patent drugs. FDA initiates its  process by issuing a written request to the drug sponsor to study an off- patent drug. If the sponsor declines to study the drug, FDA can refer the  study of the drug to NIH for funding. NIH initiates the BPCA process for  off-patent drugs by prioritizing the list of drugs that need to be studied.
subsections: section_title: Written Requests for Studies of Off-Patent Drugs under BPCA
paragraphs: BPCA includes a provision that provides for the funding of the study of off- patent drugs by NIH. BPCA requires that NIH—in consultation with FDA  and other experts—publish an annual list of drugs for which additional  studies are needed to assess their safety and effectiveness in children.  FDA can then issue a written request for pediatric studies of the off-patent  drugs on the list. If the written request is declined by the drug sponsor,  NIH can fund the studies.
Few off-patent drugs identified by NIH as in need of study for pediatric use  have been studied. From 2003 through 2006, NIH has listed off-patent  drugs that were recommended for study by experts in pediatric research  and clinical practice. By 2005, NIH had identified 40 off-patent drugs that  it believed should be studied for pediatric use. Through 2005, FDA issued  written requests for 16 of these drugs. All but one of these written  requests were declined by drug sponsors. NIH funded pediatric drug  studies for 7 of the remaining 15 written requests declined by drug  sponsors through December 2005.
NIH provided several reasons why it has not pursued the study of some  off-patent drugs that drug sponsors declined to study. Concerns about the  incidence of the diseases that the drugs were developed to treat, the  feasibility of study design, drug safety, and changes in the drugs’ patent  status have caused the agency to reconsider the merit of studying some of  the drugs it identified as important for study in children. For example, in  one case NIH issued a request for proposals to study a drug but received  no response. In other cases, NIH is awaiting consultation with pediatric  experts to determine the potential for study.
Further, NIH has not received appropriations specifically for funding  pediatric drug studies under BPCA. Rather, according to agency officials,  NIH uses lump sum appropriations made to various institutes to fund  pediatric drug studies under BPCA. In fiscal year 2005, NIH spent  approximately $25 million for these pediatric drug studies.
section_title: Funding for Studies of Off- Patent Drugs under BPCA
paragraphs: NIH anticipates spending an estimated $52.5 million for pediatric drug  studies following seven written requests to drug sponsors issued by FDA  from January 2002 through December 2005. These pediatric drug studies  were designed to take from 3 to 4 years and will be completed in 2007 at  the earliest. Where possible, NIH identifies another government agency or  institute within NIH that might be able to meet the requirements of the  written requests and conduct the pediatric drug studies. In cases where a  government agency will conduct the pediatric drug studies, NIH institutes  enter into intra- or interagency agreements for the studies. If those efforts  fail, the agency develops and publishes requests for proposals for others to  conduct the pediatric studies. NIH anticipates spending approximately  $16.0 million for the funding of pediatric drug studies of four additional  off-patent drugs for which FDA did not issue written requests—and  therefore are not covered by the requirements of BPCA—but three of  these drugs have since been listed by NIH in the Federal Register as  needing study in children. (See table 6.)
The drugs whose study NIH is funding without written requests were  selected because of special circumstances that raised their priority for  funding. NIH funded the study of daunomycin and methotrexate—both  cancer drugs—before placing them on its 2006 list of drugs for study in  children. NIH officials told us that the Children’s Oncology Group of the  National Cancer Institute was already working with an appropriate group  of patients and was at a critical stage in developing the pediatric drug  studies that would produce data for both drugs, so pediatric drug studies  were funded before the drugs were placed on the priority list. NIH officials  also told us that ketamine is administered to more than 30,000 children for  sedation each year. Studies done in animals, however, have suggested that  the drug may lead to cell death in the brain. As a result, the drug cannot be  ethically tested in children. NIH is therefore collaborating with FDA to  conduct studies in nonhuman primates. NIH officials report that  methylphenidate is used by an estimated 2.5 million school-aged children  to treat attention deficit hyperactivity disorder. However, a recent study  suggested some potential genetic toxicity of the drug. Because of these  findings, the drug was targeted as a priority and NIH was able to fund  some of the planned studies related to this drug.
section_title: Appendix V: Status of Pediatric Drug Studies Requested by FDA
paragraphs: From January 2002 through December 2005, FDA issued 214 written  requests for the study of on-patent drugs. The agency also issued 16  written requests for the study of off-patent drugs. Fewer written requests  were issued and more were declined by drug sponsors under BPCA than  under FDAMA.
subsections: section_title: Written Requests Issued under BPCA Compared to FDAMA
paragraphs: From January 2002, when BPCA was enacted, through December 2005,  FDA issued or reissued 214 written requests for on-patent drugs, and drug  sponsors declined 41 of those. FDA issued 68 written requests under BPCA  for the study of on-patent drugs, 20 (29 percent) of which were declined  by the drug sponsors. FDA reissued 146 written requests for on-patent  drugs that were originally issued under FDAMA because the pediatric drug  studies had not been completed at the time BPCA went into effect.  Included in the 146 were 21 (14 percent) written requests that were  subsequently declined by the drug sponsors. Therefore, drug sponsors  accepted 173 written requests for the study of on-patent drugs under  BPCA during this period. Under FDAMA, FDA issued 227 written requests.  Drug sponsors did not conduct pediatric drug studies or submit study  results for 30 of the 227 (13 percent) written requests issued under  FDAMA (see fig. 3).
section_title: Reasons for Decline in Written Requests Issued and Accepted under BPCA Compared to FDAMA
paragraphs: FDA officials offered two primary reasons why fewer written requests  were issued under BPCA than under FDAMA. First, according to FDA  officials, when FDAMA was enacted, FDA and some drug sponsors had  already identified a large number of drugs that they believed needed to be  studied for pediatric use. By the time BPCA was enacted, written requests  for the study of these drugs had already been issued. Second, FDA officials  said there was a surge of written requests prior to the sunset of FDAMA.  Agency officials expect the same surge to occur prior to the sunset of the  pediatric exclusivity provisions of BPCA in 2007.
FDA officials also offered a number of reasons that the proportion of  written requests issued under BPCA that were declined was greater than  that for those issued under FDAMA. While FDA does not track the reasons  that drug sponsors decline specific written requests, FDA officials expect  that a major reason that the written requests were declined is that the  agency sometimes requests more extensive pediatric drug studies, and  therefore more costly studies, than the sponsors would like to do. This  may be the case even when the drug sponsors initiated the written request  process. FDA officials said that upon consideration of FDA’s written  requests, drug sponsors may make a business decision not to conduct the  requested pediatric drug studies because they may be too costly for the  expected return associated with pediatric exclusivity. Agency officials  reported that since the drugs studied under FDAMA were more likely to be  those with the greatest expected financial return or the easiest to study,  they are not surprised at the higher proportion of pediatric drug studies  declined under BPCA. Further, under BPCA drug sponsors are required to  pay user fees—as high as $767,400 in fiscal year 2006—when study results  are submitted for pediatric exclusivity consideration. As a result, the  process of gaining pediatric exclusivity has become more expensive than  it was under FDAMA when drug sponsors were exempt from such fees for  pediatric drug studies.
FDA officials said they are not discouraged by the increase in the number  of written requests that have been declined. In 2001, FDA reported to  Congress that the agency expected drug sponsors to conduct pediatric  drug studies for 80 percent of written requests. The rate at which written  requests for studies of on-patent drugs were accepted under BPCA—  71 percent—is close to the target of 80 percent, and it is substantially  larger than the 15 to 30 percent of drugs that FDA officials have reported  were labeled for pediatric use prior to the authorization of pediatric  exclusivity under FDAMA and BPCA.
section_title: Appendix VI: Complexity of Completed Pediatric Drug Studies
paragraphs: The pediatric drug studies conducted under BPCA were complex and  sizable, involving a large number of study sites and children. From July  2002 through December 2005, drug sponsors submitted study reports to  FDA in response to 59 written requests. FDA made pediatric exclusivity  determinations for 55 of those written requests by December 2005, and  most—51, or 93 percent—were made in 90 days or less.
For the 59 written requests for which study results were submitted to  FDA, a total of 143 pediatric drug studies were conducted at 2,860  different study sites with more than 25,000 children participating (see  table 7). In December 2005, FDA projected that for the drugs for which  studies had not yet been submitted for review, there would be nearly  20,000 more children participating in the studies.
section_title: Appendix VII: Strengths of and Suggested Changes for BPCA
paragraphs: Officials from FDA and NIH discussed a number of important strengths of  BPCA. In our interviews with industry group representatives and in a  public forum, a number of suggestions have also been made for ways that  BPCA could be improved.
subsections: section_title: Strengths of BPCA Identified by FDA and NIH Officials
paragraphs: FDA officials identified a number of important strengths of BCPA.  Specifically, they commented on the following:    Economic incentives to conduct pediatric drug studies. Because of the  economic incentives in BPCA, FDA officials argue that many logistical  issues inherent in conducting pediatric drug studies have been overcome.  FDA may also issue a written request for pediatric drug studies for rare  conditions, offering an additional incentive to develop medications for  rare diseases that occur only in children.
Availability of summaries of pediatric drug studies. FDA officials  reported that the public dissemination of study summaries has ensured  that study information is available to the health care community and has  been useful to prescribers to know what has been learned about drugs’ use  in children.
Broad scope of pediatric drug studies. BPCA allows FDA to issue written  requests for pediatric drug studies for the treatment of any disease,  regardless of whether the drug in question is currently indicated to treat  that disease in adults. For example, FDA issued a written request for the  study of a drug currently indicated to treat prostate cancer. The drug is  being tested in children to see if it is effective in treating early puberty in  boys.
Use of dispute resolution as a negotiating tool in ensuring labeling  changes. Although FDA has never invoked its authority under BPCA to use  the dispute resolution process for making labeling changes, it has been an  important negotiating tool. FDA officials indicated that when the agency  has expressed its intention to use the process, the issues that had been  raised in labeling negotiations were effectively resolved.
Improved safety through focused pediatric safety reviews. BPCA’s  requirement that FDA conduct additional monitoring of adverse event  reports for 1 year after a drug is granted pediatric exclusivity has been  useful to FDA in prioritizing safety issues for children. For example, an  analysis of a drug 1 year after pediatric exclusivity was granted showed  that there were deaths among children as a result of overuse or misuse of  the drug. This led the agency to amend the labeling regarding the  appropriate population for the drug.  NIH officials said they have found the process of developing the list of  drugs important for study in children to be extremely helpful. NIH officials  told us that since the inception of BPCA, they have learned a great deal  about existing gaps in the drug development process for children,  including a lack of data about which drugs are used by children and how  frequently. To gather additional information, NIH has contracted for  literature reviews to decrease the possibility that unnecessary pediatric  drug studies are conducted. These officials also stated that BPCA and the  development of the priority list have helped to solidify an alliance between  NIH and FDA, which has led to discussions and resolutions of scientific  and ethical issues relating to pediatric drug studies.
section_title: Suggestions for Changes to BPCA
paragraphs: The Institute of Medicine convened a forum on pediatric research in June  2006 where forum participants made suggestions for how BPCA could be  improved. In addition, we discussed suggestions for improving BPCA with  interest group representatives. Forum participants suggested that the  timing of the determination of pediatric exclusivity should parallel the  scientific review of a drug application and that both should be within   180 days of FDA receiving the results from the pediatric drug studies.  FDA’s ability to assess the overall quality of the pediatric drug studies in  the 90 days currently allotted for the review was questioned. Some forum  participants also stated that a longer review period could result in  different determinations in some cases. For example, FDA’s scientific  review of data related to the study of one drug showed that the children  participating in the pediatric drug studies had not received the treatments  as the drug sponsors had suggested in their description of the study  results. While the agency had granted the drug sponsor pediatric  exclusivity based on its 90-day review to determine pediatric exclusivity, it  might not have done so based on what was learned during the longer,   180-day scientific review.
In addition, it was suggested that drug sponsors be required to submit  their study results for pediatric exclusivity determination at least 1 year  prior to patent expiration. This would allow the generic drug industry time  to better plan its release of drugs. We were told that sometimes generic  drugs have had to be destroyed because pediatric exclusivity  determinations were made after the generic version of the drug had been  manufactured and the drug’s expiration date would not allow the product  to be sold.
Representatives from interest groups would like the written requests to be  public information and would also like FDA to publicly announce when it  receives study results that have been submitted in response to a written  request. This would allow the generic drug industry to better schedule the  introduction of generic drugs into the market.
Other suggestions for how the study of off-patent drugs could be more  effectively encouraged were offered at the forum. A forum participant  suggested that methods similar to those being adopted by the European  Union be implemented. According to forum participants, under new  legislation in Europe, companies that study off-patent drugs will be offered  a variety of incentives, such as 10 years of data protection (meaning that  the data generated to support the marketing of the drug cannot be used to  support another drug, in an effort to delay competition), the right to use  the existing brand name (to enable the drug sponsor to capitalize on  existing brand recognition), and the ability to add a symbol to the drug  labeling indicating the drug has been studied in children.
Another suggestion was that current fees paid by drug sponsors for review  of their drug applications could be used to fund the study of off-patent  drugs (as well as on-patent drugs that drug sponsors decline to study).  These fees—$767,400 for a new drug application and $383,700 for a  supplemental drug application in fiscal year 2006—are collected from drug  sponsors when study results are submitted to FDA for review and  consideration of pediatric exclusivity.
section_title: Appendix VIII: Comments from the Department of Health and Human Services
section_title: Appendix IX: GAO Contact and Staff Acknowledgments
subsections: section_title: Acknowledgments
paragraphs: In addition to the contact named above, Thomas Conahan, Assistant  Director; Shaunessye Curry; Cathleen Hamann; Martha Kelly; Julian  Klazkin; Carolyn Feis Korman; Gloria Taylor; and Suzanne Worth made  key contributions to this report.