Pediatric Drug Research: The Study and Labeling of Drugs for Pediatric Use under the Best Pharmaceuticals for Children Act
Published: 2007-05-22T00:00:00

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, placing 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 also provides for the study of off-patent drugs. GAO was asked to testify on the study and labeling of drugs for pediatric use under BPCA. This testimony is based on Pediatric Drug Research: Studies Conducted under Best Pharmaceuticals for Children Act, GAO-07-557 (Mar. 22, 2007). GAO assessed (1) the extent to which pediatric drug studies were being conducted under BPCA for on-patent drugs, (2) the extent to which pediatric drug studies were being conducted under BPCA for off-patent drugs, and (3) the impact of BPCA on the labeling of drugs for pediatric use and the process by which the labeling was changed. GAO examined data about the drugs for which FDA requested studies under BPCA from 2002 through 2005 and interviewed relevant federal officials.
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 such studies under BPCA, but no drugs were studied when 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. Few off-patent drugs identified by the National Institutes of Health (NIH) that need to be studied for pediatric use have been studied. BPCA provides for NIH to fund studies when drug sponsors decline written requests for off-patent drugs. While 40 such off-patent drugs were identified by 2005, FDA had issued written requests for 16. One written request was accepted by the drug sponsor. Of the remaining 15, NIH funded studies for 7 through December 2005. Most drugs granted pediatric exclusivity under BPCA (about 87 percent) 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. For 18 drugs that required labeling changes (about 40 percent), it took from 238 to 1,055 days for information to be reviewed and labeling changes to be approved.

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, the Food and Drug  Administration (FDA) is prohibited from approving 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. However, FDA can also request pediatric drug studies for  off-patent drugs—drugs for which the patent or market exclusivity has  expired. 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 on that drug. When a drug sponsor accepts a written request  and conducts studies, FDA reviews the report from the pediatric drug  studies to determine whether to grant pediatric exclusivity to the drug. If  FDA is satisfied that the studies have been conducted and reported  properly, 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.
BPCA provides for pediatric drug studies when the drug sponsor declines  the written request. First, if a drug sponsor declines a written request from  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. Sponsors cannot receive pediatric  exclusivity for on-patent drugs that drug sponsors decline to study.  Second, BPCA provides for the funding of the study of off-patent drugs by  the National Institutes of Health (NIH), which, in consultation with FDA  and experts in pediatric research, identifies off-patent drugs that need to  be studied for pediatric use.
My remarks today provide an overview of the study and proper labeling of  drugs for pediatric use under BPCA. I will focus on (1) the extent to which  pediatric drug studies were being conducted under BPCA for on-patent  drugs, (2) the extent to which pediatric drug studies were being conducted  under BPCA for off-patent drugs, and (3) the impact of BPCA on the  labeling of drugs for pediatric use and the process by which the labeling  was changed. My remarks are based upon our report assessing the effect  of BPCA on pediatric drug studies and labeling.
In carrying out the work for our 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 from January 2002  through December 2005. Our work focused on actions regarding these  drugs prior to 2006. 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. In addition, to assist with our review in  general, we interviewed officials from FDA, NIH, and FNIH. The work  done for this statement was performed from September 2005 through  March 2007 in accordance with generally accepted government auditing  standards.
In summary, most of the on-patent drugs for which FDA requested  pediatric drug studies under BPCA were being studied, but no studies  resulted when the requests were declined by drug sponsors. Drug  sponsors agreed to study 173 of the 214 on-patent drugs (81 percent) for  which FDA issued written requests for pediatric drug studies from January  2002 through December 2005. Drug sponsors completed pediatric drug  studies for 59 of the 173 accepted written requests—studies for the  remaining 114 written requests 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. In addition, of the 41 on-patent drugs that drug sponsors  declined to study, FDA referred 9 to FNIH, which had not funded the study  of any, as of December 2005.
Few of the off-patent drugs identified by NIH as in need of study for  pediatric use have been studied. By 2005, NIH had identified 40 off-patent  drugs it recommended be studied for pediatric use. Through 2005, FDA  issued written requests for 16 of these drugs, and all but one of these  written requests were declined by drug sponsors. NIH funded pediatric  drugs studies for 7 of the remaining 15 written requests declined by drug  sponsors through December 2005.
Almost all the drugs that have been granted pediatric exclusivity under  BPCA—about 87 percent—have had important labeling changes as a result  of pediatric drug studies conducted under BPCA, but the process for  reviewing the study results and making these changes can be lengthy. The  labeling of drugs was often changed because the pediatric drug studies  revealed that children may have been exposed to ineffective drugs,  ineffective dosing, overdosing, or previously unknown side effects. The  review process took from 238 to 1,055 days when FDA required additional  information to support changes in the drug labeling.
subsections: section_title: Background
paragraphs: BPCA was enacted on January 4, 2002, to encourage drug sponsors to  conduct pediatric drug studies. BPCA allows FDA to grant drug sponsors  pediatric exclusivity—6 months of additional market exclusivity—in  exchange for conducting and reporting on pediatric drug studies. BPCA  also provides mechanisms for pediatric drug studies that drug sponsors  decline to conduct.
subsections: section_title: BPCA Process
paragraphs: The process for initiating pediatric drug studies under BPCA formally  begins when FDA issues a written request to a drug sponsor to conduct  pediatric drug studies for a particular drug. When a drug sponsor accepts  the written request and completes the pediatric drug studies, it submits to  FDA reports 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: BPCA includes two provisions to further the study of drugs when drug  sponsors decline written requests. FDA cannot extend pediatric  exclusivity in response to written requests for any drugs for which the  drug sponsors declined to conduct the requested pediatric drug studies.
First, 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. FNIH, which is a nonprofit corporation and independent of  NIH, supports the mission of NIH and advances research by linking private  sector donors and partners to NIH programs. FNIH and NIH collaborate to  fund certain projects. As of December 2005, FNIH had raised $4.13 million  to fund pediatric drug studies under BPCA.
Second, to further the study of off-patent drugs, NIH—in consultation with  FDA and experts in pediatric research—develops a list of drugs, including  off-patent drugs, which the agency believes need to be studied 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 pediatric drug studies.  Drug sponsors generally decline written requests for off-patent drugs  because the financial incentives are considerably limited.
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 events that could result from taking the drug. FDA may  determine that the drug is not approved for use by children, which would  then be reflected in any labeling changes.
The agency refers to its review to determine the need for labeling changes  as its scientific review. BPCA specifies that study results submitted as a  supplemental new drug application—which, according to FDA officials,  most are—are subject to FDA’s general performance goals for a scientific  review, which in this case is 180 days. FDA’s process for reviewing study  results submitted under BPCA for consideration of labeling changes is not  unique to BPCA. FDA’s action can include approving the application,  determining that the application is approvable, or determining that the  application is not approvable. A determination that an application is  approvable may require that drug sponsors conduct additional analyses.  Each time FDA takes action on the application, a review cycle is ended.
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 have resulted  when the requests were declined by drug sponsors. 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. Of these 41, FDA referred 9 written  requests to FNIH for funding and FNIH had not funded any of those  studies as of December 2005.
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 pediatric exclusivity determinations 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.
Drugs were studied under BPCA for their safety and effectiveness in  treating children for a wide range of diseases, including some that are  common—such as asthma and allergies— and serious or life threatening in  children—such as cancer, HIV, and hypertension. 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. Analyses of two national  databases shows that about half of the 10 most frequently prescribed  drugs for children were studied under BPCA.
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, but as of December 2005,  FNIH had not funded the study of any of these drugs. NIH has estimated  that the cost of studying these 9 drugs would exceed $43 million, but FNIH  had raised only $4.13 million for pediatric drug studies under BPCA.
section_title: Few Off-Patent Drugs Have Been Studied under BPCA
paragraphs: Few off-patent drugs identified by NIH as in need of study for pediatric use  have been studied. 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 1 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 disease 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 responses. 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. NIH anticipates spending an estimated  $52.5 million for pediatric drug studies associated with 7 written requests  issued by FDA from January 2002 through December 2005.
section_title: Most Drugs Granted Pediatric Exclusivity under BPCA Had Labeling Changes, but the Process for Making Changes Was Sometimes Lengthy
paragraphs: Most drugs that have been granted pediatric exclusivity under BPCA— about 87 percent—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 from drug sponsors to support the  changes.
Of the 52 drugs studied and granted pediatric exclusivity under BPCA from  January 2002 through December 2005, 45 (about 87 percent) had labeling  changes as a result of the pediatric drug studies. In addition, 3 other drugs  had labeling changes prior to FDA making a decision on granting pediatric  exclusivity. FDA officials said that the pediatric drug studies conducted up  to that time provided important safety information that should be reflected  in the labeling without waiting until the full study results were submitted  or pediatric exclusivity determined.
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. For example, studies of the drug Sumatriptan, which is used  to treat migraines, showed that there was no benefit derived from this  drug when it was used in children. There were also certain serious adverse  events associated with its use in children, such as vision loss and stroke,  so the labeling was changed to reflect that the drug is not recommended  for children under 18 years old.
Other drugs have had labeling changes indicating that the drugs 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 in the pediatric drug studies conducted under BPCA.
Although FDA generally completed its first scientific review of study  results—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 approve labeling changes. For 13  drugs (about 29 percent), FDA completed this scientific review process  and approved labeling changes within 180 days. It took from 181 to 187  days for the scientific review process to be completed and labeling  changes to be approved for 14 drugs (about 31 percent). For the remaining  18 drugs (about 40 percent), FDA took from 238 to 1,055 days 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.
While the first scientific reviews were generally completed within   180 days, it took 238 days or more for 18 drugs. For those 18 drugs, FDA  determined that it needed additional information from the drug sponsors  in order to be able to approve the drugs for pediatric use. This often  required that the drug sponsor conduct additional analyses or pediatric  drug studies. FDA officials said they could not approve any changes to  drug labeling until the drug sponsor provided this information. Drug  sponsors sometimes took as long as 1 year to gather the additional  necessary data and respond to FDA’s request.
Mr. Chairman, this concludes my prepared remarks. I would be pleased to  respond to any questions that you or other members of the Subcommittee  may have.
For further information regarding this testimony, please contact   Marcia Crosse 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 testimony. Thomas Conahan, Assistant Director;  Carolyn Feis Korman; and Cathleen Hamann made key contributions to  this statement.
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