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. 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. 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. 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. 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. 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. 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. This is a work of the U.S. government and is not subject to copyright protection in the United States. It may be reproduced and distributed in its entirety without further permission from GAO. However, because this work may contain copyrighted images or other material, permission from the copyright holder may be necessary if you wish to reproduce this material separately.

Summary: 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. 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.