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. 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. 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.) 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. 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. 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.) 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.