Future of Pediatric Therapeutics: Reauthorization of BPCA and PREA

Two companion pieces of legislation critical to pediatric therapeutics are scheduled to sunset (automatically terminate) on 1 October 2007 unless reauthorized by Congress. Th e Best Pharmaceuticals for Children Act (BPCA) of 2002 and the Pediatric Research Equity Act (PREA) of 2003, along with the preceding pediatric provisions of the FDA Modernization Act (FDAMA) of 1997, have had an unprecedented impact on pediatric medicine over the past 8 years. It is essential that Congress renew the provisions of these statutes to ensure availability of safe and effective therapies for children in the coming decades. Th e importance of this legislation to the future of children’s health can be appreciated only in the context of the history of limited new drug development for children over the past 40 years before the enactment of these two pieces of legislation. Development and marketing of drugs for human consumption in the United States has been predominantly regulated for the past 40 years by the 1962 amendments to the Food, Drug, and Cosmetic (FD&C) Act, the so-called KefauverHarris amendments. Th ese amendments, when implemented in 1966, introduced several new regulatory mandates, including the requirement to prove effi cacy as well as safety of a drug by conducting scientifi cally rigorous, well-controlled clinical trials before marketing approval. In addition, pharmaceutical companies were for the fi rst time prohibited from making effi cacy claims for a new drug that were not supported by scientifi c evidence and included in the offi cial label approved by the FDA. It is clear from a review of the legislative history of the 1962 amendments that Congress intended for children to be included in the protections provided under the amended FD&C Act. However, this was not the case in practice. In the absence of specifi c requirements for studies in all age groups who would benefi t from a new drug, children were largely excluded from clinical trials and drugs were labeled only for adults with a disclaimer that safety and effi cacy in children had not been established. In 1968, merely 2 years aft er implementation of the 1962 amendments, Dr. Harry Shirkey, then chair of the American Academy of Pediatrics Committee on Drugs, called attention to the exclusion of children and coined the term “therapeutic orphan.” Dr. Shirkey went on to point out the irony that, although passage of the 1962 FD&C amendments was precipitated by the thalidomide phocomelia tragedy aff ecting thousands of children, children were now being systematically excluded from studies to establish safety and effi cacy of new drugs. Several published surveys between 1975 and 1999 have consistently documented that approximately 80% of prescription medicines are approved and labeled for adults with no pediatric safety or prescribing information and a disclaimer regarding use in children. Th e result has been routine and widespread “off -label” use of medications in infants and children in the absence of adequate safety, effi cacy, and dosing information with the ever-present risk of adverse outcomes due to underdosing, overdosing, or unanticipated adverse events unique to children and not predicted from experience in adults. Th is situation has prevailed for the past 40 years. Reasons for excluding children from new drug development are complex. Among those most commonly mentioned are ethical constraints, medical-legal risks, technical and logistical diffi culties, and economic disincentives. However, the ultimate rate-limiting factor has been the economics of drug development in children, given the small market for most drugs in the pediatric age group relative to the adult market size. Ethical guidelines for conducting clinical studies involving children have been available for nearly 30 years. In 1974 the American Academy of Pediatrics first published “Guidelines for the Evaluation of Drugs to Be Approved for Use During Pregnancy and for Treatment of Infants and Children”. Th is was followed by publication in 1977 of “Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations,” which were revised in 1995. Federal regulations for protections for children involved as subjects in research were published in 1983 and subsequently incorporated into the “Common Rule” codifi ed in CFR 45 Part 46, subparts A–D. In 2000, similar