Background of the Best Pharmaceuticals for Children Act (BPCA)
Federal legislation and U.S. Food and Drug Administration (FDA) regulations require that drugs be tested for safety and efficacy in a specific population, at a specific dosage, and for a specific time period before the drugs are approved for clinical use. Use of drugs without appropriate testing is considered "off-label" use.
Testing drugs in children presents considerable scientific, clinical, ethical, technical, and logistical challenges. Over the years, several practical challenges have discouraged the testing of drugs in pediatric populations. These include:
- Lack of incentives for companies to study drugs in neonates, infants, and children
- Lack of necessary technology to monitor patients and assay very small amounts of blood
- Lack of suitable infrastructure for conducting pediatric pharmacology drug trials.
As a result, the majority of drugs used in children today are used off label, without adequate understanding of appropriate dose, safety, or efficacy.
In 1994, the FDA issued a Pediatric Rule that allowed the labeling of drugs for pediatric use based on extrapolation of efficacy in adults and additional pharmacokinetic (PK), pharmacodynamic (PD), and safety studies in pediatric populations, if the course of the disease and the response to the drug are similar in children and adults. However, only a small number of well-designed and well-conducted studies resulted from this rule. Difficulty predicting dose-response or concentration-response relationships by extrapolation of data obtained in adults and the unforeseeable nature of some clinical responses in immature individuals have led to unexpected challenges in appropriately labeling some products for pediatric use.
In 1997, the FDA Modernization Act (FDAMA) offered a financial incentive for pharmaceutical companies to conduct pediatric studies: an additional 6 months of market exclusivity. Many drugs have received and continue to receive pediatric labeling under this provision. However, many trials have failed to show efficacy in pediatrics, demonstrating the need for improvements in study designs, determination of outcome measures, and/or additional PK/PD and safety studies in children to determine appropriate dosages and endpoints.
The BPCA 2002
The BPCA, enacted in 2002, provided mechanisms for studying on- and off-patent drugs in children. The Act extended the provision from the 1997 FDAMA offering an additional 6 months of patent exclusivity for on-patent drugs being tested for pediatric use.
The BPCA 2002 directed the Secretary of the U.S. Department of Health and Human Services, acting through the Director of the National Institutes of Health (NIH), to establish a program for pediatric drug development. The Director of the NIH delegated to the Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) the authority and responsibility to establish and conduct pediatric drug development activities set forth under Part B, Title IV, Section 409I (a) and (b) of the Public Health Service Act.
BPCA 2002 activities related to pediatric drug development and testing of off-patent drugs fell into three categories:
- Identifying and prioritizing drugs needing study
- Developing study requests in collaboration with experts at NIH, FDA, and other organizations
- Conducting studies on priority drugs after manufacturers decline to do so.
Since the BPCA 2002 was enacted, the NICHD has awarded many diverse projects to organizations and institutions for the purpose of gathering information to improve pediatric drug labeling (see the BPCA in Action for more details).
The BPCA 2007
The BPCA was reauthorized in Title V of Public Law 110-85 as part of the FDA Amendments Act of 2007. The BPCA 2007 extends the provision offering additional patent exclusivity for on-patent drugs being tested for pediatric use. The reauthorization extends and expands the research program at the NIH, established in the BPCA 2002. The NICHD continues to administer the research program and works with other NIH Institutes and Centers with significant pediatric research portfolios to improve the knowledge in pediatric therapeutics.
Relevant changes in the BPCA 2007 include the following:
- The NIH must publish a priority list of needs in pediatric therapeutics, including drugs or indications that require study, every 3 years.
- The NIH can submit a proposed pediatric study request (PPSR) to the FDA. A PPSR is a draft Written Request (WR) that describes the clinical trials needed to improve pediatric labeling. The FDA issues a WR, and, if the manufacturer does not respond, the NIH can go forward with conducting this research.
NICHD Responsibilities Under the BPCA
The NICHD has responsibility for approximately 25 percent of BPCA funding from its annual budget. The NICHD also organizes study design teams with the FDA and with other NIH Institutes. More than 20 NIH Institutes provide funding for these studies.
The NICHD has primary responsibility for administering, contracting, and monitoring studies to develop Investigational New Drug application data for potential label modification. The NICHD is also responsible for drafting label modifications for specific ages and indications for BPCA studies.
The NICHD leads BPCA efforts in part because of its strengths in conducting safe and effective clinical trials in populations thought to be fragile, such as children and pregnant women. The NICHD also has a record of success in the Pediatric Pharmacology Research Unit (PPRU) Network. The PPRU Network was a group of 13 sites and a data coordinating center that conducted pediatric clinical trials from 1994 to 2009. The BPCA Program has gained valuable knowledge and insight into the intricacies of pediatric pharmacology and the design of pediatric drug trials through the work of the PPRU. The PPRU is no longer in existence, but the NICHD Obstetric and Pediatric Pharmacology Branch is assembling a similar network of sites, called the Specialized Centers in Research and Pediatric Developmental Pharmacology Program (U54), to perform research in pediatric developmental pharmacology.