Pediatric Therapeutics Still working to get it right for kids Bridgette L. Jones, MD MS Associate Professor Pediatrics, University of Missouri Kansas City American Academy of Pediatrics Chair, Committee on Drugs

No relevant conflicts of interest

FDA Medical Reviewer Pediatrician/Pediatric Clinical pharmacologist Chair of AAP Committee on Drugs 1990s

Kefauver Harris Amendment "Drug Efficacy Amendment“ 1962 stipulated that both efficacy and safety must be demonstrated before approval by the FDA for marketing in the United States for drug approval Had unintended consequence of exclusion of children from drug labeling as they were not included in clinical trials therefore approved medications did not include information on safety and efficacy in children and in fact often warned against use in this population

Therapeutic Orphans Harry Shirkey.Pediatrics. 72(1).1968

American Academy of Pediatrics (AAP) Professional organization of 66,000 pediatricians Dedicated to the health, safety, and well-being of infants, children, adolescents, and young adults since its founding in 1930 66 Chapters in U.S. & Canada Made up of numerous organized committees, councils and sections Officially incorporated in July 1930 initial membership about 400 Pediatricians To create reciprocal and friendly relations with all professional and lay organizations that are interested in the health and protection of children. To foster and encourage pediatric investigation, both clinically and in the laboratory, by individuals and groups. Organization of 66,000 primary care pediatricians, pediatric medical subspecialists and pediatric surgical specialists dedicated to the health, safety and well-being of infants, children, adolescents and young adults. Mission The mission of the AAP is to attain optimal physical, mental, and social health and well-being for all infants, children, adolescents, and young adults. To accomplish this mission, the AAP shall support the professional needs of its members.

AAP Committee on Drugs reviews all aspects of pediatric pharmacology including drug indications, contraindications, absorption rates, routes of administration, dosing, use precautions and mode of action as they apply to children. advises the Board of Directors in matters related to drug labeling, safety and efficacy for both prescription and over-the-counter drugs monitors federal legislation related to the drug approval process; and promotes the need for expanded pediatric drug trials.

1974 AAP Committee on Drugs issues guidelines for evaluating drugs for pediatric use

1977 AAP issues guidelines for ethical conduct in pediatric studies “It is morally imperative, therefore, to formally study drugs in children so that they can enjoy appropriate access to existing and new therapeutic agents”

1979 AAP Committee on Drugs provides report of therapeutic categories with pediatric need

PEDIATRIC LABELING 30 YEAR EXPERIENCE UNITED STATES 1973: 78% Rx DRUGS NOT LABELED FOR CHILDREN 1992: 81% Rx DRUGS NOT APPROVED FOR CHILDREN 1984-95: 80% OF NME’s APPROVED WITHOUT PEDIATRIC LABELING 1996-98: >80% OF NME’s APPROVED WITHOUT PEDIATRIC LABELING

WORKSHOP ON DRUG DEVELOPMENT AND PEDIATRIC POPULATIONS RECOMMENDATIONS 1990 FDA commissioner, PMAF Pharmaceutical Manufacturers Association, and AAP sponsored a three-day workshop in Washington, DC to look at the impediments to doing drug studies in children FDA FACILITATE APPROVAL OF DRUGS FOR CHILDREN LEGISLATION TO ADDRESS ECONOMIC ISSUES PROACTIVE STANCE BY PHARMACEUTICAL INDUSTRY NIH FUND CENTERS FOR PEDIATRIC STUDIES

Pediatric Labeling Legislation The FDA Modernization Act of 1997, provided marketing incentives to manufacturers who conduct studies of drugs in children (patent exclusivity for 6 months) The Pediatric Rule of 1998, required pediatric studies and labeling of new drugs with therapeutic benefit to children struck down in the courts due to lack of authority The Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA) in 2002 passed by Congress preserved the voluntary patent exclusivity incentive program and provided the FDA the authority to require studies in children to evaluate safety/efficacy of new drugs BPCA and PREA were made into permanent law in 2012

These legislations have resulted in over 700 products with labeled pediatric safety/efficacy data since 1998 Lynne Yao, MD

>50% of approved drugs without pediatric labeling Neonatal population, 80-90% Children with rare diseases

RACE for Children Act • Incorporated as Title V of the FDA Reauthorization Act (FDARA), enacted August 18, 2017 • Requires evaluation of new molecularly targeted drugs and biologics “intended for the treatment of adult cancers and directed at a molecular target substantially relevant to the growth or progression of a pediatric cancer.” • Molecularly targeted pediatric cancer investigation: clinically meaningful study data, “using appropriate formulations, regarding dosing, safety and preliminary efficacy to inform potential pediatric labeling.” [FDARA Title V Sec 504 (a)(3)(A) or FD&C Act Sec. 505B (a)(3)(A)]. • Elimination of orphan exemption from pediatric studies for cancer drugs directed at relevant molecular targets.

Rare diseases Revise OTC monograph Pediatric medical and surgical devices 

AAP/FDA/NIH stakeholder meeting

This is the reason