Pediatric Clinical investigator training workshop Susan McCune, M.D. Director, OPT, OC/FDA Welcome and Introduction February 28, 2019 www.fda.gov

Disclaimer The views presented here are personal and do not necessarily reflect the views of the Agency All specific drug development questions should be discussed with the relevant review division www.fda.gov

Drug Development Overview www.fda.gov Nwaka S and Ridley RG. Virtual drug discovery and development for neglected diseases through public-private partnerships. Nat. Rev. Drug Discov. 2:919-928, 2003

Need For Collaboration www.fda.gov Nwaka S and Ridley RG. Virtual drug discovery and development for neglected diseases through public-private partnerships. Nat. Rev. Drug Discov. 2:919-928, 2003

Pediatric Historical Milestones and Legislation 1962 The FD&C Act amended: Drugs not tested in children should not be used in children 1974 AAP Committee on Drugs issues guidelines for evaluating drugs for pediatric use 1977 AAP issues guidelines for ethical conduct in pediatric studies 1979 FDA requires sponsors to conduct pediatric clinical trials before including pediatric information in the labeling 1992 Agency proposed Pediatric Labeling Rule and proposes extrapolation of efficacy from other data 1994 Final Rule on Pediatric Labeling. Formalizes Extrapolation of Efficacy; manufacturers to update labeling if pediatric data existed; HOWEVER, it allowed a disclaimer to the labeling for drugs not evaluated in children 1994 Pediatric Plan to encourage voluntary development of pediatric data 1997 FDAMA creates pediatric exclusivity provision (voluntary), provides 6-month exclusivity incentive 1998 Pediatric Rule (mandatory): products are required to include pediatric assessments if the drug is likely to be used in a ‘‘substantial number of pediatric patients’’ (50,000) or if it may provide a ‘‘meaningful therapeutic benefit’’ 2002 Pediatric Rule declared invalid by DC Federal Court; the rule exceeded FDA’s authority 2002 FDAMA reauthorized as BPCA. Maintains 6-month exclusivity added to patent life of the active moiety. Creates Office of Pediatric Therapeutics (including ethicist). Mandates pediatric focused safety reviews 2003 PREA re-establishes many components of the FDA’s 1998 pediatric rule. Orphan products are exempted 2007 FDAAA Reauthorizes BPCA & PREA for 5 years. Pediatric Review Committee (PeRC) formed. Studies submitted will result in labeling. Negative and positive results of pediatric studies will be placed in labeling 2012 FDASIA legislation makes permanent BPCA and PREA www.fda.gov

PREA vs. BPCA PREA BPCA Drugs and biologics Required studies Studies may only be required for approved indication(s) Products with orphan designation are exempt from requirements* Pediatric studies must be labeled Drugs and biologics Voluntary studies Studies relate to entire moiety and may expand indications Studies my be requested for products with orphan designation Pediatric studies must be labeled * RACE for Children Act – Elimination of orphan exemption from pediatric studies for cancer drugs directed at relevant molecular targets www.fda.gov

NICHD BPCA For the NIH to prioritize therapeutic areas and sponsor clinical trials and other research about on- and off-patent drug products that need further study in children www.fda.gov

NICHD BPCA More than 100 drugs/therapeutics and 46 conditions/indications prioritized for further study More than 30 clinical trials funded to improve the knowledge of medicines used in children BPCA activities have resulted in 7 labeling changes In 2018, Pediatric Trials Network (PTN) at the Duke Clinical Research Institute received an 8 year grant for $96 million Focus on breastfeeding women and mental health for children Over the previous 8 years (given $95 million in 2010) 26 clinical trials in 13 different therapeutic areas Enrolling over 8,000 children Focus on neonatal and obesity trials www.fda.gov

BPCA/PREA Pediatric Labeling Changes 1998-2017 www.fda.gov

BPCA/PREA Pediatric Labeling Changes 1998 – 6/2018 www.fda.gov

Drug Development Paradigm www.fda.gov

Pediatric Drug Labels Impact to Patients Clinical Trials Innovative Designs Biomarkers Clinical Outcome Assessment Tools Network Sites Basic Science Research Natural History Pathophysiology of Disease Ontogeny of Metabolic Pathways Micro-assays Definition of Endpoints Clinically Meaningful Short Term/Long Term Safety Assessments Consortia Leverage Insights Academia Government Industry Patient Advocacy Groups Modeling and Simulation Ontogeny of Metabolic Pathways PK-PD Studies IT Delivery Systems Interoperable Systems Standardized Data Standardized Case Report Forms Impact to Patients Better Dosing More Appropriate Use of Current Drugs Increased Access to New Drugs Pediatric Drug Labels www.fda.gov

Workshop Agenda Setting the Stage Hot Topics The Basics Funding and Engagement Practical Applications www.fda.gov

Office of Pediatric Therapeutics To contact us: Susan McCune, M.D. Office of Pediatric Therapeutics OC/FDA OPT@fda.hhs.gov www.fda.gov