Pediatric Regulations

Two pediatric regulations, the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children’s Act (BPCA) have resulted in over nine hundred labeling changes since their implementation. These two regulations mirror the stick-and-carrot approach to encouraging sponsors to include pediatric studies in their drug development. 

PREA (“the stick”) requires certain new drugs and biologic applications to contain a pediatric assessment- the data necessary to label the product in pediatric patients- unless the requirement for conducting pediatric studies is waived or deferred.  PREA is triggered by applications with a new active ingredient, formulation, dosage form, dosing regimen or route of administration. PREA requirements apply only to the indication that is the subject of the application.  Except for oncologics, orphan products are exempt from PREA.  In order to reach agreement with FDA on any planned waivers or deferrals, as well as the type of studies and age groups required to complete the pediatric assessment, an initial Pediatric Study Plan (iPSP) must be submitted no later than 60 days after an end-of-phase 2 meeting.   For life-threatening conditions, an iPSP should be submitted earlier.  Agreement on the iPSP must be reached before an NDA or BLA is submitted.  Guidance for the content of an iPSP can be found at:

BPCA (“the carrot”) permits sponsors to potentially obtain 6 months of marketing exclusivity (“pediatric exclusivity”) for voluntarily performing pediatric studies. The scope of BPCA is broader than PREA.  For that reason, studies can be requested for any indication for which the drug or biologic confers a public health benefit and not solely the indication which may be the focus of the NDA or BLA.  In addition, studies for orphan products and/or rare diseases may be part of studies requested by FDA.  To qualify for pediatric exclusivity, a sponsor must “fairly respond” to study requirements delineated in a Written Request (WR) issued by FDA.  The sponsor can submit a Proposed Pediatric Study Request (PPSR) to FDA that outlines the indications to be addressed and studies that they intend to conduct in order to receive a WR.  FDA will respond to a PPSR by either issuing a WR or an inadequate letter that outlines any deficiencies in the program.

If adult efficacy has been established, a “stand-alone” pediatric program may not be required to support a pediatric indication.  Efficacy may be extrapolated from adequate and well controlled studies in adults (or an older pediatric population) if the disease course and pathophysiology, along with response to treatment is sufficiently similar between the two populations.  The type of evidence to support extrapolation depends on the certainty that if a drug works in adults, it is likely to work in children.  Neither dosing nor safety can be fully extrapolated; therefore, typically pharmacologic and safety data in pediatric patients is necessary to establish dosing and safety.  However, data from other populations can be leveraged.  The approach to pediatric extrapolation is evolving as more pediatric data in different conditions and drug classes are available. 

Both BPCA and PREA have labeling and formulation requirements.  The results of any pediatric studies performed in response to either a PREA requirement or BPCA Written Request must be incorporated in labeling, regardless of the findings (positive, negative or inconclusive).  A public notice for formulations not introduced into the market within 1 year of the granting of pediatric exclusivity is posted, as well as the list of PREA waivers granted due to the inability to develop a pediatric formulation.