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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:  https://www.fda.gov/media/86340/download.

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.

**Link to additional FDA Guidance Documents and other regulatory guidance:

http://lists all official FDA Guidance Documents and other regulatory guidance.

Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act - MAY 2023

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pediatric-drug-development-regulatory-considerations-complying-pediatric-research-equity-act-and

FDA Guidance - Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations - MAY 2023

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pediatric-drug-development-under-pediatric-research-equity-act-and-best-pharmaceuticals-children-act

FDA Guidance - Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans - JULY 2020

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pediatric-study-plans-content-and-process-submitting-initial-pediatric-study-plans-and-amended

FDA Guidance - General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products - SEPTEMBER 2022

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/general-clinical-pharmacology-considerations-pediatric-studies-drugs-including-biological-products

FDA Draft Guidance - Ethical Considerations for Clinical Investigations of Medical Products Involving Children - Draft Guidance for Industry, Sponsors, and IRBs - SEPTEMBER 2022

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ethical-considerations-clinical-investigations-medical-products-involving-children

FDA Guidance - Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsor - AUGUST 2023

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent

U.S. Department of Health and Human Services -

Informed Consent FAQs

https://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/informed-consent/index.html

FDA Guidance -E11A Pediatric Extrapolation - AUGUST 2022

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e11a-pediatric-extrapolation

FDA Guidance -Cancer Clinical Trial Eligibility Criteria: Minimum Age Considerations for Inclusion of Pediatric Patients - JULY 2020

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cancer-clinical-trial-eligibility-criteria-minimum-age-considerations-inclusion-pediatric-patients

FDA Guidance - FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act - Guidance for Industry - MAY 2021

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fdara-implementation-guidance-pediatric-studies-molecularly-targeted-oncology-drugs-amendments-sec

Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies
Draft Guidance for Industry - JUNE 2024

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-action-plans-improve-enrollment-participants-underrepresented-populations-clinical-studies?utm_medium=email&utm_source=govdelivery

FDA Guidance - Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products - Guidance for Industry - AUGUST 2023

 (also applies to pediatrics)

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-real-world-data-and-real-world-evidence-support-regulatory-decision-making-drug

The purpose of this guidance is to assist industry in developing data and obtaining information needed to support approval of drug products in pediatric populations. This guidance addresses selected clinical, scientific, and ethical issues regarding the development of drugs for pediatric use when such drugs are subject to the Pediatric Research Equity Act (PREA) and/or the Best Pharmaceuticals for Children Act (BPCA). In 2010, the Biologics Price Competition and Innovation Act of 2009 extended provisions of the BPCA to biological products.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pediatric-drug-development-under-pediatric-research-equity-act-and-best-pharmaceuticals-children-act

This guidance is intended to assist industry developing drug products to comply with the pediatric study requirements under the Pediatric Research Equity Act (PREA), and to describe the process for qualifying for pediatric exclusivity and the protections that pediatric exclusivity offers under the Best Pharmaceuticals for Children Act (BPCA). In 2010, the Biologics Price Competition and Innovation Act of 2009 extended provisions of the BPCA to biological products.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pediatric-drug-development-regulatory-considerations-complying-pediatric-research-equity-act-and

The purpose of this guidance is to provide recommendations to sponsors regarding the submission of an initial pediatric study plan (iPSP) and any amendments to the iPSP. Specifically, this guidance provides the current thinking of the Food and Drug Administration (FDA) regarding implementation of the requirement for sponsors to submit an iPSP, described in section 505B(e) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
This guidance addresses the following:

 • Applications for which an iPSP is required
• Timing of an iPSP submission
• Content of an iPSP
• Content and timing of a requested amendment to an agreed iPSP
• A template that is recommend to be used for an iPSP submission

The number of medicinal products currently labeled for pediatric use is limited. This guidance is intended to encourage and facilitate timely pediatric medicinal product development internationally. The guidance provides an outline of critical issues in pediatric drug development and approaches to the safe, efficient, and ethical study of medicinal products in the pediatric population.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e11-clinical-investigation-medicinal-products-pediatric-population

About the Pediatric Cluster

In 2007, the FDA and the European Medicines Agency (EMA) established monthly teleconferences among regulators called the Pediatric Cluster to discuss product-specific pediatric development and general topics related to product classes under the terms of a Confidentiality Commitment (view applicable Commitments under Related Links below). Since inception, other international agencies have become members of the Pediatric Cluster, which now includes five international regulatory agencies.

This collaboration provides a robust forum to discuss ethical, scientific, and regulatory issues related to global pediatric medical product development. The Pediatric Cluster teleconferences are usually held monthly, although additional teleconferences may be held to accommodate different agency review timelines. 

https://www.fda.gov/science-research/pediatrics/international-collaboration-pediatric-cluster