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FDA Clarifies Approach to Pediatric Drug Development

On May 17, the U.S. Food & Drug Administration (FDA) issued two important draft guidance documents, which clarify the agency’s approach to requirements and incentives in the realm of pediatric drug development — “Regulatory Considerations Guidance”[1] and “Scientific Considerations Guidance,”[2] respectively. These guidance documents replace FDA’s previous draft guidance on the subject,[3] issued in 2005, and clarify requirements and recommendations for bringing pediatric drugs to market. FDA will be accepting public comment on the Regulatory Considerations Guidance and Scientific Considerations Guidance through July 17 of this year.[4]

The Challenge: Why Does Pediatric Drug Development Need to Be Regulated?

Historically, the United States has seen a lack of drugs labeled for pediatric use, as compared to drugs labeled for adult use. The cause is two-fold. First, FDA requires clinical trials showing that a drug is safe and effective for its intended use as a condition of approving a drug’s label;[5] however, drug manufacturers and practitioners have been dis-incentivized from performing clinical trials on pediatric populations due to ethical issues, fear of increased liability, and other age-specific factors that complicate the clinical trial process. Second, FDA permits practitioners to prescribe adult drugs to pediatric populations[6] as a so-called “off-label use” if the practitioner determines that the adult drug is medically appropriate for the pediatric patient.[7] Thus, manufacturers of these adult drugs have not been incentivized to perform clinical trials to support a separate pediatric label and, in turn, safety and efficacy data for drugs intended for pediatric use has been largely unavailable.

The Solution: How Do Congress and FDA Regulate and Incentivize Pediatric Drug Development?

In order to address the lack of safety and efficacy data available for pediatric-use drugs and, in turn, the lack of pediatric-use information in drug product labeling, Congress and FDA have historically enacted a combination of statutes, regulations, and guidance. This regulatory scheme consists primarily of (i) the Food and Drug Modernization Act (the FDAMA), (ii) the Pediatric Research Equity Act (the PREA), (iii) the Best Pharmaceuticals for Children Act (the BPCA), (iv) the Rare Pediatric Disease Priority Review Voucher Program, and (v) implementing regulations. Although the Regulatory Considerations Guidance and Scientific Considerations Guidance only address the PREA and the BPCA, the FDAMA and the Rare Pediatric Disease Priority Review Voucher Program are necessary elements of any discussion on the FDA’s regulatory scheme for regulating and incentivizing pediatric drug development and, as such, are briefly summarized below.

Pediatric Exclusivity

In 1997, Congress first introduced the concept of pediatric exclusivity in a law known as the “Pediatric Exclusivity Provision,” enacted as part of the FDAMA.[8] The Pediatric Exclusivity Provision (i.e., Section 111 of the FDAMA) amended the Federal Food, Drug, and Cosmetic Act (the FDCA) to establish an incentive of additional market exclusivity for sponsors who conduct voluntary studies that might expand pediatric indications for a drug.[9] The provision gave FDA discretionary authority to grant sponsors an additional six (6) months of market exclusivity on top of any of the sponsor’s listed patents or non-expired grants of regulatory exclusivity on drug products containing the active moiety that was studied.[10]

However, the Pediatric Exclusivity Provision contained a sunset provision requiring it to expire in 2002. In response, Congress subsequently enacted (i) the BPCA in 2004 to temporarily extend the Pediatric Exclusivity Provision, (ii) the Biologics Price Competition and Innovation Act (the BPCIA) in 2010 to expand the pediatric exclusivity incentive to apply to biologics as well as drugs, and (iii) the FDA Safety and Innovation Act (the FDASIA) in 2012 to make the BPCA, and, thus, the pediatric exclusivity incentive, permanent (i.e., remove the applicable sunset provision).[11]

Thus, Section 505A of the FDCA provides the current, permanent statutory framework for the pediatric exclusivity provision.[12] The current statutory framework mirrors the pediatric exclusivity incentive established in 1997 with two notable additions – (i) the current statute includes biologic products and (ii) the current statute clarifies that FDA may approach the sponsor with a study request or the sponsor may submit a proposed pediatric study request (PPSR) for FDA’s consideration.[13]

Required Clinical Trials

The PREA, which was introduced in 2003 and made permanent by the FDASIA in 2012, requires sponsors to conduct and report pediatric assessments as a condition of approval for bringing a drug or biologic to market on the grounds of a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration.[14] Under the law, a pediatric assessment must contain data, gathered using appropriate formulations for each applicable age group, that are adequate (i) to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, and (ii) to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective.[15] Notably, sponsors may request a deferral or complete/partial waiver of the pediatric assessment requirement, and the requirement does not apply to drugs granted orphan drug status.[16]

Additionally, the PREA gives special consideration to molecularly targeted pediatric cancer investigations, requiring that such investigations be designed “to yield clinically meaningful pediatric study data, gathered using appropriate formulations for each age group for which the study is required, regarding dosing, safety, and preliminary efficacy to inform potential pediatric labeling.”[17]

Priority Review Vouchers

The FDASIA also codified the Rare Pediatric Disease Priority Review Voucher Program, which grants a sponsor who receives approval for a rare pediatric disease drug or biologic a priority review voucher that may be redeemed to receive priority review of a subsequent marketing application for a different product.[18] Significantly, the voucher is fully transferrable and, since 2012, at least seven rare pediatric disease priority review vouchers have been sold to fellow industry participants by the original sponsors for sums ranging from $65 million to $350 million, making the voucher a valuable financial incentive for the development of drugs and biologics to address rare pediatric diseases, even for sponsors who do not intend to develop additional products.[19]

Recent Developments: What Notable Changes Are Included in the New Guidance Documents? 

On May 17, FDA issued official guidance on its intended application of requirements and incentives under the PREA and the BPCA for the first time in almost two decades. The most notable change is FDA’s intent to increase the clinical trial requirements for obtaining pediatric exclusivity. Additionally, FDA has expanded the scope of its guidance relating to requirements and incentives under the PREA and the BPCA, touching on some categories for the very first time.

Pediatric Exclusivity Will Be More Challenging to Obtain

Most notably, the Regulatory Considerations Guidance announced FDA’s intent to limit the scope of studies that will be eligible for pediatric market exclusivity under the BPCA. Previously, FDA had periodically granted pediatric market exclusivity to sponsors who conducted studies that were already required by the PREA, even if there were no other indications expected to produce health benefits in pediatric populations. However, FDA recently clarified that it does not expect to issue or approve BPCA study requests “solely for studies or planned studies that are required under PREA.”[20] Instead, FDA will reserve BPCA requests and approvals, and thus eligibility for pediatric market exclusivity, for “those sponsors who conduct additional pediatric studies – beyond what is required under PREA – that may produce health benefits in children.”[21]

Expanded Scope of Administrative Guidance

The Regulatory Considerations Guidance expands on topics covered in FDA’s 2005 guidance, including (i) the pediatric assessment, (ii) the pediatric plan, (iii) obtaining PREA waivers and/or deferrals, (iv) common compliance issues, and (v) the application of PREA-required studies to eligibility for pediatric market exclusivity.[22] In addition, the Regulatory Considerations Guidance clarifies FDA’s intended approach with respect to the following statutory requirements, which were not codified until 2012 and, thus, were not addressed in FDA’s previous guidance: (i) adverse event reporting, (ii) pediatric study plans, (iii) deferral extensions, and (iv) repercussions for noncompliance with PREA requirements.[23]

The Scientific Considerations Guidance similarly expands FDA’s guidance on the PREA and BPCA by clarifying clinical, scientific, and ethical issues related to the development of pediatric drugs and biologics. Specifically, the guidance elaborates on FDA’s requirements regarding formulation development, clinical and non-clinical information, and safety information, and clarifies conditions under which sponsors of pediatric drugs and biologics may extrapolate data from studies of drugs and biologics intended for adult use.[24]

Takeaways for Industry Participants

In light of FDA’s revised approach to regulating pediatric drug development, industry participants can benefit from the following takeaways.

Developing the Pediatric Study Plan

Sponsors of all drugs and biologics – not exclusively pediatric drugs and biologics – should use the Regulatory Considerations Guidance and Scientific Considerations Guidance to map out the design of the Pediatric Study Plan (the PSP) for a pediatric assessment required by the PREA. Likewise, sponsors of pediatric drugs and biologics should use these guidance documents to map the Pediatric Study Plan for any additional clinical trial necessary to obtain pediatric exclusivity under the BPCA.

Pediatric Extrapolation: In developing the PSP, sponsors should consider the scope of clinical and non-clinical data that can be reliably extrapolated from adult studies in order to increase efficiency and ensure that children only participate in clinical trials when necessary to further the scientific understanding of the product’s use in pediatric populations.

Neonatal Populations: Sponsors should be aware that the PREA technically requires sponsors to conduct studies in the neonatal population (i.e., children twenty-seven (27) days old and younger). If a sponsor intends not to conduct such studies (for example, because of the difficulties associated with conducting neonatal studies), the sponsor must include rationale and supporting data explaining why the drug is not appropriate for use in the neonatal population in the PSP.

Special Scenarios: Sponsors of drugs that fall within any of the following categories should consider engaging in early discussions with FDA, as FDA has identified the following scenarios as potentially warranting modifications to the clinical trial requirements under the PREA and/or the BPCA: (i) drugs for life-threatening or severely debilitating conditions and unmet medical needs, (ii) drugs for diseases or conditions that occur primarily in pediatric populations, (iii) neonatal studies, (iv) orphan products,[25] (v) drugs developed in foreign countries, and (vi) drugs for diseases and conditions that occur only in adults.

Waivers and Deferrals: Sponsors who wish to request a full or partial waiver and/or deferral of any PREA-required clinical trial should also engage in discussions with FDA as early as possible. Typically, the grounds for granting a waiver are centered on difficulty and/or risk involved in conducting testing on pediatric populations. On the other hand, FDA typically grants a deferral when it determines that it would be appropriate for pediatric assessments to be conducted after approval, considering factors such as whether the drug is ready for approval for use in adults before pediatric studies are complete and/or whether pediatric studies should be delayed until additional safety or effectiveness data have been collected.

Pediatric Exclusivity

Sponsors of pediatric drugs and/or biologics whose current business models rely on obtaining six-month market exclusivity should be aware that FDA will no longer grant pediatric exclusivity to sponsors who simply conduct PREA-required pediatric trials. As clarified by the Regulatory Considerations Guidance, FDA will only grant the six-month market exclusivity under the BPCA if (i) the sponsor conducts pediatric studies beyond those required by the PREA, (ii) FDA agrees that the additional studies are likely to produce health benefits in children, (iii) the studies are conducted pursuant to a written request issued by FDA or an approved PPSR from the sponsor, and (iv) the exclusivity determination is made at least nine (9) months before the expiration date of the patient and/or regulatory exclusivity protection to which the pediatric exclusivity will attach.

Priority Review Vouchers

Sponsors weighing the pros and cons of marketing a rare pediatric disease drug and/or biologic should keep in mind that marketing a rare pediatric drug and/or biologic automatically grants the sponsor a priority review voucher, which could have significant monetary value for the sponsor due to the transferrable nature of the voucher.


[1] 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, U.S. Food & Drug Administration (May 17, 2023).

[2] Guidance – Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations, U.S. Food & Drug Administration (May 17, 2023).

[3] See Guidance – How to Comply with the Pediatric Research Equity Act, U.S. Food & Drug Administration (September 2005).

[4] 88 Fed. Reg. 31766.

[5] See 21 CFR 201.23201.57(c)(7)(ii)(a).

[6] FDA defines “pediatric population” as the age group from birth to younger than seventeen years of age. See 21 CFR 201.57(c)(9)(iv)(A); Regulatory Considerations Guidance at FN 1.

[7] See Unofficial Guidance – Understanding Unapproved Use of Approved Drugs “Off Label”, U.S. Food & Drug Administration (Feb. 5, 2018).

[8] See Status Report – The Pediatric Exclusivity Provision, U.S. Food & Drug Administration (Jan. 2001); FDAMA Public Law 105-115, 111 Stat. 2296 (Nov. 21, 1997).

[9] 21 U.S.C. 355a(b),(c).

[10] See Status Report – The Pediatric Exclusivity Provision at FN 8.

[11] See Status Report – BPCA and PREA, U.S. Food & Drug Administration (July 2016).

[12] See 21 U.S.C. 355a(b),(c).

[13] Regulatory Considerations Guidance at p. 24.

[14] 21 U.S.C. 355c(a)(1).

[15] 21 U.S.C. 355c(a)(2)(A).

[16] 21 U.S.C. 355c(a)(3)-(4), (k).

[17] 21 U.S.C. 355c(a)(3)(A).

[18] See Guidance – Rare Pediatric Priority Review Vouchers, U.S. Food & Drug Administration at p. 18 (July 2019).

[19] See id. At p. 19;Pediatric Drug Development: Challenges and Opportunities, National Library of Medicine (December 28, 2018).

[20] See Regulatory Considerations Guidance at p. 4.

[21] See id. at p. 21.

[22] See id. at p. 2.

[23] See id.

[24] See Scientific Considerations Guidance.

[25] Despite the fact that the PREA requirements typically do not apply to orphan drugs, a sponsor that submits an application to market a drug for an orphan indication may still be eligible to qualify for pediatric exclusivity. Additionally, if orphan designation is granted after approval of a drug, and post-marketing studies were required under the PREA at the time of the drug’s approval, the granting of orphan designation does not alter the already existing requirement for such studies.

Copyright © 2023, Sheppard Mullin Richter & Hampton LLP.National Law Review, Volume XIII, Number 157

About this Author

Dominick DiSabatino Healthcare Lawyer Sheppard Mullin

Dominick DiSabatino is a partner on the Life Sciences team in the firm's Washington, D.C. office.

Areas of Practice

Dominick’s practice focuses on complex FDA and healthcare regulatory, compliance and legal matters in the life sciences industry. Drawing from in-house secondments with clients of various growth stages, Dominick counsels pharmaceutical, biotechnology, cosmetics and medical device companies on critical business decisions spanning the entire product life cycle, from research and development to product launch and commercialization.


Audrey Crowell Associate Dallas Sheppard, Mullin, Richter & Hampton LLP

Audrey Crowell is an associate in the Corporate Practice Group in the firm's Dallas office and a member of the Healthcare team.

Audrey represents clients in the healthcare industry through business and transactional matters, including mergers & acquisitions and corporate governance. She also advises clients on regulatory compliance under federal and state law, including licensure and fraud and abuse compliance. Audrey earned her J.D. form Southern Methodist University Dedman School of Law in Dallas, Texas, where she graduated with honors. She was the recipient...