PREA FDA requirements for pediatric studies, waivers and BPCA

PREA FDA requirements come from the Pediatric Research Equity Act. Covered drug and biological-product applications need pediatric assessments unless an exemption or waiver applies, and a deferral only postpones submission. FDA explains the requirement, and section 355c sets the exceptions and deferral rules.

PREA creates an obligation. The Best Pharmaceuticals for Children Act (BPCA) offers a separate, conditional pediatric-exclusivity incentive through an FDA Written Request. Completing PREA requirements alone doesn't earn that incentive. Section 355a lets the same studies serve both purposes only when BPCA's own conditions are met.

Which applications trigger PREA?

PREA is section 505B of the Federal Food, Drug, and Cosmetic Act, codified at 21 U.S.C. §355c. Its standard application and supplement triggers are a:

• New active ingredient.
• New indication.
• New dosage form.
• New dosing regimen.
• New route of administration.

The duty applies to covered drug applications under FD&C Act section 505 and biological-product applications under Public Health Service Act section 351, subject to the statutory exceptions. FDA also has separate authority to require pediatric assessments for certain already-marketed products, so PREA is not limited to original approvals. See section 355c(a) and (b).

The assessment must provide adequate safety and effectiveness data for the claimed indications in all relevant pediatric subpopulations, using appropriate formulations, and it must support dosing and administration for each subpopulation in which the product is safe and effective. But that does not automatically require a separate efficacy trial in every age group. The law permits appropriately justified extrapolation from adults and between pediatric groups. Section 355c(a)(2) sets these assessment standards.

Orphan indications and targeted oncology

The general orphan exemption is indication-specific, not product-wide, and FDA may otherwise require assessments by regulation. See section 355c(k). A separate rule covers original applications for a new active ingredient submitted on or after August 18, 2020, when the product is intended for an adult cancer and FDA determines that the molecular target is substantially relevant to pediatric cancer growth or progression. The required investigation addresses dosing, safety and preliminary efficacy. Orphan designation does not exempt these applications, although waivers and deferrals remain possible. The targeted-oncology provisions appear in section 355c(a) and (k).

When to submit the initial pediatric study plan

The initial pediatric study plan, or iPSP, is due no later than 60 calendar days after the end-of-Phase 2 meeting, or at another time agreed with FDA. Submit it before the required assessments or investigation. Section 355c(e) sets the timing.

The iPSP outlines planned studies, including age groups and other study elements to the extent practicable. It also includes waiver or deferral requests and supporting information. FDA's written confirmation of an agreed plan includes a recommendation on whether a waiver or deferral request meets the statutory standards. That recommendation is not the final grant. Section 355c(e)(4) is that recommendation.

Waivers and deferrals have different effects

A deferral postpones submission of an assessment. It leaves the requirement in place. Grounds include readiness for adult approval before pediatric work finishes, a need for additional safety or effectiveness information, or another appropriate reason. The applicant must provide grounds, a plan, evidence of due diligence and a completion timeline. An approved deferral also requires annual progress information. See section 355c(a)(4).

For the new-application requirements, a full waiver instead rests on FDA findings after applicant certification. The statutory grounds are:

• Necessary studies are impossible or highly impracticable.
• Strong evidence shows the product would be ineffective or unsafe in all pediatric age groups.
• The product offers no meaningful therapeutic benefit over existing pediatric therapies and is unlikely to be used in substantial numbers of pediatric patients.

The last ground requires both conditions. Low expected use alone does not satisfy it. Section 355c(a)(5)(A) states the full-waiver criteria.

A partial waiver removes the requirement for a specific age group when the waiver criteria for that group are met. Failed reasonable attempts to produce a necessary pediatric formulation provide an additional ground. That formulation-based waiver covers only the groups needing that formulation. See section 355c(a)(5)(B).

Deferred PREA studies are postmarketing requirements

FDA distinguishes postmarketing requirements (PMRs) from postmarketing commitments (PMCs). PMRs are required by statute or regulation. PMCs are agreed studies or trials without that legal requirement. An assessment filed with the application is not a postmarketing study. A deferred PREA study is a PMR, not a voluntary PMC. FDA's PMR and PMC overview lists deferred PREA studies among required postmarketing studies.

PREA versus BPCA pediatric exclusivity

FDA describes BPCA studies as voluntary studies outlined in a Written Request. The comparison follows 21 U.S.C. §355c and 21 U.S.C. §355a.

A proposed pediatric study request, or PPSR, is the sponsor's proposal. It is not the FDA-issued Written Request. FDA must review and act on a PPSR, or on a proposed amendment to a Written Request, within 120 calendar days of submission. That clock is not an exclusivity decision. The 120-day duty is in section 355a(d)(3).

Pediatric exclusivity still needs an FDA Written Request, sponsor agreement, timely completion using appropriate formulations, submission of reports, and FDA acceptance. Protection and timing conditions apply as well. FDA's acceptance concerns whether the studies fairly respond to the request and meet scientific, protocol and reporting standards. A positive efficacy result is not an express acceptance criterion. Those conditions are in section 355a(b) through (d).

A Written Request may include studies already required under PREA. Those studies can serve both purposes, but only if the BPCA conditions are met on their own. Finishing the PREA package does not show that the Written Request was satisfied. Section 355a(h) allows that overlap and still requires a Written Request.

Timing can still block the incentive after the studies are finished. The drug statute bars the extension if FDA's relevant determination comes later than nine months before the protection period expires. See section 355a(b) and (c).

The six months attach to qualifying drug protection. They are not a blanket patent-term extension. Biological-product pediatric exclusivity has its own statute, 42 U.S.C. §262(m), so the drug patent provisions do not automatically carry over to a BLA.

Which pediatric age groups does FDA use?

For prescription labeling, 21 CFR §201.57(c)(9)(iv)(A) defines pediatric patients as "from birth to 16 years." That includes age 16, so the upper bound is younger than 17, not younger than 16. The provision names neonates, infants, children and adolescents, and it does not set numeric boundaries for those four names. Read the definition in section 201.57(c)(9)(iv)(A).

Use that definition only for the labeling provision it governs. It does not prove safety, effectiveness or approval for every child. For a given product, use the labeling and the agreed pediatric plan, measured against PREA's demand for all relevant pediatric subpopulations and appropriate formulations. Section 355c(a)(2) is the assessment standard.

RegAffairs AI provides a cited answer on PREA, BPCA and pediatric age groups.

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