PREA Pediatric Requirements in Recent FDA Dermatology Approvals

PREA pediatric requirements in recent FDA dermatology approvals (2022 to 2026)

Nearly every dermatology approval reviewed here triggered the Pediatric Research Equity Act (PREA), and FDA handled them in a broadly consistent way. It waived the youngest ages where studies were impossible or highly impracticable. It deferred the remaining pediatric ages, often including adolescents, as required postmarketing studies under FD&C Act section 505B(a). It declared PREA fulfilled only when pediatric patients were enrolled in the pivotal program. The details vary by modality and disease: maximal-use pharmacokinetic (PK) studies for topicals, PK/safety extrapolation trials for biologics, large adolescent efficacy trials for oral JAK inhibitors in alopecia areata, and juvenile animal toxicity studies placed inside the PREA postmarketing requirement (PMR) package itself.

This article reviews PREA terms in approval letters and multidisciplinary reviews for selected dermatology products approved or supplemented from 2022 through mid-2026, not every dermatology approval in that window.

Key takeaways

• Every new active ingredient, new indication, dosage form or route triggered PREA. Tapinarof triggered it as a new molecular entity ¹⁶¹. Roflumilast cream triggered it as a new indication, dosage form and route relative to oral roflumilast ¹⁹⁵. Hidradenitis suppurativa (HS) supplements for secukinumab and bimekizumab triggered it as new indications ⁸⁶. Otezla XR triggered it as a new dosage form and dosing regimen ²⁸⁴²⁸⁵.
• Waiver rationales are almost always "impossible or highly impracticable". FDA cited low prevalence or diagnostic difficulty in the youngest patients. Two exceptions used the "no meaningful therapeutic benefit and not likely to be used in a substantial number of patients" basis: lebrikizumab below 6 months ²⁵⁴ and dupilumab in chronic spontaneous urticaria (CSU) below 2 years ³⁰¹.
• Adolescents are either studied before approval or deferred with specific designs. Where adolescents were enrolled in pivotal trials, FDA found PREA fulfilled for ages 12 to 17. Examples are Litfulo ¹³², Opzelura in vitiligo ²⁶¹²⁵⁹ and Cabtreo. Where they were not, FDA required dedicated adolescent studies, ranging from PK/safety trials (Bimzelx ²²⁵, Cosentyx HS ¹⁴⁹) to 300-subject, 52-week randomized trials (the JAK inhibitors in alopecia areata ²⁰³¹¹⁷).
• Nonclinical and formulation work can sit inside the PREA package. Juvenile rat toxicity studies were issued as PREA PMRs for deuruxolitinib ¹¹⁶ and remibrutinib ¹⁷². Apremilast XR carries a PMR to develop an age-appropriate formulation ²⁸⁴.
• Milestones slip and PMRs close. The lebrikizumab PK/safety trial's completion date moved from 01/2026 ²⁴⁴ to 01/2027 in a 2026 letter ¹⁶⁶. Tralokinumab ²⁵⁸, ruxolitinib cream ¹⁶⁸¹⁶⁹ and dupilumab in CSU ³⁰¹ show FDA formally closing PREA PMRs once it received final reports.

Summary table of PREA terms

Atopic dermatitis: two tracks for topicals and biologics

Topical agents: infant waivers and maximal-use PK deferrals

The recent topical AD approvals follow a consistent template. FDA waives the first few months of life because AD is difficult to diagnose there. It finds PREA fulfilled from age 2 onward when pivotal data cover that group. It defers the 3-month-to-2-year cohort.

• Vtama (tapinarof) for AD: FDA waived ages 0 to <3 months because AD is difficult to diagnose in infants under 3 months. It deferred ages 3 to <24 months because studies in patients 2 years and older were complete and ready for approval ²⁸¹. PMR 4772-1 requires an efficacy, safety and PK study in patients aged 3 to <24 months. The milestones are final protocol 06/2025, study completion 06/2028 and final report 12/2028 ²⁸¹.
• Zoryve (roflumilast) cream for AD: FDA waived birth to <3 months on the same diagnostic grounds. It deferred ages 3 months to <2 years because the product was ready for approval in patients aged 2 to 5 years ¹⁹⁰. PMR 4913-1 is a 4-week open-label safety trial of the 0.05% cream in 100 evaluable subjects aged 3 months to <2 years with at least 3% BSA involvement (Study ARQ-151-218), with study completion 07/2026 and final report 02/2027 ³⁰³.
• Adquey (difamilast) ointment: FDA waived 0 to 3 months because AD is rare in that population. It deferred 3 months to <2 years ²¹⁰²¹³. PMR 4963-1 requires an adequate and well-controlled U.S. trial evaluating safety and PK under maximal-use conditions in subjects with disease at the upper range of severity. The milestones are final protocol 06/2026, completion 01/2029 and final report 06/2029 ²⁰⁸. Requiring the study to be conducted in the United States is unusual in this set.

Ruxolitinib cream shows the end of the cycle. The September 2025 Opzelura supplement added labeling for patients aged 2 to <12 years with AD pursuant to PREA ¹⁶⁹. FDA noted it had received final reports for PMR 4147-1 and PMR 4147-2 ¹⁶⁸. PMR 4147-1 was a randomized, double-blind 8-week trial with a 44-week safety extension in 250 subjects (Study INCB 18424-305). PMR 4147-2 was a maximal-use PK study with at least 16 completers ¹⁶⁸.

Biologics: deferrals tied to safety data and weight

For systemic AD biologics, FDA deferred pediatric studies more broadly and sometimes cited the need for more safety data first.

• Ebglyss (lebrikizumab): FDA waived birth to <6 months on the "no meaningful therapeutic benefit and unlikely to be used in a substantial number of patients" basis. Its reasoning was that establishing failure of topical therapy in infants that young is difficult ²⁵⁴. It deferred ages 6 months to <12 years and adolescents aged 12 to <18 years who weigh less than 40 kg, because studies should wait until more safety or effectiveness data were available ²⁵⁴. PMR 4514-1 is a randomized, double-blind, placebo-controlled PK/safety trial. PMR 4514-2 is an open-label long-term extension ²⁴⁴. The weight cutoff means adolescent PREA coverage is split: adolescents weighing 40 kg or more were not deferred, while lighter adolescents remain under PMRs.
• Nemluvio (nemolizumab): FDA waived birth to <6 months because eligible children would be difficult to identify. It deferred 6 months to <12 years ¹⁰⁰. There are two single-arm, open-label PK/safety trials of at least 52 weeks. PMR 4721-1 covers 2 to <12 years, with final report 10/2025. PMR 4721-2 covers 6 months to <2 years, with final report 05/2028 ¹⁰⁰.
• Dupixent (dupilumab) for prurigo nodularis: FDA waived 0 to <6 months because prevalence is low. It deferred the full 6-month-to-<18-year range because the product was ready for adult approval ⁸⁵. PMR 4329-1 is an open-label PK/safety trial, with final report due 03/2028 ⁸⁵.
• Adbry (tralokinumab): A December 2023 letter confirmed that PMR 4015-1 (ECZTRA 6) was fulfilled after FDA reviewed the final report received January 14, 2022. ECZTRA 6 was a Phase 3, randomized, placebo-controlled monotherapy study in adolescents with moderate-to-severe AD. The letter noted the pediatric requirement was fulfilled for ages 12 to 18 years ²⁵⁸.

Psoriasis: extrapolation-based PK/safety designs

• Vtama (tapinarof) for plaque psoriasis: FDA waived ages 23 months and younger because plaque psoriasis is uncommon and hard to diagnose in the youngest children. It deferred ages 2 to 17 ¹⁶¹. PMR 4283-1 requires an open-label long-term safety and PK study in at least 100 patients aged 2 to <18 years with at least 52 weeks' exposure. It includes a maximal-use PK subset of at least 16 adolescents with body surface area (BSA) of 10% or more and at least 8 children aged 2 to <12 with BSA of 3% or more. Study completion was 09/2024 and final report 03/2025 ³⁰².
• Zoryve (roflumilast) cream for plaque psoriasis: FDA waived patients younger than 2 years because very few patients are in that age group. It deferred ages 2 to <12 years because of recruitment problems ¹⁹²¹⁹⁵. Adolescents were counted as fulfilled even though enrollment was limited: FDA considered the safety data adequate to label ages 12 and older ¹⁹⁵. The PMRs are two 4-week maximal-use PK studies, 4314-1 (ages 6 to 11, 20 subjects) and 4314-2 (ages 2 to 5, 10 subjects), plus 4314-3, a long-term safety extension in ages 2 and older ¹⁹²¹⁹⁶.
• Bimzelx (bimekizumab): FDA waived 0 to <6 years for low prevalence and deferred 6 to <18 years ²²⁵. PMR 4268-1 is an open-label PK/safety trial in adolescents, with final report 12/2025. PMR 4268-2 is a randomized, blinded, active-controlled safety and PK trial in ages 6 to <18, with final report 08/2031 ²²⁵²²¹. The review states that pediatric efficacy may be extrapolated from adults, so PMR 4268-2 does not include an efficacy assessment ²²⁴.
• Otezla XR (apremilast extended-release): FDA waived 0 to <6 years ²⁸⁹. It deferred patients aged 6 to 17 weighing 20 to 50 kg, because the product was ready for adults and for pediatric patients over 50 kg ²⁸⁴. The PMR package is formulation-driven. PMR 4885-1 requires development of an age-appropriate ER formulation for patients weighing 20 to 50 kg, with a report due 09/2026. PMR 4885-2 is a relative-bioavailability study in healthy adults to set pediatric dosing, with final report 02/2028 ²⁸⁴.

Alopecia areata: large adolescent efficacy trials for JAK inhibitors

The oral JAK inhibitors approved for severe alopecia areata carry the heaviest adolescent obligations in this set.

• Olumiant (baricitinib): FDA waived 0 to <6 years and deferred 6 to <18 years ²⁰⁴. PMR 4289-1 is a randomized controlled trial of safety, efficacy and PK in at least 300 adolescents (12 to <18) exposed for at least 52 weeks, with final report 06/2027. PMR 4289-2 is a parallel trial in at least 100 children aged 6 to <12, with final report 11/2031 ²⁰³.
• Leqselvi (deuruxolitinib): FDA waived 0 to <6 years and deferred 6 to 17 years, citing the need to collect more safety or effectiveness data first. The PMRs mirror the baricitinib design: PMR 4655-2 is a 300-subject adolescent RCT with final report 10/2029, and PMR 4655-3 is a 100-subject RCT in ages 6 to <12 with final report 07/2035 ¹¹⁷. PMR 4655-3 may not start until adolescent clinical data and data from PMR 4655-1, a juvenile rat toxicity study of growth, development and reproduction, have been submitted ¹¹⁶¹¹⁷.
• Litfulo (ritlecitinib): This is the counterexample. Adolescents were in the Phase 3 program: 172 patients aged 12 to <18 were treated with ritlecitinib 50 mg or more, including 133 for at least 12 months ¹³⁵. FDA therefore found PREA fulfilled for ages 12 and older ¹³². FDA waived 0 to <6 years and deferred 6 to <12 years ¹⁴². Three PMRs cover that younger group: a long-term extension of up to 3 additional years (4463-1), a placebo-controlled safety study (4463-2), and a PK exposure-matching study with at least 12 evaluable subjects (4463-3) ¹³². A separate PMR (4463-4) includes adolescents, but it is a 505(o)(3) safety PMR, not a PREA requirement ¹³⁷.

Hidradenitis suppurativa: adolescent-only PREA scope

Both recent HS supplements waived all patients under 12 and limited PREA obligations to adolescents.

• Cosentyx (secukinumab): FDA waived under-12s because HS usually begins after puberty and is rarely diagnosed in young children. It deferred ages 12 to <17 years, pending PK-based extrapolation studies ¹⁴⁹. PMR 4543 requires an open-label PK/safety study in at least 80 adolescents at the highest approved dosage (300 mg every 2 weeks) for at least 52 weeks. The final report is due 02/2030 ¹⁴⁹.
• Bimzelx (bimekizumab): FDA waived 0 to <12 years for low prevalence and deferred 12 to <18 years ⁸⁹. PMR 4704-1 is an open-label PK/safety trial, with final report 11/2031 ⁸⁹.

Other dermatology indications

• Vitiligo (Opzelura): FDA waived 0 to <2 years for very low prevalence. It found PREA fulfilled for ages 12 to 17 and deferred 2 to <12 years ²⁶¹²⁵⁹. PMR 4304-1 is a 24-week, double-blind, vehicle-controlled trial in 150 children with a 28-week safety extension. It has specific facial and non-facial depigmentation criteria and a final report due 03/2027 ²⁶¹.
• Acne vulgaris (Cabtreo): FDA waived ages 0 through 8 years 11 months because there are very few patients, and found PREA fulfilled for ages 12 through 17. It deferred ages 9 through 11 years 11 months to PMR 4500-1, an open-label safety, PK and treatment-effect study in 100 patients, with final report 12/2027 ²⁷¹.
• Seborrheic dermatitis (Zoryve foam): FDA waived birth to <9 years because the condition is uncommon at those ages ²⁹⁷. Patients aged 9 to <18 were included in studies ARQ-154-214 and ARQ-154-304, so PREA was fulfilled and PeRC recommended no PMR ²⁹⁵.
• Molluscum contagiosum (Zelsuvmi): Molluscum largely affects children, so the pediatric program was the pivotal program. FDA waived only 0 to 1 year and found PREA fulfilled for ages 1 to 18 ¹⁸⁷. PeRC agreed that no PREA PMR was needed. Before approval, the proposed waiver boundary moved from under 6 months to under 1 year ¹⁸⁶.
• Chronic spontaneous urticaria (Rhapsido): FDA waived birth to <6 years because CSU is hard to diagnose there and antihistamine failure is hard to establish. It deferred 12 to 17 years because the adult product was ready, and deferred 6 to 11 years until adolescent data and a juvenile toxicity study were available ¹⁷⁷¹⁷². PMR 4896-1 is a 24-week placebo-controlled adolescent study. PMR 4896-2 is a 24-week open-label PK study in ages 6 to <12. PMR 4896-3 is a juvenile rat toxicity study with ophthalmic and neurobehavioral endpoints ¹⁷².
• Chronic spontaneous urticaria (Dupixent): FDA waived patients younger than 2 years on the no-meaningful-benefit basis. It later found PMR 4843-1, a PK and safety study in children aged 2 to <12, fulfilled after receiving the final report on June 27, 2025 ³⁰¹.

Cross-cutting patterns for sponsors

Waiver boundaries follow disease epidemiology. Waiver cutoffs ranged from 3 months (AD topicals) to 12 years (HS) and up to 9 years (seborrheic dermatitis and acne). They tracked the age at which the disease can be reliably diagnosed or becomes prevalent ^281149297. A waiver request should rest on disease-specific prevalence and diagnostic data.

Adolescent enrollment in pivotal trials is the main way to avoid adolescent PMRs. Litfulo, Zoryve cream, Opzelura in vitiligo, Cabtreo and Zoryve foam all obtained PREA fulfillment for adolescents at approval ^132195261295. Where adolescents were excluded, FDA required studies ranging from an 80-patient PK/safety study (Cosentyx HS) ¹⁴⁹ to 300-patient, 52-week efficacy RCTs (baricitinib, deuruxolitinib) ²⁰³¹¹⁷.

Extrapolation reduces, but does not remove, pediatric obligations. For IL-17 biologics in psoriasis and HS, FDA accepted PK- and safety-based designs without pediatric efficacy endpoints ²²⁴¹⁴⁹. For JAK inhibitors in alopecia areata, FDA required pediatric efficacy data ²⁰³¹¹⁷.

Staged sequencing is common. FDA gated younger-cohort studies on adolescent data or juvenile toxicology for deuruxolitinib ¹¹⁷ and remibrutinib ¹⁷⁷¹⁷². Younger-cohort final reports often fall 5 to 10 years after approval, for example 07/2035 for Leqselvi PMR 4655-3 ¹¹⁷ and 11/2031 for Olumiant PMR 4289-2 ²⁰³.

Administrative requirements are standard. Letters require annual status reporting. Protocols go to the IND with a cross-reference letter to the NDA or BLA. Final reports are submitted as an NDA/BLA or supplement, with any labeling changes, and labeled "SUBMISSION OF REQUIRED PEDIATRIC ASSESSMENTS" ^281282203167. The lebrikizumab milestone revision from 01/2026 to 01/2027 ²⁴⁴¹⁶⁶ shows that PREA timelines can be renegotiated, and that later action letters record the current dates.

Open questions worth pursuing

Two points remain open: the final-protocol dates for several deferred studies, and whether the Vtama psoriasis PMR 4283-1, with a final report due 03/2025 ³⁰², has since supported pediatric labeling. Sponsors comparing their own pediatric plans against these precedents may also want to review the underlying Pediatric Review Committee (PeRC) discussions and Written Requests for each product.