PREA's Orphan Exemption and the RACE Act: Pediatric Study Plans for Orphan Oncology Programs

PREA's orphan exemption and the RACE Act: which orphan oncology programs still need a pediatric study plan

Orphan designation still exempts most applications from the Pediatric Research Equity Act (PREA). That changed in one area. Under section 504 of the FDA Reauthorization Act of 2017 (FDARA), often called the RACE for Children Act, orphan status no longer shields certain molecularly targeted adult oncology drugs. For an original NDA or BLA for a new active ingredient, submitted on or after August 18, 2020, whose molecular target FDA considers substantially relevant to a pediatric cancer, the sponsor must plan a molecularly targeted pediatric cancer investigation. This applies even when the adult indication is orphan-designated and even when the adult cancer does not occur in children ⁸¹⁸²⁷. Recent approval packages show that FDA applies this rule in practice. Sponsors of orphan-designated programs such as DECNUPAZ, BEQALZI, AVMAPKI FAKZYNJA CO-PACK and REVUFORJ had to agree to an initial pediatric study plan (iPSP). They then came away with deferrals and postmarketing requirements (PMRs), partial waivers, or a finding that submitted data met the requirement ²⁹¹¹¹³¹³⁹¹⁵².

The baseline: how the PREA orphan exemption works

Section 505B(k)(1) says PREA does not apply to an application or supplement for a drug or biologic for the indication for which orphan designation has been granted. This holds even when the application would otherwise trigger PREA through a new active ingredient, indication, dosage form, dosing regimen or route of administration ¹⁸⁵⁵. The exemption applies "unless the Secretary requires otherwise by regulation". FDA's May 2023 draft guidances state that FDA had not issued any regulation narrowing it ²⁵⁵⁵.

The iPSP requirement follows the same rule. A sponsor must submit an iPSP for a PREA-triggering application or supplement unless the drug is for an orphan-designated indication ³⁴.

The exemption has several built-in limits:

It applies indication by indication. If an application seeks several indications and only some are orphan-designated, the sponsor owes pediatric assessments for the non-orphan indications unless they are waived or deferred ²⁵. FDA's 2005 draft PREA compliance guidance stated the same principle ⁵⁷. An orphan-designated drug seeking a non-orphan indication falls outside the exemption and needs an iPSP ³⁴.
It is not retroactive. FDA decides whether the exemption applies at the time it assesses whether PREA is triggered. Orphan designation granted after approval does not cancel PREA postmarketing studies properly required at approval ²⁵.
Pediatric subpopulation designations. Suppose a sponsor holds orphan designation for a pediatric subpopulation of a common disease. FDA has interpreted the exemption to cover an application for the adult population of that same disease ¹⁸.
BPCA stays available. An orphan-designated product can still earn pediatric exclusivity under the Best Pharmaceuticals for Children Act (BPCA) if FDA issues a Written Request and the sponsor accepts it ²⁵.
Earlier waivers and deferrals do not carry over. Each new application or supplement subject to PREA needs its own iPSP, even if the same drug received waivers or deferrals before ³⁴.

The RACE Act carve-out: section 505B(a)(1)(B) and 505B(k)(2)

FDARA section 504 moved pediatric oncology obligations away from an indication-based trigger to one based on the drug's molecular target ¹¹. It did this in two ways:

It created section 505B(a)(1)(B), the requirement for a molecularly targeted pediatric cancer investigation.
It added section 505B(k)(2), which removes the orphan exemption for products that trigger 505B(a)(1)(B) ¹⁸²⁷.

The requirement applies when all of the following are true ⁸²⁷:

The application is an original NDA or BLA submitted on or after August 18, 2020.
The drug is a new active ingredient.
It is intended to treat an adult cancer.
It is directed at a molecular target FDA determines is substantially relevant to the growth or progression of a pediatric cancer.

If these criteria are met, the sponsor must submit reports of the investigation unless FDA waives or defers them. This applies even if the adult cancer does not occur in children and even if the adult indication has orphan designation ⁸²⁷. FDA repeats this point in its final guidance on developing drugs for acute myeloid leukemia (October 2022) ²³. A supplemental application does not trigger the molecularly targeted reporting requirement ⁸.

The investigation should produce clinically meaningful pediatric data on dosing, safety and preliminary efficacy. It should use formulations suited to each age group, so the results can support pediatric labeling ²⁷. When a new active ingredient is developed in combination with a previously approved product and meets the criteria, the iPSP should describe the planned pediatric study of either the new ingredient or the combination, whichever is appropriate. It should also include any request for deferral or waiver ⁵².

FDA approval letters state the combined effect of the two provisions in standard language. Orphan-designated applications that would otherwise fall under 505B(a)(1)(A) are exempt under 505B(k)(1). But orphan-designated applications "subject to the requirements of section 505B(a)(1)(B), however, will not be exempt from PREA (see section 505B(k)(2)) and will be required to include plans to conduct the molecularly targeted pediatric investigations as required, unless such investigations are waived or deferred" ⁷³⁹⁴¹³⁸¹⁵¹.

The Pediatric Molecular Target Lists

FDA publishes two target lists, developed with NCI and the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee ⁷¹⁵:

Relevant Molecular Target List. Targets that FDA has enough data to consider substantially relevant to one or more pediatric cancers. These include gene abnormalities, cell-lineage determinants, targets on immune cells or in the tumor microenvironment, and targets tied to specific pathways ¹⁵.
Non-Relevant Molecular Target Leading to Waiver List. Drugs directed at these targets get an automatic waiver. FDA expects to agree to full-waiver requests set out in the iPSP ¹⁵.

The lists guide planning, but they do not decide the question on their own. A target on the Relevant List may still justify a waiver. A target missing from that list can still trigger the requirement if FDA finds it substantially relevant ⁷. FDA sets no minimum evidence threshold. It looks at ²²:

the target's association with pediatric cancers
its biological role in cancer origin, growth or treatment resistance
in vitro and in vivo nonclinical data, including data on biologically rational combinations
adult clinical activity tied to target modulation

Waiver, deferral and iPSP timing

Waiver. FDA can waive the requirement for a target on the Relevant List ⁷. In approval letters, age-based partial waivers usually rest on the finding that studies would be "impossible or highly impracticable" because the cancer is very rare in the youngest age groups ²¹⁵⁵.
Deferral. Sponsors request deferral when they submit the NDA or BLA. FDA does not formally grant a deferral during iPSP review. It grants the deferral in the approval letter, for example when the drug is ready for adult approval before pediatric studies are finished ²⁸. If a sponsor plans to request deferral, the iPSP must say so, and the agreed iPSP must accompany the application ²⁸.
Timing. The iPSP is due no later than 60 calendar days after the end-of-phase 2 meeting unless FDA agrees to another time. Without that meeting, submit it as early as practicable and before phase 3 starts. If those studies are not run, or not run under an IND, it is due at least 210 days before the marketing application ³³³⁸. FDA correspondence warns that failing to include an agreed iPSP "could result in a refuse to file action" ¹⁴⁸.

Orphan-designated programs that still needed a pediatric study plan

The approval packages below confirm orphan designation and a pediatric obligation handled through an iPSP. OPDUALAG is the weak case: its letter cites section 505B(a) and does not expressly cite 505B(a)(1)(B).

Product (application)	Orphan designation	Molecular target and pediatric plan	FDA outcome
DECNUPAZ, pivekimab sunirine (BLA 761460), approved May 27, 2026 ⁹³	BPDCN, granted November 17, 2020 ¹¹⁹¹²⁰	CD123. Monotherapy study with an age-appropriate formulation in patients 6 months to under 17 years with relapsed/refractory CD123-positive AML ²	Partial waiver under 6 months. Deferral for ages 6 months to under 17 years under PMR 4996-1, with final report due March 2030 ²
BEQALZI, sonrotoclax (NDA 220711), approved May 13, 2026 ¹¹⁵	Granted December 21, 2023; the designated indication is not restated in the review ¹⁵⁴. Approved for adults with relapsed or refractory mantle cell lymphoma after at least two prior lines including a BTK inhibitor	BCL2 is on FDA's Relevant Pediatric Molecular Target List. The applicant submitted an iPSP and FDA agreed ¹⁵². FDA aligned on the iPSP on August 26, 2025. It covers combination therapy in relapsed/refractory AML and ALL ¹⁵³	Partial waiver from birth to under 6 months. Deferral for 6 months to under 17 years ¹⁵² under PMR 4994-2 ¹¹⁵
AVMAPKI FAKZYNJA CO-PACK, avutometinib + defactinib (NDA 219616), approved May 8, 2025 ¹¹³	Low-grade serous ovarian cancer, granted March 5, 2024 ¹⁴⁶¹⁴²	iPSPs for monotherapy and the combination were agreed before filing. They request deferral for RAS/MAPK pathway-driven pediatric cancers in patients 2 to under 17 years ¹³⁹	Waived under 2 years. Deferred under PMR 4835-2, with final report due September 2034 ¹¹³
REVUFORJ, revumenib (NDA 218944), approved November 15, 2024 ⁷³	AML, granted April 20, 2020 ¹²⁴¹²⁶¹²⁷¹²⁹	KMT2A translocation. FDA found the drug subject to the FDARA molecularly targeted provisions ⁹¹	FDA found the submitted data met FDARA requirements for patients 1 year and older, with a waiver under 1 year because of very low incidence ⁹¹
OPDUALAG, nivolumab + relatlimab (BLA 761234), approved March 18, 2022 ⁶⁸	Stage IIB to IV melanoma, granted August 18, 2017 ¹³³¹³⁵	The pediatric biomarker assessment evaluated LAG-3 expression ⁸²	Partial waiver for ages 0 to 11. Deferral for ages 12 to 17. PMR 4222-1 is a study in relapsed/refractory Hodgkin lymphoma in patients 0 to under 30 years. PMR 4222-2 is a modeling and extrapolation study. The letter cites section 505B(a) and does not expressly cite 505B(a)(1)(B) ⁸⁰

Several points stand out:

Orphan designation dated before FDARA's effective date did not help. REVUFORJ's AML designation (April 2020) and OPDUALAG's melanoma designation (2017) both predate August 18, 2020. Both products still carried pediatric obligations at approval ⁸⁰⁹¹¹²⁴¹³³. What matters is the application's submission date and the drug's target, not when orphan designation was granted ⁸.
Adult orphan approvals still led to pediatric studies in a different disease. DECNUPAZ is approved for adults with BPDCN, its orphan-designated condition. Its pediatric PMR, however, studies relapsed/refractory CD123-positive AML ²⁹⁶. This matches the RACE Act's target-based logic, which does not require the adult cancer to occur in children ⁸.
Outcomes varied. The results range from full deferral with long PMR timelines (AVMAPKI through 2034) to FDA accepting submitted data at approval (REVUFORJ) ⁹¹¹¹³.
Later supplements can still use the ordinary exemption. For a later REVUFORJ supplement, FDA stated that the drug "for this indication" had orphan designation and was exempt from standard PREA assessments. This fits the rule that supplements do not trigger 505B(a)(1)(B) ⁸⁹².

Where the orphan exemption still applied to targeted oncology drugs

Orphan designation did not bring the RACE Act requirement into every oncology approval. The approval letters for KRAZATI (adagrasib, KRAS G12C-mutated NSCLC), ELREXFIO (elranatamab) and TALVEY (talquetamab) each state that the product was exempt from required pediatric assessments because of orphan designation for the approved indication ⁸⁵⁸⁶¹⁰³¹¹⁰. FDA's published reviews for these products address the requirement only in the standard PREA and FDARA language. They do not show a product-specific decision on target relevance or the original submission date ⁷⁸⁷⁶¹⁰¹. The records therefore cannot say whether FDA found 505B(a)(1)(B) inapplicable or waived it on other grounds. Readers who need that answer should check each product's regulatory history and iPSP correspondence.

Related molecularly targeted pediatric requirements

Several other recent oncology approvals carry molecularly targeted pediatric PMRs. Drugs@FDA flags ZENBEXUS (NDA 221075) and CAVHANZA (NDA 217379) as orphan approvals; nilotinib D-tartrate (NDA 218922), ENSACOVE and LAZCLUZE are not flagged as orphan. Their approval letters cite section 505B(a) generally rather than 505B(a)(1)(B). They show the range of outcomes FDA uses under the same framework:

ZENBEXUS (NDA 221075): Deferred investigation of iberdomide with chemoimmunotherapy in neuroblastoma for patients age 1 and older under PMR 5041-2, with final report due June 2033. Waived under age 1 ¹.
CAVHANZA (NDA 217379) and nilotinib D-tartrate (NDA 218922): Deferred molecularly targeted investigations that include developing an age-appropriate nilotinib formulation. Both have waivers under age 1 ¹¹⁴¹¹⁶¹³⁶¹⁵⁵. Neither is a new molecular entity: Drugs@FDA classes them as a new formulation and a new dosage form of nilotinib.
ENSACOVE (NDA 218171): Deferred Pediatric MATCH sub-study in ALK- or ROS1-altered solid tumors under PMR 4752-1 ¹¹⁷.
LAZCLUZE (NDA 219008): Full waiver for all pediatric age groups. FDA found pediatric studies impossible or highly impracticable given how rarely EGFR mutations occur in children. This waiver rested on impracticability, not on an orphan exemption ⁹⁹.

Practical takeaways for orphan oncology sponsors

Treat orphan designation as covering only the indication-based PREA trigger in 505B(a)(1)(A). For a new active ingredient in adult oncology, assess target relevance against the Relevant and Non-Relevant Molecular Target Lists early in development, whatever the orphan status ⁷¹⁵¹⁸.
Build the iPSP around the pediatric cancers that share the target, not around the adult orphan indication ²⁸.
Put deferral and age-based partial waiver requests in the iPSP. FDA formalizes deferrals only in the approval letter ²⁸.
Plan iPSP submission around the end-of-phase 2 meeting. Without an agreed iPSP, the marketing application risks a refuse-to-file action ³³¹⁴⁸.