Breakthrough Therapy Designation Since 2020: Review Outcomes and the National Priority Voucher

Breakthrough Therapy Designation since 2020: notable approvals, review timelines, and how BTD compares with the Commissioner's National Priority Voucher

Key findings

• Breakthrough Therapy Designation (BTD) remains a regular feature of FDA novel approvals. CDER reports that 14 of 50 novel approvals in 2021 (28%), 13 of 37 in 2022 (35%), 9 of 55 in 2023 (16%), 18 of 50 in 2024 (36%) and 15 of 46 in 2025 (33%) carried BTD ^{223224222217218}. CDER counts 337 cumulative BTD approval actions through December 31, 2025, and another 15 in the first half of 2026. These counts include supplements, so they are approval actions, not distinct products ²¹⁵²²⁰.
• BTD does not confer priority review. FDA guidance states that a BTD product is eligible for priority review only if it separately meets the priority review criteria when the application is submitted ⁵⁶. Most BTD approvals reviewed here did receive priority review, but several went through on a standard clock (Olinvyk, Camzyos, Krazati, Rivfloza, Pombiliti + Opfolda, Redemplo, Jideytro, Leqselvi) ^{1204140154688482}.
• In practice, BTD shortened the time before submission more than it shortened the review. Most BTD products used rolling submission, and many BTD/priority applications reached action about 8 months after the final component arrived, which matches the priority NME clock of 60-day filing plus 6 months ^{9115923821221014189}.
• BTD does not protect against a complete response. Kisunla, Tzield and Olinvyk each needed two cycles, and FDA rescinded or moved to rescind BTD for Fintepla, Leqselvi and Olinvyk ^{18319817511782177}.
• The Commissioner's National Priority Voucher (CNPV), announced June 17, 2025, works differently. It is a nontransferable voucher with a target of 1 to 2 months from filing to action, reviewed through a "tumor board-style" council, and eligibility rests on five national-priority criteria that include domestic manufacturing and affordability ³⁷³⁸³⁶. A Hernexeos (zongertinib) first-line expansion was approved 44 days after a January 13, 2026 filing, and Foundayo (orforglipron) 50 days after filing ⁴²⁴⁴. Hernexeos's original approval was August 8, 2025.

What BTD provides, and what it does not

BTD may be granted to a drug intended to treat a serious condition when preliminary clinical evidence indicates it may demonstrate substantial improvement over available therapy on one or more clinically significant endpoints. This is not the approval standard ⁴⁷⁶². The preliminary evidence generally comes from Phase 1 or Phase 2 trials. Comparative data are preferred, but a persuasive single-arm study against a well-documented historical control can suffice when the difference is large ⁵⁴.

Designation brings all Fast Track features plus ⁴⁸⁵⁵:

• intensive FDA guidance on an efficient development program, from as early as Phase 1;
• organizational commitment, meaning senior managers and experienced review staff are involved, with a cross-disciplinary project lead where appropriate;
• rolling review of portions of the marketing application before the full application is submitted.

Sponsors may request BTD with the IND or at any time afterward. FDA prefers to receive the request before the trials that will provide primary efficacy evidence begin, and ideally no later than the end-of-phase 2 meeting. FDA responds within 60 calendar days ^4959221. Designation can be rescinded if later data no longer support it, for example when a newly approved therapy removes the "substantial improvement" margin or a confirmatory trial fails ⁵¹⁶³.

Priority review is a separate decision made at filing. It applies when the drug, if approved, would significantly improve the safety or effectiveness of treatment for a serious condition ⁹¹. For NME NDAs and original BLAs, FDA's goal is to act on 90% of applications within 6 months of the 60-day filing date under priority review, compared with 10 months under standard review. Non-NME NDAs run from receipt ⁹¹. These are goals for FDA to review and act, and the action may be an approval or a complete response letter ⁹¹. One Division's BTD review states directly that BTD "does not guarantee priority-review status" ⁶⁷.

Notable BTD approvals since 2020

The table shows a selection of original NDA/BLA approvals where the FDA review record explicitly documents BTD.

The pattern holds across therapeutic areas. Oncology BTDs often pair designation with Real-Time Oncology Review (RTOR) or rolling submission (Krazati, Rezurock, Inlexzo, Jideytro) ^4118984. Rare-disease and non-oncology BTDs mostly rely on rolling BLA/NDA segments (Evkeeza, Nexviazyme, Xenpozyme, Nulibry, Zurzuvae) ^{1181015131157}.

How BTD affected priority review and review cycles

Priority review usually followed, but not always

Most BTD approvals in the sample received priority review, which is expected given that both designations rely on a serious condition and meaningful improvement. The exceptions show that the filing-stage decision is made separately:

• Krazati had BTD but a standard review classification. FDA had agreed the sponsor could propose priority review after the initial NDA review ⁴.
• For Redemplo, the Division indicated it was likely to grant priority review if requested, yet the application record shows standard review ⁶⁸.
• Rivfloza, Pombiliti + Opfolda and Jideytro all carried BTD and were reviewed on standard timelines ^14015484.
• Leqselvi lost its BTD before review. After FDA rescinded the designation on March 14, 2024, the agency planned and conducted a standard rather than priority review ⁸².

The time saving comes before and during submission, not in the review clock

Where the record shows both the date the final rolling component was received and the action date, BTD/priority applications generally reached action on the standard priority NME timeline:

The main contribution of BTD is therefore earlier, often multi-year, interaction on development plans. Rolling review then lets the sponsor lodge nonclinical and CMC modules months before clinical data are complete. For example, the Leqembi BLA was opened with nonclinical information in September 2021 and completed in May 2022 ²³⁹. Once the application is complete, the PDUFA clock applies as usual. Major amendments can still extend it by three months, as happened with Tecvayli (REMS) and Avlayah ¹⁶³⁸⁶.

BTD does not prevent complete responses or rescission

• Kisunla: The original BLA received a complete response on its January 18, 2023 goal date because of an inadequate long-term safety database. After a Class 2 resubmission, FDA classified additional data as a major amendment, moving the goal date to March 12, 2024. Approval came on July 2, 2024 ^183184179.
• Tzield: A first-cycle complete response on July 2, 2021 cited lack of PK comparability between commercial and clinical product, together with product-quality and facility inspection deficiencies. FDA identified no clinical deficiencies. Approval followed the February 2022 resubmission ^198207197.
• Olinvyk: FDA notified the sponsor in September 2018 of its intent to rescind BTD because Phase 3 data no longer showed substantial improvement over morphine. A complete response on November 2, 2018 cited the safety database and QT prolongation. The drug was approved on the second cycle in August 2020 ^177175170.
• Fintepla: The first submission was refused to file. BTD was rescinded after two other drugs were approved for Dravet syndrome and the sponsor had not shown superiority to both. A major amendment then pushed the goal date to June 25, 2020 ²¹³¹¹⁷.

For comparison, CDER's first-cycle approval rate for all novel approvals ranged from 74% to 86% between 2021 and 2025 ^{223224222217218}. The approvals reviewed here show that BTD programs are exposed to the same CMC, safety-database and comparability risks as any other application.

The Commissioner's National Priority Voucher

FDA announced the CNPV pilot on June 17, 2025. It is an ultra-accelerated review pathway for drug and biologic applications, including certain supplements, that serve U.S. national priorities. It does not change the statutory standards for approval ³⁷³⁸³⁹. Products are selected against five priorities ³⁶³⁷:

1. response to a public-health crisis or emerging threat;
2. innovative or transformative therapies;
3. large unmet medical need;
4. onshoring and supply-chain resilience;
5. affordability or improved access.

Operationally, CNPV applicants are expected to engage early and support rolling review. CMC information and proposed labeling are due at least 60 days before the final module is submitted ³⁶³⁸⁴⁰. The outlined sequence is a 60-day presubmission phase, a 14 to 21 day filing period and a 30 to 60 day review phase ^36373840. The Center's regular review team prepares its own recommendation and presents it to a multidisciplinary CNPV Review Council in a one-day tumor board-style meeting. The Council's recommendation is nonbinding, and the Center keeps the approval decision ^36373840. Vouchers are nontransferable. FDA may issue them for a named product or, under the original announcement, as an undesignated voucher for a future product ³⁷³⁸⁴³. FDA reported 18 vouchers awarded by April 1, 2026 ⁴¹.

Recipients and early results

The first cohort (October 16, 2025) included teplizumab, DB-OTO, RMC-6236, bitopertin, cytisinicline, cenegermin-bkbj, Pergoveris, ketamine and Augmentin XR. The last two were selected for domestic manufacturing ³⁴. The second cohort (November 6, 2025) included zongertinib, pediatric bedaquiline, dostarlimab for rectal cancer, Casgevy, orforglipron and Wegovy ²⁸²⁹. Awards made in December 2025 included a Tecvayli/Darzalex combination for relapsed/refractory multiple myeloma ³¹³³.

FDA's program page lists ten CNPV approvals as of August 26, 2026 ³⁷: a U.S.-manufactured Augmentin XR (December 9, 2025), Hernexeos (February 26, 2026), Tec-Dara, teclistamab with daratumumab hyaluronidase (March 5, 55 days after filing), Wegovy 7.2 mg (March 19), Foundayo/orforglipron (April 1, the first new molecular entity approved under the program, 50 days after filing) ⁴⁴, Otarmeni/lunsotogene parvec-cwha for OTOF-related hearing loss (April 23), Bizengri for NRG1-fusion cholangiocarcinoma (May 8), Casgevy for patients 2 years and older (July 1), Lipfendra/enlicitide (July 17) and Rasonque/daraxonrasib (August 26). Trade-press tallies from earlier in 2026 do not match this list (some included products FDA approved through standard review), so check product-level status against FDA's program page. Hernexeos was filed January 13, 2026 and approved 44 days later ³⁰⁴².

A voucher guarantees neither approval nor the target timeline. Disc Medicine's bitopertin received a complete response on February 13, 2026, about four months into review ³⁰³³.

Critics have raised several concerns ^30313233:

• selection criteria were unclear, and the Staff Manual Guide was published after most products had already been selected;
• the program lacks congressional authorization;
• non-scientific criteria such as pricing and manufacturing location influence selection;
• a 1 to 2 month review could strain reviewer resources and delay other applications.

BTD and CNPV side by side

Where the two programs overlap

The programs are complementary rather than alternatives, and several products have held both. Teplizumab received BTD in 2019 and was later selected in the first CNPV cohort ⁵³⁴. Teclistamab (Tecvayli) was approved with BTD in 2022, and a Tecvayli/Darzalex combination later received a CNPV ¹³¹. Zenocutuzumab (Bizengri) was first approved in December 2024 with BTDs for NRG1+ PDAC and NSCLC, then gained a CNPV approval for NRG1-fusion cholangiocarcinoma in May 2026 ⁶⁵³⁰.

The regulatory implications for sponsors:

• BTD affects how quickly and efficiently a sponsor reaches a complete, reviewable application.
• CNPV compresses the time from filing to action, provided the dossier is complete early (CMC and labeling at least 60 days before final submission) ³⁸⁴⁰.
• A BTD program with a CNPV could combine both effects. Neither designation lowers the evidentiary bar, and the Kisunla, Tzield and bitopertin records show that CMC, comparability and safety-database gaps still lead to complete responses ^18319830.