CBER Accelerated Approvals for Cell and Gene Therapies: Surrogate Endpoints, Confirmatory Requirements and Post-Approval Status

CBER accelerated approvals for cell and gene therapies: surrogate endpoints, confirmatory requirements and post-approval status (through September 2026)

Key findings

• CBER has used accelerated approval (21 CFR 601.41, subpart E) across every major cell and gene therapy modality: CD19-directed CAR-T products in later-line lymphomas, the first TCR-T product (TECELRA), the first TIL product (AMTAGVI), in vivo and ex vivo gene therapies for rare diseases, and an oncolytic HSV immunotherapy (TUDRIQEV; accelerated approval August 6, 2026).
• In oncology the basis is almost always objective response rate (ORR) supported by duration of response (DOR) from a single-arm study ^427374407614. In rare-disease gene therapy, CBER has accepted a wider range of endpoints: protein expression (micro-dystrophin) ⁴⁴⁶, neutrophil CD18/CD11a expression ⁴⁷⁸, and intermediate clinical endpoints such as motor milestones ⁵¹⁹, MFD-free survival ³⁰⁰ and pure-tone audiometry ³⁹⁴.
• Five conversions to traditional approval are documented: CARTICEL for knee cartilage defects (June 2007, almost ten years after its 1997 accelerated approval) ⁹²⁵, ELEVIDYS for ambulatory patients (June 2024) ³⁵⁴, BREYANZI for follicular lymphoma (February 2026) ⁹²⁷, TECARTUS for mantle cell lymphoma (April 2026) ⁴³⁵, and TECELRA for synovial sarcoma (June 2026, with a pediatric expansion) ²⁵.
• One accelerated-approval indication has been removed: ELEVIDYS in non-ambulatory patients (November 2025). The removal came with a hepatotoxicity boxed warning, not a failed confirmatory trial ³⁵².
• One accelerated-approval indication has been narrowed: since August 2025, SKYSONA is limited to boys without an available HLA-matched donor for allogeneic stem cell transplant, a change made with a hematologic malignancy safety labeling update ⁹³⁰⁹³¹.
• Class-wide safety changes (the April 2024 T-cell malignancy boxed warning and the June 2025 elimination of the CAR-T REMS) apply to the accelerated-approval CAR-T products whatever their accelerated or traditional status ^{416636694696697}.

Summary table

CAR-T products

TECARTUS (brexucabtagene autoleucel): mantle cell lymphoma

TECARTUS received accelerated approval on July 24, 2020 (STN 125703/0) for adult relapsed/refractory mantle cell lymphoma, based on ORR and durability of response ⁴²⁷. FDA described a favorable ORR, with limited follow-up, as an intermediate endpoint reasonably likely to predict clinical benefit. It said longer follow-up of response durability was needed to verify benefit ⁴²⁹. In the ZUMA-2 inferential set (n=60), ORR was 87% (95% CI 75.4% to 94.1%) and the CR rate was 62%. Median DOR was not reached at about 8 months of follow-up from first response ⁸⁴⁵. FDA also required an observational registry for long-term safety, including secondary malignancies ⁴²⁹.

On April 1, 2026, FDA approved sBLA 125703/464, converting the MCL indication to traditional approval on the completed final report of accelerated-approval PMR #2 (ZUMA-2) ⁴³⁵. The later B-cell precursor ALL indication (STN 125703/91) was a regular approval based on complete response and durability in ZUMA-3 ^420424434.

YESCARTA (axicabtagene ciloleucel): follicular lymphoma

The follicular lymphoma indication (adults, after two or more lines of systemic therapy) was approved under accelerated approval via BL 125643/248, effective March 5, 2021 ⁷⁰³. In the USPI primary efficacy analysis (Study 3/ZUMA-5, n=81), IRC-assessed ORR was 91% (95% CI 83% to 96%) and the CR rate 60%. The confirmatory PMR is a randomized Phase 3 trial of axi-cel versus investigator's choice of standard-of-care regimens. PFS is the primary endpoint, with ORR and OS as secondary endpoints. The milestones were final protocol by August 31, 2021, study completion by June 30, 2027 and final report by September 30, 2027 ⁶¹². FDA's list of ongoing cancer accelerated approvals, current as of September 17, 2026, still includes this indication ⁹²⁶. YESCARTA's large B-cell lymphoma indications, including the April 2022 second-line indication based on ZUMA-7, are regular approvals ⁷⁰⁵⁷¹¹.

KYMRIAH (tisagenlecleucel): follicular lymphoma

Supplement 125646/663 (approval letter May 27, 2022) granted accelerated approval for adults with relapsed/refractory follicular lymphoma after two or more lines of therapy ⁶³⁸. FDA characterized ORR in Study E2202, supported by durability of response, as an intermediate clinical endpoint reasonably likely to predict clinical benefit ³⁷⁴. Median DOR was not estimable, with at least 9 months of response follow-up for all but one subject ⁶⁵⁴. The confirmatory PMR is a randomized Phase 3 trial against investigator's-choice standard care with PFS as the primary endpoint. Protocol submission was due December 31, 2022, completion March 31, 2028 and final report September 30, 2028 ⁶⁵¹. The pediatric/young adult ALL and adult LBCL indications were regular approvals ^646647637.

BREYANZI (lisocabtagene maraleucel): CLL/SLL and follicular lymphoma

BREYANZI received two accelerated approvals in 2024. The CLL/SLL indication is still accelerated; the follicular lymphoma indication was converted to traditional approval on February 20, 2026:

• CLL/SLL (BL 125714/205). The effective approval date is March 14, 2024; a replacement letter was issued March 21, 2024 ⁸⁸⁶. The indication covers patients after at least two prior lines, including a BTK inhibitor and a BCL-2 inhibitor ³²⁴. Clinical benefit is to be verified through ORR and durability in a single-arm study of 50 treated patients, with at least 15 months of follow-up after first response. The final report is due May 31, 2027 ³²⁶.
• Follicular lymphoma (BL 125714/225). Approved May 15, 2024 under 21 CFR 601.41 for adults after two or more prior lines of systemic therapy ³²⁷. The FDA analysis showed ORR 96% (95% CI 90 to 99) and CR 73%, with median DOR not reached in 94 patients ⁷⁹⁹. The PMR requires final TRANSCEND FL data with at least 24 months of follow-up for all responders. Study completion was due May 31, 2025 and the final report August 31, 2025 ⁶²⁶. FDA said the additional data were needed "for consideration of conversion to traditional approval" ⁶²⁸. On February 20, 2026, FDA approved supplement 125714/703, which fulfilled this PMR and converted the FL indication to traditional approval ⁹²⁷.

FDA narrowed the requested populations at approval for both the FL and the May 30, 2024 mantle cell lymphoma supplements (125714/227) ⁶¹⁸⁶³³. A marginal zone lymphoma indication followed on December 4, 2025 (125714/644). The approval letter does not invoke 21 CFR 601.41, and the current label, unlike for CLL/SLL, does not make the MZL indication contingent on confirmatory trials. The letter does impose a 15-year, 300-patient secondary-malignancy safety study ^805809811.

Class-wide CAR-T safety actions

On April 12, 2024, FDA approved class safety labeling changes adding T-cell malignancies to the Boxed Warning for TECARTUS (125703/361), KYMRIAH (125646/854) and YESCARTA (125643/640). The changes followed the January 2024 notifications under FDCA 505(o)(4) ^416636694. On June 26, 2025, FDA eliminated the YESCARTA/TECARTUS REMS. FDA found that ETASU, including hospital certification and on-site tocilizumab, were no longer necessary given established management guidelines and clinical experience ⁶⁹⁶⁶⁹⁷. The ABECMA REMS was eliminated the same day ⁴⁴⁹.

TCR-T: TECELRA (afamitresgene autoleucel)

TECELRA was granted accelerated approval in August 2024 (STN 125789/0) ⁶¹³²⁵. The indication covers adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A02:01P, -A02:02P, -A02:03P or -A02:06P positive, and have MAGE-A4-expressing tumors as determined by an FDA-approved or cleared companion diagnostic ⁶¹⁴. The basis was ORR supported by DOR from ADP-0044-002 Cohort 1 ⁶¹⁴. On FDA-requested independent re-review, ORR was 43.2% (19/44; 95% CI 28.3% to 59.0%) and median DOR was 6.0 months ⁸⁷⁸.

The PMR was unusual in that it did not require a randomized trial. The sponsor had to submit the final report and datasets from ADP-0044-002 Cohorts 2 and 3, giving a more precise independent estimate of ORR and mature DOR with at least 15 months of follow-up. The final report was due December 31, 2025 ⁶¹³. FDA converted the approval to traditional approval on June 17, 2026 (STN 125789/136) on the basis of Cohorts 1 to 3. The same action expanded the indication to pediatric patients 12 years and older and widened the dose range ²⁵. A related PMC requires a MAGE-A4 in vitro diagnostic validated for adolescents, with the report due September 30, 2026 ⁶⁸¹. FDA did not require a REMS ⁶⁶².

TIL: AMTAGVI (lifileucel)

AMTAGVI (BLA 125773) received accelerated approval for unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody and, if BRAF V600-positive, a BRAF inhibitor with or without a MEK inhibitor ⁴⁰⁷. FDA accepted ORR supported by durability from Study C-144-01 as the intermediate clinical endpoint ⁴⁰⁷. In the primary efficacy analysis (Cohort 4, n=82), IRC-assessed ORR was 28.0% (95% CI 18.7% to 39.1%) and median DOR was not reached ⁹²⁴. The USPI reports the same 23 responders against a 73-patient efficacy set limited to the labeled dose range (7.5 × 10^9 to 72 × 10^9 viable cells): ORR 31.5% (95% CI 21.1% to 43.4%).

The confirmatory PMR is IOV-MEL-301, a randomized Phase 3 trial of lifileucel plus pembrolizumab versus pembrolizumab in previously untreated advanced melanoma. It has dual primary endpoints of ORR and PFS, with OS as the key secondary endpoint ⁴⁰³⁴⁰⁷. Final OS analysis is due March 31, 2030 and the final report March 31, 2031 ⁴⁰³. The confirmatory population (first-line, combination) differs from the accelerated-approval population (post-PD-1 monotherapy), which RA teams tracking indication-specific verification should note. Safety risk was addressed with a Boxed Warning and inpatient administration requirements rather than a REMS. FDA identified 12 treatment-related deaths (7.5%) in C-144-01 ^561567405.

Autologous chondrocytes: CARTICEL

CARTICEL (autologous cultured chondrocytes) appears on FDA's list of accelerated approvals with verified clinical benefit. FDA lists the indication as articular cartilage defects in the knee, with accelerated approval on August 22, 1997 and traditional approval on June 21, 2007 ⁹²⁵. FDA's table does not describe the endpoint basis or the confirmatory study.

Gene therapies

SKYSONA (elivaldogene autotemcel)

SKYSONA's accelerated approval (September 16, 2022) covers slowing neurologic dysfunction progression in boys 4 to 17 years with early, active CALD ²⁹⁸. The basis was an intermediate clinical endpoint: slowed progression to major functional disabilities (MFDs) or death at 24 months from symptom onset, compared with natural-history controls ³⁰⁰. The confirmatory PMRs are 10-year event-free survival follow-up of ALD-102/ALD-104 patients (final report July 31, 2032) and a new study in 24 boys with more advanced early active CALD (final report December 31, 2038) ²⁹⁶. A separate 15-year, 120-patient secondary-malignancy safety study runs to 2048 ²⁹⁷. Supplement 125755/34 (April 5, 2024) updated the hematologic malignancy safety labeling ⁸³⁶. Supplement 125755/91 (August 7, 2025), a further hematologic malignancy safety labeling change, also revised the Indications and Usage section ⁹³⁰. The indication now covers only boys 4 to 17 years with early, active CALD who do not have an available HLA-matched donor for allogeneic hematopoietic stem cell transplant, and the label still describes it as an accelerated approval ⁹³¹.

ELEVIDYS (delandistrogene moxeparvovec-rokl)

ELEVIDYS received accelerated approval on June 22, 2023 for ambulatory patients aged 4 through 5 years with DMD. The surrogate was micro-dystrophin expression at Week 12 ⁴⁴⁶. The confirmatory study was SRP-9001-301 Part 1, a randomized, placebo-controlled trial with change in NSAA total score at Week 52 as the primary endpoint ⁴⁴⁶³⁶⁵.

• June 20, 2024 (STN 125781/34). FDA converted the ambulatory indication to traditional approval for patients 4 years and older. At the same time it granted a new accelerated approval for non-ambulatory patients 4 years and older, based on micro-dystrophin expression ³⁵⁴³⁶⁹. Study 301 missed its NSAA primary endpoint. Review staff concluded that benefit had not been verified. The Center Director found the totality of evidence, including secondary timed-function measures, sufficient for traditional approval ^35536636882. The non-ambulatory confirmatory trial had a projected final report date of November 30, 2027 ³⁵⁴³⁶².
• November 14, 2025 (STN 125781/189). Following a June 2025 Safety Labeling Change Notification on hepatotoxicity, including fatal acute liver failure, FDA restricted the indication to ambulatory patients. It stated that non-ambulatory use "will no longer be licensed under the BLA." It also added acute liver failure to the Boxed Warning ³⁵². A new safety PMR (at least 200 patients) targets a final report by April 30, 2030 ⁹¹¹⁹¹³.

ELEVIDYS is the clearest example in this set of an accelerated-approval indication being withdrawn on post-marketing safety grounds before the confirmatory trial read out.

KEBILIDI (eladocagene exuparvovec-tneq)

KEBILIDI received accelerated approval on November 13, 2024 for adult and pediatric AADC deficiency ⁵²⁵. FDA rejected the sponsor's proposed surrogate, CSF homovanillic acid at Week 8, because post-treatment values stayed below normal and did not correlate with motor outcomes ^519530536. FDA instead relied on an intermediate clinical endpoint: gross motor milestone achievement at Week 48, which 8 of 12 children (67%) reached, compared with none in an external untreated cohort ⁵¹⁹⁵³⁰. The PMR requires clinical study reports from US-treated patients covering serious manifestations, including motor function. The final report is due September 30, 2029 ⁵¹⁶. Some reviewers favored a narrower label limited to severe pediatric disease, but the approved indication is broad ⁵¹⁹⁵²⁵.

KRESLADI (marnetegragene autotemcel)

KRESLADI was approved on March 26, 2026 under 21 CFR 601.41 for pediatric severe LAD-I due to biallelic ITGB2 variants in patients without an HLA-matched sibling donor ⁴⁸². FDA described restoration of LFA-1 function (neutrophil CD18 and CD11a surface expression) as a novel surrogate reasonably likely to predict improved survival ⁴⁷⁸. Clinical endpoints (HSCT-free survival, serious infections) were not interpretable because of design limitations ⁴⁸⁵. PMR 1 requires long-term follow-up to age 10 plus at least four newly treated infants, with comparison against a suitable comparator; the final report is due June 30, 2034 ⁴⁷⁷⁴⁸⁴. PMR 2 requires further validation of the flow cytometry assay, reflecting how much the approval depends on the biomarker ⁷³⁰.

OTARMENI (lunsotogene parvec-cwha)

OTARMENI received accelerated approval on April 23, 2026 ³⁷⁹³⁸⁹. The indication covers pediatric and adult patients with severe-to-profound sensorineural hearing loss associated with biallelic OTOF variants, preserved outer hair cell function and no prior cochlear implant in the treated ear ⁴⁰⁰. The intermediate clinical endpoint was Week-24 pure-tone audiometry: 16 of 20 evaluable patients (80%) reached an average PTA below 70 dB HL, and 14 (70%) reached click-ABR below 90 dB nHL ³⁹⁷. The PMR requires 104-week analyses in at least 30 pediatric and at least 5 newly treated patients aged 16 and older, compared against untreated patients. The final report is due August 30, 2030 ³⁹¹. FDA included adults in the indication by extrapolation ³⁸¹.

GENGLYCOS (pariglasgene brecaparvovec-opnr)

GENGLYCOS was approved on August 19, 2026 to reduce daily cornstarch intake as an adjunct to nutritional management in patients 8 years and older with GSDIa ⁴⁹⁴. The label states that continued approval depends on confirmation of benefit ⁴⁹⁶⁴⁹⁷. The confirmatory trial is randomized against standard-of-care nutritional management. Its co-primary endpoints are change in daily cornstarch doses and time to hypoglycemia during a controlled fasting challenge. Study completion is due August 31, 2031 and the final report December 31, 2031 ⁴⁹⁵³²⁰.

Oncolytic viral immunotherapy: TUDRIQEV (vusolimogene oderparepvec-wtpg)

TUDRIQEV (RP1, BLA 125827) received a Complete Response Letter on July 21, 2025. FDA cited unreliable response assessment, the inability to isolate RP1's contribution to the combination with nivolumab, and a heterogeneous single-arm population ³³⁴⁸³⁴. A second CRL followed on April 10, 2026 ³⁴⁷. After a June 2026 resubmission, OCE's August 2026 memorandum recommended accelerated approval in combination with nivolumab for adults with unresectable advanced cutaneous melanoma that progressed on a PD-1-based regimen ⁸³⁵³²⁹. The basis was ORR and DOR from IGNYTE. The applicant reported an ORR of 33.6% ³³⁴. FDA's conservative sensitivity analysis gave an ORR of 24.7% (95% CI 16.2% to 35.0%) and a median DOR of 14.1 months ³⁴⁸. The confirmatory PMR is the randomized Phase 3 IGNYTE-3 (RP1-104) trial (RP1 plus nivolumab versus physician's choice) with OS as the primary endpoint. The final report is due March 2031 ^329338929. IGNYTE-3 was about 10% enrolled at the last reported update ³⁴¹.

The review file shows real internal disagreement. The clinical review recommended another Complete Response, while other memoranda recommended accelerated approval ^9089790791. FDA issued the accelerated approval letter on August 6, 2026 (STN 125827/0), for use with nivolumab in the indication above ⁹²⁸.

IMLYGIC, the earlier oncolytic HSV, is described in the FDA record as supported for traditional approval ⁸⁶. ADSTILADRIN, an intravesical adenoviral-vector gene therapy for BCG-unresponsive NMIBC, received traditional approval based on CR rate and DOR ⁷⁶⁸.

Programs that sought or were considered for accelerated approval but received traditional approval

• PAPZIMEOS (zopapogene imadenovec-drba), August 14, 2025. Precigen sought accelerated approval. FDA converted the application to traditional approval during review, based on 12-month (51%) and 24-month (43%) complete response rates, so no confirmatory study was required ^596606610.
• ROCTAVIAN (valoctocogene roxaparvovec-rvox). The 2020 CRL rejected Week 23 to 26 FVIII activity as a surrogate reasonably likely to predict bleeding outcomes ⁴¹¹⁴¹⁵. The 2023 approval was a regular approval based on annualized bleeding rate from Study 270-301 ⁵⁴⁷⁵⁴².
• ABECMA (idecabtagene vicleucel). Regular approval in 2021 based on MM-001 response depth and durability ⁴⁶²⁴⁶⁷. In 2024 the indication was expanded to two or more prior lines on the basis of KarMMa-3, with an early-mortality warning added ⁴⁴⁸⁴⁶⁶.

Implications for regulatory strategy

• Endpoint selection. For hematologic malignancies and solid tumors, CBER consistently accepts ORR plus DOR from single-arm trials, with the magnitude and durability of response weighed against the available therapy ^427374407614. For rare genetic diseases, CBER has accepted biomarker surrogates where there is a mechanistic link (micro-dystrophin, CD18/CD11a) ⁴⁴⁶⁴⁷⁸. It has rejected biomarkers that did not track clinical outcomes (CSF HVA, early FVIII activity) and in those cases moved to intermediate clinical endpoints or required clinical outcomes ⁵¹⁹⁴¹¹.
• Confirmatory designs vary. Several PMRs require only longer follow-up or added single-arm cohorts (TECARTUS, TECELRA, BREYANZI) ^435613326. Others require randomized trials with PFS or OS endpoints (KYMRIAH, YESCARTA, AMTAGVI, TUDRIQEV, GENGLYCOS) ^{651612403338495}. Single-arm follow-up designs converted BREYANZI follicular lymphoma and TECELRA in under two years ⁹²⁷²⁵, although TECARTUS took more than five years ⁴³⁵.
• Timelines are long. Several gene therapy final reports are not due until the 2030s (SKYSONA 2032 and 2038, KRESLADI 2034) ²⁹⁶⁴⁸⁴. Sponsors should budget for 180-day AA PMR progress reports and the due-diligence expectations that now come with accelerated approval ³²¹⁵¹⁵.
• Safety can override the accelerated-approval pathway. The ELEVIDYS non-ambulatory removal shows that FDA can remove an accelerated-approval indication through a safety labeling action before confirmatory data are available ³⁵².