Comprehensive Analysis of FDA CRLs in 2025: Patterns, Sponsor Responses, and Outcomes
The FDA’s 2025 rejection of 20 drugs via Complete Response Letters (CRLs) highlighted challenges in efficacy and manufacturing. This review covers each case, post-CRL strategies, and the success of Elamipretide’s approval, offering insights into biopharma resilience and supply chain risks.
【Update October 1, 2025】Added the FDA CRL for CUTX-101 (Copper Histidinate; Cyprium Therapeutics/Fortress Biotech)
In 2025, the U.S. Food and Drug Administration (FDA) advanced its “radical transparency” initiative by publishing more than 200 historical Complete Response Letters (CRLs) in July and committing to release new CRLs promptly after issuance.
From January through October 2025, the agency issued at least 20 notable CRLs for new drug applications (NDAs) and biologics license applications (BLAs). Alongside more than 289 historical and recent letters made public, these rejections underscore recurring hurdles in drug development—most commonly insufficient clinical efficacy (48% of cases, per FDA analyses), manufacturing deficiencies, and gaps in U.S.-specific data. Under Commissioner Marty Makary, the July and September disclosures shed light on issues such as unreported adverse events and trial design flaws, providing sponsors with clearer guidance for remediation.
Post-CRL actions demonstrate resilience: Sponsors typically request Type A meetings (within 30 days) for feedback, supplement applications with new data or fixes, and resubmit within 3–6 months, with ~60% historical success rates. Manufacturing issues dominated (~70% of 2025 CRLs), exacerbated by third-party vendor audits (e.g., Catalent, Catalent Indiana), while rare disease therapies faced data hurdles due to small cohorts. Elamipretide's turnaround exemplifies success: Rejected in May for trial gaps and inspections, Stealth BioTherapeutics resubmitted in August with endpoint alignments, securing accelerated approval on September 19 as Forzinity—the first Barth syndrome therapy—affecting ~500 U.S. patients.
Full List of FDA-Rejected Drugs in 2025 (Latest to Earliest)
Below is the comprehensive list of 20 confirmed FDA-rejected drugs in 2025. Each entry includes the rejection reason and 1–2 post-CRL actions, ordered from latest to earliest, based on public sources as of October 1, 2025.
- CUTX-101 (Copper Histidinate; Cyprium Therapeutics/Fortress Biotech) – October 1, 2025
- Indication: Menkes disease (rare pediatric disorder of copper transport)
- Rejection Reason: cGMP deficiencies at the manufacturing facility; no issues identified with clinical efficacy or safety data.
- Post-CRL Actions:
- Sponsor will request a Type A meeting with FDA to discuss remediation and resubmission following a September 2025 re-inspection.
- Under the existing partnership with Sentynl, approval would trigger transfer of a Rare Pediatric Disease Priority Review Voucher (PRV) and up to US$129 million in milestones to Cyprium.
- High-Dose Spinraza (Nusinersen; Biogen) – September 24, 2025
- Rejection Reason: Chemistry, Manufacturing, and Controls (CMC) issues related to formulation scalability for spinal muscular atrophy (SMA), not clinical data concerns.
- Post-CRL Actions:
- Biogen plans resubmission after FDA feedback on technical CMC updates, targeting Q1 2026.
- No impact on standard Spinraza; leveraging long-term safety data.
- Apitegromab (Scholar Rock) – September 23, 2025
- Rejection Reason: Problems at a contract manufacturing organization (CMO, Catalent Indiana), despite intact efficacy data from Phase 3 SAPPHIRE trial for SMA.
- Post-CRL Actions:
- Intends BLA resubmission upon Catalent’s facility remediation, completed August 2025.
- No other approvability barriers; competitive SMA market focus.
- Rexulti (Brexpiprazole; Otsuka/Lundbeck) – September 20, 2025
- Rejection Reason: Insufficient efficacy evidence for PTSD adjunct with sertraline, per FDA review and 10:1 PDAC vote.
- Post-CRL Actions:
- Evaluating regulatory paths; no safety issues raised.
- Potential new trials to address efficacy for ~7M U.S. PTSD patients.
- ONS-501 (Bevacizumab; Outlook Therapeutics) – August 28, 2025
- Rejection Reason: Failure to meet primary efficacy endpoint in NORSE EIGHT trial for wet age-related macular degeneration (wAMD).
- Post-CRL Actions:
- Requested Type A meeting to clarify CRL remedies.
- Collaborating with FDA; no new trials mandated yet.
- Vatiquinone (PTC Therapeutics) – August 19, 2025
- Rejection Reason: Lack of substantial efficacy evidence for Friedreich’s ataxia (FA) in MOVE-FA trial, requiring a new controlled study.
- Post-CRL Actions:
- Plans FDA discussions on trial design for resubmission.
- Targeting mitochondrial dysfunction in ~5,000 U.S. patients.
- TLX250-CDx (Zircaix; Telix Pharmaceuticals) – August 2025
- Rejection Reason: CMC deficiencies needing comparability data for scaled-up production vs. Phase 3 ZIRCON trial for kidney cancer imaging.
- Post-CRL Actions:
- Immediate remediation; Type A meeting scheduled for Q1 2026 resubmission.
- Breakthrough therapy status intact; second Telix CRL.
- Odronextamab (Regeneron) – August 1, 2025
- Rejection Reason: Third-party manufacturing issues (Catalent Indiana) for follicular lymphoma (FL) and DLBCL, delaying 80% response rate review.
- Post-CRL Actions:
- Addressing observations; impacts Eylea HD PDUFA (Q4 2025).
- No clinical data concerns; bispecific platform unaffected.
- DTX401 (UX111; Ultragenyx Pharmaceutical) – July 11, 2025
- Rejection Reason: Manufacturing site inspection failures and insufficient production data for Sanfilippo syndrome type A, no clinical issues.
- Post-CRL Actions:
- Supplementing manufacturing data for 2026 resubmission.
- Rolling BLA for related glycogen storage disease initiated August 2025.
- Columvi (Glofitamab; Roche/Genentech) – July 18, 2025
- Rejection Reason: Insufficient U.S.-specific efficacy in STARGLO trial for DLBCL (9% North American enrollment).
- Post-CRL Actions:
- Evaluating options; confirmatory studies ongoing for durability.
- T-cell engager avoids full rejection; conditional approval context.
- Blenrep (Belantamab Mafodotin; GSK) – July 17, 2025
- Rejection Reason: High eye toxicity, low U.S. enrollment (<5%), and failure to meet overall survival endpoint in DREAMM-8 for multiple myeloma.
- Post-CRL Actions:
- PDUFA extended to October 23, 2025, for additional data review.
- Addressing dose adjustments; prior 2022 withdrawal reversed.
- RP1 (Replimune; with Opdivo) – July 2025
- Rejection Reason: Insufficient efficacy in IGNYTE trial for advanced melanoma, with trial design and heterogeneity issues.
- Post-CRL Actions:
- Type A meeting held September 18; addressing concerns for resubmission.
- Stock impact mitigated; oncolytic virus platform focus.
- Deramiocel (Capricor Therapeutics) – July 11, 2025
- Rejection Reason: Insufficient efficacy data for DMD cardiomyopathy (HOPE-2), plus disputed CMC defects.
- Post-CRL Actions:
- Aligned on HOPE-3 endpoints; topline data mid-Q4 2025 for resubmission.
- Advocacy from DMD community; BLA accepted March 2025.
- Oxylanthanum Carbonate (OLC; Unicycive Therapeutics) – June 30, 2025
- Rejection Reason: Third-party vendor deficiencies for hyperphosphatemia in CKD, no safety/efficacy concerns.
- Post-CRL Actions:
- Requested Type A meeting; Q4 resubmission targeted.
- Orphan fee waiver saved $4M; dialysis market focus.
- Elamipretide (Stealth BioTherapeutics) – May 29, 2025
- Rejection Reason: Inadequate clinical trial data for Barth syndrome (SPIBA-201), with efficacy endpoint gaps and third-party cGMP issues.
- Post-CRL Actions:
- Resubmitted NDA August 15 with knee strength endpoint; FDA granted accelerated approval September 19 as Forzinity.
- First mitochondrial therapy; impacts ~500 U.S. patients.
- TLX101-CDx (Telix Pharmaceuticals) – April 28, 2025
- Rejection Reason: Need for confirmatory clinical evidence and manufacturing comparability for glioma imaging.
- Post-CRL Actions:
- Agreed resubmission pathway (data reanalysis); Q4 2025 NDA planned.
- Expanded access program ongoing.
- EYLEA HD (Aflibercept 8mg; Regeneron) – April 18, 2025
- Rejection Reason: Insufficient justification for 24-week dosing extension from QUASAR Phase 3, no safety/efficacy issues.
- Post-CRL Actions:
- Review extended to Q4 2025; Novo Nordisk response submitted August 2025.
- Strong Q2 2025 sales from existing approvals.
- Reproxalap (Aldeyra Therapeutics) – April 3, 2025
- Rejection Reason: Methodological issues in dry eye chamber trial (baseline differences), requiring additional symptom trial.
- Post-CRL Actions:
- Resubmitted NDA June 17 with new Phase 3 data (P=0.002); FDA accepted July 17 (PDUFA December 16, 2025).
- No safety/manufacturing concerns; second CRL.
- Cardamyst (Etripamil; Milestone Pharmaceuticals) – March 28, 2025
- Rejection Reason: CMC issues, including nitrosamine impurities and equipment inspection failures for PSVT nasal spray.
- Post-CRL Actions:
- Submitted response June 13 with in-vitro studies; FDA accepted July 11 (PDUFA December 13, 2025).
- Type A meeting informed fixes.
- Camrelizumab/Rivoceranib (Hengrui/HLB/Elevar) – March 21, 2025
- Rejection Reason: CMC and quality control issues at production site for unresectable HCC, consistent with prior rejection.
- Post-CRL Actions:
- Addressing manufacturing deficiencies for resubmission.
- Synergistic combo; U.S. entry delayed.
- Ebvallo (Tabelecleucel; Atara Biotherapeutics) – January 16, 2025
- Rejection Reason: Third-party manufacturing inspection issues for EBV+ PTLD, no clinical/safety concerns.
- Post-CRL Actions:
- Resubmitted BLA; FDA accepted July 31 (PDUFA pending).
- Type A meeting scheduled May 2025; $40M milestone eligible.
Trends and Implications
CRLs clustered mid-year, with oncology/rare diseases prominent (60%). Resubmission success like Elamipretide boosts morale, but delays (e.g., 3–6 months) strain small biotechs amid 20% FDA staff cuts. Transparency aids avoidance of pitfalls (e.g., 85% undisclosed safety issues historically). Patient access via expanded programs (e.g., Telix) mitigates gaps. Future: Real-time CRL postings from September onward may accelerate fixes, though advisory committee reductions spark scrutiny concerns.
Category | Count | Common Post-CRL Action | Example Drugs |
|---|---|---|---|
Manufacturing/CMC | 13 | Vendor remediation & Type A meetings | Apitegromab, Odronextamab |
Efficacy/Trial Design | 7 | New data/resubmission | Vatiquinone, RP1 |
Overall Success Rate (Historical) | ~60% | Accelerated paths for rares | Elamipretide |
Sources
- Fortress Biotech and Cyprium Therapeutics Announce an Update on the NDA for CUTX-101, https://www.fortressbiotech.com/investors/news-events/press-releases/detail/719/fortress-biotech-and-cyprium-therapeuticsannounce-an
- FDA Grants Accelerated Approval to Forzinity (Elamipretide): https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-treatment-barth-syndrome
- Stealth BioTherapeutics Announces FDA Approval: https://stealthbt.com/stealth-biotherapeutics-announces-fda-accelerated-approval-of-forzinity-elamipretide-hcl-the-first-therapy-for-progressive-and-life-limiting-ultra-rare-genetic-disease-barth-syndrome/
- Biogen Regulatory Update on High-Dose Spinraza: https://investors.biogen.com/news-releases/news-release-details/biogen-provides-regulatory-update-high-dose-regimen-nusinersen
- Scholar Rock CRL Announcement: https://investors.scholarrock.com/news-releases/news-release-details/fda-issues-complete-response-letter-crl-apitegromab-treatment
- Otsuka/Lundbeck Rexulti CRL: https://www.otsuka-us.com/news/otsuka-and-lundbeck-receive-complete-response-letter-us-fda-snda-rexultir-brexpiprazole
- Outlook Therapeutics ONS-501 Update: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-provides-regulatory-update-us-food-and-drug
- PTC Therapeutics Vatiquinone CRL: https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-receives-complete-response-letter-vatiquinone?mobile=1
- Telix TLX250-CDx Regulatory Update: https://ir.telixpharma.com/static-files/6264a633-04e6-4eb2-81c5-f9fc40d113d2
- Regeneron Odronextamab CRL: https://www.onclive.com/view/fda-issues-crl-for-odronextamab-in-relapsed-refractory-follicular-lymphoma
- Ultragenyx DTX401 CRL: https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-receives-complete-response-letter-fda-ux111-aav-gene
- Roche Columvi Update: https://www.gene.com/media/press-releases/15070/2025-07-18/genentech-provides-update-on-supplementa
- GSK Blenrep PDUFA Extension: https://us.gsk.com/en-us/media/press-releases/gsk-announces-extension-of-us-food-and-drug-administration-review-period-for-blenrep-belantamab-mafodotin-blmf-in-relapsedrefractory-multiple-myeloma/
- Replimune RP1 Type A Update: https://ir.replimune.com/news-releases/news-release-details/replimune-provides-update-following-type-meeting-fda
- Capricor Deramiocel Regulatory Update: https://www.capricor.com/investors/news-events/press-releases/detail/326/capricor-therapeutics-provides-regulatory-update-on
- Unicycive OLC CRL: https://ir.unicycive.com/news/detail/104/unicycive-therapeutics-announces-receipt-of-complete
- Telix TLX101-CDx Resubmission: https://telixpharma.com/news-views/telix-and-fda-agree-on-resubmission-pathway-for-tlx101-cdx-pixclara-u-s-nda/
- Regeneron EYLEA HD Extension: https://investor.regeneron.com/news-releases/news-release-details/eylea-hdr-aflibercept-injection-8-mg-applications-expanded-us
- Aldeyra Reproxalap Resubmission: https://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-resubmits-reproxalap-new-drug-application-0
- Milestone Cardamyst Response: https://investors.milestonepharma.com/news-releases/news-release-details/milestone-pharmaceuticals-submits-response-fdas-crl-cardamyst
- Hengrui Camrelizumab Second CRL: https://www.cancernetwork.com/view/fda-issues-second-camrelizumab-rivoceranib-crl-in-hepatocellular-carcinoma
- Atara Ebvallo Resubmission: https://investors.atarabio.com/news-events/press-releases/detail/371/atara-biotherapeutics-provides-regulatory-updates-on
Disclaimer: This analysis is provided for informational and educational purposes only. This content does not constitute medical advice, treatment recommendations, or investment advice. Readers should consult qualified professionals for medical or financial decisions and verify information with primary sources for the most current and accurate details.