A Complete Response Letter (CRL) is a regulatory action taken by the FDA for new drug/biologic (NDA, BLA) marketing applications, indicating that the application will not be approved in its current form. However, it is not a complete rejection, as further actions are required. According to incomplete statistics, at least 26 drugs (including supplemental applications) were rejected by the FDA in 2024.
The reasons for rejection generally fall into two categories: doubts about the drug's efficacy and safety, or Chemistry, Manufacturing, and Controls (CMC) deficiencies at third-party suppliers/manufacturers. While manufacturing issues may not be as critical as safety and efficacy concerns and can often be addressed later, they still lead to delays in drug approval.
Rejection of a drug application not only affects commercialization but can be devastating for smaller pharmaceutical companies heavily reliant on a single product. Many such companies suffered significant setbacks upon receiving CRLs.
On January 9, Astellas' Claudin18.2 monoclonal antibody, Zolbetuximab, received a CRL from the FDA, temporarily rejecting its approval as a first-line treatment for Claudin18.2-positive, HER2-negative, locally advanced, unresectable, or metastatic gastric/gastroesophageal junction adenocarcinoma.
The CRL cited unresolved deficiencies at a third-party manufacturing facility but did not raise concerns regarding the clinical data or request additional trials. Astellas stated that the manufacturing issues do not pose safety or efficacy risks and is working closely with the FDA and the manufacturer to resolve them.
However, Zolbetuximab was approved in Japan on March 26, 2024, for treating Claudin18.2-positive unresectable advanced or recurrent gastric cancer.
On January 18, Satsuma Pharmaceuticals' STS101 NDA received an FDA CRL, rejecting its approval for acute migraine treatment.
STS101 contains dihydroergotamine mesylate, a previously approved migraine medication, administered intranasally using Satsuma's proprietary device.
The rejection was due to CMC issues, with no safety concerns or requests for additional clinical trials.
Following a Type A meeting with the FDA, Satsuma resubmitted its NDA on November 9, and it was accepted, with a PDUFA target date of April 30, 2025.
On January 30, Defender Pharmaceuticals announced that it received an FDA CRL rejecting the approval of DPI-386 for preventing nausea and vomiting caused by motion sickness. The specific reason for rejection was not disclosed.
DPI-386 contains scopolamine, an anticholinergic drug administered intranasally to inhibit glandular secretions and smooth muscle spasms.
A Phase III double-blind, placebo-controlled trial showed a significantly higher proportion of patients in the DPI-386 group did not vomit or request rescue medication. Defender plans to continue evaluating DPI-386 for indications such as traumatic brain injury and postoperative nausea and vomiting.
On February 23, Venatorx Pharmaceuticals and Melinta Therapeutics announced that the FDA issued a CRL for their NDA submission of cefepime-taniborbactam for complicated urinary tract infections.
The FDA requested additional CMC data and information on testing methods and manufacturing processes but raised no concerns regarding safety, efficacy, or the need for new clinical trials.
Cefepime-taniborbactam is an antibiotic combination therapy, where cefepime (a β-lactam) is active against Gram-positive and Gram-negative bacteria, and taniborbactam (a β-lactamase inhibitor) enhances its activity against resistant strains.
On February 27, Theratechnologies announced that the FDA issued a Refusal to File (RTF) letter for its supplemental BLA (sBLA) seeking approval for intramuscular administration of Trogarzo.
The FDA stated that the sBLA lacked sufficient data to demonstrate pharmacokinetic equivalence between intramuscular and intravenous administration.
Trogarzo is a long-acting post-attachment HIV-1 inhibitor targeting CD4, originally approved by the FDA in 2018 for patients with multidrug-resistant HIV.
On February 27, Minerva Neurosciences received an FDA CRL rejecting its NDA for Roluperidone, intended to treat negative symptoms of schizophrenia.
The FDA requested at least one additional clinical trial to support the safety and efficacy of Roluperidone and further data to establish its safety and efficacy in combination with other antipsychotics.
This marks Minerva’s second rejection. In October 2022, the FDA issued an RTF, refusing to accept the NDA. After a Type A meeting with the FDA, the agency maintained its rejection stance.
Roluperidone is a 5-HT2A and σ2 receptor antagonist designed to avoid direct dopamine receptor blockade while targeting specific serotonin receptor subtypes.
On March 11, Viatris and Mapi Pharma announced that the FDA issued a CRL for their NDA submission of GA Depot for relapsing forms of multiple sclerosis (MS).
GA Depot is a long-acting version of Glatiramer Acetate (GA), reducing injection frequency from three times per week to once every four weeks. GA, developed by Teva, was FDA-approved in 1996 for reducing MS relapse frequency.
The companies are reviewing the CRL to determine the next steps.
On March 6, Vanda Pharmaceuticals announced that the FDA issued a CRL for its sNDA for Hetlioz as an insomnia treatment, citing label deficiencies as the reason for rejection.
Hetlioz is a melatonin receptor agonist approved in 2014 for non-24-hour sleep-wake disorder and in 2020 for nighttime sleep disturbances in Smith-Magenis Syndrome.
On March 25, Regeneron announced that the FDA rejected accelerated approval of its CD20×CD3 bispecific antibody, Odronextamab, for relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma.
The rejection was solely due to the lack of an ongoing confirmatory trial, with no issues raised regarding efficacy, safety, clinical design, labeling, or manufacturing.
However, on August 26, Odronextamab was approved in Europe for the same indications, making it the fourth CD20/CD3 bispecific antibody to be approved.
On April 8, Supernus Pharmaceuticals announced that the NDA for its Parkinson's drug SPN-830 received a CRL from the FDA, stating that SPN-830 was not ready for market approval in its current form.
SPN-830 is an apomorphine injection designed to provide continuous treatment for motor fluctuations (ON-OFF episodes) in Parkinson's patients.
The regulatory approval process for SPN-830 has been challenging, facing three rejections so far. The first rejection was an RTF, where the FDA refused to review the submission due to incomplete data. The second rejection was a CRL, requesting additional information related to the infusion device, labeling, manufacturing quality, and risk analysis.
On April 22, Abeona Therapeutics received a CRL from the FDA for its cell therapy EB-101, intended to treat recessive dystrophic epidermolysis bullosa (RDEB). The rejection was due to CMC issues, with no deficiencies in clinical efficacy or safety data.
On October 29, after an FDA Type A meeting, Abeona resubmitted the BLA for EB-101, which was accepted. The PDUFA date is set for April 29, 2025.
Pz-cel is an autologous cell therapy that uses a retroviral vector to introduce the COL7A1 gene into a patient's skin cells, restoring normal type VII collagen expression to promote wound healing.
On May 17, Elevar Therapeutics subsidiary HLB received a CRL from the FDA for its BLA of the combination therapy "Camrelizumab + Apatinib" for first-line treatment of unresectable or metastatic hepatocellular carcinoma (HCC).
The rejection was due to travel restrictions affecting the FDA’s biological monitoring inspection (BIMO) process.
The combination was approved by China’s NMPA in 2023 as the first PD-1 inhibitor and small-molecule anti-angiogenic combination therapy for advanced HCC. Elevar resubmitted the NDA in October 2024, with a new PDUFA date of March 23, 2025.
On June 26, Daiichi Sankyo and Merck received a CRL from the FDA for HER3-DXd, an HER3-ADC drug, for the treatment of EGFR-mutated NSCLC.
The rejection was due to issues with a third-party manufacturing facility, with no concerns about safety or efficacy.
HER3-DXd is Daiichi Sankyo’s first HER3 ADC, and in October 2023, Merck and Daiichi Sankyo signed a $22 billion global commercialization agreement.
On June 25, AbbVie announced that it received an FDA CRL for its ABBV-951 NDA, rejecting approval for the treatment of motor fluctuations in Parkinson’s disease patients.
The rejection was due to issues at a third-party manufacturer, with no safety or efficacy concerns related to ABBV-951.
This is the second CRL for ABBV-951. In March 2023, the FDA issued the first CRL, citing issues with the drug’s delivery pump.
ABBV-951 is a prodrug of Foscarbidopa/foslevodopa and has been approved in over 34 countries.
Despite setbacks, ABBV-951 was ultimately approved by the FDA on October 17 under the name Vyleesi, becoming the first and only subcutaneous therapy delivering continuous 24-hour dosing of Foscarbidopa.
On June 28, Rocket Pharmaceuticals announced that it received an FDA CRL for its gene therapy Kresladi’s BLA, requiring additional limited CMC data to complete the review.
Previously, the FDA had extended the PDUFA date by three months due to CMC concerns.
Kresladi is a gene therapy for leukocyte adhesion deficiency type I (LAD-I), using a lentiviral vector to genetically modify a patient’s autologous hematopoietic stem cells to deliver a functional copy of the ITGB2 gene encoding β-2 integrin CD18.
On July 10, Novo Nordisk announced that the FDA issued a CRL for the BLA of its once-weekly insulin Icodec, requiring additional data on Icodec’s manufacturing process and its application in type 1 diabetes.
In May 2024, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee did not support Icodec’s approval for type 1 diabetes, citing insufficient benefit/risk data.
Icodec has already been approved in the EU, China, Canada, Australia, Japan, and Switzerland for treating type 1 and type 2 diabetes.
Novo Nordisk stated that it will work closely with the FDA but does not expect to meet the required conditions before the end of 2024.
On July 16, Orexo announced that it received an FDA CRL rejecting its NDA for OX124, a high-dose naloxone nasal spray for opioid overdose treatment.
The CRL requested additional HF studies and more technical data related to the final commercial product but did not require additional clinical or non-clinical studies.
This is the second CRL for OX124. In April 2023, the FDA rejected it due to technical issues with secondary packaging equipment.
Orexo stated that it will consult with the FDA to resolve the issue and resubmit the NDA as soon as possible.
On July 18, Agenus announced that the FDA rejected the accelerated approval application for its CTLA-4 + PD-1 combination therapy (Botensilimab + Balstilimab) for relapsed/refractory microsatellite-stable colorectal cancer.
The FDA noted that the therapy’s response rate did not always translate into survival benefits and requested a Phase III clinical trial to confirm the treatment’s benefit.
Agenus has temporarily halted its Phase III trial plans but remains committed to seeking approval in the U.S. while also pursuing regulatory approval in Europe.
On August 20, Regeneron announced that the FDA rejected its BLA for Linvoseltamab, a BCMA/CD3 bispecific antibody for relapsed/refractory multiple myeloma (R/R MM) in patients who had undergone at least three prior treatments.
The rejection was due to issues identified at a third-party fill-finish manufacturer during a pre-approval inspection. These issues were related to another company’s product, not Linvoseltamab itself.
Regeneron stated that the FDA raised no concerns about safety, efficacy, or the ongoing validation clinical trials.
The third-party manufacturer has since addressed these issues, but a reinspection is required.
On August 9, Lykos Therapeutics announced that the FDA rejected its NDA for Midomafetamine (MDMA) as an adjunctive therapy for post-traumatic stress disorder (PTSD).
The FDA requested an additional Phase III clinical trial to further confirm MDMA’s safety and efficacy.
MDMA is a synthetic drug primarily composed of methylenedioxy-methamphetamine. If approved, it would become the first psychedelic-assisted therapy in the U.S.
Lykos is still pursuing FDA approval but has outsourced much of the regulatory work.
On September 19, the FDA rejected Vanda Pharmaceuticals’ NDA for its gastroparesis drug, Tradipitant, requiring additional clinical trials.
Vanda maintains that Tradipitant has demonstrated sufficient efficacy and a favorable benefit/risk profile.
The company requested an FDA advisory committee review, but this was denied. Patients currently on the drug have filed a citizen petition urging the FDA to reconsider.
Tradipitant is a neurokinin-1 (NK1) receptor antagonist originally developed by Eli Lilly and licensed to Vanda in 2012.
In November 2024, the FDA rejected the full approval application for Intercept Pharmaceuticals’ Ocaliva for the treatment of primary biliary cholangitis (PBC).
Ocaliva is a potent farnesoid X receptor (FXR) agonist conditionally approved by the FDA in May 2016, making it the first PBC treatment approved in 20 years.
Prior to the FDA’s rejection, expert advisory committee members had expressed opposition to full approval.
On November 27, Applied Therapeutics announced that the FDA issued a CRL for its NDA for Govorestat, rejecting approval due to deficiencies in the clinical application.
Govorestat is a central nervous system-penetrant aldose reductase inhibitor (ARI) developed to treat galactosemia.
However, in April 2023, a Phase III trial (ACTION-Galactosemia Kid) failed to meet its primary endpoint, raising concerns about the drug’s approval.
In March 2024, the FDA extended the review period by three months.
Applied Therapeutics stated that it plans to meet with the FDA to discuss resubmission or appeal options.
On December 17, the FDA rejected AstraZeneca’s application for full approval of Andexxa.
Andexxa is a reversal agent for Factor Xa inhibitors, conditionally approved by the FDA in 2018 for treating acute bleeding complications from apixaban and rivaroxaban.
The CRL cited a major safety concern: data showed that Andexxa treatment doubled the incidence of thrombotic-related deaths compared to standard therapy.
Despite this, AstraZeneca stated that Andexxa will remain on the U.S. market while the company works with the FDA to collect further safety and efficacy data.
On December 16, Johnson & Johnson received an FDA CRL for the subcutaneous (SC) version of Amivantamab for EGFR-mutant non-small cell lung cancer (NSCLC).
The CRL was related to observations made during a pre-approval inspection of the manufacturing facility and was not related to the formulation, efficacy, or safety data submitted in the application.
The intravenous version, RYBREVANT, remains unaffected.
In August 2024, the FDA had granted priority review to the SC formulation for NSCLC with EGFR exon 19 deletions or L858R substitutions.
On December 19, Zealand Pharma received an FDA CRL for its long-acting GLP-2 agonist Glepaglutide for short bowel syndrome (SBS).
The FDA concluded that existing clinical evidence was insufficient for approval and requested an additional clinical trial to provide more safety and efficacy data.
