FDA’s Published CRLs Deliver Insight Into the Drug Approval Process

Dive into each of the oncology-related CRLs that were recently released by the FDA, as well as relevant subsequent FDA decisions.

On July 10, 2025, the FDA published 202 complete response letters (CRLs), many of which were tied to oncology-related drug and biologic product applications (BLAs) submitted within the past decade.1 This marked the first time that the FDA has made many of these letters available to the public.

Read on for a deeper dive into each of the oncology-related CRLs that were released, as well as the subsequent FDA decisions that show where each agent currently stands in its treatment paradigm.

Tivozanib Hydrochloride for Advanced RCC

On June 13, 2013, the FDA issued a CRL to the new drug application (NDA) seeking the approval of tivozanib hydrochloride capsules (Fotivda) for the treatment of patients with advanced renal cell carcinoma (RCC).2 Issues precluding approval included data from the phase 3 TIVO-1 trial (NCT01030783) showing a potential overall survival (OS) decrease with tivozanib vs sorafenib (Nexavar), which was also inconsistent with the progression-free survival benefit seen with tivozanib; and insufficient data to support product quality. The FDA suggested the drug developer perform an additional adequate, well-controlled, randomized clinical trial of tivozanib in this population.

On March 10, 2021, the FDA approved tivozanib for the treatment of adult patients with relapsed/refractory advanced RCC who had received at least 2 prior systemic therapies.3 This regulatory decision was backed by data from the phase 3 TIVO-3 trial (NCT02627963).

Melphalan for Injection for Hepatic-Dominant Metastatic Ocular Melanoma

On September 12, 2013, the FDA issued a CRL to the NDA seeking the approval of melphalan for injection (Melblez Kit) for the treatment of patients with hepatic-dominant metastatic ocular melanoma.4 Issues precluding approval included a lack of clinical data demonstrating substantial efficacy; a lack of sufficient information to characterize the pharmacokinetic profile of melphalan for injection at the proposed dose and route of administration; a lack of adequate safety data; missing information about the GEN2 filter cartridge; insufficient information about testing for filter particle size; a lack of catheter information; insufficient information about the extracorporeal circuit; a lack of information to determine the biocompatibility of the product; insufficient information about filter pressure; a lack of detailed colorant information; concerns regarding the drug substance manufacturing, processing, packing, or holding; a lack of data from an adequate human factors study to support the safety of the product in its proposed labeling; and manufacturing facility deficiencies.

Bortezomib Injection for Multiple Myeloma and MCL

On December 17, 2014, the FDA issued a CRL to the NDA seeking the approval of a bortezomib injectable (Boruzu) at a dose of 3.5 mg/vial referencing bortezomib (Velcade) for the treatment of patients with multiple myeloma or mantle cell lymphoma (MCL).5 Issues precluding approval included Drug Master File deficiencies regarding the identity of the drug substance. On May 4, 2016, the FDA issued another CRL to same NDA, citing issues including data discrepancies between different batches of Boruzu, missing information in the manufacturing flow diagram, concerns regarding potential discrepancies between the end-of-shelf-life physicochemical characteristics of the proposed biosimilar and reference bortezomib, and manufacturing facility deficiencies.

On March 10, 2020, the FDA issued a CRL to another NDA seeking the approval of a bortezomib injectable referencing bortezomib for the treatment of patients with multiple myeloma or MCL.6 Issues precluding approval included missing gross content test criteria in the drug product specification. Other issues were cited but were redacted in the version of the CRL released to the public.

On September 6, 2024, the FDA approved Boruzu at a dose of 3.5 mg/vial for the treatment of patients with multiple myeloma or MCL.7

Leuprolide Acetate for Palliative Advanced Prostate Cancer Management

On May 29, 2015, the FDA issued a CRL to the NDA seeking the approval of leuprolide acetate for injection (Lutrate Depot) for the palliative treatment of patients with advanced prostate cancer.8 Issues precluding approval included the product’s inability to achieve and maintain castrate testosterone levels in an acceptable percentage of patients, discrepancies between product batches, a lack of information about overfill, a lack of information regarding the chemical physical properties of the drug substance, and a lack of stability data for the drug substance.

On November 2, 2022, the FDA approved leuprolide acetate injection for the palliative treatment of patients with advanced prostate cancer.9

Gemcitabine Hydrochloride Injection for Patients With Cancer

On November 24, 2015, the FDA issued a CRL to the NDA seeking the approval of gemcitabine hydrochloride injection (Infugem).10 Issues precluding approval included manufacturing facility deficiencies. On May 23, 2017, the FDA issued a second CRL to the same NDA, again citing manufacturing facility deficiencies.

On July 16, 2018, the FDA approved this formulation of gemcitabine hydrochloride injection as monotherapy or in combination with other agents for the treatment of select patients with advanced ovarian cancer, metastatic breast cancer, non–small cell lung cancer (NSCLC), and pancreatic cancer.11

Romidepsin Injection for Lymphoma

Between June 1, 2016, and November 4, 2019, the FDA issued 3 CRLs to the NDA seeking the approval of romidepsin injection (Istodax) for patients with lymphoma.12 Issues precluding approval included product quality concerns and manufacturing facility deficiencies.

LA-EP2006 for Decreasing Infection Incidence in Nonmyeloid Malignancies

On June 24, 2016, the FDA issued a CRL to the BLA seeking the approval of LA-EP2006 (pegfilgrastim-bmez; Ziextenzo), a biosimilar referencing pegfilgrastim (Neulasta), to decrease infection risk in patients with nonmyeloid malignancies.13 Issues precluding approval included a lack of data showing pharmacokinetic similarity between LA-EP2006 and reference pegfilgrastim, a lack of media fill data, insufficient microbial challenge data, an inadequate method validation study for the dye ingress container closure integrity test method, and a lack of adequate data from the simulated air transportation study.

On November 5, 2019, the FDA approved LA-EP2006 for decreasing infection incidence exhibited by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer therapy that is associated with a clinically significant incidence of febrile neutropenia.14

CHS-1701 for Patients With Cancer Receiving Myelosuppressive Chemotherapy

On June 9, 2017, the FDA issued a CRL to the BLA seeking the approval of CHS-1701 (pegfilgrastim-cbqv; Udenyca), a biosimilar referencing pegfilgrastim (Neulasta), for the treatment of patients with cancer receiving myelosuppressive chemotherapy.15 Issues precluding approval included discrepancies in immunogenicity data that were not sufficient to demonstrate a lack of clinically meaningful differences between CHS-1701 and reference pegfilgrastim, a lack of anti–granulocyte cology–stimulating factor antibody titer and neutralizing antibody data, and inadequate neutralizing antibody assay validation reports.

On November 5, 2018, the FDA approved CHS-1701 for the treatment of patients with cancer receiving myelosuppressive chemotherapy.16

Pemetrexed Injection for Patients With Cancer

On September 26, 2017, the FDA issued a CRL to the NDA seeking the approval of pemetrexed injection at a dose of 25 mg/mL.17 Issues precluding approval included manufacturing facility deficiencies and microbiology concerns, which were redacted in the version of the CRL released to the public. On June 26, 2018, the FDA issued a second CRL to the same NDA, citing concerns with chemistry, manufacturing, controls, and microbiology.

On June 24, 2021, the FDA issued a CRL to another NDA seeking the approval of pemetrexed injection.18 Issues precluding approval included a lack of product quality data, as well as manufacturing facility deficiencies. On April 14, 2022, the FDA issued a second CRL to the same NDA, citing product quality deficiencies, such as a lack of adequate long-term stability data and a lack of an acceptable leachables study.

Fulvestrant Injection for Patients With Cancer

On October 26, 2017, the FDA issued a CRL to the NDA seeking the approval of fulvestrant (Faslodex) injection.19 Issues precluding approval included inadequate justification for the safety of the proposed level of the medium chain triglycerides excipient in the drug product; a lack of design requirements and/or specifications for the prefilled syringe; an inadequate review of device constituents; a lack of information about the administration needle; missing risk assessment data; missing information regarding the material composition and supplier.

Bortezomib Injection for Multiple Myeloma

On November 3, 2017, the FDA issued a CRL to the NDA seeking the approval of bortezomib injection at a dose of 2.5 mg/vial for the treatment of patients with multiple myeloma.20 Issues precluding approval included manufacturing facility deficiencies. On November 22, 2018, the FDA issued another CRL to the same NDA, citing issues with the test method for elemental impurities as part of the drug product specification.

CT-P10 for Advanced Follicular Lymphoma

On February 28, 2018, the FDA issued a CRL to the BLA seeking the approval of CT-P10 (Truxima; rituximab-abbs), a biosimilar referencing rituximab (Rituxan) for the treatment of patients with advanced follicular lymphoma.21 Issues precluding approval included manufacturing facility deficiencies; inadequate information and scientific justification to demonstrate an absence of clinically meaningful differences in safety, purity, and potency between CT-P10 and reference rituximab; and product quality validation issues.

On November 28, 2018, the FDA approved CT-P10 as monotherapy or in combination with chemotherapy for the treatment of adult patients with CD20-positive, B-cell non-Hodgkin lymphoma (NHL).22 Notably, CT-P10 was approved for all approved indications for reference rituximab, including relapsed/refractory, low-grade, or follicular lymphoma and untreated follicular lymphoma.

CT-P6 for HER2-Overexpressing Breast Cancer

On March 30, 2018, the FDA issued a CRL to the BLA seeking the approval of CT-P6 (Herzuma; trastuzumab-pkrb), a biosimilar referencing trastuzumab (Herceptin), for the treatment of patients with HER2-overexpressing breast cancer.23 Issues precluding approval included manufacturing facility deficiencies, insufficient data and information regarding the product’s manufacturing process and controls, and manufacturing qualities known to adversely affect drug potency.

On December 17, 2018, the FDA approved CT-P6 for the treatment of patients with HER2-overexpressing breast cancer.24

PF-05280014for HER2-Overexpressing Breast/Gastric/GEJ Cancers

On April 20, 2018, the FDA issued a CRL to the biologics license application (BLA) seeking the approval of the trastuzumab biosimilar PF-05280014 (trastuzumab-qyyp; Trazimera) for the treatment of patients with HER2-overexpressing breast cancer or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.25 Issues precluding approval included insufficient information and data regarding the suitability of the biosimilar’s Working Cell Bank for commercial production of the agent; manufacturing concerns; concerns regarding the maintenance of drug product quality during shipping and distribution; drug activity concerns; concerns about the drug’s shelf life criteria; concerns about the drug’s proposed storage conditions; missing media fill simulation data; conflicts between the maximum hold time of the biosimilar proposed in the BLA and that supported by relevant microbiology data; concerns regarding capping process parameters; missing vial washing parameters and washing validation summary data; missing bioburden action limits; missing data from the low endotoxin recovery study.

At the time the CRL was issued, Pfizer shared a statement noting its intentions to work with the FDA to address the contents of the letter, which were summarized at the time as a need for additional technical information.26 On March 11, 2019, the FDA approved PF-05280014 for the treatment of patients with HER2-overexpressing breast cancer or metastatic gastric or GEJ adenocarcinoma.27

Theragrastim for Patients With Cancer Undergoing Chemotherapy

Between May 10, 2018, and August 2, 2021, the FDA issued 4 CRLs to the BLA seeking the approval of theragrastim (Releuko; filgrastim-ayow), a biosimilar referencing filgrastim (Neupogen).28 Issues precluding approval included manufacturing facility deficiencies, product quality concerns, data audit concerns, and shipping validation deficiencies.

On March 1, 2022, the FDA approved theragrastim for the treatment of patients with cancer receiving chemotherapy who are at risk for developing febrile neutropenia.29

ABP 980 for Breast, Gastric, and GEJ Cancers

On May 25, 2018, the FDA issued a CRL to the BLA seeking the approval of ABP 980 (Kanjinti; trastuzumab-anns), a biosimilar referencing trastuzumab, for the treatment of patients with HER2-overexpressing breast, gastric, or GEJ carcinoma.30 Issues precluding approval included manufacturing facility deficiencies.

On June 13, 2019, the FDA approved ABP 980 for the treatment of patients with HER2-overexpressing breast, gastric, and GEJ cancers.31

Cyclophosphamide Injection for Patients With Cancer

Between July 24, 2018, and April 18, 2022, the FDA issued 6 CRLs to an NDA seeking the approval of cyclophosphamide injection at doses of 500 mg/mL, 1g/2mL, and 2g/4mL.32 Issues precluding approval mainly included manufacturing facility deficiencies.

Sacituzumab Govitecan for mTNBC

On January 17, 2019, the FDA issued a CRL to the BLA seeking the approval of sacituzumab govitecan-hziy (Trodelvy) powder for intravenous (IV) infusion at a dose of 180 mg for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) who have received at least 2 prior therapies.33 Issues precluding approval included product quality concerns, many of which were redacted in the version of the CRL released to the public.

On April 22, 2020, the FDA granted accelerated approval to sacituzumab govitecan for the treatment of adult patients with mTNBC who have received 2 or more prior therapies for metastatic disease.34

Cyclophosphamide Injection for Patients With Cancer

On July 18, 2019, the FDA issued a CRL to the NDA seeking the approval of cyclophosphamide injection at doses of 500 mg/2.5 mL and 1 g/5 mL.35 Issues precluding approval included objectionable manufacturing facility conditions, as well as content and format issues in the proposed prescribing information.

Additionally, between April 26, 2018, and October 1, 2019, the FDA issued 3 CRLs to another NDA seeking the approval of cyclophosphamide injection at doses of 500 mg/2.5 mL and 1 g/5 mL.36 Issues precluding approval included product quality concerns and manufacturing facility deficiencies.

On July 5, 2023, the FDA approved 200-mg/mL vials of cyclophosphamide injection for use in combination regimens in the treatment of patients with various types of cancers, including multiple myeloma, malignant lymphoma, and select types of leukemia.37

TX01 for Reducing Infection Risk on Nonmyeloid Malignancies

Between September 24, 2019, and February 14, 2023, the FDA issued 3 CRLs to the BLA seeking the approval of TX01 (Nypozi), a biosimilar referencing filgrastim.38 Issues precluding approval including manufacturing facility deficiencies, product quality data analysis and management concerns, concerns about the analytical assays used to assess free thiol content, and inadequate scientific justification for the relevance of animal data included in the application.

On July 1, 2024, the FDA approved TX01 to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs that are associated with a significant incidence of severe neutropenia and fever.39

Sodium Thiosulfate for Pediatric Cisplatin-Related Ototoxicity Prevention

On August 10, 2020, the FDA issued a CRL to the NDA seeking the approval of sodium thiosulfate injection (Pedmark) for the prevention of cisplatin-related ototoxicity in pediatric patients at least 1 month of age with localized, nonmetastatic tumors.40 Issues precluding approval included product quality deficiencies and manufacturing facility deficiencies. On August 26, 2021, the FDA issued a second CRL to the same NDA, citing manufacturing facility deficiencies and a lack of data regarding the product’s safety profile.

On September 20, 2022, the FDA approved sodium thiosulfate to reduce the risk of cisplatin-associated ototoxicity in pediatric patients at least 1 month of age with localized, nonmetastatic tumors.41

Carmustine Injection for Brain Tumors, Multiple Myeloma, and Lymphoma

On April 30, 2021, the FDA issued a CRL to the NDA seeking the approval of carmustine (BiCNU) injection for the treatment of patients with brain tumors, multiple myeloma, Hodgkin lymphoma, and NHL.42 Issues precluding approval included product quality factors that were redacted in the version of the CRL released to the public.

On May 16, 2022, the FDA approved carmustine injection as monotherapy or in combination with other approved chemotherapeutic agents for the treatment of patients with brain tumors (including glioblastoma, brain stem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors), multiple myeloma, relapsed/refractory Hodgkin lymphoma, and relapsed/refractory NHL.43

Treosulfan for allo-HSCT Preparation in AML and MDS

On July 30, 2021, the FDA issued a CRL to the NDA seeking the approval of treosulfan (Grafapex) as a preparative regimen for allogeneic hematopoietic stem cell transplant (allo-HSCT) for adult and pediatric patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).44 Issues precluding approval included insufficient marrow and complete blood cell results from the event-free survival (EFS) analysis of the registrational phase 3 Study MC-FLudT-14/L Trial II (NCT00822393). Notably, EFS served as the trial’s primary end point. Additionally, OS data were deemed insufficient as the sole basis for approval because the study’s statistical design positioned OS as an exploratory end point.

On January 24, 2025, the FDA approved treosulfan plus fludarabine as a preparative regimen for allo-HSCT in adult and pediatric patients at least 1 year of age with MDS or AML.45

BAT1706 for mCRC, NSCLC, and mRCC

On November 19, 2021, The FDA issued a CRL to the BLA seeking the approval of the bevacizumab (Avastin) biosimilar BAT1706 (bevacizumab-tnjn; Avzivi).46 Issues precluding approval included insufficient pharmacokinetics data to quantitate concentrations of the drug in normal human serum and support a demonstration of biosimilarity between BAT1706 and bevacizumab. Issues regarding microbiology and product quality were also cited but were redacted in the version of the CRL released to the public.

On December 7, 2023, the FDA approved BAT1706 for the treatment of patients with first- or second-line metastatic colorectal cancer (mCRC) in combination with IV fluorouracil-based chemotherapy; mCRC in combination with fluoropyrimidine-irinotecan– or fluoropyrimidine-oxaliplatin–based chemotherapy following progression on a first-line bevacizumab product–containing regimen; first-line unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC in combination with carboplatin and paclitaxel; recurrent glioblastoma; metastatic RCC in combination with interferon alfa; persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel plus cisplatin, or paclitaxel plus topotecan; platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan following no more than 2 prior chemotherapy regimens.47

Toripalimab for NPC

On April 29, 2022, the FDA issued a CRL to the BLA seeking the approval of toripalimab-tpzi (Loqtorzi) plus gemcitabine and cisplatin for the treatment of patients with nasopharyngeal carcinoma (NPC).48 Issues precluding approval included manufacturing control strategy deficiencies.

On October 27, 2023, the FDA approved first-line toripalimab plus gemcitabine and cisplatin for the treatment of adult patients with metastatic or recurrent locally advanced NPC.49

Denileukin Diftitox for Relapsed/Refractory CTCL

On July 28, 2023, the FDA issued a CRL to the BLA seeking the approval of Denileukin diftitox-cxdl (Lymphir) for the treatment of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL).50 Issues precluding approval included product quality factors that were redacted in the version of the CRL released to the public.

On August 8, 2024, the FDA approved denileukin diftitox for the treatment of patients with relapsed/refractory CTCL who have received 1 or more prior systemic therapies.51

Cosibelimab for Metastatic or Locally Advanced CSCC

On December 15, 2023, the FDA issued a CRL to the BLA seeking the approval of cosibelimab-ipdl (Unloxcyt) for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or radiation.52 Issues precluding approval included manufacturing facility deficiencies leading to concerns regarding the reliability of data generated at the manufacturing facility.

On December 13, 2024, the FDA approved cosibelimab for the treatment of adult patients with metastatic or locally advanced CSCC who are not eligible for curative surgery or radiation.53

Zolbetuximab in CLDN18.2+ Gastric/GEJ Cancer

On January 4, 2024, the FDA issued a CRL to the BLA seeking the approval of zolbetuximab-clzb (Vyloy) for the treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors are Claudin 18.2 (CLDN18.2) positive.54 Issues precluding approval chiefly included manufacturing facility deficiencies.

On October 18, 2024, the FDA approved zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma with CLDN18.2-positive disease, as determined by an FDA-approved test.55

Penpulimab in Metastatic Non-Keratinizing NPC

On January 19, 2024, the FDA issued a CRL to the BLA seeking the approval of penpulimab-kcqx for the treatment of patients with metastatic non-keratinizing NPC who have disease progression on or after platinum-based chemotherapy and 1 or more prior lines of therapy.56 Issues precluding approval included a lack of data showing a meaningful advantage with penpulimab vs currently available therapy for this patient population; the unavailability of an adequate, well-controlled, and stable production cell bank for penpulimab manufacturing; and additional quality control concerns.

On April 24, 2025, the FDA approved penpulimab plus cisplatin or carboplatin and gemcitabine in the first-line setting for the treatment of adult patients with recurrent or metastatic non-keratinizing NPC, as well as penpulimab monotherapy for the treatment of adult patients with metastatic non-keratinizing NPC who experienced disease progression on or after platinum-based chemotherapy and 1 or more prior lines of therapy.57

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  36. FDA. Complete Response Letter for NDA 210735. AuroMedics Pharma LLC. Accessed July 16, 2025. https://open.fda.gov/apis/other/approved_CRLs/
  37. Nevakar Injectables announces FDA approval of cyclophosphamide RTD solution. News release. Nevakar Injectables. July 3, 2023. Accessed July 16, 2025. https://nevakarinjectables.com/news/nevakar-injectables-announces-fda-approval-of-cyclophosphamide-rtd-solution/
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  39. Tanvex received BLA approval from FDA. News release. July 1, 2024. Accessed July 16, 2025. https://www.tanvex.com/PDF/News/Tanvex%20received%20BLA%20approval%20from%20FDA.pdf
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  41. FDA approves sodium thiosulfate to reduce the risk of ototoxicity associated with cisplatin in pediatric patients with localized, nonmetastatic solid tumors. News release. FDA. September 20, 2022. Accessed July 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sodium-thiosulfate-reduce-risk-ototoxicity-associated-cisplatin-pediatric-patients
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  45. Medexus announces FDA approval of Grafapex (treosulfan) for injection and provides business update. News release. Medexus Pharmaceuticals. January 22, 2025. Accessed July 16, 2025. https://www.medexus.com/en_US/news-media/press-releases/detail/176/medexus-announces-fda-approval-of-grafapex-treosulfan-for
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  47. FDA approves Bio-Thera Solutions’ Avzivi (bevacizumab-tnjn), a biosimilar referencing Avastin. News release. Bio-Thera Solutions, Ltd. December 8, 2023. Accessed July 16, 2025. https://bio-thera.com/plus/view.php?aid=919
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  49. Coherus and Junshi Biosciences announce FDA approval of Loqtorzi (toripalimab-tpzi) in all lines of treatment for recurrent or metastatic Nasopharyngeal carcinoma (NPC). News release. Coherus BioSciences and Shanghai Junshi Biosciences. October 27, 2023. Accessed October 27, 2023. https://investors.coherus.com/news-releases/news-release-details/coherus-and-junshi-biosciences-announce-fda-approval-loqtorzitm#:~:text=(Junshi%20Biosciences%2C%20HKEX%3A%201877,and%20as%20monotherapy%20for%20the
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  51. Citius Pharmaceuticals receives FDA approval for Lymphir (denileukin diftitox-cxdl) immunotherapy for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals. August 8, 2024. Accessed July 16, 2025. https://citiuspharma.com/investors/news-media/news/release-details/2024/Citius-Pharmaceuticals-Receives-FDA-Approval-for-LYMPHIR-denileukin-diftitox-cxdl-Immunotherapy-for-the-Treatment-of-Adults-with-Relapsed-or-Refractory-Cutaneous-T-Cell-Lymphoma/default.aspx
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