US Approved Gene Therapies and Summary Basis for Approvals

The FDA presentation by Dr Gopa Raychaudhuri, "Facilitating Development of Gene Therapies for Rare Diseases," summarized all Gene Therapies approved by the US FDA. There were 19 approved gene therapies: 6 stem cell therapies, 6 T cell therapies, and 7 directly administered therapies.  

Gene therapy therapies are reviewed and approved by FDA Center for Biologicals Evaluation and Research (CBER), especially the Office of Therapeutic Products (OTP) - Approved Cellular and Gene Therapy Products are listed here. 

For each approved gene therapy, FDA publishes the product approval and review information on their website by year. The clinical evidence of effectiveness is provided to the public for transparency. For those 19 approved gene therapies, "Summary Basis for Regulatory Action" documents were reviewed and some basic information was summarized in the table below. 

Sponsor	Product & Indication	Study Design	Sample Size	FDA approval date/Brand Drug Name
Pfizer	Adeno-associated virus vector-based gene therapy.   Adults with moderate to severe hemophilia B.	Phase 1/2a Study C0371005 (Safety)  - open-label, single-dose, single-arm, multi-center.   Phase 3 Study C0371002 (Efficacy and Safety), open label, single-dose, multi-national study .   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/beqvez	15 subjects     45 subjects	April 2024 Beqvez
Orchard Therapeutics	Stem cell-based gene therapy.   Children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile, metachromatic leukodystrophy.	Data from an adequate and well-controlled investigation comprised of two single arm, single-center, open-label studies, a European Union Expanded Access Program (EAP), and one ongoing long-term follow-up study and a natural history study. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy	Study OTL-200-201222 (n=18) and Study 205756 (n=10)	March 2024 Lenmeldy
Vertex	Stem cell-based gene therapy-genome editing using CRISPR/Cas9 and SPY101. Patients aged 12 years and older with transfusion-dependent β-thalassemia (TDT).	Multinational, single-arm, open-label, phase 1/2/3 study. https://www.fda.gov/vaccines-blood-biologics/casgevy	52 dosed, 35 evaluable.	Jan 2024 Casgevy
Vertex	Stem cell-based gene therapy -genome editing using CRISPR/Cas9/SPY101 technology. Sickle cell disease in patients aged 12 years or older with recurrent vaso-occlusive crises.	Multinational, single-arm, phase 1/2/3 study.     https://www.fda.gov/vaccines-blood-biologics/casgevy	44 treated, 31 evaluable.	Dec 2023 Casgevy
Bluebird Bio	LVV gene therapy. Sickle cell disease in patients aged12 years or older with a history of vaso-occlusive events.	Study Hgb 206, an ongoing Phase 1/2, open label, multicenter. https://www.fda.gov/vaccines-blood-biologics/lyfgenia	Safety: 54 subjects.   Efficacy: 32 subjects.	Dec 2023 Lyfgenia
BioMarin	Adeno-associated virus vector-based gene therapy.   Adults with severe hemophilia A.	Open-label, single-dose, single-arm, multinational phase 3 study.   https://www.fda.gov/vaccines-blood-biologics/roctavian	112 subjects dosed and constituted the rollover population evaluated.	June 2023 Roctavian
Sarepta	Adeno-associated virus vector-based gene therapy. Ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.	Open-label study 101. Randomized, double-blind, placebo-controlled study 102. Open label study 103.  https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/elevidys	Safety: 85 subjects. 73 subjects received intended dose and 12 received lower doses.	June 2023 Elevidys
Krystal Biotech	Vector-based gene therapy.   Wounds in patients 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.	First-in-human, single-center, open-label, randomized, intra-subject, placebo (vehicle) controlled phase 1/2 study (KB103-001). Multicenter, intra-subject randomized, placebo-controlled, double-blind open-label phase 3 study (B-VEC-03). https://www.fda.gov/vaccines-blood-biologics/vyjuvek	9 subjects.           Safety: 31 subjects.	May 2023 Vyjuvek
Ferring Pharmaceuticals A/S	Vector-based gene therapy. Adult patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.	Single-arm trial study (CS-003).   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/adstiladrin	107 subjects enrolled. 98 subjects evaluable. Efficacy: 55 subjects.	Dec 2022 Adstiladrin
CSL Behring	Adeno-associated virus vector-based gene therapy.   Adults with Hemophilia B (congenital Factor IX deficiency).	Open-label, single-dose, single-arm, multi-center phase 2b study. Open-label, single-dose, multi-center, multinational phase 3 study. https://www.fda.gov/vaccines-blood-biologics/vaccines/hemgenix	3 subjects.     54 subjects.	Nov 2022 Hemgenix
Bluebird bio	Stem cell-based gene therapy. Slowing the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy.	Open-label, multicenter, single-arm phase 2/3 study. Open-label, multicenter, single-arm phase 3 study.   https://www.fda.gov/vaccines-blood-biologics/skysona	Safety: 67 subjects. Efficacy: 61 subjects.	Sept 2022 Skysona
Bluebird Bio	LVV Gene Therapy Beta-thalassemia. B cell maturation antigen-directed genetically modified. Adult and pediatric patients with ß-thalassemia who require regular red blood cell (RBC) transfusions.	Two open-label, multicenter, single-arm phase 3 studies. https://www.fda.gov/vaccines-blood-biologics/zynteglo	18 in HGB-212 study and 23 in HGB 207 study.	Aug 2022 Zynteglo
Janssen Biotech	Autologous T cell immunotherapy. Adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy.	Single-arm, phase 1b-2 multicenter study.   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/carvykti	Efficacy: 97 subjects.	Feb 2022 Carvykti
Celgene Corporation	B cell maturation antigen-directed genetically modified autologous T cell immunotherapy. Adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody	Single-arm, multicenter phase 2 study.   https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel	Safety: 127 subjects. Efficacy: 100 subjects.	March 2021 Abecma
Juno Therapeutics	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.	Single-arm, multicenter phase 1 study.   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel	Safety: 268 subjects. Efficacy: 256 subjects.	Feb 2021 Breyanzi
Kite Pharma	CD19-directed genetically modified autologous T cell Immunotherapy.   Adult patients with relapsed or refractory Mantle Cell Lymphoma.	Single-arm, multicenter, phase 2 study.   https://public4.pagefreezer.com/browse/FDA/27-12-2021T03:59/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel	68 subjects treated. Efficacy: 60 subjects.	July 2020 Tecartus
AveXis	Adeno-associated virus vector-based gene therapy.  Pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 gene.	Open-label, single-arm, ascending-dose, phase 1 study. Open-label, single-arm, phase 3 study. https://public4.pagefreezer.com/browse/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/zolgensma	15  subjects.     44 subjects.	May 2019 Zolgensma
Spark Therapeutics	Adeno-associated virus serotype 2 vector gene therapy.  Confirmed biallelic RPE65 mutation-associated retinal dystrophy.	Open-label, dose-escalation, phase 1 study. Open-label, randomized, controlled, cross-over, phase 3 study. https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna	12 subjects.   29 subjects.	Dec 2017 Luxturna
Kite Pharma	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy	Single-arm, open-label, multicenter phase 1/2 study.   https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel	Safety: 108 subjects. Efficacy: 101 subjects.	Oct 2017 Yescarta
Novartis Pharmaceuticals	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with relapsed or refractory follicular lymphoma after two or more lines of therapy.	Multicenter, open-label, single-arm, trial.   https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel	63 subjects.	Aug 2017 Kymriah

The clinical evidence for the effectiveness of gene therapies often comes from multi-center, open-label, single-arm studies with relatively small sample sizes, as shown in the table above. In some cases, phases of clinical development are combined.

FDA Office of Scientific Investigations (OSI) Requests for Bioresearch Monitoring (BIMO) Data for NDA/BLA Submission

FDA has a Bioresearch Monitoring (BIMO) program and the BIMO program is managed by the Office of Scientific Investigations (OSI). 

BIMO program is a comprehensive, FDA-wide program of on-site inspections and data audits, designed to monitor all aspects of the conduct and reporting of FDA-regulated research. 

Objectives of the BIMO program includes: 

• Protect the rights, safety, and welfare of human research subjects
• Verify the accuracy, reliability, and integrity of clinical and non-clinical trial data submitted to FDA
• Assess compliance with FDA's regulations governing the conduct of clinical and non-clinical trials, including regulations for informed consent and ethical review

BIMO program has become a cornerstone of the FDA preapproval process for new medicines, medical devices, food and color additives, veterinary products and, tobacco products introduced to the U.S. consumer.

The BIMO program also takes part in pharmacovigilance activities for postmarketing drug products. These activities serve to detect, understand, and prevent drug-related problems.

The BIMO program is managed and executed differently at different review centers (namely CDER and CBER). CBER's BIMO program was described in a FDA presentation by Dr Triet Tran "The Center for Biological Evaluation and Research (CBER) Bioresearch Monitoring (BIMO) Program". CDER's BIMO program was described in a Youtube video by Dr Kelly Nolen "Center for Drug Evaluation and Research (CDER) Bioresearch Monitoring (BIMO) Program - A General Overview".

For NDA or BLA submissions to CDER, sponsors are often asked to provide site-specific information to support the FDA’s Bioresearch Monitoring (BIMO) program and aid in selecting sites for inspection. The FDA typically includes standard language about this (see below) in their communications, such as in letters to the sponsor or the minutes of pre-NDA or pre-BLA meetings.

OFFICE OF SCIENTIFIC INVESTIGATIONS (OSI) REQUESTS

The Office of Scientific Investigations (OSI) requests that the items described in the draft guidance for industry, Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions, and the associated conformance guide, Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications, be provided to facilitate development of clinical investigator and sponsor/monitor/CRO inspection assignments, and the background packages that are sent with those assignments to the FDA ORA
investigators who conduct those inspections. This information is requested for all major trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials). Please note that if the requested items are provided elsewhere in submission in the format described, the Applicant can describe location or provide a link to the requested information.

Please refer to the draft guidance for industry Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications.

Sponsor's statistical programming group will need to prepare the BIMO related data sets and data listings - all by sites. 

• A data set containing general study related information and comprehensive clinical investigator information
• Subject level data listing by site
• Site level dataset

Details about BIMO datasets and data listings can be found in the FDA CDER guidance titled Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications (see the table of contents below). It’s important to note that this guidance applies only to CDER and not to other FDA review divisions like CBER. Since the BIMO technical conformance guide is regularly updated, the statistical programming team must ensure they are following the most current version when preparing the BIMO package for NDA or BLA submissions.

There has been extensive discussion about using SAS programming to generate the BIMO package, including the creation of BIMO datasets and data listings:

• BIMO Package: Challenges and Perspectives While Keeping Up with the Upgrades in the BIMO Technical Conformance Guide and the BDRG Guidelines 
• BIMO SAS® Macros and Programming Tools 
• Development of standard BIMO process to create clinsite dataset 
• Preparing a Successful BIMO Data Package 
• Bioresearch Monitoring (BIMO) Data Reviewer’s Guide