New FDA Pilot Program Will Provide Hands-On Regulatory Guidance for Cell and Gene Therapy Trials in Rare Disease

The Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program, an FDA initiative newly announced on September 29, 2023, includes provisions that may help smooth and speed up the path to approval for several clinical trials evaluating investigational cell therapies and/or gene therapies for rare disease indications.¹

The program, which will initially allow a total of 6 selected sponsors of clinical trials to participate, will provide sponsors with the opportunity for frequent advice and regular communication as needed with regard to clinical trial design and other development issues particular to the investigational product being evaluated. The program will enroll up to 3 sponsors each from 2 groups of potential applicants that have an eligible product being evaluated in a clinical trial via an active investigational new drug application. The first group includes sponsors whose relevant investigational product is a cell therapy or gene therapy product regulated by the Center for Biologics Evaluation and Research (CBER) that is directed at an unmet medical need in a rare disease or other serious condition from which death or significant disability in the first decade of life is probable. The second group includes sponsors whose relevant investigational product is regulated by the Center for Drug Evaluation and Research (CDER) that is directed at a rare neurodegenerative condition, with rare genetic metabolic diseases included.

“We hope the insight gained from this pilot will provide information on how best to facilitate more efficient development of potentially life-saving therapies with rare disease indications and help sponsors generate high-quality, compelling data to support a future marketing application,” Peter Marks, MD, PhD, the director of CBER, said in a statement.¹ “These are complex products and we recognize the importance of sponsor communication with the FDA to facilitate development of products for patients with unmet medical needs.”

Sponsors who hope to participate will be able to apply from January 2 to March 1, 2024. The criteria for selection will be applicants’ demonstrated ability to progress their program to a biologics license application or other marketing application. Once the participating sponsors reach an agreed upon significant regulatory milestone, the sponsor’s role in the program will be finished. The FDA listed initiation of a pivotal stage in the trial or the regulatory stage prior to marketing application submission as examples of such milestones. After the completion of the program for all participating sponsors, a second run of the pilot program may be initiated based on a review of the initial run and feedback from the sponsors.

"We look forward to increased engagement with sponsors developing these important products for the rare disease community," Patrizia Cavazzoni, MD, the director of CDER, added to the statement.¹ "We share the goal of delivering potentially life-saving products to patients, and are committed to helping sponsors achieve regulatory milestones, while ensuring the safety, effectiveness, and quality of these products."

Notably, several sponsors seeking regulatory approval of cell therapy products from the FDA have encountered significant difficulties recently. Just last week, an FDA Cellular, Tissue, and Gene Therapies Advisory Committee voted against BrainStormCell Therapeutics’ debamestrocel (NurOwn), an investigational autologous mesenchymal stem cell neurotrophic factor–secreting cell therapy product intended to treat amyotrophic lateral sclerosis.² During the meeting, the FDA pointed out that BrainStorm’s main argument in favor approval was based on posthoc analyses, which the agency does not consider sufficient evidence to support a biologics license application (BLA). The meeting concluded with a discussion of potential design decisions for future clinical trials evaluating the therapy that could more effectively demonstrate efficacy.

Also in September, Mesoblast announced plans for a third attempt to seek approval for its mesenchymal stromal cell therapy remestemcel-L for the treatment of pediatric and adult steroid-refractory acute graft versus host disease.³ Mesoblast had just participated in a Type A meeting with the FDA after receiving a complete response letter (CRL) from the agency regarding a BLA for remestemcel-L in August.⁴ This marked the second CRL Mesoblast had received for the therapy after originally submitting a BLA in 2020.⁵

REFERENCES
1. FDA launches pilot program to help further accelerate development of rare disease therapies. News release. FDA. September 29, 2023. Accessed October 2, 2023. https://www.fda.gov/news-events/press-announcements/fda-launches-pilot-program-help-further-accelerate-development-rare-disease-therapies
2. 74th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. September 27, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-september-27-2023-meeting-announcement
3. Key outcomes from FDA Type A meeting and Mesoblast next steps to achieve RYONCIL approval. News release. Mesoblast. September 21, 2023. Accessed October 2, 2023.https://www.globenewswire.com/news-release/2023/09/21/2746995/0/en/Key-Outcomes-From-FDA-Type-A-Meeting-and-Mesoblast-Next-Steps-to-Achieve-RYONCIL-Approval.html
4. Mesoblast receives complete response from U.S. Food and DrugAdministration for biologics license application for steroidrefractory acute graft versus host disease in children. News release. Mesoblast Limited. August 4, 2023. Accessed October 2, 2023.https://investorsmedia.mesoblast.com/static-files/422cd6da-a0b9-49cf-a177-7fd106f111f2
5. Mesoblast receives complete response letter from the FDA for biologics license application for steroid-refractory acute graft versus host disease in children. News release. Mesoblast. October 1, 2020. Accessed October 2, 2023. https://www.asx.com.au/asxpdf/20201002/pdf/44n8xx22956c1c.pdf