FDA Eyes New Strategies to Boost Gene Therapy Development

FDA Eyes New Strategies to Boost Gene Therapy Development

June 06, 2023

The increasing number of applications for new gene therapies submitted to the FDA has put a strain on the agency's resources, underscoring the necessity for updated policies and operational procedures to fully harness the potential of these groundbreaking treatments. In response to this demand, the FDA recently granted accelerated approval for Biogen's Qalsody (tofersen), an amyotrophic lateral sclerosis (ALS) treatment.

Extensive testing over several years demonstrated the drug's ability to inhibit the production of a specific protein associated with ALS in approximately 500 out of 30,000 ALS patients with a particular gene mutation (1). Concurrently, bluebird bio is seeking FDA approval for their lovo-cel gene therapy, designed to treat a specific form of sickle cell disease (SCD). This therapy involves injecting the patient's bloodstream with genetic material to stimulate the production of anti-sickling hemoglobin (2).

CBER's Quest for Additional Resources and Innovative Strategies

In their quest to drive progress, officials at the Center for Biologics Evaluation and Research (CBER) are actively seeking additional resources and innovative approaches to expedite the delivery of groundbreaking therapies to patients. CBER Director Peter Marks, in various presentations over recent months, has expressed concerns regarding the sluggish pace and exorbitant costs associated with the development and testing of new gene therapies.

During a webinar sponsored by the Alliance for a Stronger FDA on April 4, 2023, Marks highlighted that the FDA has thus far granted approval to approximately a dozen of these state-of-the-art treatments (3). However, given the two-decade-long efforts invested in this domain, he emphasized the need for changes that would enable the approval of more than just a few new products each year. Marks stressed the urgency, stating that there is limited time for experimentation and emphasizing the necessity to "transform the environment" for accelerated endpoints and regulatory flexibility in the development of these therapies.

How the "Super" Office of Therapeutic Products is Transforming CBER

One notable recent development involves the establishment of a new "super" Office of Therapeutic Products (OTP) within CBER, which supersedes the smaller Office of Tissues and Advanced Therapies (OTAT). The OTP comprises six offices overseeing 14 divisions and 33 branches, strategically designed to accommodate a larger workforce capable of swiftly evaluating new research initiatives and guiding promising therapies through the regulatory pathway. In order to bolster the expertise dedicated to gene therapies, advanced manufacturing technologies, and associated programs, the latest iteration of the user fee program for drugs and biologics includes supplementary funding (4).

Marks has also put forth a proposal for CBER to adopt certain innovations implemented by the FDA's Oncology Center of Excellence (OCE), specifically highlighting the FDA's accelerated approval pathway for promising therapies. While recognizing that not all rapid approvals will necessarily translate into long-term benefits, he remains optimistic that this approach can expedite access to crucial treatments for many critically ill patients. Additionally, there are plans to initiate a new iteration of Operation Warp Speed for rare diseases, with the aim of supporting the development of gene therapies targeting conditions that affect small patient populations.

This initiative will commence by prioritizing a select few high-need programs that could benefit from increased collaboration with the FDA. The recent deliberation on the accelerated approval of Sarepta's novel treatment for Duchenne muscular dystrophy underscored the ongoing tension between approving a potentially significant therapy for children afflicted with a debilitating rare genetic disease based on preliminary evidence, or awaiting further clinical trials to validate its benefits. Notably, the FDA advisory committee approved Sarepta's treatment by a narrow 8-6 vote last month.

Furthermore, CBER is actively engaged in promoting international collaboration among regulatory authorities to facilitate the evaluation and regulation of new gene therapy applications, with the aim of broadening the scope of patients participating in testing and receiving these treatments on a global scale. This effort involves incorporating aspects of the FDA's Project Orbis program, originally established within the OCE, to establish a framework for regulatory agencies to collaborate in the concurrent assessment of biotech product submissions beyond the field of oncology.

Modernizing Production

However, the significant expense associated with developing gene therapies for small patient populations poses a major challenge for both CBER and manufacturers in bringing more innovative gene therapies to patients. While the FDA does not consider cost when evaluating the safety and efficacy of a medicine for market approval, Marks has expressed concerns about the lengthy timeline and costly methods involved in producing treatments for a mere 30 to 40 patients annually.

He acknowledges that this process differs greatly from manufacturing monoclonal antibodies for thousands of individuals. Notably, some gene therapies successfully navigate the clinical development phase only to be abandoned by sponsors due to prohibitively high production costs. As a result, these promising treatments become "commercially non-viable," making it unfeasible for small companies, nonprofit disease organizations, and foundations to sponsor clinical trials.

A key focus for Marks is to address the bottlenecks in gene therapy production and offer increased support to sponsors grappling with manufacturing challenges. To facilitate this, the expanded OTP now includes three offices dedicated to chemistry, manufacturing, and controls (CMC). These offices cover gene therapy, cell therapy and human tissue, as well as plasma protein therapeutics. The intention behind this expansion is to accommodate a larger workforce with specialized knowledge in biotech manufacturing, ensuring the provision of prompt and precise information in this domain.

CBER has also organized virtual "town hall" meetings for OTP personnel to provide clear guidance on the specific technical aspects necessary for investigational and market applications related to cell and gene therapies. During presentations held in September 2022 and April 2023, reviewers from the Office of Gene Therapy CMC within OTP addressed inquiries regarding guidance documents, assay qualification and validation, product characterization and release testing, as well as stability studies at various stages of product development and utilization (5). Additionally, another session slated for June 8, 2023, will concentrate on CMC considerations for cell and tissue products (6).

Marks envisions a time frame of two to three years to propel progress and bring about transformative changes in the manufacturing process and environment for gene therapies. The existing approaches pose ongoing challenges in terms of cost and pricing, exemplified by Biogen's new ALS drug priced at nearly $200,000 per year of treatment. Marks emphasizes that if the necessary measures are implemented successfully, the FDA will achieve its objectives in advancing gene therapies, thereby making a substantial impact on the bio-economy and expediting improvements in patients' lives.


1. FDA. FDA Approves Treatment of Amyotrophic Lateral Sclerosis Associated with a Mutation in the SOD1 Gene. Press Release. April 25, 2023.

2. bluebird bio. bluebird bio Submits Biologics License Application (BLA) to FDA for lovotibeglogene autotemcel (lovo-cel) for Patients with Sickle Cell Disease (SCD) 12 years and Older with a History of Vaso-Occlusive Events. Press Release. April 24, 2023.

3. Alliance for a Stronger FDA Webinar with Dr. Peter Marks, Director of the FDA Center for Biologics Evaluation and Research. April 4, 2023.

4. FDA. Establishment of the Office of Therapeutic Products. FDA.gov (accessed May 3, 2023).

5. FDA. OTP Town Hall: Gene Therapy Chemistry, Manufacturing, and Controls–April 2023. Town Hall. April 25, 2023.

6. FDA. OTP Town Hall: Gene Therapy Chemistry, Manufacturing, and Controls–June 2023. Town Hall. June 8, 2023.