FDA Expands Oversight of Cell and Gene Therapies

FDA’s Center for Biologics Evaluation and Research (CBER) is updating how it manages a growing volume of cell and gene therapy (CGT) development programs, seeking added resources and revisions in its oversight of these cutting-edge therapies. Most visible in the elevation of CBER’s Office of Tissues and Advanced Therapies (OTAT) into a new “super” Office of Therapeutic Products (OTP). The change aims to improve functional alignment, increase review capabilities, and add expertise on new CGTs by establishing multiple branches and divisions in the expanded regulatory unit, as announced in the Federal Register on Sept. 28.¹

Stated goals are to help CBER address the “substantial growth in innovative, novel products” that present new “scientific, medical, and regulatory challenges that require changes to its structure,” including strategies to advance the Regenerative Medicine Advanced Therapy (RMAT) program. The added resources are needed to oversee more than 2,000 development programs involving CGTs, many involving innovative testing and manufacturing processes. This soaring workload has overtaxed CBER staffers, resulting in serious difficulties in retaining and hiring capable scientists.

The structural changes at CBER reflect agreed-on plans to hire new staffers with funding from recently reauthorized user fee programs. The PDUFA VII commitment letter calls for an additional 132 new hires for CBER in this coming year and another 48 employees the following year, mostto support CGT reviews at OTP. The reorganization plan calls for OTP to have seven offices—for therapeutic products, clinical evaluation, review management, pharmacology/toxicology, and two for chemistry, manufacturing, and controls (CMC)—for gene therapy, cellular therapy, and human tissues. There will be 14 divisions and 32 branches within those offices, providing attractive supervisory opportunities for new and experienced staffers.

These changes come in the wake of FDA approval of two new gene therapies that have drawn wide attention for both their therapeutic potential and for million-dollar price tags. Bluebird Bio’s Zynteglo was approved by FDA in August for patients with beta thalassemia, an inherited blood disorder causing serious anemia. That was followed a few weeks later with approval of Bluebird’s Skysona to treat a rare neurological disorder afflicting young boys. Zynteglo carries a $2.8 million price tag, Skysona’s list price is $4 million, but both therapies are expected to target less than 1,500 patients, limiting the overall cost impact for the US healthcare system. A greater spending effect would come from FDA approval of a new treatment for sickle cell disease from Vertex Pharmaceuticals and CRISPR Therapeutics, which plan to begin a rolling review by FDA in the coming months. The important potential benefits of these treatments, along with concerns about their impact on healthcare spending and access, speaks to the need for a highly capable and sufficiently resourced FDA oversight program.

CMC controls key

These developments also highlight the importance of sound testing and production methods for therapies made from living organisms, which are inherently variable and difficult to control and measure to assure product safety, identify, quality, purity, and strength. The surge in applications from a broad range of firms, moreover, has made it difficult for CBER staffers to schedule formal meetings with each sponsor seeking advice on how best to perform manufacturing and testing processes. And publishing new guidance on these changing and emerging issues also takes time and resources.

In response, FDA looks to engage a broad range of sponsors on topics related to product development through a series of virtual town hall meetings. The first was held Sept. 29 and addressed how manufacturers should describe and inform FDA about CMC in applications for gene therapies.² Wilson Bryan, OTAT (now OTP) director, opened the session by describing plans for establishing OTP as a super office to increase review capabilities and enhance expertise on CGTs and set the stage for OTP branch chiefs to field a broad range of queries, ranging from basic CMC policies for various stages of development, to the scope of potency assays and impact of delivery devices on dose potency and quality.

Main topics were comparability testing, assays for product characterization, and process controls. OTP staffers emphasized the importance of determining process requirements early in development to avoid late changes and analytical method variability that could raise uncertainties likely to delay clinical trials. Products with complex mechanisms of action, they advised, stand to benefit from early product characterization and potency assay development. And developers of CGTs should use multiple production lots during a clinical study to ensure product consistency and quality, even for treatments for very small patient populations.

Manufacturers raised questions about differing CMC issues between early Phase I and late-stage clinical trials and voiced concerns about product characterization related to autologous cell-based gene therapies. A main theme from FDA was the importance of sponsors establishing a well-controlled manufacturing process and qualified analytical testing well before administering any new gene product. While CBER plans to issue guidance on manufacturing changes and comparability for CGT products, the information provided at this session provides unofficial guidance for implementing changes in product manufacturing and the scope of comparability assessments and development studies expected to support such changes.

References

1. https://www.govinfo.gov/content/pkg/FR-2022-09-28/pdf/2022-20997.pdf
2. https://www.fda.gov/news-events/otat-town-hall-gene-therapy-chemistry-manufacturing-and-controls-09292022