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FDA works with industry on strategies for assuring high-quality regenerative medicines.
Amid mounting excitement over remarkable efficacy rates for new genetically modified cellular therapies, regulators and manufacturers alike face continuing challenges for ensuring consistent potency, purity, and identify of these complex therapies. More than 100 experimental chimeric antigen receptor T-cell (CAR-T) therapies are in development, generating optimism that regenerative medicine will transform treatment and lead to cures for many deadly diseases. Such advances, though, require further clarification of regulatory policies governing gene therapy production and quality assurance.
FDA is considering at least three CAR-T applications, and more are on the way. An FDA advisory committee voted unanimously to recommend approval of Novartis’ new CAR-T, despite concerns about the firm’s ability to process patient T-cells consistently and safely (1). Similar issues have been discussed related to applications for Kite Pharma’s therapy for aggressive non-Hodgkin lymphoma and Spark Therapeutics’ new gene therapy to treat a rare condition causing blindness, which are moving through the FDA approval process.
FDA will address these regulatory developments further in a comprehensive framework for oversight of regenerative medicine slated for publication in September 2017. This will be part of a comprehensive Innovation Initiative, Commissioner Scott Gottlieb announced in July in presenting FDA’s plan for implementing the 21st Century Cures Act (2). New guidance documents will be part of the framework, which covers therapeutic tissue engineering products, human cell and tissue products, and certain combination products intended to treat serious or life-threatening diseases or conditions. Genetically modified cellular therapies, such as those manipulating CAR-T cells, fall under the regenerative medicine advanced therapy (RMAT) umbrella.
FDA’s Center for Biologics Evaluation and Research (CBER) is implementing this program, including a RMAT designation process to identify experimental advanced therapies that warrant special attention and advice from FDA. Gottlieb noted in early July 2017 that manufacturers have filed nearly two dozen requests for RMAT designation, and that CBER’s Office of Tissues and Advanced Therapies (OTAT) had granted four. Similar to FDA support for breakthrough therapies, the RMAT designation offers early interactions with FDA staff and the potential for priority review and accelerated approval based on strong preliminary clinical evidence. CBER Director Peter Marks and other FDA officials applaud the RMAT program established in Cures for providing FDA with flexibility in evaluating these cutting-edge products, including the ability to accept a variety of endpoints for RMAT clinical trials.
The larger issue for regulators is to ensure consistency in critical quality attributes (CQAs) for identity and purity of these products, a task that has prompted FDA and a number of research organizations to collaborate on setting standards and methods for defining and characterizing these complex therapies and for conducting assays able to measure performance. A Forum on Regenerative Medicine established in 2016 by the National Academies for Science, Engineering, and Medicine (NASEM) is addressing these issues as part of its broader examination of the state of science and strategies for facilitating development of therapies able to generate, repair, or replace patients’ tissues. A June 2017 workshop on “Navigating the Manufacturing Process and Assuring the Quality of Regenerative Medicine Therapies” discussed challenges in evaluating the quality and purity of unique cell populations. The experts examined possible mechanisms and technologies for improving methods and capabilities for measuring CQAs and for setting standards to help advance development of these promising therapies (3).
The federal government’s National Institute of Standards and Technology (NIST) is working with academics and industry to develop measurements critical to characterization of advanced cellular and gene therapies (4). A provision in the Cures legislation directs FDA and NIST to collaborate with stakeholders in developing standards for regenerative medicine, and in 2016 NIST formed a public-private partnership with a group related to the Alliance for Regenerative Medicine (ARM) to advance such industry-wide standards.
FDA’s Oncologic Drug Advisory Committee meeting on July 11, 2017 to evaluate Novartis’ CAR-T therapy, tisagenlecleucel-T, addressed difficulties in dealing with variability in the potency and other quality measures related to gene therapy production. From the outset, FDA reviewers said that efficacy was not an issue due to overwhelming patient response to treatment, and that safety would involve long-term post-market assessment. But the experts sought assurance of security, accuracy, and reliability for Novartis’ complex system for removing blood T-cells from the patient, cryopreserving them for transport to a company processing facility, and shipping transduced T-cells back to the clinic for re-injection into the patient.
FDA’s staff memorandum on the product emphasized the importance of establishing a well-controlled manufacturing process that can consistently produce high-quality CAR-T cells that are safe, pure, and potent (5). FDA notes that the product has unique quality attributes that can directly impact final product safety and potency, and that several manufacturing failures occurred at Novartis facilities in the United States and Germany. Novartis scientists explained how each batch of patient tissue is handled in dedicated equipment, materials, and personnel in an enrichment process to obtain a highly pure T-cell population and to ensure that the right cells go to the right patient (6).
These issues were explored further at the July 2017 CMC strategy forum organized by CASSS on manufacturing quality and regulatory considerations for cell and gene therapies (7). The meeting attracted a record number of participants, reflecting heightened industry interest in discoveries that promise to revolutionize the treatment of serious health conditions. Participants explored strategies for analytical method development, assay validation, product characterization, specification setting, and for establishing relevant manufacturing controls for these highly perishable and biologically complex products.
Experts from biopharma companies and research organizations discussed the importance of advanced analytics in evaluating product consistency and purity and in avoiding process variations. They debated the relevance of quality standards set by the International Council for Harmonization (ICH) and how well quality-by-design concepts can help understand and manage change. There were many questions about dealing with variability in raw materials, evaluation of stability, and addressing unique supply chain issues.
Bryan Silvey, senior director for quality compliance at Kite Pharma, emphasized that personalized cell therapy production, utilizing a “one lot-one patient” manufacturing platform with a 15-day rapid manufacturing cycle and “a new world of cold chain” transport, must provide a high level of assurance that the patient receives back the correct cells as quickly as possible. Anne Plant, division chief for biosystems and biomaterials at NIST, observed that comparability assessment is key to determining that changes in a production process do not undermine quality and safety, but that such measurements are difficult to define.
Mohammad Heidaran, CMC reviewer in CBER’s OTAT, described manufacturing challenges for cellular therapies related to cell variability, lack of reference standards, small lot sizes, limited material for testing, and an often poor understanding of the product. Comparability protocols are important for managing change and can benefit from FDA input on the design and risk that a change poses for product quality. He advised manufacturers to “know your product,” including CQAs and critical process parameters, and to conduct a full risk assessment that links all these factors to product quality.
1. PharmTech, “Novartis CAR-T Cell Therapy CTL019 Recommended for FDA Approval,” pharmtech.com, July 12, 2017.
2. S. Gottlieb, “How FDA Plans to Help Consumers Capitalize on Advances in Science,” FDAVoice, FDA.gov, July 7, 2017.
3. NASEM, Navigating the Manufacturing Process and Assuring the Quality of Regenerative Medicine Therapies-A Workshop, June 26, 2017.
4. NIST, Regenerative Medicine Biomanufacturing, NIST.gov.
5. FDA, FDA Briefing Document, Oncologic Drugs Advisory Committee Meeting, BLA 125646.
6. Novartis, “Oncologic Drugs Advisory Committee Briefing Document, Tisagenlecleucel (CTL019),” July 12, 2017.
7. CASSS, CMC Forum Summer 2017: Scientific Program.
Vol. 41, No. 9
When referring to this article, please cite it as J. Wechsler, "Manufacturing Standards Key to Advancing Cellular and Gene Therapies," Pharmaceutical Technology 41 (9) 2017.