Awakening from REMS: ASTCT 80/20 Ongoing Recommendations for Safe Use of Chimeric Antigen Receptor T Cells.

Abstract

The first 6 chimeric antigen receptor T cell (CAR-T) therapies approved in the United States have Risk Evaluation Mitigation Strategies (REMS) programs mandated by the US Food and Drug Administration (FDA). REMS programs aim to ensure the safe use of CAR-T therapy through timely recognition and management of unique severe risks and toxicities that cannot be mitigated by labeling alone, such as cytokine release syndrome and neurotoxicity syndromes. At the launch of each of the first 6 products, CAR-T REMS programs mandated product-specific education and training for clinical staff, patients, and caregivers; adequate access to medications to treat expected toxicities; and reporting of toxicities either to the product manufacturer or to the FDA. Each manufacturer ensures that treatment centers comply with the REMS program for their individual product in different ways, involving time-consuming and often redundant training, testing, and audits. The American Society for Transplantation and Cellular Therapy (ASTCT) 80/20 Subcommittee convened its second workshop in June 2023, inviting approximately 70 cellular therapy stakeholders to discuss whether safety and quality workflows embedded in existing resources within the cellular therapy field could replace FDA-mandated and company-monitored REMS programs. Attendees were clinicians at large academic medical centers experienced in cellular therapy, regulators, members of accrediting bodies and professional societies, and manufacturers of immune effector cell (IEC) therapies at multiple stages of development. Discussion centered on (1) educational requirements for safe delivery and management, (2) goals and mechanisms for data reporting and to whom, and (3) what entities should oversee these quality safeguards around CAR-T administration and management. Broad support was voiced for (1) conducting training programs administered by treatment centers and/or professional societies to replace manufacturers' product training; (2) reporting standardized data points into a central, accessible repository for tracking of safety trends and identification of new signals; and (3) enabling accrediting bodies to attest to programs' quality and ongoing compliance with field safety expectations, thereby replacing intensive manufacturer initial evaluation and ongoing REMS audits. The strong consensus of the second multidisciplinary ASTCT 80/20 Workshop was that such measures would allow elimination, or at least significant reduction and simplification, of current CAR-T REMS programs. Development of educational resources and funding for data reporting outside of a mandated REMS structure were identified as critical, particularly to support treatment centers new to cellular therapy, as were ongoing collaborations with FDA and manufacturers. These consensus recommendations were shared with the FDA at the Cell Therapy Liaison Meeting and in multiple professional society meetings and other public forums with regulators, manufacturers, and FDA representatives. Recently the FDA scaled back several of the features of existing CAR-T REMS programs redundant to standard clinical practice, specifically requirements related to manufacturer-created training, product-specific testing of trained staff, and data reporting to manufacturers. The seventh commercial CAR-T product (Aucatzyl, or obecabtagene autoleucel) was the first approved without a REMS program as of November 8, 2024. Continued streamlining of already widespread CAR-T safety standards for existing and future approved CAR-T cells and other unique cellular therapy products and ensuring their adoption at new and existing treatment centers will be required to maintain and increase access to the ever-growing number of effective adoptive cellular therapies.