Quality By Design Pilot Analysis of FDA Regulatory Guidance Web Data Usability for Innovators in Non-Hodgkin Lymphoma: Overcoming Challenges to CAR-T Development

Background: Non-Hodgkin lymphoma (NHL) remains a challenging hematological disease due to varied presentation and etiologies. Historically, cell/gene therapy guidance from the U.S. Food and Drug Administration (FDA) have partial utility in CAR-T development owing to the unique nature of cell-based gene modification but overlap with some key regulatory tenants of broader gene therapy. Inability to identify and apply appropriate guidance poses a challenge for next generation CAR-T immuno- and targeted therapy developers and start-ups, who are situated in a uniquely dynamic regulatory compliance landscape. Methods: A pragmatic Quality by Design (QbD) approach was taken to analyzing the usability and utility of publicly available web-based regulatory guidance via ethnographic observation of an asynchronous industry focus groups ( N = 14) of quality and translational research professionals seeking NHL regulatory guidance and/or regulatory approval information relevant to development of new CAR-T therapeutics (Fig. 1, top) over the course of approximately 10 minutes per observation. Further, a database of innovator and generic approval timelines was created for the 93 currently FDA-approved therapies based on ease of finding corresponding information. Results: Within the focus group, 7% (1/14) rated their team's confidence high in differences between recent specific FDA guidance for early phase CAR-T (Mar 2022) and prior gene and cell therapy guidance agnostic to gene therapy vs CAR-T and 79% (11/14) felt additional CAR-T manufacturing change guidance was needed. QbD stepwise analysis showed experienced users ( N = 9) clicked 10±3 pages before arriving at a desired FDA web-based guidance from the relevant framework (Fig. 1, bottom); remaining inexperienced users were unable to locate the guidance within the test period, primarily due to discrepancies in identifying appropriate classification and center (i.e. FDA CDER/CDER/CDRH) to locate the target guidance. Users had more difficulty locating information on biosimilars and generic drugs, owing in part to confusion between generic terminology on drug vs biologics/vaccines web portals. Conclusions: While current guidance has improved clarity of translational development, additional clarity and ease of access is needed for guidance on manufacturing change and implementation at non-traditional GMP sites for CAR-T to further streamline and scale these therapies. Further, generics developers, in particularly in biosim