Identifying and Managing Sources of Variability in Cell Therapy Manufacturing and Clinical Trials

• Published in: Regenerative engineering and translational medicine Vol. 5; no. 4; pp. 354 - 361
• Main Authors: Silverman, Lara Ionescu, Flanagan, Flagg, Rodriguez-Granrose, Daniel, Simpson, Katie, Saxon, Lindsey Hart, Foley, Kevin T.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2019; Springer Nature B.V
• Subjects: Biomaterials; Biomedical Engineering and Bioengineering; Chemistry and Materials Science; Clinical trials; Commercialization; Forum on Regenerative Medicine; Manufacturing; Materials Science; Regenerative Medicine/Tissue Engineering; Regulatory approval; Therapy; Variability; Clinical trials; Cell therapy; Manufacturing; Regenerative medicine
• ISSN: 2364-4133; 2364-4141
• DOI: 10.1007/s40883-019-00129-y

Identifying and managing cell therapy variability can be a significant challenge for a company seeking to commercialize a new product. Failure to address this issue can lead to negative consequences such as delayed approval due to unsuccessful clinical investigations, or failed product lots that do not meet release criteria. Allogeneic cell therapies can be particularly prone to variability challenges due to the use of variable input material. In order to support the manufacturers of cell therapies, the FDA has identified two primary regulatory pathways (351 vs 361) that reflect the relative risk of the product. In this review, we will discuss criteria that separate the two potential regulatory pathways for cell therapy products in the USA. Also, we will discuss what aspects of manufacturing and clinical trial execution might introduce undesired variability that can derail the path towards licensure and commercialization, along with tools to minimize these potential sources of variability. ClinicalTrials.gov Identifier: NCT03347708 and NCT03955315 Lay Summary Therapies that utilize live cells as the active ingredient, known as cell therapies, are a promising approach to treating many diseases that cannot be addressed with traditional medicines. However, with this great potential comes specific challenges associated with cell therapy, including identifying the appropriate regulatory approval pathway, manufacturing it in a reproducible way, and successfully executing clinical trials. In this review, we describe potential sources of variability that can negatively impact the translation of a cell therapy, and ways to minimize those risks.