Mechanism of action, potency and efficacy: considerations for cell therapies

Abstract

One of the most challenging aspects of developing advanced cell therapy products (CTPs) is defining the mechanism of action (MOA), potency and efficacy of the product. This perspective examines these concepts and presents helpful ways to think about them through the lens of metrology. A logical framework for thinking about MOA, potency and efficacy is presented that is consistent with the existing regulatory guidelines, but also accommodates what has been learned from the 27 US FDA-approved CTPs. Available information regarding MOA, potency and efficacy for the 27 FDA-approved CTPs is reviewed to provide background and perspective. Potency process and efficacy process charts are introduced to clarify and illustrate the relationships between six key concepts: MOA, potency, potency test, efficacy, efficacy endpoint and efficacy endpoint test. Careful consideration of the meaning of these terms makes it easier to discuss the challenges of correlating potency test results with clinical outcomes and to understand how the relationships between the concepts can be misunderstood during development and clinical trials. Examples of how a product can be "potent but not efficacious" or "not potent but efficacious" are presented. Two example applications of the framework compare how MOA is assessed in cell cultures, animal models and human clinical trials and reveals the challenge of establishing MOA in humans. Lastly, important considerations for the development of potency tests for a CTP are discussed. These perspectives can help product developers set appropriate expectations for understanding a product's MOA and potency, avoid unrealistic assumptions and improve communication among team members during the development of CTPs.

Keywords: Cell therapy product; Efficacy; Efficacy endpoint; Efficacy endpoint test; Mechanism of action; Potency; Potency test.

Fig. 1

Relationship between potency test results and efficacy endpoint for Kymriah clinical trial for the treatment of pediatric acute lymphoblastic leukemia after three months. The potency test was interferon-γ (IFN) production by test article upon stimulation with CD19 + cells. Data are adapted from FDA Advisory Committee Meeting materials [10]. Data are from 63 patients: 52 CR/CRi, 5 NR and 6 Unknown. CR = complete remission; CRi = complete remission with incomplete blood count recovery; NR = nonresponder; Unknown = unknown response

Fig. 2

Potency and efficacy process charts. Comparison of potency and efficacy definitions and processes for two example products demonstrates the parallelism between the two processes. a Definitions of the components of a potency and efficacy process chart. b Potency and efficacy process charts for treating leukemia with a CAR T-cell therapy (based on Kymriah). c Potency and efficacy process charts for a product for treating knee cartilage defects with chondrocytes on a collagen membrane (based on MACI). The figure graphically represents the relationships among the three inherent components of any analytical assessment: effect; attribute (measurands); and measurement; for both potency and efficacy. The examples are meant to illustrate concepts and are not intended as recommendations for potency tests or efficacy endpoint tests. The charts are not comprehensive and there may be other MOAs, attributes or tests that are not mentioned. CT computed tomography scan, ELISA enzyme linked immunosorbent assay, IL5 interleukin 5, KOOS knee injury and osteoarthritis outcome score, MHC major histocompatibility, MRI magnetic resonance imaging, PCR polymerase chain reaction. The cited sources were used to assemble the content for (b) Kymriah [, , –32] and (c) MACI [–37]