What level of regulatory oversight is needed for bioanalytical flow cytometry in support of drug development, specifically cell and gene therapies?
Drug development is dependent upon robust and reproducible bioanalytical results. In 2017 the first FDA approved, commercially available cellular therapy in the United States, Novartis’ Chimeric antigen receptor T cell therapy (CAR-T) coined Kymriah, ignited a debate around the type of regulatory requirements necessary for flow cytometric support of gene and cell therapies. That is not to say that small molecules, large molecules, ADCs, and everything in between have not utilized flow cytometry at some point along the development pathway, however, the difference for gene and cell therapies is that flow cytometry is used for PD/biomarker analysis in the absence of PK analysis. Additionally, flow cytometry has historically been a laboratory developed test run by CLIA labs supporting physicians making diagnostic conclusions. As GLP labs adopt imaging and flow cytometry platforms, confusion around the need for CLIA versus GLP support of drug development and clinical trials for cell and gene therapies, poses issues for our clinical and pharmaceutical partners.
The primary focus of GLP bioanalytical laboratories is support of drug development where a CLIA lab’s primary focus is providing physician driven test results to aid diagnostic conclusions. While many CLIA labs are able to provide services to support drug development, it is not the primary focus of CLIA regulations. The lack of clarity around the purpose of the applicable guidelines has created a lot of mystery as to what type of lab is needed and which regulatory guidelines are required for gene and cell therapy trials. The good news is the approved version of Clinical and Laboratory Standards Institute (CLSI) Guideline H62: The Validation of Assays Performed by Flow Cytometry will be available in 2020. This guideline will harmonize cytometry parameters needed and acceptance criteria for GLP validation in support of drug development and clinical studies. The guidance describes GLP validation of the flow cytometer instrument, development of the panel for quantitation of biomarkers, limits of detection for subpopulations, and validation of a flow method through accuracy and precision similar to other ligand binding assays which support of drug development.
The take away is that for the majority of cytometric testing during drug development and clinical trials, the PD/biomarker should be tested in a GLP laboratory unless or until the marker is intended to be a true companion diagnostic test or In Vitro Diagnostic (IVD) cleared test. Then the expectation shifts from drug development to physicians who will order the test and be reimbursed for it, which requires testing by a CLIA laboratory.
At KCAS we have over 90 years of collective cytometry experience, in both CLIA and GLP environments. In addition to our off-the-shelf qualified flow panels we are able to design de novo panels while using in vitro tools to cut down on development costs. We have solutions to storage and shipment challenges, and find cost effective ways to batch samples. We at KCAS have adopted the guidelines, while still in draft format, and we proudly offer GLP validation of flow cytometry methods in support of drug development, specifically custom panels for cell and gene therapies. Start a conversation with our business development team today and let us help you find the “right fit” for your flow cytometric needs!