TY - JOUR T1 - Validation of biomarkers to predict response to immunotherapy in cancer: Volume II — clinical validation and regulatory considerations JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-016-0179-0 VL - 4 IS - 1 SP - 77 AU - Kevin K. Dobbin AU - Alessandra Cesano AU - John Alvarez AU - Rachael Hawtin AU - Sylvia Janetzki AU - Ilan Kirsch AU - Giuseppe V. Masucci AU - Paul B. Robbins AU - Senthamil R. Selvan AU - Howard Z. Streicher AU - Jenny Zhang AU - Lisa H. Butterfield AU - Magdalena Thurin Y1 - 2016/12/01 UR - http://jitc.bmj.com/content/4/1/77.abstract N2 - There is growing recognition that immunotherapy is likely to significantly improve health outcomes for cancer patients in the coming years. Currently, while a subset of patients experience substantial clinical benefit in response to different immunotherapeutic approaches, the majority of patients do not but are still exposed to the significant drug toxicities. Therefore, a growing need for the development and clinical use of predictive biomarkers exists in the field of cancer immunotherapy. Predictive cancer biomarkers can be used to identify the patients who are or who are not likely to derive benefit from specific therapeutic approaches. In order to be applicable in a clinical setting, predictive biomarkers must be carefully shepherded through a step-wise, highly regulated developmental process. Volume I of this two-volume document focused on the pre-analytical and analytical phases of the biomarker development process, by providing background, examples and “good practice” recommendations. In the current Volume II, the focus is on the clinical validation, validation of clinical utility and regulatory considerations for biomarker development. Together, this two volume series is meant to provide guidance on the entire biomarker development process, with a particular focus on the unique aspects of developing immune-based biomarkers. Specifically, knowledge about the challenges to clinical validation of predictive biomarkers, which has been gained from numerous successes and failures in other contexts, will be reviewed together with statistical methodological issues related to bias and overfitting. The different trial designs used for the clinical validation of biomarkers will also be discussed, as the selection of clinical metrics and endpoints becomes critical to establish the clinical utility of the biomarker during the clinical validation phase of the biomarker development. Finally, the regulatory aspects of submission of biomarker assays to the U.S. Food and Drug Administration as well as regulatory considerations in the European Union will be covered.Abbreviations:CAPCollege of American PathologistsCDRHCenter for Devices and Radiologic HealthCDxCompanion diagnosticCLIAClinical laboratory improvement amendmentsCMSCenters for Medicare and Medicaid ServicesEMAEuropean Medicines AgencyERCC1Excision repair cross-complementing 1FDAU.S. Food and Drug AdministrationFISHFluorescence in situ hybridizationFPRFalse positive rateIDEInvestigational device exemptionIHCImmunohistochemistryIVDIn vitro diagnosticIVDMIAIVD Multivariate Index AssayLDTLaboratory-developed testMARVELMarker Validation of Erlotinib in Lung CancerMIAMultivariate Index AssayNCINational Cancer InstituteNGSNext generation sequencingNPVNegative predictive valueNSCLCNon-small cell lung cancerPD-1Programmed cell death protein 1PD-L1Programmed cell death ligand 1PMAPremarket approval applicationPPVPositive predictive valueROCReceiver operative characteristicsSCNPSingle cell network profilingTPRTrue positive rate ER -