title: Validation of biomarkers to predict response to immunotherapy in cancer: Volume II - clinical validation and regulatory considerations.
abstract: 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.
authors.affiliation: Department of Epidemiology and Biostatistics, College of Public Health, The University of Georgia, 101 Buck Road, Athens, 30602 GA USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Dobbin
authors.affiliation: NanoString, Inc., 530 Fairview Avenue N, Seattle, WA 98109 USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cesano
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA 19477 USA.
authors.forename: John
authors.initials: J
authors.lastname: Alvarez
authors.affiliation: Nodality, Inc., 170 Harbor Way, South San Francisco, 94080 CA USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Hawtin
authors.affiliation: ZellNet Consulting, Inc., 555 North Avenue, Fort Lee, 07024 NJ USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Janetzki
authors.affiliation: Adaptive Biotechnologies, Inc, 1551 Eastlake Ave. E., Seattle, WA 98102 USA.
authors.forename: Ilan
authors.initials: I
authors.lastname: Kirsch
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Giuseppe V
authors.initials: GV
authors.lastname: Masucci
authors.affiliation: Pfizer, San Diego, CA USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Robbins
authors.affiliation: Omni Array Biotechnology, 15601 Crabbs Branch Way, Rockville, 20855 MD USA.
authors.forename: Senthamil R
authors.initials: SR
authors.lastname: Selvan
authors.affiliation: National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, 20892 MD USA.
authors.forename: Howard Z
authors.initials: HZ
authors.lastname: Streicher
authors.affiliation: Covaris Inc., 14 Gill St, Woburn, MA 01801 USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Surgery and Immunology, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213 USA.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.affiliation: National Cancer Institute, Cancer Diagnosis Program, DCTD, National Institutes of Health, 9609 Medical Center Drive, Bethesda, 20892 MD USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Thurin
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D001681:Biological Assay / Q000379:methods / Q000592:standards; D014408:Biomarkers, Tumor; D005062:European Union; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy*; D011379:Prognosis; D012372:ROC Curve; D015203:Reproducibility of Results; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human
keywords: Assay; Biomarker; Cancer; Immunotherapy; Regulatory; Validation