title: Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals.
abstract: Recent advances in our understanding of disease biology, biomarkers, new therapeutic targets, and innovative modalities have each fueled a dramatic expansion in the development of novel human therapeutics. Many are biotechnology-derived biologics possessing high selectivity and affinity for their intended target; as such they often pose challenges in the development path to approval. One challenge is the selection of the first-in-human (FIH) dose. This process has come under increased scrutiny as a result of a FIH trial with a super-agonist monoclonal antibody (TGN1412), which resulted in significant injury to healthy volunteers. Regulatory agencies have responded with supplemental guidance for the development of novel therapeutics. The intent of this paper is to provide experience-based insight, with relevant examples, for those planning the first administration of novel biopharmaceuticals in humans.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Bioanalytical Sciences, Genentech, Inc., South San Francisco, CA 94080, USA. tibbitts@gene.com
authors.forename: Jay
authors.initials: J
authors.lastname: Tibbitts
authors.forename: Joy A
authors.initials: JA
authors.lastname: Cavagnaro
authors.forename: Christine A
authors.initials: CA
authors.lastname: Haller
authors.forename: Ben
authors.initials: B
authors.lastname: Marafino
authors.forename: Paul A
authors.initials: PA
authors.lastname: Andrews
authors.forename: John T
authors.initials: JT
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products / Q000008:administration & dosage* / Q000009:adverse effects; D001702:Biopharmaceutics / Q000379:methods; D001709:Biotechnology / Q000379:methods; D002986:Clinical Trials as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; C509303:TGN-1412