title: The combination of exposure-response and case-control analyses in regulatory decision making.
abstract: To reduce the bias introduced by confounding risk factors, a case-control comparison was incorporated in the exposure-response (ER) analysis to evaluate the recommended dosing regimen for trastuzumab in a pivotal trial. Results of Kaplan-Meier survival analysis suggest that patients with metastatic gastric cancer (mGC) in the lowest quartile trough concentrations of trastuzumab in cycle 1 (C(min 1) ) had shorter overall survival (OS) than did those in other quartiles. The result of the case-matched control comparison suggests that adjusting for these risk factors, patients with the lowest quartile of trastuzumab exposure did not benefit from addition of trastuzumab treatment to chemotherapy. The identified subgroup without survival benefit and the ER relationship support the recommendation on conducting clinical trials to identify a treatment regimen with greater exposure and acceptable safety profiles and to prospectively evaluate whether this treatment regimen will result in survival benefit for the identified subgroup.
authors: Office of Clinical Pharmacology, Office of Translational Sciences, Food and Drug Administration, Silver Spring, MD 20903, USA.
authors: Jun
authors: J
authors: Yang
authors: Hong
authors: H
authors: Zhao
authors: Christine
authors: C
authors: Garnett
authors: Atiqur
authors: A
authors: Rahman
authors: Jogarao V
authors: JV
authors: Gobburu
authors: William
authors: W
authors: Pierce
authors: Genevieve
authors: G
authors: Schechter
authors: Jeffery
authors: J
authors: Summers
authors: Patricia
authors: P
authors: Keegan
authors: Brian
authors: B
authors: Booth
authors: Yaning
authors: Y
authors: Wang
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003657:Decision Making; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053208:Kaplan-Meier Estimate; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab