title: Analysis of clinical trials with biologics using dose-time-response models.
abstract: Biologics such as monoclonal antibodies are increasingly and successfully used for the treatment of many chronic diseases. Unlike conventional small drug molecules, which are commonly given as tablets once daily, biologics are typically injected at much longer time intervals, that is, weeks or months. Hence, both the dose and the time interval have to be optimized during the drug development process for biologics. To identify an adequate regimen for the investigated biologic, the dose-time-response relationship must be well characterized, based on clinical trial data. The proposed approach uses semi-mechanistic nonlinear regression models to describe and predict the time-changing response for complex dosing regimens. Both likelihood-based and Bayesian methods for inference and prediction are discussed. The methodology is illustrated with data from a clinical study in an auto-immune disease.
authors.affiliation: Statistical Methodology, Development, Novartis Pharma AG, Basel, Switzerland.|Institute for Biometry, Hannover Medical School, Hannover, Germany.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Lange
authors.affiliation: Statistical Methodology, Development, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Heinz
authors.identifier: http://orcid.org/0000-0003-0934-1066
authors.initials: H
authors.lastname: Schmidli
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001499:Bayes Theorem; D001688:Biological Products / Q000008:administration & dosage*; D002986:Clinical Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016013:Likelihood Functions; D017711:Nonlinear Dynamics; D015990:Placebo Effect; D012107:Research Design; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; C541220:canakinumab
keywords: Bayesian inference; KPD model; clinical trial; monoclonal antibody; nonlinear regression; pharmacodynamic; pharmacokinetic