title: Improvement in latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint in rheumatoid arthritis.
abstract: Improving the quality of exposure-response modeling is important in clinical drug development. The general joint modeling of multiple endpoints is made possible in part by recent progress on the latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate, when modeling a continuous and a categorical clinical endpoint, the level of improvement achievable by joint modeling in the latent variable IDR modeling framework through the sharing of model parameters for the individual endpoints, guided by the appropriate representation of drug and placebo mechanism. This was illustrated with data from two phase III clinical trials of intravenously administered mAb X for the treatment of rheumatoid arthritis, with the 28-joint disease activity score (DAS28) and 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria were used as efficacy endpoints. The joint modeling framework led to a parsimonious final model with reasonable performance, evaluated by visual predictive check. The results showed that, compared with the more common approach of separately modeling the endpoints, it is possible for the joint model to be more parsimonious and yet better describe the individual endpoints. In particular, the joint model may better describe one endpoint through subject-specific random effects that would not have been estimable from data of this endpoint alone.
authors.affiliation: Quantitative Sciences, Janssen Research & Development, LLC, PO Box 776, 1400 McKean Road, Spring House, PA, 19477, USA. chu25@its.jnj.com.
authors.forename: Chuanpu
authors.initials: C
authors.lastname: Hu
authors.affiliation: Quantitative Sciences, Janssen Research & Development, LLC, PO Box 776, 1400 McKean Road, Spring House, PA, 19477, USA.
authors.forename: Honghui
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000465:Algorithms; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology*; D017326:Clinical Trials, Phase III as Topic; D023381:Endpoint Determination / Q000379:methods*; D006801:Humans; D007596:Joints / Q000473:pathology*; D008954:Models, Biological; D015990:Placebo Effect; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents
keywords: Discrete variable; Multivariate analysis; NONMEM; Population pharmacokinetic/pharmacodynamic modeling; Rheumatoid arthritis