A systems approach to designing effective clinical trials using simulations. Circulation 2013 Jan 29;127(4):517-26
Date
12/25/2012Pubmed ID
23261867Pubmed Central ID
PMC3747989DOI
10.1161/CIRCULATIONAHA.112.123034Scopus ID
2-s2.0-84873180434 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
BACKGROUND: Pharmacogenetics in warfarin clinical trials have failed to show a significant benefit in comparison with standard clinical therapy. This study demonstrates a computational framework to systematically evaluate preclinical trial design of target population, pharmacogenetic algorithms, and dosing protocols to optimize primary outcomes.
METHODS AND RESULTS: We programmatically created an end-to-end framework that systematically evaluates warfarin clinical trial designs. The framework includes options to create a patient population, multiple dosing strategies including genetic-based and nongenetic clinical-based, multiple-dose adjustment protocols, pharmacokinetic/pharmacodynamics modeling and international normalization ratio prediction, and various types of outcome measures. We validated the framework by conducting 1000 simulations of the applying pharmacogenetic algorithms to individualize dosing of warfarin (CoumaGen) clinical trial primary end points. The simulation predicted a mean time in therapeutic range of 70.6% and 72.2% (P=0.47) in the standard and pharmacogenetic arms, respectively. Then, we evaluated another dosing protocol under the same original conditions and found a significant difference in the time in therapeutic range between the pharmacogenetic and standard arm (78.8% versus 73.8%; P=0.0065), respectively.
CONCLUSIONS: We demonstrate that this simulation framework is useful in the preclinical assessment phase to study and evaluate design options and provide evidence to optimize the clinical trial for patient efficacy and reduced risk.
Author List
Fusaro VA, Patil P, Chi CL, Contant CF, Tonellato PJMESH terms used to index this publication - Major topics in bold
AnimalsAnticoagulants
Computer Simulation
Drug Evaluation, Preclinical
Humans
Models, Theoretical
Pharmacogenetics
Randomized Controlled Trials as Topic
Systems Theory
Thrombosis
Warfarin
