title: A systems approach to designing effective clinical trials using simulations.
abstract: 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.
  
  
  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.
authors.affiliation: Center for Biomedical Informatics Harvard Medical School, 10 Shattuck Street, Boston, MA 02115, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Fusaro
authors.forename: Prasad
authors.initials: P
authors.lastname: Patil
authors.forename: Chih-Lin
authors.initials: CL
authors.lastname: Chi
authors.forename: Charles F
authors.initials: CF
authors.lastname: Contant
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonellato
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008962:Models, Theoretical; D010597:Pharmacogenetics / Q000379:methods*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D013598:Systems Theory; D013927:Thrombosis / Q000188:drug therapy* / Q000235:genetics; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin