Clinical Trial Simulations.pdf

AAPS Advances in the Pharmaceutical Sciences SeriesVolume I:Clinical Trial Simulations:Applications and TrendsHolly H.C.Kimko and Carl C.PeckHolly H.C.KimkolCarl C.PeckEditorsClinical Trial SimulationsApplications and TrendsEditorsHolly H.C.KimkoJohnson&Johnson PharmaceuticalResearch&Development,LLCAdvanced Modeling&SimulationRaritan,NJUSACarl C.PeckCenter for Drug Development ScienceDepartment of Bioengineeringand Therapeutic SciencesSchools of Pharmacy and MedicineUniversity of CaliforniaSan Francisco,CAUSAISSN 2210 7371e ISSN 2210 738XISBN 978 1 4419 7414 3e ISBN 978 1 4419 7415 0DOI 10.1007/978 1 4419 7415 0Springer New York Dordrecht Heidelberg London#American Association of Pharmaceutical Scientists 2011All rights reserved.This work may not be translated or copied in whole or in part without the writtenpermission of the publisher(Springer Science+Business Media,LLC,233 Spring Street,New York,NY 10013,USA),except for brief excerpts in connection with reviews or scholarly analysis.Use inconnection with any form of information storage and retrieval,electronic adaptation,computer software,or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names,trademarks,service marks,and similar terms,even if they arenot identified as such,is not to be taken as an expression of opinion as to whether or not they are subjectto proprietary rights.Printed on acid free paperSpringer is part of Springer ScienceBusiness Media()PrefaceDuring the seven years following the inaugural publication of Simulation forDesigning Clinical Trials:A Pharmacokinetic-Pharmacodynamic Modeling Per-spective,acceptance and application of clinical trials modeling and simulation(M&S)in drug development and regulation have greatly expanded.Biopharmaceu-tical companies have employed M&S in all phases of drug development to achievegreater efficiency and dosage optimization.The food and Drug Administrations(FDA)visionary 2004 Critical Path Initiative highlighted clinical trial simulations(CTS)in“model based drug development”to facilitate efficient development.Inthe meantime,FDA and the European Medicines Agency have encouraged use ofCTS via regulatory guidances,and have employed M&S for labeling and approvaldecisions.On the backdrop of these developments,the title of this edition has beenchosen to reflect how CTS is being employed in drug development and regulation,and trends for expanded applications in the future.This edition includes updates,new uses,and issues concerning CTS,along withcasestudiesonhowclinicaltrialsimulationsarebeingappliedinvarioustherapeuticandapplicationareas.Importantly,thebookexpandsontheuseofCTSforinformingdecisions during drug development and regulatory review.Each chapter author wasselectedonthebasisofdemonstratedexpertiseinstate-of-the-artapplicationofCTS.Editors opinions on advances and impactful trends of CTS in model-based drugdevelopment and regulation are introduced(Chap.1).Regulatory agencies havebeen proactive in promoting use of CTS,and Chaps.2 and 3 present the perspec-tives and experiences of FDA and European regulatory agencies by the authorsworking in these agencies.Methods to facilitate decision making in drug development are discussed bypointing out the importance of assessing uncertainty of predicted trial performanceand outcomes in planning of prospective trials(Chap.4).For quantitative decision-making,constructing clinical utility curves(Chap.5)can be useful.Adaptive trialdesign has gained attention as a method for more efficient and informative drugdevelopment,and its current status is reviewed in Chap.6.Chapter 7 illustrates anM&S application case where personnel from biostatistics,clinical research andclinical PK-PD could collaborate to make better informed decisions on trial designsvthroughout a clinical development.Chapter 8 illustrates how preclinical data can beintegrated in a model-based drug development program to optimize early stagedevelopment,using CTS to simulate a first-in-human study.Many successful cases employing CTS in guiding drug development decisionshave been published in the literature and presented at conferences.Representativecases in selected therapeutic areas provide a general background on how to benefi-cially employ CTS,followed by the authors experiences.Applications of CTS ineight therapeutic areas(Chaps.9 16)are covered:diabetes,cardiovascular dis-eases,viral infections,antimicrobial chemotherapy,cancer,hematology,anxietydisorder,and epilepsy.Chapter 17 discusses how CTS can be used in therapeutic biologics develop-ment.Designing ethical and informative pediatric studies requires integrating allavailable information,while gaining pediatric specific knowledge from a limitednumber of observations.The factors to consider in using CTS for pediatrics studiesare described in Chap.18.The final section of the book includes chapters that describe evolving methodol-ogies in CTS.The importance of incorporation of disease progression elements inCTS models is emphasized,especially when the evolution of disease during a trialis considered in evaluating treatment effects attributable to the drug(Chap.19).The systems biology approach incorporates high resolution mechanistic models,involving fundamental dynamics of cells and biological signaling systems.Usingsuch models,predictions of clinical responses may ultimately be made by simula-tions(Chap.20).Recent advances in in vitro,ex vivo,and in silico methods toprovide input variable information have significantly increased the applicability ofthe traditional whole-body physiology-based pharmacokinetic modeling approach,and its practical implementation is reviewed in the Chap.21.Simulating drugresponses in a virtual patient population and how to collect and utilize datasetsfor construction of covariate distribution models are presented(Chap.22).Thetargetaudienceforthisvolume,ClinicalTrialSimulationsincludesresearch-ers and scientists who wish to consider use of simulations in the design,analysis,orregulatory review and guidance of clinical trials.This book does not embrace allaspects of trial design,nor is it intended as a complete recipe for using computers todesign trials.Rather,it is an information source that enables the reader to gainunderstanding of essential background and knowledge for practical applications ofsimulation for clinical trial design and analysis.It is assumed that the reader has aworking understanding of pharmacokinetics and pharmacodynamics,modeling,pharmacometric analyses,and the drug development and regulatory processes.We express our sincere gratitude to all the authors who have contributed to thisbook.Many thanks go to the Springer publication team.Lastly,on behalf of all thecontributors of this book,we appreciate the readers interest in the application ofclinical trial simulations in order to improve the way we develop useful drugs.Raritan,NJHolly H.C.KimkoSan Francisco,CACarl C.PeckviPrefaceContents1Clinical Trial Simulation and Quantitative Pharmacology.1Carl C.Peck and Holly H.C.KimkoPart IApplication of M&S in Regulatory Decisions2Contribution of Modeling and Simulation Studiesin the Regulatory Review:A European Regulatory Perspective.15Siv Jo nsson,Anja Henningsson,Monica Edholm,and Tomas Salmonson3Contribution of Modeling and Simulation in the RegulatoryReview and Decision-Making:U.S.FDA Perspective.37Christine E.Garnett,Joo-Yeon Lee,and Jogarao V.S.GobburuPart IIStrategic Applications of M&S in Drug Development4Decision-Making in Drug Development:Applicationof a Model Based Framework for AssessingTrial Performance.61Mike K.Smith,Jonathan L.French,Kenneth G.KowalskiMatthew M.Hutmacher,and Wayne Ewy5Decision-Making in Drug Development:Applicationof a Clinical Utility IndexSM.85Timothy J.Carrothers,F.Lee Hodge,Robert J.Korsan,William B.Poland,and Kevin H.Dykstra6Adaptive Trial Designs.109Jose C.Pinheiro,Frank Bretz,and Chyi-Hung Hsuvii7Keys of Collaboration to Enhance Efficiency and Impactof Modeling and Simulation.131Anthe S.Zandvliet,Rik de Greef,Anton F.J.de Haan,Pieta C.IJzerman-Boon,Maya Z.Marintcheva-Petrova,Bernadette M.J.L.Mannaerts,and Thomas Kerbusch8Leveraging Pharmacometrics in Early PhaseAnti-inflamatory Drug Development.149Ene I.Ette and Christopher J.GodfreyPart IIIApplication of M&S in Selected Therapeutic Areas9The Application of Drug-Disease Models in theDevelopment of Anti-Hyperglycemic Agents.175Jenny Y.Chien and Vikram P.Sinha10Modeling and Simulation in the Developmentof Cardiovascular Agents.199Diane R.Mould,Bill Frame,and Timothy Taylor11Viral Dynamic Modeling and Simulations in HIVand Hepatitis C.227Philippe Jacqmin and Eric Snoeck12A Model-Based PK/PD Antimicrobial ChemotherapyDrug Development Platform to SimultaneouslyCombat Infectious Diseases and Drug Resistance.251N.Lntshotshole “Shasha”Jumbe and George L.Drusano13PKPD and Disease Modeling:Conceptsand Applications to Oncology.281Oscar E.Della Pasqua14Application of PharmacokineticPharmacodynamic Modelingand Simulation for Erythropoietic Stimulating Agents.311Juan Jose Pe rez-Ruixo,Sameer Doshi,and Andrew Chow15Model Based Development of an Agent for theTreatment of Generalized Anxiety Disorder.329Peter A.Lockwood and Jaap W.Mandema16Balancing Efficacy and Safety in the Clinical Developmentof an Atypical Antipsychotic,Paliperidone Extended-Release.345Filip De Ridder and An VermeulenviiiContentsPart IVExpanded Applications of M&S17Application of Modeling and Simulation in the Developmentof Protein Drugs.365Lorin K.Roskos,Song Ren,and Gabriel Robbie18Modeling and Simulation in Pediatric Researchand Development.401Jeffrey S.BarrettPart VEvolving Methodologies in M&S19Disease Progression Analysis:Towards Mechanism-BasedModels.437Stephan Schmidt,Teun M.Post,Massoud A.Boroujerdi,Charlotte van Kesteren,Bart A.PloegerOscar E.Della Pasqua,and Meindert Danhof20Using a Systems Biology Approach to Explore HypothesesUnderlying Clinical Diversity of the Renin AngiotensinSystem and the Response to Antihypertensive Therapies.461Arthur Lo,Jennifer Beh,Hector De Leon,Melissa K.Hallow,Ramprasad Ramakrishna,Manoj Rodrigo,Anamika Sarkar,Ramesh Sarangapani,and Anna Georgieva21Recent Developments in Physiologically BasedPharmacokinetic Modeling.487Vikash Sinha and Holly H.C.Kimko22Covariate Distribution Models in Simulation.505Peter L.BonateIndex.527ContentsixContributorsJeffrey S.BarrettDepartment of Pediatrics,The Childrens Hospital of Philadelphia,Division of Clinical Pharmacology and Therapeutics,University of Pennsylvania Medical School,Philadelphia,PA,USAJennifer BehEntelos,Inc.,Foster City,CA,USAPeter L.BonateClinical Pharmacology,Modeling,and Simulation,GlaxoSmithKline,Research Triangle Park,NC,USAMassoud A.BoroujerdiLeiden/Amsterdam Center for Drug Research,Division of Pharmacology,Leiden University,2300 RA,Leiden,The NetherlandsFrank BretzStatistical Methodology/IIS,Novartis Pharma AG,Basel,SwitzerlandTimothy J.CarrothersPharsight Consulting Services,PharsightA Certara Company,100 Mathilda Place,Suite 160,Sunnyvale,CA 94086,USAJenny Y.ChienLilly Research Laboratories,Eli Lilly and Co.,Lilly Corporate Center,Indianapolis,IN 46285,USAAndrew T.ChowPharmacokinetics and Drug Metabolism,Amgen Inc,Thousand Oaks,CA,USAMeindert DanhofLeiden-Amsterdam Center for Drug Research,Division of Pharmacology,Leiden University,Leiden,The NetherlandsxiOscar E.Della PasquaDivision of Pharmacology,Leiden-Amsterdam Center for Drug Research,Gorlaeus Laboratories,Einsteinweg 55,2300 RA Leiden,The NetherlandsandClinical Pharmacology&Discovery Medicine,GlaxoSmithKlineR&D,1-3 Ironbridge Road Stockley Park,UB11 1BT Uxbridge,United KingdomSameer DoshiPharmacokinetics and Drug Metabolism,Amgen Inc,Thousand Oaks,CA,USAGeorge L.DrusanoOrdway Research Institute,Albany,NY,USAKevin H.DykstraPharsight Consulting Services,PharsightA Certara Company,100 Mathilda Place,Suite 160,Sunnyvale,CA 94086,USAMonica EdholmMedical Products Agency,Uppsala,SwedenEne I.EtteAnoixis Corporation,Natick,MA,USAWayne EwyPharmacometrics,Pfizer Inc.(Retired),Ann Arbor,MI,USABill FrameWolverine Pharmacometrics Corporation,Projections Research Inc.,Phoenixville,PA,USAJonathan L.FrenchPharmacometrics,Pfizer Ltd.,Groton,CT,USAChristine E.GarnettCenter for Drug Evaluation and Research,Food and Drug Administration,Silver Spring,MD,USAAnna GeorgievaNovartis Pharmaceuticals,East Hanover,NJ,USAJogarao V.S.GobburuCenter for Drug Evaluation and Research,Food and Drug Administration,Silver Spring,MD,USAChristopher J.GodfreyAnoixis Corporation,Natick,MA,USARik de GreefPharmacokinetics,Pharmacodynamics&Pharmacometrics(P3),Global Drug Metabolism and Pharmacokinetics,Merck Research Labs,Merck Sharp and Dohme,AP1110,5340 BH,Oss,The NetherlandsxiiContributorsAnton F.J.de HaanBiostatistics and Research Decision Sciences(BARDS),Early Development Statistics,Merck Research Labs,Merck Sharp&Dohme,Oss,The NetherlandsMelissa K.HallowNovartis Pharmaceuticals,East Hanover,NJ,USAAnja HenningssonMedical Products Agency,Uppsala,SwedenF.Lee HodgePharsight Consulting Services,PharsightA Certara Company,100 MathildaPlace,Suite 160,Sunnyvale,CA 94086,USAChyi-Hung HsuStatistical Methodology/IIS,Novartis Pharmaceuticals Corporation,East Hanover,NJ,USAMatthew M.HutmacherAnn Arbor Pharmacometrics Group,Ann Arbor,MI,USAPieta C.IJzerman-BoonBiostatistics and Research Decision Sciences(BARDS),Late Development Statistics,Womens Health&Endocrine,Merck Research Labs,Merck Sharp&Dohme,Oss,The NetherlandsPhilippe JacqminExprimo NV,Mechelen,BelgiumSiv JonssonMedical Products Agency,Uppsala,SwedenN.Lntshotshole “Shasha”JumbeRoche,Palo Alto,CA,USAThomas KerbuschPharmacokinetics,Pharmacodynamics&Pharmacometrics(P3),Global Drug Metabolism&Pharmacokinetics,Merck Research Labs,Merck Sharp&Dohme,Oss,The NetherlandsCharlotteVan KesterenLeiden/Amsterdam Center for Drug Research,Division of Pharmacology,Leiden University,2300 RA,Leiden,The NetherlandsHolly H.C.KimkoJohnson&Johnson Pharmaceutical Research&Development,LLC,Advanced Modeling&Simulation,Raritan,NJ,USARobert J.KorsanDecisions,Decisions!,1966 Tice Valley Blvd,Walnut Creek,CA 94595,USAContributorsxiiiKenneth G.KowalskiAnn Arbor Pharmacometrics Group,Ann Arbor,MI,USAJoo Yeon LeeCenter for Drug Evaluation and Research,Food and Drug Administration,Silver Spring,MD,USAHector De LeonEntelos,Inc.,Foster City,CA,USAArthur LoEntelos,Inc.,110 Marsh Drive,Foster City,CA,USAPeter A.LockwoodPfizer Global Research and Development,Clinical Pharmacology,Primary Care Business Unit,New London,CT,USAJaap W.MandemaQuantitative Solutions,Menlo Park,CA,USABernadette M.J.L.MannaertsGlobal Clinical Research,Womens Health&Endocrine,Merck Research Labs,Merck Sharp&Dohme,Oss,The NetherlandsMaya Z.Marintcheva-PetrovaBiostatistics and Research Decision Sciences(BARDS),Late Development Statistics,Womens Health&Endocrine,Merck Research Labs,Merck Sharp&Dohme,Oss,The NetherlandsDiane R.MouldProjections Research Inc.,535 Springview Lane,Phoenixville,PA 19460,USACarl C.P