Clinical Trial Simulations: Applications and Trends PDF
Preview Clinical Trial Simulations: Applications and Trends
AAPS Advances in the Pharmaceutical Sciences Series Volume I:Clinical TrialSimulations: Applications andTrends HollyH.C. KimkoandCarl C. Peck Holly H. C. Kimko Carl C. Peck l Editors Clinical Trial Simulations Applications and Trends Editors HollyH.C.Kimko CarlC.Peck Johnson&JohnsonPharmaceutical CenterforDrugDevelopmentScience Research&Development,LLC DepartmentofBioengineering AdvancedModeling&Simulation andTherapeuticSciences Raritan,NJ SchoolsofPharmacyandMedicine USA UniversityofCalifornia [email protected] SanFrancisco,CA USA [email protected] ISSN2210-7371 e-ISSN2210-738X ISBN978-1-4419-7414-3 e-ISBN978-1-4419-7415-0 DOI10.1007/978-1-4419-7415-0 SpringerNewYorkDordrechtHeidelbergLondon #AmericanAssociationofPharmaceuticalScientists2011 Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewritten permissionof the publisher (SpringerScience+Business Media, LLC, 233 SpringStreet, New York, NY10013,USA),exceptforbriefexcerptsinconnectionwithreviewsorscholarlyanalysis.Usein connectionwithanyformofinformationstorageandretrieval,electronicadaptation,computersoftware, orbysimilarordissimilarmethodologynowknownorhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,eveniftheyare notidentifiedassuch,isnottobetakenasanexpressionofopinionastowhetherornottheyaresubject toproprietaryrights. Printedonacid-freepaper SpringerispartofSpringerScienceþBusinessMedia(www.springer.com) Preface During the seven years following the inaugural publication of Simulation for Designing Clinical Trials: A Pharmacokinetic-Pharmacodynamic Modeling Per- spective, acceptance and application of clinical trials modeling and simulation (M&S)indrugdevelopmentandregulationhavegreatlyexpanded.Biopharmaceu- ticalcompanieshaveemployedM&Sinallphasesofdrugdevelopmenttoachieve greater efficiency and dosage optimization. The food and Drug Administration’s (FDA)visionary2004CriticalPathInitiativehighlightedclinicaltrialsimulations (CTS) in “model based drug development” to facilitate efficient development. In the meantime,FDA and the EuropeanMedicines Agencyhave encouraged use of CTSviaregulatoryguidances,andhaveemployedM&Sforlabelingandapproval decisions.Onthebackdropofthesedevelopments,thetitleofthiseditionhasbeen chosentoreflecthowCTSisbeingemployedindrugdevelopmentandregulation, andtrendsforexpandedapplicationsinthefuture. Thiseditionincludesupdates,newuses,andissuesconcerningCTS,alongwith casestudiesonhowclinicaltrialsimulationsarebeingappliedinvarioustherapeutic andapplicationareas.Importantly,thebookexpandsontheuseofCTSforinforming decisionsduringdrugdevelopmentandregulatoryreview.Eachchapterauthorwas selectedonthebasisofdemonstratedexpertiseinstate-of-the-artapplicationofCTS. Editors’opinionsonadvancesandimpactfultrendsofCTSinmodel-baseddrug development and regulation are introduced (Chap. 1). Regulatory agencies have been proactive in promotinguse of CTS, and Chaps. 2 and 3 present the perspec- tives and experiences of FDA and European regulatory agencies by the authors workingintheseagencies. Methods to facilitate decision making in drug development are discussed by pointingouttheimportanceofassessinguncertaintyofpredictedtrialperformance andoutcomesinplanningofprospectivetrials(Chap.4).Forquantitativedecision- making,constructingclinicalutilitycurves(Chap.5)canbeuseful.Adaptivetrial design has gained attention as a method for more efficient and informative drug development,anditscurrentstatusisreviewedinChap.6.Chapter7illustratesan M&S application case where personnel from biostatistics, clinical research and clinicalPK-PDcouldcollaboratetomakebetterinformeddecisionsontrialdesigns v vi Preface throughoutaclinicaldevelopment.Chapter8illustrateshowpreclinicaldatacanbe integrated in a model-based drug development program to optimize early stage development,usingCTStosimulateafirst-in-humanstudy. Many successful cases employing CTS in guiding drug development decisions havebeenpublishedintheliteratureandpresentedatconferences.Representative casesinselectedtherapeuticareasprovideageneralbackgroundonhowtobenefi- ciallyemployCTS, followed bythe authors’ experiences.Applications ofCTSin eight therapeutic areas (Chaps. 9–16) are covered: diabetes, cardiovascular dis- eases, viral infections, antimicrobial chemotherapy, cancer, hematology, anxiety disorder,andepilepsy. Chapter 17 discusses how CTS can be used in therapeutic biologics develop- ment. Designing ethical and informative pediatric studies requires integrating all available information, while gaining pediatric specific knowledge from a limited numberofobservations.ThefactorstoconsiderinusingCTSforpediatricsstudies aredescribedinChap.18. Thefinalsectionofthebookincludeschaptersthatdescribeevolvingmethodol- ogiesinCTS.Theimportanceofincorporationofdiseaseprogressionelementsin CTSmodelsisemphasized,especiallywhentheevolutionofdiseaseduringatrial is 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. Using suchmodels,predictionsofclinicalresponsesmayultimatelybemadebysimula- tions (Chap. 20). Recent advances in in vitro, ex vivo, and in silico methods to provideinputvariableinformationhavesignificantlyincreasedtheapplicabilityof thetraditionalwhole-bodyphysiology-basedpharmacokineticmodelingapproach, and its practical implementation is reviewed in the Chap. 21. Simulating drug responses in a virtual patient population and how to collect and utilize datasets forconstructionofcovariatedistributionmodelsarepresented(Chap.22). Thetargetaudienceforthisvolume,ClinicalTrialSimulationsincludesresearch- ersandscientistswhowishtoconsideruseofsimulationsinthedesign,analysis,or regulatory review and guidance of clinical trials. This book does not embrace all aspectsoftrialdesign,norisitintendedasacompleterecipeforusingcomputersto design trials. Rather, it is an information source that enables the reader to gain understandingofessentialbackgroundandknowledgeforpracticalapplicationsof simulationforclinicaltrialdesignandanalysis.Itisassumedthatthereaderhasa working understanding of pharmacokinetics and pharmacodynamics, modeling, pharmacometricanalyses,andthedrugdevelopmentandregulatoryprocesses. Weexpressoursinceregratitudetoalltheauthorswhohavecontributedtothis book.ManythanksgototheSpringerpublicationteam.Lastly,onbehalfofallthe contributors of this book, we appreciate the reader’s interest in the application of clinicaltrialsimulationsinordertoimprovethewaywedevelopusefuldrugs. Raritan,NJ HollyH.C.Kimko SanFrancisco,CA CarlC.Peck Contents 1 ClinicalTrialSimulationandQuantitativePharmacology............ 1 CarlC.PeckandHollyH.C.Kimko PartI ApplicationofM&SinRegulatoryDecisions 2 ContributionofModelingandSimulationStudies intheRegulatoryReview:AEuropeanRegulatoryPerspective...... 15 SivJo¨nsson,AnjaHenningsson,MonicaEdholm, andTomasSalmonson 3 ContributionofModelingandSimulationintheRegulatory ReviewandDecision-Making:U.S.FDAPerspective.................. 37 ChristineE.Garnett,Joo-YeonLee,andJogaraoV.S.Gobburu PartII StrategicApplicationsofM&SinDrugDevelopment 4 Decision-MakinginDrugDevelopment:Application ofaModelBasedFrameworkforAssessing TrialPerformance......................................................... 61 MikeK.Smith,JonathanL.French,KennethG.Kowalski MatthewM.Hutmacher,andWayneEwy 5 Decision-MakinginDrugDevelopment:Application ofaClinicalUtilityIndexSM.............................................. 85 TimothyJ.Carrothers,F.LeeHodge,RobertJ.Korsan, WilliamB.Poland,andKevinH.Dykstra 6 AdaptiveTrialDesigns................................................... 109 Jose´ C.Pinheiro,FrankBretz,andChyi-HungHsu vii viii Contents 7 KeysofCollaborationtoEnhanceEfficiencyandImpact ofModelingandSimulation............................................. 131 AntheS.Zandvliet,RikdeGreef,AntonF.J.deHaan, PietaC.IJzerman-Boon,MayaZ.Marintcheva-Petrova, BernadetteM.J.L.Mannaerts,andThomasKerbusch 8 LeveragingPharmacometricsinEarlyPhase Anti-inflamatoryDrugDevelopment.................................... 149 EneI.EtteandChristopherJ.Godfrey PartIII ApplicationofM&SinSelectedTherapeuticAreas 9 TheApplicationofDrug-DiseaseModelsinthe DevelopmentofAnti-HyperglycemicAgents........................... 175 JennyY.ChienandVikramP.Sinha 10 ModelingandSimulationintheDevelopment ofCardiovascularAgents................................................ 199 DianeR.Mould,BillFrame,andTimothyTaylor 11 ViralDynamicModelingandSimulationsinHIV andHepatitisC............................................................. 227 PhilippeJacqminandEricSnoeck 12 AModel-BasedPK/PDAntimicrobialChemotherapy DrugDevelopmentPlatformtoSimultaneously CombatInfectiousDiseasesandDrugResistance ..................... 251 N.L’ntshotshole´ “Shasha”JumbeandGeorgeL.Drusano 13 PKPDandDiseaseModeling:Concepts andApplicationstoOncology........................................... 281 OscarE.DellaPasqua 14 ApplicationofPharmacokinetic–PharmacodynamicModeling andSimulationforErythropoieticStimulatingAgents ............... 311 JuanJose´ Pe´rez-Ruixo,SameerDoshi,andAndrewChow 15 ModelBasedDevelopmentofanAgentforthe TreatmentofGeneralizedAnxietyDisorder........................... 329 PeterA.LockwoodandJaapW.Mandema 16 BalancingEfficacyandSafetyintheClinicalDevelopment ofanAtypicalAntipsychotic,PaliperidoneExtended-Release ....... 345 FilipDeRidderandAnVermeulen Contents ix PartIV ExpandedApplicationsofM&S 17 ApplicationofModelingandSimulationintheDevelopment ofProteinDrugs.......................................................... 365 LorinK.Roskos,SongRen,andGabrielRobbie 18 ModelingandSimulationinPediatricResearch andDevelopment......................................................... 401 JeffreyS.Barrett PartV EvolvingMethodologiesinM&S 19 DiseaseProgressionAnalysis:TowardsMechanism-Based Models....................................................................... 437 StephanSchmidt,TeunM.Post,MassoudA.Boroujerdi, CharlottevanKesteren,BartA.Ploeger OscarE.DellaPasqua,andMeindertDanhof 20 UsingaSystemsBiologyApproachtoExploreHypotheses UnderlyingClinicalDiversityoftheReninAngiotensin SystemandtheResponsetoAntihypertensiveTherapies............. 461 ArthurLo,JenniferBeh,HectorDeLeon,MelissaK.Hallow, RamprasadRamakrishna,ManojRodrigo,AnamikaSarkar, RameshSarangapani,andAnnaGeorgieva 21 RecentDevelopmentsinPhysiologicallyBased PharmacokineticModeling.............................................. 487 VikashSinhaandHollyH.C.Kimko 22 CovariateDistributionModelsinSimulation.......................... 505 PeterL.Bonate Index............................................................................ 527
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