Clinical Trial Simulations: Applications and Trends

539 Pages·2011·8.422 MB·English

by  Carl C. Peck, Holly H. C. Kimko (auth.), Holly H. C. Kimko, Carl C. Peck (eds.)

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
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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