PrinciplesofBiomedicalSciencesand Industry
TranslatingIdeasintoTreatments
Editedby MarkusHinder
AlexanderSchuhmacher
JörgGoldhahn
DominikHartl
Editors
Prof.Dr.MarkusHinder NovartisGlobalDrugDevelopment ChiefMedicalOffice&PatientSafety PostfachForum1 4002Basel Switzerland
Prof.Dr.AlexanderSchuhmacher TechnischeHochschuleIngolstadt THIBusinessSchool Esplanade10 85049Ingolstadt Germany
Prof.Dr.JörgGoldhahn ETHZürich InstituteforTranslationalMedicine HCPH15.3Leopold-Ruzicka-Weg4 ETH-Hönggerberg 8093Zürich Switzerland
Prof.Dr.DominikHartl UniversityHospitalTübingen DepartmentofPediatricsI Hoppe-Seyler-Strasse1 72076Tübingen Germany
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Contents
Foreword xvii
AbouttheEditors xix
ListofAbbreviations xxi
1BiopharmaceuticalInnovationataGlance 1
MarkusHinder,DominikHartl,andAlexanderSchuhmacher Summary 1
1.1BiopharmaceuticalInnovationandDrugDevelopment,thePastand Present 2
1.2WhyWeWroteThisBookandWhatReadersCanExpecttoGainfrom ReadingIt 4
References 5
2PharmacologyandDrugTargets–TheBasisof Therapeutics 7
LenaHartl,MartinA.Fink,andSandraBeer-Hammer Summary 7
2.1Introduction 8
2.2Pharmacodynamics 10
2.3ReceptorsandIonChannels 11
2.3.1G-protein-CoupledReceptors(GPCRs) 11
2.3.2IonChannels 12
2.3.3Enzyme-AssociatedReceptors 12
2.3.4Non-receptor-MediatedEffects 14
2.4ReceptorAgonismandAntagonism 15
2.5ImplicationsforDrugDevelopment 18
2.6Pharmacokinetics 19
2.6.1LiberationandAdministration 19
2.6.2Absorption 21
2.6.3Distribution 21
2.6.4Metabolism/Biotransformation 22
2.6.5PhaseIReaction 23
2.6.5.1Oxidation 23
2.6.5.2ReductionandHydrolysis 24
2.6.5.3PhaseIIReaction 24
2.6.5.4PhaseIIIReaction 25
2.6.6Excretion 25
2.6.6.1RenalElimination 25
2.6.6.2BiliaryElimination 27
2.6.6.3IntestinalElimination 27
2.6.6.4PulmonaryElimination 27
2.7QuantitativePharmacokinetics 27
2.7.1DosingRegimen 27
2.7.2Clearance(CL) 27
2.7.3ExposureasAreaUndertheCurve 28
2.7.4Bioavailability 28
2.7.5 Cmax , Ctrough ,andPeak-to-Trough-Ratio 28
2.7.6VolumeofDistribution 29
2.7.7Half-Life 29
2.7.8AccumulationandLoadingDose 29
2.7.9InductionandMaintenanceDose 30
2.8PharmacokineticModels 30
2.9ImplicationsforDrugDevelopment 31
2.9.1PK/PDModelling 31
2.9.2CharacteristicsofPharmacokineticsinAge,DiseaseandOthers 33
2.9.3DoseFinding/DeterminationofDosingRegimens 33
2.9.4IndividualizedDosingandTherapeuticDrugMonitoring 34
2.10Conclusions 34 References 34
3PrinciplesandMethodsofthePharmaceuticalDrugDiscovery Process–FromIdeaoverTargettoaDevelopment Candidate 37
WernerKramer Summary 37
3.1WhatisthePurposeofDrugDiscovery? 38
3.2PhasesoftheDrugDiscoveryProcess 38
3.3TargetIdentification 40
3.3.1WhatisaPharmaceuticalTarget? 40
3.3.2SourcesforTargetIdentification 41
3.3.2.1AnExtensiveInquiryofAllPublishedDataonaParticularTargetandIts Pathway(s) 41
3.3.2.2(Pharmaco)-GeneticLinkstoaPhenotype 41
3.3.2.3PhenotypicScreening 41
3.3.3TargetValidation 42
3.3.3.1GeneticTargetValidation 42
3.3.3.2ChemicalTargetValidation(‘ChemicalGenomics’) 42
3.4StrategiestoModulateBiologicalTargets 43
3.4.1PreventingFormationoftheTargetProtein 43
3.4.2TargetingtheLigandBindingSiteoftheProtein 44
3.4.3TargetingProtein–ProteinInteractions(PPI) 44
3.4.4MaskingProteins 44
3.5TheLeadIdentificationProcess 44
3.6StrategiestoIdentifyLeadCompounds 45
3.6.1High-ThroughputScreening(HTS) 45
3.6.1.1AssayCriteriaforScreeningApproaches 47
3.6.1.2Structure-BasedRationalDrugDesign 49
3.6.1.3PhenotypicScreening 51
3.6.2ChemicalLibraries 52
3.6.2.1CriteriafortheCompoundsinaChemicalLibrary 53
3.6.2.2DNA-EncodedChemicalLibraries(DELLibraries) 54
3.7DrugCandidates 55
3.7.1LeadOptimizationandCandidateSelection 56
3.8Outlook 59 References 60
4Biomarkers:DefinitionsandUtilityforDrugDevelopment 63 DominikHartl Summary 63
4.1Introduction 64
4.2BiomarkerModalities 69
4.2.1MolecularBiomarkers 71
4.2.2ImagingBiomarkers 72
4.2.3DigitalBiomarkers 73
4.3BiomarkersinDrugDevelopment 73
4.4BiomarkerUseCases 75
4.5Outlook 78 References 78
5ToxicologyinDrugDevelopment–UnderstandingaDrug’s ToxicityandManagingSafetyandRisks 81 ElisabethRosner Summary 81
5.1IntroductiontoToxicologyandDefinitions 82
5.2TheGeneralToxicologicalFramework 83
5.3TheConceptoftheTherapeuticIndex 84
5.4TheInternationalRegulatoryFrameworkforSafetyEvaluations 85
5.4.1TheDataPackageRequiredforFirstinHuman(FIH)Trials 86
5.4.2TheDataPackageRequiredforStudiesBeyondFIH 87
5.4.2.1TheDataPackageRequiredforStudiesBeyondFIHforLarge (Bio)moleculesandOncologyCompounds 87
5.5AnimalSpeciesSelection 89
5.6BasicConceptsforNon-clinicalStudiestoSupportClinicalTrials 89
5.7WhatActivityatWhichStageofDevelopment? 92
5.8EstimatingtheSafeStartingDoseinFIHTrials 93
5.8.1Anti-cancerDrugs 93
5.9ToxicologicalEvaluationsDuringLate-StageDrugDevelopment 94
5.10Outlook 96 References 97
6IntroductiontoChemistryManufacturingandControls–From CompoundandDevelopmentCandidatetoDrug 99 ThomasEichinger Summary 99
6.1CMCIntroductionandBackground 100
6.2SomeBasicThoughts 100
6.2.1TransitionfromResearchtoDevelopment 100
6.2.2SomeFundamentalsAboutPhysico-chemicalCharacteristics 101
6.2.3TheBiopharmaceuticalClassificationSystem(BCS) 102
6.2.4StabilityInvestigations 104
6.2.5ThePhysicalAppearance:MorphologyandPolymorphism 105
6.3PreclinicalDevelopmentandtheClinicalPhase1fromaCMC Perspective 107
6.3.1TheActivePharmaceuticIngredient(API) 107
6.3.2TheDrugProduct 108
6.3.3AnalyticalDevelopment 109
6.3.4RegulatoryGreenLightforFIHStudy 110
6.4PreclinicalDevelopmentandtheClinicalPhase2fromaCMC Perspective 110
6.4.1TheActivePharmaceuticIngredient(API) 111
6.4.2TheDrugProduct 111
6.4.3AnalyticalDevelopment 111
6.5PreclinicalDevelopmentandtheClinicalPhase3fromaCMC Perspective 111
6.6TheCompilationandAuthoringoftheSubmissionDossierfor MarketingAuthorization 112
6.7TheNDASubmissionandtheStepstoProductLaunch 116 References 117
7TranslationalMedicine–TheBridgingDiscipline.Roleand ToolsintheDrugDevelopmentProcess 119 MarkusHinderandDominikHartl Summary 119
7.1TranslationalMedicine,DefinitionsandHistory 120
7.2TheTranslationalGap 122
7.2.1FailedTranslation:WhyItHappensandWhyWeNeedtoAvoidIt 122
7.2.2PredictivityofModelsandtheTranslatabilityGap 123
7.2.3TheLearningandConfirmingParadigm 124
7.3PathsofTranslation 126
7.3.1ForwardvsReverse/Back-Translation 126
7.4TranslationalMedicineinDrugDevelopment 129
7.4.1BenchtoBedsideandBackorForwardandBackwardTranslation 129
7.4.1.1ExamplesofClassicalForwardTranslation 129
7.4.1.2ExamplesofBedsidetoBenchorBackwardTranslation 130
7.5Serendipity 132
7.5.1SerendipityExamples:SildenafilandtheSGLT2inhibitors 133
7.6Conclusions 134
References 136
8Decision-Making:WhataretheKeyDriversAround Decision-MakinginDrugDevelopment? 139
NigelMcCracken
Summary 139
8.1Background 140
8.1.1DrugDevelopmentProcess 140
8.1.2TargetProductProfile 141
8.2KeyDecisionPoints 142
8.3MovingTowards‘GoINDEnabling’ 143
8.4MovingTowardsGo/NoGoFirstinHuman(FIH) 144
8.5MovingTowardsGo/NoGoPhase2 146
8.6MovingTowardsGoConfirmatoryDevelopment 148
8.7ConcludingRemarks 150
References 150
9ClinicalDrugDevelopment–ClinicalCharacterizationfor RegulatoryApproval 151
WernerSeiz
Summary 151
9.1ClinicalDrugDevelopment,Definition,andFramework 152
9.2TheDifferentStagesofClinicalDevelopment 153
9.3TheBasicFrameworkandElementsforClinicalTrials 155
9.4TheClinicalStudyProtocol 156
9.5WrittenSubjectInformation 156
9.6GraphicalStudyDesignandScheduleofActivities 156
9.7DefinitionofPatientPopulationandSampleSizeCalculation 160
9.8StudyDesign 161
9.9GeneralMethodsandStatisticalTools 163
9.9.1AnalysisPopulations 163
9.9.2ClinicalOperations 163
9.10TargetProductProfile,ClinicalDevelopmentPlan,andOther DocumentsDuringDevelopment 166
9.11ChangingEnvironment:Sensors,Digitalization,andCOVID-19 Pandemic 166
x Contents
9.12KeyStudiesDuringClinicalDevelopment 167
9.12.1First-In-HumanStudy 167
9.12.2MechanisticStudy 169
9.12.3ClinicalProof-of-Concept 169
9.12.4Dose-RangingStudies 170
9.12.5EfficacyStudies 171
9.12.6SpecificApproaches–AdaptiveTrialDesigns 171
9.12.7OncologyTrials 173
9.12.8Basket,Umbrella,andPlatformTrials 173
9.13AdvisoryBoards,SteeringCommittees,DataandSafetyMonitoring Boards 174
9.13.1AdvisoryBoards 174
9.13.2SteeringCommittees 174
9.13.3EndpointAdjudicationCommittees 174
9.13.4DataSafetyandMonitoringBoards/DataMonitoringCommittee 174
9.14SummaryofInformation 175 References 175
10RegulatoryAffairs–CommunicatingwithHealth Authorities 177
Hans-JuergenFuelleandValerieLanctin Summary 177
10.1RegulatoryEnvironment–GettingStarted 178
10.2TheRoleofRegulatoryAffairsinEarlyDrugDevelopment 180
10.3TheCommonTechnicalDocument 182
10.4InvestigationalNewDrug 184
10.5ClinicalTrialApplication 184
10.6EarlyConsultationswithHealthAuthorities 185
10.7RegulatoryRequirementsforPaediatricDiseases 186
10.8RegulatoryPathwaysforDrugDevelopmentforOrphan/Rare Diseases 187
10.9AcceleratedPathwaysforExpeditedClinicalDevelopmentand RegulatoryReview 188
10.10TheRoleofRegulatoryAffairsinLate-StageDrugDevelopment 190
10.11TheRoleofRegulatoryAffairsBefore,DuringandAfter Registration 194
10.12Pre-submissionMeetingswithHealthAuthorities 195
10.13AdditionalSubmission-EnablingRegulatoryAffairsActivities 196
10.14HealthAuthorityReviewofRegistrationDossiers 196 References 200
11RegulatoryAffairsinDeviceDevelopment–HowtoDesign MedicalDevicesCapabletoEntertheMarket 203 DietmarSchaffarczyk
Summary 203
11.1Introduction 204
11.2ProductCommercialization 206
11.3TenThingstoKnowandConsiderWhenDevelopingaDevice 208
11.4ObtainingQualifiedInputfromInterestedParties 212
11.5PlanningandExecutingAllImportantDevelopmentMilestones 216
11.6DesignandDevelopmentVerification:DidIMAKEtheProduct Right? 218
11.7DesignandDevelopmentValidation:DidIMAKEtheRight Product? 219
References 222
12MarketEntryandReimbursement:MakingDrugsAvailablefor PatientsAfterDrugApproval 225 AhmadBecharaandRolaHaroun
Summary 225
12.1Introduction 226
12.2HealthcareChallenges 226
12.3WhatDoesMarketAccessMean? 227
12.4MarketAccessGatekeepers 228
12.5DrugPurchasing 228
12.6PayersandValueAssessment 229
12.7HealthEconomicsasaDecisionToolforMarketAccess 231
12.7.1WhatIsHealthEconomics? 232
12.7.2WhatIstheAimofaHTA? 232
12.7.3HTAProcess 233
12.8SettingtheRightPrice 234
12.8.1PricingPolicy 234
12.8.2TherapeuticReferencePricing(Internal) 234
12.8.3International/ExternalReferencePricing 235
12.8.4Value-BasedPricing 235
12.8.5OverviewofthePricingandReimbursementProcessinKeyEuropean Markets 236
12.9HowDoesthePharmaIndustryPrepareforMarketEntries? 237
12.10EarlyPatientAccess 240
12.11ManagedEntryAgreements 240
12.12MarketAccessTrends 242
12.12.1USAandCanada 242
12.12.2Europe 242
12.13FutureMarketAccessChallenges 243 References 243
13PricinginGermany–KeyLearningsforOptimizingPrice PotentialAftertheIntroductionofAMNOG 247 JacquelineJones Summary 247
13.1Introduction 247
13.2StructureofthePricingandReimbursementProcessinGermany 249
13.3AnalysisofEffectsoftheAMNOGProcessonDrugPricesin Germany 251
13.4LearningsfromAMNOGtoEnsureSuccessintheGermanMarket 253
13.5StudyDesign 254
13.6DossierPreparation 254
13.7Pre-launchStrategy 254
13.8Post-launch 255
13.9PriceNegotiation 255
13.10Post-negotiation 255
13.11KeyTakeaways 256 KeyResources 256 References 256
14Project,Risk,andPortfolioManagement–ManagingR&D ProjectsToday 257
AlexanderSchuhmacherandMarkusHinder Summary 257
14.1Introduction 258
14.2ThePhasesofthePharmaR&DProcess 259
14.3ProjectsandProjectManagement 263
14.4ProjectLifeCycleandProjectPhases 270
14.5RiskManagement 272
14.6PortfolioManagement 274 References 279
15IntellectualProperty–HowtoProtectInnovationinthe BiopharmaceuticalIndustry 281 CharlesE.JeffriesandKarenD.Larbig Summary 281
15.1IntroductiontoIntellectualPropertyRights 282
15.2PatentRights 284
15.2.1WhatisaPatent? 284
15.2.2PatentabilityCriteria 285
15.2.3WhyandHowtoApplyforaPatent? 286
15.2.4PatentingProcedure 287
15.2.4.1FromInventionHarvestingtoPatentFiling 287
15.2.4.2PatentProsecutionandGrantProcedure 288
15.2.5ValueandUseofPatentRights 291
15.3The‘FreedomtoOperate’Principle 292
15.4IntellectualPropertyProtectionintheBiopharmaceuticalIndustry 294
15.4.1PatentProtectionforaPharmaceuticalDrugProduct 296
15.4.2LifeCycleManagement 298
15.4.3PatentTermExtensions 298
15.4.4RegulatoryDataProtection 299
15.4.5LossofExclusivity 299
15.4.6FTOIssuesintheBiopharmaceuticalIndustry 300
15.4.7RoleofanIn-houseIntellectualPropertyDepartment 301
15.5Conclusion 302
KeyResources 302
16PatentsintheBiomedicalSciencesandIndustry–TheCaseof theSwissLifeScienceCompanyPrionics 305 MartinA.BaderandOliverGassmann Summary 305
16.1PatentsintheBiomedicalSciencesandIndustry 306
16.2TheSwissLifeScienceCompanyPrionics 309
16.3SuccessFactorsandFailures 312
16.4ConsequencesandInsights 313 KeyResources 314 References 314
17PharmaceuticalBusinessDevelopmentand Licensing–OverviewofaCross-FunctionalandMultifaceted RoleandItsKeyElementsinBiopharmaceuticalIndustry 317 MonikaSchuessler Summary 317
17.1Introduction 318
17.2TypesofCollaborations 318
17.3LicensingAgreements 319
17.4CommercialorDistributionPartnerships 320
17.5ResearchCollaborations 321
17.6OtherTypesofAgreements 321
17.7TechTransferAgreements 322
17.8StructuredApproach–HowtoStartaTransaction? 322
17.9EvaluationProcess 324
17.10DueDiligence 327
17.11LetterofIntentandTermSheet 329
17.12NegotiationandContractClosure 330
17.13AllianceManagement 331
17.14Conclusions 332 References 332
18TheEntrepreneur’sGuideThroughtheGalaxyofBiotech Funding 333
MathiasSchmidt Summary 333
18.1Introduction 334
18.2SeedFunding–fromaResearchConcepttoValidationofaBusiness Idea 335
18.3GettingSerious–SeriesA 336
18.3.1Valuation 338
18.3.2BuildingtheTeam 338
18.3.3AlternativestoVentureFinancing 338
18.4GettingmoreSerious–SeriesB 339
18.5VentureDebtasanAlternativetoaSeriesB 341
18.6GettingmostSerious–SeriesC 341
18.7ExitOptions 342
18.8ClosingRemarks 343 Reference 343
19MedicalTechnologies–KeyLearningfromTwoCase Studies 345
GünterLorenzandAndreasSchüle
19.1CaseStudy1–MedicalGradePlastics(MPG) 345
19.1.1ConsistencyofFormulation 347
19.1.2SecurityofSupply 348
19.1.3Appendix–ISO10993 349
19.2CaseStudy2–VitrectomyUsingFastPneumatic-DrivenCutter Systems 350
19.3InnovativeValveTechnology 352
19.4IntegrationTechnology 353
20LaboratoryDiagnostics–ToolsforClinicalDecision-Making andClinicalTrialEndpoints 357 BhuwneshAgrawal Summary 357
20.1DefinitionofDiagnostics,WhyDiagnostics,ImportanceofDiagnostics, SampleTypes 358
20.2TheDiagnosticsIndustry–KeyFiguresandKeyPlayers 361
20.3BriefHistoryofDiagnostics 362
20.4ElementsoftheLaboratoryWorkflow(Pre-analytics,Analytics,and Post-analytics) 362
20.5VariousTypesofDiagnosticTestsintheLaboratory 363
20.5.1ClinicalChemistry 363
20.5.2Immunology 364
20.5.3HaematologyandCoagulation 364
20.5.4Microbiology 365
20.5.5MolecularDiagnostics 365
20.5.6Histopathology 366
20.6PlaceofDiagnosticsintheClinicalWorkflow 366
20.7QualityManagement 367
20.7.1CommercialTests 367
20.7.2Laboratory-DevelopedTests(LDTs) 367
20.7.3TestPerformanceCharacteristics 369
20.8RegulatoryApprovalofDiagnostics 370
20.9TheDiagnosticsR&DProcess–StageGateandAgileDevelopment Processes 373
20.9.1TheStage-GateProcess 373
20.9.2TheAgileDevelopmentProcess 373
20.10TheFutureofDiagnostics–KeyTechnologiesandTrends,Personalized Diagnostics 375
20.10.1Automation 375
20.10.2MolecularTesting 375
20.10.3Personalized/PrecisionMedicine 375
20.10.4PointofCareTesting 375
20.10.5DigitizationandArtificialIntelligence 376
20.11Conclusions 376 References 376
21Vaccination:TowardsanImprovedInfluenzaVaccine 377 PierreA.Morgon Summary 377
21.1Influenza–ADeadlyDiseasewithaLongHistory 378
21.2TheAnnualChallenge 383
21.3MechanismsoftheImmuneResponse 384
21.4AntigenContent 385
21.5AlthoughInfluenzaVaccineFormulationEvolvestoReflectthe CirculatingStrains,InnovationisRare 386
21.6MedicalRationaleforIntradermalAdministration(ID) 386
21.7SearchforGreaterAcceptability 387
21.8AcceptabilityoftheNewDevice 389
21.9AcceptabilityinRealLife 391
21.10OutlookandTrends 393 References 394
Index 397
Foreword
Thisbookwithmanycriticallyimportantchaptersisaddressingkeytopicsin biopharmaceuticalresearch&developmentandinnovation.Itaimsatexplaining newmodalitiestodiagnose,prevent,andtreathumandiseases.Italsoprovides realexamples(case-in-points)ofprototypesofinnovativeapproachesthatare testedinbiologicalsystemsofincreasingsize,complexity,andrelevancewhere theearlyphasespansfromindividualreceptorsovercell,organsystemstofirst therapeuticexplorationinsmallandwell-definedpatientpopulations.Itdebates thelatestknow-howandthecommoncommitmenttothevisionofarevitalizedand impactfulbiopharmaceuticaldevelopmentaswellasothercharacterssuchasregulatoryandhealthtechnologyagenciesinstrumentaltocompletingthejourneyof medicinesdevelopment,i.e.deliveringtotherespectivepatientpopulation.Thisisa recognitionofthecurrentenvironmentwherepatientadvocacygroupsdemanding equitableaccesstoaffordable,qualityproductsinreasonabletimeframes.
Theeditors’visionofrecognizingthescienceofdecision-makingor‘decision science’asanimportantprocessinmedicinesdevelopmentiscommendable.This isoftenneglectedinbooksaddressingtheprocessofmedicinesdevelopment.The qualitydecision-makingprocessasanintegralpartofmedicinesdevelopmenthas amuchhigherchanceofleadingtoqualityoutcomes.Itcanbearguedthatapoor qualityorbaddecision-makingprocesscouldleadtoagoodoutcome;however, thiscouldonlyhappenbychance.Forexample,applyingqualitydecision-making processbyincorporatingvalidatedmethodologiesforbenefit-riskassessmentinto guidanceforregulatoryreview.Suchapproachesarealltwentyfirstcenturybest practices,whichwillhavetheoutcomesofimprovedpredictability,accountability, consistency,andtransparencyofapublichealthfocused,science-basedmedicines development.
Thebook’seditorsareactiveorformerpharmaceuticalexecutiveswhohave beenlecturingbiopharmaceuticalinnovation,pharmacology,andpharmaceutical medicineoverdecadesandwhohavebroughttogether27expertsinmedicines developmenttowritethe21chaptersaddressingdevelopmentofbiopharmaceuticals/pharmaceuticalsfrommoleculetomarketplace.Thechaptershavefocused ontheevaluationofmanyaspectsofpre-clinicalandclinicaldevelopmentvery helpfultostudentsinbiopharmaceuticalsciences,pharmaceuticalmedicine,and lifesciencemanagement.Thesechaptersalsoprovideinsightsthatcanbeofbenefit
tonotonlythoseengagedinbiomedicalpostgraduatestudiesbutalsotothose earlycareerresearchersinvolvedinmedicinesdevelopment.Undoubtedly,this comprehensivebodyofworkwillimprovescientific,regulatory,andreimbursement processesandmoreefficientlyfacilitateaccesstoqualityversionsofneededmedical products.
Itismyhopethatthisbookandtheresearchitcontainswillprovidesignificant insightintopre-clinicalandclinicaldevelopmentofbiopharmaceuticalsaswell asfosteringinnovationandqualitydecision-makingpracticesappliedtokey milestonesofmedicinesdevelopment.Ibelievetheroadmapprovidedinthisbook couldbeconsideredasablueprintforotherhealthtechnologyinnovations,whether anewactivesubstanceoranincrementalinnovation.
ProfessorSamSalek,PhD,RPh,FFPM,GFMD,FRPS,FESCP,MCMS ProfessorofPharmacoepidemiology
Head–PublicHealthandPatientSafetyResearchGroup SchoolofLifeandMedicalSciences UniversityofHertfordshire,UK
VisitingProfessor–EstateofHessen,Germany Vice-President,PharmaTrainFederation
AbouttheEditors
Prof.Dr.MarkusHinder studiedmedicineatthe UniversitiesofHeidelberg,Paris,andZürichand obtainedadoctoraldegreeinpharmacologyfrom HeidelbergUniversity.Aftergraduation,hetrained inclinicalpharmacology,cardiology,andemergency medicineandunderwentpostgraduatetrainingin clinicaltrialmethodologyandstatisticsattheUniversitiesofBaselandBrussels.Markusjoinedthe pharmaceuticalindustrymorethan20yearsagoand heldseniorleadershippositionsinclinicalpharmacology,translationalmedicine,clinicaldevelopment, medicalaffairs,drugsafetyandprojectmanagement. HehasbeenlecturingpharmacologyandpharmaceuticalR&Dsince2004.In2010,hewasappointed professoratCardiffUniversity/HochschuleFresenius.Heservesasareviewerfor severaljournalsandasanassociateeditorfortheJournalofTranslationalMedicine.
Prof.Dr.AlexanderSchuhmacher graduatedin biologyfromtheUniversityofKonstanz(Germany), inpharmaceuticalmedicineattheUniversityof Witten/Herdecke(Germany)anddidaPh.D.in molecularbiologyattheUniversityofKonstanz;he isalsoagraduateoftheExecutiveMBAprogramat theUniversityofSt.Gallen(Switzerland).Alexander holdsafullprofessorshipinLifeScienceManagementattheTHIBusinessSchool(Germany).His researchfocusisonbiopharmaceuticalinnovation managementwithaspecializationonR&Defficiency,artificialintelligence,andopeninnovation. Priortothat,Alexanderworked9yearsasprofessor atReutlingenUniversity(Germany)and14years invariousseniorR&Dleadershippositionsinthe pharmaceuticalindustry.
Photo:MarkusHinder.
Photo:Alexander Schuhmacher.
Prof.Dr.JörgGoldhahn receivedhisM.D.in1997 fromtheFriedrich-SchillerUniversityinJena,Germany,finishedapostgraduatecourse(MAS)inMedicalPhysicsandBiomechanicsattheETHZürichin 2000,receivedthepostdoctorallecturequalification (Habilitation)in2008,andbecameafacultymember ofthedepartmentforhealthsciencesandtechnology(D-HEST)asadjunctprofessor2014.Heworked asatranslationalmedicineexpertattheNovartis InstitutesforBiomedicalResearch(NIBR)inBasel inadditiontomorethan15yearsinclinicalresearch. HeiscurrentlytheheadoftheInstituteforTranslationalMedicineandmedicaldirectorofthebachelor inmedicineatETHinZurich,Switzerland.
Prof.Dr.DominikHartl studiedMedicineatthe UniversitiesofRegensburg,Munich,andMelbourne andobtainedhisdoctoraldegreeinImmunology fromMunich/LMUUniversity.Heisboardcertified inPediatricsandInfectiousDiseasesandworkedas PhysicianScientist/Post-DocScholaratYaleUniversity.Hejoinedthepharmaceuticalindustrymore thansevenyearsagoandgainedextensiveexperienceinhispositionsinDrugDiscovery,TranslationalMedicine,Biomarkers,ClinicalDevelopment andPrecisionMedicine/PersonalizedHealthcarein BiotechandBigPharma.Inadditiontoworkingin thepharmaceuticalindustry,DominikisaProfessor forPediatricImmunology/InfectiousDiseasesatthe UniversityofTübingen.
Photo:JörgGoldhahn.
Photo:DominikHartl.
ListofAbbreviations
AbbreviationsMeaning
AAALACAssociationforAssessmentandAccreditationof LaboratoryAnimalCare
ACEAngiotensin-convertingenzyme
ADHAutosomaldominanthypercholesterolaemia
ADMEAbsorption,distribution,metabolismand excretion
ADMETAbsorption,distribution,metabolism,excretion, toxicity
AEMPSSpanishAgencyforDrugsandMedicalProducts
AIArtificialintelligence
AIDSAcquiredimmunodeficiencysyndrome
AIFAItalianMedicinesAgency
AISArztinformationssystem
AMNOGArzneimittelmarktNeuordnungsgesetz
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(receptor)
APAnginapectoris
APIActivepharmaceuticalingredient
ARAssessmentreport
ASMFActivesubstancemasterfile
ASMRAméliorationduServiceMédicalRendu
ATCAnatomicaltherapeuticchemical
ATMPAdvancedtherapymedicinalproduct
ATPAdenosinetriphosphate
AUCAreaunderthecurve
BABioavailability
BBBBlood-brainbarrier
Morethan onemeaning
xxii ListofAbbreviations
AbbreviationsMeaning
BCSBiopharmaceuticalclassificationsystem
BESTBiomarker, endpoints andother tools
BLABiologicslicenseapplication
BMPBonemorphogeneticprotein
BNPBrainnatriureticpeptide
BPCABestPharmaceuticalsforChildrenAct
BQPBiomarkerqualificationprogram
BSEBovinespongiformencephalopathy
CACompetentauthority
CAPCollegeofAmericanPathologists
CAPACorrectiveandpreventiveaction
CAR-TChimericantigenreceptorT-cell(therapy)
CASChemicalabstractservice(registrationnumber)
CATCommitteeforadvancedtherapies
CBACost–benefitanalysis
CBERCenterforBiologicsEvaluationandResearch
CD4Clusterofdifferentiation4(cell)
CDAConfidentialityagreement
CDERCenterforDrugEvaluationandResearch
CDPClinicaldevelopmentplan
CDRHCenterforDevicesandRadiologicalHealth
CEConformitéEuropéenne
CEACost-effectivenessanalysis
CEDCoveragewithevidencedevelopment
CEOChiefexecutiveofficer
CEREPInhibitoryactivityandselectivityofcompoundson thePDEsuperfamily
CETPCholesteryl-ester-transfer-protein
cGMPCyclicguanosinemonophosphate
CJDCreutzfeldt–Jakobdisease
CKD-EPIChronickidneydiseaseepidemiology collaborationequation
CKLClearance
CLIAClinicalLaboratoryImprovementAct
clogP Partitioncoefficientbetween n-octanolandwater
CMACriticalmaterialattributesorcost-minimization analysis
CMCChemistry,manufacturing,andcontrol
CNSCentralnervoussystem
COGsCostofgoods
COMPCommitteefororphanmedicinalproducts
ListofAbbreviations
AbbreviationsMeaning Morethan onemeaning
CPCentralizedprocedure
CPPCriticalprocessparameters
CQACriticalqualityattributes
CROContractresearchorganization
CRPC-reactiveprotein
CSECystathionine-γ-lyase
CSPClinicalstudyprotocol
CTComputedtomography
CTAClinicaltrialapplication
CTDCommontechnicaldocument
CUACost–utilityanalysis
CYPCytochromeP450
CyTOFCytometrybytime-of-flight
DCDSDevelopmentcoredatasheet
DDDuediligence
DDIDrug–druginteraction
DDPDrugdevelopmentpathwayordesignand developmentplan 1
DELDNA-encodedchemicallibraries
DLTsDose-limitingtoxicities
DMCDatamonitoringboard
DMFDrugmasterfile
DMSODimethylsulphoxide
DNADeoxyribonucleicacid
DoHDeclarationofHelsinki
DPDrugproductordecentralizedprocedure1
DRFDose-rangefinding
DSMBDatasafetymonitoringboard
EACEndpointadjudicationcommittee
EAPEarlyaccessprogram
ECEthicscommittee
ECGElectrocardiogram
ECHAEuropeanChemicalAgency
EDExectiledysfunction
ED5050%ofthetestobjectsshowtheexpectedeffect
EDMFEuropeandrugmasterfile
EFDEmbryofetaldevelopment
EGFEpidermalgrowthfactor
ELISAEnzyme-linkedimmunosorbentassay
EMAEuropeanMedicinesAgency
EoPEnd-of-phase
xxiv ListofAbbreviations
AbbreviationsMeaning
EPCEuropeanPatentConvention
EPOEuropeanPatentOffice
EQAExternalqualityassurance
ERAEnvironmentalriskassessment
ERKExtracellularsignal-regulatedkinase
ERPExternalreferencepricing
ESTsExpressedsequencetags
eTOCElectronictableofcontent
EUDAMEDEuropeanDatabaseforMedicalDevices
EUnetHTAEuropeanNetworkforHealthTechnology Assessment
FACSFluorescence-activatedcellsorting
FasFS-7-associatedsurfaceantigen
FDA(American)FoodandDrugAdministration
FEEDFertilityandearlyembryonicdevelopment
FGFFibroblastgrowthfactor
FIBCFullyintegratedBiopharmaceuticalCompany
FIHFirstinhuman
FIMFirstinmen
FISHFluorescenceinsituhybridization
FlunetFluenetwork
FPEFirstpasseffect
FRETFluorescenceresonanceenergytransfer
FTEFull-timeemployee
FTOFreedomtooperate
GABAGammaaminobutyricacid
G-BAGermany,FederalJointCommittee
GCGaschromatography
GCPGoodclinicalpractice
GDPGuanosinediphosphateorgrossdomesticproduct1
GDPRGeneralDataProtectionRegulation
GFRGlomerularfiltrationrate
GHTFGlobalHarmonizationTaskForce
GIGastrointestinal
GIRKG-protein-coupledinwardlyrectifyingK+ channel
GKV-SVUmbrellaOrganizationoftheStatutoryHealth Insurers
GLPGoodlaboratorypractice
GMPGoodmanufacturingpractice
GPCRG-protein-coupledreceptor
GTMPGenetherapymedicinalproduct
AbbreviationsMeaning
GTPGuanosinetriphosphate
GxPGood practice
HAHemagglutinin
HAVHepatitisAvirus
HbA1cHemoglobinA1c
HCPHealthcareproviders
HCVHepatitisCvirus
HEDHumanequivalentdose
hERGhumanether-a-go-go-relatedgene(channel)
HIHemagglutinationinhibition
HIVHumanimmunodeficiencyvirus
HMG-CoAHydroxy-methyl-glutaryl-coenzyme-A
HNSTDHighestnonseverelytoxicdose
HPLCHigh-performanceliquidchromatography
HRHumanresources
HTAHealthtechnologyassessment
HTSHigh-throughputscreening
HVHealthvolunteer
i.p.Intraperitoneal
i.v.Intravenous
IBInvestigator’sbrochure
IC50Halfmaximalinhibitoryconcentration
ICANNInternetCorporationforAssignedNamesand Numbers
ListofAbbreviations xxv
Morethan onemeaning
ICERIncrementalcost-effectivenessratioorInstitutefor ClinicalandEconomicReview 1
ICHInternationalConferenceonHarmonization
IDIntradermaladministration
IDPIntegrateddevelopmentplan
IFCCInternationalFederationofClinicalChemistryand LaboratoryMedicine
IGFInsulin-likegrowthfactor
Il-6Interleukin6
IMDRFInternationalMedicalDeviceRegulatorsForum
IMPInvestigationalmedicinalproduct
IMPDInvestigationalmedicinalproductdocumentation
INDInvestigationalNewDrug
INNInternationalnon-proprietaryname
INTERACTINitialTargetedEngagementforRegulatory AdviceonCBERproducTs
xxvi ListofAbbreviations
AbbreviationsMeaning
IPIntellectualproperty
IPISwissFederalInstituteofIntellectualProperty
IPOInitialpublicoffering
IPRIntellectualpropertyright(s)
IPRPInternationalpreliminaryreportonpatentability
iPS(cell)Inducedpluripotentstemcells
IQVIACompanyname,formerlyQuintilesandIMS Health,Inc.
IQWiGInstitutfürQualitätundWirtschaftlichkeitim Gesundheitswesen
IRBInstitutionalReviewBoard
ISOInternationalOrganizationforStandardization
ISPIndication-specificpricing
ISRInjectionsitereactions
ITTIntent-to-treatpopulation
IVDInvitrodiagnostics
IVDRInvitroDiagnosticDeviceRegulation
JAKJustanotherkinase(Januskinase)
JNKc-JunN-terminalkinases
KCNQPotassiumchannel,voltage-gated,KQT-like subfamily
Kir-channelInwardlyrectifyingK+ channel
KmMichaelisconstant
KOLKeyopinionleader
LADMELiberation/absorption/distribution/ metabolism/elimination
LCMLifeCycleManagement
Morethan onemeaning
LDLoadingdoseorleaddiscovery1
LD50Lethaldosefor50%oftheanimals
LDLLow-densitylipoprotein
LDTLabdevelopedtest
LOLeadoptimization
LoELossofexclusivity
LoILetterofintent
LRVLowerreferencevalue
MA&PMarketaccessandpricingteam
MAAMarketingauthorizationapplication
mAbMonoclonalantibody
MABELMinimumanticipatedbiologicaleffectlevel
MADMultipleascendingdoses
MALDI-TOFMatrix-associatedlaserdesorption/ionization
AbbreviationsMeaning
MAP-kinaseMitogen-activatedproteinkinase
MDMedicaldevice
MDGMedicalgradeplastics
MDRMedicalDeviceRegulation
MDRDModificationofdietinrenaldisease
MEAManagedentryagreements
MedDRAMedicalDictionaryforRegulatoryActivities
ListofAbbreviations
Morethan onemeaning
MHLW(Japanese)MinistryofHealth,Labour,andWelfare
MIC90Minimuminhibitoryconcentration
mMMillimolar
MoAMechanism/modeofaction
MRIMagneticresonanceimaging
mRNAMessengerribonucleicacid
MRSAMethicillin-resistant Staphylococcusaureus
MTAMaterialtransferagreement
MTDMaximumtolerateddose
NANeuraminidase
NADPHNicotinamideadeninedinucleotidephosphate
NAT N -acetyltransferase
NBNotifiedbody
NBTSNon-bindingtermsheet
NCANon-compartmentalanalysis
NDANewdrugapplicationornon-disclosureagreement1
NeeSNon-eCTDelectronicsubmissionformat
NEPNuclearexportprotein
NICENationalInstituteforHealthandCareExcellence
NIHNationalInstitutesofHealth(US)
NMDA N -methyl-D-aspartate
NMENewmolecularentity
NMPANationalMedicalProductsAdministration(China)
NNTNumbers-needed-to-treat
NONitricoxide
NOAELNo-observed-adverse-effectlevel
NPVNet-presentvalueornegativepredictivevalues1
NRTLNationallyRecognizedTestingLaboratory
NSAIDNon-steroidalanti-inflammatorydrug
NTELNotoxiceffectlevel
OATOrganicaniontransporter
OBAOutcomes-basedagreement
OCTOrganiccationtransporter
ODOrphandrug
xxviii ListofAbbreviations
AbbreviationsMeaning
ODAOrphanDrugAct
OECDOrganisationforEconomicCo-operationand Development
OGTTOralglucosetolerancetest
OOPDOfficeofOrphanProductsDevelopment
OSHAOccupationalSafetyandHealthAdministration’s
PAHPulmonaryarterialhypertension
PAIPre-approvalinspection
PASPatientaccessscheme
PBBPolybrominatedbiphenyls
PBDEPolybrominateddiphenylether
PBMPharmacyBenefitManager
PBPKPhysiologicallybasedPK
PCParisconvention
PCRPolymerasechainreaction
PCSK9Proproteinconvertasesubtilisin/kexintype9
PCTPatentCooperationTreaty
PDPharmacodynamics
PDCOPaediatricCommittee
PDE5Phosphodiesterasetype5
PDGFPlatelet-derivedgrowthfactor
PEPolyethylene
PETPositron-emissiontomography
Ph.Eur.EUPharmacopeia
PIPrincipalinvestigator
PIPPaediatricinvestigationplan
PKPharmacokinetics
pKapKaisthenegativelogoftheaciddissociation constant
PKPDPharmacokinetic––Pharmacodynamic
PMDAPharmaceuticalsandMedicalDevicesAgency
PMIProjectManagementInstitute
PoCProofofconcept(study)
PoCTPointofcaretesting
PoMProof-of-mechanism
PopPKPopulationPK
PoSProbabilityofsuccess
PPPer-protocol
PPBPlasmaproteinbinding
PPIProtein–proteininteraction
PPNDPeri-andpostnataldevelopment
AbbreviationsMeaning
PPQProcessperformancequalification
PPVPositivepredictivevalue
PREAPediatricResearchEquityAct
PRIME(EMA’s)Prioritymedicines
PRNProrenata
PROPatient-reportedoutcomes
PSPPaediatricstudyplan
PSURPeriodicsafetyupdatereports
PTEPatenttermextensions
PTRSProbabilityoftechnicalandregulatorysuccess
QALYQuality-adjustedlifeyear
QbDQualitybydesign
QDMQuantitativedecisionmaking
QEDquoderatdemonstrandum
QIVQuadrivalentinfluenzavaccine
QMSQualitymanagementsystem
QSEQuality,safetyefficacy(requirements)
QSPQuantitativesystemspharmacology
QTPPQualitytargetproductprofile
R&DResearchanddevelopment
RARegulatoryaffairs
RAPSRegulatoryAffairsProfessionalsSociety
RDPRegulatorydataprotection
REACHRegistration,evaluation,authorization,and restrictionofchemicals
RIPReceptor-interactingprotein
RMATRegenerativemedicineadvancedtherapy
RMSReportingmemberstate
RNARibonucleicacid
rNPVRiskadjustednetpresentvalue
ROCReceiver-operatingcharacteristics(curve)
RohSRestrictionofcertainhazardoussubstances
ROIReturnofinvestment
RP2DRecommendedphase2dose
RUOResearchuseonly
RWEReal-worldevidence
s.c.Subcutaneous
SADSingleascendingdoses
SARStructure–activityrelationship
SBDDStructure-baseddrugdesign
SCSteeringcommittee
ListofAbbreviations xxix
Morethan onemeaning
AbbreviationsMeaning Morethan onemeaning
scRNAseqSingle-cellRNAsequencing
SCTMPSomaticcelltherapymedicinalproduct
SESubstantiallyequivalent
SGLTSodium-glucoselinkedtransporter
siRNASmallinterferingRNA
SISHSilverinsituhybridization
SLCSolutecarrier
SMESmall-andmedium-sizedenterprises
SmPCSummaryofproductcharacteristics
SNPSingle-nucleotidepolymorphism
SoCStandardofcare
SOPStandardoperatingprocedure
SPSafetypopulation
SPASpecialProtocolAssessment
SPCSupplementalprotectioncertificate
SPECTSingle-photonemissioncomputedtomography
STATSignaltransducersandactivatorsoftranscription
STD10Severelytoxicdosein10%oftherodent
STDISexuallytransmittedinfectiousdiseases
STISexuallytransmittedinfection
SVHCSubstancesofveryhighconcern
T2DType2diabetes
TEPTissue-engineeredproduct
TET2Tetmethylcytosinedioxygenase2
TGATherapeuticGoodsAdministration(Austria)
TGFTransforminggrowthfactor
TITherapeuticindexortargetidentification1
TIVTrivalentinfluenzavaccine
TMTranslationalmedicine
TMPTargetmarketingprofile
TNFTumornecrosisfactor
TOPTargetout-licensingprofile
TPPTargetproductprofile
TRADDTNF(tumornecrosisfactor)R1(receptortype 1)-associateddeathdomain
TRAFTNFreceptor-associatedfactor
TRFTime-resolvedfluorescence
TRPTherapeuticreferencepricing
TRVTargetreferencevalue
TSTermsheet
TVTargetvalidation
AbbreviationsMeaning
UGEUrinaryglucoseexcretion
UGTUDP-glucuronosyltransferase
UPOVConventionoftheInternationalUnionforthe ProtectionofNewVarietiesofPlants
USPIUSpackaginginsert
ListofAbbreviations xxxi
Morethan onemeaning
USPUnitedStatesPharmacopeiaoruniqueselling point(contextdependent) 1
USPTOUnitedStatesPatentandTrademarkOffice
UVUltraviolet(radiation)
VBPValue-basedpricing
VDIAssociationofGermanEngineers
VEGFVascularendothelialgrowthfactor
VFAVerbandderforschendenPharma-Unternehmen
VHPVoluntaryharmonizationprocess
VNVirusneutralization
VoCVoice of customer
WBSWorkbreakdownstructure
WIPOWorldIntellectualPropertyOrganization
WoCBPWomenofchildbearingpotential
WRWrittenrequest
