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Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
ICH OverviewICH Overview& Impacts of & Impacts of Efficacy Guideline in Global Drug Efficacy Guideline in Global Drug
DevelopmentDevelopment
Yoshiaki Uyama, Ph.D.Yoshiaki Uyama, Ph.D.Pharmaceuticals & Medical Devices Agency (PMDA)Pharmaceuticals & Medical Devices Agency (PMDA)
JapanJapan
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
OutlineOutline
ICH ICH overviewoverviewIntroduction of ICH Efficacy Introduction of ICH Efficacy GuidelineGuideline
Key MessageKey Message
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
ICH OverviewICH Overview
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
I C HI C HINTERNATIONAL CONFERENCE ONINTERNATIONAL CONFERENCE ONHARMONIHARMONIS/ZS/ZATIONATIONof of Technical Requirements Technical Requirements for the Registration of for the Registration of Pharmaceuticals for Human UsePharmaceuticals for Human Use
http://http://www.ich.orgwww.ich.orgHosted by ICH SecretariatIFPMA, Geneva, Switzerland
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
ICH BackgroundICH BackgroundUnique Unique harmonisationharmonisationproject involving the regulators project involving the regulators
and researchand research--based industries of US, EU and Japan based industries of US, EU and Japan Started in 1990 (20 year Anniversary Next Year)Started in 1990 (20 year Anniversary Next Year)WHO, Canada, and EFTA are observersWHO, Canada, and EFTA are observers
WellWell--defined objectives: defined objectives: To improve efficiency of new drug development and To improve efficiency of new drug development and registration processregistration process
To To promotepromotepublic public healthhealth, , preventpreventduplication of duplication of clinicalclinicaltrials in trials in humanshumansand minimise the use of and minimise the use of animal animal testingtestingwithoutwithoutcompromisingcompromisingsafetysafetyand and effectivenesseffectiveness
Accomplished through the development and Accomplished through the development and implementation of implementation of harmonisedharmonisedguidelines and standardsguidelines and standards
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
EuropeEU/EMEA EFPIA
JapanMHLW/PMDA JPMA
United States FDA PhRMA
Observers: WHO, Canada, EFTA
ICH MembershipICH Membership
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
ICH StructureICH Structure
SafetyQuality Efficacy Multi-disciplinary
Coordinators Secretariat
EWG(Expert WorkingGroups):DevelopmentIWG(Implementatyion Working Group): Q&A, Implementation
Observers
Decision-making body SteeringCommitee(SC)
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
Steps in the ICH ProcessSteps in the ICH Process
STEP 1 -Building Scientific Consensus>SC APPROVES establishment of EWG<
STEP 2 -Agreeing Six Party Consensus>SC SIGN OFF<
STEP 3 -Consulting with Regional Regulatory Agencies –Comment Period
After adoption After adoption of a topic by of a topic by the Steering the Steering CommitteeCommittee
STEP 5 -Implementing Guidelines in ICH RegionsSTEP 4 -Adopting
HarmonisedGuidelines>SC SIGN OFF<
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
Over 50 guidelines on Over 50 guidelines on technicaltechnicalrequirementsrequirementson: on: Quality, Safety and EfficacyQuality, Safety and Efficacy
Examples: Examples: E2B: E2B: Electronic Standards for the Transfer of Electronic Standards for the Transfer of Regulatory Information (ESTRI)Regulatory Information (ESTRI)
CTD & eCTD: (electronic) CTD & eCTD: (electronic) Common Technical Common Technical Document (Document (M4 & M2)M4 & M2)
MedDRA: MedDRA: Medical dictionary for adverse event Medical dictionary for adverse event reporting and coding of clinical trial datareporting and coding of clinical trial data
ICH ICH OutcomesOutcomes
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
ICH: ICH: KeysKeysto to successsuccessEffective management and administrationEffective management and administration
Through ICH Secretariat and Steering Through ICH Secretariat and Steering CommitteeCommittee
Joint Joint participation of regulators and industryparticipation of regulators and industryScience based and consensus drivenScience based and consensus drivenFrequent, Frequent, regular basis, regular basis, concurrent meetings concurrent meetings of SC and Working Groups that are outcomes of SC and Working Groups that are outcomes basedbased
Commitment of all parties to implement Commitment of all parties to implement harmonized guidelinesharmonized guidelines
WellWell--defined process and proceduresdefined process and procedures
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
A Introduction ofA Introduction ofICH Efficacy GuidelineICH Efficacy Guideline
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
ICH Efficacy GuidelineICH Efficacy Guideline
E8
E7E9
E10E11
and more……
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
ICH Efficacy GuidelineICH Efficacy GuidelineCover the wideCover the wide--range of issues relating to range of issues relating to clinical efficacy and safety of a drug clinical efficacy and safety of a drug
e.g.e.g.E5E5: Ethnic Factors: Ethnic FactorsE4, E8, E9, E10: Clinical Trial DesignsE4, E8, E9, E10: Clinical Trial DesignsE6: GCPE6: GCPE7, E11: Special PopulationE7, E11: Special PopulationAnd MoreAnd More
Q&A maybe provided for more detailed Q&A maybe provided for more detailed explanation, if necessary (e.g.; E5 Q&A)explanation, if necessary (e.g.; E5 Q&A)Guideline maybe also updated or new Q&A Guideline maybe also updated or new Q&A maybe added to catch up with the latest maybe added to catch up with the latest science, if appropriate (e.g.; E5, E7(on going)) science, if appropriate (e.g.; E5, E7(on going))
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
E3: E3: Structure and Content of Clinical Structure and Content of Clinical Study ReportsStudy Reports
ObjectivesObjectivesAllow the compilation of a single core Allow the compilation of a single core clinical clinical study reportstudy reportacceptable to all regulatory acceptable to all regulatory authorities of the ICH regions. authorities of the ICH regions. STRUCTURE AND CONTENT OF STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTSCLINICAL STUDY REPORTS
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
E6: E6: Guideline forGuideline forGood Clinical PracticeGood Clinical Practice
ObjectivesObjectivesGood Clinical Practice (GCP)Good Clinical Practice (GCP)is an is an international ethical international ethical and scientific quality standardand scientific quality standardfor clinical trials that for clinical trials that provides assurance that the data and reported results are provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. confidentiality of trial subjects are protected.
Compliance with this standard provides public assurance Compliance with this standard provides public assurance that the rights, safety and wellthat the rights, safety and well--being of trial subjects are being of trial subjects are protected. protected.
The objective of this ICH GCP Guideline is to provide a The objective of this ICH GCP Guideline is to provide a unified standard for the ICH regions to facilitate unified standard for the ICH regions to facilitate the mutual the mutual acceptance of clinical dataacceptance of clinical databy the regulatory authorities in by the regulatory authorities in these jurisdictions. these jurisdictions.
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
Globalization of Clinical TrialsGlobalization of Clinical Trials
Nature Rev Drug Discovery, 7: 13, 2008
Japan15.7; 10.3%
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
E4: DoseE4: Dose--Response Information to Support Response Information to Support Drug Registration Drug Registration
ObjectivesObjectivesTo describe the importance of To describe the importance of DoseDose--Response Response InformationInformationin drug developmentin drug developmentMinimum effective dose, maximum useful Minimum effective dose, maximum useful dose dose
To describe To describe trial designstrial designsto obtain doseto obtain dose--response informationresponse informationParallel/CrossParallel/Cross--over/Titrationover/Titration
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
E8: General Considerations for E8: General Considerations for Clinical TrialsClinical Trials
ObjectivesObjectivesDescribe Describe internationally accepted principles and internationally accepted principles and practicespracticesin the conduct of both individual clinical trials in the conduct of both individual clinical trials and overall development strategy for new medicinal and overall development strategy for new medicinal productsproducts
Facilitate Facilitate the evaluation and acceptance of foreign the evaluation and acceptance of foreign clinical trial dataclinical trial databy promoting common understanding of by promoting common understanding of general principles, general approaches and the definition general principles, general approaches and the definition of relevant terms.of relevant terms.
Present an overview of the ICH clinical safety and Present an overview of the ICH clinical safety and efficacy documents and efficacy documents and facilitate the user's accessfacilitate the user's accessto to guidance pertinent to clinical trials within these guidance pertinent to clinical trials within these documents. documents.
Provide a separate glossary of terms used in the ICH Provide a separate glossary of terms used in the ICH clinical safety and efficacy related documents that clinical safety and efficacy related documents that pertain to clinical trials and indicate which documents pertain to clinical trials and indicate which documents contain them.contain them.
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices AgencyPhaseⅠ PhaseⅡ PhaseⅢ PhaseⅣ
Therapeutic Use
Therapeutic Confirmatory
Therapeutic ExploratoryHuman Pharmacology
Time
ReportAnalysisConductDesign
Objectives
Individual Study
E8: Drug Development: E8: Drug Development: Phases & Types of StudyPhases & Types of Study
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
E9: Statistical Principles for Clinical TrialsE9: Statistical Principles for Clinical TrialsDescribe Describe general statistical principlesgeneral statistical principlesfor for conducting clinical trials: E9conducting clinical trials: E9Trial design, Endpoint, Minimization of Bias, Trial design, Endpoint, Minimization of Bias, Sample size, Monitoring etc.Sample size, Monitoring etc.
Describe issues for Describe issues for selecting a control groupselecting a control groupin in clinical trials: E10clinical trials: E10Advantage & Disadvantage of each control Advantage & Disadvantage of each control groupgroup
E10: Choice of Control Group and Related E10: Choice of Control Group and Related Issues in Clinical TrialsIssues in Clinical Trials
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
EE1010: Usefulness of Specific Concurrent : Usefulness of Specific Concurrent Control Types in Various SituationsControl Types in Various Situations
Type of Control
Objective Placebo Active Non-
inferiority Active
Superiority Dose
Response (D/R)
P+A P+D/R A+D/R P+A+D/R
Absolute Effect Size ○ × × × ○ ○ × ○
Existence of Effect ○ △ ○ ○ ○ ○ ○ ○
Dose- Response relationship
× × × ○ × ○ ○ ○
Compare Therapy × △ ○ × ○ × △ ○
Assay Sensitivity ○ × ○ ○ ○ ○ ○ ○
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
E5: Ethnic Factors in the Acceptability of E5: Ethnic Factors in the Acceptability of Foreign Clinical DataForeign Clinical Data
OBJECTIVEOBJECTIVETo describe the characteristics of To describe the characteristics of foreign clinical dataforeign clinical datathat will facilitate theirthat will facilitate theirextrapolationextrapolationto different to different populations and support their acceptance as a basis populations and support their acceptance as a basis for registration of a medicine in a new region. for registration of a medicine in a new region. To describe regulatory strategies that To describe regulatory strategies that minimize minimize duplication of clinical dataduplication of clinical dataand facilitate acceptance of and facilitate acceptance of foreign clinical data in the new region. foreign clinical data in the new region. To describe the use of To describe the use of bridging studiesbridging studies, when , when necessary, to allow extrapolation of foreign clinical necessary, to allow extrapolation of foreign clinical data to a new region. data to a new region. To describe development strategies capable of To describe development strategies capable of characterizing characterizing ethnic factor influencesethnic factor influenceson safety, on safety, efficacy, dosage and dose regimen. efficacy, dosage and dose regimen.
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
Classification of intrinsic and extrinsic ethnic factorsINTRINSICINTRINSIC EXTRINSICEXTRINSIC
GeneticGenetic Physiological and pathological Physiological and pathological conditioncondition EnvironmentalEnvironmental
GenderGender ClimateClimateHeightHeight SunlightSunlight
Body weightBody weight PollutionPollutionLiverLiver CultureCultureKidneyKidney Socioeconomic statusSocioeconomic status
Cardiovascular functionsCardiovascular functions Educational statusEducational statusLanguageLanguage
ADMEADMEReceptor sensitivityReceptor sensitivity Medical practiceMedical practice
Disease definition/DiagnosticDisease definition/DiagnosticRaceRace Therapeutic approachTherapeutic approach
Drug complianceDrug complianceSmokingSmokingAlcoholAlcohol
Genetic polymorphism of the Genetic polymorphism of the drug metabolismdrug metabolism
Food habitFood habitStressStress
Genetic diseasesGenetic diseases DiseasesDiseases Regulatory practice/GCPRegulatory practice/GCPMethodology/EndpointsMethodology/Endpoints
ICH E5 guidelineICH E5 guideline
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
E5: Bridging ConceptE5: Bridging Concept
Foreign RegionPhasePhase
ⅠⅠ
Phase IIPhase IIDoseDose--Finding Finding StudyStudy
New Region
Special Special PopulationPopulation
Phase IIIPhase IIIConfirmatory Confirmatory
StudyStudy
No need to repeat a later phase of clinical trials No need to repeat a later phase of clinical trials in a new region, if bridging was success.in a new region, if bridging was success.
LongLong--TermTermStudyStudy
PK PK StudyStudy
Phase IIPhase IIDoseDose--Finding Finding StudyStudy
(Bridging (Bridging Study)Study)
Similarity Bridging Extrapolation
Special Population
Phase IIIConfirmatory
StudyLong-TermStudy
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
E5 Q&A (Question 11)E5 Q&A (Question 11)Bridging Concept can be applied in MultiBridging Concept can be applied in Multi--Regional Regional Clinical TrialsClinical TrialsA bridging study can be done at the beginning, A bridging study can be done at the beginning, during or at the end of a global development during or at the end of a global development programprogram
Points to consider in Planning, Analysis, Points to consider in Planning, Analysis, Evaluation of the MultiEvaluation of the Multi--Regional Clinical Trials Regional Clinical Trials are providedare providedNeed to include sufficient numbers of Need to include sufficient numbers of subjectssubjects
Evaluate consistency of effects (e.g.; doseEvaluate consistency of effects (e.g.; dose--response) across regionsresponse) across regions
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
ICH E7 & E11 guidelineICH E7 & E11 guideline
General principles in drug development for special General principles in drug development for special populationspopulationsGeriatric Geriatric population: population: E7E7
Patient numbers, Age distribution etc.Patient numbers, Age distribution etc.
PediatricPediatricpopulation: population: E11E11Timing, Formulation, Age, Ethics etc.Timing, Formulation, Age, Ethics etc.
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
Other EfficacyOther Efficacy--related guidelinerelated guidelineE14:E14: The Clinical Evaluation of The Clinical Evaluation of QT/QTcQT/QTcInterval Interval Prolongation and Proarrhythmic Potential for Prolongation and Proarrhythmic Potential for NonNon--Antiarrhythmic Drugs (May 2005)Antiarrhythmic Drugs (May 2005)
E15:E15:DefinitionsDefinitionsfor Genomic Biomarkers, for Genomic Biomarkers, PharmacogenomicsPharmacogenomics, Pharmacogenetics, , Pharmacogenetics, Genomic Data and Sample Coding Categories Genomic Data and Sample Coding Categories (Nov. 2007) (Nov. 2007)
E16E16::Genomic BiomarkersGenomic BiomarkersRelated to Drug Related to Drug Response: Context, Structure, and Format of Response: Context, Structure, and Format of Qualification Submissions Qualification Submissions (Step 2, June 2009)(Step 2, June 2009)
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
Key MessageKey Message
Global drug developmentGlobal drug developmentwill be more will be more increased and more importantincreased and more important
MoreMorecooperation/collaborationcooperation/collaborationisiskey to key to successful successful global drug developmentglobal drug development
HHarmonisationarmonisationcan reduce duplication and can reduce duplication and increase shared expertise and promote increase shared expertise and promote public healthpublic health
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
Key messagesKey messages
Proper implementationProper implementationof ICH guidelines is of ICH guidelines is necessary to conduct scientific and ethical necessary to conduct scientific and ethical MultiMulti--regional clinical trialsregional clinical trials
Common understandingCommon understandingof principles and of principles and contents of ICH guidelines is important for contents of ICH guidelines is important for the proper implementationthe proper implementation
TrainingTrainingis key to the proper implementationis key to the proper implementation
Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency
InformationInformation
PMDA HOMEPAGE (English Version)PMDA HOMEPAGE (English Version)http://http://www.pmda.go.jp/english/index.htmlwww.pmda.go.jp/english/index.html(Renewal on March 6, 2009)(Renewal on March 6, 2009)
EE--mail:mail:[email protected]@pmda.go.jp
Thank you for your attention