ich overview& impacts of efficacy guideline in global...

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


OutlineOutline

ICH ICH overviewoverviewIntroduction of ICH Efficacy Introduction of ICH Efficacy GuidelineGuideline

Key MessageKey Message


ICH OverviewICH Overview


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


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


EuropeEU/EMEA EFPIA

JapanMHLW/PMDA JPMA

United States FDA PhRMA

Observers: WHO, Canada, EFTA

ICH MembershipICH Membership


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)


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<


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


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


A Introduction ofA Introduction ofICH Efficacy GuidelineICH Efficacy Guideline


ICH Efficacy GuidelineICH Efficacy Guideline

E8

E7E9

E10E11

and more……


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))


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


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.


Globalization of Clinical TrialsGlobalization of Clinical Trials

Nature Rev Drug Discovery, 7: 13, 2008

Japan15.7; 10.3%


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


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


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


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 ○ × ○ ○ ○ ○ ○ ○


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.


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


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


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


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.


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)


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


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


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

ich overview& impacts of efficacy guideline in global...

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