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PMDA’s experiences to review data ofbridging study based on ICH E5 guideline.Yoshiaki Uyama, Ph.D.Pharmaceuticals & Medical Devices Agency (PMDA)Visiting Professor, Graduate School of Advanced Clinical Science, Chiba UniversityVisiting Professor, Graduate School of Medicine, Nagoya University1Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
E5: Ethnic Factors in the Acceptability ofForeign Clinical Data 2Describes factorswhen extrapolatingforeign clinical data toa new regionFacilitatesacceptance of foreignclinical data in thenew region.Describesdevelopmentstrategies for ethnicfactor-sensitive drugPharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
ICH E5 guidelineClassification of intrinsic and extrinsic ethnic factorsINTRINSICEXTRINSICPhysiological and pathologicalconditionGeneticGenderHeightBody weightLiverKidneyCardiovascular functionsADMEReceptor ltureSocioeconomic statusEducational statusLanguageMedical practiceDisease definition/DiagnosticTherapeutic approachDrug complianceSmokingAlcoholRaceGenetic polymorphism of thedrug metabolismGenetic diseases3DiseasesFood habitStressRegulatory practice/GCPMethodology/EndpointsPharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
E5: Typical Bridging ConceptForeignRegionNewRegion 4PhaseⅠPhase IIDose-FindingStudySimilarityBridgingPKStudyPhase ExtrapolationPhase IIDose-FindingStudy(BridgingStudy)No need to repeat later phase clinical trials in anew region, if bridging was successful.Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Criteria for Successful Bridging Strategy No major impacts of ethnic factors in drugresponses (Efficacy & Safety) Extrinsic ethnic factors Medical Practices, Culture, etc. Intrinsic ethnic factors Genetic profiles, Disease, etc.Effects of ethnic factors in drug responses canbe confirmed in the bridging study5Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Approved Drugs basedon the bridging strategy in Japan6Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Approval Cases based on ICH E5 in JapanIn Japan, drug approval based on the bridgingstrategy has rapidly increased in early 2000,since ICH E5 guideline was established in 19987Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Target Disease Area for Bridging StudyAD: Alzheimer’s diseaseMI: MigrainePD: Parkinson’s DiseasePC: Prostate CancerBC: Breast CancerCC: Colon CancerLC: Lung CancerRh: RhinitisUr: UrticariaRT: Renal transplantationRA: Rheumatoid ArthritisOP: OsteoporosisDM: Diabetes MellitusED: Erectile DysfunctionFlu: Influenza Infection,RSV: Respiratory SyncytialVirus InfectionGC: Glaucoma and OcularHypertensionAMD: Age-related MacularDegenerationHp: H pylori eradicationFor Approved NDA in 1999-2003:8Uyama Y et al, Clin Pharmacol Ther 78:102-113,2005Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Combination Patterns ofPK study and Bridging studyFor Approved NDA in 1999-2003:9Uyama Y et al, Clin Pharmacol Ther 78:102-113,2005Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Patient Numbers enrolled in a Bridging StudyFor Approved NDA in 1999-2003:10Uyama Y et al, Clin Pharmacol Ther 78:102-113,2005Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
A Bridging Strategy shorten a period ofclinical development in JapanDevelopmentbased onBridging Strategyin JapanFull Developmentin JapanNDAMedian: 32 M24 MMedian: 56 MNDATime from starting Phase II to NDA submissionUyama Y et al, Clin Pharmacol Ther, 78: 102-113, 200511Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Actual review cases of the bridging data12Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
SPIRIVA (tiotropium bromide) An anticholinergicwith specificity formuscarinic receptorsChronic obstructivepulmonary disease(COPD)JapanForeignPhase IPhase IIDB, Placebo 3doses, Single,FEV1.0, PKN 27Phase II (Dose Response)DB, Placebo 4doses, SingleFEV1.0, PKN 35Phase IIbridge Phase IIDB, 2 doses Active control,DB, Placebo 4 doses, 4W4W, FEV1.0FEV1.0N 201N 169Phase IIIDB, Placebo 1 dose, 1 Year,FEV1.0N 471 and N 451 (2 studies)Phase IIILong-term safety studyN 161ExtrapolationPhase IIIDB, 1 dose Active control,1 Year, FEV1.0N 288 and N 247 (2 studies)Phase IIIDB, Placebo 1 dose Activecontrol, 6MN 623 and n 584 (2 studies)FEV1.0Other studies13Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Actonel (risedronate sodium) : bisphosphonateJapanPhase I(PK)Phase IIDoseFindingPhase IIIBMDBoneFracture14ForeignBridgingSingle DosePK studyRepeated DoseDietary EffectDietary EffectOther studiesOther studiesEarly Phase IILate Phase IILong term trialBMD trialBridgingBMD trial 1BMD trial 2Bone Fracture trial 1 & 2Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Conc.PK comparison on Risedronate2.5mg; ForeignClinicalTrial5.0mg; ForeignClinicalTrial2.5mg; JapaneseClinicalTrial5.0mg; JapaneseClinical Trial(h) 2.5mg15for Japanese is comparable to 5.0mg for foreign clinical data.Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
PD comparison on Risedronate For BMD change rate, 2.5mg for Japanese is similar to5.0mg for Foreign data5BMD Change Rate 2.5mg5.0mgPharmaceuticals & Medical Devices AgencyDoseFIP Regulatory Science Workshop,Nov. 27th, 2013
BMD change rate (%)BMD Change rate for RisedronateJapanese2.5mg DataForeign 5mgData017(Month)Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Examples of Different Approved Dose in JapanYearDrugIndicationReasonDifferencein Japanese dose1999SildenafilErectiledysfunctionSafetyA half of Caucasian dose（25-50 mg）2002RisedronateOsteoporosisPK/EfficacyA half of Caucasian dose（2.5 mg OD）2002EletriptanMigraineSafetyA half of Caucasian dose（20 mg, Max: 40 RosuvastatinHypercholesterolemiaPK18Japan: 10-25 mg/dayCaucasian: 25 mg/dayA half of Caucasian dose（Initial: 2.5-5 mg OD、Maintenance: 2.5-10 mgOD、Max: 20mg/day）Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Arava （Leflunomide) 19Dihydroorotate dehydrogenase inhibitorTarget Disease： Rheumatoid Arthritis (RA)Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Ethnic Factor Considerations on effects ofleflunomide in Rheumatoid ArthritisJapanDiagnosisUS/EUACR criteriaDiseaseSimilar SymptomNo major differences in Epidemiological dataStandard DrugTherapyDMARDs(MTX), Steroid, NSAIDs or SurgeryClinical EndpointPatient Background(age, gender, bodyweight etc.)Clinical Trial20ACR20, 50, 70 More serious and longer length of diseasepatients were enrolled in Japanese study,and BW is lighter in Japanese, but nomajor impacts in drug responses the other factors were no major differenceICH-GCPPharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Clinical Data Package forLeflunomide in Rheumatoid ArthritisPK studyPK StudyDose-Response StudyPlacebo-controlled Dose-ResponseStudy (YU203) n 419Dose-Response Studyn 2561Y Long-term Safety Studyn 110ExtrapolationPlacebo-controlled ConfirmatoryStudy (US301) n 485Placebo and Active controlledConfirmatory Study (MN301) n 359Active-controlled Confirmatory Studyn 1000Active-controlled Long-term StudySpecial Population etc.21Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Blood Concentration of A771726(μg/mL)PK Comparison in Single AdministrationJapanese populationJapanese populationCaucasianDaysBlood concentration of A771726 in single administration of Leflunomide20mg in Japanese and Caucasian populations 22No Major Differences on PK in leflunomide administrationSimilar PK have been also confirmed in multiple administrationPharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
ACR 20 response rateEfficacy Comparison at 28 weeksLeflunomide Dose (mg) 23Logistic analysis indicates similar dose-responserelationship between populationsPharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Safety Comparison between populations 24Risks in hepatotoxicity, bone marrowsuppression were major concerns in the foreignstudy and these points were also carefullyreviewed in JapanRisks of infectious diseases have been alsodiscussed In the submitted data, no major differencesin seriousness and event rates But, sample size of Japanese populationswas smallerPharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Conclusion of the bridging data in leflunomide review The foreign data can be extrapolated into Japanesepopulations in terms of dose-response effects ofleflunomideHowever, risks in hepatotoxicity, bone marrowsuppression as well as infectious diseases wereidentifiedIn terms of safety, because of small sample size inJapanese, it is difficult to conclude that safety profiles ofleflunomide in Japanese are similar to foreign population.Leflunomide was approved with the condition(mandatory post-market surveillance)25Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
In post-marketing stage of leflunomide All leflunomide-administered patients must beregistered into the survey before startingleflunomide therapy.Serious cases of interstitial lung diseases (ILD)have been reported 5 death cases in 3 month after launch. 16 ILD cases in 3412 patients enrolled in thesurvey“Box Warning” in the label were revised to increasethe precaution level about ILD26Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Examples of Different Risks Japanese have higher risks of drug-inducedInterstitial lung disease (ILD) than foreignpopulationAzuma A, Japan Med Associate J, 50: 405-411, 200727Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Factors affecting to safety measureon post-approval in JapanSafety-RelatedRegulatory ActionPatient Population Estimate inmillion patientsLaunch LagSimilar Mode of ActionBridging Study1.18 0.07 (p 0.01)0.28 0.18 (p 0.05)0.23 0.10 (p 0.01)2.50 1.24 (p 0.1)Modified from data published by Yamada T et al , Ann Pharmacother, 44, 1976-1985, 201028Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Lessons learned (Bridging data review)29 More than 45 NDAs have been approved based on ICHE5 strategy to extrapolate foreign clinical data toJapanese population Comparison of PK profiles among populations is useful toexpect similarities/differences in safety and to enable toset appropriate dose range in dose-finding study. Data regarding dose response relationships in Japanesepopulation is critical and important information todetermine an optimal dosePharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Lessons learned (Bridging data review) 30A drug behaves sometimes differently in Japanesefrom foreign population Number of Japanese patients in “Bridging NDA”is smaller than that in full NDA (full developmentin Japan) Possibility to have unexpected serious adverseevent after drug approval is higher in “BridgingNDA” than that in full NDA An approved drug based on Bridging Strategyshould be closely monitored at post-marketstagePharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Information HOMEPAGE (English)http://www.pmda.go.jp/english/index.html Regulatory Science Pagehttp://www.pmda.go.jp/regulatory/index.html E-mail:uyama-yoshiaki@pmda.go.jpThank you for your attention31Pharmaceuticals & Medical Devices AgencyFIP Regulatory Science Workshop,Nov. 27th, 2013
Placebo-controlled Dose-Response Study (YU203) n 419. Placebo-controlled Confirmatory Study (US301) n 485. Active-controlled Confirmatory Study n 1000. PK Study. Dose-Response Study . n 256. 1Y Long-term Safety Study. n 110. Placebo and Active controlled Confirmatory Study (MN301) n 359. Active-controlled Longterm Study-Special Population etc .
