pharmacogenomics relating to drug evaluation · harmonization of regulatory approaches dia 3rd...

BIO Japan, Yokohama, Sep 9, 2005Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency

Pharmacogenomics Relating to Pharmacogenomics Relating to Drug EvaluationDrug Evaluation

Yoshiaki Yoshiaki UyamaUyama, Ph.D, Ph.D..Office of New Drug IIIOffice of New Drug III

Pharmaceuticals & Medical Devices AgencyPharmaceuticals & Medical Devices Agency(PMDA)(PMDA)


Recent Topics relating to PGxRecent Topics relating to PGx


TarcevaTarceva ((erlotiniberlotinib))

Approved by FDA in Nov 2004 for NSCLCRandomized, Double-Blind, Placebo-Controlled Trial: 731 patients (488 Tarceva, 243 Placebo)

** ** p<0.001p<0.001

TarcevaTarceva PlaceboPlacebo Hazard Ratio (95% Hazard Ratio (95% CI)CI)

Overall SurvivalOverall Survival 6.7 M6.7 M 4.7 M4.7 M7.9 W7.9 W

0.73 (0.610.73 (0.61--0.86)**0.86)**ProgressionProgression--Free Free

SurvivalSurvival9.9 W9.9 W 0.59 (0.500.59 (0.50--0.70)**0.70)**


EGFR Expression Status EGFR Expression Status

In about 1/3 of the patients (238), EGFR expression In about 1/3 of the patients (238), EGFR expression status was characterized by use of DAKO EGFR status was characterized by use of DAKO EGFR pharmDxpharmDxTMTM kitkit

EGFR EGFR PositivePositive EGFR EGFR NegativeNegative


Label for Label for TarcevaTarcevaData in subgroups including EGFR expression status are described in detail.

Indication & UsageThe treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen

No mandatory test for EGFR expression status is required

The DAKO EGFR pharmDxTM kit has not been validated


Camptosar®(irinotecan HCl)

CYP3A4CYP3A4APC, NPC etcAPC, NPC etc

CarboxyesteraseCarboxyesterase

1/501/50--1/100 1/100 cytotoxicitycytotoxicity

of SN38of SN38

Active MetaboliteActive Metabolite

GlucuronideGlucuronide MetaboliteMetabolite

SAE: SAE: NeutropeniaNeutropenia, Diarrhea, Diarrhea



InnocentiInnocenti F et al, J F et al, J ClinClin OncolOncol, 22: 1382, 2004, 22: 1382, 2004

GroupGroup PrevalencePrevalence Risk of Risk of NeutropeniaNeutropenia

All PatientsAll Patients ---------- 10 %10 %

Patients *1/*1Patients *1/*1 50 %50 % 0 %0 %

Patients *1/*28Patients *1/*28 40 %40 % 12.5 %12.5 %

Patients *28/*28Patients *28/*28 10 %10 % 50 %50 %



LabelLabelClinical Pharmacology / Metabolism and ExcretionClinical Pharmacology / Metabolism and Excretion

SN38 is conjugated by SN38 is conjugated by UGT1A1UGT1A1UGT1A1 UGT1A1 activityactivity is is reducedreduced with UGT1A1with UGT1A1*28*28polymorphismpolymorphism10 %10 % of North American is of North American is homozygoushomozygous for for the the UGT1A1*28 alleleUGT1A1*28 alleleIn a In a prospectiveprospective study, patients who were study, patients who were homozygous for UGT1A1homozygous for UGT1A1*28*28 had a had a higher higher exposure to SN38exposure to SN38 than patients with the than patients with the wildwild--typetype UGT1A1 allele (See WARNING and UGT1A1 allele (See WARNING and DOSAGE AND ADMINISTRATION) DOSAGE AND ADMINISTRATION)



LabelLabelWARNINGWARNING

Individuals who are homozygous for the Individuals who are homozygous for the UGT1A1UGT1A1*28*28 allele are at allele are at increased riskincreased risk for for neutropenianeutropeniaA A reduced initial dosereduced initial dose shouldshould be considered be considered for patients known to be for patients known to be homozygous homozygous for the for the UGT1A1UGT1A1*28*28 allele (see DOSAGE AND allele (see DOSAGE AND ADMINISTRATION)ADMINISTRATION)Heterozygous Heterozygous patients may be at the increased patients may be at the increased risk for risk for neutropenianeutropenia, however, clinical results , however, clinical results have been variable and such patients have have been variable and such patients have been toleratebeen tolerate normal starting dosenormal starting dose



LabelLabelDOSAGE AND ADMINISTRATIONDOSAGE AND ADMINISTRATION

AA reductionreduction in the in the starting dosestarting dose by at least by at least one levelone level# # of CAMPTOSARof CAMPTOSAR® should be should be consideredconsidered for patients known to be for patients known to be homozygous homozygous for the UGT1A1for the UGT1A1*28*28 allele (See allele (See Clinical Pharmacology and WARNING) Clinical Pharmacology and WARNING)

#: 350 mg/m#: 350 mg/m22→→300 300 mg/mmg/m22→→250 250 mg/mmg/m22

The The appropriate doseappropriate dose reduction in this patient reduction in this patient population is population is not knownnot known


UGT1A1*28 in JapaneseSaiSai K et al, K et al, ClinClin PharmacolPharmacol TherTher, 75: 501, 2004, 75: 501, 2004

(N=84)(N=84)

FrequencyFrequency1A1*11A1*1 58.2 % 58.2 % 1A1*61A1*6 15.1 %15.1 %

1A1*281A1*28 13.1 %13.1 %1A1*601A1*60 13.6 %13.6 %

UGT1A1*28 is also important in JapaneseUGT1A1*28 is also important in JapaneseOther alleles such as UGT1A1*6 and *27 have Other alleles such as UGT1A1*6 and *27 have been reported to be useful for predicting been reported to be useful for predicting severe toxicity by severe toxicity by irinotecanirinotecan in Japanesein Japanese

Ando Y et al, Cancer Ando Y et al, Cancer ResRes, 60: 6921, 2000, 60: 6921, 2000


BiDilBiDil ((isosrobideisosrobide dinitratedinitrate and and hydralazinehydralazine hydrochloride)hydrochloride)

VasodilationVasodilationNONO cGMPcGMP

Indication & Usage:The treatment of heart failure as an adjunct to stand therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status


Clinical Trial for Clinical Trial for BiDilBiDil

VV--HeFTHeFT IINo overall significant in mortality between No overall significant in mortality between placebo and placebo and BiDilBiDil groupsgroupsBetter effect in blacks (retrospective analysis) Better effect in blacks (retrospective analysis)

VV--HeFTHeFT IIIIInferior to Inferior to enalaprilenalaprilNo difference in blacks (retrospective analysis)No difference in blacks (retrospective analysis)

AA--HeFTHeFTPlaceboPlacebo--controlled studycontrolled study1050 self1050 self--identified black patientsidentified black patients


Clinical Trial for Clinical Trial for BiDilBiDil

The trial was terminated early (mean followThe trial was terminated early (mean follow--up: 12 M) up: 12 M) because significant improvements were observed in because significant improvements were observed in BiDilBiDilgroupgroup


PGxPGx--based Medicinebased Medicine

“PGx-based medicine is not a dream”

However, to realize it, pharmacogenomics should be appropriately applied in clinical trials


Do not exclude a possible drug target!Do not exclude a possible drug target!

Out of TargetOut of TargetPh I: PGx PK/PDPh I: PGx PK/PD

Ph II: PGx Dose findingPh II: PGx Dose finding

Ph III: PGx Target SelectionPh III: PGx Target Selection

Ph IV: PGx Safety ConfirmationPh IV: PGx Safety Confirmation

Why can not most of my patients Why can not most of my patients be administered the drug?be administered the drug?


How to use PGHow to use PGｘｘ in drug developmentin drug development

PGxPGx

How many capsules are appropriate?How many capsules are appropriate?


Prospective Design for PGx clinical trialProspective Design for PGx clinical trialRandomized, Double Blind, PlaceboRandomized, Double Blind, Placebo--control Trialcontrol Trial

samplingsampling

Genetic Genetic analysisanalysis

(+)(+)

((--))

PlaceboPlacebo

Drug ADrug A

PlaceboPlacebo

Drug ADrug A

rand

omiz

edra

ndom

ized

Treatment periodTreatment period


Results are confirmativeResults are confirmativeBenefit/Risk for gene(Benefit/Risk for gene(--) patients can be ) patients can be evaluatedevaluated

Enough numbers of gene (Enough numbers of gene (--) patients ) patients should be includedshould be included

Enrichment effect is still presentEnrichment effect is still presentAnalyze data in gene(+) patientsAnalyze data in gene(+) patients

→→This types of data would be useful for regulatory This types of data would be useful for regulatory decisiondecision


Establishment of guidance for appropriate Establishment of guidance for appropriate Pharmacogenomic approach Pharmacogenomic approach

in Clinical Trial & Review in Japanin Clinical Trial & Review in Japan


““Submission of Information to Submission of Information to Regulatory Authorities for Preparation of Regulatory Authorities for Preparation of

Guidance for the Use of Pharmacogenomics Guidance for the Use of Pharmacogenomics in Clinical Studiesin Clinical Studies””

June 8, 2004 June 8, 2004 Official announcement was made for inviting the Official announcement was made for inviting the commentscomments

July 9, 2004July 9, 2004 Comment submission was closedComment submission was closed

March 18, 2005March 18, 2005 Final version was notified Final version was notified


Final Version of the NotificationFinal Version of the Notification

PurposePurposeCorrectly understand situations of Correctly understand situations of pharmacogenomic activitiespharmacogenomic activitiesEstablish reasonable & appropriate Establish reasonable & appropriate guidancesguidancesfocusing on Pharmacogenomic Clinical Trialfocusing on Pharmacogenomic Clinical Trial

ContentsContentsRecommend to submit information (List) about Recommend to submit information (List) about Pharmacogenomic Study under conducting, Pharmacogenomic Study under conducting, conducted in the past or planningconducted in the past or planningInformation include a target disease, a target Information include a target disease, a target gene, sample size, purpose of a study. gene, sample size, purpose of a study.


MHLW/PMDA may ask to MHLW/PMDA may ask to provide more dataprovide more data after after submission of the listsubmission of the listThe information is The information is protected to discloseprotected to disclose to the to the publicpublicThe submitted The submitted informationinformation is is not usednot used for for regulatory regulatory decisiondecision for approvalfor approvalDataData having having direct impactdirect impact to indication, dosage or to indication, dosage or safety safety should be submittedshould be submitted in accordance with in accordance with requirement of the law (Pharmaceutical Affair Law)requirement of the law (Pharmaceutical Affair Law)

Remark in the NotificationRemark in the Notification1st deadline for submission1st deadline for submission

September 30, 2005September 30, 2005Even after this period, data submission are Even after this period, data submission are

also appreciated also appreciated


Format of list for submission (1)Format of list for submission (1)

Drug Code/name

Category(types of

drug)

IND No. Phase Trial Period

Country (Race)

Target Size(genetic

test)

AAA 232　Gastric Ulcer

AA0011 IV 1998.1～1998.12(complete)

Japan(Japanese)

Healthy 20(20)

BBB H+ pump inhibitor

-BBB-JPN-22(PPPP)

III 1999.1～2001.12(complete)

Japan(Japanese)

GERD 250(250)

CCC CCC Antagonist

CCC-123-456

II 2003.10～2005.3(on going)

UK, NL, DE and other 3 countries in EU (multi-race including Japanese)

RA 200(200)

DDD TTT Inhibitor

DDD-778899

II 2005.4～2006.3(planning)

Japan(Japanese)

Gastric Cancer

45(20)


Format of list for submission (2)Format of list for submission (2)

Target Gene/Marker

Purpose Method Banking(year)

Schedule for Analysis

Impact on

label

IC Co-dev. of device

CYP2C19

(Exploratory) PK/PD difference

PCR None Complete None Y N

CYP2C19

(Exploratory) Responder rate/Randomized by genotype

PCR None Complete None Y N

Unk (Exploratory)Genetic influence on SAE

DNA Banking(unknown)

Yes(15 y)

Not done(unknown)

None Y N

Unk (Exploratory) Detect genetic biomarker

Microarray Yes(10 y)

Not done(after trial completion)

None Y N


PMDA PDGPMDA PDG (Pharmacogenomics Discussion Group)(Pharmacogenomics Discussion Group)

15 members from Review Offices (New 15 members from Review Offices (New Drug, Safety & Devices) Drug, Safety & Devices)

－－MissionMission－－Share information regarding Share information regarding PGxPGx issuesissuesExchange & Discuss a view of Exchange & Discuss a view of PGxPGxregulationregulationKeep consistency for PMDA consultation & Keep consistency for PMDA consultation & review on review on PGxPGxPromote appropriate Promote appropriate PGxPGx Clinical TrialClinical Trial


Steps for Steps for PGxPGx--based medicinebased medicine

PGPGｘｘ datadata

ReviewReview

Guidance etcGuidance etc

Practical UsePractical Use

PGPGｘｘ TrialTrial

Prescribing Prescribing InformationInformation

(Label)(Label)


International HarmonizationInternational Harmonization


Harmonization of Regulatory ApproachesHarmonization of Regulatory Approaches

DIA 3DIA 3rdrd workshop on Pharmacogenomics workshop on Pharmacogenomics (Apr. 11(Apr. 11--13, 2005)13, 2005)

Session 3 Session 3 ––Global Drug Development & PGGlobal Drug Development & PGPresenters from 3 ICH Regulatory Agencies Presenters from 3 ICH Regulatory Agencies (FDA: Dr Lesko, EMEA: Dr (FDA: Dr Lesko, EMEA: Dr PapalucaPapaluca, PMDA: Dr , PMDA: Dr UyamaUyama))

PGxPGx is useful approach for improving is useful approach for improving Benefit/Risk ratioBenefit/Risk ratioEach Agency works for promoting a use of Each Agency works for promoting a use of PGxPGx in Drug Developmentin Drug DevelopmentHarmonization of Regulatory Approach is Harmonization of Regulatory Approach is possible and necessarypossible and necessary


PGxPGx in ICHin ICH

ICH in May 2005 at BrusselsICH in May 2005 at BrusselsInformal Brain StormingInformal Brain Storming Session on EfficacySession on Efficacy

The group discussed about how to handle The group discussed about how to handle PGxPGx issues in ICHissues in ICHSteering Committee agreed to have anSteering Committee agreed to have aninformal WG on informal WG on PGxPGx at the at the next ICH next ICH meetingmeeting in Chicago (Nov. 2005)in Chicago (Nov. 2005)An An possible topicspossible topics for harmonization will be for harmonization will be discussed (e.g. discussed (e.g. ““TerminologyTerminology””, , ““Information Information for regulatory submissionfor regulatory submission”” etc.)etc.)


R&D stage and clinical trial consultationR&D stage and clinical trial consultation

（Synthesis)（Preparation）（Pharmacology）（Toxicology)etc

Pre P-I

IND

IND

Clinical

PhaseⅠ

PhaseⅡ

End of P-II

PhaseⅢ　　

Pre NDA

ND

AN

DA

Non-Clinical

Review

Pre P-II

Post-Market

PhaseⅣ　　

Pre PMC

End of PMC

Many chances to discuss about Many chances to discuss about PGxPGx issuesissues


InformationInformation

PMDA HOMEPAGEPMDA HOMEPAGEhttp://http://www.pmda.go.jwww.pmda.go.jpp//

PMDA DRUG InformationPMDA DRUG Informationhttp://http://www.info.pmda.go.jpwww.info.pmda.go.jp//EE--mail: mail:

[email protected]@pmda.go.jp

http://www.pmda.go.jp/

http://www.info.pmda.go.jp/

mailto:[email protected]

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