4th kitasato-harvard symposium on october 29, 2003 japan issues and counter measure for real...
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4th Kitasato-Harvard symposium on October 29, 2003
Japan Issues and Counter Measure Japan Issues and Counter Measure for Real Implementation for Real Implementation
of Genome Based Clinical Trialsof Genome Based Clinical Trials
Sanae Yasuda, PhD Eisai Co., Ltd.
Clinical Pharmacology Group, JPMA
4th Kitasato-Harvard symposium on October 29, 2003
AgendaAgenda
• Significance of PG on clinical development– To rationalize dosage regimen– For patient selection
• Construction of infrastructure
PG is used as an abbreviation of ‘pharmacogenetics/pharmacogenomics’
Rationalized dosage regimen
+
Drug metabolizing enzymes, transporters, etc.
Selection of patientsDrug-response related
genes
Pharmacokinetics related genes
For personalized medicineFor personalized medicine
Dosageregimen
Plasmaconcen-tration
EffectsSite ofaction
PharmacokineticsPharmacokinetics PharmacodynamicsPharmacodynamics
4th Kitasato-Harvard symposium on October 29, 2003
To rationalize dosage regimenTo rationalize dosage regimen
Clinical significance of DME polymorphism (1)Clinical significance of DME polymorphism (1)
Plasma concentrations in the different CYP2C19 genotype Plasma concentrations in the different CYP2C19 genotype after omeprazole 20 mg dosingafter omeprazole 20 mg dosing
Omeprazole is mainly metabolized by CYP2C19.Distinct differences in plasma concentration are
observed between CYP2C19 genotypes.
Clin Pharmacol Ther 1999;65:552-561.
DME: drug metabolizing enzyme
Clinical significance of DME polymorphism (2)Clinical significance of DME polymorphism (2)
Median data on 24-hour intragastric pH profiles in the Median data on 24-hour intragastric pH profiles in the different CYP2C19 genotype after omeprazole 20 mg dosingdifferent CYP2C19 genotype after omeprazole 20 mg dosing
Genotype is required to rationalize the dosingGenotype is required to rationalize the dosing
PK difference between CYP2C19
genotype
PD differenceClin Pharmacol Ther 1999;65:552-561.
PK: pharmacokinetics, PD: pharmacodynamics
Exposure
No
. of
pat
ien
ts
low medium high
DOSE RESPONSE STUDY
Exposure
Tomorrow
genotyping EM
PM
Exposure
Yesterday
No
. of
pat
ien
tsClinical significance of DME polymorphism (3)Clinical significance of DME polymorphism (3)
ex)EM only
Exposure
low medium high
Important to evaluate the exposure-response Important to evaluate the exposure-response relationship with genetic demographicsrelationship with genetic demographics
in patientin patient
• Genotype could not fully predict patient’s metabolic capacity because many other factors influence pharmacokinetics.
• Pharmacokinetic comparison between genotypes is not sufficient in small number of healthy volunteers.
• What evidence supports the efficacy of a lower dose in patients with poor metabolic capacity?
Points of concern in clinical development Points of concern in clinical development considering DME polymorphism considering DME polymorphism
Non-clinicalNon-clinical Suggested genetically variability in PK
ProductProductLaunchLaunch
No necessity to consider genotype
No
Exploratory Exploratory &&
Confirmatory Confirmatory StudiesStudies
Clin Pharm Clin Pharm StudiesStudies
PK comparison between genotypes
large
Dosage regimen by genotype,etc.
Δlarge
•Dosage regimen by genotypeDosage regimen by genotype•Pharmacogenomics-oriented TDM Pharmacogenomics-oriented TDM
Population PK/PD:genotype
as covariateTo confirm To confirm
utility of utility of genotypinggenotyping
small
Genotype data collection
as demographics
Δsmall
No
Genotyping is useful?
No necessity to consider genotype
Yes
Ideal flow considering PK-related polymorphism Ideal flow considering PK-related polymorphism
4th Kitasato-Harvard symposium on October 29, 2003
Useful to obtain public perception of significance of personalized medicine
Significance of Significance of genotyping PK-related genotyping PK-related
genesgenes
•Useful for understanding PK variability•Necessary to rationalize the dosage regimen
Rationalized dosage regimen
+
Selection of patientsDrug-response related
genes
Pharmacokinetics related genes
For personalized medicineFor personalized medicine
target molecule, etc.
4th Kitasato-Harvard symposium on October 29, 2003
For Patient SelectionFor Patient Selection
• In case of identifying the drug-response genomic marker in clinical development
• In case of genetically targeted population has been clearly determined
4th Kitasato-Harvard symposium on October 29, 2003
Impact of drug-response genomic markersImpact of drug-response genomic markers
Yesterday Tomorrow
Subjects who can benefit from drug
Subjectscan’t
benefit.ineffectiveand/or
side-effect
Subjects who can benefit from drug
genomic marker
Benefit / Riskimprovement
Power UP & Safety UP
EnrichmentEnrichment
Enrichment & IndicationEnrichment & Indication
EnrichmentIndication
• Possibility to prove efficacy & safety↑• Narrow indication
• Possibility to prove efficacy & safety↓• Broad indication
Proof of concept vs. practical effectiveness?Safety should be evaluated in all population, not
limited to enriched subject?
How could we keep balance between enrichment & indication?
4th Kitasato-Harvard symposium on October 29, 2003
How to find the genomic marker?How to find the genomic marker?
Clinical trial
DNA analysis
・・・G G T A A C T ・・・ RESPONDER
NON-RESPONDER
Drug-responsephenotype
Association?・・・G G C A A C T ・・・
Retrospective analysis to find an association between phenotype & genotype
Population without mutation
Population with mutation
<Example><Example>
4th Kitasato-Harvard symposium on October 29, 2003
Issues for genomic marker discoveryIssues for genomic marker discovery
Association ≠Causality!!!Association ≠Causality!!!
Prospective confirmatory trial Prospective confirmatory trial
with fully informative populationwith fully informative population
Retrospective analysis starting from drug-response phenotype →Multiplicity/Sensitivity →Confounding
NecessaryNecessary
4th Kitasato-Harvard symposium on October 29, 2003
What products are genomic marker What products are genomic marker especially valuable for?especially valuable for?
Products with• marginal efficacy• narrow therapeutic window
Products for • disease with irreversible progression• disease which needs long term to
evaluate the drug-response
4th Kitasato-Harvard symposium on October 29, 2003
What products are easyWhat products are easy to find genomic marker?to find genomic marker?
With objective & quantitative end point With objective & quantitative end point
for phenotype determinationfor phenotype determination
ex) diabetes, hyperlipemia, etc.
But, easy to monitor without genomic marker?
• Highly needed for CNS drug• Cancer would be difficult to predict response
by analysis of blood specimen.
4th Kitasato-Harvard symposium on October 29, 2003
Increasing trend in clinical developmentIncreasing trend in clinical development
Using identical protocol
We have no option to postpone PG application We have no option to postpone PG application in trials conducted in Japanin trials conducted in Japan
Bridging strategy Multinational
study
PK/PD comparison with foreign data
4th Kitasato-Harvard symposium on October 29, 2003
What kind of infrastructure is necessaryWhat kind of infrastructure is necessary
to advance PG application to advance PG application
in clinical trials in Japan?in clinical trials in Japan?
4th Kitasato-Harvard symposium on October 29, 2003
Ethical issuesEthical issues
Ethical Guidelines for Analytical Research on the Human Genome/Genes (March 29, 2001)
The present Guidelines do not apply to the registration-oriented clinical studies and post-marketing surveillance of drugs to be conducted under the Pharmaceutical Affairs Law.
<Ethical guidelines by three ministries>
However, • In actual PG applied clinical trials, it is considered
that this ethical guideline should be followed. • Many different interpretations of this ethical
guideline exist in industries, clinical study sites, etc.
4th Kitasato-Harvard symposium on October 29, 2003
When Ethical Guideline is applied to When Ethical Guideline is applied to GCP trialGCP trial ・ ・ ・・ ・ ・
• Should we ask IRB to satisfy the Ethics Review Committee’s criteria?
• Could we prepare counseling in all PG applied clinical trials?
• Personal information manager is required?・・・・・・・・・・ etc.etc.
For example in clinical trials,
How should we conduct clinical trials ethically, respecting the patient’s rights and decisions?
Common language is necessary Common language is necessary for genomic samples and datafor genomic samples and data
Harmonization of terminology/concept
is necessary at first.
Security level Japan EU/US
Low
High
•Identified Samples/Data
• Anonymity that may be linked to subjects
•Coded Samples/Data•De-Identified Samples/Data
• Anonymity that cannot be linked to subjects
•Anonymized Samples/Data •Anonymous Samples/Data
4th Kitasato-Harvard symposium on October 29, 2003
How to manage information securityHow to manage information security
• Genomic data for registration should be auditable to confirm data reliability.
• How should we collect and handle personal genomic samples and data with high security?
Patient privacy & confidentiality Data reliability
Study qualityStudy qualityEthical guidelineEthical guideline
Harmonized procedures of sample collection, storage, Harmonized procedures of sample collection, storage, analysis are necessary.analysis are necessary.
RegulatoryRegulatory
4th Kitasato-Harvard symposium on October 29, 2003
What kind of guideline is necessary?What kind of guideline is necessary?
Prior to ‘Genomic Data Submission Guideline’‘Genomic Data Submission Guideline’ ・・・• Interpretation of ethical guideline when it is applied to
clinical trials• Basic elements for protocol & informed consent • Harmonized procedures of samples & data handling
with care of patient’s privacy & confidentiality
Now, J-PMA is making its policy
Penetration into each clinical study site
Dialogue between industry and regulatory
4th Kitasato-Harvard symposium on October 29, 2003
Need for EducationNeed for Education • Industry• Regulatory• Investigator, Clinical Research Coordinator• IRB members
Frequent opportunities for exchange of information & discussion are necessary
4th Kitasato-Harvard symposium on October 29, 2003
How to find the genomic marker?How to find the genomic marker?
Clinical trial
DNA analysis
・・・G G T A A C T ・・・ RESPONDER
NON-RESPONDER
Drug-responsephenotype
Association?・・・G G C A A C T ・・・
Retrospective analysis to find an association between phenotype & genotype
Population without mutation
Population with mutation
4th Kitasato-Harvard symposium on October 29, 2003
ResponderResponder // non-responder?non-responder?
Clinical evaluation
Study design
Protocol compliance
Clinical responseClinical response
•Placebo-effect•Spontaneous remission
•Dosing compliance•Observation schedule
• Patient’s impression• Variability in physician’s
evaluation
If the same drug exposure is obtained in each subject…
Medical Medical progressprogress
HighHighqualityqualityclinicalclinicaltrialstrials
4th Kitasato-Harvard symposium on October 29, 2003
Medical Medical progressprogress
High quality High quality clinical trialsclinical trials
Advanced Advanced genome genome
technologytechnology
Bioethics
PG to lead to a real innovationPG to lead to a real innovation
PersonalizedPersonalizedMedicineMedicine
4th Kitasato-Harvard symposium on October 29, 2003
市原伴子( Tomoko Ichihara, Chugai Pharmaceuticals Co., Ltd. )今井康彦( Yasuhiko Imai, Yamanouchi Pharmaceutical Co., Ltd..)
貝原徳紀( Atunori Kaibara, Fujisawa Pharmaceutical Co., Ltd. )川合良成( Ryosei Kawai, Novartis Pharma K.K. )谷河賞彦( Takahiko Tanigawa, Bayer Yakuhin, Ltd. )朝野芳郎( Yoshiro Tomono, Pfizer Japan Inc. )平岡聖樹( Masaki Hiraoka, Bristol-Myers K.K. ) 平山正史( Masashi Hirayama, Takeda Chemical Industries, Ltd. )安田早苗( Sanae Yasuda, Eisai Co., Ltd. )
アイウエオ順,敬称略
Clinical Pharmacology Group, Clinical Pharmacology Group, Clinical Evaluation Subcommittee, Clinical Evaluation Subcommittee,
Drug Evaluation Committee of the JPMADrug Evaluation Committee of the JPMA