4th Kitasato-Harvard symposium on October 29, 2003 Japan Issues and Counter Measure for Real...

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


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


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


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.


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


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?


How to find the genomic marker?How to find the genomic marker?

Clinical trial

DNA analysis

・・・ＧＧＴＡＡＣＴ・・・ RESPONDER

NON-RESPONDER

Drug-responsephenotype

Association?・・・ＧＧＣＡＡＣＴ・・・

Retrospective analysis to find an association between phenotype & genotype

Population without mutation

Population with mutation

<Example><Example>


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


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


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.


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


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?


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.


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


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


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


Need for EducationNeed for Education • Industry• Regulatory• Investigator, Clinical Research Coordinator• IRB members

Frequent opportunities for exchange of information & discussion are necessary


How to find the genomic marker?How to find the genomic marker?

Clinical trial

DNA analysis

・・・ＧＧＴＡＡＣＴ・・・ RESPONDER

NON-RESPONDER

Drug-responsephenotype

Association?・・・ＧＧＣＡＡＣＴ・・・

Retrospective analysis to find an association between phenotype & genotype

Population without mutation

Population with mutation


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


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


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

4th Kitasato-Harvard symposium on October 29, 2003 Japan Issues and Counter Measure for Real...

Documents

Transcript of 4th Kitasato-Harvard symposium on October 29, 2003 Japan Issues and Counter Measure for Real...