How should we consider pharmacogenomics

Japan Issues and Counter Measure
for Real Implementation
of Genome Based Clinical Trials
Sanae Yasuda, PhD
Eisai Co., Ltd.
Clinical Pharmacology Group, JPMA
4th Kitasato-Harvard symposium on October 29, 2003
Agenda
• 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’
4th Kitasato-Harvard symposium on October 29, 2003
For personalized medicine
Drug-response related
genes
Selection of patients
＋
Rationalized dosage regimen
Pharmacokinetics
related genes
Drug metabolizing enzymes,
transporters, etc.
Dosage
regimen
Plasma
concentration
Pharmacokinetics
Site of
action
Effects
Pharmacodynamics
To rationalize dosage regimen
4th Kitasato-Harvard symposium on October 29, 2003
Clinical significance of DME polymorphism
(1)
Plasma concentrations in the different CYP2C19 genotype
after omeprazole 20 mg dosing
Clin Pharmacol Ther
1999;65:552-561.
Omeprazole is mainly metabolized by CYP2C19.
Distinct differences in plasma concentration are
observed between CYP2C19 genotypes.
DME: drug metabolizing enzyme
Clinical significance of DME polymorphism
(2)
Median data on 24-hour intragastric pH profiles in the
different CYP2C19 genotype after omeprazole 20 mg dosing
PK difference
between CYP2C19
genotype
PD difference
Clin Pharmacol Ther 1999;65:552-561.
Genotype is required to rationalize the dosing
PK: pharmacokinetics, PD: pharmacodynamics
Clinical significance of DME polymorphism (3)
Yesterday
No. of patients
Tomorrow
EM
genotyping
PM
DOSE RESPONSE STUDY
No. of patients
low
medium
low
high
ex)
EM only
medium
high
Points of concern in clinical development
considering DME polymorphism
• 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?
Important to evaluate the exposure-response
relationship with genetic demographics
in patient
Ideal flow considering PK-related polymorphism
Non-clinical
Suggested genetically variability in PK
large
Clin Pharm
Studies
small
PK comparison
between genotypes
Δlarge
Exploratory
&
Confirmatory
Studies
No No necessity
to consider
genotype
Genotype data
collection
as
demographics
Δsmall
Dosage regimen
by genotype,etc.
Population PK/PD:
genotype
To confirm
as covariate
utility of
genotyping
Yes
Product
Launch
•Dosage regimen by genotype
•Pharmacogenomics-oriented TDM
Genotyping
is useful?
No
No necessity
to consider
genotype
Significance of
genotyping PK-related genes
•Useful for understanding PK variability
•Necessary to rationalize the dosage regimen
Useful to obtain public perception of
significance of personalized medicine
4th Kitasato-Harvard symposium on October 29, 2003
For personalized medicine
Selection of patients
Drug-response related
genes
target molecule, etc.
＋
Rationalized dosage regimen
Pharmacokinetics
related genes
For 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 markers
Yesterday
Tomorrow
Subjects who can benefit
from drug
ineffective
and/or
side-effect
Subjects
can’t
benefit.
Subjects who can
benefit from drug
genomic marker
Enrichment
Power UP &
Safety UP
Benefit／Risk
improvement
4th Kitasato-Harvard symposium on October 29, 2003
Enrichment & Indication
Indication
Enrichment
• 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?
Clinical trial
Drug-response
phenotype
DNA analysis
<Example>
Population without mutation
RESPONDER
・・・ＧＧＴＡＡＣＴ・・・
Association?
・・・ＧＧＣＡＡＣ
Ｔ・・・
NON-RESPONDER
Population with mutation
Retrospective analysis to find an association
between phenotype & genotype
4th Kitasato-Harvard symposium on October 29, 2003
Issues for genomic marker discovery
Association ≠Causality!!!
Retrospective analysis starting
from drug-response phenotype
→Multiplicity/Sensitivity
→Confounding
Necessary
Prospective confirmatory trial
with fully informative population
4th Kitasato-Harvard symposium on October 29, 2003
What products are genomic marker
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 easy
to find genomic marker?
With objective & quantitative end point
for 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 development
PK/PD comparison with foreign data
Bridging strategy
Multinational study
Using identical protocol
We have no option to postpone PG application
in trials conducted in Japan
4th Kitasato-Harvard symposium on October 29, 2003
What kind of infrastructure is necessary
to advance PG application
in clinical trials in Japan?
4th Kitasato-Harvard symposium on October 29, 2003
Ethical issues
Ethical Guidelines for Analytical Research on
the Human Genome/Genes (March 29,
2001)
The present Guidelines do not apply to the registrationoriented 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
GCP trial・・・
For example in clinical trials,
• 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.
How should we conduct clinical trials ethically,
respecting the patient’s rights and decisions?
4th Kitasato-Harvard symposium on October 29, 2003
Common language is necessary
for genomic samples and data
Security level
Japan
•Identified Samples/Data
Low
High
EU/US
• 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
Harmonization of terminology/concept
is necessary at first.
How 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?
Harmonized procedures of sample collection, storage,
analysis are necessary.
Patient privacy &
confidentiality
Data reliability
Study quality
Ethical guideline
Regulatory
4th Kitasato-Harvard symposium on October 29, 2003
What kind of guideline is necessary?
Prior to ‘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
Dialogue between industry and regulatory
Penetration into each clinical study site
4th Kitasato-Harvard symposium on October 29, 2003
Need 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?
Clinical trial
Drug-response
phenotype
DNA analysis
Population without mutation
RESPONDER
・・・ＧＧＴＡＡＣＴ・・・
Association?
・・・ＧＧＣＡＡＣ
Ｔ・・・
NON-RESPONDER
Population with mutation
Retrospective analysis to find an association
between phenotype & genotype
4th Kitasato-Harvard symposium on October 29, 2003
Responder／non-responder?
If the same drug exposure is obtained in each subject…
Clinical response
Medical
progress
High
quality
clinical
trials
Clinical
evaluation
Protocol
compliance
Study design
• Patient’s impression
• Variability in physician’s
evaluation
•Dosing compliance
•Observation schedule
•Placebo-effect
•Spontaneous remission
4th Kitasato-Harvard symposium on October 29, 2003
PG to lead to a real innovation
Medical
progress
Advanced
genome
technology
Personalized
Medicine
High quality
clinical trials
Bioethics
4th Kitasato-Harvard symposium on October 29, 2003
Clinical Pharmacology Group,
Clinical Evaluation Subcommittee,
Drug Evaluation Committee of the JPMA
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
4th Kitasato-Harvard symposium on October 29, 2003

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