japan perspective on pgt/pgx in the drug development and approval process j. azuma m.d. osaka...
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Japan Perspective on Japan Perspective on PGt/PGx PGt/PGx
in the Drug Development in the Drug Development and Approval Processand Approval Process
J. Azuma M.D. Osaka University, Osaka, JAPAN
OSAKA UNIVERSITY
22
Non responderNon responder
Asthma β2 adrenergic agonist 4 〜 75 5-LO, LTD4
Cancer Various 70 〜 100( breast,lung,brain) Depression SSRIs, Tricyclics, MAOs 20 〜 40 Diabetes Sulfonylurea, Biguanides, 50 〜 75
GlitazonesDuodenal ulcer H2 antagonists, 20 〜 70 Proton pump inhibitorsHyperlipidemia HMGCoA reductase, 30 〜 75
Resins, Niacin
Disease Drug Class Non responder (%)
Pharmacogenomics eds. Kalow, Tyndale, Meyer (p17, Marcel Dekker, May 2001)
33
Paradox of Modern Drug Paradox of Modern Drug DevelopmentDevelopment
● Clinical trials provide evidence of efficacy and safety at usual doses in populationspopulations
● Physicians treat iindividual ndividual patients who can vary widely in their response to drug therapy
Lawrence J. Lesko; International Pharmacogenomics Symposium
Tokyo, Japan April 25, 2003
44
Overview of TalkOverview of Talk
Treatment of tuberculosis with isoniazid and rifampicin
Treatment of chronic heart failure with β-adrenergic receptor blockers
Japan Pharmacogenomics Consortium (JPGC)Pharmacogenetics (PGx)-Pharmacoeconomics (PEx) Working Group
Pharmacogenome Tip Top Inc. (P-TipTop)
5
Treatment of Pulmonary Tuberculosis
•Approximately 20% of the patients treated with Rifampicin and INA develop hepatotoxicity.
•Metabolic enzyme of INH is NAT2.
•Rifampicin strongly induces many drug metabolizing enzymes.
6
Metabolic pathways of isoniazid
EnzymeAcetylation
Acetylation
Acetyl-
glycineIsonicotinyl
Rifampicin
Acetylhydrazine (AcHz)NH2NHCOCH3
NAT2
(NHCOCH3)2Diacetylhydrazine
N
COOHisoniazid
induction
N
CONHNHCOCH3
N
CONHNH2
NAT2 Hydrazine (Hz)
NH2NH2
Hepatotoxic
Isoniazid (INH) Hydrolysis
NAT2
Hydrolysis
7
Mutation of N-acetyltransferase 2
803
481C→ T
590G→A
857G→A
845
434
341
282
191G→A
C→T
A→C
A→C
A→G
A→C111T→C
190C→T
499
G→A
759 C→T
* * *** * * *** * * *
SNPs
8
Frequency of the NAT2 genotypes in Frequency of the NAT2 genotypes in patients patients
Genotype
NAT2*4 / *4NAT2*4 / *5NAT2*4 / *6NAT2*4 / *7
NAT2*5 / *5
NAT2*5 / *6
NAT2*5 / *7
NAT2*6 / *6
NAT2*6 / *7
NAT2*7 / *7
n %
RA type (40.3%)
IA type (46.5%)
SA type (13.2%)
46
43415
020742
114
40.3
3.529.813.2
0.01.80.06.13.51.8
100.0
9
Incidence of INH-Rifampicin (RFP) induced Incidence of INH-Rifampicin (RFP) induced hepatotoxicity and NAT2 genotypehepatotoxicity and NAT2 genotype
normal hepatotoxicity
criteria: serum AST and/or ALT > 1.5 x upper limits of normal and 2 x before administration.
Incidence (%)0 20 40 60 80 100
Total(n=114)
RA type(n=46)
SA type(n=15)
IA type(n=53) *
*
* P<0.01
10
Trough plasma concentration of INH and
hydrazine metabolites in relation toNAT2 gene polymorphisms
RAIASA
*p < 0.05 vs RA & IA
mean±SD
(n=29)
(n=31)
(n= 7)
Pla
sma
conc
ent
r ati o
n (
M)
0
2
4
6
8
INH AcHz Hz
**
**
**
11
Hydrazine induced cytotoxicity on HepG2 cells
1 2 3 4 5 6 7 8 9 10 111213
M*5
KpnⅠ*6
TaqⅠ*7
BamHⅠ
2,6,10 : w/w 3,7,11 : w/m4,8,12 : m/m 5,9,13 : HepG2
Genotype of HepG2 NAT2 *5/ *6 ( slow acetylator )Culture : MEM/Earle’s salt (10% FBS) 5% CO2 -95% Air 37 °C
Stimulus : Hz, AcHz
Incubation time : 48 hour
Assay : AST, ALT, and LDH leakage Cell proliferation
12
Toxic effects of hydrazine on HepG2 cells
Mean±S.E. (n=12) Incu. 48h * P < 0.05
Cell proliferation ALT
Cont AcHz
Ra
tio to
th
e n
ontr
eate
d co
ntr
ol (
%) *
Cont
En
zym
e le
aka
ge
into
the
me
diu
m (
IU/L
) *
HzHz AcHz0
100
50
0
10
20
0.3 mM 0.1 mM 0.3 mM 0.1 mM
13
INH(mg/day) 400 100 200
RFP(mg/day) 450 450 300
Case 1( female 69years)
Day0 20 4030 50 60 70 80 9010
250
300
350
200
150
100
50
0Se
rum
am
ino
tran
sfe
ras
e (
IU/L
)
ASTALT
drug monitoring
Case in SA type
検出菌数(蛍光法) 2+ 1+ ±
発疹のため投与中止
NAT2*6/*6 (SA type)
14
0 5 10 15
5
6
7
4
3
2
1
0
Time after administration (hr)
INH
co
nce
ntr
atio
n (g
/mL
)
400mg/day200mg/day
Plasma INH concentration-time profile observed in patient of case1
Reduced
15
Cases in RA type
INH 400mg/day(po)
+200mg/day(inhalation)
+RFP+SM
Case 5 (male 62years)
: NAT2*4/*4 (RA type)
INH 400mg/day (po)+RFP+SM
Poor Response
Cured
Time after administration (hr)
INH
con
c. (g
/mL)
0 5 10 15
Case 5Mean of RA type(400 mg/day)
2
1
3
1616
INH + RFP
slow acetylator (SA type)
intermediate acetylator (IA type)
rapid acetylator (RA type)
Continue
Chenge regimen
Delayed Cured
INH-RFP induced hepatotoxicityINH-RFP induced hepatotoxicity
Liver Toxicity
RFP:rifampicin
How to Rationalize Dosing
How to Rationalize Dosing ??
Increase dose
1717
Plasma INH concentration-time profile Plasma INH concentration-time profile
Time after administration (hr)
10
0 5 10 15
1
0.1
0.01
0.001
INH
co
nce
ntr
atio
n (g
/mL
)
RA typeIA typeSA type
Same dosebut different plasma concentrations
(1 – 4 points/person)
Patients (n ) : 114
Sparse plasma (n ) : 278
Dose: INH 200 mgat steady state
Therapeutic range
Minimal inhibitory concentration (MIC)
1818
Simulation of dose Simulation of dose adjustment of adjustment of INHINH based on NAT2 genotype based on NAT2 genotype
(preliminary)(preliminary)
200 mg x 2 /day
All types RA-typeI A-typeSA-type
500 mg x 2 /day 250 mg x 2 /day 100 mg x 2 /day
Present Simulated
0.2
3.0
INH
con
c. (g
/mL
)
0 12 24
Css
min
0 12 24
max
hr hr
19
Standard dose of INH
Frequency of slow acetylator(SA-type)
Japan
300 mg/day
400 mg/day(8 mg/kg/day)
(5 mg/kg/day)Europe& USA
Japanese
Caucasians
10 %
50 %
Trou
gh c
onc.
of
INH
(mg/
mL)
MIC0.05-0.2 g/mL
RA-typeIA-typeIA-type + HT
SA-type + HT0 2 4 6 8
Dose (mg/kg)
10
1
0.1
0.01
0.001
n=60
HT: hepatotoxicity
Trough plasma concentration of INH
in relation to NAT2 genotype
2020
BenefitBenefit
◆ Effect on pharmacoeconomics 〈 t.b. 〉
◆ Decrease the incidence of drug resistance in Micobacterium tuberculosis
◆ Decrease the incidence of drug-induced hepatotoxicity
◆ Decrease of relapse rate of pulmonary tubercurosis
Newly diagnosed patients in Japan = about 40,000 persons/year
Incidence of drug-induced hepatotoxicity in Slow acetylator( about 10% of Japanese) = 100% ( about 4,000 persons/year )Increase on the cost for remedy followed by drug-induced hepatotoxicity (/year)20,000 yen ( 1day ) ×60 days×4,000 persons = 4.8 billion yen ?Cost for NAT2 genotyping
~ 10,000 yen ( 1time ) × 40,000 persons = ~ 0.4 billion yen
4.4 billion yen
◆ Inprove therapeutic effect
2121
Clinical trial for genotype based Clinical trial for genotype based chemotherapy against pulmonary tuberculosischemotherapy against pulmonary tuberculosis
Patients with pulmonary tuberculosis
NAT2 genotyping NAT2Gene chip
◆ Multi-center prospective randomized clinical trial
◆ Rationalized dosing of isoniazid based on NAT2 gene polymorphism
◆ Safety, Efficacy, Pharmacoeconomics
SA-typeIA-typeRA-type
2222
Clinical trials for β-blocker therapy in chronic heart failure
MERIT-HF
COPERNICUS
NYHA
II ~ III
IV
metoprolol
carvedilol
Mortality
US Carvedilol II ~ IIIcarvedilol - 65%
CIVIS II IIIbisoprolol - 34%
- 34%
- 35%
23
Individual Difference in β-blocker Effect
0
5
10
15
20
25Before
After
(%)
( 33 例:41.8 %)
( 41 例:51.9 %)
( 5 例:6.3 %)
β-bloker ( 79cases )%FS ±3%
Responde
r
Non-
responder
Bad-
responder
11.8
21.7
14.9 15.0
19.3
12.2
For Individualized Medications
Genotyping
Responder ; improvement of
3 % in the fractional shortening
%FS
24
β1AR Polymorphism
Ser49Gly
Arg389Gly
J Mol Med 2000;78:87-93.
2525
CodonCodon Amino acid Amino acid changechange Function change (in vitro)Function change (in vitro)
ββ1 1 ARAR4949 Ser→GlySer→Gly Increased down regulationIncreased down regulation
389389 Arg→GlyArg→Gly Decreased G-protein couplingDecreased G-protein coupling
ββ2 2 ARAR1616 Arg→GlyArg→Gly Increased down regulationIncreased down regulation
2727 Gln→GluGln→Glu Decreased down regulationDecreased down regulation
αα2c 2c ARAR 322-325322-325 deletiondeletion Reduced agonist binding and Reduced agonist binding and decreased G-protein couplingdecreased G-protein coupling
Adrenergic Receptor PolymorphismsAdrenergic Receptor Polymorphisms
2626
Drug metabolizing enzymes for β-blocker
metoprololbisoprolol
CYP2D6
CYP2D6/3A4/1A2
β-blocker Drug metabolizing enzymes
carvedilol
27
Effect of CYP2D6Effect of CYP2D6**10 allele 10 allele on PK of S-metoprololon PK of S-metoprolol
0
100
200
300
400
500
Conc
entr
atio
n in
pla
sma
(nM
)
0 2 4 6 8 10 12 14Time (hr)
CYP2D6*10/*10
2D6*1/*1
Clin Pharmacol Ther 1999 ; 65 : 402-407
2828
Chronic Heart Failure
βblokerβbloker
responderresponder non-respondernon-responder
CAUSEPlasma Concentration
of β blocker
Function of Target Molecules of β blocker
PolymorphismsAR and Target Molecules
PolymorphismsDrug Metabolizing Enzyme
29
β1AR Ser49Gly and Risk in CHF
Eur Heart J 2000;21:1853-8.
0 1 2 3 4 5
20
40
60
0
p = 0.016
p = 0.12
Follow-up (years)
Risk of end-point (%
)
△
▲
☆
Ser49 homozygotes without b-blockers (n=63)
Gly49 variant without b-blockers (n=28)
Ser49 homozygotes with b-blockers (n=59)
Gly49 variant with b-blockers (n=33)
△
▲
☆
★
★β-blocker is more effectivein Patients with Gly allele
Increased down Increased down regulationregulation
3030
Kaye, DM, et al Pharmacogenetics (2003) 13 ; 379-382
β2 adrenergic receptor
polymorphism
Responder; Improved LVEF by 10% Improved FS by 5%
Ratio of Responders
Gln/Gln
Gln/Glu Glu/Glu
26%
62%
Gln27Glu is a potential determinant for
the response to carvedilol in heart failureDecreased down Decreased down
regulationregulation
3131
Heart failure and Polymorphism Heart failure and Polymorphism ofof α α2c2c ARAR
α2c AR Del322-325
Allele frequencyAllele frequency
CHFCHF healthyhealthy
BleckBleck 0.620.62 0.410.41
WhiteWhite 0.110.11 0.040.04
YellowYellow ?????? ??????
Japanese ? N Engl J Med (2002) 347, 1135-42
( 2002,10 reported )
α2C
α2A
Norepinephrine
β1 β3β2
Cardiac-cellmembrane
Sympatheticnerve
α2CDel322-325
Decreased Function in vitro
β 1Arg389 GlyIncreasedFunction in vitro
These two polymorphism of receptors act synergistically to increase the risk
of heart failure in black.
3232
Allelic frequency of adrenergic receptor polymorphismsin healthy and CHF and CHF
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Ser49Gly Arg389Gly Arg16Gly Gln27Glu α2c Del
Allelic
frequency
CHF (n = 36)Healthy (n = 96‐101)
β1 AR β2 AR α2 c AR
Allelic frequency of αAllelic frequency of α2c 2c AR Del322-AR Del322-325 in healthy Japanese is 0.14.325 in healthy Japanese is 0.14.
Black and WhiteBlack and White :: CHFCHF >> HealthyHealthy
3333
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Ser49GlyArg389GlyArg16GlyGln27Glu
Responder (n=21)non-Responder (n=13)
Allelic frequency of adrenergic receptor polymorphisms
in Responder and non-ResponderResponder and non-ResponderAllelic
frequency
β1 AR β2
ARα2 c AR
α2c Del
Responder :improvement of 3% in the fractional shortening
3434
Scientific Basis for Using PGt to Scientific Basis for Using PGt to Rationalize DosingRationalize Dosing
Top 27 drugs frequently cited in ADR Top 27 drugs frequently cited in ADR reportsreports59% (16/27) metabolized by at least 59% (16/27) metabolized by at least
one enzyme having poor metabolizer one enzyme having poor metabolizer (PM) genotype(PM) genotype
38% (11/27) metabolized by 38% (11/27) metabolized by CYP 2D6CYP 2D6mainly drugs acting on CNS and mainly drugs acting on CNS and
cardiovascular systemscardiovascular systems
Phillips et al, JAMA, 286 (18), 2001, 2270-2279
3535
Summary of CYP2D6 Summary of CYP2D6 activityactivity
Multiple active genes
*10/ PM gene (about 3 % )
High
CaucasiansJapanese
PM PM
hetEM: wt / PM gene
IM
EM
UM
wt / wt ( wild type)
phenotype
EM
Mainly (CYP2D6*5 )1%>
*10/*10 (about 15 % ) hetEM: wt / PM gene
wt / wt ( wild type )
Ultra Rapid (low frequency )
activity
5-10%*3,*4,*5 etc
Ultra Rapid ( ethnic difference )UM
??? ( *2 with -1584CG SNP)
wt /*10
Low
phenotypeGenotype Genotype
3636
Clinical significances of polymorphisms in β-blocker therapy against
Chronic Heart Failure
Patient : NYHA II or III EF<40%, 1500 patients (multicenter, 300 hospitals )
Drug : Carvedilol (2.5mg 、 5mg 、 20mg/day) Endpoint : Mortality, Cardiovascular death, Mobility
Surrogate Marker : Cardiac functionSub analysis : Genotyping
Directed by A Kitabatake MD, PhD (Hokkaido University)Supported by Japanese Circulation Society
Mega trial of β-Blocker Treatment in Japanese Patients with Chronic Heart Failure (J-CHF)
37
PharmacogenomicsPharmacogenomics: systemic genomic : systemic genomic analysis in populations of treated subjects to analysis in populations of treated subjects to identify variants that predict drug response identify variants that predict drug response
including the occurrence of adverse including the occurrence of adverse reactionsreactions
Potential Use of PGx in Drug Development
Drug Discovery Drug Therapy Drug Selection
New Drug TargetsNew Biomarkers
Rationalize Dosing
Class of Drugs
Cause of Disease Differential Diagnosis
By 2010 By 2005 By 2008
Lawrence J. Lesko International Pharmacogenomics Symposium
Tokyo, Japan April 25, 2003
3838
Overview of TalkOverview of Talk
Treatment of tuberculosis with isoniazid and rifampicin
Treatment of heart failure with β-adrenergic receptor blockers
Japan Pharmacogenomic Consortium (JPGC)Pharmacogenetics (PGx)-Pharmacoeconomics (PEx) Working Group
Pharmacogenome Tip Top Inc. (P-TipTop)
JPGC OutlineJPGC Outline(( Japan Pharmaco-genomics Consortium)Japan Pharmaco-genomics Consortium)
Rep. Fujisawa Yukio
40
JPGJPG CC BackgroundBackground
Perspective ・ Globalized competition ・ Genomic, ‘tailor-made’ medicine to be realized with Pharmaco-genomics/genetics evolution
Urgent Need to create a better climate for performing quality clinical trials on pharmaco-
genomics/genetics (PG) in drug development as well as in post-marketing Collaboration among pharmaceutical companies
to solve problems and develop techniques
41
Participating companiesParticipating companies
Otsuka Pharmaceutical Co., Ltd. Sanwa Kagaku Kenkyusho Co., Ltd. Shionogi & Co., Ltd. Sumitomo Pharmaceuticals Senju Pharmaceutical Co., Ltd. Dainippon Pharmaceutical Co., Ltd. Takara Bio Inc. Takeda Chemical Industries, Ltd. Tanabe Seiyaku Co., Ltd. Fujisawa Pharmaceutical Co., Ltd.
* as of Sep., 2003
42
Research PointsResearch Points
● Technological requirements for PG trials● Correlation analysis method between clinical and genetic data
● Method of selecting genes targeted for analysis
● Standards of ethical review and personal information management
● Analysis of PG trial data and construction of useful database for clinical evaluation
● Analytic engineering to utilize the database
Foundations and Standardization
Pilot study on clinical pharmacology
● Clinical trial to verify a hypothesized relation between marketed drug and genetic polymorphism
43
JPGJPG C Action PlanC Action Plan
Jun. Sep. Dec. Mar. Jun. Sep. Dec. Mar. Jun.
2003 2004 2005
Founded on Jul.14
Ethical matters, PG trial groundwork & internal standard
Plan to perform a test study on clinical pharmacology
Building a common DB as well as study DB on CP*
WG-IWG-II
WG-III
*Clinical Pharmacology=CP
PG
Clin
ical stud
ysu
pp
ort cen
ter
44
CIOMS The Council for International Organizations of Medical
Sciences
• Established by WHO and UNESCO in 1949• Activities :
– Bioethics– Health Policy, Ethics and Human Values - An
International Dialogue– Drug Development and Use
• Safety requirements for the use of drugs• Assessment, monitoring and reporting of adverse drug
reactions• Reporting and terminology of adverse drug reactions• Ethical criteria for drug promotion• Surveillance and assessment of drug safety data from
clinical trials• Pharmacogenetics and Pharmacoeconomics
– International Nomenclature of Diseases
45
CIOMS Working Group on Pharmacogenetics and Pharmacoeconomics
• Membership: Academia (3), drug regulatory agencies (14) and the
pharmaceutical industry (13) –University of Tokyo, MHLW, Yamanouchi
• Targets: Terminology, impact, cost, regulation, ethics etc. of pharma
cogenomics and pharmacogenetics
• Pharmacoeconomic issues in Pharmacogenetics–Database relating Pharmacogenetics–Regulatory Perspectives–Pharmacogenetics: Unresolved Issues and Barriers to Progress–Ethical Issues–Progress reports regarding pharmacogenetics
CIOMS が作成するレポートは、国際的な強制力は持たないものの、 ICH 等を通じて各国の医薬品行政に影響を及ぼす可能性が強いので、その動向に注意する必要がある。
46
Rational Use of Rational Use of Pharmacogenomics in Drug Pharmacogenomics in Drug
Development and RegulationDevelopment and Regulation Aim: Develop ethical, social and economical infrastructure for
appropriate use of pharmacogenetics and pharmacogenomics Scope: examine and analyze efforts of regulatory authorities a
nd industries relating to pharmacogenetics and pharmacogenomics and establish its proper use in drug development and clinical practice.
Schedule: FY2003 - FY2005 (3 years-term) Budget: 6 million yen (FY2003) Supporter: Ministry of Health, Labor and Welfare Project Leader: Tsutani, Kiichiro (Tokyo University) Participant: Junichi Azuma (Osaka University), Tohru Masui (N
ational Institute of Health Sciences), Hiroshi Gushima (Kurume University), Mieko Tamaoki (Yamanouchi Pharmaceutical)
47
Pharmacogenomic trails in our laboratoryapproved by the ethical committee in Osaka
University
Category Category TitleHeart failureHeart failure 心不全の個別治療のためのゲノム解析に関する臨床研究
AsthmaAsthma ロイコトリエン拮抗薬ブラングカストにおける薬効の個体差の解明
TuberculosisTuberculosis 薬効ゲノム情報に基づく結核治療の個別適正化プロジェクト
DepressionDepression 精神疾患患者に対する個別化適正薬物投与のための薬物感受性遺伝子に関する研究
ArteriosclerosisArteriosclerosis ホモシステインを標的とした動脈硬化治療法の確立
Adverse event Adverse event 小児におけるアセトアミノフェン副作用発現の個人差の解明
Drug metabolismDrug metabolism 日本人健康男性志願者におけるチトクロム P450を介した薬物代謝能の検討を目的とした臨床薬理試験
SmokingSmoking 有効な禁煙指導を行うための遺伝子多型の解析
Cohort StudyCohort Study 離島における薬物応答性遺伝子多型に関する情報の体系的収集と解析の試み
New Genotyping New Genotyping SystemSystem
新規遺伝子解析システムによる遺伝子多型判定法の開発
4848
PGt/PGx Clinical Study PGt/PGx Clinical Study on going and conducted so on going and conducted so
far far Number of protocol
Collaborate with Original
s or support
Units
CYP2D6 10 Agent Unit for Phase I trial
other metabolic enzyme
3 Agent Unit for Phase I trial
other metabolic enzyme
2 no Unit for Phase I trial
Tuberculosis In progress ( Agent) Public Hospital
Heart Failure In progress ( Agent) University hospital( Multiple trial)
Depression In progress ( Agent) University hospital
Asthma In progress ( Agent) Public Hospital
Diabetes In progress Public Hospital
Cohort study In progress Local clinic
49
Case 1 Dose-dependency : Inconsistency of plasma concentration
was observed in dose escalation. → We could explain this phenomenon by different number of the
subjects with decreased CYP450 activity enrolled at different dose groups. (→ Go forward )
Case 2 Bio-equivalence Study→ We could complete our goal by enrolling small number of
subjects genotyped as same before the trial, for additional formula application or generic drug development.
Case 3 Undesirable contribution of genetic factor → The finding suggested that the candidate compound should be
changed positively to a backup derivative in an early stage. Case 4 Suggestive in vitro data of contribution
polymorphic CYP450→ We could not find the contribution of the genotypes in vivo on
the level of plasma concentration (→ Go forward safely )
Have genetic testing aided drug development ?? ?
5050
Bood samples(I.D.)
Clinical trials
/Treatmentsbased on genetic variationPatients(I.D.)
DoctorsPharmacis
ts
Genotyping
Published Evidence
New Evidencefrom research institute
IT Network
Data Bank on Genetic Variation
Genetic Information Center(I.D.)
・ Process information・ Bioinformatics・ Expect pharmacokinetics/ adverse effects in vivo・ Simulate response in silico
Personalized Medication
right treatment for the right right treatment for the right patient patient at the right time. at the right time.
Patent obtaining
New Drug Discovery & Development
Application of PGx/PGt providing tailored Application of PGx/PGt providing tailored medicines medicines
for individualsfor individuals
薬効ゲノム情報(株)
Creation of database for Creation of database for pharmacogenetic knowledge pharmacogenetic knowledge
5151
52
・ Establish Japan standard for PG study (trial) Corporate・ Request cooperation from collaboration medical institutions and administration in working is ・ Found a practical support center indispensable!
Tasks to be coped by JPGCTasks to be coped by JPGC
・ Ethical system (in medical institutions
and industries)
・ IC ・ personal information, Sample
storage
・ Evaluation method on genomic data
Know-how, TechniquesKnow-how, Techniques
・ Screening method of gene analysis
・ Correlation analysis between genetic
data and clinical information
・ Finding SNPs with strong correlation
/association
TasksTasks
Japan (Internal) Consortium ( JPG ) founded
Better Climate, Standardization
53
JPG Consortium GoalJPG Consortium Goal
● Improve the basic conditions and establish a Japan standard for promoting PG study in development and post-marketing The essential items on Informed Consent and an explanation
Method of screening target genes
Correlation analysis method ・ Clinical evaluation standard
● Found a support center to help companies in performing PG clinical studies with genetic
analysis. Utilities for each member company to perform PG trials, including stored products of consortium activities
54
OrganizationOrganization
Groundwork G.
Domestic interchange
Legal affairs Pilot Study G. International Public Relations
Database Establishment G. Logistics
General Meeting
Steering Committee
Working Group Liaison Group Admin. Group
SecretariatAdvisory Board
55
Concept on the use of JPGC productsConcept on the use of JPGC products
JPGCJPGC
Co. A
Co. B
Co. C
Co. D
Particip
atio
n
Use o
f the
Institu
tion
Univ. & Medical Institution
Overseas ConsortiumThe more use,
the better inquality and cost
Support & Promotion
Mo
HL
WM
oH
LW
PG study
Support
Center
Standardization ・ Storage of Data & Know-how
Know-how introduction
56
TRI TRI UtilizationUtilization
● To build a frequency analysis database
on healthy subjects
● To make the database more complete
with the data from pilot studies
● To lay the foundation of the DB, based on
the support center plan
Use of TRI facilities, services and software for linkage analysis
57
Collaboration with Collaboration with TRTRII
the TRI’s goal & role:・ Build data foundation for Translational research from basic research to clinical or practical use ・ Perform studies in cure and care field,
Consortium activities consist with
including public relations about PG, SNPs study and their benefit to promote the
Translational Research.
5858
個別化医療
患者BA遺伝子B遺伝子×
レスポンダー
治癒
ゲノム解析
治療法
治癒
レスポンダー
匙加減 ( 質・量)
患者A
B遺伝子× A遺伝子
治療法
薬剤X
薬剤Y
Drug SelectionRationalize Dosing
Class of Drugs
診断
5959
Translation of PGx to Bedside Translation of PGx to Bedside Medicine: Predict Drug Response in Medicine: Predict Drug Response in
AdvanceAdvance
From McLeod and Evans, Ann Rev of Pharmacol and Toxicol, 2001: 41,101-121
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DNA 自動検査装置 GenelyzerTM の開発