Expectations of Asian Collaboration and Contribution to ...
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1 JPMA Expectations of Asian Collaboration and Contribution to New Medicines October 13, 2006 Kazuhiko Nakajima Chairperson, Drug Evaluation Committee JPMA
Transcript of Expectations of Asian Collaboration and Contribution to ...
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JPMA
Expectations of Asian Collaboration and Contribution to New Medicines
October 13, 2006
Kazuhiko NakajimaChairperson, Drug Evaluation Committee
JPMA
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JPMA
Key WordsKey Words for for JPMAJPMA
The pharmaceutical industry contributes to improve the health and wealth of people all over the world, through the effort to develop innovative and useful pharmaceuticals, and deliver them to patients.
((http://www.jpma.or.jphttp://www.jpma.or.jp))
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JPMA
Source: Pharma Future No.163, Utobrain 2006Reference: OPIR research paper No.23 2004.10
CY1997 ($m)
Ranking ProductCompany
(Developed by)
Sales
3 Mevalotin Sankyo 2,748
8 Gaster Yamanouchi 1,708
15 Leuplin Takeda 1,181
29 Takepron Takeda 857
30 Herbesser Tanabe 848
Japan-originated Drugs Total 5 7,342
CY2003 ($m)
Ranking ProductCompany
(Developed by)
Sales
3 Takepron Takeda 5,142
6 Mevalotin Sankyo 4,746
26 Harnal Yamanouchi 2,247
32 Leuplin Takeda 1,989
33 Cravit Daiichi 1,954
43 Actos Takeda 1,660
44 Clarith Taisho 1,656
47 Blopress Takeda 1,616
54 Pariet Eisai 1,406
58 Aricept Eisai 1,323
82 Prograf Fujisawa 975
86 Campto Yakult 938
99 Gaster Yamanouchi 827
117 Sevofrane Maruishi 712
145 Basen Takeda 532
149 Meropen Sumitomo 511
150 Cefzon Fujisawa 507
Japan-Originated Drugs Total 17 28,741
JapanJapan--Originated Drugs Sold OverseasOriginated Drugs Sold Overseas(Sales over $500m(Sales over $500m））
15.8%
Top 40 total: $139,463M (CY2005)Japan-originated drugstotal: $22,000M
（8 products）
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JPMATrend for Clinical Trial Notification in JapanTrend for Clinical Trial Notification in Japan
Clinical trials in Japan are declining
160
115104
9695
7154 52 63
43
60 60 56
497
782722
500
406 391463 424 438
361414
1,080
1,200
18161524233939
211524254540
0
50
100
150
200
250
300
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 (Year)
# of NCEs
0
200
400
600
800
1,000
1,200
1,400
# of clinical testings
NCEs
# of clinical testings
＃ of NCEs for which saleswere approved.
New drug price calculation review
New GCP issued
Complete implementation of new GCPExpanded acceptance of foreign clinical data
Source: Yakumu Koho
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JPMADevelopment status of Development status of
Japanese pharmaceutical companiesJapanese pharmaceutical companiesActual status of overseas advanced development
18.3%
43.2%
36.4%
35.7%20.4%
46.0%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1993 2000
Domestic advanceddevelopment/domesticonly
Domestic and overseassimultaneous development
Overseas advanceddevelopment/overseasonly
Rat
io o
f N
o. o
f co
mpo
nent
s
Source: Office of pharmaceutical Industry Research, JPMA
(23 components)
(58 components)
(45 components)
(33 components)
(59 components)
(70 components)
(23 components)
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JPMAProblems and current status of clinical trials Problems and current status of clinical trials in Japanin Japan
Quality Markedly improved Over-quality
Speed Partially improved Ads for recruiting subjectsContribution of CRC，SMO，CRO
Cost Markedly increased Abovementioned costsFrequent visits by CRAs
J-GCP Improved very little
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JPMACurrent status of clinical trials in Asia (1)Current status of clinical trials in Asia (1)
Patient RecruitmentPatient Recruitment
Asia* EU US
Hepatitis B 2.4 0.3 0.3
Acute MI 4 2 2
Acute MI 2.5 2 2
Pain relief 5 2.5 3
Recruitment Rate (pts/site/mth)Indication
* Except for Japan and China
Source: Quintiles Translational （partially modified）
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JPMACurrent status of clinical trials in Asia (Current status of clinical trials in Asia (22))
Development CostsDevelopment CostsHypothetical protocol for treatment of patients with mild to moderate essential hypertension
China
MainlandKorea Hong Kong
Chinese
TaipeiSingapore Thailand Malaysia Japan
Costs of facilities and investigators*
Costs incurred before starting trial
Regulation-related costs
Monitoring cost
Total
*In Japan, these costs correspond to clinical trial/research costs and investigator drug management cost at participating institutions.
0.18 0.29 0.270.26 0.27 0.19 0.21 1
0.24 0.27 0.230.27 0.23 0.24 0.27 1
0.48 0.27 0.160.16 0.14 0.17 0.18 1
0.24 0.27 0.240.27 0.24 0.24 0.27 1
0.22 0.28 0.250.26 0.25 0.21 0.23 1
Costs of CRO
Comparison estimated by a large size CRO
Source: Study Result by Drug Evaluation Committee, JPMA (2004)
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JPMA
Rapid increase of clinical trials in Korea since 2003Many multinational trials are Phase III and Phase IV
Trend in Korean Clinical Trial Notification & Trend in Korean Clinical Trial Notification & Taiwanese Clinical Trial ApprovalTaiwanese Clinical Trial Approval
Current status of clinical trials in Asia (3)Current status of clinical trials in Asia (3)
Source: CDE Data, Taiwan
18
4557
42 42 4231 28 27
38
97
755
18
17
46
62
0
25
50
75
100
125
150
`93 `94 `95 `96 `97 `98 `99 `00 `01 `02 '03 '04
Local Multinational
Multinational trials by European and US companies begin
GCP implementation
61 57
34
6962
86
0
25
50
75
100
125
150
175
'03 '04 '05
0
50
100
150
200
250
300Korea
Chinese Taipei# of site
LocalMultinational
＃ of site carrying out multinational trials
# of trial
# of trial
Source: KFDA Data
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JPMAResults of JPMA Investigation in Asia: Fall 2004Results of JPMA Investigation in Asia: Fall 2004
Clear awareness of the pharmaceutical industry as a customer
Key infrastructure such as Clinical facilities and Clinical Trial Centers have been established
Multi-national CROs have expanded their business all around Asia
Many Asian clinical sites can conduct clinical trials of good quality(inspected several times by sponsors or the FDA)
Clinical studies characterized by fast patient recruitment with less cost
Multi-national clinical studies have increased since introduction of ICH-GCP or domestic GCP in conformity with ICH-GCP in Asian countries following the ICH-GCP agreement in 1996
Source: Study Result by Drug Evaluation Committee, JPMA (2004)
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JPMASituations of key medical institutionsinvolved with clinical researches and trials in the U.S., South Korea and Chinese Taipei
Clinical Research/Trial CenterCore Center
U.S. NIH clinical center GCRC/CRCApprox. 80 facilities
South Korea Clinical research centers9 15 facilities (up to ‘14)
Accredited clinical trial centers
109 facilities
Chinese Taipei General clinical research centers
15 facilities
Qualified hospitals134 facilities
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JPMAStagnation of Clinical Research Activities in JapanStagnation of Clinical Research Activities in Japan
Clinical StudyClinical Study
Clinical ResearchClinical Research
Current situation in Japan:Due to the lack of an appropriate infrastructure for clinical research, clinical research of high quality aimed to develop new diagnoses and treatments for clinical applications has hardly been implemented in Japan.
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JPMAAdministrative initiatives to improve the clinical trial environment in Japan:
- Major initiatives -
3 Year Plan for Clinical Trial Activation: FY2003～2005MHLW, MECSST
Planning for Next Clinical Trial Activation :Including Clinical Research Infrastructure Improvement
FY2006MHLW, MECSST
Clinical Research Infrastructure Improvement Plan:FY2006～2008MHLW
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JPMAEthnic Similarity in Asia (1)Ethnic Similarity in Asia (1)
Distribution of HBV genotype
ADAD
F
ADG
C B
A
G
HAD
CB
E
Source: KAN･TAN･SUI 49(4): 425–430 (2004) (modified)
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JPMAEthnic Similarity in Asia (2)Ethnic Similarity in Asia (2)
Comparison in terms of human genomes
few SNPs many SNPs
Source: Nature 437, 1300-1320(2005)
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JPMAEthnic Similarity in Asia (3)Ethnic Similarity in Asia (3)
1 2 3 4 5
Hong Kong Cancer(33.0%)
Heart disease(16.3%)
Braindisease(10.5%)
Pneumonia (8.9%)
Suddenaccident/Poisoning(5.6%)
Japan Cancer(31.0%)
Heart disease(15.3%)
Brain disease(13.6%)
Pneumonia(8.8%)
Suddenaccident(4.1%)
Japan Hong Kong
Male 77.6
Female84.6
Male78.0
Female83.9
Life expectancy
Cause of death
54.6kg153.0cm64.6kg165.7cm50’s
54.5kg155.7cm68.2kg169.3cm40’sJapanese
59.6kg158.6cm67.7kg169.7cmAdultChinese
WeightHeightWeightHeight
FemaleMale
Height & Weight
Source: J.Clin.Therap.Med. 22, 597-606 (2006)
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JPMAComparison of Max. Daily Doses Comparison of Max. Daily Doses
in Japan and US/EUin Japan and US/EU JapanUS/EU
GastrointestinalCardiovascular
Statin ACE-I Ca-B PPI H2-RB
Om
epra
zole
Lans
opra
zole
Rabe
praz
ole
Cinet
idin
e
Ranit
idin
eFa
mot
idin
e
50
mg/day
1200
300
600
900
00
50
100
150
Pravas
tatin
Sinvasta
tin
Captop
rilEna
lapril
Nifedip
ineAmlod
ipine
mg/day
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JPMADifferences in views on optimal doses between Differences in views on optimal doses between Japan and Europe/USJapan and Europe/US
Using Captopril as an example
1971 Separated teprotide (nonapeptide) from snake toxin and synthesized it
1973 Administered teprotide intravenously to healthy people and hypertension patients1973 Launched R&D of oral ACE-I1974 Discovered lead compounds1975 Synthesized captopril. Succeeded in optimizing lead compounds.
1977 Clinical trial of captopril1981 Squibb: Obtained approval as a hypotensive agent (with usage restrictions)1982 Sankyo: Obtained approval as a hypotensive agent (no usage restrictions)1985 Squibb: Usage restrictions are lifted
～ 150 mg ～ 75 mg ～ 37.5 mg ～
High incidence of adverse drug reactions
Usage restrictions Source: Jap.J. Pharmacol 125, 104-106 (2003)
Pyr-Trp-Prp-Arg-Pro-Gln-Ile-Pro-Pro
CH3
HS-CH2-CH-CO-NCOOH
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JPMAViews on optimal dosage: Image Views on optimal dosage: Image
Other countries South Korea Japanin Asia Chinese Taipei
It’s about time we begin considering doses suited for us
Accept doses used in Europe and the US
Seek doses suited to own country Rigorous process to determine optimal dosage
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JPMAThe Purpose of ICH• Ensure a more timely introduction of new medicinal products to patients• Contribute to the protection of public health• Lead to a greater mutual acceptance of research and development
to reduce and obviate the need for duplicate testing• Maintain safeguards on quality, safety and efficacy
Source: ICH website (modified)
The Situation of Clinical Trials in Asia• Quality : ICH-GCP• Speed• Cost• Ethnic Similarity
It is natural for Asian countries to collaborate.
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JPMARole of Role of EEarly arly CClinical linical TTrialsrials
• Comprehensive clinical assessment for establishment of a late clinical trial plan
Tolerability, safety and pharmacokinetics
Effects of meals and drug interactions
Evaluation of the efficacy and therapeutic doses
• Determinants for a global development strategy Evaluation of the similarity between Japanese and non-Japanese in terms of tolerability, safety and pharmacokinetics
global cooperative trials or regional trials
• Selection of projects with a high probability of success
Important stage for development strategy and investment decisions
The aim is to enable implementation of early clinical trials in Asia under the same strategy.
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JPMAProblems for Japan’s in collaborating with Asia
Clinical trialJ-GCP different from ICH-GCP: Essential documents, contracts, safety information, reliability survey, managementSmall number of patients enrolled for each siteDistinct safety assessment methodRigorous views on optimal dosage
Scientific adviceNot implemented in a timely manner
There are numerous problems that must be actively resolved in order for
Japan to participateActively promote country -country
dialogues in Asia
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JPMAPromote approach to collaboration
and mutual acceptance in Asia
Aim at attaining even more comprehensive
mutual acceptance in the future
So as to efficiently provide new therapeutic means to citizens of various countries
•Clinical data for NDA：acceptance•GCP inspection：acceptance, recognition (MOU)•P-IV study：usage, acceptance
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JPMA
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Treatment Satisfaction Level
Dru
g C
ontri
butio
n Le
vel t
o Tr
eatm
ent
herpes virus infection
tuberculosis
dermatophytosis
chlamydia infectioncandidiasis
uterine myoma
diabeteshyperlipidemia
epilepsy
hypertensive
angina pectoris
miocardial infarction
irregular heartbeat
allergic rhinitisbronchitic asthma
gout
peptic ulcer
benign prostatic hypertrophyMRSA infection
gastric cancer
AIDS
colon cancer
liver cancerlung cancer
breast cancer
uteris cancer
prostatic cancer
leukemia
diabetic neuropathy
diabetic retinopathydiabeticnephropathy
schizophrenia
depression
anxiety neurosis
Parkinson’s Disease
Alzheimer Disease Senile dementiamultiple sclerosis
autonomic disorder
neuromusculardisorder / myopathy
cerebral apoplexy(including subarachnoid bleeding)
brain infarction
atopic dermatitispressure gangrene
chronic rheumatoid arthritis
osteoarthritis
SLE
spondylopathy
lumbar pain
osteoporosis
liver cirrhosis chronic hepatitis B
chronic hepatitis C
nephrosis syndropme
chronic glomerulonephritis
chronic renal failure
urinaryincontinence/ frequence
endometriosis
glaucoma
cataract
Research: Survey via mailTime frame: Oct 15, 1999 – Dec 22, 1999Subject: Doctors (128 responses)
Source: Japan Health Sciences Foundation: Domestic Fundamental Technology Research Report – Medical Needs Outlook in 2010 (2000)
－Correlation between Treatment Satisfaction Level and Drug Contribution Level to Treatment－
Existence of Unmet Medical NeedsExistence of Unmet Medical Needs
0%
10%
20%
30%
40%
50%
60%
70%
0% 10% 20% 30% 40% 50% 60%Treatment Satisfaction Level
Dru
g Co
ntrib
utio
n Le
vel t
o Tr
eatm
en MRSA infection
gastric cancer
AIDS
colon cancer
liver cancerlung cancer
breast cancer
uteris cancer
prostatic cancer
leukemia
diabetic neuropathy
diabetic retinopathydiabeticnephropathy
schizophrenia
depression
anxiety neurosis
Parkinson’s Disease
Alzheimer Disease Senile dementiamultiple sclerosis
autonomic disorder
neuromusculardisorder / myopathy
cerebral apoplexy(including subarachnoid bleeding)
brain infarction
atopic dermatitispressure gangrene
chronic rheumatoid arthritis
osteoarthritis
SLE
spondylopathy
lumbar pain
osteoporosis
livercirrhosis chronic hepatitis B
chronic hepatitis C
nephrosis syndropme
chronic glomerulonephritis
chronic renal failure
urinaryincontinence/ frequence
endometriosis
glaucoma
Asian Collaboration
Asian Dialogue
Asian Evolution
