revolution in asian drug development: a korea and japan experience henk de koning gans, md vp,...
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Revolution in Asian drug development:A Korea and Japan experience
Henk de Koning Gans, MDVP, Process Management
Global Development JapanPharmacia KK, Japan
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Agenda
•Background
•Regulatory considerations
•Trial design and results
•Implementation in Korea and Japan
•Conclusions
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ICH in US-EU-Japan
• Japan is a part of ICH• Korea is implementing ICH standards• Pan-European studies are universally accepted• Pan-Asian studies including Japan are a novelty in
regulatory submissions
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The drug: Tolterodine
• Developed specifically for overactive bladder• Selective for bladder over salivary glands• Approved for the treatment of overactive bladder or
unstable bladder in 57 countries, with more than 6 million people treated worldwide
Nilvebrant L et al. Life Sci. 1997;60:1129-1136.
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The disease: Overactive Bladder
Overactive bladder (OAB) is a symptom syndrome characterized by:
• Urgency, with or without urge incontinence, usually with frequency and nocturia
Abrams et al. Neurourology and Urodynamics. 2002; 21:167-78.
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Messelink EJ. BJU Int. 1999;83(suppl 2):48-52.
Overview of TolterodineGlobal Clinical Program
• Largest clinical development program ever conducted for an overactive bladder (OAB) compound
• 32 registration studies conducted (17 phase I; 4 phase II; 11 phase III) in 16 countries
• More than 4,000 patients treated; more than 3,000 received tolterodine in controlled studies
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Tolterodine Extended Release (ER)
• Provides improved efficacy and tolerability• Provides constant plasma over 24 hours • Significantly greater reduction in incontinence
episodes than with tolterodine immediate release (IR)
• Lower incidence of dry mouth than tolterodine IR• Convenience of once-daily dosing
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Regulatory Considerations
• Traditional development:
- EU/US file + Japan development program
- Korean registration study for NCEs
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Japanese Trial Environment after 1998
• Slow implementation of ICH GCP infrastructure• Slow patient recruitment in all therapeutic areas• Other key hurdles
– comparator drug
- difficulty to obtain informed consent
- patients reluctant to participate in
placebo controlled trials
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Korean Trial Environment• GCP legislation since 1995
• ICH standard implementation since 2000• Institutions designated by KFDA for clinical research
– Phase I: 17 centers, Phase II: 49 centers, Phase III: 72 centers with regular IRB review and training (Korean Association of IRB)
• Faster patient enrollment than Japan
• Reasonable cost
• Hurdles
– relatively long clinical trial authorization (5-6 ms)– low public awareness of the need for clinical trials
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Korean Trial EnvironmentNew regulations on Evaluation of
Safety and Efficacy of Drugs
• Major implications & benefits
Possible to join global development programWaiver for a local registration trial Accelerated product approval in Korea
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ICH in US-EU-Japan
• Japan is a part of ICH• Korea is implementing ICH standards• Pan-European studies are universally accepted• Pan-Asian studies including Japan are a novelty in
regulatory submissions
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Regulatory Considerations
• A combined Korean-Japanese Phase III registration study was proposed
• Agreement needed with the health authorities in both Korea and Japan (i.e. KFDA and KIKO)
– Primary study endpoint agreed– Korean and Japanese populations comparable– ICH GCP compliance
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Clinical Efficacy and Safety of Tolterodine ER in Korean and Japanese Patients With OAB
A phase III, 12-week, randomized, double-blind, double dummy, placebo- and active (oxybutynin)-controlled, multicenter study
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Study Design
• Design similar to previous Phase III study in Europe, US, Australia, and New Zealand1
• Double-blind, double dummy, randomized, parallel design • Study periods:
– 1- to 2-week wash-out/run-in period– 12-week treatment period– 1- to 2-week post-treatment follow-up
• Treatments:– tolterodine ER 4 mg qd (approved dose in the US and EU)– oxybutynin 3 mg tid (approved dose in Korea and Japan)– placebo
1. Van Kerrebroeck P et al. Urology. 2001;57:414-421.
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Study Design
Tolterodine ER 4 mg QD
n = 240
Placebo
n = 122
Oxybutynin IR 3 mg TID
n = 246
N = 608
12-week double-blind treatment
1-2 week follow-
up
No statistically significant difference between groups in demographics or baseline disease characteristics.
1–2 week washout/run-in
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Summary of patient distribution
Country Number of Centers
Number of patients
Placebo Tolterodine ER 4 mg qd
Oxybutynin3 mg t.i.d. Total
Korea 12 65 126 124 315
Japan 57 57 114 122 293
Total 69 122 240 246 608
Data on file, Pharmacia Corporation.
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Demographics and Baseline Characteristics
Placebo(n = 122)
Tolterodine ER
4 mg q.d.(n = 240)
Oxybutynin3 mg t.i.d.(n = 246)
Sex (%)Male 31.1 38.2 27.5
Female 68.9 67.8 72.5
Age (years)
Mean 58.4 61.2 57.9
Range 25.9-88.2 29.2-84.4 26.8-84.6
Micturition Chart Variables
(%)
8 micturitions/24 hrs
99.2 99.2 98.8
5 incontinence episodes/wk 100 98.7 99.6
200 mL mean volume voided per micturition
99.2 97.5 98.4
Data on file, Pharmacia Corporation.
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Efficacy Variables
Primary:• Median % change in number of incontinence
episodes per week Secondary:• Number of micturitions per 24 hours • Volume voided per micturition • Number of pads used per 24 hours • Patient’s perception of bladder condition, treatment
benefit, and urgency
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Decrease in Urge Incontinence Episodes
-46
-79 -77-90
-80
-70
-60
-50
-40
-30
-20
-10
0
Med
ian
% C
hang
e Fr
om B
asel
ine
* **
*P<0.005 versus placebo**P<0.05 versus placebo
Placebo(n=122)
Tolterodine ER(n = 239)
Oxybutynin(n = 244)
Data on file, Pharmacia Corporation.
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Decrease in Micturitions Per 24h
-1.1
-2.0 -2.1-2.5
-2
-1.5
-1
-0.5
0
Med
ian
Cha
nge
From
Bas
elin
e
Placebo(n=122)
Tolterodine ER(n = 239)
Oxybutynin(n = 244)
***
*P<0.001 versus placebo**P<0.05 versus placebo
Data on file, Pharmacia Corporation.
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Change in Mean Volume Voided Per Micturition
6.6
17.2
22.3
0
5
10
15
20
25
Med
ian
% C
hang
e Fr
om B
asel
ine
Placebo(n=122)
Tolterodine ER(n = 239)
Oxybutynin(n = 244)
*P<0.005 versus placebo**P<0.001 versus placebo
*
**
Data on file, Pharmacia Corporation.
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Incidence and Severity of Dry Mouth
6.6
25.1
33.2
3.3
7.9
12.3
0.4
8.2
00
5
10
15
20
25
30
35
Placebo (n=122) Tolterodine ER (n=239) Oxybutynin (n=244)
Mild
Moderate
Severe
Data on file, Pharmacia Corporation.
% o
f P
atie
nts
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Other Adverse Events
0
1.3
2.9
0
1.3
3.3
11.5
8.4
12.7
0
2
4
6
8
10
12
14
Placebo (n=122) Tolterodine ER (n=239) Oxybutynin (n=244)
Dry eyes
Blurred vision
Nervous system disorders
Data on file, Pharmacia Corporation.
% o
f P
atie
nts
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Premature Withdrawals
16.4
9.010.4
5.0
23.2
17.1
0
5
10
15
20
25
Per
cent
of P
atie
nts
Placebo
Tolterodine ER
Oxybutynin
Total Withdrawals Withdrawals Due to AEs
Data on file, Pharmacia Corporation.
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Decrease in Urge Incontinence EpisodeComparison of EU/US and K/J trials
-46
-79 -77-90
-80
-70
-60
-50
-40
-30
-20
-10
0
* ***P<0.005 versus placebo**P<0.05 versus placebo
Placebo(n=122)
Tolterodine ER(n = 239)
Oxybutynin(n = 244)
Data on file, Pharmacia Corporation. Van Kerrebroeck et al. Urology. 2001;57:414-421.
*P < 0.01 vs placebo†P < 0.05 vs IR
Me
dia
n %
Re
du
cti
on
fro
m B
as
eli
ne
–70
–80
–60
–50
–30
–20
–10
0
Tolterodine ER
Tolterodine IR
Placebo
–40
* †
*–71%
–60%
–33%
Me
dia
n %
ch
an
ge
Fro
m B
as
eli
ne
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Conclusions I
• First ever Korean-Japanese study for registration in Asian countries
• Tolterodine ER is equally effective to, and better tolerated than, oxybutynin IR in Korean and Japanese patients with OAB
• Total withdrawals and withdrawals due to AEs were 2- and 3-fold higher, respectively, with oxybutynin IR than with tolterodine ER
• Similar response between Korean and Japanese patient populations
• Results are also consistent with those of Western studies of these agents
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Enrollment chart in Korea and Japan
0 1 2 7 10 10 11 1129
58
91114
137
170
202220
244
276 281 288 293
0
50
100
150
200
250
300
Japan enrolled
2nd Adv.8 April
1st Adv.11
March
3rd Adv.12 May
0 14 3161 72 83
107132
149
184
212230
253 260272 272
300314
0
50
100
150
200
250
300
350
January February March April May
Korea enrolled
Adv.March
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Enrollment chart in Japan
0
50
100
150
200
250
3003rd Advertisement2nd Advertisement1st AdvertisementNo Advertisement
11
114
220
3rd Adv12 May
2nd Adv8 April
1st Adv.11
March
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Clinical trials are speeding up – experience in Japan
0
50
100
150
200
250
300
350
400
450
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
month
Accu
mul
ated
No.
of e
nrol
lmen
ts
Migraine - 2001
Hypertension - 1999
Anti-fungal - 1999
Anti-fungal - 2001
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Key success factors for this Korea-Japan trial
1. Trial center selection and preparation
2. Investigator training
3. Newspaper ads and call / referral center
4. Global data management
5. Global team
6. Think the unthinkable!
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Conclusion II
1. High quality data obtained in Korea and Japan
2. Study results confirm global consistency of drug profile
3. Study completed in record time (5 months FPI-LPI)
New approaches used successfully:
1. Trial center selection
2. Investigator training
3. Newspaper ads and call / referral center