Transcript Spectrum of Overactive Bladder - kitasato

Revolution in Asian drug development:
A Korea and Japan experience
Henk de Koning Gans, MD
VP, Process Management
Global Development Japan
Pharmacia KK, Japan
Agenda
•Background
•Regulatory considerations
•Trial design and results
•Implementation in Korea and Japan
•Conclusions
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
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.
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.
Overview of Tolterodine
Global 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
Messelink EJ. BJU Int. 1999;83(suppl 2):48-52.
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
Regulatory Considerations
• Traditional development:
- EU/US file + Japan development program
- Korean registration study for NCEs
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
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
Korean Trial Environment
New regulations on Evaluation of
Safety and Efficacy of Drugs
• Major implications & benefits
Possible to join global development program
Waiver for a local registration trial
Accelerated product approval in Korea
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
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
Clinical Efficacy and Safety of
Tolterodine ER in Korean and
Japanese Patients With OAB
A phase III, 12-week, randomized, doubleblind, double dummy, placebo- and active
(oxybutynin)-controlled, multicenter study
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.
Study Design
Tolterodine ER 4 mg QD
n = 240
N = 608
Oxybutynin IR 3 mg TID
n = 246
1–2 week
washout/run-in
Placebo
n = 122
12-week double-blind
treatment
1-2 week
followup
No statistically significant difference between groups
in demographics or baseline disease characteristics.
Summary of patient distribution
Country
Number of
Centers
Number of patients
Placebo
Tolterodine
ER 4 mg qd
Oxybutynin
3 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.
Demographics and Baseline
Characteristics
Sex (%)
Age
(years)
Placebo
(n = 122)
Tolterodine
ER
4 mg q.d.
(n = 240)
Oxybutynin
3 mg t.i.d.
(n = 246)
Male
31.1
38.2
27.5
Female
68.9
67.8
72.5
Mean
58.4
61.2
57.9
Range
25.9-88.2
29.2-84.4
26.8-84.6
99.2
99.2
98.8
100
98.7
99.6
99.2
97.5
98.4
 8 micturitions/24 hrs
Micturition
 5 incontinence
Chart
episodes/wk
Variables
 200 mL mean
volume voided per
(%)
micturition
Data on file, Pharmacia Corporation.
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
Decrease in Urge Incontinence Episodes
Median % Change From Baseline
0
Placebo
(n=122)
Tolterodine ER
(n = 239)
Oxybutynin
(n = 244)
-10
-20
-30
-40
-50
-60
-46
-70
-80
-90
*P<0.005 versus placebo
**P<0.05 versus placebo
-79
-77
*
**
Data on file, Pharmacia Corporation.
Decrease in Micturitions Per 24h
Placebo
(n=122)
Tolterodine ER
(n = 239)
Oxybutynin
(n = 244)
Median Change From Baseline
0
-0.5
-1
-1.1
-1.5
-2
-2.5
*P<0.001 versus placebo
**P<0.05 versus placebo
-2.0
*
-2.1
**
Data on file, Pharmacia Corporation.
Change in Mean Volume Voided
Per Micturition
**
22.3
Median % Change From Baseline
25
*
17.2
20
15
10
6.6
5
0
Placebo
(n=122)
*P<0.005 versus placebo
**P<0.001 versus placebo
Tolterodine ER
(n = 239)
Oxybutynin
(n = 244)
Data on file, Pharmacia Corporation.
Incidence and Severity
of Dry Mouth
33.2
35
Mild
Moderate
Severe
% of Patients
30
25
25.1
20
15
10
5
0
12.3
8.2
7.9
6.6
3.3
0
Placebo (n=122)
0.4
Tolterodine ER (n=239)
Oxybutynin (n=244)
Data on file, Pharmacia Corporation.
Other Adverse Events
Dry eyes
14
11.5
% of Patients
12
12.7
Blurred vision
Nervous system disorders
10
8.4
8
6
4
2.9
1.3
2
0
0
3.3
1.3
0
Placebo (n=122)
Tolterodine ER (n=239)
Oxybutynin (n=244)
Data on file, Pharmacia Corporation.
Premature Withdrawals
23.2
25
Percent of Patients
20
Placebo
Tolterodine ER
Oxybutynin
17.1
16.4
15
10.4
10
5.0
5
0
9.0
Total Withdrawals
Withdrawals Due to AEs
Data on file, Pharmacia Corporation.
Decrease in Urge Incontinence Episode
Comparison of EU/US and K/J trials
Placebo
(n=122)
Tolterodine ER
(n = 239)
Oxybutynin
(n = 244)
Placebo
0
Median % Reduction from Baseline
Median % change From Baseline
0
-10
-20
-30
-40
-50
-46
-60
-70
-80
-90
Tolterodine Tolterodine
IR
ER
-77
-79
–10
–20
–30
–40
–33%
–50
–60
–70
–60%
*
–80
–71%
*†
**
*
*P<0.005 versus placebo
**P<0.05 versus placebo
Data on file, Pharmacia Corporation.
*P < 0.01 vs placebo
†P < 0.05 vs IR
Van Kerrebroeck et al. Urology. 2001;57:414-421.
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
Enrollment chart in Korea and Japan
350
Korea enrolled
300
300
250
Adv.
March
200
253
212
260
272
314
272
230
184
150
149
132
100
107
50
0
14
61
31
72
83
0
January
February
March
April
May
288 293
276 281
300
3rd Adv.
12 May
Japan enrolled
250
244
220
202
200
2nd Adv.
8 April
150
170
137
114
1st Adv.
11 March
100
91
58
50
29
0
1
2
7
10
10
11
11
0
January
Februar y
March
April
May
June
Enrollment chart in Japan
300
250
200
3rd Adv
12 May
3rd Advertisement
2nd Advertisement
1st Advertisement
No Advertisement
220
2nd Adv
8 April
150
114
100
1st Adv.
11 March
50
11
ne
Ju
ay
M
ril
Ap
ch
ar
M
Fe
b
ru
ar
y
0
Clinical trials are speeding up – experience in Japan
450
AccumulatedNo. of enrollments
400
Migraine - 2001
350
300
250
Hypertension - 1999
200
150
100
50
Anti-fungal - 2001
Anti-fungal - 1999
0
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
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!
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