Revolution in Asian drug development:A Korea and Japan experience

Henk de Koning Gans, MDVP, Process Management

Global Development JapanPharmacia 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.

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

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 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

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, double-blind, 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

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

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.

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.

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

-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.

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.

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.

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

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

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.

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

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

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

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

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

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