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:

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:

Messelink EJ. BJU Int. 1999;83(suppl 2): 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

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, 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 Zealand 1 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:

Study Design Tolterodine ER 4 mg QD n = 240 Placebo n = 122 Oxybutynin IR 3 mg TID n = 246 N = 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 CountryNumber of Centers Number of patients PlaceboTolterodine ER 4 mg qd Oxybutynin 3 mg t.i.d.Total Korea Japan Total Data on file, Pharmacia Corporation.

Demographics and Baseline Characteristics Placebo (n = 122) Tolterodine ER 4 mg q.d. (n = 240) Oxybutynin 3 mg t.i.d. (n = 246) Sex (%) Male Female Age (years) Mean Range Micturition Chart Variables (%)  8 micturitions/24 hrs  5 incontinence episodes/wk  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 * ** *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 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 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 Data on file, Pharmacia Corporation. % of Patients

Other Adverse Events Data on file, Pharmacia Corporation. % of Patients

Premature Withdrawals Total Withdrawals Withdrawals Due to AEs Data on file, Pharmacia Corporation.

Decrease in Urge Incontinence Episode Comparison of EU/US and K/J trials * ** *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: *P < 0.01 vs placebo † P < 0.05 vs IR Median % Reduction from Baseline –70 –80 –60 –50 –30 –20 –10 0 Tolterodine ER Tolterodine IR Placebo –40 * †* † * –71% –60% –33% Median % change From Baseline

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 2 nd Adv. 8 April 1 st Adv. 11 March 3 rd Adv. 12 May Adv. March

Enrollment chart in Japan rd Adv 12 May 2 nd Adv 8 April 1 st Adv. 11 March

Clinical trials are speeding up – experience in Japan Migraine Hypertension Anti-fungal Anti-fungal

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