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Revolution in Asian drug development : A Korea and Japan experience

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.

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Revolution in Asian drug development : A Korea and Japan experience

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  1. Revolution in Asian drug development:A Korea and Japan experience Henk de Koning Gans, MD VP, Process Management Global Development JapanPharmacia KK, Japan

  2. Agenda • Background • Regulatory considerations • Trial design and results • Implementation in Korea and Japan • Conclusions

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. Regulatory Considerations • Traditional development: - EU/US file + Japan development program - Korean registration study for NCEs

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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 4mg qd (approved dose in the US and EU) • oxybutynin 3mgtid (approved dose in Korea and Japan) • placebo 1. Van Kerrebroeck P et al. Urology. 2001;57:414-421.

  16. 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 follow-up No statistically significant difference between groups in demographics or baseline disease characteristics.

  17. Summary of patient distribution Data on file, Pharmacia Corporation.

  18. Demographics and Baseline Characteristics Data on file, Pharmacia Corporation.

  19. 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

  20. Decrease in Urge Incontinence Episodes Placebo (n=122) Tolterodine ER(n = 239) Oxybutynin(n = 244) ** * *P<0.005 versus placebo **P<0.05 versus placebo Data on file, Pharmacia Corporation.

  21. 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.

  22. 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.

  23. Incidence and Severity of Dry Mouth % of Patients Data on file, Pharmacia Corporation.

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

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

  26. Decrease in Urge Incontinence Episode Comparison of EU/US and K/J trials Placebo (n=122) Tolterodine ER(n = 239) Oxybutynin(n = 244) Tolterodine IR Tolterodine ER Placebo 0 –10 –20 –30 –40 –33% Median % Reduction from Baseline Median % change From Baseline –50 –60 –60% * –70 –71% *† –80 ** * *P < 0.01 vs placebo †P < 0.05 vs IR *P<0.005 versus placebo **P<0.05 versus placebo Data on file, Pharmacia Corporation. Van Kerrebroeck et al. Urology. 2001;57:414-421.

  27. 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

  28. Enrollment chart in Korea and Japan Adv. March 3rd Adv. 12 May 2nd Adv. 8 April 1st Adv. 11 March

  29. Enrollment chart in Japan 3rd Adv 12 May 220 2nd Adv 8 April 114 1st Adv. 11 March 11

  30. Migraine - 2001 Hypertension - 1999 Anti-fungal - 2001 Anti-fungal - 1999 Clinical trials are speeding up – experience in Japan

  31. Key success factors for this Korea-Japan trial • Trial center selection and preparation • Investigator training • Newspaper ads and call / referral center • Global data management • Global team • Think the unthinkable!

  32. Conclusion II • High quality data obtained in Korea and Japan • Study results confirm global consistency of drug profile • Study completed in record time (5 months FPI-LPI) New approaches used successfully: • Trial center selection • Investigator training • Newspaper ads and call / referral center

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