Progress and Challenges to approve a drug based on data from global clinical trials: PMDA s experience

Transcription

1 Progress and Challenges to approve a drug based on data from global clinical trials: PMDA s experience Dr Yoshiaki Uyama Pharmaceuticals & Medical Devices Agency (PMDA) Visiting Professor, Graduate School of Advanced Clinical Science, Chiba University Visiting Professor, Graduate School of Medicine, Nagoya University

2 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Pharmaceuticals and Medical Devices Agency (PMDA), Drug Information Association, Inc. ( DIA ), its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or affiliated. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners. 2

3 Globalization of Drug Developments Japan 15.7; 10.3% Nature Rev Drug Discovery, 7: 13,

4 APEC MRCT Road Map -Gap Analysis- Target Economies: Canada, Chinese Taipei, Indonesia, Japan, Malaysia, Mexico, Peru, Singapore, Korea, Thailand, and the United States Period : October 2013 ~ April 2014 Methodology : Questionnaire by Responses received : 8 regions Collection rate : 72.7 % (8/11 regions) 4

5 Q: Please propose the number of CTs conducted in your country from 2010 to 2012 by phases and starting years. Please list the number by starting years. Among those CTs, how many MRCTs were included in each figure? 5

6 Q: Please propose the number of CTs conducted in your country from 2010 to 2012 by phases and starting years. Please list the number by starting years. Among those CTs, how many MRCTs were included in each figure? Phase I Phase II Phase III Non MRCT MRCT Non MRCT MRCT Non MRCT MRCT 6

7 Q: Please describe the annual number of new drugs approved in your country from 2010 to New Drug Approved CAN IDN KOR MYS SGP TWN THA JPN 7

8 Basic principles on Global Clinical Trials Japanese version English version Japanese: English: 8

9 Trend of new drug application approvals in Japan 15 % of % of Bridging % of FY2007 FY2008 FY2009 FY2010 FY2011 FY2012 FY2013 Total MRCT Bridging (Year) 9

10 Approved new drugs based on in Japan Guidance Guidance RC 2006~ Tolterodine Losartan Trastuzumab Insulin - Glulisine Tadalafil Peramivir Everolimus Panitumumab Travoprost/ Timolol Temsirolimus Laninamivir Nilotinib Dabigatran Trastuzumab Pramipexole Edoxaban Dasatinib Indacaterol Linagliptin Gefitinib Everolimus Red: Asian Clinical Trial Guidance: Basic Principles on Global Clinical Trials Guidance RC: Basic Principles on Global Clinical Trials Reference Cases Denosumab Aripiprazole Olanzapine Exenatide Crizotinib Budesonide/ Formoterol EsomeprazoleApixaban Formoterol Axitinib Budesonide/ Formoterol Atomoxetine Aflibercept Insulin - Degludec Glycopyrronium Pazopanib Everolimus Fesoterodine Everolimus Insulin- Degludec+Aspart Paclitaxel Pregabalin Tofacitinib Regorafenib Bevacizumab Pertuzumab Lixisenatide Regorafenib Indacaterol/ Glycopyrronium Paliperidone Vilanterol/ Fluticasone Bevacizumab Aflibercept 59 applications were approved as of March 1, 2014 Riociguat Tadalafil Afatinib Turoctocog alfa Ranibizumab 10

11 Riociguat: Example of (1) New active ingredient indicated for the treatment of persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Soluble guanylate cyclase (sgc) stimulator Orphan drug Application date: Feb 2013 (US/EU) May 2013 (JP)

12 N Change from baseline to last visit a Difference between groups b All region Riociguat (-376, 335) [ 24.74, 66.63] Placebo (-389, 226) Japan Primary endpoint: 6MWD (m) Riociguat (-376, 217) Placebo (6, 85) N PIII: Efficacy Change from baseline to last visit Change from baseline: Median (Min, Max), Difference between groups: LS mean [ 95 CI] a:last observed value (not including follow-up) for subjects who completed the study or withdrew, except imputed worst value in case of death or clinical worsening without a termination visit or a measurement at that termination visit. b:ancova model with baseline value, treatment group, and region as fixed effects - Difference between groups b All region Riociguat ( , 511.0) [ , ] Placebo (-679.6, 969.2) Japan Secondary endpoint: PVR (dyn sec cm -5 ) Riociguat (-291.5, 146.8) Placebo (-125.6, 205.1) - 12

13 Tofacitinib: Example of (2) Japan Ph2 ( study) Placebo, 1mg, 3mg, 5mg, 10mg BID with MTX Duration:12weeks Endpoint: ACR20% N=317 US/EU Ph2 ( study) Placebo, 1mg, 3mg, 5mg, 10mg, 15mg, 20mg BID with MTX Duration:24weeks Endpoint: ACR20% N=507 Ph3 ( study) Placebo, 5mg, 10mg BID with MTX Duration: DB 6months, Open 18months Endpoint: ACR20, structural damage, physical function N=797 (Japanese 118) 13

14 Dose response of tofacitinib 70 ACR20 ACR50 ACR70 FAS Japanese mg N=277 10mg N=290 5mg N=44 10mg N= Average & 95%CI FAS Japanese Modified Total Sharp Score (vs placebo) 14

15 Review experiences of data Ethnic factor consideration is important even in Asian s Extrinsic ethnic factors such as concomitant therapies sometimes have impacts on data evaluation PPK data are useful for ethnic factor consideration Confirming efficacy in overall population and consistency evaluation in Japanese sub-population limitation in evaluating data when sample size of Japanese was so small Differences in adverse event rate are not uncommon; partly due to difference on categorization or data collection process of adverse events in s 15

16 New Guidance (Sep 5 th 2012): Basic principles on Global Clinical Trials (Reference Cases) Japanese: English: 16

17 Future Drug Development 17

18 Regulatory Perspective: PMDA and FDA US FDA PMDA Clin Pharmacol Ther. 2013;94: Clin Pharmacol Ther. 2013;94:

19 Honig, P.K. Clin Pharmacol Ther 95, (2014). Ueno, T et al, Clin Pharmacol Ther 95, (2014). 19

20 s can contribute to reducing the lag in drug development The lag in drug development (days) ** 1000 ** * 1111 days Local trial (n = 69) Local and foreign trials (n = 59) Bridging study (n = 19) Global clinical trial (n = 18) Foreign trial (n = 13) Clinical development strategy No efficacy/safety trial (n = 5) 20

21 Simultaneous global drug development is a useful strategy to provide a drug earlier to Japanese patients But, we are facing some challenges in the future drug development 21

22 Challenges for better s Effects of ethnic factors on drug efficacy/safety should be more characterized Methods for planning/evaluation should be established Sample size calculation, consistency evaluation etc. Regulatory harmonization Advancing regulatory science 22

23 PMDA Project Team 12 members as a representative from various offices (New drug, Biologics, Conformity audit) Discuss various regulatory issues relating to s Responsible for a guideline relating to s Periodically hold meetings with industries for discussion Promoting conduct of s more appropriately for drug approval 23

24 PMDA s New Initiative: Advanced workflow of review/consultation Analysis by PMDA Giving additional scientific value to submitted data NDA etc. e-submission of study data Data Accumulation 24 Database Regulatory Science Sophisticated review Cooperation with Academia Each reviewer utilizes innovative assessment techniques Cross-Products Analysis Advanced evaluation methods Active utilization of Modeling & Simulation Disease model Objective B/R assessment Identifying AE-related factors etc. Sophisticated Consultation More evidence-based consultation Practical use of Innovative Medical Products More rational & effective evaluation process for regulatory decision More effective and high quality Review More predictable efficacy/safety after approval Reduction of applicant s work load More scientific regulatory decision More efficient and Successful Development Epoch-making proposal leading the world Proactive publication of guideline

25 25 Possible Development Strategy Japan Other Asia US/EU PK, Safety Exploratory, Dose-Finding Confirmatory POC Japan only West only J/W J/W Japan/West W/J/E W/J/E West/Japan/ Asia Asian Asian Asia Asian Asian Early Asia Asian W/J/E W/J/E Asia Leading East Asian Asian Asian Real Asia Asian Asian J/W J/W Early Japan/West J/W

26 PMDA s proposal: New ICH guideline on MRCTs 26

27 Drugs from Asia to the world EU North America USA Canada Asia Cooperation for better drug development 27

28 Information HOMEPAGE (English) Regulatory Science Page Thank you for your attention 28