Regulatory Highlights and Drug Development in China


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Regulatory Highlights and Drug Development in China was presented at the 5th China Clinical Trials Outsourcing Congress March 4-5, 2013 by Xiaoxiong (Jim) Wei, MD, PhD, Medical Director at Medpace.

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Regulatory Highlights and Drug Development in China

  1. 1. FOCUSED. TRUSTED. GLOBAL.EXPERTS Regulatory Highlights and Drug Development in China 5th China Clinical Trial Outsourcing Congress March 4-5, 2013 Presented by Jim Wei, MD, PhD
  2. 2. FOCUSED. TRUSTED. GLOBAL. Agenda o The current status of the China regulatory environment for conducting clinical trials in China o Clinical facilities accredited by China SFDA to conduct trials o Outcomes regarding US FDA site inspections in China o Advantages and disadvantages of conducting trials in China o Strategic partnership with China domestic pharma companies
  3. 3. FOCUSED. TRUSTED. GLOBAL. China Regulatory Highlights o Regulatory timeline are shortened recently. However, 6~12 months Clinical Trial Application (CTA) approval time are still needed o All CTA, NDA submission packages are required in Chinese o ICH-CTD format for application package has been accepted o Need source country approval of Certified Pharmaceutical Product (CPP) to complete the NDA process o Predetermined minimal patient number and newly required statistical significance
  4. 4. FOCUSED. TRUSTED. GLOBAL. China Drug Registration Classification and Requirement Class 1 A NME, which has never been •Phase I – SAD: 20-30 approved and marketed in any •Phase I –MAD: 20-30 country •Phase II: >100 (test group) Class 2 Change in administration route and •Phase III: > 300 + statistically not yet approved to be marketed in •Significant any country Class 3 A drug has been approved and •PK: 20-30 market in foreign market (e.g. US and •Phase III: >200 (>100 / arm) EU) but new to China •Multiple indications (>60 / arm) Class 4 Change acidic or alkaline radicals of Same as above the salt Class 5 Change in dosage form without Same as above change in administration Class 6 Generic product
  5. 5. FOCUSED. TRUSTED. GLOBAL. Process for Approval of Clinical Trial Applications China SFDA Center for Center for Center for Drug Filing Drug Evaluation Registration (CDE) Admin Review Review Registration 90 B-days 30 B-days 30 B-days (4.5 months) (1.5 months) (1.5 months) -It takes 7.5 month by default -It takes 9-12 months when no additional information is requested -It took shorter time in 2012
  6. 6. FOCUSED. TRUSTED. GLOBAL. China SFDA vs. US FDA NDA Review Process Review Process US FDA China SFDA Filing Review Review Team Center for Filing Technical Review Division Center for Drug Evaluation (CDE) SFDA Administrative Review Office or Division Department of Drug Registration
  7. 7. FOCUSED. TRUSTED. GLOBAL. China SFDA vs. US FDA Regulatory Focus o Type of Products: Generic vs. New Drugs o New Drugs: Domestic/imported vs. IND/NDA o Data Requirements: Dependent vs. Independent o Processing Unit: Application vs. Drug/Indication o Definition of Drug/Review Focus: CMC vs. Clinical o Interaction: Agency-initiated vs. Sponsor-initiated o Conditional Approval: No vs. Yes o Ability to Minimize Risk: Limited vs. Continuous o Approval: Manufacturing vs. Marketing authorization
  8. 8. FOCUSED. TRUSTED. GLOBAL. SFDA Center for Drug Evaluation (CDE) o Has improving its functions:  Green Channel Approach and approval time is shortened  Pre-IND consultation  Sponsored training workshops to promote GMP, GLP, GCP and new drug development  Participating in major international conferences • - DIA, AAPS, and many regional workshops  More harmonization with ICH • - More ICH/FDA guidances translated in Chinese  Established in-house statistical group  Expanding review staff  Implementing Good Review Practice • More Science-based approach • Openness, fairness, rightfulness
  9. 9. FOCUSED. TRUSTED. GLOBAL. Time Needed for First-Round Evaluation of Initial IND in 2012 2012年化药IND品种首轮审评结束所需时间的分析 审评中心自2012年1月1日至2012年12月10日共完成化药IND(包括化药注册分类1类和2类)品种首轮审评幵 已有结论 (结论包括会议讨论、发补、批准、不批准),按化合物计共47个。现对上述首轮审评所用时间 分析如下: 下图所示的时间为品种正式进入中心到各部门完成首轮审评幵已有结论的时间。 >9 months 9 months 8 months 7 months 6 months <5 months Compound [Jan. 1 – Dec. 10, 2012]
  10. 10. FOCUSED. TRUSTED. GLOBAL. 2012 SFDA/CDE : Initial 47 INDs 34 Applications were 1.1 New Drug Class (72% of the total INDs) Average Time Shortest Time Indication Percent (%) (Month) (Month) 适应症 所占比例 平均用时(月) 最短用时(月) Anti-cancer 32% 6.1 4.2 抗肿瘤 Endocrine 17% 6.7 5.8 内分泌 Psychiatry/CNS 15% 7.3 5.8 精神神经 GI 13% 7.6 5.6 消化
  11. 11. FOCUSED. TRUSTED. GLOBAL. FDA Alumni Association and China SFDA Joint Training Annual Workshop of Science-based Regulatory Decision-making, Beijing since 2009 o FDA Alumni Association (FDAAA) and SFDA/CDE co- sponsored a successful pilot regulatory science educational workshop for SFDA reviewers in Beijing in 2009  The three lectures and group discussion topics • Vaccine Development Issues by Florence Houn • Science-based Decision-making for Anti-Infective Products by Mark J. Goldberger • New Treatment for Cancer: US Regulatory Considerations by Robert J. DeLap o The FDAAA International Network (FDAAA IN) will continue to explore ways to do outreach and provide education to China SFDA regarding establishment and operations of regulatory programs
  12. 12. FOCUSED. TRUSTED. GLOBAL. Certified Institutions for Clinical Trials in China o Site: 550 hospitals  To certify therapeutic areas to qualify conduct of studies  Re-certification every 3 yeas o Phase I Units: about 115 units with 8-24beds per unit o About 20 centers focus on anticancer drug (Phase II/III),  A few centers are capable of conducting both Phase I and Phase II/III, o >13500 investigators and their staffs were trained for GCP
  13. 13. FOCUSED. TRUSTED. GLOBAL. FDA GCP Site Inspection in China o US FDA inspected clinical investigators in China:  8 PIs before 2008  10 PIs between 2009 and 2012 o Regulatory actions were not necessary although there were a few minor problems (Classification: Voluntary Action Indicated, VAI) o Problems found:  Inadequate drug accountability  Inadequate and inaccurate records o FDA Clinical Investigator Inspection List (CIIL)at
  14. 14. FOCUSED. TRUSTED. GLOBAL. FDA GCP Inspection on China Sites as of 2012 Investigator Information Inspection Information ZIP or Deficiency Investigator Inspection Name Location Address City Postal Type Classification Codes ID No. Date Code 432986 Ding, Ju-Hong Jiangsu Family 277 Feng Huan Nanjing 210029 07-Jun-1999 DA VAI 04,06,16 Planning Institute Zi jic 487467 Lu, Zhi-meng Ruijin Hospital - Shanghai - 13-Dec-2004 DA VAI 06 486375 Li, Zhanquan Liao Ning Province 33 Wenyi rd Shenyang 110016 20-Mar-2006 DA VAI 04,06 Peoples Hosp 499597 Wang, Fengde Jilin Chemical Corp. no.32 datong Tiedong area 132022 27-Mar-2006 DA VAI 04,06 road 499599 Zhao, Ruiping Baotou Central no.61 ring road Baotou city 014040 13-Mar-2006 DA VAI 04,06 Hospital west 499748 Zheng, Liwen Shenyang Military number 171 Changchun 130062 29-Mar-2006 DA VAI 04,06 208 Hospital, Jilin xian street prov. 500052 Zhong, Jianhon Mei County Hospital Sikeng Songkou 514755 03-Apr-2006 DA VAI 04,06 g economic development zone 520953 Xiu-Qing, Jiao Institute Of No. 20 Fengtai Bejing - 09-Nov-2008 DA VAI 06 Microbiology And Street Epidemiology 519006 Shen, Keng Peking Union Med 1 Shuai Fu Yuan Beijing 100730 30-Mar-2009 DA NAI 00 Coll Hosp Wangfujing
  15. 15. FOCUSED. TRUSTED. GLOBAL. FDA GCP Inspection on China Sites as of 2012 - cont’d Investigator Information Inspection Information ZIP or Deficiency Investigator Inspection Name Location Address City Postal Type Classification Codes ID No. Date Code 463257 Zeng, Bingfang Shanghai Baotou 600 Yi Shan Rd Shanghai 200233 16-Feb-2009 DA VAI 05,06 Hospital 509832 Yang, Renchi Hemat & Blood 288 Nanjing Rd Tianjin 300020 12-Aug-2009 DA NAI 00 Diseases Hosp Inst 521447 Sun, Aining The First Affiliated Hosp 188# Shizi St Suzhou 215006 10-Aug-2009 DA NAI 00 Of Soochow Univ 519006 Shen, Keng Peking Union Med Coll 1 Shuai Fu Yuan Beijing 100730 30-Mar-2009 DA NAI 00 Hosp Wangfujing 524066 Shen, Zhixiang Rui Jin Hospital 197 Rui Jin Er Rd Shanghai 200025 03-Aug-2009 DA NAI 00 Hematology Department 534903 Xiao, Rui Lianong Angang No. 32 Liaoning 014040 15-Aug-2011 DA NAI 00 Lishan Hospital Shuangshan Rd, Lishan District 534904 Lou, Fengyun Jilin Province Jilin City No. 4 Nanjing Jilin City 132001 26-Jul-2011 DA VAI 05,18 Central Hospital Street 525437 Jing, Zhicheng Shanghai Pulmonary 507 Zhengmin Shanghai 200433 24-Sep-2012 DA NAI 00 Hosp Univ Rd, Yangpu Dist 538295 Jin, Zimeng Peking Union Medical No. 1 Shuai Fu Beijing 100730 11-Apr-2012 DA VAI 03,03,05,15 College Hospital Yuan Wan Fu Jing
  16. 16. FOCUSED. TRUSTED. GLOBAL. US FDA Clinical Investigator Inspection List (CIIL) - Deficiency Code  00: No deficiencies noted  03: Inadequate informed consent form (21 CFR 50.25)  04: Inadequate drug accountability (21 CFR 312.60, 312.62)  05: Failure to follow investigational plan (21 CFR 312.60)  06: Inadequate and inaccurate records(21 CFR 312.62)  15: Failure to notify IRB of changes, failure to submit progress reports (21 CFR 312.66)  16: Failure to report adverse drug reactions(21 CFR 312.64, 312.66)
  17. 17. FOCUSED. TRUSTED. GLOBAL. Advantages to Conducting Clinical Trials in China o Large patient populations o Patient enrollments are rapid o Experienced investigators are increasing o Sites and clinical investigators are motivated o Competitive cost compared to US and EU  Relatively lower expenses for travel, monitoring, project management fees, clinical investigator fees, and procedural fees for diagnostic and therapeutic interventions o Large market for new drug products
  18. 18. FOCUSED. TRUSTED. GLOBAL. Disadvantages o Ethnic differences o Ethical issues  Placebo o GCP and protocol training is a must and may take longer time to implement  Take long time to Initiate a clinical trial o A clinical trial application must be approved with a written notice by SFDA  it can be long time o Investigator:  Clinical investigators must be in the therapeutic departments that are certified by China SFDA o Clinical trials vs. marketing in China
  19. 19. FOCUSED. TRUSTED. GLOBAL. China Pharma Industry o Revenue: 10 millions – 1 billion US$ for most firms o In-house pipelines for new drug development  Increasing interest in acquiring new drug candidates from R&D firms  Increasing co-development for drug products with foreign firms for China market
  20. 20. FOCUSED. TRUSTED. GLOBAL. China Pharma Industry - cont’d o State-owned:  Sinopharm, Shanghai Pharm Group, Harbin Pharma Group o API-focused:  Hisun pharma, Huahai Pharma  Shifting to new drug development:  HengRui, HEC Pharma  Specialty:  Fudan-Zhangjiang Biopharma  Biotech:  Hutchison MediPharma
  21. 21. FOCUSED. TRUSTED. GLOBAL. Chinese Government Initiatives for New Drug Development (Invented in China) o Central Government  Flood of Funding • Billion US$ government grants in the 5-year plan starting 2012 o Provincial and local governments  Matching funds to the projects funded by the central government o Incubators for new drug development in Economic Development Zones in every province and major metropolitan areas:  Shanghai  Taizhou  Suzhou  Beijing
  22. 22. FOCUSED. TRUSTED. GLOBAL. Summary o China regulatory environment is improving o Clinical trial infrastructure is getting more mature o Patient population, good drug compliance, faster enrollment are rewards o Ethnic difference, placebo issues, long regulatory approval and language are obstacles. o Planning, training and close monitoring are essential for success in conducting clinical trials in China o China domestic pharma firms are ready for acquiring or co-developing drug candidates in China market
  23. 23. FOCUSED. TRUSTED. GLOBAL. Thank You! Medpace