EXPERTS FOCUSED. TRUSTED. GLOBAL. Regulatory Highlights and Drug Development in China 5 th China Clinical Trial Outsourcing Congress March 4-5, 2013 Presented by Jim Wei, MD, PhD
May 25, 2015
EXPERTS
FOCUSED. TRUSTED. GLOBAL.
Regulatory Highlights and Drug Development in China
5th China Clinical Trial Outsourcing Congress March 4-5, 2013Presented by Jim Wei, MD, PhD
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
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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
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Class 1 A NME, which has never been approved and marketed in any country
•Phase I – SAD: 20-30•Phase I –MAD: 20-30•Phase II: >100 (test group)•Phase III: > 300 + statistically•Significant
Class 2 Change in administration route and not yet approved to be marketed in any country
Class 3 A drug has been approved and market in foreign market (e.g. US and EU) but new to China
•PK: 20-30•Phase III: >200 (>100 / arm)•Multiple indications (>60 / arm)
Class 4 Change acidic or alkaline radicals of the salt
Same as above
Class 5 Change in dosage form without change in administration
Same as above
Class 6 Generic product
China Drug Registration Classification and Requirement
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Process for Approval of Clinical Trial Applications
China SFDA
Center for Filing
Admin Review
30 B-days(1.5
months)
Center for Drug
Evaluation(CDE)
Review
90 B-days(4.5
months)
Center for Drug
Registration
Registration
30 B-days(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
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NDA Review ProcessChina SFDA vs. US FDA
Review Process US FDA China SFDA
Filing Review Review Team Center for Filing
Technical Review Division Center for Drug Evaluation (CDE)
Administrative Review
Office or DivisionSFDA
Department of Drug Registration
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Regulatory FocusChina SFDA vs. US FDA
o Type of Products: Generic vs. New Drugso New Drugs: Domestic/imported vs. IND/NDAo Data Requirements: Dependent vs. Independento Processing Unit: Application vs. Drug/Indicationo Definition of Drug/Review Focus: CMC vs. Clinicalo Interaction: Agency-initiated vs. Sponsor-
initiatedo Conditional Approval: No vs. Yeso Ability to Minimize Risk: Limited vs. Continuouso Approval: Manufacturing vs. Marketing
authorization
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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
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2012年化药 IND品种首轮审评结束所需时间的分析Time Needed for First-Round Evaluation of Initial IND in 2012
>9 months
9 months
8 months
7 months
6 months
<5 months
Compound [Jan. 1 – Dec. 10, 2012]
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)品种首轮审评并已有结论 (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并已有结论的时间。
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34 Applications were 1.1 New Drug Class (72% of the total INDs)
2012 SFDA/CDE : Initial 47 INDs
Indication
适应症
Percent
(%)所占比例
Average Time
(Month)
平均用时(月)
Shortest
Time(Month)
最短用时(月)Anti-cancer
抗肿瘤 32% 6.1 4.2
Endocrine
内分泌17% 6.7 5.8
Psychiatry/CNS
精神神经15% 7.3 5.8
GI
消化13% 7.6 5.6
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Annual Workshop of Science-based Regulatory Decision-making, Beijing since 2009
FDA Alumni Association and China SFDA Joint Training
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
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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
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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 www.fda.gov
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as of 2012FDA GCP Inspection on China Sites
Investigator Information Inspection Information
Investigator ID No.
Name Location Address CityZIP or Postal Code
InspectionDate
Type ClassificationDeficiency
Codes
432986 Ding, Ju-Hong Jiangsu Family Planning Institute
277 Feng Huan Zi jic
Nanjing 210029 07-Jun-1999 DA VAI 04,06,16
487467 Lu, Zhi-meng Ruijin Hospital - Shanghai - 13-Dec-2004 DA VAI 06
486375 Li, Zhanquan Liao Ning Province Peoples Hosp
33 Wenyi rd Shenyang 110016 20-Mar-2006 DA VAI 04,06
499597 Wang, Fengde Jilin Chemical Corp. no.32 datong road
Tiedong area 132022 27-Mar-2006 DA VAI 04,06
499599 Zhao, Ruiping Baotou Central Hospital
no.61 ring road west
Baotou city 014040 13-Mar-2006 DA VAI 04,06
499748 Zheng, Liwen Shenyang Military 208 Hospital, Jilin
prov.
number 171 xian street
Changchun 130062 29-Mar-2006 DA VAI 04,06
500052 Zhong, Jianhong
Mei County Hospital Sikeng economic
development zone
Songkou 514755 03-Apr-2006 DA VAI 04,06
520953 Xiu-Qing, Jiao Institute Of Microbiology And
Epidemiology
No. 20 Fengtai Street
Bejing - 09-Nov-2008 DA VAI 06
519006 Shen, Keng Peking Union Med Coll Hosp
1 Shuai Fu Yuan
Wangfujing
Beijing 100730 30-Mar-2009 DA NAI 00
http://www.accessdata.fda.gov/scripts/cder/CLIIL/index.cfm?fuseaction=Search.Search&SortField=EntityId&DataField=CountryCode&Keywords=CH&SortRequest=1
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as of 2012 - cont’dFDA GCP Inspection on China Sites
Investigator Information Inspection Information
Investigator ID No.
Name Location Address CityZIP or Postal Code
InspectionDate
Type ClassificationDeficiency
Codes
463257 Zeng, Bingfang Shanghai Baotou Hospital
600 Yi Shan Rd Shanghai 200233 16-Feb-2009 DA VAI 05,06
509832 Yang, Renchi Hemat & Blood Diseases Hosp Inst
288 Nanjing Rd Tianjin 300020 12-Aug-2009 DA NAI 00
521447 Sun, Aining The First Affiliated Hosp Of Soochow
Univ
188# Shizi St Suzhou 215006 10-Aug-2009 DA NAI 00
519006 Shen, Keng Peking Union Med Coll Hosp
1 Shuai Fu Yuan Wangfujing
Beijing 100730 30-Mar-2009 DA NAI 00
524066 Shen, Zhixiang Rui Jin Hospital Hematology Department
197 Rui Jin Er Rd Shanghai 200025 03-Aug-2009 DA NAI 00
534903 Xiao, Rui Lianong Angang Lishan Hospital
No. 32 Shuangshan Rd, Lishan District
Liaoning 014040 15-Aug-2011 DA NAI 00
534904 Lou, Fengyun Jilin Province Jilin City Central Hospital
No. 4 Nanjing Street
Jilin City 132001 26-Jul-2011 DA VAI 05,18
525437 Jing, Zhicheng
Shanghai Pulmonary Hosp Univ
507 Zhengmin Rd, Yangpu Dist
Shanghai 200433 24-Sep-2012 DA NAI 00
538295 Jin, Zimeng Peking Union Medical College Hospital
No. 1 Shuai Fu Yuan Wan Fu
Jing
Beijing 100730 11-Apr-2012 DA VAI 03,03,05,15
http://www.accessdata.fda.gov/scripts/cder/CLIIL/index.cfm?fuseaction=Search.Search&SortField=EntityId&DataField=CountryCode&Keywords=CH&SortRequest=1
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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)
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Advantages to Conducting Clinical Trials in China
o Large patient populationso Patient enrollments are rapid o Experienced investigators are increasingo 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
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Disadvantages
o Ethnic differenceso 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
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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
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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
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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
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Summary
o China regulatory environment is improvingo Clinical trial infrastructure is getting more matureo Patient population, good drug compliance, faster
enrollment are rewardso 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
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Thank You!Medpace
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