regulatory highlights and drug development in china

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Regulatory Highlights and Drug Development in China

5th China Clinical Trial Outsourcing Congress March 4-5, 2013Presented by Jim Wei, MD, PhD


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


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


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


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


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


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


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


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。


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


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


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


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


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




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




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)


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


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


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


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


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


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


Thank You!Medpace

www.medpace.com

regulatory highlights and drug development in china

Health & Medicine

china o advantages

china o us fda

o ability

agenda o

china o clinical facilities

vai o problems

clinical o interaction

continuous o approval