Transcript S6-3_Joan Shen_Clinical Development in China Myths and Facts

Asia Clinical Development
Strategy and Experiences
– China Perspective
Joan Shen, MD, PhD
China Development Head,
Janssen Pharmaceutical
Johnson & Johnson
Disclaimer
• The views and opinions expressed in the following Power
Point slides are those of the presenter’s own and should
not be attributed to the organization with which the
presenter is employed or affiliated
Agenda
• Current Landscape of China Drug Development
• China Guideline on Multiregional Clinical trials (MRCT)
• Opportunity and Considerations on MRCT
• Case Study
Current Landscape
of China Drug Development
President Xi stressed at National Health & Wellness Conference
that Health is the Top Priority of Chinese Development Strategy
National Health and Wellness Conference
19Aug, 2016
Central Government Key Aspirations
 Promote healthy life-style
 Improve healthcare services
 Strengthen healthcare coverage
 Establish healthy environment
President Xi made important speech indicating
improving people’s health status to bring
wellbeing to the general public is top priority
 Develop healthcare industry
China Healthcare Market Overview
Key Trends
Players Landscape
Manufacturers
7,511
Distributors
13,508
Hospitals & Clinics Pharmacies
983,528
448,057
Healthcare Expenditure: The investment
in health industry and expenditure will
increase.
Provincialization: China has built up
national health strategy; and policy will be
tailored at provincial and city level.
Upgrade Quality System: Quality will be
more emphasized. Manufacturers and
distributors will be more concentrated
Unit: Billion
RMB
Source:
1. 2015Drug Distribution Industry Statistics Report (by Ministry of Commerce)
2. 2015 China Health and Birth Control Development Report (by NHFPC)
3. Annual report of Chinese medical statistics 2015
*PH: public hospitals
PvH: private hospitals
Channel evolution : the composition of
channels (PH vs. PvH*, hospitals vs.
pharmacies, market in different city tiers)
will be evolutionized
Evolution of China Regulatory Environment
2000
2001
2002
Traditional post CoPP
registration pathway;
Drug lag >6 years
2010
2011
2012
2013
2014
2015
2016
2017
2018
IMCT pathway recognized by
CFDA; Reduction of drug lag 3-review cycle for
by 4 years
IMCT leading to delaye
d regulatory approvals
under IMCT pathway
CFDA Reform announced
By 3 years
: Reduce application
backlog and encourage
innovation
Recent news from CFDA (generally seen as positive):
•Speed up regulatory reviews for drugs with high clinical demand
•Improve quality of review & approval process
•Resolve registration application backlog
•Encourage new drug research & invention
•Increase review and evaluation transparency
Opportunities of CFDA Reforms
• Shortened CTA/NDA review timeline; priority review channel
• Sample size requirement negotiable for rare disease
• Potential removal of 2nd submission
• Imported Cat 1 path
• CMO-local manufacture capability
• CMC change during development
China Guideline
on Multiregional Clinical Trials
(MRCT)
Why Multiregional Clinical Trials (MRCT)?
Purpose and Scope of MRCT
• China Food and Drug Administration (CFDA) issued the new
Guidance for International Multicenter Clinical Trials (IMCT)
in January 30, 2015
• This Guidance is to guide the application, implementation and
management of the IMCT in China.
• Sponsor are encouraged to conduct IMCT in China in the areas
with unmet medical needs, to evaluate the feasibility in the early
stage of conducting global pivotal studies and regional studies
in China, and to consider conducting pivotal studies in China as
well as regional clinical trials targeted for Chinese patient
populations.
China Guideline on MRCT
• To encourage to conduct MRCT in China in the areas with unmet
medical needs
• MRCT study requires at least two countries including China.
• MRCT for registration purpose:
– Besides MRCT dataset, trending analysis of Asian vs
Non-Asian subjects and Chinese subjects vs other countries
are required. Detailed requirements will be published in the
future.
– MRCT study needs to meet statistic requirement and the
trending analysis of local subgroup should be consistent with
the entire MRCT population.
– According to guidance, local sample size should be big
enough to evaluate safety and efficacy in China and meet the
requirement of statistical and local regulation
China Guideline on MRCT
Draft version for public
Effective date:
comment:
Mar/01/2015
Nov/21/2014
Formal pilot version approved by CFDA:
Jan/30/2015& released on website:
Feb/06/2015
Chapters
Contents
Chapter 1
Background
Chapter 2
Purpose and Scope
Chapter 3
General Requirements
Chapter 4
Considerations on Trial Scientific
Chapter 5
Considerations on Trial Standardization
Chapter 6
Clinical Trial Protocol Amendment
Chapter 7
Registration Application
Chapter 8
On-Site Inspection
Chapter 9
Glossary
CFDA MRCT Guidance Key Points
Chapter 1: Background
• Global development could reduce duplicated clinical trial and
shorten drug lag.
• Type of global study
–
Global pivotal study
–
For scientific and safety considerations, the sponsor may conduct the
regional clinical trials
• Drug registration in China supported by MRCT data should
fulfill Drug Registration Regulation.
Chapter 2: Purpose and Scope
• Sponsor are encouraged to conduct MRCT in China in the areas
with unmet medical needs, global pivotal studies and regional cli
nical trials targeted for Chinese patient populations.
• Improve local development capacity, intellect and globalization.
CFDA MRCT Guidance Key Points Cont.
Chapter 3: General Requirements
•
At least two countries including China: China plus 1
•
No need ICH country for China+ and CFDA does not comment HK or
TW as China+.
•
Early evaluation for development strategy, such as disease epidemiolo
gy and medical practices.
•
MRCT for registration purpose:
– Besides global CSR, analysis for AP and China population is requir
ed, especially for China’s medical practice, i.e. whether the study p
opulation is representative
– Local sample size: big enough to evaluate safety and efficacy in
China and meet the requirement of statistical and local regulation
– Oversea inspection for all MRCT sites (risk and route cause drive
n spot-check).
CFDA MRCT Guidance Key Points Cont.
Chapter 4: Considerations on Trial Scientific
•
Disease epidemiology: focus on Incidence/prevalence, Etiology and risk factors and Prognosis
•
Differences in medical practice: local guideline and local experts
•
Differences in drug metabolism: internal and external factors which may cause differences
•
Dose selection: the rational of dose selection
•
Selection of control drug: conduct full argumentation based on approved indications, availabili
ty and usage
•
Efficacy evaluation： independent and unified evaluation of the primary efficacy indicators an
d central laboratories.
•
Sample size considerations: the minimal sample size need to meet regulation requirement an
d the Chinese proportion need to be considered as well. CFDA will be more prudent for samp
le size reduction.
•
Statistical considerations: the whole study need to meet statistic requirement and the trendin
g analysis of local data should be consistent with the results of entire MRCT.
•
Collection and evaluation of adverse events/reactions: ICH guidance
•
IDMC and EAC: Suggest to have Chinese experts sit in IDMC and EAC if Chinese subjects is
more than 20% of total subjects (Not mandatary)
CFDA MRCT Guidance Key Points Cont.
Chapter 5: Considerations on Trial Standardization
• Sponsor should register the drug clinical trial and disclose related information
on the clinical trial information platform of the CFDA
(website: http://www.chinadr
ugtrials.org.cn/). The information required to be
registered includes domestic and overseas principal investigators and clinical
trial institutions.
• IRB approval could be in parallel with CTA review in after the effective of new
GCP guidance (still seeking comments).
• Need to evaluate the possibility to shipping out the bio samples
Chapter 6: Clinical Trial Protocol Amendment
• Protocol amendment need to submit supplementary application before
implementation. The pathway is not very clear based on the current regulation..
–
Big impact to subjects safety
–
Significant change to ratio of risk/benefit
–
Large increase of Chinese subjects
Notes: We checked with CFDA in Mar 02 2015, CFDA reception center still not
accepted this kind of application at this moment
CFDA MRCT Guidance Key Points Cont.
Chapter 7: Registration Application
• Global clinical trial report, statistical analysis reports, databases of MRCT need to submitted
and subgroup analysis.
• Dossier should follow ICH CTD Format
• Additional documents required are as below:
– An evaluation of the entire MRCT dataset.
– Trending analysis of Asia and Non-Asia subjects.
– Trending analysis of Chinese subjects and other countries subjects.
• Notification and clarification is required for the early terminated or failure MRCT
Chapter 8: On-Site Inspection
• CFDA will strengthen clinical trial inspection basing risk and review requirement
• Besides site, the inspection will also focus on sponsor, documentation ie GDP and CRO.
Chapter 9: Glossary
• Pivotal Study, IDMC, EAC, ICH-CTD
Opportunity and Considerations
on MRCT
Opportunity and Considerations on MRCT
• ICH E17 is under discussion
• MRCT basic principles:
– Acceptability
• Design & implementation of MRCT need to satisfy the requirement of
EC/ ICH GCP, to ensure the quality and reliability of the clinical trial
– Applicability
• MRCT data can be applicable to similar patients in the country/region,
HA can make the NDA approval basing these data.
• MRCT main challenge: Scientific and rigorous Statistical
analysis of MRCT data
– Overall result of MRCT
– Results in all relevant areas and samples configuration
– Results “consistence” in different regions
The Future Opportunities of MRCT
Case Studies
Potential Ethnic Differences in Asian vs. Western
Populations must be Carefully Evaluated in Pivotal Trials
Basic principles on global
clinical trials (2007)
ICH E5 (1998)
ICH E17 open for
comments (2016)
Stand Alone
Bridging
Global Clinical
Development
Strategy
Trials
• CFDA use ICH guidelines as reference
• All three options are being implemented in china R&D
Early Ethnicity Consideration
to Avoid Potential Delay
Integrated Global Development Strategies
1st Assess Ethnic Sensitivity
based on ICH E5 including
target/ disease difference
cross-ethnicity ?
Lower R
isk
Global
Phase 1
NDA
PoC/
Phase 2a
Global
Phase 2b
Global Ph3
including CN (in Ch
ina)
NDA
China
CN Phase 1
26
Integrated Global Development Strategies
1st Assess Ethnic Sensitivity bas
ed on ICH E5 including
target/disease difference
cross-ethnicity ?
2nd Assess Ethnic Sensitivity
impact based on PK then
Efficacy/safety results?
High Risk
Global
Phase 1
PoC /
Phase 2a
NDA
Cross ethnic
PKPD study
including
oversea CN
Global
Phase 2b
including
oversea CN
Global Ph3 including
CN (in China)
NDA
China
CN Phase 1
Navigating through Dynamic Environment
Limited selfinspection
resources
Supply chain
change in
July2015
IMCT CTA su
b sep 2012
Internal
QC sample delay
due to unexpected
manufactory issues
AVT Strategy
2012
Supply chain
change in July
2016
2013
IMCT CTA app
Apr 2013
2014
CoPP CTA/CTW
Sub Dec 2013
2015
2017
CFDA query Respond quer Last site stamp/CTW
app/NDA sub Sep/Oct 2016
Nov 2015
y
Mar 2016
Backlog of application in CFDA
CDE formal
consultation
2016
Early issued
query
Priority review
New package
regulation
CFDA enhance site inspection
Complex procedure for site
stamps due to CFDA enhancing
site inspection
CFDA site
inspection
External
Summary
• Fully understand the regulatory requirement is
the key for innovative drug development in
China
• MRCT is an efficient way to pursue registrations
in China
• Detailed clinical plans and study designs are
needed