ClinActis - Chinese E5 Bridging Study

ClinActis Pte Ltd - 112 Robinson Road - #06-04 - Singapore 068902
Telephone: +65 6436 5500 - info@clinactis.com
Conduct Chinese E5 Bridging Study
(Outside China)

ClinActis is exclusively focused on Asia Pacific, with solid expertise in applying international quality
standards to regional specificities. ClinActis is flexible in our approach to work scope and budgeting and
contracting process.
Delivering Quality to Our Clients
ClinActis is committed to implementing international standards in clinical trials. Our ability to deliver high
quality results to our clients is based on recruiting and maintaining the best talent within our
organization. ClinActis’ senior management is fully accountable for the quality of deliverables to our
clients.
Your Proactive Clinical Research Partner in Asia Pacific

ClinActis Pte Ltd is a full service CRO
providing clinical trial services to the
pharmaceutical, medical device, medical
nutrition and biotech companies in Asia
Pacific. Established in 2009, ClinActis Pte Ltd
is headquartered in Singapore.
ClinActis Value Proposition
ClinActis is a multicultural company. As such,
the team is able to communicate effectively
with international clients.

Mission and Vision

With headquarters based in Asia, all corporate
decisions are made within the region, in order to
better anticipate our client needs and adapt to local
specificities.
Vision
Our vision is to become the reference CRO
specialized in conducting clinical research in Asia
Pacific, offering state of the art quality services, with
cost effective solutions.
We strive to employ people with genuine expertise
in the region and with a passion for excellence, to
work with our clients in the most pro-active way, and
to build a relationship based on trust, transparency
and strong ethics.
Mission
Our mission is to provide our clients with unique
and dynamic expertise in applying global drug
development standards to the specificities of
each country in the Asia Pacific region.

Christophe Tournerie, MD – Owner and CEO
Dr. Tournerie has more than 20 years experience in clinical research in Europe
and Asia Pacific including Japan, working with biotechnology companies,
pharmaceutical companies and clinical research organizations.
After completion of his medical studies in Paris and various hospital
assignments in France, Dr. Tournerie spent a period of 3 years at the National
Medical Research Institute in France in the field of drug development in anti-HIV
products.
About Our Founder
His introduction to the pharmaceutical industry was as Medical Director in an American biotechnology
company developing anti-HIV products. Then, he moved to a large global CRO, heading the Project
management Department for South Europe, and then as Head of Operations in the Japan affiliate.
Later, Dr. Tournerie headed the Asian clinical research activity for a multi-national Pharmaceutical
Company, based in Singapore.
More recently, Dr. Tournerie was Vice President Asia Pacific for a large global CRO, based in
Singapore. During this assignment, Dr. Tournerie developed the business strategy for the region,
successfully established and directed operations in 12 countries and built a highly professional team.

Operational Expertise – Regional Footprint
ClinActis Experience
§  33 years experience in clinical
research in pharmaceutical and
biotechnology companies as well as
CROs
§  27 years experience in Asia Pacific,
including Australia/New Zealand,
China, Malaysia, Hong Kong, India,
Indonesia, the Philippines,
Singapore, South Korea, Taiwan,
Thailand, Japan and Vietnam
§  Extensive knowledge of regulatory
frameworks, best KOLs and sites
across the region
§  Vast therapeutic experience including
Oncology, Infectious diseases, CNS,
Cardiovascular, Endocrinology, and
Respiratory

Agenda
■  Introduction of Clinical Trial Country/Site Selection
■  Select the Accredited Sites Outside China
■  Understand the Submission Requirements in Targeted
Countries (Authorized by CFDA)
■  Challenges and Consideration to Conduct E5 Bridging
Study Outside China
■  Estimation of the Patient Cost in Targeted Countries
■  Conclusion on the Country/Site Selection

Traditional Approach in China
SAD
MAD
China
Phase II
Phase III
NDA in China
IND in China
Approval Timeline for
Chemical drug (based on
RDPAC survey)
• IDL-CTA: 36±4 mths
• IDL-NDA: 29±4 mths
• IMCT-CTA: 20±2 mths
• IMCT-NDA: 36±4 mths
CTA = Clinical Trial Application, IDL = Import Drug License, IMCT = International Multi-country Clinical Trial, NDA =
New Drug Application, RDPAC = R&D-based Pharmaceutical Association Committee

Traditional IND and NDA Approach in China
First in Human/ SAD
MAD
RoW
(Outside China)
Phase I results
China
SAD
(In Local population)
MAD
Phase II
Phase III
NDA in China
IND in China
Sequential Submission
(delay in drug development)
Impact of
“ethnic factors”

Why We Need a Bridging Study in China
■  Accelerating Regional Drug Approvals
■  Efficient and Cost-Effective Drug Development
■  Increasing Patent Life
■  Cross Use of Early Data
■  Solving the “Drug Lag” Issue with Global Simultaneous Drug Development
■  Complete Clinical Data Package Required by Local Authority
■  To Meet the ICH E5 Guideline Pertaining to:
−  Impact of “Ethnic Factors” on the Acceptability of Foreign Clinical Data (FCD)
−  Minimize Duplication of Clinical Data
−  Bridging Requirements for Extrapolation of FCD to New Region
−  Enhance Global Development
■  Provide Adequate Characterization of:
−  PK/PD
−  Efficacy and Safety
−  Dose-Response
−  Clinical Disorders Evaluated Using Medical & Diagnostic Definitions Acceptable in the
Region

New E5 Bridging Concept in China
SAD/MAD
Phase I results
China
First in Human/ SAD
MAD
Phase II
Phase III
NDA in
China
IND in China.Bridging Study
Skip Phase I Studies in China
(1)  Cost down
(2)  Shorten timeline to NDA
Timeline of Traditional NDA
Approach
Timeline of New E5 Bridging
Concept for NDA
•  Start with Phase I
•  IMCT-CTA: 20±2 m
•  IMCT-NDA: 36±4m
•  Directly into Phase 2
•  IMCT-CTA: 20±2 m
•  IMCT-NDA: 24±4 m
Total Duration = 56 months Total Duration = 44 months
CTA = Clinical Trial Application, IMCT = International Multi-country
Clinical Trial, NDA =New Drug Application

What Are the Benefits to Conduct Bridging Studies in Other
Regions Outside China?
■  Faster Clinical Trial Approval in Other Regions Outside China
■  Faster Start Up Time of a Clinical Trial Compare to the
Lengthy Approval Process in China
■  Saves an Average of One Year in the NDA Application Time
Compare with a Typical NDA Application in China
■  Non-Complex Submission Dossier/Requirement in other
Regions Outside China

Introduction of Clinical Trial
Country/Site Selection

Introduction of Clinical Trial Country/Site Selection
■  Cost, speed of approvals and the shortcoming of the local
requirement/limitations in different countries are the actual weight of
the factors that may impact clinical trial country/site selection.
■  Although CFDA has announced on 17 May 2017 a new CTD
directive (recommendations) to simplify and harmonize the
administrative provisions governing clinical trials inside China or
bridging the data from countries outside China, it is not clear which
specific recommendations will be implemented or are being
implemented successfully as of today.
■  There are 4 factors influencing clinical trial country/site selection to
conduct Chinese PK Bridging study in regions outside China,
including:
−  Select the accredited sites outside China
−  Understand the submission requirements in targeted countries (Authorized
by CFDA)
−  Challenges and Consideration to conduct PK Bridging study outside China
−  Estimation of the Patient Cost outside China

Select the Accredited Sites
Outside China

Select Accredited Sites Outside China
■  According to the requirement of CFDA, the primary centres (outside
China regions) affiliated with the agency that are directly involved in
the clinical trial application must be accredited by the CFDA, if we
plan to submit the clinical trial data/results obtained from these
primary centers to CFDA in future (either for the purpose of
registration or clinical trial application)
■  There are only 2 hospitals in Hong Kong and 4 hospitals in Taiwan
being accredited by CFDA to conduct the clinical trial in the regions
outside China

Accredited Sites in Hong Kong
■  Queen Mary Hospital
■  Prince of Wales Hospital

Accredited Sites in Taiwan
■  National Taiwan University Hospital
■  Taipei Veterans General Hospital
■  Linkou Chang Gung Memorial Hospital
■  Tri-Service General Hospital

Understand the Submission
Requirements in Targeted Countries
(Authorized by CFDA)

Submission Requirements in Hong Kong (Parallel)
ETHICS COMMITTEE
Principal Investigator (PI)
Documents required for submission:
•  Submission letter for initial review
•  Clinical study categorization form
•  Clinical Research Ethics Review application form
•  Supplementary information sheet for Phase 1 study (if
applicable)
•  Curriculum Vitae (CV) of Principal Investigator(s) and Co-
Investigators
•  Principal Investigator and Co-Investigator(s) conflict of interest
declaration form
•  Indemnity agreement for Clinical study
•  Certificate of insurance for Clinical study
•  Clinical Study Protocol
•  Investigator’s Brochure
•  Informed Consent Form (English and Traditional Chinese)
•  Subject recruitment materials (English and Traditional Chinese)
•  Documents/materials for use by subjects in the study (English
and Traditional Chinese)
APPROVAL:
Average 24 weeks
INDIVIDUAL INSTITUTION EC’s
REGULATORY AUTHORITY
Sponsor / CRO
•  Clinical Trial Checklist & Application form
•  Clinical Study Protocol and Investigator’s Brochure
•  Letter of Intent
•  Curriculum Vitae (CV) of Principal Investigators (PI) and Co-
Investigators(s)
•  Authorization letter from PI to authorize ClinActis Pte Ltd to
handle the Clinical Trial Certificate Application
•  Informed Consent Form (English and Traditional Chinese)
•  Recruitment materials intended to be seen or heard by
potential subjects (English and Traditional Chinese)
•  Written information intended to be provided to subjects
(English and Traditional Chinese)
•  Certificate of insurance for clinical study
•  Sample of Investigational Medicinal Product (IMP)
•  Good Manufacturing Practice (GMP) Certificate from relevant
manufacturing sites
•  Certificate of Analysis (CoA) and Certificate of Compliance
(CoC)
•  EC approval letter (to be submitted once available)
DEPARTMENT OF HEALTH (DOH)
APPROVAL:
Average 36 weeks

Submission Requirements in Taiwan (Parallel)
ETHICS COMMITTEE
Principal Investigator (PI)
•  Application form
•  Checklist
•  Study Protocol / amendment(s) to protocol / administrative changes
•  Protocol summary in English and Chinese
•  Subject Informed Consent Form (Chinese)
•  CV and GCP certificate of PI, Sub-I and SC
•  Clinical Investigator’s Brochure (English)
•  Data collection forms or case report forms
•  Insurance Certificate & Indemnity Letter
•  Relevant Publications (if requested)
•  Questionnaire/diaries if used (Chinese)
•  Advertisement if applicable
•  Study budget details
•  Some EC’s may request RA approval before EC submission
•  Power of Attorney or Letter of Authorization
•  DSMB Charter (if requested)
•  ADR form
APPROVAL:
Average: 8-12 weeks
INDIVIDUAL INSTITUTION EC’s
REGULATORY AUTHORITY
CRO
•  Application form/Introduction
•  Physical-chemical or biological properties (including placebo)
•  Non-clinical (pharmacology, ADME, toxicity)
•  Test method & Specification
•  Clinical experiences (if applicable)
•  Clinical Study Protocol
•  Patient Information and Informed Consent Form
•  Questionnaires, Diary Cards
•  Investigator's Brochure (IB) (English)
•  Indemnity Letter
•  Importer or Manufacturer's Certificate (IMP and lab kits)
•  Patient compensation rule (Indemnity Letter)
•  IMPD (include description of Manufacturing process, Control
process, product specifications, stability information (test and
results), description and composition of the drug product and risk-
benefit information)
•  CV and GCP (PI, Sub-I and SC)
TAIWAN FDA
APPROVAL:
Average: 12 weeks

Challenges and Consideration to
Conduct PK Bridging Study
Outside China

Challenges and Consideration to Conduct PK Bridging
Study Outside China
■ The objective of Chinese PK bridging study is to extrapolate the foreign clinical
trial data to the Chinese population to show there is NO difference in ethnicity in
Asia and Caucasian data by making a comparison between Caucasian and
Asian data.
■ In order to increase the success rate to supplement this bridging data for
Sponsor submission to CFDA in future, there are some considerations we need
to be aware of before the study conduct, as listed in the next presentation slides.
■ After obtaining CFDA approval, we will need to indicate the CFDA approval
number in the INITIAL submission dossiers to the local IRB and regulatory
■ the challenges to be considered to conduct PK Bridging study are :
−  Prior approval of CFDA (length approval timeline)
−  Selection of PK lab
−  Meeting the minimum subject number

Prior Approval of CFDA
§  All clinical trials (including PK studies) need to obtain CFDA approval before
we can submit the initial application of PK Bridging study to the local
authority in Taiwan and Hong Kong.
§  There is no specific document required for applying CFDA but to indicate the
No. of Drug Clinical Trial Approval Document and the date of approval in the
CA submission form.
§  The timeline to obtain CFDA approval from the China authority might be a
challenging factor as it can range from 4 weeks to 12 weeks. This will
indirectly delay the initial submission to the local authority in Taiwan and
Hong Kong.
§  To overcome this issue, we will need to set up frequent face to face
meetings with CFDA to follow up the progress and status of the approval.

Prior Approval of CFDA
§  The objective of Chinese PK bridging study is to extrapolate the foreign
clinical trial data to the Chinese population to show there is NO difference in
ethnicity in Asia and Caucasian data by making a comparison between
Caucasian and Asian data.
§  In order to increase the success rate to supplement this bridging data for
Sponsor submission to CFDA in future, there are some considerations we
need to be aware of before the study conduct, as listed in the next
presentation slides.
§  After obtaining CFDA approval, we will need to indicate the CFDA approval
number in the INITIAL submission dossiers to the local IRB and regulatory
§  The challenges to be considered to conduct PK Bridging study are :
§  Prior approval of CFDA (length approval timeline)
§  Selection of PK lab
§  Meeting the minimum subject number

Selection of PK Lab
§  It is recommended to select PK lab that comply with GLP requirement as per
Chinese guideline.
§  CFDA is willing to accept the PK data from the lab that can produce the
results of Pharmacokinetic and Pharmacodynamic analysis according to the
Chinese guideline.
§  This PK and PD analysis should include the format on how the expert PK
from the lab should provide the input to preclinical and clinical development
plans, evaluation of safety data and animal tissue distribution data, study
design: sample size calculation, optimized sampling schedule, non-
compartmental and compartmental analysis, PK/PD modelling and
simulation (including population approach)

Meeting the Minimum Subject Number
§  There is no requirement from Taiwan or Hong Kong regulatory body
pertaining to the minimum subject required in the PK Bridging study if we
choose to conduct the study in Taiwan or Hong Kong
§  However, if we choose to conduct the study in a region outside China and
plan to use the data for submission to CFDA, we’ll try to meet the minimum
cases as per requirements to conduct similar clinical trials in China

Estimation of the Patient Cost
in Targeted Countries

Estimated Site Fees (USD) (Includes PI Fees, Administrative Fees, Lab Fees,
PK Handling Fees)
COUNTRY INDICATION PI FEES
(USD)
ADMIN
FEES
(USD)
- Per year
LAB FEES
(USD)
- 4 x Lab
test + 3 x
Imaging
test
PK HANDLING
FEES
(USD)
- Assume 2 x
24H PK + 2 bed
Hospitalisation
PATIENT
TRANSPORTAT
ION FEES/BED
for PK
SAMPLING
(USD)
-  Assume 5
trips
TOTAL FEES PER
SUBJECT
(USD)
- Plus 15%
overhead cost
Taiwan PK
Bridging
Study
$ 3,680 $2,800 $ 2,350 $ 1,430 $ 500 $12,374
Hong
Kong
PK
Bridging
Study
$ 4,500 $ 3,500 $ 3,580 $ 3,111 $ 500 $17,469

Definition of PI Fees, Admin Fees, Lab and Imaging Fees
and PK Handling Fees
ITEMS DESCRIPTION
PI Fees Fees to pay the PI to perform the screening, enrolment and
follow up patient status as per the procedures in the protocol
Admin Fees Including the administrative charges, startup fees, and
pharmacy cost
Lab & Imaging
Fees
Including the lab testing including biochemistry, hematology,
immunology, urine, X-ray, will be used for this study
PK handling
and other
related Fees
Including the blood taking at each PK timepoint as well as
the cost associated with the PK blood drawing including
hospitalization, bed fees and etc.

Conclusion on the
Country/Site Selection

Criteria for Site Selection
Sites That:
§  Are equipped with PK facility (bed, imaging lab, storage) and experienced
team members ready to conduct or select the best lab vendor for PK lab
sampling.
§  That keep a list of patient database that are ready to perform screening.
§  Have no conflict on the protocol treatment and procedures when compared
to local medical treatment or requirements.
§  Have a majority of patient pools meeting the inclusion/exclusion criteria of
the protocol (precise feasibility activity and questionnaires are required) for
recruitment in future.

Alternative Study Submissions to Local IRB
§  As the pre-approval timeline from CFDA is unknown and/ or maybe lengthy,
we will recommend not to apply pre-approval registration number from
CFDA before we proceed to do Initial submission in Hong Kong and Taiwan.
§  With the above-mentioned strategy, we can just submit the PK Bridging
study in Hong Kong and Taiwan as per the standard requirement IRB and
HA submission in these 2 countries.
§  The data from the PK Bridging study from Hong Kong or Taiwan will be
submitted as part of the supplementary dossier during the initial submission
to the CFDA in China (to conduct Phase II and Phase III in China)

Conclusion of the Country/Site Selection
Country Recommendation to Conduct Chinese PK Bridging Study:
§  1st Country Selection: Taiwan
§  2nd Country Selection: Hong Kong

Why Taiwan Before Hong Kong?
§  Taiwan carries more advantages than Hong Kong to conduct the PK
Bridging studies:
§  There are 4 hospitals in Taiwan accredited by CFDA and we can enroll
more sites into this study.
§  Bigger patient population allows sufficient patients being recruited in the
study.
§  Shorter duration of IRB and CA review and approval timeline compared
to Hong Kong.
§  Cheaper per patient cost in Taiwan than Hong Kong.
§  Ethnically, Chinese and Taiwanese are considered to be the same. They will
be no ethical issue to be challenged for submission of the Taiwanese PK
data to CFDA in future.

Contact Us for More Information

Imen Jelassi, PharmD, MSc
EU Director, Strategic Relations
M: +33 6 28 11 13 71
E: ijelassi@clinactis.com
Bill Van Nostrand
Head of Business Development,
North America
M: +1 908-229-5220
E: bvannostrand@clinactis.com

ClinActis - Chinese E5 Bridging Study

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (20)

Ähnlich wie ClinActis - Chinese E5 Bridging Study

Ähnlich wie ClinActis - Chinese E5 Bridging Study (20)

Kürzlich hochgeladen

Kürzlich hochgeladen (20)

ClinActis - Chinese E5 Bridging Study