An Issue in Multi-Regional
Clinical Trial Design:
Sample Size of Japanese patients
2011 APEC MRCT TOKYO Workshop
November 2nd, 2011
Kihito Takahashi, MD, PhD
GSK-Japan, JAPhMed, JCPM
Disclaimer and Acknowledgement
The views and opinions expressed in the following
presentation are those of the individual presenter and should
not be attributed to any organization with which the presenter
is employed or affiliated.
This slides were created with the strong support from the
following individuals:
– Dr. Masao Yarita (GSK)
– Dr. Yoshio Tsukada (GSK)
– Dr. Tomoya Masaki (GSK)
2
Background of the Issue
Currently, sample size determination of Japanese patients in
MRCT is one of the most controversial issues among
pharmaceutical companies.
– Before Japan’s participation in MRCT, determination in regional sample
size was not a major issue
Recent References regarding this issue:
– 13 Sep 2010, APEC Multi-Regional Clinical Trials Seoul Workshop
Multi-Regional Clinical Trials in Global Drug Development: Experience in
Japan. Yuki Ando. PMDA
– 19 Nov 2010, The Biometric Society Seminar
Issues in synchronized global development and multi-regional studies from
regulator’s viewpoint. Yuki Ando. PMDA
– 30 Sep 2011, The Tenth Kurume Biostatistics Forum
Statistical aspects in drug review. Yuki Ando. PMDA
3
Description in ICH guidelines
ICH-E5 Q&A11 (5-Oct-2006 )
– discussion of a multi-regional clinical trial.
Q11： … It may be desirable in certain situations to achieve the goal of
bridging by conducting a multi-regional trial under a common protocol that
includes sufficient numbers of patients from each of multiple regions to
reach a conclusion about the effect of the drug in all regions.
Please provide points to consider in designing, analyzing and evaluating
such a multi-regional trial.
A11:
………. For a multi-regional trial to serve as a bridging study for a particular region,
it would need to have persuasive results in that region, because it is these
regional results that can convince the regulators in that region that the drug is
effective, and can “bridge” the results of trials in other regions in the registration
application..
4
Description in Japanese Guidelines
Basic Principles on Global Clinical Trials
– (28-Sep-2007)
6. When conducting an exploratory trial like a dose-finding study or a
confirmatory trial as a global clinical trial, how is it appropriate to
determine a sample size and a proportion of Japanese subjects?
– In a global trial, sample size can be calculated assuming results from
the entire study population across regions. In this case, a sufficient
statistical power to detect statistically significant difference should
not necessarily be secured within the Japanese subpopulation.
5
Sample Size Calculation
Method 1
DALL
DJapan
Dother
０
↑criteria
DJapan >
All regions
1
DAll
2
Japan
Differences
between placebo and treatment
Method 2
DJapan > 0, DChina > 0, DKorea > 0
DJapan
DKorea
All regions
Japa
n
DChina
０
↑criteria
Korea
China
Differences
between placebo and treatment
6
Sample Size Determination:
Reference in the guideline
Example:
In case of clinical trial with the following characters:
– the size of a few hundred patients
– two-arm
– placebo-controlled parallel group design
– similar efficacy across regions
For a scientifically appropriate evaluation based on the existing study
results,
– (1) by the method 1, if attempting to minimize the Japanese
sample size while to an adequate extent preventing increase of
the total sample size, Japanese subjects are needed to account
for about 20 %;
– (2) by the method 2, when conducting a trial in three regions, with
the power of the trial as 90 % for the total sample size, Japanese
subjects are needed to account for about 15 % or more.
2007, Guideline
7
Positive Impact of Guideline on MRCT
The number of MRCTs steeply increased after the publication of the guideline
60
Time course on % of MRCT in Japan
Ratio (%)
50
40
30
55.2
20
28.6
10
7.1
5.6
4.9
5.6
2003
2004
2005
2006
0
2007
2008
EFPIA-J 2010
8
Dependency on the Guideline :
Survey Results from 11 Companies
Base
Comply (both DE and
SS)
Not
Foreign based
5(3)
2
Domestic
2(0)
2
Result from internal interview survey (SS=sample size, DE=data extrapolation)
Summary:
– Companies tend to follow the guideline regarding the
feasibility assessment of data extrapolation
– Companies do not necessarily follow regarding sample size
calculation:
Simulation and/or confidence limit
Consultation with PMDA
Practicality
9
Proportion of Japanese Patients by Therapeutic
Area
Ando, 2010
10
An Example in a pharmaceutical company
Japanese sample size in MRCT :
– Not correlated with the whole sample size of the study
– Proportion of Japanese patients decreases as the whole size increases
1
Japanese proportion vs. total sample
size in MRCT
0.9
0.8
N Japan (proportion)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
5000
10000
15000
N total
11
Consultation with PMDA : Major Route for
Japanese Sample Size Determination
2006, ICH-E5Q&A11, Planning
– Minor differences in design (e.g., age inclusion criteria, concomitant medication,
etc.) may be acceptable and prior discussion with regulatory agencies is
encouraged.
2007, Guideline
– since FY2006, the Pharmaceuticals and Medical Devices Agency (PMDA) has
given priority status to sponsors’ requests for clinical trial consultation on global
clinical trials. It is important that sponsors and PMDA sufficiently discuss the
clinical study design and data handling, etc. for individual development programs
through the clinical trial consultations, assuming conduct of a global clinical trial.
– For individual cases, issues identified in this notification, such as development
strategies and trial designs, should be considered in advance, and the clinical
trial consultations with PMDA should be utilized as soon as possible.
– If results from a Japanese subgroup are markedly different from those in the entire
study population, the reasons for it should be examined and in this case, because
an additional clinical trial may be needed where necessary, it is recommended to
utilize the clinical trial consultation with PMDA.
– Specific sample size setting for individual cases can be discussed with PMDA on
the clinical trial consultation.
12
Trend in Number of Consultation on MRCT
Moriyama, 2011
13
Possible Direction for Japanese Sample Size in
MRCT
Large sample size where ethnic difference exists
Smaller sample size where ethnic difference does not exist
More experiences are needed to confirm this direction
14
Summary
Determination of Japanese sample size remains as a
controversial issue.
MRCT Guideline provides a guidance for the Japanese
sample size determination and contributed to increase
MRCTs.
Approach for sample size determination varies among
companies.
In reality, sample size seems to be determined through
PMDA consultation based on simulation, statistical approach
and practicality etc.
Further research and accumulation of MRCT cases will
hopefully provide more scientific solution for the regional
sample size determination.
15
References
1.
2.
3.
4.
5.
6.
7.
ANDO Yuki. Multi-Regional Clinical Trials in Global Drug Development:
Experience in Japan. 2010 Multi-Regional Clinical Trials Seoul Workshop 13-Sep2010 slide (http://www.pmda.go.jp/english/presentations/index.html)
ICH. E5 (Ethnic Factors) Implementation Working Group Questions & Answers
(R1). 2-Jun-2006
MHLW. Basic principles on Global Clinical Trials. 28-Sep-2007
OOSAWA Shino. A study on statistical consideration for Japanese sample size in
global clinical trial. 14-Feb-2009. Slide for master thesis defense (Japanese)
ISHIBASHI Keita. Current situation and issue about global clinical trials. Office of
Pharmaceutical Industry Research News No.26. 2008
KATOH. Chairperson press conference. 4-Mar-2010 slides (Japanese)
(http://efpia.jp/link/100303Press%20conference_J_fin.pdf)
MORIYAMA Yusuke. Clinical Trial Notifications and Scientific Consultation
System in Japan. The Second China-Japan Symposium on Drug Development
focusing on IND, Pre-Consultation, GMP and DMF system 12-Apr-2011 slide
(http://www.pmda.go.jp/english/past/2011beijing_sympo.html)
16