Implementation of ICH E17 -PMDA’s perspective-

7th Joint Conference of Taiwan and Japan

on Medical Products Regulation

October 1st, 2019

Shuji Kamada Reviewer, Office of New Drug V

Pharmaceuticals and Medical Devices Agency (PMDA)

1

Disclaimers

The views expressed in this presentation are those of the presenter and do not necessarily reflect the official views of Pharmaceuticals and Medical Devices Agency (PMDA).

2

Guidelines on MRCTs in Japan

3

Guideline Issued

year Contents

Basic principles on Global

Clinical Trials 2007

Basic requirements to

conduct a MRCT

Basic points to consider in

designing a MRCT

Basic principles on Global

Clinical Trials

(Reference Cases)

2012

Points to consider for

MRCTs in East Asia

General points to consider

for MRCTs

Basic principles for Conducting

Phase1 Trials in the Japanese

Population Prior to Global

Clinical Trials

2014

Reference cases regarding

the necessity of conducting

a phase1 trial in the

Japanese population

https://www.pmda.go.jp/english/rs-sb-std/standards-development/cross-sectional-project/0010.html

ICH E17 guideline

4

ICH HARMONISED TRIPARTITE GUIDELINE 1

2

3

4

5

General Principles 6

for Planning and Design of 7

Multi-Regional Clinical Trials 8

E17 9

(FINAL) 10

11

November 16th, 2017 12

Started in June 2014

Draft in June 2016

Finalized in November 2017

Implemented (reached step

5) in June 2018 in Japan

Trends of MRCT-related Clinical Trial Notifications in Japan

5 MRCT : Multi-Regional Clinical Trial

38

82 113

134 124 138 173 181

276 240

323

389

508 524

560

632

689

556

601 601

657 645

693 764

7.5

15.6

20.2 21.2

18.0

24.8

28.8 30.1

42.0 37.2

46.6

50.9

0.0

10.0

20.0

30.0

40.0

50.0

60.0

0

100

200

300

400

500

600

700

800

900

FY2007 FY2008 FY2009 FY2010 FY2011 FY2012 FY2013 FY2014 FY2015 FY2016 FY2017 FY2018

MRCT Total % of MRCT

Trends of new drug application based on MRCTs in Japan

6

81 79

107

114

130 134

138

119 115

112

104

113

1 0 4

7

12

19 22

32

23 26

41 44

1.2 0

3.7

6.1

9.2

14.1

15.9

26.9

20.0

23.2

39.4 38.9

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

45.0

0

20

40

60

80

100

120

140

160

FY2007 FY2008 FY2009 FY2010 FY2011 FY2012 FY2013 FY2014 FY2015 FY2016 FY2017 FY2018

%

Nu

mb

er

of

Ap

pro

ve

d D

rug

s

Total MRCT % of MRCT

ICH E17 training materials

7

An extensive set of training materials has been developed to

promote the efficient and consistent implementation of the

E17 in the context of an evolving drug development

environment.

Published in September 2019 !!

8

ICH E17 training materials

Training material intended to

provide clarity on key aspects of

the guideline in order to facilitate a

harmonized interpretation and

implementation by industry and

regulators in the ICH and non-ICH

regions

Training material does not provide

additional guidance beyond E17

9

Overview of Training material

General modules

Animated video; Main message of MRCTs

Module 1; Overview of training material/Basic principles

Technical modules

Module 2; Preconsideration of regional variability when

recruiting diverse populations in global drug development

Module 3; Selection of doses

Module 4; Sample size allocation

Module 5; Pooling strategies

Module 6; Evaluation of Consistency

Module 7; Selection of Comparators

10

Not only intrinsic factors but also extrinsic factors may have a potential to affect the treatment effect

Major intrinsic and extrinsic factors

(From Appendix A of ICH E5)

11

Phase III trial assessing the clinical efficacy and safety of

bevacizumab added to chemotherapy for first-line treatment

of advanced gastric cancer

J Clin Oncol. 2011: 29: 3968-76

Example : AVAGAST Trial

AVAGAST was a prospective,

random-assignment, double-blind,

placebo-controlled global phase III

clinical trial.

Primary endpoint: Overall survival

774 patients with

previously untreated

advanced gastric

cancer

R 1:1

Bevacizumab + Standard Chemotherapy

Placebo + Standard Chemotherapy

Asia-

Pacific

(49%) Europe

(32%)

Pan-America

(19%)

12

Example : AVAGAST Trial

Bevacizumab did not significantly prolong OS in the

overall population.

13

0.87 (95%CI, 0.73-1.03, P = 0.1002)

0.97 (95%CI, 0.75-1.25)

0.85 (95%CI, 0.63-1.14)

0.63 (95%CI, 0.43-0.94)

Hazard ratio

Bevacizumab seems to be effective in Pan-American patients, but not in Asian patients.

Example : AVAGAST Trial

Subgroup analysis according to region

14

Characteristic

Asia (%) Europe (%) Pan-America (%)

bevacizu

mab

n=188

placebo

n=188

bevacizu

mab

n=125

placebo

n=124

bevacizu

mab

n=74

placebo

n=75

Liver

metastases 29 26 35 38 42 41

Prior

gastrectomy 32 31 22 25 31 23

Poststudy

therapies:

Patients with

at least one

treatment

59 67 24 29 24 15

Primary tumor

site:

Stomach 93 95 77 78 85 83

Gastroesopha

-geal junction 7 5 23 22 15 17

Example : AVAGAST Trial

Baseline characteristics by region (intention-to-treat population)

15

Example : AVAGAST Trial

Although gastric cancer is a global disease,

it is not uniform. There are differences in

the presentation and management of

gastric cancer patients in different countries

and regions.

Author’s explanation about the inconsistent

result on overall survival among populations

(J Clin Oncol. 2011: 29: 3968-76)

16

Example : AVAGAST Trial

Asian patients • more commonly receive second and further

lines of therapy

• more frequently have a prior history of

gastrectomy

• less frequently have liver metastases or

proximal or gastroesophageal junction tumors

Author’s explanation about the inconsistent

result on overall survival among populations

(J Clin Oncol. 2011: 29: 3968-76)

17

Example : AVAGAST Trial

These differences in ethnic factors

might have caused the inconsistent

result.

So, can you conclude these factors

affected the treatment effect?

18

Example : Conclusion

Exactly, there are some differences in

the distribution of intrinsic and extrinsic

factors among regions in AVAGAST

Trial.

However, it is difficult to conclude that

those factors affect the treatment effect

of bevacizumab with confidence.

It is necessary to carefully examine the

impact of those factors based on

available data.

19

How to identify intrinsic and extrinsic factors which

may affect the treatment effect and mitigation

strategies

Collect available

information about

intrinsic and

extrinsic factors

which may affect

the treatment effect

Examine the impact

of these intrinsic and

extrinsic factors for the

drug development

based on collected

information

Decide which

intrinsic and extrinsic

factors may affect

the treatment effect

and should be

reflected in the

study design

Step 1 “Collect” Step 3 “Reflect” Step 2 “Examine”

Process of identifying ethnic factors

(From E17 training material module2)

20

Current Challenges

How to identify intrinsic and extrinsic factors important to the drug development programme?

How to define pooled regions?

How to determine the adequate number of specific local (e.g., Japanese) patients in MRCT and total clinical data package to meet the regulatory requirements of the region?

How to consider when different results may be seen among regions?

Accumulation of examples is necessary

21

Thank You!