2018/3/14

Outline Background and Key Principles in E17

ICH E17
General Principles for Planning and Designof Multi-Regional Clinical Trials

 Some case studies of Gastric Cancer inFuture MRCTs Based on E17 Guideline

MRCT conducted by Roche- Definition of Region & Consideration of Ethnic Differences  Impact of ICH-E17 Guideline on Global

Industry and Biostatisticians

Hideharu Yamamoto, PhD
E17 JPMA EWG
Chugai Pharmaceutical Col, Ltd
生物統計学シンポジウム Mar.14, 20182Outline

Regulatory Guidelines and ICH E171998 ICH E5 “bridging”
Ethnic Factors in the Acceptability of Foreign Clinical Data Background and Key Principles in E172006 ICH E5 Q&A No.11

 Some case studies of Gastric Cancer in2007 Japan PMDA/MHLW guidance:
Basic Principles on Global Clinical Trials

MRCT conducted by Roche2009 EU
Reflection paper on the extrapolation of results from clinical studies
conducted outside of the EU to the EU population

 Impact of ICH-E17 Guideline on Global

Industry and Biostatisticians2015 CFDA IMCT guidance
Guidance for International Multicenter Clinical Trials (IMCT)
Coming ICH E17: To provide common points to consider inplanning/designing MRCTs and minimizing conflicting opinions fromregulatory bodies
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2018/3/14

Possible causes of difference
among regions

How to look at the results from MRCT

Non-compliance with
GCP and/or protocol

Apparent Differences(Play of chance)

Real differences

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What makes differences?

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Our Question is...

Non-compliance with
GCP and/or protocol

We don’t want to put those causeson the table we are going to discuss
So, E17 guideline emphasizes the importance of[Planning] Risk assessment, Common training etc.
[Conducting] Monitoring, Quality Management System

Apparent Differences(Play of chance)

Real differences

The smaller the local
sample sizes,
the more likely
false signals areobserved

Real differences areforeordained byinfluential
ethnic factor(s)or those distribution

But we always need to keep in mind this possibility
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2018/3/14

Real differences illustrated in Fig.2

Forest Plot: Summary of subgroup analyses
Overall result

The overall results belong to everyone.
However, the meanings of the results
may be different among regions.

By region/country

Country A
Country B
Regulatory Region C (e.g., EU)
Pooled Region D(Country P+Q+R+ ...)

influences

By gender

FemaleMale

By severity

influences

SevereMild
Moderate
Yes

By a specific med.history

No

Intrinsic
FactorTend to be milder in countries WITH universal health insurance coverage
Tend to be severer in countries WITHOUT universal health insurance coverage

Test drug worse

Extrinsic
FactorTest drug better

910

If you found influential factor(s)...

If you found influential factor(s)...

Can we explain like this?

Try to explain by different distribution of influential
intrinsic ethnic factor(s) among regions
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2018/3/14

Structured exploration

Outlineof regional differences Background and Key Principles in E17

Preplanned analysis
for Known factors

 Some case studies of Gastric Cancer inMRCT conducted by Roche

Ad hoc analysis
for possible factors

 Impact of ICH-E17 Guideline on Global

Prognostic factors

Industry and Biostatisticiansof the disease

Further Ad hoc
investigation

Predictive factors(subgroup analysis,info. outside the MRCT)of the treatment outcome

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Example：ToGA Trial (2005-2008)
5-FU or capecitabine+ cisplatin(n=290)3807 patients screened
810 HER2-positive (22.1%)

HER2-positive
advanced GC
n=584

R
5-FU or capecitabine+ cisplatin+ trastuzumab(n=294)

 ToGA was an open-label, international, phase 3, randomized controlled trial
undertaken in 24 countries in Asia, Europe and Central and South America.
 Patients with gastric or gastro-oesophageal junction cancer were eligible forinclusion if their tumors overexpressed the HER2 receptor
 Primary endpoint was OS (overall survival)

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14ToGA Sample Size in Japan
 ToGA Overall Sample Size
 MST: 10 months vs 13 months (HR=0.77)
 460 events (a=5% 1-b=80%, log-rank test), 584 pts
 Japanese Sample Size
 Pre-specification of Japanese sample size “Signal” of efficacy in Japan is at least needed when the overall
population demonstrates a significant difference

P1=Pr( HRJapan < 0.88｜true HRJapan=HROverseas=0.77)
P0=Pr( HRJapan < 0.88｜true HRJapan=1.0)#eventP1P0Sample size

60

0.697

0.310

76

700.712

0.296

8980

0.725

0.284

102900.737

0.272

114

100

0.748

0.261

127

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Primary Endpoint: OS

OS for Japanese Population
erated_20_2211 Kaplan Meier Curve for Overall Survival

Protocol: BO18255 (ToGA): Trastuzumab in HER2 Positive Advanced Gastric Cancer
Analysis: Full Analysis Set - Country: JapanEvent

1.0
0.9
0.8
0.7
0.60.50.4
0.30.20.1
0.0

EventsFP + TFP

167
182

MedianHROS
13.8
11.1

95% CI

p value

0.74 0.60, 0.910.0046

Japanese Result
EventsXP + TXP

2827

Log-Rank Test
P = 0.9876

HRJapan=1.00, p=0.98
11.1
024

6

13.8

8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)No.
at risk

294 277 246 209 173 147 113 90
290 266 223 185 143 117 90 64

71
4756
32

43
2430
1621
14

137

12665

40100017

Fluoro/Cisp:
Fluoropyrimidine/Cisplatin
Tras/Fluoro/Cisp: Trastuzumab/Fluoropyrimidine/Cisplatin
Fluoropyrimidine: Investigator preference of Capecitabine or 5-FU

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Program : $HOME/cdp12032/bo18255/erated_20.sas / Output : $HOME/cdp12032/bo18255/reports/erated_20_2211.cgm
24APR2009 19:11

Pre-planned Analysis in Japanese
Population

OS Subgroup Analysis
CategoryAll

Subgroup
AllN584

HR0.74

95% CI0.60, 0.91

RegionAsia
EuropeC/S America
Other319
52
190
23

0.82
0.44
0.63
1.22

0.61, 1.11
0.21, 0.90
0.44, 0.89
0.48, 3.08

84

0.72

0.40, 1.29

1221010.79
1.00

0.47, 1.33
0.59, 1.69

ChinaKorea
Japan0.2
Favors T

0.4

0.6

1Risk ratio

23 Document similar to the protocol that addresses

particular matters concerning Japan (additionalinformation for conducting ToGA study in Japan)
 Possibility that some demographic or baseline factors

might be imbalanced because of the small number ofJapanese patients Pre-planning to use an adjustment HR in the Japanese

4 5Favors no T

subgroup using multivariate Cox regression with 15
factors

No benefits of Trastuzumab for Japanese patients?
 All factors were pre-specified in the ToGA study protocol
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Preplanned & Post hoc Analysis forJapanese Population

OS and PFS in Preplanned & Post hocAnalysis for Japanese Population

 As a result of Multivariate analysis, adjusted HR for Japan

subgroup changed to 0.68 from 1.00
 Estimates of effects were extremely unstable for covariatesthat contained a category which include only one patient To ensure stability of the model, a post hoc analysis wasconducted

HER2 status was divided into two categories: high vs low expression
Covariates that contained a category with only one patient wereexcluded from the model Adjusted HR=0.82 (95%CI: 0.45-1.50)
 PFS had a similar result to OS Adjusted HRs for Korea and China subgroup were not

These results suggest that the same benefit was obtained in the Japanesesubgroup as in the overall population

changed so large
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22Conclusion: ToGA Trial

Why were Different HRs Observed?
 Some factors with imbalanced in the ratio of enrollment to Pre-planned and post-hoc analyses suggest thateach arm in the Japanese population (GC type, priorgastrectomy, PS 0 vs. 1, No. of metastatic sites) Chemo arm was imbalanced towards a better prognosis forthese factors compared with Herceptin arm

the benefits of Herceptin are of the same
magnitude in Japanese patients Herceptin can be considered a new standard
therapy for Japanese patients with HER2 + mGC

 To confirm that the HR is robust, it is necessary to analyze

different combinations of factors


We found that the HRs were approximately 0.7 for all combinationsof factors, supporting the robustness of our results (Sawaki, et.al2011)23

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Herceptin for mGC was approved in Japan inMarch 201124

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Examples: AVAGAST Trial (2007-2008)

Examples: AVAGAST Trial

Phase III trial assessing the clinical efficacy and safety ofbevacizumab added to chemotherapy for first-line treatment ofadvanced gastric cancer
J Clin Oncol. 2011: 29: 3968-76

AVAGAST was a prospective, randomassignment, double-blind, placebocontrolled global phase III clinical trial.
774 Pts withpreviously untreatedadvanced gastric cancer
R1:1

Pan-America (19%)
Europe (32%)

Asia-Pacific(49%)

Hazard ratio
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)

Bevacizumab + Standard Chemotherapy
Placebo + Standard Chemotherapy

Primary endpoint: Overall survival
Stratification factors: Geographical region (Asia, Europe, Pan-America)
PMDA-ATC MRCT Seminar 2018 (APEC Center of Excellence Workshop) より引用

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OSAuthor’s explanation about the inconsistent result on overall
survival among populationsRegion(J Clin Oncol. 2011: 29: 3968-76)

 Although gastric cancer is a global disease, it is not uniform.
There are differences in the presentation and management ofgastric cancer patients in different countries and regions.
 Asian patients• more commonly receive second and further lines of therapy• more frequently have a prior history of gastrectomy• less frequently have liver metastases of proximal or
gastroesophageal junction tumors.

⇒ These difference in extrinsic ethnic factors might havecaused the inconsistent result.
PMDA-ATC MRCT Seminar 2018 (APEC Center of Excellence Workshop) より引用

Bevacizumab seems to be effective in Pan-American patients, but
not in Asian patients.
PMDA-ATC MRCT Seminar 2018 (APEC Center of Excellence Workshop) より引用

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Examples: AVAGAST Trial

Examples: AVAGAST Trial

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Subgroup analysis
according to region

PL
BV(months) (months)

PFS
HR(95%CI)

PL
BV(months) (months)

HR(95%CI)

Asia / Pacific

12.1

13.9

0.97
(0.75-1.25)

5.6

6.7

0.92
(0.74-1.14)

Japan

14.2

15.4

0.96
(0.67-1.39)

5.7

6.8

0.99
(0.73-1.35)

Korea

10.9

13.80.89(0.60-1.33)

5.4

6.60.79(0.56-1.11)

Non- Asia / Pacific

8.0

11.1

0.76(0.60-0.97)

4.4

6.8

0.69(0.56-0.85)

Europe

8.6

11.1

0.85
(0.63-1.14)

4.4

6.9

0.71
(0.54-0.93)

Americas

6.8

11.5

0.63
(0.43-0.94)

4.4

5.9

0.65
(0.46-0.93)

Especially no benefits of Bevacizumab for Japanese patients?
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Example: JACOB study

Example: JACOB study (2013-2017)
blind, placebo-controlled global phase III clinical trial.
780 Pts withpreviously untreatedadvanced gastric cancerR

1:1

Pertuzumab + Trastuzumab + Standard
Chemotherapy
Placebo + Trastuzumab + Standard
Chemotherapy

Overall survival (%)

100

 JACOB was a prospective, random-assignment, double-60
40

PLA + H + CT(n = 392)

Events, n242

262

Median, mo

17.5

14.2

HR (95% CI)

0.84 (0.71–1.00)
0.0565P-value (log-rank)

P + H + CT (n = 388)
PLA + H + CT (n = 392)
Censored200

P + H + CT(n = 388)

ITT population

8002468101214161820 22 24Months

2628303234363840No. at risk
P + H + CT 388
PLA + H + CT 392

363
359

342
339

323
306

297
279

266
252

243
221

209
175

175
143

149
118

114
95

54
47

36
38

27
31

1623

1014

67443292
76

67
60

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 Primary endpoint: Overall survival
 Key eligibility criteria: HER2-positive mGC/GEJC
 Stratification factors: Geographical region, Prior gastrectomy Asia [excluding Japan]
 Japan North America/Western Europe/Australia
 South America/Eastern Europe(ESMO 2017)⇒ Author’s explanation was that OS was generally consistent in subgroups. It isdifficult to conclude the Japanese patient has no benefit for gastric cancer.
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Outline30

ICH E17 – Think Globally Promote MRCT Background and Key Principles in E17

 Reduce the need to conduct standalone regional or

national studies, including bridging studies

 Build up scientific capabilities and infrastructure globally Some case studies of Gastric Cancer in Promote international harmonization

MRCT conducted by Roche A globally harmonized approach to drug development

should be considered first Impact of ICH-E17 Guideline on Global

 Provide better evidences for drug approval in eachIndustry and Biostatisticiansregion Encourage better planning and design of MRCTs basedon the latest scientific knowledge and experiences

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Significant Factors to Consider for a
Successful MRCT

From a Global Industry Perspective
 Big differences between

 Timing of participation to the MRCT late timing of participation to the MRCT can not keep the prespecified sample size

”Multi-National Clinical Trials” and MRCT under E17
 Some points to consider for the global industry
 Global industry

 How to manage the speed of subject enrollment

among regions

 will take care of regional differences and ethnic factors

more than before
 will consider acceptability from every participating
region/country more than before should define the region (pooled region) and determine
the sample size allocation to each region at theplanning stage
 should obtain HA’s agreement with the proposed
analysis strategy about regional consistencydifferent speed of enrollment among regions could result indifficulties in evaluating the consistency

 How to manage to obtain the homogeneous

baseline characteristics among regions as much aspossible

different baseline characteristics could influence the consistency ofresults

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Significant Factors to Consider for a
Successful MRCT How to interpret a regional difference in the efficacy

among regions


important to be able to explain the regional difference

Thank you for your attention!

 Pre-specify in the Protocol/SAP not only subgroup

analysis but also model analysis adjusted byprognostic factors
ad-hoc analysis or exploratory analysis are very helpful to interpretthe regional difference35

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