ethnic factors, consideration in asian mrct and global

ARDDS 2015, Sep 8th 2015, Shanghai, ChinaPharmaceuticals & Medical Devices Agency

Ethnic factors, Consideration in Asian MRCTand Global Drug Development Strategies

Dr Yoshiaki UyamaDirector

Office of Medical Informatics and EpidemiologyPharmaceuticals and Medical Devices Agency (PMDA)

Visiting Professor, Graduate School of Medicine, Chiba UniversityVisiting Professor, Graduate School of Medicine, Nagoya University

1


Japanese：http://www.pmda.go.jp/files/000157901.pdfEnglish：http://www.pmda.go.jp/files/000157520.pdf

2007 Guideline

Japanese：http://www.pmda.go.jp/files/000157000.pdfEnglish：http://www.pmda.go.jp/files/000157900.pdf

2012 GuidelineJapanese guidelines on MRCTs

Japanese: http://www.pmda.go.jp/files/000157480.pdfEnglish: http://www.pmda.go.jp/files/000157777.pdf

2014 Guideline

2


Drug Approval based on Global Clinical Trials in Japan

3

FY2007 FY2008 FY2009 FY2010 FY2011 FY2012 FY2013 FY2014

0

5

10

15

20

25

30%

of C

linic

al T

rials

Year

% of GCT % of Asian GCT % of Bridging

Total 81 79 107 114 130 134 138 119

MRCT 1 0 4 7 12 19 22 33Bridging 4 2 3 6 2 3 1 1


0

100

200

300

400

500

600

700

Phase I

Non MRCT MRCT

4

050

100150200250300350400450500

Phase II

Non MRCT MRCT

0100200300400500600700800900

Phase III

Non MRCT MRCT

APEC MRCT Road Map -Gap Analysis-, 2014

Number of clinical trials started in 2010-2012

Clinical Trial Situations in Asia


Conduct of MRCT has contributed to decreasing “Drug Lag”

Clinical development strategy

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

Lag

in d

rug

deve

lopm

ent

(day

s)

1111 days

Local

trial

(n = 69)

Local and

foreign trials

(n = 59)

Bridging

study

(n = 19)

Global

clinical

trial

(n = 18)

Foreign

trial

(n = 13)

No

efficacy/safety

trial (n = 5)

***

**

Ueno T et al, Clin Pharmacol Ther, 95, 533-41 (2014)

Drug approved in FY2007-FY2012

5


Recent experiences to review MRCT data for regulatory approval

6


Paliperidone Schizophrenia Phase III trial

Chinese Taipei, Korea, Japan Sample Size

Total: N=323,Japan: N=156, Chinese Taipei: N=96, Korea: N=71

Primary Endpoint：Changes from baseline on total score of Positive and Negative Syndrome Scale (PANSS)

Pre-consideration suggested no major ethnic differences among populations

Review report (in Japanese): http://www.pmda.go.jp/drugs/2013/P201300116/800155000_22500AMX01791000_A100_1.pdf

7


Efficacy

N Change of PANNS total scorea

Difference between groups b

All region

Placebo 164 6.9 ±19.13-9.7[ -14.0, -5.4]

Paliperidone 159 -3.1 ±20.32

JapanPlacebo 79 8.8 ±23.26

-11.6[ -18.4, -4.8] Paliperidone 77 -3.0 ±19.72

KoreaPlacebo 38 5.3 ±11.93

-12.5[ -20.6, -4.3] Paliperidone 33 -7.6 ±20.94

TaiwanPlacebo 47 5.0 ±15.87

-4.7[ -12.2, 2.7] Paliperidone 49 -0.1 ±20.68

a: Mean ± SDb: LS mean [95CI]

Change of PANSS total score from baseline

8


Safety

9

All region Japan Korea Taiwan

Placebo Paliperi-done Placebo Paliperi

-done Placebo Paliperi-done Placebo Paliperi

-done

N 164 159 79 77 38 33 41 49

Total 81.7 85.5 77.2 79.2 84.2 81.8 87.2 98.0

Insomnia 15.2 17.0 3.8 6.5 23.7 24.2 27.7 28.6Injection site pain 6.7 13.2 5.1 6.5 5.3 24.2 10.6 16.3

Nasopharyngitis 6.1 12.6 8.9 18.2 5.3 9.1 2.1 6.1

Psychiatric symptom 26.2 11.3 39.2 18.2 23.7 3.0 6.4 6.1

Extrapyramidal disorder 4.9 10.1 2.5 7.8 5.3 9.1 8.5 14.3

Anxiety 7.9 6.3 1.3 0 23.7 18.2 6.4 8.2

%

Main adverse events in subgroups (country)


Discussion in the review

10

Efficacy Efficacy in Japanese and Korean was similar to that in overall

population The changes in Taiwanese was smaller than that in overall

population Exacerbation in a part of the population likely cause a

negative impacts The responder rate was same among populations

Safety Differences on the rate of some adverse events among

populations insomnia, psychiatric syndrome, anxiety

The rate of patients who had one of these was same among populations Each of these phenomena relates to a primary disease


Summary of MRCT Data Review Experiences

Accumulated a lot of regulatory experiences to review MRCTdata

Confirming efficacy in overall population followed byconsistency evaluation between sub-populations

limitation in evaluating data when sample size was small

Extrinsic ethnic factors such as concomitant therapiessometimes have impacts on data evaluation

PPK data are useful for ethnic factor consideration

Differences in adverse event rate are not uncommon; partlydue to difference on categorization or data collection processof adverse events in GCTs

Ethnic factor consideration is important even in Asian GCTs

11


Ethnic Similarities/Differences on Drug Responses

12


Example; Ethnic difference on PK and safety

Generic name PK Efficacy/SafetyApproved

dose: US/Japan

Afatinib(NSCLC)

No major difference on PK

Incidence of interstitial lung disease Asian (2.1%) > non-Asians (1.2%).

40mg/40mg

Eltrombopagolamine

(thrombocytopenia)

East Asian 50-55% higher > non-East Asian

A reduction in the initial dose is recommended for East Asian patientsMore reduced dose in East Asian patients with hepatic impairment.

50mg/12.5mg

Simeprevir(Anti-viral,

HCV infection)

Asian 3.4-fold higher > Caucasians.

Higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity.

150mg/100mg

Modified from the article by Ramamoorthy A et al. Clin Pharmacol Therapeut 2015; 97: 263–273

13


Genetic similarities among East-Asian populations

The frequencies of 1936 variants representing 225 genes encoding drug-metabolizing enzymes and transporters were determined from 786 healthy participants (448 Korean, 208 Japanese, and 130 Chinese)

No major ethnic differences among Chinese, Korean and Japanese populations

Correlation of minor allele frequencies between population

Yi, S. et al. Pharmacogenetics and Genomics 24, 477-85 (2014).

14


Effects of Green Tea on β-blocker, nadolol responses

Misaka, S. et al. Clin Pharmacol Ther 95, 432-8 (2014).

OATP1A2-mediated [3H]-nadolol uptake

15


Toward for an international harmonizationICH E17 guideline

(General principles on planning/designing Multi-Regional Clinical Trials)

16


Regulatory Perspective

Clin Pharmacol Ther. 2013;94:230-42.

US FDA

Clin Pharmacol Ther. 2013;94:195-8.

PMDA

17

EMA


China Guideline: IMCT

18

I. BackgroundII. Purpose and ScopeIII. General RequirementsIV. Considerations on Trial

ScientificityV. Considerations on Trial

StandardizationVI. Clinical Trial Protocol

AmendmentVII. Registration ApplicationVIII.On-Site InspectionIX. Glossary

Jan 2015


E17 EWG: established in June 2014 Rapporteur: PMDA

Provide common points to consider in planning/designing MRCTs and minimize conflicting opinions from regulatory bodies.

ICH E17 Guideline: MRCTs

General principle on planning/designing Multi-Regional Clinical Trials

Basic Concept:• Encourages to conduct MRCTs in drug development • Science based‐consideration for better planning/designing MRCTs

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October 2014 1st Web-conference November 2014 1st F2F meeting in LisbonFebruary 2015 2nd Web-conferenceMarch 2015 3rd Web-conferenceJune 2015 2nd F2F meeting in Fukuoka

E17 Past Activities

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General principles on planning/designing Multi-Regional Clinical Trials (E17)

Table of Contents

1. INTRODUCTION ................................................................................................... - 3 -1.1 Objective(s) of the Guideline ................................................................................. - 3 -1.2 Background ........................................................................................................... - 3 -1.3 Scope of the Guideline .......................................................................................... - 4 -1.4 General Principles ................................................................................................. - 4 -

2. General recommendations in planning/designing a MRCT .................................. - 5 -2.1 Strategy-related points .......................................................................................... - 5 -

2.1.1 The value of MRCTs in drug development .................................................... - 5 -2.1.2 The basic requirements and key considerations to conduct a MRCT .......... - 7 -2.1.3 Scientific consultation meetings with regulatory agencies ........................... - 8 -

2.2 Clinical trial design and protocol-related points .................................................... - 9 -2.2.1 Pre-consideration of regional variability on efficacy/safety ........................... - 9 -2.2.2 Subject selection ......................................................................................... - 10 -2.2.3 Selection of doses for use in confirmatory MRCTs ............................... - 11 -2.2.4 Choice of endpoint ...................................................................................... - 12 -2.2.5 Estimation of an overall sample size and allocation to each region/country in a

MRCT .......................................................................................................... - 14 -2.2.6 Collecting and handling efficacy/safety information in MRCTs ................... - 17 -2.2.7 Statistical analysis plans that specifically address the features of MRCTs - 18 -2.2.8 Selection of comparator ............................................................................. - 19 -2.2.10 Handling concomitant medications ........................................................... - 21 -

3. GLOSSARY ......................................................................................................... - 22 -


Current Timeline of E17

First face-to-face EWG Meeting in November 2014 in Lisbon Discussion by e-mail and web-based conference:

4Q 2014 - 1Q 2015 Second F2F EWG Meeting in June 2015 in Fukuoka for

coordinating opinions of all parties and delivering draft Step 1 document

Third F2F EWG meeting in December 2015 for adoption of Step 2document (in Florida, US)

Public consultation: 4Q 2015 - 2Q 2016 Revision of the guideline based on comments: 2Q 2016 - 4Q 2016

(depending on contents of comments recieved) Fourth face-to-face EWG Meeting for adoption of Step 4 document

in 4Q 2016 or 2Q 2017

22

ARDDS 2015, Sep 8th 2015, Shanghai, ChinaPharmaceuticals & Medical Devices Agency23

Future drug development strategy


Case A: Asia-leading drug development

• In some therapeutic area whose prevalence is higher in Asia (e.g.; gastric cancer, hepatitis etc.), can early phase of drug development (PI, POC, ePII etc.) be initiated in Asia?

• If yes, can later phase clinical trials be conducted globally, based on a hypothesis established by Asian data?


Japan

Other Asia

US/EU

PK, Safety

Exploratory, Dose-Finding ConfirmatoryPOC

W/J/EGCT

W/J/EGCTAsian

GCT

25



PROS：

More appropriately design a confirmatory trial based on Asian data Dose selection, Target population etc.

Provide more scientific evidences in Asian population CONS (Challenges)

Uncertainty about effects of extrinsic ethnic factors How to define Asia? How much Japanese data are

required? Acceptability of a hypothesis based on Asian data in

non-Asian countries

Pros/Cons



Case B Genome-defined population

Can we define a population based on a specific genotype relating to drug responses rather than an ethnicity/race?

e.g.; molecular-target drug EGFR (+)

EGFR (-)Gefitinib

Calboplastin+Paclitaxel


Gefitinib


Gefitinib

Gefitinib: IPASS study


PROS：

Maybe not necessary to consider strictly about subject number from a country in a clinical trial

Can select more objectively a target population based on genomic test results

CONS (Challenges): Need to develop CDx simultaneously Uncertainty about effects of extrinsic ethnic factors How much Japanese data are required?

Pros/Cons

Case B Genome-defined population

Pharmaceuticals & Medical Devices Agency

Possible Development Strategy

Japan

Other Asia

US/EU

PK, Safety

Exploratory, Dose‐Finding ConfirmatoryPOC

Japan only

West onlyJ/WGCT

J/WGCT

Japan/West

W/J/EGCT

W/J/EGCT

West/Japan/Asia

AsianGCT

AsianGCT Asia

AsianGCT

AsianGCT Early

Asia

AsianGCT

W/J/EGCT

W/J/EGCT

AsiaLeadingEast

AsianGCT

AsianGCT

AsianGCT

RealAsia

AsianGCT

AsianGCT

J/WGCT

J/WGCT

EarlyJapan/West

J/WGCT

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Prepare for various strategies of drug development


Steps for International Harmonization

• More experiences• Sharing experiences

Real Global/Harmonization

• Accumulating more scientific data

• International collaboration (ICH, Collaborative research etc.)

• Accumulating experiences• Review existing data• Task identification

Local guideline

Revise and more local guideline

International guideline

30


Harmonization: Can-do Spirit！

PMDA web site (English) http://www.pmda.go.jp/english/index.html

E-mail:[email protected]

Thank you for your attention

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ethnic factors, consideration in asian mrct and global

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