Progress and Challenges to approve a drug based on data from global clinical trials: PMDA’s experience

Dr Yoshiaki Uyama

Pharmaceuticals & Medical Devices Agency (PMDA)Visiting Professor, Graduate School of Advanced Clinical Science, Chiba University

Visiting Professor, Graduate School of Medicine, Nagoya University

Disclaimer• The views and opinions expressed in the following PowerPoint slides

are those of the individual presenter and should not be attributed to

Pharmaceuticals and Medical Devices Agency (PMDA), Drug

Information Association, Inc. (“DIA”), its directors, officers, employees,

volunteers, members, chapters, councils, Communities or affiliates, or

any organization with which the presenter is employed or affiliated.

• Drug Information Association, Drug Information Association Inc., DIA

and DIA logo are registered trademarks. All other trademarks are the

property of their respective owners.

2

Globalization of Drug Developments

Nature Rev Drug Discovery, 7: 13, 2008

Japan

15.7; 10.3%

3

APEC MRCT Road Map

-Gap Analysis-

4

• Target Economies:

– Canada, Chinese Taipei, Indonesia, Japan, Malaysia, Mexico, Peru, Singapore, Korea, Thailand, and the United States

• Period : October 2013 ~ April 2014

• Methodology : Questionnaire by e-mail

• Responses received : 8 regions

• Collection rate : 72.7 % (8/11 regions)

Q: Please propose the number of CTs conducted in your

country from 2010 to 2012 by phases and starting years.

Please list the number by starting years. Among those

CTs, how many MRCTs were included in each figure?

5

0

100

200

300

400

500

600

700

Phase I

Non MRCT MRCT

Q: Please propose the number of CTs conducted in your

country from 2010 to 2012 by phases and starting years.

Please list the number by starting years. Among those

CTs, how many MRCTs were included in each figure?

0

50

100

150

200

250

300

350

400

450

500

Phase II

Non MRCT MRCT

0

100

200

300

400

500

600

700

800

900

Phase III

Non MRCT MRCT

6

Q: Please describe the annual number of new

drugs approved in your country from 2010 to 2012.

0

20

40

60

80

100

120

140

160

2010 2011 2012

New Drug Approved

CAN IDN KOR MYS SGP TWN THA JPN

7

Japanese：http://www.pmda.go.jp/operations/notice/2007/file/0928010.pdf

English：http://www.pmda.go.jp/operations/notice/2007/file/0928010-e.pdf

Japanese version English version

Basic principles on Global Clinical Trials

8

9

Trend of new drug application approvals

in Japan

FY2007 FY2008 FY2009 FY2010 FY2011 FY2012 FY2013

0

5

10

15

% o

f G

CT

% of GCT

% of Bridging

Total 81 79 107 114 130 134 133

MRCT 1 0 4 7 12 18 21

Bridging 4 2 3 6 2 3 1

(Year)

Approved new drugs based on GCT

in Japan

10

2006～2009 20112010 2012

Tolterodine

Losartan

Trastuzumab

Insulin -

Glulisine

Tadalafil

Peramivir

Everolimus

Panitumumab

Travoprost/

Timolol

Temsirolimus

Laninamivir

Nilotinib

Dabigatran

Trastuzumab

Pramipexole

Edoxaban

Dasatinib

Indacaterol

Linagliptin

Gefitinib

Everolimus

Denosumab

Aripiprazole

Olanzapine

Exenatide

Crizotinib

Budesonide/

Formoterol

Formoterol

Esomeprazole

Axitinib

Budesonide/

Formoterol

Atomoxetine

Aflibercept

Insulin -

Degludec

Glycopyrronium

Pazopanib

• 59 applications were approved as of March 1, 2014

Red: Asian Clinical Trial

Everolimus

Fesoterodine

Everolimus

Apixaban

Insulin-

Degludec+Aspart

Paclitaxel

Pregabalin

Tofacitinib

Regorafenib

2013

Guidance

Guidance: “Basic Principles on Global Clinical Trials”

Guidance RC

Guidance RC: “Basic Principles on Global Clinical

Trials –

Reference Cases”

2014

Bevacizumab

Pertuzumab

Lixisenatide

Regorafenib

Indacaterol/

Glycopyrronium

Paliperidone

Vilanterol/

Fluticasone

Bevacizumab

Aflibercept

Riociguat

Tadalafil

Afatinib

Turoctocog alfa

Ranibizumab

• New active ingredient indicated for the treatment of

persistent/recurrent Chronic Thromboembolic

Pulmonary Hypertension (CTEPH)

• Soluble guanylate cyclase (sGC) stimulator

• Orphan drug

• Application date: Feb 2013 (US/EU)

May 2013 (JP)

Riociguat: Example of GCT (1)

11

http://www.info.pmda.go.jp/shinyaku/P201300173/630004000_22600AMX00013000_A100_2.pdf

http://www.info.pmda.go.jp/shinyaku/P201300173/index.html

NChange from

baseline to last visita

Difference between

groups b

All regionRiociguat 173 42.0 (-376, 335)

45.69 [ 24.74, 66.63] Placebo 88 5.0 (-389, 226)

JapanRiociguat 11 64.0 (-376, 217)

－Placebo 5 14.0 (6, 85)

Primary endpoint: 6MWD (m)

Change from baseline: Median (Min, Max), Difference between groups: LS mean [ 95 CI]

a:Last observed value (not including follow-up) for subjects who completed the study or withdrew, except imputed worst

value in case of death or clinical worsening without a termination visit or a measurement at that termination visit.

b:ANCOVA model with baseline value, treatment group, and region as fixed effects

PIII: Efficacy

NChange from

baseline to last visit

Difference between

groups b

All regionRiociguat 151 -175.94 (-1753.2, 511.0)

-246.43 [-303.33, -189.53] Placebo 82 14.89 (-679.6, 969.2)

JapanRiociguat 9 -159.16 (-291.5, 146.8)

－Placebo 5 -14.18 (-125.6, 205.1)

Secondary endpoint: PVR (dyn∙sec∙cm-5)

12

Ph2 (3921039 study)

Placebo, 1mg, 3mg, 5mg,

10mg BID with MTX

Duration:12weeks

Endpoint: ACR20%

N=317

Ph3 (3921044 study)

Placebo, 5mg, 10mg BID with MTX

Duration: DB 6months, Open 18months

Endpoint: ACR20, structural damage, physical function

N=797 (Japanese 118)

Japan US/EUPh2 (3921025 study)

Placebo, 1mg, 3mg, 5mg, 10mg,

15mg, 20mg BID with MTX

Duration:24weeks

Endpoint: ACR20%

N=507

13

Tofacitinib: Example of GCT (2)

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

5mg

N=277

10mg

N=2905mg

N=44

10mg

N=44

JapaneseFAS

Dose response of tofacitinib

0

10

20

30

40

50

60

70ACR20 ACR50 ACR70

FAS JapaneseModified Total Sharp Score (vs placebo)

14

Average & 95%CI

Review experiences of GCT data

• Ethnic factor consideration is important even in AsianGCTs

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

• PPK data are useful for ethnic factor consideration

• Confirming efficacy in overall population and consistencyevaluation in Japanese sub-population– limitation in evaluating data when sample size of Japanese was

so small

• Differences in adverse event rate are not uncommon;partly due to difference on categorization or datacollection process of adverse events in GCTs

15

New Guidance (Sep 5th 2012): Basic principles on Global Clinical Trials

(Reference Cases)

Japanese：http://www.pmda.go.jp/regulatory/file/guideline/new_drug/GCT_jirei.pdf

English：http://www.pmda.go.jp/regulatory/file/english_guideline/new_drug/GCT-jirei_en.pdf

16

17

Future Drug Development

Regulatory Perspective: PMDA and FDA

Clin Pharmacol Ther. 2013;94:230-42.Clin Pharmacol Ther. 2013;94:195-8.

18

US FDA PMDA

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

Honig, P.K. Clin Pharmacol Ther 95, 467-9 (2014).

19

GCTs can contribute to reducing the lag

in drug development

20

Clinical development strategy

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

The

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)

***

**

• Simultaneous global drug development is a

useful strategy to provide a drug earlier to

Japanese patients

• But, we are facing some challenges in the future

drug development

21

• Effects of ethnic factors on drug efficacy/safety

should be more characterized

• Methods for planning/evaluation should be

established

– Sample size calculation, consistency evaluation

etc.

• Regulatory harmonization

22

Challenges for better GCTs

Advancing regulatory science

PMDA GCT Project Team

• 12 members as a representative from various offices

(New drug, Biologics, Conformity audit)

• Discuss various regulatory issues relating to GCTs

• Responsible for a guideline relating to GCTs

• Periodically hold meetings with industries for discussion

23

Promoting conduct of GCTs more appropriately

for drug approval

PMDA’s New Initiative: Advanced workflow of review/consultation

More rational & effective

evaluation process for

regulatory decision

Giving additional

scientific value to

submitted data Regulatory Science

e-Submission

of study data

Each reviewer utilizes innovative

assessment techniques

Sophisticated review

Advanced evaluation methods

Active utilization of Modeling &

Simulation Disease model

Objective B/R assessment

Identifying AE-related factors etc.

NDA

etc.

• More predictable

efficacy/safety after approval

• Reduction of applicant’s

work load

• More scientific regulatory

decision

• Epoch-making proposal

leading the world

• Proactive publication of

guideline More evidence-based consultation

Sophisticated Consultation

Cross-Products Analysis

Cooperation with

Academia

Practical use of Innovative

Medical Products Analysis by PMDA

More effective and high quality

Review

More efficient and Successful

Development Database

Data

Accumulation

24

25

Possible Development Strategy

Japan

Other

Asia

US/EU

PK,

Safety

Exploratory,

Dose-FindingConfirmatoryPOC

Japan only

West only

J/W

GCT

J/W

GCTJapan/West

W/J/E

GCT

W/J/E

GCTWest/Japan/

Asia

Asian

GCT

Asian

GCT Asia

Asian

GCT

Asian

GCTEarly

Asia

Asian

GCT

W/J/E

GCT

W/J/E

GCT

Asia

LeadingEast

Asian

GCT

Asian

GCT

Asian

GCTReal

Asia

Asian

GCT

Asian

GCT

J/W

GCT

J/W

GCT

Early

Japan/West

J/W

GCT

26

PMDA’s proposal: New ICH guideline on MRCTs

EU North America

USA

Canada

Asia

Drugs from Asia to the world

Cooperation for better drug development

27

28

Information

• HOMEPAGE (English)

http://www.pmda.go.jp/english/index.html

• Regulatory Science Page

http://www.pmda.go.jp/regulatory/index.html

• E-mail:

uyama-yoshiaki@pmda.go.jp

Thank you for your attention