development of orphan drugs – regulatory viewpoints from ...orphan drugs • “in all, more than...

Development of Orphan Drugs – Regulatory Viewpoints from PMDA

Ken SakushimaOffice of Cellular and Tissue-based Products,Office of New Drug IIIPharmaceuticals and Medical Devices Agency(PMDA)

11th Annual Meeting DIA JAPAN 2014 | November 16-18 | Tokyo Big Sight | Ariake 2

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Disclaimer/Disclosure

• The views and opinions expressed in this presentation are those of the speaker and are not necessarily those of the PMDA.

• No conflict of interest.


Outline of the presentation

• From Small Clinical Trials• Global Clinical Trial in Asia • Clinical development with Academia• Conclusion


Orphan drugs

• “In all, more than one-third of new drugs approved by the FDA last year were orphans.”

• “In the near future, the more orphan drugs we see, the better.”

Nature. 2014;508:16-7.


From Small Clinical Trials

• Small Clinical Trials is key issue in the drug development where the clinical context does no provide a sufficient number of research participants.

• Study design, conduct, statistical analysis and clinical importance should be considered.

• Academia, pharmaceutical companies, patients advocacy and regulatory bodies should work together.



Orphanet J Rare Dis. 2013; 8: 48.


Other than Small Clinical Trials

Orphan drug development

DevelopmentalStrategies

Where Who/

Work together

Small Clinical Trials

Study designStatistical analysis


Where: Japan or Global?

• Clinical Trials in Japan• Good: feasibility• Bad: limitation in target population

• Global Clinical Trial (GCT)• Good: number of target population• Bad: Resources & Costs• Bad: Difference in race & ethnicity

• Asian Gobal Clinical Trial (Asian GCT)• Happy Medium• A certain number of genetically similar population


Asian Clinical Trial in GCT (not only orphan)

http://www.pmda.go.jp/regulatory/file/RS_data/MRCT/MRCT_FY2007-FY2012.pdf


Approved drugs by Asian GCT in JAPAN

* First Approval


Support for Orphan drug developments in Asia

• Korea• Less than 20,000 people in Korea• 128 products (Dec. 2011)• Limitation of total production

• Taiwan• Prevalent in 1:10,000 or less • 77 products (Apr. 2006)• FDA approved orphan drugs – no need of Clinical Trial

• Singapore• Very limited number of patients in life-threatening conditions• A rough estimate of the number of patients should be provided

J Pharm Bioallied Sci. 2010, 2(4): 290–299.希少疾患／難病の診断・治療と製品開発（技術情報協会）


Designated orphan drugs in JPN/Korea

• Galsulfase - Mucopolysaccharidosis VI – Clinical Research of 3 cases

• Dasatinib - CML/ALL– Clinical Trial of 41 CML cases & 13 ALL cases

• Rufinamide - Lennox-Gastaut syndrome– Clinical Trial of 59 cases– Placebo controlled trial


Promoting Global Clinical Trial within APEC


Expectation for Asian GCT

• Population in (East) Asia are similar genetically• Among Asia, supports for orphan drugs are not

only in Japan• Global Clinical Trial is a topic in APEC

Asian GCT can be useful for orphan drug developments regarding target population and costs



• Small Clinical Trials is key issue in the drug development where the clinical context does no provide a sufficient number of research participants.

• Study design, conduct, statistical analysis and clinical importance should be considered.

• Academia, pharmaceutical companies, patients advocacy and regulatory bodies should work together.


Trend of CT Notification

76112 112

129 128 129159 165

132

330

422387 379

396431

473

524

424406

534

499 508524

560

632

689

556

0

100

200

300

400

500

600

700

800

2004FY 2005FY 2006FY 2007FY 2008FY 2009FY 2010FY 2011FY 2012FY

Initial CT Notification

Other CT Notification

Total Number of CT Notification


Trend of CT Notification of Investigator Initiated CT

2 50 1 0 1

5 3

135

6

5

14

8

14 6

56

18

6 6

4

9

6

10

7

17

26

0

5

10

15

20

25

30

0

10

20

30

40

50

60

70

2004FY 2005FY 2006FY 2007FY 2008FY 2009FY 2010FY 2011FY 2012FY

Other CT Notification

Initial CT Notification

Total Number of CT


Advantage and Disadvantage of Academia

Advantage• Clinical practice and its network• Academic Research Organization (ARO)• Various supports from government and PMDADisadvantage• Less experienced staff and management• Budget


Role of Academia in development

They can be …• Provider of New Molecular Entity (NME)• Explorer of new indication for known drugs

---(Drug repositioning)• Co-developer in early phase developments

→ ARO• Collaborator of pivotal study

→ Patient registries


Typical Case 1

ⅠPhase Ⅱ Ⅲ

Japan

Foreign PKSafety

Dose findingEfficacy

EfficacySafety

EfficacySafety

Company-oriented


Typical Case 2

ⅠPhase Ⅱ Ⅲ

Japan

Foreign PKSafety


EfficacySafety

Company-oriented

PKDose findingEfficacy

Company


Ideal Case of Academia-oriented

ⅠPhase Ⅱ Ⅲ

Japan

Foreign

PKSafety


EfficacySafety

Academia-oriented

PKDose findingEfficacy

Company


Pragmatic Case for drug repositioning 1

ⅠPhase Ⅱ Ⅲ

Japan

Foreign Dose findingEfficacy

EfficacySafety

Academia-oriented


Company


Pragmatic Case for drug repositioning 2

ⅠPhase Ⅱ Ⅲ

Japan


EfficacySafety

Academia-oriented


Company

Foreign

Asia


Pragmatic Case for NME

ⅠPhase Ⅱ Ⅲ

Japan

Foreign

PKSafety


EfficacySafety

Academia-oriented

Asia


Expected role of patient registries

• Epidemiology• Prevalence• Incidence

• Natural course data• For patient selection • As baseline data

• Patient recruitment• Exact estimation of potential subjects• Rapid inclusion


Patient registries for rare disease in Japan

• Japanese Intractable Diseases Information Center• Based on “Tokutei Shikkan” system

• Academia - Patients collaboration• Remudy• HAM net• JaCALS• J-RARE

etc...

http://www.remudy.jp/

http://hamtsp-net.com/

http://www.jacals.jp/

https://j-rare.net/


Academia and PMDA

To enhance Regulatory Science Activities between Academia and PMDA


Points

Strategies for orphan drug development• Where

• Not only Japan• Asian GCTs to increase potential subjects

• Who• Collaboration of Academia & Pharmaceutical companies• Collaboration with patient registries

Who connect the Academia/AROs in Asia→Regulatory agencies are connecting…


Take Home Message

• The concept of Small Clinical Trials is important … but it can’t solve problems by itself

• Asian Global Clinical Trial is usefulregarding target population and costs

• Academia can undertake the early phase of drug development• Collaborating with pharmaceutical companies• Along with patient registries• Supported by PMDA/MHLW


Thank you for your attention

development of orphan drugs – regulatory viewpoints from ...orphan drugs • “in all, more than...

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