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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11th Annual Meeting DIA JAPAN 2014 | November 16-18 | Tokyo Big Sight | Ariake 3
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.
11th Annual Meeting DIA JAPAN 2014 | November 16-18 | Tokyo Big Sight | Ariake 4
Outline of the presentation
• From Small Clinical Trials• Global Clinical Trial in Asia • Clinical development with Academia• Conclusion
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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.
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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.
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From Small Clinical Trials
Orphanet J Rare Dis. 2013; 8: 48.
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Other than Small Clinical Trials
Orphan drug development
DevelopmentalStrategies
Where Who/
Work together
Small Clinical Trials
Study designStatistical analysis
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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
11th Annual Meeting DIA JAPAN 2014 | November 16-18 | Tokyo Big Sight | Ariake 10
Asian Clinical Trial in GCT (not only orphan)
http://www.pmda.go.jp/regulatory/file/RS_data/MRCT/MRCT_FY2007-FY2012.pdf
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Approved drugs by Asian GCT in JAPAN
* First Approval
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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)
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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
11th Annual Meeting DIA JAPAN 2014 | November 16-18 | Tokyo Big Sight | Ariake 14
Promoting Global Clinical Trial within APEC
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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
11th Annual Meeting DIA JAPAN 2014 | November 16-18 | Tokyo Big Sight | Ariake 16
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.
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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
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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
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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
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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
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Typical Case 1
ⅠPhase Ⅱ Ⅲ
Japan
Foreign PKSafety
Dose findingEfficacy
EfficacySafety
EfficacySafety
Company-oriented
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Typical Case 2
ⅠPhase Ⅱ Ⅲ
Japan
Foreign PKSafety
Dose findingEfficacy
EfficacySafety
Company-oriented
PKDose findingEfficacy
Company
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Ideal Case of Academia-oriented
ⅠPhase Ⅱ Ⅲ
Japan
Foreign
PKSafety
Dose findingEfficacy
EfficacySafety
Academia-oriented
PKDose findingEfficacy
Company
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Pragmatic Case for drug repositioning 1
ⅠPhase Ⅱ Ⅲ
Japan
Foreign Dose findingEfficacy
EfficacySafety
Academia-oriented
Dose findingEfficacy
Company
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Pragmatic Case for drug repositioning 2
ⅠPhase Ⅱ Ⅲ
Japan
Dose findingEfficacy
EfficacySafety
Academia-oriented
Dose findingEfficacy
Company
Foreign
Asia
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Pragmatic Case for NME
ⅠPhase Ⅱ Ⅲ
Japan
Foreign
PKSafety
Dose findingEfficacy
EfficacySafety
Academia-oriented
Asia
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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
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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/
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Academia and PMDA
To enhance Regulatory Science Activities between Academia and PMDA
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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…
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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
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Thank you for your attention