1. ASENT
11th Annual Meeting
March 5-7, 2009
Arlington, VA

2. International Clinical Trials
I t ti l Cli i l T i l
A Regulatory Perspective
James Ottinger, RPh
Vice President, Consulting and Compliance
Premier Research G
P i R h Group

3. Agenda
• The case for international clinical trials
• Items for consideration
• Global country venues
y
• Clinical trials in the European Union
• Submission of foreign data
• Regulatory acceptance of foreign data
• Conclusion
• Questions

4. International Clinical Trials
• The case for international clinical trials
− Patient access, patient access, patient access!
− Availability of patients not in the U.S.
− Trials in Multiple Sclerosis
− Regulatory requirements include DB PC trials of two years
duration
− Most patients in the U.S. will not enroll in a trial of this
design
− Trials in Alzheimer’s Disease
− Most donepezil-naïve patients are outside the U.S. and
Western Europe

5. International Clinical Trials
• Patent Access (continued)
− Speed to enrollment
− Lack of adequate medical care drives patients into clinical trials
− E t
Eastern Central E
C t l Europe
− Latin America
− Parts of Asia
− Standard metric of number of patients per site per month higher
than in the U.S. or Western Europe

6. Metrics from an International Clinical
Trial
Country Number Patients Patients Time Active Patients/Site/Month
of Sites Planned Enrolled (months)
Austria 5 40 31 16 0.39
Belgium 17 136 120 12 0.59
France 13 104 118 12 0.76
Germany 27 324 255 14 0.67
Italy 13 104 28 12 0.18
Netherlands 9 72 180 12 1.67
1 67
Portugal 3 24 8 13 0.21
Spain 14 112 92 15 0.44
United Kingdom 11 88 80 14 0.52
Czech Republic 25 500 343 14 0.98
Estonia 5 100 109 15 1.45
Hungary 10 80 299 14 2.14
Latvia 5 100 94 16 1.18
Poland 35 700 538 14 1.10
Slovakia 15 300 285 16 1.19
1 19
Bulgaria 20 400 391 15 1.30
Romania 5 100 168 17 1.98
Russia 25 500 637 16 1.59
Ukraine 25 700 781 14 2.23
Switzerland 1 12 0 0 0
TOTAL 283 4496 4557 - -

7. International Clinical Trials
• Regulatory reasons to conduct international clinical
trials
− Generates dialogue with international regulatory
authorities
th iti
− Early regulatory strategy discussions
− Issue identification and resolution
− Experience with key opinion leaders
− Supports clinical development, regulatory and marketing efforts
− F ilit t approval
Facilitates l
− Trials are required in some countries
− China India, Taiwan, Japan and others
China, India Taiwan

8. International Clinical Trials
• Cost per patient
− In ECE, Latin America, and parts of Asia
− Trials can be cost effective relative to the U.S.
− A center in I di will charge $1500 t 2000 per patient,
t i India ill h to ti t
1/10 the comparable rate in the U.S.1
− NDAs will have thousands of patients,
− The cost advantage can add up
− An exception to this rule is Japan
1Garnier JP. Rebuilding the R&D engine in big pharma. Harv Bus Rev 2008;86:68-76

9. International Clinical Trials
• Quality of clinical trials
− Are we being “penny wise, pound foolish”
− Sites from pivotal clinical trials (Phase 3) will be
inspected b th regulatory authorities i th U S and
i t d by the l t th iti in the U.S. d
Europe
− FDA Bioresearch Monitoring Program
g g
− EU National Authority Inspections
− Will the data pass a regulatory inspection?

10. Quality – Analysis of FDA Inspections
FDA Geographical area
inspections:
p Number of Number Findings per
inspections
i i of findings
f fi di inspection
i i
Central & Eastern
23 36 1.56
Europe (incl. Russia)
Latin America 21 53 2.52
Western Europe
W t E 263 547 2.07
2 07
US and Canada 5302 9778 1.84
Total (1981-2001) 5,609 10,414 1.85

11. Considerations for International
Clinical T i l
Cli i l Trials

12. International Clinical Trial - Considerations
• Placebo-Controlled Studies
− Required for regulatory approval of most drugs
− Declaration of Helsinki
− “The use of placebo, or no treatment, is acceptable in studies
where no current proven intervention exists”
− Regulatory Authorities and IRBs in some countries may not
approve a placebo-controlled trial
− e.g. Major Depressive Disorder, Multiple Sclerosis

13. International Clinical Trials - Considerations
• Disease incidence and medical practice
− Consider differences in disease incidence
− MS trials in Latin America
− MDD i A i
in Asia
− Local acceptance of disease
− Fibromyalgia trials in some countries
y g
− Treatment differences
− Other treatments
− U of psychotherapy i E
Use f h th in Europe
− Concomitant medications
− Approved dose of Aricept in Japan is half that in other
countries

14. International Clinical Trials - Considerations
• Primary endpoints
− Do the authorities agree on primary endpoints?
− Rating scales
− Validated in the local language
− ADAS-Cog
− Familiarity by investigators
y y g
− Montgomery-Asberg Scale vs. Hamilton Depression
• Statistical considerations
− Do the statistical tests and imputation methods meet
regulatory scrutiny
− LOCF not an acceptable imputation method for analgesic trials
in the US

15. International Clinical Trials - Considerations
• Other issues
− Infrastructure
− Local representation needed for clinical trial monitoring
− Interaction with the local regulatory authorities
− Contract Research Organizations
− Drug Importation issues
− Qualified Person in Europe to approve clinical trial importation
− DEA Scheduled drugs pose additional challenges
− Multiple languages
− Informed consents, rating scales, etc
− Ethical issues
− Ethical oversight in developing countries
− Recent case of Pfizer and Nigeria

16. Clinical Trial Venues

17. International Clinical Trials - Venues
Open Phase 3 Trials Sponsored by the 20 Largest U.S. Corporations
Glickman et al, Ethical and Scientific Implications of the Globalization of Clinical Research.
N Engl J Med 2009;360:816-849

18. Venue Selection
• Australia/New Zealand
− Relatively cost effective, matches U.S. population
− Regulatory pathway easier than most
− General use
• Canada
− Excellent sites and investigators
− Use for specialty centers, rare diseases, global
programs
− Different IND application, possible pre-IND meeting,
French language requirements
− Tax incentives for local offices

19. Venue Selection
• Japan
− Not to be used for additional sites
− Reserve for Japanese registration
• China
− Huge patient population, but dissimilar to the U.S.
− Long regulatory lead times
− Mandatory for Chinese registration
• Oth Asia/Pac countries
Other A i /P ti
− Use for global programs, rare diseases, special
circumstances
− Cost effective, esp for Pan-Asian registration

20. Venue Selection
• India
− Very cost effective
− Huge p p
g population, g good enrollment
− Longer regulatory lead times
− General use
• Latin America
− Cost effective
− Good enrollment
− Regulatory lead times vary by country
− General use

21. Venue Selection
• Other areas
− Africa
− South Africa
− Q lifi d i
Qualified investigators
ti t
− General use
− Other countries
− Special situations – HIV, malaria
− Middle East
− Israel has good infrastructure
− Qualified sites
− General use

22. Initiation of Clinical Trials in
Europe

23. European Studies
• Why conduct studies in Europe
− Qualified investigators and sites
− Large pool of patients
− Open a dialogue with the European Regulators in
advance of a marketing application
− Among the world s largest pharmaceutical market as a region
world’s
− Differing regulatory requirements and medical practice

24. Lost in Translation
• IND • CTA
• IND Summaries • IMPD
• IND Number • EudraCT Number
• FDA • Competent Authority
• IRBs • Ethics Committees
• Country • Member States
• --------- • EMEA/CHMP
• Federal Regulations • EU Directives and
National Legislation

25. Development of the EU
• 1957 European Economic Community
Germany, France, Italy, Netherlands,
Belgium, Luxembourg
• 1973 European Community. United Kingdom, Denmark, Ireland
p y g , ,
• 1981 Greece
• 1986 Spain, Portugal
• 1995 European Union. Austria, Finland, Sweden
• 2004 Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta,
Poland, Slovak Republic, Slovenia
• 2007 Bulgaria and Romania
27 Member States
M b St t
3

26. European Regulatory Overview
• To conduct Investigational clinical research in the
European Union, a sponsor must have
− Offices in an EU Member State, or
− EU Legal Representative
− EU Applicant
− Qualified Person
− An approved Clinical Trial Application
− Unlike marketing applications, there is no option for European-
wide CTA approval
id l
− Approval of the Ethics Committees (EC) in every
member state in which the trial is being conducted
g

27. European Union Regulatory Overview
• Clinical Trial Directive (2004)
− Goal was to harmonize the requirements
− The 27 member states have implemented the Clinical Trial Directive
in their national legislation differently
− Each member state may have its own submission requirements
− EC approval and Competent Authority approval
− In parallel or
− In sequence
− 23 official languages
− E li h i not accepted f all parts of th application
English is t t d for ll t f the li ti

28. Clinical Trial Application Content
• EudraCT Number
• Clinical Trial Application Form
− Web based, complicated
• Investigational Medicinal Products Dossier
− The IMPD contains a summary of
− Quality (Chemistry, M
Q li (Ch i Manufacturing and C
f i d Controls)
l )
− Pharmacology and Toxicology Data
− Clinical Data
− Overall Risk and Benefit Assessment
• Supporting Information
• Fees

29. CTA Requirements
Obtain an EudraCT Number
• Required to start the CTA process
• Obtained at: http://eudract.emea.europa.eu
• Generated automatically and consists of the year followed
by the trial number
− The 42nd trial in 2009 would be
− 2009-0000042
− This is a unique number used to refer to this study

30. EudraCT numbers issued since 2004
Total EudraCT numbers issued 2004 - 2008
10000 9334
9000
7987
To EudraCT numbers issued
d
8000
7124
7000
6214
6000
4613
5000
n
4000
3000
otal
2000
1000
0
2004 2005 2006 2007 2008
Year

31. Clinical Trial Application Content
• EudraCT Number
• Clinical Trial Application Form
− Web based, complicated
• Investigational Medicinal Products Dossier
− The IMPD contains a summary of
− Quality (Chemistry, M
Q li (Ch i Manufacturing and C
f i d Controls)
l )
− Pharmacology and Toxicology Data
− Clinical Data
− Overall Risk and Benefit Assessment
• Supporting Information
• Fees

32. Clinical Trial Application

33. Clinical Trial Application Content
• EudraCT Number
• Clinical Trial Application Form
− Web based, complicated
• Investigational Medicinal Products Dossier
− Quality (Chemistry, Manufacturing and Controls)
− Pharmacology and T i l
Ph l d Toxicology D
Data
− Clinical Data
− Overall Risk and Benefit Assessment
• Supporting Information
• Fees

34. Clinical Trial Application Content
• EudraCT Number
• Clinical Trial Application Form
− Web based, complicated
• Investigational Medicinal Products Dossier
− The IMPD contains a summary of
− Quality (Chemistry, M
Q li (Ch i Manufacturing and C
f i d Controls)
l )
− Pharmacology and Toxicology Data
− Clinical Data
− Overall Risk and Benefit Assessment
• Supporting Information
• Fees

35. Same Guidelines – Different needs

36. Clinical Trial Application Content
• EudraCT Number
• Clinical Trial Application Form
− Web based, complicated
• Investigational Medicinal Products Dossier
− The IMPD contains a summary of
− Quality (Chemistry, M
Q li (Ch i Manufacturing and C
f i d Controls)
l )
− Pharmacology and Toxicology Data
− Clinical Data
− Overall Risk and Benefit Assessment
• Supporting Information
• Fees

37. Fees
• CTA fees are applied on a national basis in each
member state
− Fees are often charged by both Competent Authorites
and EC
d ECs
− Generally individually less than $5,000, but can add up
to a substantial sum
• Regional difference – U S INDs are “free”
U.S. free

38. CTA Review
• The CTA is submitted to each Member State
− Application is validated
− There is a 60-day initial review
− Member States may have differing timelines, e.g.,shorter for
phase 1 studies
− A d fi i
deficiency l tt may b i
letter be issued
d
− Responses are submitted, an additional review is
completed
− No trial can begin until the CTA is approved by the CA
and the ECs

39. Submission and Acceptance of
International Cli i l Trials
I t ti l Clinical T i l

40. Submitting Data from International Trials
• International Conference of Harmonisation
− E3 – Structure and Content of Clinical Study Reports
− Outlines the format and reporting requirements for any clinical
trial
− Now harmonized in all regions (U.S., EU, Japan)
− M4 – The Common Technical Document
− Outlines the format for a Marketing Application (NDA,MAA)
− Now harmonized in all regions
− Additional requirements in the U.S. for an ISS and ISE

41. Submitting Data from International Trials
New FDA Requirements (April 2008)
• 21 CFR 314.106 Foreign Data
A) Acceptance of foreign data is governed by 312.120
− Foreign clinical studies not conducted under an IND. Must
submit in an NDA documentation on:
− Qualification of investigators
g
− Description of research facilities
− Protocol, Clinical Study Report, Case Report Forms as
requested
− Chemistry, Manufacturing and Controls information
− The study is adequate and well controlled
− Th study conforms with ethical principles
The t d f ith thi l i i l

42. Submitting Data from International Trials
New FDA Requirements (April 2008)
• 21 CFR 314.106 Foreign Data
B) Can be the sole basis for approval
− Foreign data are applicable to the U.S. population
− Studies have been performed by competent investigators
− FDA can validate the data (inspection)
C) Applicants are encouraged to meet with the agency

43. Submitting Data from International Trials
Regulatory acceptance of clinical data
• International Conference of Harmonisation
− E5 (R1) Ethnic Factors in the acceptability of foreign
clinical data
− Developed to establish the framework for acceptance of foreign
clinical studies by the Japanese MHLW
y p
− ICH guidelines are adopted in three regions
− European Union, Japan and the U.S.
− Widely recognized by other authorities

44. International Clinical Trials
ICH E5
• Acknowledges and balances
− Ethnic differences can affect safety, efficacy, dose or
dose regimen
− Duplication of clinical trials is inefficient and wasteful
• C
Comprehensive di
h i discussion of f t
i f factors t consider
to id
− Intrinsic factors – genetic polymorphism, age, gender,
body weight
− extrinsic factors – medical practice, diet, socioeconomic
status, exposure to pollution and sunshine

45. International Clinical Trials
ICH E5
− Data generated in a clinical program from one region will
be accepted if it resembles the population of the new
region
− A program conducted in Western Europe, will most likely be
accepted by the FDA
− A program conducted in Japan will require new studies for the
U.S.
− A program conducted in the U.S. will require new studies for
China

46. International Clinical Trials
• Conclusion
− Conducting an international development program
results in
− Add d complexity
Added l it
− But....can
− Accelerate development
p
− Reduce costs
− Facilitate global registration

47. Questions?
An International….thank you
International thank
Merci, Danke, Domo Arigato