International clinical trials_asent regulatory affairs
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ASENTASENT11th Annual Meeting
March 5-7, 2009Arlington, VA
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I t ti l Cli i l T i lInternational Clinical TrialsA Regulatory Perspective
James Ottinger, RPhVice President, Consulting and Compliance
P i R h GPremier Research Group
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Agenda
• The case for international clinical trials • Items for consideration• Global country venuesy• Clinical trials in the European Union • Submission of foreign dataSubmission of foreign data • Regulatory acceptance of foreign data• ConclusionConclusion• Questions
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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
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International Clinical Trials
• Patent Access (continued)− Speed to enrollment
− Lack of adequate medical care drives patients into clinical trialsE t C t l E− Eastern Central 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
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Metrics from an International Clinical Metrics from an International Clinical TrialTrial
CountryCountry Number Number of Sitesof Sites
Patients Patients PlannedPlanned
Patients Patients EnrolledEnrolled
Time Active Time Active (months)(months)
Patients/Site/MonthPatients/Site/Month
Austria 5 40 31 16 0.39
TrialTrial
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 67Netherlands 9 72 180 12 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 19Slovakia 15 300 285 16 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
TOTALTOTAL 283283 44964496 45574557 -- --
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International Clinical Trials
• Regulatory reasons to conduct international clinical trials− Generates dialogue with international regulatory
th itiauthorities− Early regulatory strategy discussions− Issue identification and resolution
− Experience with key opinion leaders− Supports clinical development, regulatory and marketing efforts
F ilit t l− Facilitates approval− Trials are required in some countries
− China India Taiwan Japan and othersChina, India, Taiwan, Japan and others
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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 t i I di ill h $1500 t 2000 ti t− A center in India will charge $1500 to 2000 per patient, 1/10 the comparable rate in the U.S.1
− NDAs will have thousands of patients,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
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International Clinical Trials
• Quality of clinical trials− Are we being “penny wise, pound foolish”− Sites from pivotal clinical trials (Phase 3) will be
i t d b th l t th iti i th U S dinspected by the regulatory authorities in the U.S. and Europe− FDA Bioresearch Monitoring Programg g− EU National Authority Inspections
− Will the data pass a regulatory inspection?
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Quality Quality –– Analysis of FDA InspectionsAnalysis of FDA Inspections
FDA inspections:Geographical area Number of i i
Numberf fi di
Findings per i i
pGeographical area inspections of findings inspection
Central & EasternEurope (incl. Russia) 23 36 1.56
Latin America 21 53 2.52
W t E 263 547 2 07Western Europe 263 547 2.07
US and Canada 5302 9778 1.84
Total (1981-2001) 5,609 10,414 1.85
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Considerations for International Cli i l T i lClinical Trials
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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
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International Clinical Trials - Considerations
• Disease incidence and medical practice− Consider differences in disease incidence
− MS trials in Latin AmericaMDD i A i− MDD in Asia
− Local acceptance of disease− Fibromyalgia trials in some countriesy g
− Treatment differences− Other treatments
U f h th i E− Use of psychotherapy in Europe− Concomitant medications
− Approved dose of Aricept in Japan is half that in other countries
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International Clinical Trials - Considerations
• Primary endpoints− Do the authorities agree on primary endpoints?− Rating scales
− Validated in the local language− ADAS-Cog
− Familiarity by investigatorsy 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 trialsLOCF not an acceptable imputation method for analgesic trials
in the US
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International Clinical Trials - Considerations
• Other issues− Infrastructure
− Local representation needed for clinical trial monitoring− Interaction with the local regulatory authoritiesInteraction 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 languagesMultiple languages− Informed consents, rating scales, etc
− Ethical issues− Ethical oversight in developing countries− Recent case of Pfizer and Nigeria
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Clinical Trial Venues
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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
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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
programsprograms− Different IND application, possible pre-IND meeting,
French language requirements− Tax incentives for local offices
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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 A i /P t i• Other Asia/Pac countries− Use for global programs, rare diseases, special
circumstancescircumstances− Cost effective, esp for Pan-Asian registration
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Venue Selection
• IndiaIndia− Very cost effective− Huge population, good enrollmentg p p g− Longer regulatory lead times− General use
• Latin America− Cost effective− Good enrollment− Regulatory lead times vary by country
General use− General use
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Venue Selection
• Other areas− Africa
− South AfricaQ lifi d i ti t− Qualified investigators
− General use− Other countries
− Special situations – HIV, malaria
− Middle East− Israel has good infrastructure− Israel has good infrastructure− Qualified sites− General use
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Initiation of Clinical Trials in EuropeEurope
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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 regionAmong the world s largest pharmaceutical market as a region
− Differing regulatory requirements and medical practice
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Lost in Translation
• IND • CTA• IND Summaries• IND Number
• IMPD• EudraCT Number
• FDA• IRBs
• Competent Authority• Ethics CommitteesIRBs
• Country• ---------
Ethics Committees• Member States• EMEA/CHMP
• Federal RegulationsEMEA/CHMP
• EU Directives and National LegislationNational Legislation
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Development of the EU
• 1957 European Economic Community
Germany, France, Italy, Netherlands, Belgium, Luxembourg
• 1973 European Community. United Kingdom, Denmark, Irelandp 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 M b St t27 Member States
3
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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 PersonQualified Person− An approved Clinical Trial Application
− Unlike marketing applications, there is no option for European-id CTA lwide CTA approval
− Approval of the Ethics Committees (EC) in every member state in which the trial is being conductedg
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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 orIn parallel or− In sequence
− 23 official languages E li h i t t d f ll t f th li ti− English is not accepted for all parts of the application
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Clinical Trial Application Content
• EudraCT Number• Clinical Trial Application Form
− Web based, complicated• Investigational Medicinal Products Dossier
− The IMPD contains a summary ofQ li (Ch i M f i d C l )− Quality (Chemistry, Manufacturing and Controls)
− Pharmacology and Toxicology Data− Clinical Data− Overall Risk and Benefit Assessment
• Supporting Information• Fees
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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• 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
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EudraCT numbers issued since 2004
Total EudraCT numbers issued 2004 - 2008
7987
9334
9000
10000
d
6214
7124
7987
46135000
6000
7000
8000
num
bers
issu
ed
2000
3000
4000
5000
otal
Eud
raC
T n
0
1000
2004 2005 2006 2007 2008
Year
To
Year
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Clinical Trial Application Content
• EudraCT Number• Clinical Trial Application Form
− Web based, complicated• Investigational Medicinal Products Dossier
− The IMPD contains a summary ofQ li (Ch i M f i d C l )− Quality (Chemistry, Manufacturing and Controls)
− Pharmacology and Toxicology Data− Clinical Data− Overall Risk and Benefit Assessment
• Supporting Information• Fees
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Clinical Trial Application
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Clinical Trial Application Content
• EudraCT Number• Clinical Trial Application Form
− Web based, complicated• Investigational Medicinal Products Dossier
− Quality (Chemistry, Manufacturing and Controls)Ph l d T i l D− Pharmacology and Toxicology Data
− Clinical Data− Overall Risk and Benefit Assessment
• Supporting Information• Fees
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Clinical Trial Application Content
• EudraCT Number• Clinical Trial Application Form
− Web based, complicated• Investigational Medicinal Products Dossier
− The IMPD contains a summary ofQ li (Ch i M f i d C l )− Quality (Chemistry, Manufacturing and Controls)
− Pharmacology and Toxicology Data− Clinical Data− Overall Risk and Benefit Assessment
• Supporting Information• Fees
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Same Guidelines – Different needs
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Clinical Trial Application Content
• EudraCT Number• Clinical Trial Application Form
− Web based, complicated• Investigational Medicinal Products Dossier
− The IMPD contains a summary ofQ li (Ch i M f i d C l )− Quality (Chemistry, Manufacturing and Controls)
− Pharmacology and Toxicology Data− Clinical Data− Overall Risk and Benefit Assessment
• Supporting Information• Fees
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Fees
• CTA fees are applied on a national basis in each member state− Fees are often charged by both Competent Authorites
d ECand ECs− Generally individually less than $5,000, but can add up
to a substantial sumto a substantial sum
• Regional difference – U S INDs are “free”Regional difference U.S. INDs are free
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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 l tt b i d− A deficiency letter may be issued
− Responses are submitted, an additional review is completedcompleted
− No trial can begin until the CTA is approved by the CA and the ECs
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Submission and Acceptance of I t ti l Cli i l T i lInternational Clinical Trials
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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 trialtrial
− 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 ISEAdditional requirements in the U.S. for an ISS and ISE
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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 investigatorsg− Description of research facilities− Protocol, Clinical Study Report, Case Report Forms as
requestedrequested− Chemistry, Manufacturing and Controls information− The study is adequate and well controlled
Th t d f ith thi l i i l− The study conforms with ethical principles
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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)FDA can validate the data (inspection)
C) Applicants are encouraged to meet with the agency
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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 MHLWy p− ICH guidelines are adopted in three regions
− European Union, Japan and the U.S.− Widely recognized by other authorities− Widely recognized by other authorities
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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 wastefulC h i di i f f t t id• Comprehensive discussion of factors to consider− Intrinsic factors – genetic polymorphism, age, gender,
body weightbody weight − extrinsic factors – medical practice, diet, socioeconomic
status, exposure to pollution and sunshine
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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 regionregion− 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
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International Clinical Trials
• Conclusion− Conducting an international development program
results inAdd d l it− Added complexity
− But....can− Accelerate developmentp− Reduce costs− Facilitate global registration
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Questions?
An International thank youAn International….thank you Merci, Danke, Domo Arigato