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ASENTASENT11th Annual Meeting
March 5-7, 2009Arlington, VA
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
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
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
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
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 -- --
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
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
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?
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
Considerations for International Cli i l T i lClinical Trials
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
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
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
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
Clinical Trial Venues
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
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
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
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
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
Initiation of Clinical Trials in EuropeEurope
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
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
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
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
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
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
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
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
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
Clinical Trial Application
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
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
Same Guidelines – Different needs
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
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
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
Submission and Acceptance of I t ti l Cli i l T i lInternational Clinical Trials
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
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
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
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
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
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
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
Questions?
An International thank youAn International….thank you Merci, Danke, Domo Arigato