ASENT11th Annual Meeting   March 5-7, 2009    Arlington, VA
International Clinical TrialsI t    ti   l Cli i l T i l       A Regulatory Perspective              James Ottinger, RPh  ...
Agenda•   The case for international clinical trials•   Items for consideration•   Global country venues                  ...
International Clinical Trials• The case for international clinical trials   − Patient access, patient access, patient acce...
International Clinical Trials• Patent Access (continued)  − Speed to enrollment     − Lack of adequate medical care drives...
Metrics from an International ClinicalTrial             Country   Number     Patients   Patients   Time Active   Patients/...
International Clinical Trials• Regulatory reasons to conduct international clinical  trials  − Generates dialogue with int...
International Clinical Trials• Cost per patient  − In ECE, Latin America, and parts of Asia         − Trials can be cost e...
International Clinical Trials• Quality of clinical trials   − Are we being “penny wise, pound foolish”   − Sites from pivo...
Quality – Analysis of FDA InspectionsFDA Geographical area    inspections:       p                 Number of     Number   ...
Considerations for InternationalClinical T i lCli i l Trials
International Clinical Trial - Considerations• Placebo-Controlled Studies  − Required for regulatory approval of most drug...
International Clinical Trials - Considerations• Disease incidence and medical practice  − Consider differences in disease ...
International Clinical Trials - Considerations• Primary endpoints   − Do the authorities agree on primary endpoints?   − R...
International Clinical Trials - Considerations• Other issues  − Infrastructure     − Local representation needed for clini...
Clinical Trial Venues
International Clinical Trials - Venues    Open Phase 3 Trials Sponsored by the 20 Largest U.S. Corporations   Glickman et ...
Venue Selection• Australia/New Zealand  − Relatively cost effective, matches U.S. population  − Regulatory pathway easier ...
Venue Selection• Japan  − Not to be used for additional sites  − Reserve for Japanese registration• China  − Huge patient ...
Venue Selection• India  −   Very cost effective  −   Huge p p        g population, g good enrollment  −   Longer regulator...
Venue Selection• Other areas  − Africa     − South Africa        − Q lifi d i          Qualified investigators            ...
Initiation of Clinical Trials inEurope
European Studies• Why conduct studies in Europe  − Qualified investigators and sites  − Large pool of patients  − Open a d...
Lost in Translation•   IND                   •   CTA•   IND Summaries         •   IMPD•   IND Number            •   EudraC...
Development of the EU• 1957 European Economic Community           Germany, France, Italy, Netherlands,           Belgium, ...
European Regulatory Overview• To conduct Investigational clinical research in the  European Union, a sponsor must have   −...
European Union Regulatory Overview• Clinical Trial Directive (2004)   − Goal was to harmonize the requirements   − The 27 ...
Clinical Trial Application Content• EudraCT Number• Clinical Trial Application Form   − Web based, complicated• Investigat...
CTA RequirementsObtain an EudraCT Number• Required to start the CTA process• Obtained at: http://eudract.emea.europa.eu• G...
EudraCT numbers issued since 2004                                               Total EudraCT numbers issued 2004 - 2008  ...
Clinical Trial Application Content• EudraCT Number• Clinical Trial Application Form   − Web based, complicated• Investigat...
Clinical Trial Application
Clinical Trial Application Content• EudraCT Number• Clinical Trial Application Form   − Web based, complicated• Investigat...
Clinical Trial Application Content• EudraCT Number• Clinical Trial Application Form   − Web based, complicated• Investigat...
Same Guidelines – Different needs
Clinical Trial Application Content• EudraCT Number• Clinical Trial Application Form   − Web based, complicated• Investigat...
Fees• CTA fees are applied on a national basis in each  member state  − Fees are often charged by both Competent Authorite...
CTA Review• The CTA is submitted to each Member State  − Application is validated  − There is a 60-day initial review     ...
Submission and Acceptance ofInternational Cli i l TrialsI t    ti   l Clinical T i l
Submitting Data from International Trials• International Conference of Harmonisation  − E3 – Structure and Content of Clin...
Submitting Data from International TrialsNew FDA Requirements (April 2008)• 21 CFR 314.106 Foreign Data  A) Acceptance of ...
Submitting Data from International TrialsNew FDA Requirements (April 2008)• 21 CFR 314.106 Foreign Data  B) Can be the sol...
Submitting Data from International TrialsRegulatory acceptance of clinical data• International Conference of Harmonisation...
International Clinical TrialsICH E5• Acknowledges and balances  − Ethnic differences can affect safety, efficacy, dose or ...
International Clinical TrialsICH E5  − Data generated in a clinical program from one region will    be accepted if it rese...
International Clinical Trials• Conclusion  − Conducting an international development program    results in     − Add d com...
Questions?         An International….thank you            International thank         Merci, Danke, Domo Arigato
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International clinical trials_asent regulatory affairs

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International clinical trials_asent regulatory affairs

  1. 1. ASENT11th Annual Meeting March 5-7, 2009 Arlington, VA
  2. 2. International Clinical TrialsI 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. 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. 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. 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. 6. Metrics from an International ClinicalTrial 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. 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. 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. 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. 10. Quality – Analysis of FDA InspectionsFDA Geographical area inspections: p Number of Number Findings per inspections i i of findings f fi di inspection i iCentral & Eastern 23 36 1.56Europe (incl. Russia)Latin America 21 53 2.52Western EuropeW t E 263 547 2.07 2 07US and Canada 5302 9778 1.84Total (1981-2001) 5,609 10,414 1.85
  11. 11. Considerations for InternationalClinical T i lCli i l Trials
  12. 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. 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. 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. 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. 16. Clinical Trial Venues
  17. 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. 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. 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. 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. 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. 22. Initiation of Clinical Trials inEurope
  23. 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. 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. 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. 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. 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. 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. 29. CTA RequirementsObtain 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. 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. 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. 32. Clinical Trial Application
  33. 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. 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. 35. Same Guidelines – Different needs
  36. 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. 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. 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. 39. Submission and Acceptance ofInternational Cli i l TrialsI t ti l Clinical T i l
  40. 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. 41. Submitting Data from International TrialsNew 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. 42. Submitting Data from International TrialsNew 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. 43. Submitting Data from International TrialsRegulatory 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. 44. International Clinical TrialsICH 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. 45. International Clinical TrialsICH 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. 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. 47. Questions? An International….thank you International thank Merci, Danke, Domo Arigato

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