AAPS PharmSci

, Volume 5, Issue 4, pp 13–40

AAPS/RAPS/CAPRA collaborative program: Exploring the challenges of drug regulation in a global environment: Clinical concerns



Globalization of the pharmaceutical industry has led to a need to harmonize the regulatory requirements governing the marketing of medicinal products. To minimize the barriers impeding global drug product registration, the International Conference on the Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) was established in 1990. The ICH has developed a series of guidelines that reflect agreements reached by participating nations on aspects of the chemistry and clinical technical sections that will fulfill the regulatory requirements of these various jurisdications. Nevertheless, there continue to be points of divergent perspectives and barriers that can impede the use of foreign clinical data. Given the importance of these issues, the Regulatory Science (RS) section of the American Association of Pharmaceutical Scientists (AAPS), in conjunction with the Regulatory Affairs Professional Society (RAPS) and the Canadian Association of Professional Regulatory Affairs (CAPRA) cosponsored a public forum on this topic. This manuscript provides a summary of the speaker presentations and audience discussions regarding the design of clinical trials and the extrapolation of results from these trials to support international drug registration.


clinical trials regulatory requirements international harmonization foreign clinical data 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Guidance for Industry Clinical Development of Steroidal Contraceptives Used by Women. Health Products and Food Branch. Available at: http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/steroidal_contraceptives_e.html. Accessed August 2003.Google Scholar
  2. 2.
    Therapeutic Products Programme policy, Submissions for Topical Non-Steroidal Anti-inflammatory Drugs (Topical NSAID's). Available at: http://www.he-sc.gc.ca/hpfb-dgpsa/tpd-dpt/topnsaid_e.html. Accessed August 2003.Google Scholar
  3. 3.
    Note for guidance on the clinical investigation of medicinal products in the treatment of asthma. EMEA, CPMP. Available at: http://www.emea.eu.int/pdfs/human/ewp/29220len.pdf.Accessed August 2003.Google Scholar
  4. 4.
    Points to consider on clinical investigation of medicinal products for acute stroke. EMEA, CPMP. Available at: http://www.emea.eu.int/pdfs/human/ewp/056098en.pdf. Accessed August 2003.Google Scholar
  5. 5.
    Appendix to the note for guidance on the clinical investigation of medicinal products in the treatment of schizophrenia-methodology of clinical trials concerning the development of depot preparations of approved medicinal products in schizophrenia. EMEA, CPMP. Available at: http://www.emea.eu.int/pdfs/human/ewp/004901en.pdf. Accessed August 2003.Google Scholar
  6. 6.
    White HD. International differences: selection, noise, or real? Eur Heart J. 2000;21:339–342.PubMedCrossRefGoogle Scholar
  7. 7.
    Davis AF, Long RM. Pharmacogenetics research network and knowledge base second scientific meeting. Pharmacogenomics J. 2002;2:293–296.PubMedCrossRefGoogle Scholar
  8. 8.
    Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487–491.PubMedCrossRefGoogle Scholar
  9. 9.
    ICH Topic E10: Choice of Control Group in Clinical Trials dated 27 July 2000. Available at: http://www.ich.org/ich5e.html. Accessed August 2003.Google Scholar
  10. 10.
    Berkowitz SD, Granger CB, Pieper KS, et al. Incidence and predictors of bleeding after thrombolytic therapy for myocardial infarction. Circulation. 1997;95:2508–2516.PubMedCrossRefGoogle Scholar
  11. 11.
    Graf J, Doig GS, Cook DJ, Vincent JL, Sibbald WJ. Randomized, controlled clinical trials in sepsis: has methodological quality improved over time? Crit Care Med. 2002;30:461–472.PubMedCrossRefGoogle Scholar
  12. 12.
    Medical Dictionary for Regulatory Activities. Available at: http://www.meddramsso.com/new webaug 2001/meddramsso/med dra/index.htm. Accessed August 2003.Google Scholar
  13. 13.
    Labs KH, Dormandy JA, Jaeger KA, Stuerzebecher CS, Hiatt WR. Transatlantic conference on clinical trial guidelines in PAOD (peripheral arterial occlusive disease) clinical trial methodology. Eur J Vasc Endovasc Surg. 1999;18:253–265.PubMedCrossRefGoogle Scholar
  14. 14.
    Ono S, Kodama Y, Nagao T, Toyoshima S. The quality of conduct in Japanese clinical trials: deficiencies found in GCP inspections. Control Clin Trials. 2002;23:29–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Patriarca PA, Wright PF, John TJ. Factors affecting the immunogenicity of oral poliovirus vaccine in developing countries: review. Rev Infect Dis. 1991;13:926–939.PubMedCrossRefGoogle Scholar
  16. 16.
    O'Shea JC, Califf RM. International differences in cardiovascular clinical trials. Am Heart J. 2001;141:866–874.PubMedCrossRefGoogle Scholar
  17. 17.
    O'Shea JC, Califf RM. International differences in treatment effects in cardiovascular clinical trials. Am Heart J. 2001;141:875–880.PubMedCrossRefGoogle Scholar
  18. 18.
    O'Shea JC, DeMets DL. Statistical issues relating to international differences in clinical trials. Am Heart J. 2001;142:21–28.PubMedCrossRefGoogle Scholar
  19. 19.
    Akkerhuis KM, Deckers JW, Boersma E, et al. Geographic variability in outcomes within an international trial of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes. Results from PURSUIT. Eur Heart J. 2000;21:371–381.PubMedCrossRefGoogle Scholar
  20. 20.
    Shapito ED. Protective efficacy trials. In: Ellis RW, Granoff DM, eds. Development and Clinical Uses of Haemophilus b Conjugate Vaccines. New York, NY: Marcel Dekker; 1994:339–356.Google Scholar
  21. 21.
    Points to consider on switching between superiority and noninferiority, EMEA, CPMP. Available at: http://www.emea.eu.int/pdfs/human/ewp/048299en.pdf. Accessed August 2003Google Scholar
  22. 22.
    Khan A, Khan S, Brown WA. Are placebo controls necessary to test new antidepressants and anxiolytics? Int J Neuropsychopharmacol. 2002;5:193–197.PubMedCrossRefGoogle Scholar
  23. 23.
    Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287:1807–1814.CrossRefGoogle Scholar
  24. 24.
    Simon RM, Steinberg SM, Hamilton M, et al. Clinical trial designs for the early clinical development of therapeutic vaccines. J Clin Oncol. 2001;19:1848–1854.PubMedGoogle Scholar
  25. 25.
    Haffner ME. Designing clinical trials to study rare disease treatment. Drug Inf J. 1998;32:957–960.Google Scholar
  26. 26.
    Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487–491.PubMedCrossRefGoogle Scholar
  27. 27.
    Meisel C, Gerloff T, Kirchheiner J, et al. Implications of pharmacogenetics for individualizing drug treatment and for study design. J Mol Med. 2001;81:154–167.Google Scholar
  28. 28.
    Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet. 1999;56:247–258.PubMedCrossRefGoogle Scholar
  29. 29.
    Carson PE, Flanagan CL, Ickes CE, Alvong AS. Enzymatic deficiency in primaquine sensitive erythrocytes. Science. 1956;124:484–485.PubMedCrossRefGoogle Scholar
  30. 30.
    ICH Harmonised tripartite guideline: Ethnic factors in the acceptability of foreign clinical data. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use, 5 February 1998. Available at: http://www.ich.org/pdfICH/e5.pdf. Accessed August 2003.Google Scholar
  31. 31.
    Davis AF, Long RM. Pharmacogenetics research network and knowledge base second scientific meeting. Pharmacogenomics J. 2002;2(5):293–296.PubMedCrossRefGoogle Scholar
  32. 32.
    Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet. 1999;22:168–170.PubMedCrossRefGoogle Scholar
  33. 33.
    Palmer LJ, Silverman ES, Weiss ST, Drazen JM. Pharmacogenetics of asthma. Am J Respir Crit Care Med. 2002;165:861–866.PubMedCrossRefGoogle Scholar
  34. 34.
    Kottakis J, Wood R, Le Gros V, Della Cioppa G. Clinical efficacy with formoterol in the absence of a response to salmeterol: a review. Int J Clin Pract. 2001;55:476–479.PubMedGoogle Scholar
  35. 35.
    Rutledge DR. Race and hypertension. What is clinically relevant? Drugs. 1994;47:914–932.PubMedCrossRefGoogle Scholar
  36. 36.
    Saunders E. Tailoring treatment to minority patients. Am J Med. 1990;88:21S-23S.PubMedCrossRefGoogle Scholar
  37. 37.
    Lau EMC, Lee JK, Suriwongpaisal P, et al. The incidence of hip fracture in four Asian countries: the Asian osteoporosis study (AOS). Osteoporos Int. 2001;12:239–243.PubMedCrossRefGoogle Scholar
  38. 38.
    Ross PD, Huang C. Hip fracture incidence among Caucasians in Hawaii is similar to Japanese. A population-based study. Aging (Milano). 2000;12:356–359.Google Scholar
  39. 39.
    Cummings SR, Cauley JA, Palermo L, et al. Racial differences in hip axis lengths might explain racial differences in rates of hip fracture. Study of Osteoporotic Fractures Research Group. Osteoporos Int. 1994;4:226–229.PubMedCrossRefGoogle Scholar
  40. 40.
    Glasel JA. Drugs, the human genome, and individual-based medicine. Prog Drug Res. 2002;58:1–50.PubMedCrossRefGoogle Scholar
  41. 41.
    Al Suwaidi J, Salam AM. Platelet glycoprotein IIb/IIIa receptor blockade in coronary artery disease. Curr Control Trials Cardiovasc Med. 2001;2:171–179.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Cheng JW. Efficacy of glycoprotein IIb/IIIa-receptor inhibitors during percutaneous coronary intervention. Am J Health Syst Pharm. 2002;59(suppl 7):S5-S14.PubMedGoogle Scholar
  43. 43.
    Schwartz LM, Fisher ES, Tosteson NA, et al. Treatment and health outcomes of women and men in a cohort with coronary artery disease. Arch Intern Med. 1997;157:1545–1551.PubMedCrossRefGoogle Scholar
  44. 44.
    Talley NJ, Stanghellini V, Heading R, Koch KL, Malagelada JR, Tytgat GNJ. Functional gastroduodenal disorders. Gut. 1999;45(suppl 2):I37-I42.Google Scholar
  45. 45.
    American Gastroenterological Association (AGA) Clinical Practice and Practice Economics Committe. American Gastroen-terological Association medical position statement: evaluation of dyspepsia. Gastroenterology, 1998;114:579–581.CrossRefGoogle Scholar
  46. 46.
    Veldhuyzen van Zanten SJ, Flook N, Chiba N, et al. An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori. Canadian Dyspepsia Working Group. CMAJ. 2000;162(suppl):S3–23.Google Scholar
  47. 47.
    Mark DB, Naylor CD, Hlatky MA, et al. Use of medical resources and quality of life after acute myocardial infaction in Canada and the United States. N Engl J Med. 1994;331:1130–1135.PubMedCrossRefGoogle Scholar
  48. 48.
    Rouleau JL, Moye LA, Pfeffer MA, et al. A comparison of management patterns after acute myocardial infarction in Canada and the United States. N Engl J Med. 1993;328:779–784.PubMedCrossRefGoogle Scholar
  49. 49.
    Glick HA, Polsky D, Willke RJ, Alves WM, Kassel N, Schulman K. Comparison of the use of medical resources and outcomes in the treatment of aneurysmal subarachnoid hemorrhage between Canada and the US. Stroke. 1998;29:351–358.PubMedCrossRefGoogle Scholar
  50. 50.
    Fu Y, Chang WC, Mark D, et al. Canadian-American differences in the management of acute coronary syndromes in the GUSTO IIb trial: one-year follow-up of patients without ST-segment elevation. Circulation. 2000;102:1375–1381.PubMedCrossRefGoogle Scholar
  51. 51.
    Haraoui B, for the Subcommittee on Biologic Agents, Canadian Rheumatology Association. Position on the use of biologic agents for the treatment of rheumatoid arthritis. Available at: http://www.cra.ucalgary.ca/cral/announcements/CRA FinalPositionStatement.pdf. Accessed August 2003.Google Scholar
  52. 52.
    Ontario Drug Benefit Formulary. Available at: http://www.health.gov.on.ca/english/providers/program/drugs/odb_f_mn.html. Accessed August 2003.Google Scholar
  53. 53.
    Lewis SJ. Further disquiet on the guidelines front. CMAJ. 2001;165:180–181.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Canadian Medical Association Infobase: clinical practice guidelines. Available at: http://mdm.ca/cpgsnew/cpgs/index.asp. Accessed August 2003.Google Scholar
  55. 55.
    Graham ID, Beardall S, Carter AO, et al. What is the quality of drug therapy clinical practice guidelines in Canada. CMAJ. 2001;165:157–163.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Hunt RH, Thomson ABR. Canadian Helicobacter pylori Consensus Conference. Can J Gastroenterol. 1998;12:31–41.PubMedGoogle Scholar
  57. 57.
    Hunt RH, Fallone CA, Thomson ABR, for the Canadian Helicobacter Study Group. Canadian Helicobacter pylori consensus Conference update: infection in adults. Can J Gastroenterol. 1999;13:213–217.PubMedGoogle Scholar
  58. 58.
    Thomson AB, for the Canadian Helicobacter Study Group. Risks and benefits of Helicobacter pylori eradication: current status. Can J Gastroenterol. 2002;16:57–62.PubMedGoogle Scholar
  59. 59.
    Veldhuyzen van Zanten SJ, Sherman PM, Hunt RH, Helicobacter pylori: new developments and treatments, CMAJ. 1997;156:1565–1574.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Peterson WL, Graham DY, Marshall B, et al. Clarithromycin as monotherapy for eradication of Helicobacter pylori: a randomized, double-blind trial. Am J Gastroenterol. 1993;88:1860–1864.PubMedGoogle Scholar
  61. 61.
    Lind T, Veldhuyzen van Zanten SJ, Unge P, et al. Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I Study. Helicobacter. 1996;1:138–144.PubMedCrossRefGoogle Scholar
  62. 62.
    ICH Harmonised tripartite guideline: Preclinical safety evaluation of biotechnology-derived pharmaceuticals. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use, 16 July 1997. Available at: http://www.ich.org/pdfICH/s6.pdf.Accessed August 2003.Google Scholar
  63. 63.
    Kirby JT, Mutnick AH, Jones RN, Biedenbach DJ, Pfaller MA. Geographic variations in garenoxacin (BMS284756) activity tested against pathogens associated with skin and soft tissue infections: report from the SENTRY Antimicrobial Surveillance Program (2000). Diagn Microbiol Infect Dis. 2002;43:303–309.PubMedCrossRefGoogle Scholar
  64. 64.
    Diekema DJ, Pfaller MA, Schmitz FJ, et al. Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis. 2001;32(suppl 2):S114-S132.PubMedCrossRefGoogle Scholar
  65. 65.
    Gales AC, Jones RN, Turnidge J, Rennie R, Ramphal R. Characterization of Pseudomonas aeruginosa isolates: occurrence rates, antimicrobial susceptibility patterns, and molecular typing in the global SENTRY antimicrobials surveillance program, 1997–1999 Clin Infect Dis. 2001;32(suppl 2):S146-S155.PubMedCrossRefGoogle Scholar
  66. 66.
    Pfaller MA, Diekema DJ, Jones RN, et al. International surveillance of blood infections due to Candida species: frequency of occurrence and in vitro susceptibilities to fluconazole, ravuconazole, and voriconazole of isolates collected from 1997 through 1999 in the SENTRY antimicrobial surveillance program. J Clin Microbiol. 2001;39:3254–3259.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Meis J, Petron M, Bille J, Ellis D, Gibbs D. A global evaluation of the susceptibility of Candida species to fluconazole by disk diffusion. Diagn Microbiol Infect Dis. 2000;36:215–223.PubMedCrossRefGoogle Scholar
  68. 68.
    Liebowitz LD, Ashbee HR, Evan EGV, et al. A two-year global evaluation of the susceptibility of Canadida species to fluconazole by disk diffusion. Diagn Microbiol Infect Dis. 2001;40:27–33.PubMedCrossRefGoogle Scholar
  69. 69.
    Winokur PL, Canton R, Casellas J-M, Legakis N. Variations in the prevalence of strains expressing an extended-spectrum β-lactamase phenotype and characterization of isolates from Europe, the Americas, and the Western Pacific region. Clin Infect Dis. 2001;32(suppl 2):S94-S103.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2003

Authors and Affiliations

  1. 1.Center for Veterinary MedicineFood and Drug AdministrationRockville
  2. 2.McGilveray Pharmacon IncOntarioCanada

Personalised recommendations