Potential Factors Influencing Regional Differences and Similarities in Multiregional Clinical Trials


In a multiregional clinical trial (MRCT), determining whether regional differences occur by chance or whether they are due to differences in pharmacokinetics, pharmacodynamics, or other prognostic factors is important to accurately evaluate the true efficacy of a drug in patients of each region. The general probability that regional results will differ from total results has been studied using statistical simulation. Consideration from the pharmacokinetic perspective is necessary as well to investigate the causes of regional differences. Patient characteristics may vary among regions, and differences in medical environment such as commonly used drugs and treatment guidelines can affect regional efficacy and safety results. Moreover, bias may be introduced in the data collected due to differences such as in diagnosis, assessment criteria, and reporting conditions. In this research, the factors and mechanism potentially influencing results by region in MRCT are examined, referring to the results of MRCTs already published.

This is a preview of subscription content, access via your institution.


  1. 1.

    MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999;353:2001–2007.

    Article  Google Scholar 

  2. 2.

    Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure. JAMA. 2000;283:1295–1302.

    CAS  Article  Google Scholar 

  3. 3.

    Wedel H, DeMets D, Deedwania P, et al. Challenges of subgroup analyses in multinational clinical trials: experiences from the MERIT-HF trial. Am Heart J. 2001;142:502–511.

    CAS  Article  Google Scholar 

  4. 4.

    Anello C, O’Neill RT, Dubey S. Multicentre trials: a US regulatory perspective. Stat Methods Med Res. 2005;14:303–318.

    Article  Google Scholar 

  5. 5.

    International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonized Tripartite Guideline E5 on Ethnic Factors in the Acceptability of Foreign Clinical Data. 1998. https://doi.org/www.ich.org/products/guidelines.html.

  6. 6.

    Losartan Review Report. Pharmaceuticals and Medical Devices Agency; 2006. https://doi.org/www.info.pmda.go.jp/shinyaku/P200600021/63015300_21000AMZ00678_Q101_1.pdf.

  7. 7.

    Brenner BM, Cooper ME, Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–869.

    CAS  Article  Google Scholar 

  8. 8.

    Tolterodine Review Report. Pharmaceuticals and Medical Devices Agency; 2006. https://doi.org/www.info.pmda.go.jp/shinyaku/P200600014/40007900_21800AMY10088_Q101_1.pdf.

  9. 9.

    Homma Y, Paick JS, Lee JG, et al. Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: a randomized, placebo-controlled trial. Br J Urol Int. 2003;92:741–747.

    CAS  Article  Google Scholar 

  10. 10.

    Tadalafil Review Report. Pharmaceuticals and Medical Devices Agency; 2009. https://doi.org/www.info.pmda.go.jp/shinyaku/P200900050/530471000_22100AMX02266000_A100_1.pdf.

  11. 11.

    Marschner IC. Regional differences in multinational clinical trials: anticipating chance variation. Clin Trials. 2010;7:147–156.

    Article  Google Scholar 

  12. 12.

    Ministry of Health, Labor and Welfare. Basic Principles on Global Clinical Trials. 2007. https://doi.org/www.pmda.go.jp/operations/notice/2007/file/0928010-e.pdf.

  13. 13.

    Flockhart DA. Drug interactions and the cytochrome P450 system: the role of cytochrome P450 2C19. Clin Pharmacokinet. 1995;29(suppl 1):45–52.

    CAS  Article  Google Scholar 

  14. 14.

    World Health Organization. International Society of Hypertension guidelines for the management of Hypertension. J Hypertens. 1999;17:151–183.

    Google Scholar 

  15. 15.

    Kawai N, Chuang-Stein C, Komiyama O, et al. An approach to rationalize partitioning sample size into individual regions in a multiregional trial. Drug Information Journal. 2007;42:139–147.

    Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Masahiko Ohishi PhD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ohishi, M. Potential Factors Influencing Regional Differences and Similarities in Multiregional Clinical Trials. Ther Innov Regul Sci 46, 565–572 (2012). https://doi.org/10.1177/0092861512443747

Download citation


  • multiregional clinical trials
  • regional differences
  • potential factors of regional differences