On Evaluation of Bioequivalence for Highly Variable Drugs

변이가 큰 약물의 생물학적 동등성 평가에 관한 연구

  • Received : 20110900
  • Accepted : 20111100
  • Published : 2011.12.31


This paper reviews the definition of highly variable drug(HVD), the present regulatory recommendations and the approaches proposed in the literature to deal with the bioequivalence issues of HVD. The concept and the statistical approach of scaled average bioequivalence(SABE) is introduced and discussed with the current regulatory methods. The recommendations for SABE approach are proposed and the further study topics related to HVDs are also presented.


Bioequivalence;highly variable drugs;scaled average bioequivalence


  1. 박상규, 남봉현, 정윤노, 이재영, 정규진 (2010). 생물학적 동등성 시험의 추가시험에 대한 통계적 고찰, 한국통계학회논문집, 17, 107-115.
  2. 박상규, 임남규, 이재영, 김병천 (2005). $2{\times}2$ 교차설계법에서 모집단 생물학적 동등성 검정방법 비교, 응용통계연구, 18, 1-13.
  3. 식품의약품안전청 (2010). 생물학적동등성시험기준 (고시 제2010-43호).
  4. 정규진, 박상규, 김관엽 (2011). 공변량을 고려한 $2{\times}2$ 교차설계법에 평균 생물학적 동등성 평가, 응용통계연구, 24, 161-167.
  5. 정규진, 박상규, 우화형 (2009). $2{\times}2$ 생물학적 동등성 시험에서 이상치 검출을 위한 통계적 방법, 한국통계학회논문집, 16, 745-751.
  6. 정규진, 임남규, 박상규 (2010). $3{\times}2$ 교차설계법에서 개인 생물학적 동등성 검정, 응용통계연구, 21, 139-150.
  7. Arieta, A. G. (2006). Highly variable drugs. Understanding Bioequivalence of Generic Drugs, A Worldwide Review, Monte Carlo.
  8. Benet, L. (1993). Bioavailability and bioequivalence: Definitions and difficulties in acceptance criteria. In Midha KK. Blume HH, editors, Bio-International 92: bioavailability, bioequivalence and pharmacokinetics, Medpharm, Stuttgart, 27-35.
  9. Benet, L. (1999). Individual bioequivalence: An overview, AAPS International Workshop on Individual Bioequivalence: Realities and Implementation, Montreal, Quebec.
  10. Benet, L. (2006). Why highly variable drugs are safer. Meeting of FDA Committee for Pharmaceutical Science, http:// 3/17/2011).
  11. Bio-international (1992). Conference on Bioavailability, Bioequivalence and Pharmacokinetic Studies, Bad Homburg, Germany, May 20-22.
  12. Blume, H. H. (2010). Highly variable drugs: reasons for high variability and solutions to overcome BE problems, Modern Strategies for the Development of Generic Drugs 20th AGAH Annual Meeting, Hamburg, - HV D_AGAH_2010_Einleitung1.pdf (assessed 3/17/2011).
  13. Boddy, A. W., Snikeris, F. C., Kringle, R. O., Wei, G. C. G., Oppermann, J. A. and Midha, K. K. (1995). An approach for widening the bioequivalence acceptance limits in the case of highly variable drugs, Pharmaceutical Research, 12, 1865-1868.
  14. Chow, S. C. and Liu, J. P. (2008). Design and Analysis of Bioavailability and Bioequivalence Studies, 3rd edition, CRC press.
  15. Chow, S. C., Shao, J. and Wang, H. (2002). Individual bioequivalence testing under $2{\times}3$ designs, Statistics in Medicine, 21, 629-648.
  16. Chow, S. C. and Tse, S. K. (1990). Outliers detection in bioavailability/bioequivalence studies, Statistics in Medicine, 9, 549-558.
  17. Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences, Lawrence Erlbaum Associates, Hillsdale, New Jersey.
  18. Davit, B. M. (2004). Highly variable drugs: FDA case studies. Advisory Committee for Pharmaceutical Sciences. Office of Generic Drugs. US FDA Center for Drug Evaluation and Research, (assessed 3/17/2011)
  19. Davit, B. M., Conner, D. P., Fabian-Fritsch, B., Haidar, S. H., Jiang, X., Patel, D. T., Seo, P. R. H., Suh, K., Thompson, C. L. and Yu, L. X. (2008). Highly variable drugs: Observations from bioequivalence data submitted to the FDA for new generic drug applications, The AAPS Journal, 10, 148-156.
  20. DiLiberti, C. E. (2007). BE for Highly Variable Drugs an Industry Perspective, Barr Laboratories, Inc. (assessed 3/17/2011).
  21. EMEA, European Medicines Agency, Committee for Medicinal Products for Human Use. (2008). Draft Guideline on the Investigation of Bioequivalence, London.
  22. EMEA, European Medicines Agency, Committee for Medicinal Products for Human Use. (2010). Draft Guideline on the Investigation of Bioequivalence, London.
  23. Endrenyi, L., Fritsch, S. and Van, W. (1991). Cmax/AUC is a clearer measure than Cmax for absorption rates in investigations of bioequivalence, International Journal of Clinical Pharmacology, 29, 394-399.
  24. Endrenyi, L. and Tothfalusi, L. (2009). Regulatory conditions for the determination of bioequivalence of highly variable drugs, Journal of the Pharmaceutical Sciences, 12, 138-149.
  25. Haidar, S. H., Davit, B., Chen, M. L., Conner, D., Lee, L., Li, Q. H., Lionberger, R., Makhlouf, F., Patel, D., Schuirmann, D. J. and Yu, L. X. (2008a). Bioequivalence approaches for highly variable drugs and drug products, Pharmaceutical Research, 25, 237-241.
  26. Haidar, S. H., Makhiouf, F., Schuirmann, D. J., Hyslop, T., Davit, B., Conner, D. and Yu, L. X. (2008b). Evaluation of a scaling approach for the bioequivalence of highly variable drugs, AAPS Journal, 10, 450-454.
  27. Health Canada, Ministry of Health. (1992). Guidance for industry: Conduct and analysis of bioavailability and bioequivalence studies. Part A: oral dosage formulations used for systemic effects, Ottawa, Ontario.
  28. Health Canada. Therapeutic Products Directorate (2003). Discussion paper on 'Bioequivalence requirements - highly variable drugs and highly variable drug products: issues and options'. Expert Advisory Committe on Bioavailability and Bioequivalence (EAC-BB) Meeting.
  29. Howe, W. G. (1974). Approximate confidence limits on the mean of X + Y where X and Y are two tabled independent random variables, Journal of the American Statistical Association, 69, 789-794.
  30. Hyslop, T., Hsuan, F. and Holder, D. J. (2000). A small sample confidence interval approach to assess individual bioequivalence, Statistics in Medicine, 19, 2885-2897.<2885::AID-SIM553>3.0.CO;2-H
  31. Johnson, N. L. and Kotz, S. (1970). Continuous Univariate Distributions-2, Houghton Mifflin Company, Boston.
  32. Karalis, V., Macheras, P. and Symillides, M. (2005). Geometric mean ratio-dependent scaled bioequivalence limits with leveling-off properties, European Journal of the Pharmaceutical Sciences, 26, 54-61.
  33. Karalis, V., Symillides, M. and Macheras, P. (2004). Novel scaled average bioequivalence limits based on GMR and variability considerations, Pharmaceutical Research, 21, 1933-1942.
  34. Kytariolos, J., Karalis, V., Macheras, P. and Symillides, M. (2006). Novel scaled bioequivalence limits with leveling-off properties, Pharmaceutical Research, 23, 2657-2664.
  35. Liu, J. P. and Weng, C. S. (1991). Detection of outlying data in bioavailability/bioequivalence studies, Statistics in Medicine, 10, 1375-1389.
  36. Midha, K. K. (2006). Highly Variable Drugs & Drug Products-A Rationale for Solution of a Persistent Problem, (assessed 11/3/2010).
  37. Patterson, S. D., Zariffa, N. M. D., Montague, T. H. and Howland, K. (2001). Non-traditional study designs to demonstrate average bioequivalence for highly variable drug products, European Journal of Pharmaceutical Sciences, 57, 663-670.
  38. Ramsay, T. and Elkum, N. (2005). A comparison of four different methods for outlier detection in bioequivalence studies, Journal of Biopharmaceutical Statistics, 15, 43-52.
  39. Schall, R. and Luus, H. G. (1993). On population and individual bioequivalence, Statistics in Medicine, 12, 1109-1124.
  40. Scheiner, L. B. (1992). Bioequivalence revisited, Statistics in Medicine, 11, 1777-1788.
  41. Schuirmann, D. J. (1987). A comparison of two one-sided test procedures and the power approach for assessing the equivalence of average bioavailability, Journal of Pharmacokinetics and Biopharmaceutics, 15, 657-680.
  42. Tanguay, M., Potvin, D., Haddad, J., Lavigne, J., Marier, J. F., DiMarco, M. and Ducharme, M. P. (2002). When will a drug formulation pass or fail bioequivalence criteria? Experience from 1200 studies, AAPS Pharmaceutical Science, 4, Abstract R6193.
  43. Tothfalusi, L. and Endrenyi, L. (2003). Limits for the scaled average bioequivalence of highly variable drugs and drug products, Pharmaceutical Research, 20, 382-389.
  44. Tothfalusi, L., Endrenyi, L. and Garcia Arieta, A. (2009). Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence, Clinical Pharmacokinetics, 48-11, 725-743.
  45. US FDA Center for Drug Evaluation and Research. (2001). Statistical Approaches to Establishing Bioequivalence: Guidance for Industry, Rockville, Maryland.
  46. US Government. (2009). 21 CFR Part320 - Code of Federal Regulations Title 21-Food and Drugs, Part 320-Bioavailability and Bioequivalence Requirements. FDA Home > Medical Devices > Databases에 수록, 2009년 4월 1일 최종수정.
  47. Wang, W. and Chow, S. C. (2003). Examining outlying subjects and outlying records in bioequivalence trials, Journal of Biopharmaceutical Statistics, 13, 43-56.
  48. Wellek, S. (2003). Testing Statistical Hypotheses of Equivalence, Chapman & Hall, London.

Cited by

  1. Assessing bioequivalence for highly variable drugs based on 3×3 crossover designs vol.29, pp.2, 2016,
  2. Statistical procedures of add-on trials for bioequivalence in 2×k crossover designs vol.25, pp.6, 2014,
  3. Some Statistical Considerations on 2×k Crossover Designs for Bioequivalence Trial vol.26, pp.4, 2013,