Pharmaceutical Research

, Volume 13, Issue 10, pp 1427–1437 | Cite as

Design of Biological Equivalence Programs for Therapeutic Biotechnology Products in Clinical Development: A Perspective

  • Joyce Mordenti
  • Joy A. Cavagnaro
  • James D. Green


The determination of biological equivalence requires that studies are conducted to establish that two molecules, two formulations, or two dosing regimens, for example, are indistinguishable with respect to safety and efficacy profiles that have been previously established. The criteria that are used to establish biological equivalence will depend on the nature of the change (e.g., molecular, process, formulation), the stage of the development program, the duration of treatment, and the intended clinical indications. Key components of an equivalence program include chemical characterization, in vitro and in vivo bioactivity against reference material, pharmacokinetics, and safety. Special considerations for patient populations, endogenous concentrations, environmental factors, immunogenicity, assay methodology, biochemical identity, pharmacodynamic equivalence, and statistical methodology are discussed. In addition, the role of preclinical in vivo assessments is addressed. Specific case studies provide insight into the varied nature of approaches that are currently employed.

bioequivalence biotechnology products recombinant proteins pharmacokinetics pharmacodynamics efficacy immunogenicity safety 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    J. D. Green. In P. F. D'Arcy and D. W. G. Harron (eds.) Proceedings of the Third International Conference on Harmonization, Yokohama, 1995, Queen's University of Belfast Press, Northern Ireland, 1996, pp. 230–236.Google Scholar
  2. 2.
    R. Williams. (abstract). Bio-International '92. Conference on Bioavailability, Bioequivalence and Pharmacokinetic studies.Google Scholar
  3. 3.
    L. Z. Benet. In K. Midha and H. Blume (eds.), Bio-International. Bioavailability, bioequivalence, and Pharmacokinetics. Medpharm, Stuttgart, 1993. pp. 27–37.Google Scholar
  4. 4.
    V. Steinijans, D. Hauschke, and H. Jonkman. Clin. Pharmacokinet. 22:247–253 (1992).Google Scholar
  5. 5.
    H. Blume and K. Midha. Pharm. Res. 10:1806–1811 (1993).Google Scholar
  6. 6.
    Proceedings of the FDA bioequivalence hearings, Docket number 86N-0251, Washington, DC., September 29–October 1, 1986.Google Scholar
  7. 7.
    Report by the bioequivalence task force on recommendations from the bioequivalence hearings conducted by the Food and Drug Administration, 86N-0251, RPT00002, pp. 19–21, January 1988.Google Scholar
  8. 8.
    H. Blume and K. Midha (eds.). Bio-International 2. Bioavailability, Bioequivalence, and Pharmacokinetic Studies. Medpharm, Stuttgart, 1995.Google Scholar
  9. 9.
    A. Supersaxo, W. Hein, H. Gallati, and H. Steffen. Pharm. Res. 5:472–476 (1988).Google Scholar
  10. 10.
    A. Supersaxo, W. Hein, H. and Steffen. Pharm. Res. 7:167–169 (1990).Google Scholar
  11. 11.
    J. Kahn, J. D. Allan, T. Hodges, L. Kaplan, C. Arri, H. Fitch, A. Izu, J. Mordenti, S. Sherwin, J. Groopman, and P. Volberding. Annals of Internal Medicine 112:254–261 (1990).Google Scholar
  12. 12.
    W. Saal, H-J. Glowania, W. Hengst, and J. Happ. Fertility and Sterility 56:225–229 (1991).Google Scholar
  13. 13.
    J. Mordenti, S. A. Chen, and B. Ferraiolo. In A. H. C. Kung, R. A. Baughman, and J. W. Larrick (eds.), Protein Therapeutics: Pharmacokinetics and Pharmacodynamics., W. H. Freeman and company, New York, 1993, pp. 187–199.Google Scholar
  14. 14.
    S. Beshyah, V. Anyaoku, R. Niththyananthan, P. Sharp, and D. Johnston. Clin. Endocrinol. 35:409–412 (1991).Google Scholar
  15. 15.
    T. Laursen, J. Jorgensen, and J. Christiansen. Clin. Endocrinol. 40:373–378 (1994).Google Scholar
  16. 16.
    S. Blunt, R. Clayton, and W. Butt. Clinical Endocrinology 25:589–596 (1986).Google Scholar
  17. 17.
    P. Hildebrandt, L. Sestoft, and S. Nielsen. Diabetes Care 6:459–462 (1983).Google Scholar
  18. 18.
    J. Thow and P. Home. Br. Med. Journal 301:3–4 (1990).Google Scholar
  19. 19.
    H. Kirchner, A. Korfer, P. Evers, M. M. Szamel, J. Knuver-Hopf, H. Mohr, C. R. Franks, U. Pohl, K. Resch, M. Hadam, H. Poliwoda, and J. Atzpodien. Cancer 67:1862–1864 (1991).Google Scholar
  20. 20.
    K. Lundin, L. Berger, F. Blomberg, and P. Wilton. Acta Paediatr. Scand. (suppl). 372:167–168 (1991).Google Scholar
  21. 21.
    C. M. Zwickl, K. S. Cocke, R. N. Tamura, L. M. Holzhausen, G. T. Brophy, P. H. Bick, and D. Wierda. Fundamental and Applied Toxicology 16:275–287 (1991).Google Scholar
  22. 22.
    R. Dillman. Antibody Immunoconj. Radiopharm. 3:1–15. (1990).Google Scholar
  23. 23.
    E. Muchmore, M. Milewski, A. Varki, and S. Diaz. J. Biol. Chem. 264:20216–20223 (1989).Google Scholar
  24. 24.
    Y. Kozutsumi, T. Kawano, H. Kawasaki, K. Suzuki, T. Yamakawa, and A. Suzuki. J. Biochem. 110:429–435 (1991).Google Scholar
  25. 25.
    V. Shah, K. Midha, S. Dighe, I. McGilveray, J. Skelly, A. Yacobi, T. Layloff, C. Viswanathan, C. E. Cook, R. McDowall, K. Pittman, and S. Spector. Pharm. Res. 9:588–592 (1992).Google Scholar
  26. 26.
    L. Boscato and M. Stuart. Clin. Chem. 34:27–33 (1988).Google Scholar
  27. 27.
    T. Weber, K. Kapyaho, and P. Tanner. Scand. J. Clin. Lab. Invest. 50, Suppl 201:77–82 (1990).Google Scholar
  28. 28.
    A. Chen, D. Baker, and B. Ferraiolo. In P. Garzone, W. Colburn, and M. Mokotoff (eds.), Peptides, Peptoids, and Proteins. Harvey Whitney Books, Cincinnati, OH, 1991, pp. 54–71.Google Scholar
  29. 29.
    D. Eaton, P. Hass, L. Riddle, J. Mather, M. Wiebe, T. Gregory, and G. Vehar. J. Bio. Chem. 262:3285–90 (1987).Google Scholar
  30. 30.
    R. Baughman, Jr. In B. Sobel, D. Collen, E. Grossbard (eds.) Tissue Plasminogen Activator in Thrombolytic Therapy, Marcel Dekker, Inc., New York, 1987, pp. 41–53.Google Scholar
  31. 31.
    S. Gauny, J. Andya, J. Thomson, J. Young, and J. Winkelhake. Hum. Antibod. Hybridomas 2:33–38 (1991).Google Scholar
  32. 32.
    G. Ashwell and A. Morell. In A. Meister (ed.) Advances in Enzymology and Related Areus of Molecular Biology, John Wiley and Sons, New York, 1974, pp. 99–128.Google Scholar
  33. 33.
    G. Ashwell and J. Harford. Ann. Rev. Biochem. 51:531–54 (1982).Google Scholar
  34. 34.
    D. Barbeau. Controlled Release Newsletter, Controlled Release Society, Inc., Deerfield, IL, July 1990, pp. 6–8.Google Scholar
  35. 35.
    M. Fukuda, H. Sasaki, L. Lopez, and M. Fukuda. Blood 73:84–89 (1989).Google Scholar
  36. 36.
    W. Blum and D. Gupta. J. Endocr. 105:29–37 (1985).Google Scholar
  37. 37.
    T. Sareneva, K. Cantell, L. Pyhala, J. Pirhonen, and I. Julkunen. J. Interferon Res. 13:267–269 (1993).Google Scholar
  38. 38.
    J. Henkin, D. Dudlak, D. Beebe, and L. Sennello. Thrombosis Research 63:215–225 (1991).Google Scholar
  39. 39.
    M. Mattes. J. Nat. Cancer Inst. 79:855–863 (1987).Google Scholar
  40. 40.
    M. Manning, K. Patel, and R. Borchardt. Pharm. Res. 6:903–917 (1989).Google Scholar
  41. 41.
    J. Cleland, M. Powell, and S. Shire. Crit. Rev. Therap. Drug Carrier Systems 10:3007–377 (1993).Google Scholar
  42. 42.
    S. Li, C. Schoneich, and R. Borchardt. Biotech. and Bioengineer. 48:490–500 (1995b).Google Scholar
  43. 43.
    C. Schmelzer, L. Burton, W.-P. Chan, E. Martin, C. Gorman, E. Canova-Davis, V. Ling, M. Slikowski, G. McCray, J. Briggs, T. Nguyen, and G. Polastri. J. Neurochem. 59:1675–1683, (1992).Google Scholar
  44. 44.
    C. Drinkwater, P. Barker, U. Suter, and E. Shooter. J. Biol. Chem. 268:23202–207 (1993).Google Scholar
  45. 45.
    A. Shih, G. Laramee, C. Schmelzer, L. Burton, and J. Winslow. J. Biol. Chem. 269:27679–686 (1994).Google Scholar
  46. 46.
    R. Baxter and J. Martin. Biochem. Biophys. Res. Commun. 147:408–415 (1987).Google Scholar
  47. 47.
    A. Lord, S. Bastian, L. Read, P. Walton, and F. Ballard. J. Endocrin. 140:475–482 (1994).Google Scholar
  48. 48.
    A. Rescigno. Pharm. Res. 9:925–928 (1992).Google Scholar
  49. 49.
    W. Hauck and S. Anderson. J. Pharmacokin. Biopharm. 22:551–564 (1994).Google Scholar
  50. 50.
    S. Chen, A. Izu, J. Mordenti, and A. Rescigno. Am. J. Therapeutics 2:190–195 (1995).Google Scholar
  51. 51.
    A. L. Gould. J. Pharmacokin. Biopharm. 23:57–86 (1995).Google Scholar
  52. 52.
    L. Endrenyi and P. Al-Shaikh. Pharm. Res. 12:1856–1864 (1995).Google Scholar
  53. 53.
    A. W. Boddy, F. C. Snikeris, R. O. Kringle, G. C. G. Wei, J. A. Oppermann, and K. K. Midha. Pharm. Res. 12:1865–1868 (1995).Google Scholar
  54. 54.
    R. P. Basson, B. J. Cerimele, K. A. DeSante, and D. C. Howey. Pharm. Res. 13:324–328 (1996).Google Scholar
  55. 55.
    T. N. Tozer, F. Y. Bois, W. W. Hauck, M. L. Chen, and R. L. Williams. Pharm. Res. 13:453–456 (1996).Google Scholar
  56. 56.
    R. G. Buice, V. S. Subramanian, K. L. Duchin, and S. Uko-Nne. Pharm. Res. 13: 1109–1115 (1996).Google Scholar
  57. 57.
    H. S. Pentikis, J. D. Henderson, N. L. Tran, and T. M. Ludden. Pharm. Res. 13: 1116–1121 (1996).Google Scholar
  58. 58.
    R. Schall and R. Williams. J. Pharmacokin. Biopharm. 24:133–149 (1996).Google Scholar
  59. 59.
    L. Z. Benet and J. E. Goyan. Pharmacotherapy 15:433–440 (1995).Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Joyce Mordenti
    • 1
  • Joy A. Cavagnaro
    • 2
  • James D. Green
    • 1
  1. 1.Experimental TherapeuticsGenentech, IncorporatedSouth San Francisco
  2. 2.United States Food and Drug AdministrationCenter for Biologies Evaluation and Research, HFM-5Rockville

Personalised recommendations