Advertisement

The AAPS Journal

, Volume 14, Issue 4, pp 915–924 | Cite as

Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug Administration

  • Barbara M. DavitEmail author
  • Mei-Ling Chen
  • Dale P. Conner
  • Sam H. Haidar
  • Stephanie Kim
  • Christina H. Lee
  • Robert A. Lionberger
  • Fairouz T. Makhlouf
  • Patrick E. Nwakama
  • Devvrat T. Patel
  • Donald J. Schuirmann
  • Lawrence X. Yu
Review Article Theme: Facilitating Oral Product Development and Reducing Regulatory Burden through Novel Approaches to Assess Bioavailability/B

Abstract

Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration’s Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

KEY WORDS

bioequivalence generic drugs highly variable drugs reference-scaled average bioequivalence US Food and Drug Administration 

Notes

ACKNOWLEDGMENTS

The authors thank Hoainhon Nguyen Caramenico, Parthapratim Chandaroy, Svetlana Cherstniakova, Li Gong, Heather Lim, Anitha Palamakula, and Xiaofai Wang for contributing data to the examples described throughout the manuscript. The opinions stated in this article represent those of the authors and do not necessarily represent the official position of the US Food and Drug Administration.

REFERENCES

  1. 1.
    Federal Food, Drug, and Cosmetic Act, Chapter V, Subchapter A, Drugs and Devices Section 355(j)(8)(B)(i).Google Scholar
  2. 2.
    Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15:657–80.PubMedGoogle Scholar
  3. 3.
    Westlake WJ. Bioequivalence testing: a need to rethink. Biometrics. 1981;37:589–94.CrossRefGoogle Scholar
  4. 4.
    Blume HH, Midha KK. Bio-International 92, conference on bioavailability, bioequivalence, and pharmacokinetic studies. J Pharm Sci. 1993;82:1186–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Shah VP, Yacobi A, Barr WH, Benet LZ, Breimer D, et al. Evaluation of orally administered highly variable drugs and drug formulations. Pharm Res. 1996;13:1590–4.PubMedCrossRefGoogle Scholar
  6. 6.
    Davit BM, Conner DP, Fabian-Fritsch B, Haidar SH, Jiang X, et al. Highly variable drugs: observations from bioequivalence data submitted to the FDA for new generic drug applications. AAPSJ. 2008;10:148–56.PubMedCrossRefGoogle Scholar
  7. 7.
    FDA Guidance for Industry, statistical approaches to establishing bioequivalence. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. 2001. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070244.pdf. Accessed 23 Jan 2012.
  8. 8.
    Patterson SD, Zariffa NMD, Montague TH, Howland K. Non-traditional study designs to demonstrate average bioequivalence for highly variable drug products. Eur J Clin Pharmacol. 2001;57:663–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Phillips KF. Power of the two one-sided tests procedure in bioequivalence. J Pharmacokinet Biopharm. 1990;18:137–44.PubMedGoogle Scholar
  10. 10.
    Benet L. Why highly variable drugs are safer. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 14 2004. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.htm. Accessed 23 Jan 2012.
  11. 11.
    Cook JA, Davit BM, Polli JE. Impact of Biopharmaceutics Classification System-based biowaivers. Mol Pharmaceutics. 2010;7:1539–44.CrossRefGoogle Scholar
  12. 12.
    Amidon GL. Sources of variability: physicochemical and gastrointestinal. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 14 2004. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.htm. Accessed 23 Jan 2012.
  13. 13.
    Conner DP. Bioequivalence methods for highly variable drugs and drug products. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Aug 5 2009. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM179891.pdf. Accessed 23 Jan 2012.
  14. 14.
    Diliberti CE. Why bioequivalence of highly variable drugs is an issue. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 14 2004. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.htm. Accessed 23 Jan 2012.
  15. 15.
    Tothfalusi L, Endrenyi L, Arieta AG. Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence. Clin Pharmacokinet. 2009;48:725–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Endrenyi L. Bioequivalence methods for highly variable drugs. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 14 2004 http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.htm. Accessed 23 Jan 2012.
  17. 17.
    Midha KK, Rawson MJ, Hubbard JW. The bioequivalence of highly variable drugs and drug products. Int J Clin Pharmacol Ther. 2005;43:485–98.PubMedGoogle Scholar
  18. 18.
    Tsang YC, Pop R, Gordon P, Hems J, Spino M. High variability in drug pharmacokinetic complicates determination of bioequivalence: experience with verapamil. Pharm Res. 1996;13:846–50.PubMedCrossRefGoogle Scholar
  19. 19.
    Blume H, McGilvery I, Midha K. Bio-International 94 conference on bioavailability, bioequivalence and pharmacokinetic studies. Eur J Pharm Sci. 1995;3:113–24.CrossRefGoogle Scholar
  20. 20.
    Blume HH. “One-size-fits-all” in bioavailability and bioequivalence testing. Int J Clin Pharmacol Ther. 2009;47:419–20.PubMedGoogle Scholar
  21. 21.
    Yu LX. Bioequivalence of highly variable drugs: issues and challenges. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology Meeting Transcript. Apr 14 2004. US Food and Drug Administration Dockets. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.htm. Accessed 23 Jan 2012.
  22. 22.
    Executive Secretary, Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Summary meeting minutes. In: FDA Advisory Committees meeting materials. US Food and Drug Administration Dockets. Apr 14 2004. http://www.fda.gov/ohrms/dockets/ac/04/minutes/4034M1.htm. Accessed 23 Jan 2012.
  23. 23.
    Haidar SH. FDA perspective. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript . US Food and Drug Administration Dockets. Apr 14 2004. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.htm. Accessed 23 Jan 2012.
  24. 24.
    Midha K. Bioequivalence of highly variable drugs. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 6 2006. http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4241t2-01.pdf. Accessed 23 Jan 2012.
  25. 25.
    Haidar SH. Evaluation of a scaling approach for highly variable drugs. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 6 2006. Accessed 23 Jan 2012.Google Scholar
  26. 26.
    Davit BM. FDA’s proposal. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 6 2006. http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4241t2-01.pdf. Accessed 23 Jan 2012.
  27. 27.
    Endrenyi L. Some issues on the determination of bioequivalence for highly variable drugs. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 6 2006. http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4241t2-01.pdf. Accessed 23 Jan 2012.
  28. 28.
    Benet L. Therapeutic considerations of highly variable drugs. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Apr 6 2006. http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4241t2-01.pdf. Accessed 23 Jan 2012.
  29. 29.
    Executive Secretary, Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Summary meeting minutes. In: FDA Advisory Committees meeting materials. US Food and Drug Administration Dockets. Apr 6 2006. http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4241m2.pdf. Accessed 23 Jan 2012.
  30. 30.
    Haidar SH, Davit BM, Chen M-L, Conner D, Lee LM, et al. Bioequivalence approaches for highly variable drugs and drug products. Pharm Res. 2008;25:237–41.PubMedCrossRefGoogle Scholar
  31. 31.
    Hauck WH, Hyslop T, Chen M-L, Patnaik R, Williams RL. Subject-by-formulation interaction in bioequivalence: conceptual and statistical terms. Pharm Res. 2000;17:375–80.PubMedCrossRefGoogle Scholar
  32. 32.
    Patnaik RN, Lesko LJ, Chen M-L, Williams RL. Individual bioequivalence: new concepts in the statistical assessment of bioequivalence metrics. Clin Pharmacokinet. 1997;33:1–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Chen M-L. Background and concepts of individual bioequivalence. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript .US Food and Drug Administration Dockets. Nov 29 2001. http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2_03_Afternoon_Session.pdf. Accessed 23 Jan 2012.
  34. 34.
    Patnaik R. Results from replicate design studies in ANDAs. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Nov 29 2001. http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2_03_Afternoon_Session.pdf. Accessed 23 Jan 2012.
  35. 35.
    Benet L. Individual bioequivalence: have the opinions of the scientific community changed? In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Nov 29 2001. http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2_03_Afternoon_Session.pdf. Accessed 23 Jan 2012.
  36. 36.
    Executive Secretary, Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Briefing document, bioequivalence criteria research program. In: FDA Advisory Committee Meeting Materials. US Food and Drug Administration Dockets. Nov. 29 2001. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3804b2_08_Bioequiv%20Criteria.pdf. Accessed 23 Jan 2012.
  37. 37.
    Chen M-L. Results from replicate design studies in NDAs and FDA database. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript . US Food and Drug Administration Dockets. Nov 29 2001. http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2_03_Afternoon_Session.pdf. Accessed 23 Jan 2012.
  38. 38.
    FDA Guidance for Industry, bioavailability and bioequivalence studies for orally administered drug products: general considerations. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070124.pdf. Accessed 23 Jan 2012.
  39. 39.
    Members of the FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Discussion of individual bioequivalence issues. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Nov 29 2001. http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2_03_Afternoon_Session.pdf. Accessed 23 Jan 2012.
  40. 40.
    FDA Draft Guidance for Industry, bioequivalence recommendations for progesterone oral capsules. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, Silver Spring. 2011. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM209294.pdf. Accessed 23 Jan 2012.
  41. 41.
    Davit BM, Conner DP. The United States of America. In: Kanfer I, Shargel L, editors. Generic drug product development: international regulatory requirements for bioequivalence. New York: Informa Healthcare; 2010. p. 254–81.Google Scholar
  42. 42.
    Karalis V, Sylmillides M, Macheras P. Bioequivalence of highly variable drugs: a comparison of the newly-proposed regulatory approaches by FDA and EMA. Pharm Res. 2011. doi: 10.1007/s11095-011-0651-y.
  43. 43.
    Haidar SH, Makhlouf F, Schuirmann DJ, Hyslop T, Davit B, et al. Evaluation of a scaling approach for the bioequivalence of highly variable drugs. AAPSJ. 2008;10:450–4.PubMedCrossRefGoogle Scholar
  44. 44.
    Endrenyi L, Tothfalusi L. Regulatory conditions for the determination of bioequivalence of highly variable drugs. J Pharm Pharmaceut Sci. 2009;12:138–49.Google Scholar
  45. 45.
    Tothfalusi L, Endrenyi L. Sample size for designing bioequivalence studies for highly variable drugs. J Pharm Pharmaceut Sci. 2011;15:73–84.Google Scholar
  46. 46.
    Health Canada Guidance for Industry, conduct and analysis of bioavailability and bioequivalence studies—part A: oral dosage formulations used for systemic effects. Therapeutic Products Directorate, Canada Minister of Health, Ottawa. 1997. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/bio-a-eng.pdf. Accessed 23 Jan 2012.
  47. 47.
    Howe WG. Approximate confidence limits on the mean of X + Y where X and Y are two tabled independent variables. J Amer Statist Assoc. 1974;69:789–94.Google Scholar
  48. 48.
    Liu Q, Davit BM, Cherstniakova SA, Dandamudi S, Walters JF, et al. Common deficiencies with bioequivalence submissions in abbreviated new drug applications assessed by the FDA. AAPSJ. 2011. doi: 10.1208/s12248-011-9312-7.
  49. 49.
    US Food and Drug Administration, Department of Health and Human Services. Final rule, 21 CFR Parts 314 and 320, Docket No. FDA-2003-N-0209. Fed Regist 2009; 74:2849–62.Google Scholar
  50. 50.
    FDA Guidance for Industry, submission of summary bioequivalence data for abbreviated new drug application. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, Silver Spring. 2011. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM134846.pdf. Accessed 23 Jan 2012.
  51. 51.
    US Food and Drug Administration, Department of Health and Human Services. Bioequivalence. In: Title 21 Code of Federal Regulations, Food and Drugs. Office of the Federal Register National Archives and Records Administration. Washington; 2011. p. 132–3.Google Scholar
  52. 52.
    European Medicines Agency. Guideline on the investigation of bioequivalence. 2010. http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf. Accessed 23 Jan 2012.
  53. 53.
    Morais JA, Lobato Mdo R. The new European Medicines Agency Guideline on the investigation of bioequivalence. Basic Clin Pharmacol Toxicol. 2010;106:251–60.CrossRefGoogle Scholar
  54. 54.
    Davit B. Bioequivalence of highly variable drugs case studies. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology Meeting Transcript. US Food and Drug Administration Dockets. Apr 16 2004. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4034T2.htm. Accessed 23 Jan 2012.
  55. 55.
    Davit BM, Nwakama PE, Buehler GJ, Conner DP, Haidar SH, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother. 2009;43:1583–97.PubMedCrossRefGoogle Scholar
  56. 56.
    Walker RB, Kanfer I, Skinner MF. Bioequivalence assessment of generic products: an innovative South African approach. Clin Res Regul Affair. 2006;23:11–20.CrossRefGoogle Scholar
  57. 57.
    Medicines Control Council. Human medicines guideline, biostudies. MCC Guidelines and Forms. South African Registrar of Medicines. Capetown. 2007. http://www.mccza.com/dynamism/default_dynamic.asp?grpID=30&doc=dynamic_generated_page.asp&categID=177&groupID=30. Accessed 23 Jan 2012.
  58. 58.
    Davit B. FDA Proposal for bioequivalence of generic narrow therapeutic index drug products. In: FDA Advisory Committee for Pharmaceutical Sciences and Clinical Pharmacology meeting transcript. US Food and Drug Administration Dockets. Jul 26 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM272112.pdf. Accessed 23 Jan 2012.

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Barbara M. Davit
    • 1
    Email author
  • Mei-Ling Chen
    • 2
  • Dale P. Conner
    • 1
  • Sam H. Haidar
    • 3
  • Stephanie Kim
    • 4
  • Christina H. Lee
    • 1
  • Robert A. Lionberger
    • 4
  • Fairouz T. Makhlouf
    • 5
  • Patrick E. Nwakama
    • 1
  • Devvrat T. Patel
    • 1
  • Donald J. Schuirmann
    • 6
  • Lawrence X. Yu
    • 4
  1. 1.Office of Generic Drugs, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationRockvilleUSA
  2. 2.Office of Pharmaceutical Sciences, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  3. 3.Office of Compliance, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  4. 4.Office of Generic Drugs, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationRockvilleUSA
  5. 5.Office of Biostatistics, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationRockvilleUSA
  6. 6.Office of Biostatistics, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA

Personalised recommendations