Bioequivalence for highly variable drugs: regulatory agreements, disagreements, and harmonization
- 290 Downloads
Regulatory authorities introduced procedures in the last decade for evaluating the bioequivalence (BE) for highly variable drugs. These approaches are similar in principle but differ in details. For example, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend differing regulatory constants. The constant suggested by FDA results in discontinuity of the BE limits around the switching variation at 30% observed within-subject variation of the reference product. The regulatory constant of EMA does not have these problems. The Type I error reaches 6–7% around the switching variation with the EMA constant but 16–17% with the FDA constant. Various procedures were recently suggested, especially for the EMA approach, to eliminate the inflation of the Type I error. Notably, the so-called Exact algorithms try to amalgamate the positive features of both EMA and FDA procedures without their negative sides. The computational procedure for the EMA approach is simple and has a straightforward interpretation. The procedure for the FDA approach is based on an approximation, has a bias at small degrees of freedom, and requires a suitable computer program. All regulatory agencies impose a second requirement constraining the point estimate of the ratio of geometric means. In addition, EMA and Health Canada impose an upper limit for applying the recommended procedures. These expectations have psychological motivation and political rationale but no scientific foundations. Their inclusion results in incorrect and misleading interpretation of the principal criterion which involves confidence intervals. Different regulatory authorities expect to apply their approaches either to both AUC and Cmax or only to AUC or only to Cmax. Rational resolution of the disharmonization is needed.
KeywordsBioequivalence Highly variable drugs Reference-scaled average bioequivalence Regulatory constants Type I error
We appreciate the very careful and thoughtful review of the original manuscript by two referees.
- 4.Cook CS (2011) Current issues on bioavailability and bioequivalence determination. J Bioeq Bioavail S1–003:1–5Google Scholar
- 8.Schall R (1995) A unified view of individual, population, and average bioequivalence. In: Blume H, Midha K (eds) Bio-International 2, bioavailability, bioequivalence and pharmacokinetics. Medpharm, Stuttgart, pp 91–106Google Scholar
- 15.Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, Lionberger RA, Makhlouf FT, Nwakama PE, Patel DT, Schuirmann DJ, Yu LX (2012) Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration. AAPS J 14:915–924CrossRefGoogle Scholar
- 16.Food and Drug Administration (2013) Draft guidance for industry: Bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. Center for Drug Evaluation and Research (CDER), Silver Spring, MD https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf
- 18.Food and Drug Administration (2011) Draft guidance for industry: Bioequivalence recommendations for progesterone oral capsules. Center for Drug Evaluation and Research (CDER), Silver Spring, MD https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM209294.pdf
- 21.European Medicines Agency (2010) Guideline on the investigation of bioequivalence. London, United Kingdom http://www.ema.europa.eu/docs/en_GB/document_library/2010/01/WC500070039.pdf
- 23.European Medicines Agency (2015) Questions & Answers: positions on specific questions addressed to the Pharmacokinetics Working Party (PKWP). 19 November 2015 EMA/618604/2008 Rev. 13 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002963.pdf. Accessed 7 Aug 2018
- 26.Labes D (2013) ‘Alpha’ of scaled ABE. Bioequivalence and bioavailability forum. BEBAC Consultancy Services for Bioequivalence and Bioavailability Studies, Vienna http://forum.bebac.at/mix_entry.php?id=10202
- 34.Benet L (2006) Why highly variable drugs are safer. Meeting of FDA Committee for Pharmaceutical Science. http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4241s2_2.htm. Accessed 6 Oct 2006