{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T16:08:55Z","timestamp":1762445335980,"version":"build-2065373602"},"reference-count":22,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product\u2019s AUC, and in certain cases Cmax, is included within the tighter acceptance range of 90.00\u2013111.11%. An alternative criterion, consisting of narrowed limits based on the within-subject variability of the reference product, was recently proposed. Its performance for a three-period partial replicate design was tested by simulation in terms of power to show BE, type I error (T1E) and sample size requirements. A new condition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained within the range of 90.00\u2013111.11%, was also tested. The probability of showing BE when the products differ more than 10% was increased, but only if the reference product\u2019s within-subject variability was moderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (&lt;7%) was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E. Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually did not increase the required sample size.<\/jats:p>","DOI":"10.3390\/pharmaceutics14112349","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T06:42:17Z","timestamp":1667371337000},"page":"2349","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6554-4840","authenticated-orcid":false,"given":"Paulo","family":"Paix\u00e3o","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal"},{"name":"EMA\u2019s Pharmacokinetics Working Party, 1083 HS Amsterdam, The Netherlands"}]},{"given":"Nuno","family":"Silva","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal"}]},{"given":"Rita Bento","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal"}]},{"given":"Kevin","family":"Blake","sequence":"additional","affiliation":[{"name":"European Medicines Agency (EMA), 1083 HS Amsterdam, The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6778-4266","authenticated-orcid":false,"given":"Milton","family":"Bonelli","sequence":"additional","affiliation":[{"name":"European Medicines Agency (EMA), 1083 HS Amsterdam, The Netherlands"}]},{"given":"Jos\u00e9 Augusto Guimar\u00e3es","family":"Morais","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal"}]},{"given":"Alfredo","family":"Garc\u00eda-Arieta","sequence":"additional","affiliation":[{"name":"EMA\u2019s Pharmacokinetics Working Party, 1083 HS Amsterdam, The Netherlands"},{"name":"The Spanish Agency of Medicines and Medical Devices, 28022 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5611-0047","authenticated-orcid":false,"given":"Lu\u00eds Filipe","family":"Gouveia","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/j.1742-7843.2009.00518.x","article-title":"The new European Medicines Agency guideline on the investigation of bioequivalence","volume":"106","author":"Morais","year":"2010","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.ejps.2011.09.010","article-title":"Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: Workshop summary report","volume":"44","author":"Chen","year":"2011","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_3","first-page":"73","article-title":"Sample sizes for designing bioequivalence studies for highly variable drugs","volume":"15","author":"Tothfalusi","year":"2012","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s00228-015-1832-0","article-title":"Narrow therapeutic index drugs: A clinical pharmacological consideration to flecainide","volume":"71","author":"Tamargo","year":"2015","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1007\/s00228-012-1456-6","article-title":"Bioequivalence between generic tacrolimus products marketed in Spain by adjusted indirect comparison","volume":"69","author":"Herranz","year":"2013","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_6","unstructured":"EMA (2010). Guideline on the Investigation of Bioequivalence (CPMP\/EWP\/QWP\/1401\/98 Rev. 1\/ Corr **), EMA."},{"key":"ref_7","unstructured":"Health Canada (2018). Conduct and Analysis of Comparative Bioavailability Studies, Health Canada."},{"key":"ref_8","unstructured":"WHO (2017). Fifty-First Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations, WHO."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/cpt.2451","article-title":"A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union","volume":"111","author":"Paixao","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"725","DOI":"10.2165\/11318040-000000000-00000","article-title":"Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence","volume":"48","author":"Tothfalusi","year":"2009","journal-title":"Clin. Pharmacokinet."},{"key":"ref_11","unstructured":"R Core Team (2016). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_12","unstructured":"Labes, D., Sch\u00fctz, H., and Lang, B. (2022, September 20). PowerTOST: Power and Sample Size Based on Two One-Sided t-Tests (TOST) for (Bio)Equivalence Studies. Available online: https:\/\/cran.r-project.org\/web\/packages\/PowerTOST\/PowerTOST.pdf."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1002\/sim.6834","article-title":"Consumer\u2019s risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs","volume":"35","author":"Alcaide","year":"2016","journal-title":"Stat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1007\/s11095-016-2006-1","article-title":"Inflation of Type I Error in the Evaluation of Scaled Average Bioequivalence, and a Method for its Control","volume":"33","author":"Labes","year":"2016","journal-title":"Pharm. Res."},{"key":"ref_15","first-page":"S51","article-title":"Sample size determination for bioequivalence assessment by means of confidence intervals","volume":"29","author":"Diletti","year":"1991","journal-title":"Int. J. Clin. Pharmacol. Ther. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wellek, S. (2002). Testing Statistical Hypotheses of Equivalence, Chapman and Hall\/CRC. [1st ed.].","DOI":"10.1201\/9781420035964"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1002\/cpt.884","article-title":"Generic Versions of Narrow Therapeutic Index Drugs: A National Survey of Pharmacists\u2019 Substitution Beliefs and Practices","volume":"103","author":"Sarpatwari","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1208\/s12248-008-9053-4","article-title":"Evaluation of a scaling approach for the bioequivalence of highly variable drugs","volume":"10","author":"Haidar","year":"2008","journal-title":"AAPS J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"138","DOI":"10.18433\/J3ZW2C","article-title":"Regulatory and study conditions for the determination of bioequivalence of highly variable drugs","volume":"12","author":"Endrenyi","year":"2009","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1023\/A:1016219317744","article-title":"An approach for widening the bioequivalence acceptance limits in the case of highly variable drugs","volume":"12","author":"Boddy","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1177\/0962280219871589","article-title":"Methods to control the empirical type I error rate in average bioequivalence tests for highly variable drugs","volume":"29","author":"Deng","year":"2020","journal-title":"Stat. Methods Med. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"676","DOI":"10.18433\/J31K51","article-title":"Determination of bioequivalence for drugs with narrow therapeutic index: Reduction of the regulatory burden","volume":"16","author":"Endrenyi","year":"2013","journal-title":"J. Pharm. Pharm. Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/11\/2349\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:06:32Z","timestamp":1760144792000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/11\/2349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,31]]},"references-count":22,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["pharmaceutics14112349"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14112349","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2022,10,31]]}}}