{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:23:32Z","timestamp":1790015012111,"version":"4.0.1"},"reference-count":22,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:p>The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration\u2010time curve (AUC), and in certain cases maximum plasma drug concentration (C<jats:sub>max<\/jats:sub>), to be included within the tighter acceptance range of 90.00\u2013111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This \u201cone\u2010size\u2010fits\u2010all\u201d criterion is particularly questionable when the within\u2010subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within\u2010subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00\u2013125.00% acceptance range for highly variable drugs. The 80.00\u2013125.00% acceptance range is narrowed, only if the within\u2010subject variability is lower than 30%, down to the current NTI acceptance range of 90.00\u2013111.11% when the within\u2010subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within\u2010subject variability is 20\u201330%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within\u2010subject variability are frequently exposed to bioavailability differences larger than 10%.<\/jats:p>","DOI":"10.1002\/cpt.2451","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T13:53:03Z","timestamp":1634651583000},"page":"470-476","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union"],"prefix":"10.1111","volume":"111","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 Faculty of Pharmacy University of Lisbon Lisbon Portugal"},{"name":"European Medicines Agency\u2019s Pharmacokinetics Working Party Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita Bento","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines Faculty of Pharmacy University of Lisbon Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9478-0110","authenticated-orcid":false,"given":"Nuno","family":"Silva","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines Faculty of Pharmacy University of Lisbon Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Blake","sequence":"additional","affiliation":[{"name":"European Medicines Agency Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milton","family":"Bonelli","sequence":"additional","affiliation":[{"name":"European Medicines Agency Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Augusto Guimar\u00e3es","family":"Morais","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines Faculty of Pharmacy University of Lisbon Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9702-6973","authenticated-orcid":false,"given":"Alfredo","family":"Garcia Arieta","sequence":"additional","affiliation":[{"name":"European Medicines Agency\u2019s Pharmacokinetics Working Party Amsterdam The Netherlands"},{"name":"The Spanish Agency of Medicines and Medical Devices Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5611-0047","authenticated-orcid":false,"given":"Luis Filipe","family":"Gouveia","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines Faculty of Pharmacy University of Lisbon Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,3]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-015-1832-0"},{"key":"e_1_2_11_2_1","first-page":"h3163 (2015)","article-title":"Generic immunosuppression in solid organ transplantation: systematic review and meta\u2010analysis","volume":"350","author":"Molnar A.O.","journal-title":"BMJ"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/03007995.2019.1570769"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1293"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(98)90100-X"},{"key":"e_1_2_11_6_1","volume-title":"Guideline on the investigation of bioequivalence (CPMP\/EWP\/QWP\/1401\/98 Rev. 1\/Corr**)","author":"European Medicines Agency","year":"2010"},{"key":"e_1_2_11_7_1","volume-title":"Draft Guidance on Warfarin Sodium","author":"US Food and Drug Administration","year":"2012"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.28"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01068419"},{"key":"e_1_2_11_10_1","first-page":"73","article-title":"Sample sizes for designing bioequivalence studies for highly variable drugs","volume":"15","author":"Tothfalusi L.","year":"2012","journal-title":"J. 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