{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T16:11:22Z","timestamp":1762445482597,"version":"build-2065373602"},"reference-count":25,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,4,28]],"date-time":"2024-04-28T00:00:00Z","timestamp":1714262400000},"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>In the European Union, bioequivalence (BE) for narrow therapeutic index (NTI) drugs is currently demonstrated when the 90% confidence interval for the ratio of the population geometric means of the test and reference products for AUC, and in some cases for Cmax, falls within the acceptance range of 90.00% to 111.11%. However, meeting this requirement results in an increased difficulty of demonstrating BE and a need for clinical trials with larger subject sample sizes, especially for medium-to-high variability drugs. To address this challenge, a scaled average BE based on the reference product within-subject variability for narrowing the acceptance range of NTI drugs was recently proposed. However, this approach showed increased type I error (T1E), especially close to the cut-off point between the unscaled and scaled portions of the method. Based on simulations, this limitation can be overcome by predefining the protocol the path to be followed: either the fixed 90.00\u2013111.11% acceptance range approach or the previously proposed scaled average BE approach with a slight adjustment of the one-sided significance level \u03b1 to 0.042 for a 2 \u00d7 3 \u00d7 3 partial replicate design and without a lower cut-off point. This results in a mixed approach allowing to reduce the sample size whilst not inflating the T1E.<\/jats:p>","DOI":"10.3390\/pharmaceutics16050598","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T03:57:56Z","timestamp":1714622276000},"page":"598","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Two-Way Proposal for the Determination of Bioequivalence for Narrow Therapeutic Index Drugs in the European Union"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6554-4840","authenticated-orcid":false,"given":"Paulo","family":"Paixao","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal"},{"name":"Methodology Working Party of the EMA Committee for Medicinal Products for Human Use, 1083 HS Amsterdam, The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9702-6973","authenticated-orcid":false,"given":"Alfredo","family":"Garcia Arieta","sequence":"additional","affiliation":[{"name":"Methodology Working Party of the EMA Committee for Medicinal Products for Human Use, 1083 HS Amsterdam, The Netherlands"},{"name":"The Spanish Agency of Medicines and Medical Devices, 28022 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9478-0110","authenticated-orcid":false,"given":"Nuno","family":"Silva","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2127-8605","authenticated-orcid":false,"given":"Zvonimir","family":"Petric","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6778-4266","authenticated-orcid":false,"given":"Milton","family":"Bonelli","sequence":"additional","affiliation":[{"name":"European Medicines Agency, 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, University of Lisbon, 1649-004 Lisboa, Portugal"}]},{"given":"Kevin","family":"Blake","sequence":"additional","affiliation":[{"name":"European Medicines Agency, 1083 HS Amsterdam, The Netherlands"}]},{"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, University of Lisbon, 1649-004 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,28]]},"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","unstructured":"EMA (2010). Guideline on the Investigation of Bioequivalence, European Medicines Agency, Committee for Medicinal Products for Human Use (EMEA). (CPMP\/EWP\/QWP\/1401\/98 Rev. 1\/Corr**)."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","unstructured":"Paixao, P., Silva, N., Guerreiro, R.B., Blake, K., Bonelli, M., Morais, J.A.G., Garc\u00eda-Arieta, A., and Gouveia, L.F. (2022). Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112349"},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"285","DOI":"10.18433\/jpps32892","article-title":"Critical Remarks on Reference-Scaled Average Bioequivalence","volume":"25","author":"Labes","year":"2022","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_10","unstructured":"Team, R.C. (2016). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_11","unstructured":"Labes, D., Sch\u00fctz, H., and Lang, B. (2024, March 10). PowerTOST: Power and sample size based on Two One-Sided t-Tests (TOST) for (Bio)Equivalence Studies. Available online: https:\/\/www.researchgate.net\/publication\/339776882_Package_%27PowerTOST%27_Power_and_Sample_Size_for_BioEquivalence_Studies."},{"key":"ref_12","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_13","first-page":"S51-8","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_14","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_15","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":"Munoz","year":"2016","journal-title":"Stat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4378","DOI":"10.1002\/sim.7440","article-title":"Algorithms for evaluating reference scaled average bioequivalence: Power, bias, and consumer risk","volume":"36","author":"Tothfalusi","year":"2017","journal-title":"Stat. Med."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1208\/s12248-016-9873-6","article-title":"An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence","volume":"18","author":"Tothfalusi","year":"2016","journal-title":"AAPS J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1002\/pst.1950","article-title":"Controlling type I error in the reference-scaled bioequivalence evaluation of highly variable drugs","volume":"18","author":"Ocana","year":"2019","journal-title":"Pharm. Stat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/cpt.28","article-title":"Novel bioequivalence approach for narrow therapeutic index drugs","volume":"97","author":"Yu","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/cpt.1293","article-title":"Evaluating Within-Subject Variability for Narrow Therapeutic Index Drugs","volume":"105","author":"Jayachandran","year":"2019","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_22","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_23","unstructured":"ICH (2020). Final Business Plan\u2014M13: Bioequivalence for Immediate-Release Solid Oral Dosage Forms, ICH."},{"key":"ref_24","unstructured":"FDA (2022). Draft Guidance on Statistical Approaches to Establishing Bioequivalence, Food and Drug Administration."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/cpt.1294","article-title":"Batch-to-Batch and Within-Subject Variability: What Do We Know and How Do These Variabilities Affect Clinical Pharmacology and Bioequivalence?","volume":"105","author":"Benet","year":"2019","journal-title":"Clin. Pharmacol. Ther."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/5\/598\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:35:26Z","timestamp":1760106926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/5\/598"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,28]]},"references-count":25,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["pharmaceutics16050598"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16050598","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2024,4,28]]}}}