{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:58:56Z","timestamp":1790895536234,"version":"4.1.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002460","name":"Chung-Ang University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002460","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["AAPS J"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Generic drugs offer cost-effective alternatives to brand-name medications while ensuring comparable safety and efficacy. However, narrow therapeutic index drugs (NTIDs), which require precise dosing due to narrow margins between therapeutic and toxic concentrations, present additional regulatory challenges. Concerns regarding the interchangeability of generic NTIDs are amplified by international variation in definitions, bioequivalence (BE) standards, and regulatory approaches. This systematic review compares NTID-related regulatory frameworks across major authorities to inform the development of the ICH M13C guideline and foster global harmonization of evaluation standards for generic NTIDs. A comprehensive comparative analysis was conducted of NTID-related regulatory frameworks in five ICH member countries (United States [US], European Union [EU], Japan, Canada, and South Korea), with Egypt, Jordan, and Saudi Arabia included as reference countries. Data were obtained from literature searches and official regulatory sources, focusing on NTID definitions, BE standards, and NTID lists. Marked regulatory divergence was observed. South Korea uniquely incorporates quantitative pharmacological and toxicological criteria into NTID definitions. The US employs the most stringent NTID BE standards, utilizing a fully replicated design, reference-scaled average bioequivalence (RSABE), and variability assessment. Only cyclosporine and tacrolimus are classified as NTIDs by all five core countries. Variability in NTID lists and evaluation criteria complicates global harmonization efforts. Achieving consistent evaluation and safe international use of generic NTIDs requires global alignment on definitions, BE criteria, and NTID lists. This review supports integrating real-world data into regulatory decision-making and advances the ICH M13C guideline.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1208\/s12248-025-01159-x","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T19:34:11Z","timestamp":1762889651000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Regulatory Divergence in Narrow Therapeutic Index Drugs: A Comparative Review of the US, EU, Japan, Canada, and South Korea"],"prefix":"10.1208","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1858-574X","authenticated-orcid":false,"given":"Sieun","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7708-8779","authenticated-orcid":false,"given":"Jiwon","family":"Baek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-4666","authenticated-orcid":false,"given":"Wonku","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3525-8805","authenticated-orcid":false,"given":"Eunyoung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"1159_CR1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1M141","author":"BM Davit","year":"2009","unstructured":"Davit BM, Nwakama PE, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. 2009. https:\/\/doi.org\/10.1345\/aph.1M141.","journal-title":"Annals of Pharmacotherapy"},{"key":"1159_CR2","doi-asserted-by":"publisher","unstructured":"Gothe H, Schall I, et al. The Impact of Generic Substitution on Health and Economic Outcomes: A Systematic Review. Appl Health Econ Health Policy. 2015. https:\/\/doi.org\/10.1007\/s40258-014-0147-0.","DOI":"10.1007\/s40258-014-0147-0"},{"key":"1159_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2017.07.010","author":"ML Van den Hoven","year":"2017","unstructured":"Van den Hoven ML, Pinheiro L. Ensuring patient safety with generic narrow therapeutic index drugs: A regulatory perspective. Regul Toxicol Pharmacol. 2017. https:\/\/doi.org\/10.1016\/j.yrtph.2017.07.010.","journal-title":"Regul Toxicol Pharmacol"},{"key":"1159_CR4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2008.744","author":"AS Kesselheim","year":"2008","unstructured":"Kesselheim AS, Misono AS, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: A systematic review and meta-analysis. JAMA. 2008. https:\/\/doi.org\/10.1001\/jama.2008.744.","journal-title":"JAMA"},{"key":"1159_CR5","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-015-9791-5","author":"LX Yu","year":"2015","unstructured":"Yu LX, Li BV, et al. FDA perspectives on narrow therapeutic index drugs: Bioequivalence and drug substitution. AAPS J. 2015. https:\/\/doi.org\/10.1208\/s12248-015-9791-5.","journal-title":"AAPS J"},{"key":"1159_CR6","doi-asserted-by":"publisher","DOI":"10.1093\/jpp\/rgab102","author":"S Habet","year":"2021","unstructured":"Habet S. Narrow therapeutic index drugs: clinical pharmacology perspective. J Pharm Pharmacol. 2021. https:\/\/doi.org\/10.1093\/jpp\/rgab102.","journal-title":"J Pharm Pharmacol"},{"key":"1159_CR7","unstructured":"WHO. Technical Report Series, No. 1003: Annex 6 \u2013 Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. World Health Organization (WHO). 2017. https:\/\/www.who.int\/publications\/m\/item\/annex-6-trs-1003. Accessed 28 Apr 2025."},{"key":"1159_CR8","unstructured":"ASEAN Mutual Recognition Arrangement for Bioequivalence Study Reports of Generic Medicinal Products. Association of Southeast Asian Nations (ASEAN) Secretariat. 2017. https:\/\/cil.nus.edu.sg\/wp-content\/uploads\/2019\/02\/2017-ASEAN-MRA-FOR-BIOEQUIVALENCE.pdf. Accessed 28 Apr 2025."},{"key":"1159_CR9","doi-asserted-by":"publisher","DOI":"10.3390\/healthcare10081392","author":"L Gozzo","year":"2022","unstructured":"Gozzo L, Caraci F, et al. Bioequivalence, drugs with narrow therapeutic index and the phenomenon of biocreep: a critical analysis of the system for generic substitution. Healthcare. 2022. https:\/\/doi.org\/10.3390\/healthcare10081392.","journal-title":"Healthcare"},{"key":"1159_CR10","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3460","author":"M Donnelly","year":"2024","unstructured":"Donnelly M, Fang L, et al. Narrow therapeutic index drugs: FDA experience, views, and operations. Clin Pharmacol Ther. 2024. https:\/\/doi.org\/10.1002\/cpt.3460.","journal-title":"Clin Pharmacol Ther"},{"key":"1159_CR11","doi-asserted-by":"publisher","unstructured":"Anno KA, Mina M, et al. Analysis on the impact of U.S. FDA\u2019s narrow therapeutic index bioequivalence criteria on generic drug applications. AAPS J. 2025. https:\/\/doi.org\/10.1208\/s12248-025-01020-1.","DOI":"10.1208\/s12248-025-01020-1"},{"key":"1159_CR12","doi-asserted-by":"crossref","unstructured":"ICH current Members & Observers. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). https:\/\/www.ich.org\/page\/members-observers. Accessed 15 Mar 2025.","DOI":"10.1093\/med\/9780198842255.003.0027"},{"key":"1159_CR13","unstructured":"MFDS. Guideline for Pharmaceutical Equivalence Testing. Ministry of Food and Drug Safety (MFDS). 2023. https:\/\/www.law.go.kr\/%ED%96%89%EC%A0%95%EA%B7%9C%EC%B9%99\/%EC%9D%98%EC%95%BD%ED%92%88%EB%8F%99%EB%93%B1%EC%84%B1%EC%8B%9C%ED%97%98%EA%B8%B0%EC%A4%80. Accessed 2 Apr 2025."},{"key":"1159_CR14","unstructured":"US Food and Drug Administration. 21 CFR 320.33c. Food and Drug Administration (FDA). https:\/\/www.ecfr.gov\/current\/title-21\/chapter-I\/subchapter-D\/part-320\/subpart-B\/section-320.33. Accessed 7 Apr 2025."},{"key":"1159_CR15","unstructured":"US Food and Drug Administration. FY2015 Regulatory Science Research Report: Narrow Therapeutic Index Drugs. Food and Drug Administration (FDA). 2017. https:\/\/www.fda.gov\/industry\/generic-drug-user-fee-amendments\/fy2015-regulatory-science-research-report-narrow-therapeutic-index-drugs. Accessed 22 Mar 2025."},{"key":"1159_CR16","unstructured":"Health Canada. Guidance Document - Comparative Bioavailability Standards: Formulations Used for Systemic Effects. Health Canada. 2018. https:\/\/www.canada.ca\/en\/health-canada\/services\/drugs-health-products\/drug-products\/applications-submissions\/guidance-documents\/bioavailability-bioequivalence\/comparative-bioavailability-standards-formulations-used-systemic-effects.html. Accessed 25 Mar 2025."},{"key":"1159_CR17","doi-asserted-by":"publisher","DOI":"10.1002\/jpt.56789","author":"A Jones","year":"2018","unstructured":"Jones A, Brown B. The role of metabolites in drug toxicity and efficacy: A review of regulatory guidelines. J Pharmacol Toxicol. 2018. https:\/\/doi.org\/10.1002\/jpt.56789.","journal-title":"J Pharmacol Toxicol"},{"key":"1159_CR18","unstructured":"US Food and Drug Administration. Bioequivalence Studies With Pharmacokinetic Endpoints for Drug Submitted Under an ANDA. Food and Drug Administration (FDA). 2021. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/bioequivalence-studies-pharmacokinetic-endpoints-drugs-submitted-under-abbreviated-new-drug. Accessed 5 Apr 2025."},{"key":"1159_CR19","unstructured":"EMA. Guideline on the Investigation of Bioequivalence. European Medicine Agency (EMA). 2021. https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-investigation-bioequivalence-rev1_en.pdf. Accessed 16 Apr 2025."},{"key":"1159_CR20","unstructured":"EMA. Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms. European Medicine Agency (EMA). 2015. https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-pharmacokinetic-and-clinical-evaluation-modified-release-dosage-forms_en.pdf. Accessed 23 Apr 2025."},{"key":"1159_CR21","unstructured":"PMDA. Guideline for Bioequivalence Studies of Generic. Pharmaceuticals and Medical Devices Agency (PMDA). 2012. https:\/\/www.pmda.go.jp\/english\/review-services\/regulatory-info\/0019.html. Accessed 14 Apr 2025."},{"key":"1159_CR22","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-017-0186-8","author":"R Kuribayashi","year":"2017","unstructured":"Kuribayashi R, Appleton S. Comparison of generic drug reviews for marketing authorization between Japan and Canada. Drugs R D. 2017. https:\/\/doi.org\/10.1007\/s40268-017-0186-8.","journal-title":"Drugs R D"},{"key":"1159_CR23","unstructured":"Health Canada. Conduct and Analysis of Comparative Bioavailability Studies. Health Canada. 2023. https:\/\/www.canada.ca\/en\/health-canada\/services\/drugs-health-products\/drug-products\/applications-submissions\/guidance-documents\/bioavailability-bioequivalence\/conduct-analysis-comparative.html. Accessed 14 Apr 2025."},{"key":"1159_CR24","unstructured":"MFDS. Guidelines for Bioequivalence Studies of Pharmaceutical Products. Ministry of Food and Drug Safety (MFDS). 2025. https:\/\/www.mfds.go.kr\/brd\/m_1060\/down.do?brd_id=data0011&seq=15666&data_tp=A&file_seq=2. Accessed 17 Apr 2025."},{"key":"1159_CR25","unstructured":"ICH Investigation of bioequivalence - Scientific guideline. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). https:\/\/www.ema.europa.eu\/en\/investigation-bioequivalence-scientific-guideline. Accessed 3 May 2025."},{"key":"1159_CR26","unstructured":"PSB. Guideline for bioequivalence studies for different strengths of oral solid dosage forms. Pharmaceutical and Food Safety Bureau (PSB). 2012. https:\/\/www.nihs.go.jp\/drug\/be-guide(e)\/strength\/GL-E_120229_ganryo.pdf. Accessed 17 Apr 2025."},{"key":"1159_CR27","doi-asserted-by":"publisher","DOI":"10.5414\/cpp43485","author":"KK Midha","year":"2005","unstructured":"Midha KK, Rawson MJ, Hubbard JW. The bioequivalence of highly variable drugs and drug products. Int J Clin Pharmacol Ther. 2005. https:\/\/doi.org\/10.5414\/cpp43485.","journal-title":"Int J Clin Pharmacol Ther"},{"key":"1159_CR28","unstructured":"ICH Multidisciplinary Guidelines. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). https:\/\/www.ich.org\/page\/multidisciplinary-guidelines. Accessed 21 Jul 2025."},{"key":"1159_CR29","doi-asserted-by":"publisher","DOI":"10.1162\/ajhe_a_00073","author":"SW Schondelmeyer","year":"2019","unstructured":"Schondelmeyer SW, Purvis L. Trends in prescription drug prices and generic competition. Am J Health Econ. 2019. https:\/\/doi.org\/10.1162\/ajhe_a_00073.","journal-title":"Am J Health Econ"},{"key":"1159_CR30","unstructured":"EDA. Egyptian guidelines on conducting bioequivalence studies for marketing authorization of generic products. Egyptian Drug Authority (EDA). 2017. https:\/\/www.edaegypt.gov.eg\/media\/dyihv0tm\/egyptian-guidelines-for-conducting-bioequivalence-studies-for-ma-1.pdf. Accessed 20 May 2025."},{"key":"1159_CR31","unstructured":"SFDA. Guidelines for Bioequivalence. Saudi Food and Drug Authority (SFDA). 2021. https:\/\/www.sfda.gov.sa\/sites\/default\/files\/2022-08\/GCC_Guidelines_Bioequivalence31_0.pdf. Accessed 20 May 2025."},{"key":"1159_CR32","unstructured":"EDA. Guidelines on human pharmaceuticals variations. Egyptian Drug Authority (EDA). 2023. https:\/\/www.edaegypt.gov.eg\/media\/1eabkp4o\/guide-line-of-human-pharmaceuticals-variations-fifth-edition-2024_.pdf. Accessed 20 May 2025."},{"key":"1159_CR33","unstructured":"JFDA. Medicine and Pharmacy Law No. (12). Jordan Food & Drug Administration (JFDA). 2013. https:\/\/www.scribd.com\/document\/753625989\/Drug-and-Pharmacy-Law-No-12-of-2013-and-amendments. Accessed 20 May 2025."},{"key":"1159_CR34","unstructured":"SFDA. Product Specific Bioequivalence Guidance. Saudi Food and Drug Authority (SFDA). 2022. https:\/\/www.sfda.gov.sa\/sites\/default\/files\/2022-05\/SFDAsProductSpecificBioequivalenceGuidanceV1.pdf. Accessed 21 May 2025."}],"container-title":["The AAPS Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1208\/s12248-025-01159-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1208\/s12248-025-01159-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1208\/s12248-025-01159-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T16:21:09Z","timestamp":1770826869000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1208\/s12248-025-01159-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,11]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["1159"],"URL":"https:\/\/doi.org\/10.1208\/s12248-025-01159-x","relation":{},"ISSN":["1550-7416"],"issn-type":[{"value":"1550-7416","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,11]]},"assertion":[{"value":"10 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}}],"article-number":"19"}}