{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:03:00Z","timestamp":1784955780900,"version":"3.55.0"},"reference-count":56,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The initial ICH E14 guidance described the thorough QT\/QTc (TQT) study with the purpose of evaluating whether a new drug has effects on the QTc interval. Following its adoption, concentration\u2010QTc (C\u2010QTc) modeling was applied to data from TQT studies, and results were comparable with those based on a \u201cby time point\u201d analysis. In 2014, the IQ\u2010CSRC study demonstrated that a small study in healthy subjects using C\u2010QTc as the primary analysis could detect mild drug\u2010induced QTc prolongation. The study led to the revision of the E14 guidance in 2015, allowing the use of C\u2010QTc modeling to exclude a QTc effect at the threshold of concern, 10 ms. The 2015 revision was the starting point for the use of C\u2010QTc modeling applied to data from first\u2010in\u2010human (FIH) studies with the intent to waive requests for a designated TQT study. The 2022 revision (S7B\/E14 Q&amp;A) brought non\u2010clinical studies into the decision process for a \u201cdefinitive\u201d QT evaluation. In this manuscript, the emergence of C\u2010QTc analysis applied to FIH studies with the intent to waive the TQT study is described, and a survey of FDA labels and reviews of approved drugs since 2015 is shared. The uptake has been modest, with only 30% of approved drugs for which a TQT study would be expected using this approach, while a TQT study has been conducted in \u223c70% of development programs. It can be expected that the 2022 S7B\/E14 revision will increase the number of programs for which a TQT study can be replaced.<\/jats:p>","DOI":"10.1002\/jcph.70237","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T12:17:52Z","timestamp":1783340272000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["How to Replace the TQT Study\u2014The Use of Concentration\u2010QTc Modeling to Exclude a Small Effect of a Novel Drug on QT Interval: Historical Perspective and Implementation"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5008-5052","authenticated-orcid":false,"given":"Borje","family":"Darpo","sequence":"first","affiliation":[{"name":"Clario, part of Thermo Fisher Scientific  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Ferber","sequence":"additional","affiliation":[{"name":"Statistik Georg Ferber GmbH  Riehen Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth C","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Newleos Therapeutics  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Litherland","sequence":"additional","affiliation":[{"name":"Basilea Pharmaceutica International Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nenad","family":"Sarapa","sequence":"additional","affiliation":[{"name":"Global Drug Development Consulting LLC  San Juan Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqi","family":"Xue","sequence":"additional","affiliation":[{"name":"Clario, part of Thermo Fisher Scientific  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kleiman","sequence":"additional","affiliation":[{"name":"Clario, part of Thermo Fisher Scientific  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"The Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs","author":"ICH E14","year":"2005"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/009286150503900407"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200528020-00003"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00487.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543400802020938"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13300\u2010014\u20100055\u20101"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.224"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264\u2010013\u20100016\u2010z"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.2000.00243.x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1981.tb01123.x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1980.tb04799.x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(01)56650-3"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1987.117"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270009341184"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.2165\/11634810\u2010000000000\u201000000"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12513"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270007307881"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.03148\u201025"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00934\u201022"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00087\u201025"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.361"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010019\u201009662\u20103"},{"key":"e_1_2_8_24_1","unstructured":"Cardiac Safety Research Consortium. 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