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We also evaluated the proportion of participants who completed each trial phase and their reasons for early trial exit. We analyzed these trends using mixed effects generalized linear models accounting for the influence of the number of trial sites and trial\u2010specific variability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The number of participants per site has steadily decreased over decades, with recent trials recruiting fewer than five participants per site (reduction by .16 participants\/site\/year,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.0001). Fewer participants also progressed from recruitment to randomization over time (odds ratio = .94\/year,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.014). Concurrently, there has been an increase in the placebo response over time (increase in median percent reduction of .4%\/year,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.02; odds ratio of increase in 50% responder rate of 1.03\/year,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.02), which was not directly associated with the number of sites per trial (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&gt;\u2009.20).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>This historical analysis highlights the increasing challenges with participant recruitment and retention, as well as increasing placebo response. It serves as a call to action to change clinical trial design to address these challenges.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.17716","type":"journal-article","created":{"date-parts":[[2023,7,13]],"date-time":"2023-07-13T11:43:12Z","timestamp":1689248592000},"page":"2625-2634","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Increasing challenges to trial recruitment and conduct over time"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5546-5951","authenticated-orcid":false,"given":"Wesley T.","family":"Kerr","sequence":"first","affiliation":[{"name":"Department of Neurology University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Neurology University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Biomedical Informatics University of Pittsburgh  Pittsburgh Pennsylvania 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Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3549-1642","authenticated-orcid":false,"given":"John M.","family":"Stern","sequence":"additional","affiliation":[{"name":"Department of Neurology David Geffen School of Medicine at the University of California  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0568-2795","authenticated-orcid":false,"given":"Page B.","family":"Pennell","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2242-8027","authenticated-orcid":false,"given":"Jacqueline A.","family":"French","sequence":"additional","affiliation":[{"name":"Comprehensive Epilepsy Center New York University  New York New York 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