{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:52:53Z","timestamp":1791003173350,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>Increased interest in real\u2010world evidence (RWE) for clinical and regulatory decision making and the need to evaluate long\u2010term benefits and risks of pharmaceutical products raise the importance of understanding the use of external controls (ECs) for uncontrolled extensions of randomized controlled trials (RCTs). We searched clinicaltrials.gov from 2009 to 2019 for uncontrolled extensions and assessed the use of ECs in the trial protocol registry and PubMed. We present characteristics of identified uncontrolled extensions, their adoption of ECs, and a qualitative appraisal of published uncontrolled extensions with ECs according to good pharmacoepidemiologic practice. The number of uncontrolled extensions increased slightly across the study period, resulting in a total of 1,115 studies. Most originated from phase III RCTs (62.2%) and specified safety outcomes (61.9% among those with specified outcomes). Most uncontrolled extensions incorporated no control group with only 7 out of 1,115 (0.6%) employing ECs. For those studies with ECs, all involved treatments for rare conditions and assessment of effectiveness. Attempts to balance comparison groups varied from none mentioned to propensity score matching. We noted consistent deficiencies in outcome ascertainment methods and approaches to address attrition bias. The contrast of the large and growing number of uncontrolled extensions with the small number of studies that utilized ECs showed clear opportunities for enhancement in design, measurement, and analysis of uncontrolled extensions to allow causal inferences on long\u2010term treatment effects. As extensions continue to expand within RWE regulatory frameworks, development of guidelines for use of EC with uncontrolled extensions is needed.<\/jats:p>","DOI":"10.1002\/cpt.2346","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T12:48:29Z","timestamp":1624538909000},"page":"187-199","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Uncontrolled Extensions of Clinical Trials and the Use of External Controls\u2014Scoping Opportunities and Methods"],"prefix":"10.1111","volume":"111","author":[{"given":"Ching\u2010Yu","family":"Wang","sequence":"first","affiliation":[{"name":"Pharmaceutical Outcomes &amp; Policy Center for Drug Evaluation &amp; Safety University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse A.","family":"Berlin","sequence":"additional","affiliation":[{"name":"Epidemiology Johnson &amp; Johnson Titusville New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry","family":"Gertz","sequence":"additional","affiliation":[{"name":"Blackstone Life Sciences Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kourtney","family":"Davis","sequence":"additional","affiliation":[{"name":"Global Epidemiology Janssen R&amp;D Titusville New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"US Food and Drug Administration Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy A.","family":"Dreyer","sequence":"additional","affiliation":[{"name":"Real\u2010World Solutions, IQVIA Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc. Kenilworth New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Seeger","sequence":"additional","affiliation":[{"name":"Optum Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Santanello","sequence":"additional","affiliation":[{"name":"Pharmacoepidemiology Consultant New Hope Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almut G.","family":"Winterstein","sequence":"additional","affiliation":[{"name":"Pharmaceutical Outcomes &amp; Policy Center for Drug Evaluation &amp; Safety University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,10]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200730020-00001"},{"key":"e_1_2_11_2_1","unstructured":"International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). 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