{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:48:40Z","timestamp":1785840520686,"version":"3.56.0"},"reference-count":26,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>Marketing authorizations for oncology drugs are often based on single\u2010arm trials (SATs), and real\u2010world data\u2010based external comparator cohorts (ECCs) are increasingly explored to contextualize results. In retrospective studies, comparators may be identified by time of diagnosis but included based on time of relapse; such sampling strategies can introduce bias, potentially leading to erroneous efficacy conclusions. Simulated diffuse large B\u2010cell lymphoma (DLBCL) cohorts were generated using published time\u2010to\u2010relapse and post\u2010relapse survival distributions. Three ECC sampling strategies were evaluated: na\u00efve (screening and inclusion periods coincide), delayed (inclusion period extends beyond screening), and displacement (screening and inclusion periods shifted relative to each other). Different sampling strategies caused significant changes in the time\u2010to\u2010relapse distribution in the ECC and, by proxy, the estimated 2\u2010year post\u2010relapse overall survival (22.5\u201352.2%). Na\u00efve sampling consistently resulted in oversampling of early relapses, though bias was reduced with extended inclusion periods; in hypothetical trials, it produced inflated Type I errors (10.5\u201384.9%) despite \u03b1\u2009=\u20090.025. Delayed sampling reduced bias when the inclusion period was sufficiently extended to capture late relapses, yielding unbiased estimates under long delays (Type I error of 2.5% at a 6\u2010year delay). Displacement sampling depended strongly on the degree of shift: moderate shifts minimized bias, whereas long displacements introduced substantial distortion (Type I error of 2.7% and 0.0% at displacements of 2 and 5, respectively). Real\u2010world data\u2010based ECCs in relapsed\/refractory oncology are susceptible to selection bias from sampling strategies, particularly through distortions in time\u2010to\u2010relapse, leading to erroneous efficacy conclusions; similar bias may occur in non\u2010oncology settings where time\u2010to\u2010treatment initiation is prognostic.<\/jats:p>","DOI":"10.1002\/cpt.70435","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:21:03Z","timestamp":1785838863000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Risk of Bias Associated with Varying Sampling Strategies for External Comparator Cohorts for Single\u2010Arm Trials: Insights from Aggressive Lymphoma"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1119-4782","authenticated-orcid":false,"given":"Mikkel Runason","family":"Simonsen","sequence":"first","affiliation":[{"name":"Department of Haematology, Clinical Cancer Research Center Aalborg University Hospital  Aalborg Denmark"},{"name":"Department of Mathematical Sciences Aalborg University  Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiva","family":"Leisner","sequence":"additional","affiliation":[{"name":"Department of Haematology Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8739-0421","authenticated-orcid":false,"given":"Ahmed Ludvigsen","family":"Al\u2010Mashhadi","sequence":"additional","affiliation":[{"name":"Department of Haematology Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Clinical Medicine Aalborg University  Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0466-976X","authenticated-orcid":false,"given":"Laurids \u00d8stergaard","family":"Poulsen","sequence":"additional","affiliation":[{"name":"Department of Oncology Aalborg University Hospital  Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1867-0526","authenticated-orcid":false,"given":"Matthew","family":"Maurer","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6575-7686","authenticated-orcid":false,"given":"Lasse Hjort","family":"Jakobsen","sequence":"additional","affiliation":[{"name":"Department of Haematology, Clinical Cancer Research Center Aalborg University Hospital  Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4406-380X","authenticated-orcid":false,"given":"Tarec Christoffer","family":"El\u2010Galaly","sequence":"additional","affiliation":[{"name":"Department of Haematology Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Clinical Epidemiology Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Molecular Medicine Aarhus University Hospital  Aarhus Denmark"},{"name":"Department of Clinical Medicine Aarhus University  Aarhus Denmark"},{"name":"Department of Haematology Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"e_1_2_11_1_1","unstructured":"European Medicines Agency<https:\/\/catalogues.ema.europa.eu\/catalogue\u2010rwd\u2010sources> (2025)."},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.5985"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3554"},{"key":"e_1_2_11_4_1","unstructured":"EMA.Reflection paper on establishing efficacy based on single\u2010arm trials submitted as pivotal evidence in a marketing authorisation application: Considerations on evidence from single\u2010arm trials<https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/reflection\u2010paper\u2010establishing\u2010efficacy\u2010based\u2010single\u2010arm\u2010trials\u2010submitted\u2010pivotal\u2010evidence\u2010marketing\u2010authorisation\u2010application_en.pdf> (2024). 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Poster presented at the International Society for Pharmacoepidemiology (ISPE) Annual Meeting <https:\/\/www.rtihs.org\/publications\/external\u2010control\u2010arm\u2010studies\u2010marketing\u2010authorisation\u2010applications\u2010submitted\u2010european\u20100?utm_source=chatgpt.com> (2025). 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