{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T10:23:12Z","timestamp":1777544592631,"version":"3.51.4"},"reference-count":28,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T00:00:00Z","timestamp":1594252800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Clinical Trials"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>The ICH E9(R1) addendum states that the strategy to account for intercurrent events should be included when defining an estimand, the treatment effect to be estimated based on the study objective. The estimator used to assess the treatment effect needs to be aligned with the estimand that accounted for intercurrent events. Regardless of the strategy, missing data resulting from patient premature withdrawal could undermine the robustness of the study results. Informative censoring due to dropouts in an events-based study is one such example. Sensitivity analyses using imputation methods are useful to examine the uncertainty due to informative censoring and address the robustness and strength of the study results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We assessed the effect of premature patient withdrawal in the PRECISION study, a randomized non-inferiority clinical trial of patients with chronic arthritic pain that compared the cardiovascular safety of three nonsteroidal anti-inflammatory drugs\u2013based treatment policies or paradigms. The protocol-defined use of concomitant or rescue medications was permitted since changes in pain medications due to insufficient analgesia were expected in patients in this long-term study. Anticipating that premature study discontinuations could potentially lead to informative censoring, a supplementary analysis was pre-specified in which censored outcomes due to the premature study discontinuation were imputed based on adverse events that were clinically associated with the primary endpoint (cardiovascular outcome based on the Antiplatelet Trialists Collaboration composite endpoint). Furthermore, tipping point analyses were conducted to test the robustness of the primary analysis results by assuming data censored not at random. The level of increase at which the primary study conclusion would change was estimated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>For the analysis of time to first primary endpoint event through 30 months, 4065 out of the 24,081 enrolled patients were lost to follow-up, withdrew consent, or were no longer willing to participate in the study. These withdrawals occurred gradually and resulted in a cumulative total of 5893 censored patient-years of observation (10.2%). The rate of discontinuation and the baseline characteristics of the discontinued patients were similar across the three treatment groups. The non-inferiority conclusion from the primary analysis was confirmed in the supplementary analysis incorporating relevant adverse events. Furthermore, tipping point analyses demonstrated that in order to lose non-inferiority in the primary analysis, the risk of primary endpoint events during the censored observation time would have to increase by more than 2.7-fold in the celecoxib group while remaining constant in the other nonsteroidal anti-inflammatory drugs groups, demonstrating that the scenarios where the study results are invalid appear not plausible.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Supplementary and sensitivity analyses presented to address informative censoring in PRECISION helped to further interpret and strengthen the study results.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/1740774520934747","type":"journal-article","created":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T08:57:14Z","timestamp":1594285034000},"page":"535-544","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Strengthening the interpretability of clinical trial results by assessing the effect of informative censoring on the primary estimand in PRECISION"],"prefix":"10.1177","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6331-0805","authenticated-orcid":false,"given":"Weihang","family":"Bao","sequence":"first","affiliation":[{"name":"Pfizer Inc., New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Gaffney","sequence":"additional","affiliation":[{"name":"Pfizer Inc., New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milton L","family":"Pressler","sequence":"additional","affiliation":[{"name":"Pfizer Inc., New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rana","family":"Fayyad","sequence":"additional","affiliation":[{"name":"Pfizer Inc., New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne","family":"Wisemandle","sequence":"additional","affiliation":[{"name":"Pfizer Inc., New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Beckerman","sequence":"additional","affiliation":[{"name":"Pfizer Inc., New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine E","family":"Wolski","sequence":"additional","affiliation":[{"name":"Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven E","family":"Nissen","sequence":"additional","affiliation":[{"name":"Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2020,7,9]]},"reference":[{"key":"bibr1-1740774520934747","unstructured":"ICH E9 (R1). Addendum on estimands and sensitivity analysis in clinical trials, https:\/\/database.ich.org\/sites\/default\/files\/E9-R1_Step4_Guideline_2019_1203.pdf (2019, accessed 7 March 2020)."},{"key":"bibr2-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1007\/s43441-019-00063-9"},{"key":"bibr3-1740774520934747","doi-asserted-by":"publisher","DOI":"10.2307\/2529941"},{"key":"bibr4-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.publhealth.18.1.83"},{"key":"bibr5-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1111\/j.0006-341X.2000.00779.x"},{"key":"bibr6-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1191\/1740774505cn128oa"},{"key":"bibr7-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1177\/1740774507081224"},{"key":"bibr8-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.55.6340"},{"key":"bibr9-1740774520934747","unstructured":"US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Clinical trial endpoints for the approval of non-small cell lung cancer drugs and biologics. Draft guidance, April 2015, http:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/UCM259421.pdf (2015, accessed 7 March 2020)."},{"key":"bibr10-1740774520934747","unstructured":"US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Clinical trial endpoints for the approval of cancer drugs and biologics. Clinical\/medical, December 2018, http:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/UCM071590.pdf (2018, accessed 7 March 2020)."},{"key":"bibr11-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.340"},{"key":"bibr12-1740774520934747","unstructured":"European Medicines Agency. Guideline on missing data in confirmatory clinical trials, https:\/\/www.ema.europa.eu\/documents\/scientific-guideline\/guideline-missing-data-confirmatory-clinical-trials_en.pdf (2010, accessed 7 March 2020)."},{"key":"bibr13-1740774520934747","volume-title":"The prevention and treatment of missing data in clinical trials. Panel on handling missing data in clinical trials. Committee on national statistics, division of behavioral and social sciences and education","author":"National Research Council","year":"2010"},{"key":"bibr14-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1203730"},{"key":"bibr15-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/63.3.581"},{"key":"bibr16-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611593"},{"key":"bibr17-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1177\/1740774516657336"},{"key":"bibr18-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1186\/ar2422"},{"key":"bibr19-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1111\/j.1533-2500.2011.00524.x"},{"key":"bibr20-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69666-9"},{"key":"bibr21-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)16893-1"},{"key":"bibr22-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.308.6921.81"},{"key":"bibr23-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2008.12.014"},{"key":"bibr24-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1002\/sim.6274"},{"key":"bibr25-1740774520934747","unstructured":"Burko NS, Metcalfe P, Bartlett J, et al. 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R Package Version 0.3.4, https:\/\/www.rdocumentation.org\/packages\/InformativeCensoring\/versions\/0.3.4 (2016, accessed 11 August 2016)."},{"key":"bibr27-1740774520934747","first-page":"216","volume":"34","author":"Breslow NE","year":"1972","journal-title":"J R Statist Soc B"},{"key":"bibr28-1740774520934747","doi-asserted-by":"publisher","DOI":"10.1002\/9780470316696"}],"container-title":["Clinical Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1740774520934747","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/1740774520934747","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1740774520934747","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T17:30:46Z","timestamp":1777397446000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/1740774520934747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,9]]},"references-count":28,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["10.1177\/1740774520934747"],"URL":"https:\/\/doi.org\/10.1177\/1740774520934747","relation":{},"ISSN":["1740-7745","1740-7753"],"issn-type":[{"value":"1740-7745","type":"print"},{"value":"1740-7753","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,9]]}}}