Quantifying Withdrawal of Consent, Loss to Follow-Up, Early Drug Discontinuation, and Censoring in Oncology Trials

Authors:
Brooke E. Wilson Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre, and University of Toronto, Toronto, Ontario, Canada; and
University of New South Wales, Kensington, New South Wales, Australia.

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Michelle B. Nadler Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre, and University of Toronto, Toronto, Ontario, Canada; and

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Alexandra Desnoyers Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre, and University of Toronto, Toronto, Ontario, Canada; and

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Eitan Amir Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre, and University of Toronto, Toronto, Ontario, Canada; and

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Background: Censoring due to early drug discontinuation (EDD) or withdrawal of consent or loss to follow-up (WCLFU) can result in postrandomization bias. In oncology, censoring rules vary with no defined standards. In this study, we sought to describe the planned handling and transparency of censoring data in oncology trials supporting FDA approval and to compare EDD and WCLFU in experimental and control arms. Methods: We searched FDA archives to identify solid tumor drug approvals and their associated trials between 2015 and 2019, and extracted the planned handling and reporting of censored data. We compared the proportion of WCLFU and EDD between the experimental and control arms by using generalized estimating equations, and performed logistic regression to identify trial characteristics associated with WCLFU occurring more frequently in the control group. Results: Censoring rules were defined adequately in 48 (59%) of 81 included studies. Only 14 (17%) reported proportions of censored participants clearly. The proportion of WCLFU was higher in the control group than in the experimental group (mean, 3.9% vs 2.5%; β-coefficient, −2.2; 95% CI, −3.1 to −1.3; P<.001). EDD was numerically higher in the experimental arm in 61% of studies, but there was no statistically significant difference in the proportion of EDD between the experimental and control groups (mean, 21.6% vs 19.9%, respectively; β-coefficient, 0.27; 95% CI, −0.32 to 0.87; P=.37). The proportion of EDD due to adverse effects (AEs) was higher in the experimental group (mean, 13.2% vs 8.5%; β-coefficient, 1.5; 95% CI, 0.57–2.45; P=.002). WCLFU was higher in the control group in studies with an active control group (odds ratio [OR], 10.1; P<.001) and in open label studies (OR, 3.00; P=.08). Conclusions: There are significant differences in WCLFU and EDD for AEs between the experimental and control arms in oncology trials. This may introduce postrandomization bias. Trials should improve the reporting and handling of censored data so that clinicians and patients are fully informed regarding the expected benefits of a treatment.

Submitted November 8, 2020; final revision received January 5, 2021; accepted for publication January 23, 2021. Published online September 3, 2021.

Author contributions: Study concept: Wilson, Nadler, Amir. Data extraction: Wilson, Nadler, Desnoyers. Data analysis: Wilson, Amir. Data interpretation: All authors. Manuscript preparation: All authors.

Disclosures: Dr. Amir has disclosed receiving personal fees from Genentech/Roche, Apobiologix, Myriad Genetics, and Agendia. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Dr. Wilson received support as a National Breast Cancer Foundation of Australia International Fellow. Dr. Nadler received support as a Dream Hold’em for Life clinical oncology fellow. Dr. Desnoyers received support as a Dream Hold’em for Life clinical oncology fellow.

Correspondence: Brooke E. Wilson, MBBS, MSc, Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Center, 610 University Avenue, 7-305W, Toronto, ON, Canada, M5G 2M9. Email: drbrookewilson@icloud.com

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