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. 2023 Aug:189:112920.
doi: 10.1016/j.ejca.2023.05.008. Epub 2023 May 15.

Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study

Alessandro Rossi  1 , Giacomo Aimar  2 , Marco Audisio  3 , Maristella Bungaro  4 , Andrea Caglio  5 , Raimondo Di Liello  6 , Teresa Gamba  5 , Piera Gargiulo  7 , Eleonora Ghisoni  8 , Pasquale Lombardi  9 , Laura Marandino  10 , Annapaola Mariniello  11 , Chiara Paratore  3 , Maria Lucia Reale  12 , Federica Trastu  5 , Valentina Tuninetti  5 , Fabio Turco  13 , Alessandra Fabi  1 , Francesco Perrone  7 , Massimo Di Maio  14
Affiliations

Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study

Alessandro Rossi et al. Eur J Cancer. 2023 Aug.

Abstract

Introduction: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms.

Methods: We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2).

Results: This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007).

Conclusions: Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results.

Keywords: Control arm; Meta-research; Methodology; Oncology; Randomised controlled trials.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, RDL reports honoraria from Astellas Pharma and Janssen. LM reports honoraria from Gilead and Merck; research grant from AstraZeneca; travel expenses from Janssen. CP reports support for attending meetings and/or travel from Eli Lilly and Takeda; institutional research grant from IQVIA. MLR reports honoraria from Eli Lilly, AstraZeneca and Janssen. AF reports honoraria from Roche, Pfizer, Novartis, Dompè , Astra Zeneca, Seagen, Gilead, Exact Science, Eli Lilly; support for attending meetings and/or travel from Roche, Pfizer, Novartis, Dompè , Astra Zeneca, Seagen, Gilead, Exact Science, Eli Lilly; participation on advisory boards for Roche, Pfizer, Novartis, Astra Zeneca, Seagen, Gilead, Eli Lilly. FP reports honoraria from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, Pfizer; institutional funding for work in clinical trials/contracted research from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GlaxoSmithKline and Merck. MDM reports honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, Takeda for consultancy or participation to advisory boards institutional research funding from Tesaro/GlaxoSmithKline, institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche. Other authors declare no relationships or activities that could appear to have influenced the submitted work.

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