Prevalence and implications of significance testing for baseline covariate imbalance in randomised cancer clinical trials: The Table 1 Fallacy.

Background: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials.
Methods: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy.
Results: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001).
Conclusions: This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Msaouel reported honoraria for scientific advisory board membership for Mirati Therapeutics, Bristol-Myers Squibb, and Exelixis; consulting fees from Axiom Healthcare; non-branded educational programmes supported by Exelixis and Pfizer; leadership or fiduciary roles as a Medical Steering Committee Member for the Kidney Cancer Association and a Kidney Cancer Scientific Advisory Board Member for KCCure; and research funding from Takeda, Bristol-Myers Squibb, Mirati Therapeutics, and Gateway for Cancer Research (all unrelated to this manuscript’s content). Dr. McCaw reported employment at Insitro (unrelated to this manuscript’s content). Dr. Tang reported grants from the Cancer Prevention & Research Institute of Texas (CPRIT) and the Andrew Sabin Family Foundation and being an Andrew Sabin Scholar and royalties from Wolters Kluwer and consulting fees and honoraria from Bayer, Diffusion Pharmaceuticals, and The Osler Institute Lecture Series (unrelated to this manuscript’s content). Dr. Taniguchi reports consulting fees from Phebry and Xerient and holds a patent related to radioprotection of the upper gastrointestinal tract. Dr. Rödel reported receiving research funding from German Cancer Aid (unrelated to this manuscript’s content). Dr. Fuller reported unrelated funding and salary support from: NIH NIBIB Research Education Programmes for Residents and Clinical Fellows Grant (R25EB025787-01); NIDCR Academic Industrial Partnership Grant (R01DE028290); NCI Parent Research Project Grant (R01CA258827) an NIH/NCI Cancer Centre Support Grant (CCSG); and an NSF Division of Civil, Mechanical, and Manufacturing Innovation (CMMI) grant (NSF 1933369). Dr. Fuller reported direct industry grant support, honoraria, and travel funding from Elekta AB unrelated to this project and reported direct infrastructure support from the multidisciplinary Radiation Oncology/Cancer Imaging Programme (P30CA016672-44) of the MD Anderson Cancer Centre Support (Core) Grant (P30CA016672) and the MD Anderson Programme in Image-guided Cancer Therapy. Dr. Sun reported personal fees from Boehringer Ingelheim (unrelated to this manuscript’s content). Dr. Meirson reported receiving personal fees from Purple Biotech (unrelated to this manuscript’s content). No other authors reported any conflicts of interest.
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