Negative results in cancer clinical trials—equivalence or poor accrual?

Abstract

This study was performed to evaluate randomized cancer trials resulting negative regarding inadequate accrual, unsupported assumptions of equivalence and factors implied in such assumptions. A search in PubMed electronic data base was done for a sample of 800 most recently entered studies by March 2003 indexed with MESH term “neoplasms” and categorized according to design, intervention, outcome and conclusion. Minimal detectable differences with optimized power were calculated in each comparison according to number of patients accrued. Factors related with inadequate claim for equivalence in negative comparisons were also searched. Among the papers located, 194 met requirements and 188 were analyzed leading to 392 valid comparisons addressing survival, anti cancer effect or major toxicity, 235 of which resulted “negative”. According to accrual, only 15.2% (ci95%, 9.9% to 20.3%) of negative comparisons would detect a 10% absolute difference between arms with 80% of chance. 53.6% (ci95%, 47.0% to 60.1%) of negative comparisons inadequately claimed equivalence. However, equivalence was supported by data in only 20.5% (ci95%, 12.6% to 28.4%) of negative comparisons that claimed for it. Negative comparisons based on new drugs had higher likelihood to be inadequately presented as supporting equivalence than those based in older drugs (66.7% vs. 43.5%, chi-square p=0.024). We concluded that most cancer clinical comparisons resulting negative are affected by poor accrual. They often inadequately claim for equivalence without supporting data. Comparisons involving new drugs are specially affected by this problem. Authors, editors and readers must be more rigorous regarding adequate assumptions of equivalence.