Registration Trials May Mask Toxicities, 'Real-Life Outcomes' of New Anticancer Agents
Eitan Amir, MD, of Princess Margaret Hospital, Toronto, Ontario, Canada, and colleagues conducted a metaanalysis of serious toxicity reported in pivotal trials of anticancer drugs approved by the US Food and Drug Administration between 2000 and 2010.
Three end points of safety and tolerability—treatment-related death, treatment-discontinuation related to toxicity, and grade 3 or 4 adverse events—were identified in 38 randomized controlled trials, odds ratios computed, and the data pooled. “Correlations between these end points and the hazard ratios for overall survival (OS) and progression-free survival (PFS) were also assessed,” they noted.
Odds of toxic death were greater for new agents vs controls (OR, 1.40; 95% CI, 1.15–1.70; P<0.001) as were odds of treatment-discontinuation (OR, 1.33; 95% CI, 1.22–1.45, P<0.001) and grade 3 or 4 AEs (OR, 1.52; 95% CI, 1.35–1. 71; P<0.001). Nonhematologic AEs such as diarrhea, skin reactions, and neuropathy were especially more common. No significant correlations between safety end points and OS or PFS were observed.
“Although improvements in efficacy are crucial for the approval of a new drug, this should be weighed against its toxicity leading to morbidity and mortality when drugs are reviewed by registration agencies,” the investigators wrote. “Once approved, drugs may also be prescribed by clinicians with limited training or experience, leading to the potential for greater toxicities and adverse outcomes. It is therefore not possible to predict the real-life outcomes and extent of such toxicities with the data generated by randomized controlled trials. Large population-based outcome studies should be encouraged to quantify real-life efficacy and toxicity and to detect variations in efficacy and toxicity among different populations.”
In addition, biomarkers of toxicity as well as efficacy should be investigated in future clinical trials.