Subsequent anticancer therapy in patients randomized to placebo alone or best supportive care

Oncology randomized controlled trials (RCTs) may use placebo or best supportive care (BSC) as control arms under certain conditions. The appropriateness of such comparators is uncertain when many control patients subsequently receive anticancer therapy. This study aimed to evaluate whether the use of inert control arms in recent FDA registration trials was justified, using subsequent anticancer therapy data.

We conducted a cross-sectional analysis of FDA registration trials for anticancer drugs approved between January 2009 and November 2024, identified from an internally compiled database of FDA records. Eligible trials were RCTs in advanced or metastatic disease using placebo-only or BSC as the control arm and reporting subsequent systemic therapy for at least the control group. Data on trial characteristics, crossover design, subsequent therapy, and outcomes were abstracted. Descriptive statistics and regression analyses assessed associations between subsequent therapy rates and trial outcomes.

Among 550 FDA approvals, 18 trials met inclusion criteria. Overall, 49 % of patients in control arms received subsequent systemic therapy. Trials allowing crossover reported higher rates of subsequent therapy (66.0 %) than those without crossover (40.7 %). A significant inverse association was observed, with a 0.07 decrease in hazard ratio for every 10 % increase in control patients receiving subsequent therapy.

Nearly half of patients in control arms of trials using inert comparators received subsequent active therapy, calling into question the appropriateness of these control designs. Inappropriate use of inactive controls may inflate treatment effects. Regulators and ethics committees should ensure justified comparator selection in vulnerable populations.