[Comment] Broad lessons from negative trials in rare diseases

Negative trials are often perceived as setbacks, but they can be among the most instructive and essential for recalibrating assumptions in rapidly evolving fields such as gene therapy.1 Negative trials can prompt a cautious re-evaluation of surrogate endpoints, trial design, timing of intervention, and the interpretation of early-phase data, including reliance on historical controls. In The Lancet Neurology, Francesco Muntoni and colleagues report the negative results of the CIFFREO study,2 a large, randomised, double-blind, placebo-controlled, phase 3 trial evaluating fordadistrogene movaparvovec, an adeno-associated virus 9 (AAV9)-based mini-dystrophin gene therapy, in ambulant boys with Duchenne muscular dystrophy.