Noninferiority trials: clinical understandings and misunderstandings

摘要

In many clinical settings for the treatment or prevention of disease, currently available interventions provide clinically meaningful benefits by decreasing irreversible morbidity or mortality. An important example is the setting of treatment for pneumonia, where some antibiotics provide substantive benefits by meaningfully reducing mortality in addition to improving symptoms of cough, breathlessness and chest pain. Even though existing standard interventions (hereafter called 'Standard') provide important clinical benefits in clinical settings such as pneumonia, patients and caregivers may be interested in new interventions that would essentially retain the efficacy of Standard while being substantially better in terms of safety, convenience of administration, or cost. When the goal is to replace an existing Standard that provides clinically meaningful effects on measures of irreversible morbidity or mortality, there is ethical motivation to use Standard as the control in a randomized trial evaluating the new intervention. While it would be preferable in such a trial to establish the new intervention to have superior efficacy, it may be sufficient to rule out that its efficacy is unacceptably worse than that of Standard. These are called noninferiority (NI) trials and have been discussed extensively in the literature. By design, the NI trial requires specification of the minimum threshold constituting an unacceptable loss of efficacy. This threshold is called the NI margin.