Date Published: July 12, 2019
Publisher: Public Library of Science
Author(s): Piero L. Olliaro, Michel Vaillant
Abstract: In this Collection Review for the Novel Treatments for Tuberculosis Collection, Piero Olliaro and Michael Vaillant discuss the considerations when choosing a non-inferiority margin that is meaningful from statistical, ethical, clinical, and health standpoint.
Partial Text: Identifying effective regimens for tuberculosis (TB) is challenging; trials are long between treatment and follow-up and require large sample sizes, so they take a long time to complete and are expensive. Oftentimes, they are also inconclusive. Lienhardt and Nahid  and Phillips and colleagues  call for innovation in trial design that would allow for identifying effective regimens more quickly and efficiently.
The noninferiority design has been adopted in explanatory treatment trials of active TB for newly diagnosed (expectedly drug-sensitive) TB (DSTB) (five trials completed and reported [17–21] and one systematic review ) and three for drug-resistant TB [DRTB] [23–25]. In these trials, the noninferiority margin ranged from 4% to 12% and is wider for multidrug-resistant TB (MDRTB) than DSTB (see Table 1).
This example further illustrates how critical it is to establish a noninferiority margin that is ‘meaningful’ statistically, clinically, and programmatically and is ethically acceptable. But how can the results of a trial be made to speak to clinicians and policy makers?
Using a composite end point is practical (as it summarises findings into a single message), but we must be aware of two potential issues.
Now the question is, Using the previously mentioned examples, how would stakeholders (national TB programme managers, caregivers, patients) weigh losses and gains?
Though it has been wrongly used to justify ‘me-too’ medicines, the noninferiority design is having a growing place in diseases like TB, which require treatments that are long and cumbersome for patients and health systems alike, and where attributes like adherence, user-friendliness, and tolerability are critical to real-life effectiveness. Although the noninferiority design may be applied to treatment trials in both DSTB and DRTB against the current standard of care, this does not take away the responsibility for finding both more effective and easier-to-comply regimens, especially for DRTB.