Studying new antibiotics for multidrug resistant infections: are today’s patients paying for unproved future benefits?

Concerns over the threat of antibiotic resistance have fuelled legislative and regulatory efforts to promote development of new treatments for serious infections. Fears arise that the world could face serious, multidrug resistant bacterial diseases that lack effective treatments. An optimal approach would be to develop drugs that improve on current effective therapies for today’s patients, while potentially offering benefits for future patients as antibiotic resistance evolves.

Unlike in many other therapeutic areas, however, most new antibiotics are approved without evidence of superior efficacy in clinical trials. Rather, regulatory authorities increasingly permit “non-inferiority” hypotheses. These allow lesser effectiveness than already approved drugs in trade-off for other benefits such as decreased adverse effects.12345 Indeed, some claim that superiority hypotheses are unethical for investigational antibiotics since they might expose patients in the control group to harm.6

A review evaluating US Food and Drug Administration approvals from 2009 to 2015 showed eight new antibiotics indicated for “serious and life threatening” diseases, with seven approved solely on evidence of non-inferiority. Recent FDA guidance supports extrapolating non-inferiority results in patients with effective treatments to presume superior outcomes in patients without effective options.25 But are drugs that are “non-inferior” today going to be superior tomorrow? Do non-inferiority hypotheses expose today’s patients with treatable life threatening infections to increased risk of harm by allowing investigational antibiotics with less effectiveness onto the market?