Regulating Antibiotics in an Era of Resistance: The Historical Basis and Continued Need for Adequate and Well-Controlled Investigations.

T bills introduced in Congress (the Promise for Antibiotics and Therapeutics for Health Act and the Antibiotic Development to Advance Patient Treatment Act of 2013 in the 21st Century Cures Act) propose changes in the regulatory approval of new antibiotics in the context of attempts to reengage industry amidst fears of a postantibiotic future. Despite anti-infectives having among the shortest development times and highest approval rates among therapeutic classes (1–3), some propose that the requirements of adequate and well-controlled studies make the study of new antibiotics infeasible (4). To address perceived hurdles, these bills propose a regulatory pathway in poorly defined “limited populations” without requiring demonstrated benefits in populations with resistant disease. Studies would be done in patients with effective options rather than those with unmet medical needs, allowing approval even with inferior effectiveness in the population studied. No requirement for diagnostics means that the drugs may be prescribed empirically outside the limited population. The bills would alter the standard of approval from substantial evidence to “sufficient evidence” derived from “small clinical data sets” and would consider preclinical data, animal models, and pharmacologic data to be “confirmatory evidence.” In the setting of such proposals, historical reflection is in order. Antibiotics were the leading example of post– World War II “wonder drugs,” dramatically rebranding medicine. They were the most lucrative segment of the pharmaceutical industry and transformed such companies as Pfizer and Parke-Davis. Yet, despite the advent of penicillin and broad-spectrum antibiotics, by the early 1950s staphylococcal resistance led to the perceived need for an arms race to keep up with lifethreatening diseases caused by resistant organisms (5). By the mid-1950s, pharmaceutical companies marketed antibiotic combinations, predicated on in vitro synergy, as solutions to resistant organisms. However, leading infectious disease researchers, including Maxwell Finland, Harry Dowling, and Ernest Jawetz, found them to be no more effective than their components in treating human disease; strain-dependent in their action; and, hence, not amenable to prepackaged formulations. Despite these observations, the drugs were widely promoted and used in what Finland and Dowling perceived as an evidentiary vacuum. At the time, the U.S. Food and Drug Administration (FDA) could only formally adjudicate drug safety (not efficacy), and to Finland and Dowling, the widespread marketing and uptake of these antibiotics, based on what they termed “testimonials” (case series supported by in vitro data), portended a future of style over substance that threatened the very future of rational therapeutics (5). In response, Finland called for controlled clinical trials to offset premature claims of efficacy. In 1957, he wrote on behalf of 18 leading infectious disease researchers (6):