Is There Hope for the Prevention of Future Antimicrobial Shortages?

SIR—Shlaes and Moellering [1] recently described the impact of using a 10% delta for the lower limit of the 95% CI for clinical trials of noninferiority when a newly developed antibiotic is compared with a previously approved agent. The authors discussed the high number of patients required for statistically significant data in clinical trials that use a 10% delta, and they accurately described the impracticality of conducting a clinical trial using a 10% delta for an infection such as acute meningitis, for which µ700 patients would be needed. Such a trial would require a large number of sites and would take several years to complete. Shlaes and Moellering [1] emphasized that the costs of conducting such a study and the potentially low financial return to the sponsor are imposing disincentives for development. They described current trends in private industry away from the development of antibiotics, and they predicted a future in which most pharmaceutical companies would not have programs for antibiotic development. Such trends would ultimately result in a national shortage of agents for the treatment of potentially lethal infections, the majority of which can be cured with use of appropriate antibiotics. Meanwhile, the US Food and Drug Administration (FDA) is faced with an exceptionally complex and important problem. The problem of antimicrobial shortages is highly analogous with the problem of vaccine shortages. The FDA must assure the public that the antimicrobials under development are safe. It must also set standards for meaningful comparisons of new agents with agents that are used as the standard of care or with placebo. The FDA must set these standards in a context that will not prohibit the industry from developing new agents. An approval system with standards so rigid that it stifles the development of new agents will obviously do much more harm than good to the welfare of patients with treatable infections. On 19 and 20 February 2002, the FDA convened an extremely important and productive advisory committee meeting that included representatives from the FDA Anti-Infectives Advisory Board, Pharmaceuticals Research and Manufacturers of America (PhRMA), and the Infectious Diseases Society of America (IDSA). During this meeting, the FDA fully delineated the biostatistical considerations for noninferiority trials. PhRMA offered strategies for maintaining high standards for both safety and validity of comparisons of new agents with agents used as the standard of care, and the IDSA, representing the physician specialists in infectious diseases, expressed concern regarding the availability of antimicrobials for patients with serious and potentially fatal infections. During this exceptionally well-organized and well-conducted meeting, the complexities of the problem were fully delineated. It was clear that the FDA was not planning to use a 10% delta across the board for clinical trials for anti-infectives. Creative and thoughtful strategies and alternatives were introduced and considered by all 3 groups. The FDA is to be applauded for organizing and convening this critically important meeting, which addressed a complex and multifaceted problem. After this meeting, ⩾2 major pharmaceutical companies resurrected certain antimicrobial agent evaluations. We hope that this meeting will be the first of many future working groups, advisory panels, and task forces to assure the continual development of safe and effective antimicrobials, which, in turn, will prevent shortages in a country where they should not exist.