Recommended design features of future clinical trials of antibacterial agents for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.

Nosocomial pneumonia, including HAP and VAP, is the second leading type of nosocomial infection and the leading cause of death from nosocomial infection in the United States [1–3]. An estimated 300,000 HAP and VAP infections occur per year in the United States, and the mortality rate among patients with HAP and/or VAP is ≥20% despite treatment [3, 4]. Furthermore, increasing antibacterial resistance because of the increasing incidence of MDR, XDR, or truly pan–drug-resistant gram-negative bacilli continues to increase the mortality associated with these infections [5–16]. Unfortunately, at the same time that increasing drug resistance has created a crucial need to develop new treatments, the development of new antibacterial agents has been decreasing dramatically [17, 18]. Uncertainty about regulatory requirements for the appropriate design of clinical trials testing the efficacy of antibacterial agents is a major barrier to research and development and likely has contributed to the decrease in availability of new antibacterial agents [17]. In January 2008, the IDSA and the FDA jointly convened a workshop to elucidate an appropriate clinical trial design for CAP [19]. The workshop allowed experts from academia, industry, and the FDA to share pertinent knowledge about clinical trials for CAP. On the basis of the scientific and regulatory discussions at the workshop, the IDSA published a position paper synthesizing the crucial elements of appropriate trial design for CAP [20]. Subsequently, the FDA released a draft guidance on the design of trials for CABP [21], which has greatly clarified regulatory expectations for such studies. In the guidance document, the FDA specifically referred to the disease entity as CABP rather than CAP, to emphasize the crucial need to establish a bacterial etiology of infection for noninferiority clinical trials of the disease. After the successful workshop on CABP, the FDA, the IDSA, the ATS, SCCM, and ACCP jointly sponsored a follow-up workshop focusing on HABP and VABP from 31 March through 1 April 2009. In accordance with the precedents established by the FDA guidance on CABP, the follow-up workshop focused specifically on HABP and VABP (as opposed to HAP and VAP) to underscore the need to establish a microbiological diagnosis during clinical trials of antibacterial agents for treatment of these diseases. This position paper is based on the data presented, discussions held, and opinions expressed at the HABP and/or VABP workshop and an ongoing dialogue subsequent to the workshop. Conclusions and suggestions presented in this document are those of the societies. There is no intent to represent the views of industry or the FDA. The societies’ goal is to consider the data and represent the best interests of patients by providing clarity to clinical investigators, clinicians, the pharmaceutical industry, and regulatory officials regarding appropriate clinical trial design for the study of investigational antibacterial agents in the treatment of HABP and VABP. For topics on which a clear consensus could not be achieved or on which strongly held dissenting opinion was evident, alternative design features are presented. Consideration is given to 8 specific aspects of clinical trial design for HABP and/or VABP: (1) justification for a noninferiority versus a superiority hypothesis; (2) primary and secondary end point evaluations and the patient populations in which they should be assessed; (3) enrollment criteria including microbiological diagnostic methodologies; (4) advisability and difficulties with study of HABP and VABP in the same clinical trial rather than in separate trials; (5) appropriate standard comparator and adjunctive therapy; (6) factors by which enrollment should be stratified; (7) trial integrity issues, including blinding, use of international sites, and the desirability of a clinical trials network; and (8) core components of a HABP and/or VABP clinical trials program.