Overall decisions on the clinical use of new antimicrobials depend on the validity and reliability of the evidence from appropriately designed, conducted, and analyzed clinical trials. Because pneumonia is the sixth leading cause of death in the United States and the leading cause of infectious disease–related death, appropriate design of trials in hospital-acquired pneumonia and ventilator-associated pneumonia are an important public health issue. Several issues with the current design of trials in hospital-acquired pneumonia and/or ventilator-associated pneumonia potentially bias their results and raise questions about their validity. These issues are magnified in the context of noninferiority trials, in which bias can make interventions appear more similar, giving false-positive results of safety and effectiveness. The goal of this article is to provide a scientific basis for improving the validity, reliability, and efficiency of clinical trials in hospital-acquired pneumonia and/or ventilator-associated pneumonia to provide better information for decision making for patients, clinicians, regulators, and other stakeholders.

When investigators hypothesize that experimental interventions provide advantages other than improved effectiveness, they can use noninferiority (NI) trials to determine whether one can rule out the possibility that those interventions have unacceptably worse effectiveness than the standard “active control” regimen. To conduct valid NI trials, there must be evidence from historical studies that provides reliable, reproducible, and precise estimates of the effect of the active control, compared with that of placebo, on the specific outcomes investigators plan to use in the NI trial; this effect should be of substantial magnitude, and the estimates of the active control’s effect from historical studies must represent its effect in the planned NI trial had a placebo group been included. These conditions allow formulation of an NI margin such that, if the NI trial establishes that the effectiveness of the experimental intervention is not worse than the effectiveness of the active control by more than the NI margin, then one can conclude that the experimental regimen (1) preserves a substantial fraction of the effect of the active control and (2) will not result in a clinically meaningful loss of effectiveness. After general discussion of NI trial design issues, we consider the design of NI trials to evaluate antimicrobials in the treatment of community-acquired pneumonia. We present an extensive literature review, allowing estimation of the historical effect of active control regimens in community-acquired pneumonia primarily on the basis of evidence related to use of sulfonamides or penicillin. This review allows formulation of NI margins that are specific to age and bacteremia status of patients.

Research models and regulatory measures could aid in developing antimicrobial drugs to address bacterial resistance.

Innovative regulatory and legislative measures to stimulate and facilitate the development of new antimicrobial drugs are needed. We discuss research approaches that can aid regulatory decision making on the treatment of resistant infections and minimization of resistance selection. We also outline current and future measures that regulatory agencies may employ to help control resistance and promote drug development. Pharmacokinetic/pharmacodynamic research models offer promising approaches to define the determinants of resistance selection and drug doses that optimize efficacy and reduce resistance selection. Internationally, variations exist in how regulators use drug scheduling, subsidy restrictions, central directives, educational guidelines, amendments to prescribing information, and indication review. Recent consultations and collaborations between regulators, academics, and industry are welcome. Efforts to coordinate regulatory measures would benefit from greater levels of international dialogue.

Background

Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality.

Methods

We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel.

Results

Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with ≤ 50 CD4+ cells/mm3 before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with ≥ 500 CD4+ cells/mm3). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those ≥ 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), ≤ 50 CD4+ cells/mm3 (vs. CD4+ ≥ 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log10 increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant.

Conclusions

Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival.