Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
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For treatment studies of an infectious disease, such as pneumonia, microbiologic eradication is the logical primary end point. Several problems for pneumonia in general and several more specific to VAP preclude the use of microbiologic eradication as a primary end point. These problems include no positive culture result at baseline, difficulty distinguishing colonization from infection on baseline cultures, no specimen available for testing when determining cure, and induction of colonization by antibiotic treatment. ⋯ Although promising, especially for open-label studies focused on multidrug-resistant pathogens, further research is needed before serial quantitative cultures can be used to define microbiologic failure. Of the biomarkers, procalcitonin level may be a valuable adjunct to clinical evaluation but cannot be a primary end point alone. A decreasing or low procalcitonin level after initiation of antibiotic treatment correlates well with bacterial eradication.
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Hospital-acquired pneumonia and ventilator-associated pneumonia are associated with high rates of morbidity and mortality and are often caused by drug-resistant pathogens. Trials of potential new agents to treat these serious infections are complicated by various factors associated with their design and conduct and the complex underlying conditions of the patients that can potentially obscure determination of treatment benefits. ⋯ Regulatory guidance could help to standardize the design and conduct of trials evaluating potentially efficacious agents. In this article, some of the important challenges that were faced in conducting trials of agents to treat hospital-acquired pneumonia and ventilator-associated pneumonia are described, and areas for which regulatory guidance would be most useful are discussed.
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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. ⋯ 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.
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There is an increasing focus on having quality systems in place during the planning stages of clinical trials. Such systems require the development and implementation of standards for each step. Although this is not imposing something totally new on clinical research, a systematic approach will produce a more reliable and useful end product--high-quality data obtained without compromising the protection of human subjects' rights and welfare. A suggested quality system with standards for each step is addressed in this article.