Abstract
BackgroundHospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs.MethodsA search (Pubmed-Embase-ICAAC-ECCMID) of all RCTs published between 1994 and 2016 comparing antimicrobial treatment for HAP/VAP in the intensive care unit was conducted. The populations enrolled, inclusion/exclusion criteria, statistical design and endpoints assessed were recorded. All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened.ResultsFrom the 93 abstracts reviewed, 39 potentially relevant studies were inspected, leading to 27 studies being included. As expected, illness severity or the proportion with VAP (27–100%) differed greatly among the enrolled populations. The HAP/VAP definition used various clinical and biological criteria, and only 55% of studies required a microbiological sample. The mandatory duration of prior hospital stay was variable; the mechanical ventilation duration was an inclusion criterion in only 41% of VAP studies. Nine studies had non-inferiority design, but nine studies (33%) did not have a pre-specified statistical hypothesis. Clinical cure was the primary endpoint in 24 studies, but was recorded in several populations or as the co-primary endpoint in 13 studies. The definition of clinical cure and the timing of its assessment greatly differed. This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened.ConclusionOur study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the ICU. There was significant heterogeneity in enrollment criteria, endpoints and statistical design, which may influence the ability of studies to demonstrate differences between studied drugs.
Highlights
Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval
During the past ten years, the regulatory agencies (European Medicines Agency (EMA) and Food and Drug Administration (FDA)) have repeatedly updated their guidelines for the design of randomized controlled trials (RCTs), but their recommendations remain conflicting, especially regarding the design, endpoints, or inclusion criteria that should be used [2, 3]. This is an important issue because hospital-acquired pneumonia (HAP) and VAP are ideal syndromes for clinical trials in the context of new drug approval: they are a major cause of infection, often involving multidrug-resistant pathogens (25% of intensive care unit (ICU) infections), they account for up to 50% of antibiotic prescriptions [4], identification of the causative pathogen using microbiological samples is easy, and they are sensitive to antimicrobial treatment effect [5, 6]
Main findings In this systematic review comprising 27 published RCTs addressing the efficacy of antimicrobials for treatment of HAP/VAP in critically ill patients, we found that the enrolled populations, clinical trial design, and endpoints assessed vary greatly between studies
Summary
Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. During the past ten years, the regulatory agencies (European Medicines Agency (EMA) and Food and Drug Administration (FDA)) have repeatedly updated their guidelines for the design of randomized controlled trials (RCTs), but their recommendations remain conflicting, especially regarding the design, endpoints, or inclusion criteria that should be used [2, 3] This is an important issue because HAP and VAP are ideal syndromes for clinical trials in the context of new drug approval: they are a major cause of infection, often involving multidrug-resistant pathogens (25% of ICU infections), they account for up to 50% of antibiotic prescriptions [4], identification of the causative pathogen using microbiological samples is easy, and they are sensitive to antimicrobial treatment effect [5, 6]
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