Abstract
Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18-0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies.
Highlights
The decision to initiate an early phase clinical trial requires careful evaluation of the benefits and risks of a novel intervention
We quantitatively summarized the results of all preclinical studies of mesenchymal stromal cells (MSCs) therapy for in vivo animal models of sepsis to predict effect size and establish an ethical basis for exposing high-risk patients to this novel therapy
Significant effects were seen using MSCs derived from bone marrow and umbilical cord, but the MSCs derived from adipose tissue did not demonstrate statistically significant efficacy
Summary
The decision to initiate an early phase clinical trial requires careful evaluation of the benefits and risks of a novel intervention. For first-in-human studies for which there is no prior clinical experience, the assessment of potential therapeutic efficacy must rely solely on the preclinical investigations. Regulatory guidance exists for the conduct of preclinical evaluation of novel therapies S. Department of Health and Human services, 2013), there is little guidance to help stakeholders summarize and assess the benefit and risks of novel therapies prior to first-in-human studies. The evidence from individual preclinical studies is often summarized and described in a non-systematic and potentially biased manner (Food and Drug Administration, 2015). We present an approach to transparently evaluate preclinical evidence of a therapy prior to its potential clinical translation. Our exemplar is mesenchymal stem cell (MSC) therapy for sepsis
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