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Surfactant Depletion Combined with Injurious Ventilation Results in a Reproducible Model of the Acute Respiratory Distress Syndrome ARDS
Published on: April 7, 2021
Confronting the frustrations of negative clinical trials in acute respiratory distress syndrome
1Interdepartmental Division of Critical Care Medicine, University of Toronto, Program in Trauma, Emergency, and Critical Care, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
Abstract:
Despite robust successes in trials of mechanical ventilation, pharmacologic interventions in acute respiratory distress syndrome have been disappointing. Although ineffective therapy remains the compelling explanation for these negative trials, other possible explanations exist. These negative trials, better termed "statistically negative trials" or "indeterminate trials," cannot prove that a therapy is ineffective. It is important for clinicians and investigators to appreciate the alternative explanations for negative trials of potentially effective therapies because these indicate options for improving clinical trials in acute respiratory distress syndrome. These options can be organized into strategies that increase sample size, increase the signal from the therapy, and reduce the noise or variation in the study. Each of the strategies to improve the likelihood of a positive clinical trial poses a potential tradeoff in generalizability, cost, sample size, signal, or noise.
Insights
Pharmacologic interventions for acute respiratory distress syndrome (ARDS) have yielded disappointing trial results. Alternative explanations for these statistically negative trials offer strategies to improve future ARDS clinical trial design and outcomes.
Area of Science:
- Critical Care Medicine
- Clinical Trials
- Pulmonary Medicine
Background:
- Mechanical ventilation trials for acute respiratory distress syndrome (ARDS) show success.
- Pharmacologic interventions in ARDS clinical trials have consistently disappointed.
- Negative trial outcomes do not definitively prove a therapy's ineffectiveness.
Purpose of the Study:
- To explore alternative explanations for statistically negative clinical trials in ARDS.
- To identify strategies for improving the design and success rate of future ARDS pharmacologic trials.
Main Methods:
- Analysis of reasons for negative clinical trial results in ARDS.
- Categorization of strategies to enhance the likelihood of positive trial outcomes.
Main Results:
- Negative trials in ARDS may be statistically indeterminate rather than indicative of true ineffectiveness.
- Strategies to improve trial success include increasing sample size, enhancing treatment signal, and reducing outcome variability (noise).
Conclusions:
- Understanding alternative explanations for negative ARDS trials is crucial for researchers.
- Implementing strategies to increase sample size, signal, and reduce noise can improve future ARDS clinical trial success.
- Each strategy for trial improvement involves potential tradeoffs in generalizability, cost, or statistical power.
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