Arguing for Adaptive Clinical Trials in Sepsis

Abstract

Sepsis is life-threatening organ dysfunction due to dysregulated response to infection. Patients with sepsis exhibit wide heterogeneity stemming from genetic, molecular, and clinical factors as well as differences in pathogens, creating challenges for the development of effective treatments. Several gaps in knowledge also contribute: (i) biomarkers that identify patients likely to benefit from specific treatments are unknown; (ii) therapeutic dose and duration is often poorly understood; and (iii) short-term mortality, a common outcome measure, is frequently criticized for being insensitive. To date, the majority of sepsis trials use traditional design features, and have largely failed to identify new treatments with incremental benefit over standard of care. Traditional trials are also frequently conducted as part of a drug evaluation process that is segmented into several phases, each requiring separate trials, with a long time delay from inception through design and execution to incorporation of results into clinical practice. By contrast, adaptive clinical trial designs facilitate the evaluation of several candidate treatments simultaneously, learn from emergent discoveries during the course of the trial, and can be structured efficiently to lead to more timely conclusions compared to traditional trial designs. Adoption of new treatments in clinical practice can be accelerated if these trials are incorporated in electronic health records as part of a learning health system. In this review, we discuss challenges in the evaluation of treatments for sepsis, and explore potential benefits and weaknesses of recent advances in adaptive trial methodologies to address these challenges.

Machine learning for the prediction of sepsis: a systematic review and meta-analysis of diagnostic test accuracy

“…Sepsis is one of the leading causes of death worldwide [1], with incidence and mortality rates failing to decrease substantially over the last few decades [2,3]. While the Surviving Sepsis international consensus guidelines recommend starting antimicrobial treatment within 1 h from sepsis onset given the association between treatment delay and mortality [4][5][6][7][8], early recognition can be difficult due to disease complexity in clinical context [9,10] and heterogeneity of the septic population [11].…”

Sepsis therapies: learning from 30 years of failure of translational research to propose new leads

“…Arguments are however made to increase the default P value threshold to 0.005 for claims of discovery (Benjamin et al , ), thus requiring many more patients, or reducing the sample size by a Bayesian approach (Goligher et al , ). Others argue for adaptive trial designs with simultaneous inclusion of several treatment arms and modifications justified by findings emerging during the trial (Talisa et al , ). However, adequate group sizes in such a heterogenous critical care population may prove to be problematic.…”

Editorial: Translational Insights Into Mechanisms and Therapy of Organ Dysfunction in Sepsis and Trauma

“…Finally, Kesselmeier and Scherag comment on the recently popularized "adaptive clinical trials" discussing a recent article in this journal by Talisa et al (4). The authors clearly acknowledge that adaptive trials allow modifying design elements during trial conduct, thereby possibly reducing resources, duration and sample size while simultaneously enhancing the chance of proof for an effective treatment.…”