Clinical trial design for unmet clinical needs: a spotlight on sepsis

ABSTRACT

Introduction: Despite considerable advances in our understanding of how sepsis develops and multiple clinical trials of potential therapies, no new pharmacologic agent has been consistently shown to improve survival.

Areas covered: We reviewed relevant publications identified through PubMed and from the authors’ knowledge of this field. We discuss the main reasons why clinical trials on new therapeutic interventions have failed in the past, including heterogeneity of study populations and choice of outcome measures. We discuss how changes in study design and in patient selection could help improve identification of effective agents in the future.

Expert opinion: The search for new sepsis therapies must continue but lessons must be learned from previous clinical trials so that the same mistakes are not repeated. Rather than grouping all patients with sepsis together, we should study only those most likely to benefit from the intervention. Better characterization of patients will be facilitated using modern ’omics technology and analysis of the increasingly large quantities of clinical data available, enabling more personalized patient selection for trial inclusion. New clinical trial design and inclusion of other endpoints in addition to mortality will also aid our search for the elusive positive clinical trial and effective interventions for sepsis.

KEYWORDS:

• Adaptive trial design
• heterogeneity
• mortality
• outcomes
• personalization
• phenotype
• syndrome

Article highlights

• Sepsis is a dysregulated response to infection, which results in organ failure and is associated with high short and long-term mortality and morbidity.

• As knowledge of sepsis has improved, multiple molecules have been identified as potential treatments, but despite often being shown as effective in pre-clinical studies, results from RCTs have been much less convincing.

• There are many reasons why RCTs have failed to demonstrate beneficial effects of these interventions on survival, including problems of dose and timing, heterogeneity of patients selected for inclusion, and choice of outcome endpoints.

• Better characterization of patients so that only those likely to benefit are included in trials should help in the identification of effective interventions and prevent early abandonment of potentially beneficial treatments.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.