Journal of Critical Care
Volume 23, Issue 4 , Pages 493-499, December 2008

Important issues in the design and reporting of clinical trials in severe sepsis and acute lung injury☆

  • R. Phillip Dellinger, MD

      Affiliations

    • Cooper University Hospital, Robert Wood Johnson Medical School, Camden, NJ, USA
    • Corresponding Author InformationCorresponding author.
    • ,
  • Jean-Louis Vincent, MD, PhD

      Affiliations

    • Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Belgium
    • ,
  • John Marshall, MD

      Affiliations

    • Departments of Surgery and Critical Care Medicine, University of Toronto, Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Canada
    • ,
  • Konrad Reinhart, MD

      Affiliations

    • University Hospital Jena, Friedrich Schiller University, Jena, Germany

published online 07 April 2008.

Abstract 

Severe sepsis and acute lung injury are challenging diagnoses as they relate to designing and reporting of clinical trials. The limited success in bringing forward new therapies in these areas is likely proof of that premise. The ability to use preclinical and phase I and II trial data to predict which patients and which dosing regimens are more likely to benefit is perhaps the greatest challenge. Animal models continue to be refined in attempts to more accurately reproduce human sepsis and acute lung injury. Oncology research should serve as a model for optimizing the integration of pharmacodynamics and pharmacogenetics into trial design. The European Organization for Research and Treatment of Cancer provides a valuable template for nonfunded multicenter clinical trial success. The marked heterogeneity of the patient population and small signal (tested therapy)–to-noise (comorbidities) ratio makes identification of treatment effect difficult. Dedicated investigators still enroll ineligible patients who are included in intent to treat analysis. High enrolling centers create less problems in an adequate test of a new therapy. Much has been learned from negative trials as to value of post hoc subgroup and interim analyses. Debate continues on fair and appropriate end point of trials. Extrapolation of adult positive trial results to children is problematic. Conflict of interest issues which rested dormantly for years are now at the forefront of discussion, and journal editorial board responsibility in this area is being recognized. Protocols may also help reduce heterogeneity of treatment across centers in clinical trials. This article reviews many of the problems encountered in clinical trial design and reporting and offers a perspective on dealing with them to the betterment of a clinical trial.

Keywords: Clinical trials, Severe sepsis, Acute lung injury

To access this article, please choose from the options below

Login to an existing account or Register a new account.

  • Purchase this article for 31.50 USD (You must login/register to purchase this article)

    Online access for 24 hours. The PDF version can be downloaded as your permanent record.

  • Subscribe to this title

    Get unlimited online access to this article and all other articles in this title 24/7 for one year.

  • Claim access now

    For current subscribers with Society Membership or Account Number.

  • Visit SciVerse ScienceDirect to see if you have access via your institution.
 

☆ Manuscript based partly on presentations from the 3rd Annual International Sepsis Forum Scientific Colloquium in Mougins France, June 2005. Co-Chairs: R. Phillip Dellinger, MD, Konrad Reinhart, MD. Faculty: Edward Abraham, MD, Sean Berenholtz, MD, Christian Brun-Buisson, MD, Thierry Calandra, MD, Terry Clemmer, MD, Jean-Francois Dhainaut, MD, Didier Dreyfuss, MD, Francois Lemaire, MD, John Marshall, MD, Francoise Meunier, MD, Steven Opal, MD, Adrienne Randolph, MD, William Richardson, MD, Thomas Smith, MD, Tom van der Poll, MD, Jean-Louis Vincent, MD.

PII: S0883-9441(08)00029-4

doi:10.1016/j.jcrc.2007.12.022

Journal of Critical Care
Volume 23, Issue 4 , Pages 493-499, December 2008

Article Tools