Equipoise, design bias, and randomized controlled trials the elusive ethics of new drug development.docVIP

Arthritis Research Therapy Vol 6 No 3 Fries and Krishnan Open Access Research article Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development James F Fries and Eswar Krishnan Stanford University School of Medicine, Palo Alto, California, USA Corresponding author: James F Fries (e-mail: jff@) Received: 4 Feb 2004 Revisions requested: 24 Feb 2004 Revisions received: 24 Feb 2004 Accepted: 3 Mar 2004 Published: 18 Mar 2004 Arthritis Res Ther 2004, 6:R250-R255 (DOI 10.1186/ar1170) ? 2004 Fries and Krishnan, licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the articles original URL. Abstract The concept of ‘equipoise’, or the ‘uncertainty principle’, has been represented as a central ethical principle, and holds that a subject may be enrolled in a randomized controlled trial (RCT) only if there is true uncertainty about which of the trial arms is most likely to benefit the patient. We sought to estimate the frequency with which equipoise conditions were met in industry- sponsored RCTs in rheumatology, to explore the reasons for any deviations from equipoise, to examine the concept of ‘design bias’, and to consider alternative ethical formulations that might improve subject safety and autonomy. We studied explanation for this dramatic result; this bias occurs after a study is completed. Rather, we hypothesize that ‘design bias’, in which extensive preliminary data are used to design studies with a high likelihood of being positive, is the major cause of the asymmetric results. Design ‘bias’ occurs before the trial is and is inconsistent with the equipoise principle. However, design bias increases scientific efficiency, decreases drug development costs, and limits the numb