Clinical responder studies should contribute to the translation of effective treatments and interventions to the clinic. Since ultimately this translation will involve regulatory approval, we recommend that clinical trials pre-specify a responder definition that can be assessed against the requirements and suggestions of regulatory agencies. In this paper we propose a clinical responder definition to specifically assist researchers and regulatory agencies interpret the clinical importance of statistically significant findings for studies of interventions intended to preserve β-cell function in newly diagnosed Type 1 diabetes. We focus on studies of six-month β-cell preservation in type I diabetes as measured by 2-hour stimulated C-peptide. We introduce criteria (bias, reliability and external validity) for the assessment of responder definitions to ensure they meet FDA and European Medicines Agency guidelines. Using data from several published TrialNet studies, we evaluate our definition (no decrease in C-peptide) against published alternatives and determine that our definition has minimum bias with external validity. We observe that reliability could be improved by using changes in C-peptide later than six months beyond baseline. In sum, to support efficacy claims of β-cell preservation therapies in Type I diabetes submitted to US and European regulatory agencies, we recommend use of our definition.
- Received January 21, 2014.
- Accepted April 7, 2014.
- © 2014 by the American Diabetes Association.
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