Recommendations for the definition of clinical responder in insulin preservation studies.
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 prespecify a responder definition that can be assessed against the requirements and suggestions of regulatory agencies. In this article, we propose a clinical responder definition to specifically assist researchers and regulatory agencies in interpreting 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 6-month β-cell preservation in type 1 diabetes as measured by 2-h-stimulated C-peptide. We introduce criteria (bias, reliability, and external validity) for the assessment of responder definitions to ensure they meet U.S. Food and Drug Administration 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 6 months beyond baseline. In sum, to support efficacy claims of β-cell preservation therapies in type 1 diabetes submitted to U.S. and European regulatory agencies, we recommend use of our definition.
Division of Epidemiology and Biostatistics, Department of Pediatrics, University of South Florida, Tampa, FL craig.beam@med.wmich.edu.
Craig A
CA
Beam
Department of Pediatrics, University of California, San Francisco, CA.
Stephen E
SE
Gitelman
Department of Medicine, VA Puget Sound Health Care System, Seattle, WA University of Washington, Seattle, WA.
Jerry P
JP
Palmer
D000293:Adolescent; D015982:Bias; D002096:C-Peptide / Q000378:metabolism*; D002986:Clinical Trials as Topic / Q000592:standards*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology; D008297:Male; D015203:Reproducibility of Results; D016896:Treatment Outcome
D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin