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Recommendations for the definition of clinical responder in insulin preservation studies.

ABSTRACT: 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 ?-cell function in newly diagnosed type 1 diabetes. We focus on studies of 6-month ?-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 ?-cell preservation therapies in type 1 diabetes submitted to U.S. and European regulatory agencies, we recommend use of our definition.

SUBMITTER: Beam CA

PROVIDER: S-EPMC4141373 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Recommendations for the definition of clinical responder in insulin preservation studies.

Beam Craig A CA Gitelman Stephen E SE Palmer Jerry P JP

Diabetes 20140410 9

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 importanc ...[more]

PMID: 24722251

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Project description:AimThese international clinical practice recommendations (CPR) for developmental coordination disorder (DCD), initiated by the European Academy of Childhood Disability (EACD), aim to address key questions on the definition, diagnosis, assessment, intervention, and psychosocial aspects of DCD relevant for clinical practice.MethodKey questions in five areas were considered through literature reviews and formal expert consensus. For recommendations based on evidence, literature searches on 'mechanisms', 'assessment', and 'intervention' were updated since the last recommendations in 2012. New searches were conducted for 'psychosocial issues' and 'adolescents/adults'. Evidence was rated according to the Oxford Centre for Evidence-Based Medicine (level of evidence [LOE] 1-4) and transferred into recommendations. For recommendations based on formal consensus, two meetings of an international, multidisciplinary expert panel were conducted with a further five Delphi rounds to develop good clinical practice (GCP) recommendations.ResultsThirty-five recommendations were made. Eight were based on the evidence from literature reviews (three on 'assessment', five on 'intervention'). Twenty-two were updated from the 2012 recommendations. New recommendations relate to diagnosis and assessment (two GCPs) and psychosocial issues (three GCPs). Additionally, one new recommendation (LOE) reflects active video games as adjuncts to more traditional activity-oriented and participation-oriented interventions, and two new recommendations (one GCP, one LOE) were made for adolescents and adults with DCD.InterpretationThe CPR-DCD is a comprehensive overview of DCD and current understanding based on research evidence and expert consensus. It reflects the state of the art for clinicians and scientists of varied disciplines. The international CPR-DCD may serve as a basis for national guidelines.What this paper addsUpdated international clinical practice guidelines on developmental coordination disorder (DCD). Refined and extended recommendations on clinical assessment and intervention for DCD. A critical synopsis of current research on mechanisms of DCD. A critical synopsis of psychosocial issues in DCD, with implications for clinical practice. The first international recommendations to consider adolescents and adults with DCD.

Project description:IntroductionItch associated with atopic dermatitis (AD) has a profoundly negative effect on patients of all ages. Therefore, itch is a main target for AD therapeutic approaches, and treatments are perceived as beneficial when they achieve an itch reduction. In the absence of a validated scale for children aged 6-11 years that is suitable for assessing itch intensity in clinical trial settings, the Worst Itch Scale was developed.MethodsQualitative interviews, comprising concept elicitation and cognitive debriefing, were conducted to develop and evaluate the content validity of the Worst Itch Scale. Psychometric assessments used data from the LIBERTY AD PEDS phase 3 trial of dupilumab in patients aged 6-11 years with severe AD. These included test-retest reliability, construct validity, known-groups validity and responsiveness. Thresholds for clinically meaningful change were defined using anchor- and distribution-based methods.ResultsThe Worst Itch Scale consisted of two items asking about 'worst itching' experienced 'last night' and 'today'. Worst Itch Scale scores showed large, positive correlations with existing patient-reported outcome (PRO) measures of itch, and weaker correlations with clinician-reported outcome (ClinRO) measures assessing objective signs of AD. Improvements in Worst Itch Scale scores were highly correlated with improvements in other itch PROs and moderately correlated with improvements in ClinROs. The responder definition based on the primary anchor, a 1-point improvement in the Patient Global Impression of Disease, was 2.84. Supportive anchors produced response estimates ranging from 2.43 to 4.80 points.ConclusionsThe Worst Itch Scale is a fit-for-purpose (e.g. well-defined, reliable, responsive and valid) scale for evaluating worst itch intensity in children aged 6-11 years with severe AD. The within-patient threshold for defining a clinically meaningful response was a ≥ 3-4-point change in the Worst Itch Scale score.Trial registrationNCT03345914. Video: How can we reliably assess itch intensity in children 6-11 years with severe atopic dermatitis in clinical trial settings?

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Recommendations for the definition of clinical responder in insulin preservation studies.

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Recommendations for the definition of clinical responder in insulin preservation studies.

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