Abstract
Objective The objective of this article is to provide a high-profile review and discussion on the study design and statistical analysis of pivotal clinical trials conducted to demonstrate the safety and effectiveness of closed-loop investigational artificial pancreas device systems (APDSs) in premarket approval applications. Methods The United States Food and Drug Administration (FDA) guidance on the content of investigational device exemption and premarket approval applications for APDSs is reviewed with special emphasis on study design and statistical analysis of the pivotal clinical trials. The two pivotal studies for the MiniMed 670G hybrid closed-loop system by Medtronic in their premarket approval application are summarized and discussed. Results The United States FDA established detailed recommendations on the study design and statistical analysis of pivotal clinical trials for the industry that seek market investigational APDSs and for FDA scientific reviewers that regulate the device applications. The recommendations cover specifics regarding patient population, clinical endpoints, and strategies for data analysis. However, the two pivotal studies that demonstrated the effectiveness of the FDA-approved MiniMed 670G hybrid closed-loop system were not typical randomized controlled trials as per FDA recommendations. Conclusion The development and regulation of investigational APDSs require careful and sophisticated clinical study designs and data analysis in premarket approval applications. The regulatory evaluation process of the APDSs is rather complicated since the devices consist of multiple components that collaboratively function to mimic human pancreases.
Highlights
Diabetes mellitus is a chronic disease of the body’s regulation of blood glucose levels
We examine the pivotal clinical studies conducted and reported in the premarket approval (PMA) Summary of Safety and Effectiveness Data (SSED) for the approval of the MiniMed 670G hybrid closed-loop system [8] and consider the concordance between the study design and statistical evidence used to the recommendations in the Food and Drug Administration (FDA) guidance
E patient population in the pivotal clinical studies should be selected according to the intended use of the artificial pancreas device systems (APDSs) device because the chosen study population can largely influence the study design, sample size, duration of follow-up, and final approved device indications. e FDA recommends that sponsors consider these factors while enrolling patients for the initial subject population: subjects experienced with insulin pumps for more than 6 months, subjects willing to perform more than 4 finger stick blood glucose measurements daily, subjects willing to perform manufacturer-required sensor calibrations, subjects willing to wear the system more than 6 days per week, subjects willing to keep a minimum log of sick days, days with exercise, or symptoms of low and high blood glucose episodes and medications
Summary
Study Design and Data Analysis of Artificial Pancreas Device Systems with Closed-Loop Glucose-Sensing Insulin Delivery. E objective of this article is to provide a high-profile review and discussion on the study design and statistical analysis of pivotal clinical trials conducted to demonstrate the safety and effectiveness of closed-loop investigational artificial pancreas device systems (APDSs) in premarket approval applications. E United States Food and Drug Administration (FDA) guidance on the content of investigational device exemption and premarket approval applications for APDSs is reviewed with special emphasis on study design and statistical analysis of the pivotal clinical trials. E United States FDA established detailed recommendations on the study design and statistical analysis of pivotal clinical trials for the industry that seek market investigational APDSs and for FDA scientific reviewers that regulate the device applications. E development and regulation of investigational APDSs require careful and sophisticated clinical study designs and data analysis in premarket approval applications. Conclusion. e development and regulation of investigational APDSs require careful and sophisticated clinical study designs and data analysis in premarket approval applications. e regulatory evaluation process of the APDSs is rather complicated since the devices consist of multiple components that collaboratively function to mimic human pancreases
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