Neutral diagnosis: An innovative concept for medical device clinical trials

Bo Zhang,Shangyuan Ye,Sravya B Shankara,Hui Zhang,Qingfeng Zheng

doi:10.1016/j.conctc.2019.100436

Abstract

Study design and statistical analysis are crucial in pivotal clinical trials to evaluate the effectiveness and safety of new medical devices under investigation. In recent years, innovative intraoperative in vivo breast tumor diagnostic devices have been proposed to improve the accuracy and surgical outcomes of breast tumor patients undergoing resection. Although such technologies are promising, investigators need to obtain statistical evidence for the effectiveness and safety of these devices by conducting valid clinical trials. However, the study design and statistical analysis for these clinical trials are complicated. While these trials are designed to provide real-time intraoperative diagnosis of cancerous tissue, they also have clear therapeutic objectives to lower the reoperation rate of breast cancer surgery. This research article introduces the new concept of neutral diagnosis (ND), and the ND clinical trial design as an innovative study design to evaluate the effectiveness and safety of diagnostic devices with direct therapeutic purposes. A joint modeling approach is adopted to make inferences on the effectiveness and safety of these devices for non-neutral diagnosis (non-ND) clinical trials. Simulation studies were conducted to show the efficiency of the ND trials and strength of the joint modeling approach in the non-ND clinical trials. An example on a diagnostic medical device that provides real-time, intraoperative diagnosis of breast cancer tumor tissues during breast cancer surgeries is comprehensively discussed and analyzed.

Highlights

Study design and statistical analysis are crucial in the pivotal clinical trials evaluating the effectiveness and safety of investigational medical devices
Study design and statistical analysis strategies have proven to be challenging for the devices that are based on recently developed breakthrough technologies with complex diagnostic and therapeutic features
The Center for Devices and Radiological Health (CDRH) under the U.S Food and Drug Administration (FDA) has received several applications for innovative intraoperative in vivo diagnostic devices for breast tumors, which are aimed at improving the accuracy and outcomes of surgical resection in breast tumor patients

Summary

Introduction

Study design and statistical analysis are crucial in the pivotal clinical trials evaluating the effectiveness and safety of investigational medical devices. Patients were randomized to two groups, receiving either the standard of care (SOC) or the SOC with the aid of the new device The results from this trial showed that the group receiving SOC with the new device had a significantly higher correct intraoperative surgical resection rate and a lower re-excision rate than the SOC group. The US Pivotal trial was the largest among the three clinical trials and included 596 patients from 21 sites in the US and Israel Both the US Pivotal trial and the German multicenter study concluded that the MarginProbe significantly reduced the re-excision rate and had no negative effects on the cosmetic outcomes of the patients. Other clinical trials on the MarginProbe are reported in Sebastian et al [8] and Blohmer et al [9] These studies concluded that the assessment of intraoperative margins provided by the MarginProbe during breast-conserving surgery resulted in a reduction of re-excision rates. Reviews within Pappo et al [10] and Thill et al [11] included detailed device description on the MarginProbe and other similar devices

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Discussion

Conclusion