Keywords: neutral diagnosis, joint modeling, in-vivo breast tumor diagnostic device
Study design and statistical analysis in pivotal clinical trials are crucial for evaluating the effectiveness and safety of the new medical devices under investigation. The study design and statistical analysis strategies have been proved very challenging for the diagnostic devices with direct therapeutic purposes. In recent years the innovative intraoperative in-vivo breast tumor diagnostic devices are proposed to improve the accuracy of breast tumor resection in surgery and the surgical outcome. While the technologies are promising, scientists are anxious to seek statistical evidences for effectiveness and safety of the devices from valid clinical trials. However, the study design and statistical analysis for these medical devices are complicated by the fact that not only the devices are designed to provide real-time intraoperative diagnosis on cancerous tissue but also they have clear therapeutic objectives, one of which is to lower the reoperation rate of breast cancer surgery. This project introduces a new concept, named “neutral diagnosis”, and neutral diagnosis design, an innovative study design to evaluate effectiveness and safety of the diagnostic devices with direct therapeutic purposes. A joint modeling approach is proposed to make inference on the effectiveness and safety of these devices, even when a non-neutral diagnosis study is conducted. This project conducts simulation studies to show the efficiency of the neutral diagnosis study and the strength of the joint modeling approach in the non-neutral diagnosis study. An FDA-reviewed practical example on a drug-device combination product that provides real-time, intraoperative diagnosis on breast tumor tissue is carefully discussed and analyzed. The objective of this project is to identify the scientifically valid study endpoints, pinpoint the study design strategies, and develop state-of-the-art statistical analysis methods for evaluating the effectiveness and safety of these products.