# A diagnostic phase III/IV seamless design to investigate the diagnostic accuracy and clinical effectiveness using the example of HEDOS and HEDOS II

## TL;DR

This paper introduces a new seamless study design that combines phases III and IV to evaluate a diagnostic device's accuracy and clinical effectiveness in thyroid surgery patients.

## Contribution

The paper presents the first seamless design for diagnostic studies, combining phases III and IV with statistical methodology and implementation feasibility.

## Key findings

- The HEDOS and HEDOS II studies use a seamless design to evaluate diagnostic accuracy and clinical effectiveness of a post-operative hemorrhage detector.
- Phase III data are reused as external controls in phase IV, reducing sample size and recruitment needs.
- An unblinded interim analysis is planned to recalculate sample size for phase IV after phase III completion.

## Abstract

The development process of medical devices can be streamlined by combining different study phases. Here, for a diagnostic medical device, we present the combination of confirmation of diagnostic accuracy (phase III) and evaluation of clinical effectiveness regarding patient-relevant endpoints (phase IV) using a seamless design. This approach is used in the Thyroid HEmorrhage DetectOr Study (HEDOS & HEDOS II) investigating a post-operative hemorrhage detector named ISAR-M THYRO® in patients after thyroid surgery. Data from the phase III trial are reused as external controls in the control group of the phase IV trial. An unblinded interim analysis is planned between the two study stages which includes a recalculation of the sample size for the phase IV part after completion of the first stage of the seamless design. The study concept presented here is the first seamless design proposed in the field of diagnostic studies. Hence, the aim of this work is to emphasize the statistical methodology as well as feasibility of the proposed design in relation to the planning and implementation of the seamless design. Seamless designs can accelerate the overall trial duration and increase its efficiency in terms of sample size and recruitment. However, careful planning addressing numerous methodological and procedural challenges is necessary for successful implementation as well as agreement with regulatory bodies.