Evaluation of diagnostic tests for low prevalence diseases: a statistical approach for leveraging real-world data to accelerate the study.

The evaluation of diagnostic tests usually involves statistical inference for its sensitivity. As sensitivity is defined as the probability that the test result will be positive when the target condition is present, the key study design consideration of sample size is the determination of the number of subjects with the target condition such that the estimation has adequate precision, or the hypothesis testing has adequate power. Traditionally, one may rely on prospective screening of subjects to obtain the required sample size, which means that if the prevalence of the disease is very low, a large number of subjects would need to be screened, increasing the study duration and cost. In this paper, we consider the possibility of substantially reducing the length and cost of a clinical study by leveraging subjects from a real-world data (RWD) source, focusing specifically on the diagnostic test for the cancer of interest. Using the propensity score methodology, we developed a procedure which ensures that the real-world subjects being leveraged are similar to their prospectively enrolled counterparts, thereby making the leveraging more justified. The procedure allows the down-weighting of the real-world subjects, which can be achieved by either using a Frequentist's method based on the composite likelihood or a Bayesian method based on the power prior. The proposed approach can be applied to the evaluation of any diagnostic test and it is not limited to the current clinical study regarding a cancer diagnostic test. Notably, this paper is in close alignment with a recently released draft framework by the Medical Device Innovation Consortium (MDIC) on real-world clinical evidence and in vitro diagnostics, being a showcase of appropriately leveraging real-world data in diagnostic test evaluation for diseases with low prevalence to support regulatory decision-making.