While randomized well-controlled clinical trials has been viewed as the gold standard in the evaluation of medical products, it is not uncommon for medical device clinical studies to depart from the paradigm of randomized trials, due to ethical or practical reasons. In non-randomized studies, the advantages of well designed and conducted randomized clinical trials are no longer available, and then the statistical inference obtained from such studies may have lower level of scientific assurance, compared to those from randomized trials. Apparently, there are many challenges encountered in non-randomized clinical studies in terms of study design and statistical analysis as well as regulatory issues. In this talk, some challenging issues will be discussed and illustrated from a regulatory statistical reviewer’s perspective.