In the evaluation of medical products, including drugs, biological products, and medical devices, comparative observational studies could play an important role when properly conducted randomized, well-controlled clinical trials are infeasible due to ethical or practical reasons. However, various biases could be introduced at every stage and into every aspect of the observational study, and consequently the interpretation of the resulting statistical inference would be of concern. While there do exist statistical techniques for addressing some of the challenging issues, often based on propensity score methodology, these statistical tools probably have not been as widely employed in prospectively designing observational studies as they should be. There are also times when they are implemented in an unscientific manner, such as performing propensity score model selection for a dataset involving outcome data in the same dataset, so that the integrity of observational study design and the interpretability of outcome analysis results could be compromised. In this paper, regulatory considerations on prospective study design using propensity scores are shared and illustrated with hypothetical examples.