Comprehensive safety evaluation methodologies for automated driving systems that account for the large complexity real traffic are currently being developed. This work adopts a scenario-based safety evaluation approach and aims at investigating an advanced methodology to generate test cases by applying heuristics to naturalistic driving data. The targeted requirements of the generated test cases are severity, exposure, and realism. The methodology starts with the extraction of scenarios from the data and their split in two subsets—containing the relatively more critical scenarios and, respectively, the normal driving scenarios. Each subset is analysed separately, in regard to the parameter value distributions and occurrence of dependencies. Subsequently, a heuristic search-based approach is applied to generate test cases. The resulting test cases clearly discriminate between safety critical and normal driving scenarios, with the latter covering a wider spectrum than the former. The verification of the generated test cases proves that the proposed methodology properly accounts for both severity and exposure in the test case generation process. Overall, the current study contributes to fill a gap concerning the specific applicable methodologies capable of accounting for both severity and exposure and calls for further research to prove its applicability in more complex environments and scenarios.