Follow the standards, this stuff gets subtle, doubly so if your eventual product needs to be recognised by a NRTL....
For example, we have a product where there is mains on one side (And some internal planes) of a board and both earth and isolated signal traces on the other, the creepage distances are different between the mains and the two classes of LV trace if you wish to meet UL requirements.
Same product with another 'fun' one, because there can be no single component failure resulting in a dangerous condition we were required to ensure we had TWO layers of FR4 between the HV layers and between the HV and LV doings, two cores, or core and prepreg it mattered not, but there had to be two....
Yea, the standards are complicated, hard to follow and tend to reference each other in some sort of graph theorists fever dream, but they are also the source of much empirical experience about what can happen and what it takes to prevent it from happening.
There is a reason consultants exist in this area, and a reason they are NOT cheap.