My take on it...
Slight roughness, gradual onset, no power decay?
- Check magnetos L/R, if significantly worse on either, suspect fouled plugs. Lean to proper cruise setting, wait for plugs to unfoul themselves (should take a couple mins). Would head for an airport or at least fly to/remain over suitable terrain for a forced landing at this stage while waiting for the plugs to clear, "just in case".
Sudden onset of significant roughness, or as above but didn't clear after a few mins?
- Check magnetos L/R, if significantly worse (or engine stoppage) on either, suspect magneto failure. Procede to nearest suitable airport; use single magneto if needed.
No change with magnetos L/R?
- If manual alternate air available, pull it.
- If fuel pressure fluctuations (check "fuel flow" gauge), fuel pump on.
None of the above solved it?
- Something's the matter; procede to nearest suitable airport while remaining over suitable terrain. Vary mixture, trying to find a setting that minimizes roughness (if that results in an unusual mixture setting, something is still the matter).
ATC?
- If I need their help for any reason (my prefered route takes me through controled airspace, I'm out over the sea and need to be rescued in a hurry if the engine was to fail, or some such), make a Pan Pan call.
That's how I'd do it!