I have a size 12 foot (46 Euro) and have always had difficulty with shoes and pedals. I also have flat feet, so often I can develop pressure points in my foot if things aren't properly set...

No question - the best set up for me are SPDs with a cycling sandal (I use Keenes). When cold, I use MTB shoes...preferably something with velcro and some flex in the upper. In my younger days, before SPDs, and when I was a wannabe competitive rider...I used Time pedals and Nike cycling shoes...became they came in widths and tended to run less narrow than the Euro stuff.