The prime directive prevents interference with sub-spacial civilizations, but what of the Enterprise's ongoing mission to seek out new life and new civilizations? Is it good for an advanced civilization to spread it's influence or to risk inadvertent interference (as somehow Always seems to happen)?
I believe a truly advanced civilization will concentrate on making it's own home nice and on defense. Let other life do it's own thing in it's own way. But this is all assuming life is a net positive which is unwarranted. The real answer to Fermi's question is that advanced civilizations do themselves out of existence to minimize harm. It's an open question whether they would work to end all possible life if possible, for the same reason.