Acquisition Category 1 (ACAT 1) programs are large - large is greater than $5B, yes Billion with a B. This Integrated Program Management Conference (IPMC) 2013 presentation addresses the issues of managing these programs in the presence of uncertanty.
Like all projects or programs, uncertanty comes in two forms - Irreducible (Aleatory) and Reducible (Epistemic). Both these uncertainties create risk. Both are present no matter the size - from small to mega. When we hear estimates are hard, we're not good at estimating, estimates are possibly misused, or any other dysfunction around estimating, they're just symptoms of the problem. Trying to fix the symptom does little to actually fix the problem. Find the root cause, fix that, and the symptom can then have a probability of going away.
This may look like a unique domain, but the core principles of managing in the presence of uncertainty are immutable.