Multicenter trials, guidelines, and uncertainties - Do we know as much as we think we do?

•When multinational RCTs are performed, appropriate statistical analyses are required.•Failure to do so, underestimates the associated uncertainty.•Declarations of conflicts of interest may be an inadequate measure to protect guidelines.

There is an uncritical belief that “positive” large scale multicenter randomized clinical trials provide a definitive window to the “truth”. The limitations and difficulties in performing large trials are discussed herein and the need to fully and transparently acknowledge residual uncertainties is stressed. For example, the failure to consider the regional variations that may arise with the “outsourcing” of trials may lead to false estimates of precision. As large trials form the backbone of guidelines, failure to critically evaluate the importance of evidential limitations may see a minimization of residual uncertainties and lead to inappropriate recommendations.