We have confirmed that the distribution of free energies obtained from independent replica simulations cover a wide range of values and exhibit deviation from the Gaussian behaviour usually assumed. This means that performing ensemble simulations is essential for such calculations. Another important consequence of the non-normal nature of such distributions is that the ensemble size cannot be arbitrarily small; and we recommend a minimum should comprise 5 replicas consistent with all our previous publications. We exploited the richness of our dataset to perform systematic analyses on various important factors that affect the accuracy and/or precision of alchemical calculations. Flexible ligand structures and charged groups in the alchemical region lead to large fluctuations in the predicted free energies. The error bars in such cases can be controlled by increasing the ensemble size appropriately which also translates into improved accuracy of results. Such features substantially improve the predictive power of RBFE methods which is essential if they are to be actionable.