This document discusses how randomized clinical trials that use fixed treatment protocols can produce unintended consequences and invalidate study results when current clinical practice involves titrating treatment based on patient characteristics and disease severity. Two such studies, TRICC and ARMA, are examined. For both, the document argues the trials' results were influenced by "practice misalignments" that occurred when subgroups of patients received treatment levels contrary to standard practice based on their individual presentation. This calls into question whether the studies' conclusions reflect how patients are actually treated and responds to in clinical settings. Better trial design is needed to minimize such misalignments, potentially through methods like simulating standard practices or including a current practices comparison arm.