Postregistration trials or postmarketing or phase IV trials are tools to investigate any treatment that is already approved and is, therefore, available for prescription use. The main objectives of these trials are typical effectiveness, more structured surveillance for uncommon or rare side effects, and the potential development of new indications. Several issues need to be addressed in the postregistration phase of the evaluation of a therapeutic treatment. Among those we will focus on two ethical challenges: reporting bias from industry-sponsored research and use of placebo as one of the arms in controlled studies where proven treatment already exists. The review of this topic is particularly relevant in the field of critical care because it is ongoing in the debate about the opportunity to perform a new placebo-controlled study with the recombinant human activated protein C (activated drotrecogin alfa-activated protein C). In fact, despite the approval of activated protein C for treatment of patients with severe sepsis and high risk of death, several issues regarding the efficacy and safety of its administration have been recognized by several investigators to the point that the European Medicines Agency asked for a new placebo-controlled study to further clarify the benefit/risk profile of activated protein C.