With the advancement in treatment options and therapeutic agents, particularly in the area of biologicals, defining a clinically meaningful difference between a test agent and the comparator has become increasingly difficult. However, the sample size of a study and the cost of it, and ultimately, the approval of the test agent all hinge on the accurate definition of such a difference. An accurate definition here should represent the clinical aspects of the disease and the interests of the patients, the regulators, and the company. This round table provides an opportunity for all to share their experiences and viewpoints in this difficult topic.