The success of a RA drug depends on both improvements in signs and symptoms as well as prevention of structure damage. In order to show prevention of structure damage, it is critical for the placebo + DMARDs group to demonstrate progression during the clinical trial. From historical RA trials, most placebo patients have no changes in radiographic score after 1 year. With the availability of many effective treatments currently on the market, the impact on RA trials has been, as follows: • It is harder and harder to recruit patients who would progress in structure damage during the clinical trial. It forces pharma companies to go to countries that usually do not conduct clinical trials which may cause many issues such as higher than usual placebo response rate in signs and symptoms. • The placebo-controlled period has been shortened to 6 months. In addition, many RA trials also allow patients who have worsening in signs and symptoms to escape to active treatment, making the placebo-controlled period for those patients to be as short as 4 months. Therefore, the absolute change in radiographic score is small and sample size will be very large.

Questions for discussion will include: a. What difficulties have you encountered for a RA trial to demonstrate prevention of structure damage? b. How do you enrich the study population to enroll patients who would progress? c. What kind of innovative designs or analyses have been used or considered for a RA trial to resolve the stated problem? d. Is it possible to use historical control? If so, what are the regulatory hurdles? e. Is it possible to get a claim based only on a subset of patients who have high potential to progress? If so, what are the regulatory hurdles?