Assessing lupus: developing a novel outcome approach for clinical trials

Clinical trials are an important part of testing potential treatments before they can be approved by the U.S. Food and Drug Administration for use by patients. While many clinical trials have been performed for lupus treatments, results of different studies are often difficult to compare due to differences in the criteria used to define treatment success. While these differences may seem minor, they can have a strong impact on which drugs are chosen to go on for further development to benefit patients, and which are abandoned. Dr. Kalunian’s study aims to improve the criteria used to define treatment success in clinical trials for lupus therapies. Dr. Kalunian will identify the criteria that is easiest and most helpful in determining if treatments have been successful. He intends to use these insights to create a tool that combines the most useful criteria.

What this study means for people with lupus

With his grant, Dr. Kalunian will develop a comprehensive tool to help researchers better understand and evaluate the effectiveness of potential lupus therapies in clinical trials.

Clinicians involved in the care of patients with systemic lupus erythematosus (SLE) and clinical scientists devoted to the development of new drugs to treat SLE are consistently frustrated by the complexity of the current approaches to define longitudinal outcomes in both clinical and clinical trial settings. Current practice has been shaped by the Outcome Measures in Rheumatology international consensus effort, the FDA and the EMA, who have all provided guidance for essential domains to be assessed in SLE clinical trials, including change in disease activity over time, change in the rate of organ damage accrual, change in health-related quality of life and adverse events. However, approaches to date have included several instruments that define outcome with often conflicting descriptions of the same manifestation. Furthermore, discordance between two of the prime outcome measures, the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) and the Systemic Lupus Erythematosus Responder Index (SRI), in recent clinical trials including the first phase 3 trial of anifrolumab, TULIP-1 and the phase 2 SLE trial of ustekinumab has mystified the lupus community. In a regulatory environment that requires success of a singular primary endpoint, the ability to move drug development forward is significantly hampered by such endpoint disagreement. Additionally, our current instruments originally defined activity at specific points in time and were not intended as outcome assessments in clinical trials . The complex multi-organ nature of SLE disease activity with frequent undulating flare and remission states, the user-unfriendliness of current outcome measures and the use of dichotomous variables amongst the different organ-specific criteria present significant challenges. Assigning relative weights to different manifestations of disease further complicates the process and may lead to a misrepresentation of the true state of a patient’s disease. Additionally, discordance between the patient and physician perspectives is often encountered. By understanding which aspects of current outcome instruments are useful and by determining additional criteria that are useful and clinically relevant, our ultimate goal is to develop a novel assessment tool that is easy to use and better defines outcome for clinical trials but that could also be adapted for clinical practice. The objective is to validate a new instrument that incorporates clinically meaningful elements, including some derived from current instruments and new items that embody physician- and patient-assessments. Although our preliminary data suggest that a proposed index may improve our ability to assess activity in clinical practice and clinical trials, input from the other investigators in this current effort, all of whom are leading clinical scientists in this field, will greatly enhance a refined design of this instrument or the development of an alternative index.