In the pivotal phase III international trials of Benlysta, all participants in the study received reasonably effective standard of care background medications, which could be increased in the early part of the study for the patients’ safety and comfort. Then either Benlysta or a placebo was added on to that treatment. This study was able to show that the benefits of Benlysta plus background mediations were significantly greater than those seen in patients on background medications alone, but the difference was narrow. When a trial design must allow aggressive treatment of placebo patients, this will inevitably result in a narrower difference, and a much larger trial is then needed to prove efficacy. Furthermore, any lack of training and standardization in evaluating the patients can make the difference between a positive and a negative trial.
What can be done to address these issues, expedite clinical trials, and promote the availability of more effective treatments for lupus approved by the Food and Drug Administration? The Lupus Foundation of America has been addressing these barriers in a systematic fashion:
1. Improve the quality of clinical trial sites and care of patients who participate in trials around the world. This initiative has led to an online program capable of training and certifying clinicians around the world on the most commonly used lupus disease evaluation systems: the BILAG, SLEDAI, and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). The Lupus Foundation of America’s Professional Online Instrument Training (POINT) program is now the primary tool used by companies that are conducting studies of lupus treatments. About 2,000 doctors worldwide are conducting clinical trials of lupus treatments, and this interactive educational tool has become their standard of reference.
2. Support work to improve classification criteria for SLE and outcome measures for trials and clinical practice. The Lupus Foundation of America, in conjunction with the National Institutes of Health (NIH), supported the most recent studies of classification criteria for lupus, and is working to expand definitions of diagnosis and suitability for biologic therapy to serious organ-limited lupus, and to limit such access for patients with insignificant illness, whether or not they have multiple organs involved. Additionally, in conjunction with EULAR (the European League Against Rheumatism), the Lupus Foundation of America initiated and has continued to support a large project to refine the measures for flares of lupus disease that have sometimes provided a confusing aspect to outcome measures. This work has been ongoing for more than 2 years, and has resulted in several abstracts/publications; a final validation study is planned for the near future to support an outcome measure that better matches physician opinion than the current rules allow. These studies were performed by international groups of physician experts, primarily, but not exclusively, members of the Systemic Lupus International Collaborating Clinics.
Finally, to address the problem that once treatments are on the market, simpler disease activity and outcome measures are needed for practicing clinicians to use in a real-world clinic to justify expensive biologic treatments for their patients, the Lupus Foundation of America is supporting a project called DIAL (Directed Integrated Assessment of Lupus), which allows rapid and comprehensive scaling of type and degree of illness in these complex patients.
3. Improve the understanding of the impact of background treatments on clinical trial end points, and evaluate which trial end points best differentiate between treatments. The Foundation has developed a central database of clinical trial data from placebo groups (usually patients receiving different standard of care background treatments) from multiple past clinical trials performed at different companies. By pooling this information, it may be possible to determine which background medications are most likely to result in placebo responses that limit serious flares of disease while not being so effective as to defeat the purpose of a clinical trial. Once this is achieved, it will also be possible to have accumulated enough data on patients who are treated similarly to begin to test the most effective end points in some of these clinical trials.
While clinical drug trials are designed to detect significant differences between the group assigned the treatment and the control group, lupus drug trials need to be designed to detect greater differences. Support for basic science grants remains a priority at the Lupus Foundation of America, and it joins other advocacy groups and the NIH in continuing to award grants to outstanding researchers who continue to refine our understanding of the disease process and potential biomarkers. This, in turn, helps us select and guide the new treatments in development.