Why Are Lupus Clinical Trials So Challenging?
By Stacie Bell, Ph.D., executive vice president, Lupus Therapeutics, the clinical affiliate of the Lupus Research Alliance
It is nearly impossible to watch television and not see an advertisement for a new medical treatment. But despite many attempts and millions of dollars invested, only three contemporary treatment options exist for systemic lupus erythematosus and lupus nephritis. While these advances have benefitted individuals with lupus, further effective treatment options are much needed. Over the past decades, lupus trials have been fraught with failures, often with Phase 3 results not fulfilling early signals of promise.
Why Has The Lupus Trial Journey Been So Challenging?
The complexity and heterogeneity of the disease are primary factors, but trial design and current study measures also have impacted the recruitment and the outcomes of many trials. Due to the large number of participants required for regulatory approval, many research centers were striving to recruit individuals with lupus and included many participants who may have been experiencing other immune-mediated diseases or comorbidities. Due to the heterogeneity of lupus, definition and presentation of the patients and the assessment during screening can make enrolling the “right” participants challenging for sites. Outcome measures were developed for observational or disease characteristic research, not necessarily for evaluation in trials or used for efficient clinical care. This led to further difficulties in recruiting and properly assessing the correct patient population, both highlighting the need for expert investigators and teams.
Importantly, the diverse lupus community has not been represented in clinical trials. For example, a 2018 Current Rheumatology Reports article found that despite over 40% of those living with lupus, particularly severe lupus, being Black/African American, only ~14% of clinical trial participants represent this demographic. Clinical trial criteria and requirements, and even disease characterization have often biased participation. Clinical study visits may not be easily accomplished in rural populations or in urban areas with long commutes. Many clinical trial research centers have traditionally had a prominently White patient population. Lupus manifestations may differ. For example, lupus presentation on the skin may appear differently on different skin types. Therefore, clinical trial designs need to be inclusive and mindful of equity considerations for the lupus community.
Hope On The Horizon
Despite these challenges and past failures, there is hope for new treatment options given the numerous ongoing and planned clinical studies. Several novel mechanisms of action and treatment approaches are currently being evaluated in the clinical realm. The Lupus Research Alliance (LRA) is leading the charge with clinical research affiliate Lupus Therapeutics and the Lupus Clinical Investigators Network (LuCIN), overseen by Lupus Therapeutics. By leveraging the vast expertise of the LuCIN 50+ premier research centers across North America, trials can be accelerated in many ways.
Dozens of biopharmaceutical companies have collaborated or partnered with Lupus Therapeutics to utilize the network for numerous clinical studies. LuCIN continues to evolve as a robust community of sites and research partners with extensive experience in lupus care and clinical trial conduct. The network continues to expand into new geographic areas to ensure a more diverse representation of study participants and to support new treatment paradigms such as cell therapy. Several working groups, such as the Health Equity Working Group, have been formed to ensure high-quality procedures and trial diversity. Additionally, the expertise of the network is supporting the next generation of lupus clinical trial investigators and healthcare provider education more broadly.
Collaborating With The FDA And The Lupus Community
The Lupus Accelerating Breakthroughs Consortium (Lupus ABC) is the first lupus-focused public-private partnership with the FDA, CDER, and CBER. Overseen by the LRA, this initiative unites individuals with lupus and their advocates, industry, clinicians, researchers, and government stakeholders to collaboratively identify and pursue the most effective ways to accelerate the development of urgently needed personalized treatments.
The initiative will be critical in improving study design and outcome measures to address past obstacles with recruitment and conduct. Bringing together industry developers, providers, lupus experts, and regulators is imperative to morphing the current trial and development process to plan for the future. Lupus ABC’s projects tackle specific questions related to outcome measures, new treatment paradigms, and aspects of the heterogeneity of lupus in clinical trial assessment.
With the recent excitement and emphasis on the evaluation of cell therapy, a dedicated working group is focusing on clinical assessment and development of this potentially curative treatment. Overall clinical trial design has been a focus of discussion. With so many new treatment approaches and mechanisms of action being developed, the community will need to be mindful that trials can be effectively recruited so studies can evaluate new treatments in a timely and appropriate manner, with concomitant medications, disease status/severity, and standard of care in mind.
Unraveling Lupus Heterogeneity To Personalize Treatment
Much of the future success of new lupus therapy development relates to the understanding and characterization of the disease. The heterogeneity of lupus not only involves the manifestation in multiple organ systems but also the varied presentation and severity. These factors confound inclusion/exclusion criteria to define the participant population and the timing and inclusion of clinical assessments. As the world’s largest non-governmental funder of lupus research, LRA has made unraveling the complexity of disease heterogeneity to support personalized diagnostics and treatments a priority.
A critical element of this research, as well as clinical trial advances, is ensuring that understanding and evaluation encompass the diverse lupus community. According to a 2021 Arthritis & Rheumatology meta-analysis, individuals of color are vastly underrepresented in clinical trials, despite being affected by lupus two to three times as often as white patients, and often with greater disease severity. Without diversity in lupus clinical trials, the potential new treatments being developed, tested, and advanced will not reach the people who are burdened most by the disease.
Several efforts are underway to increase access, inclusivity, and diversity of clinical trial participants in lupus clinical research. One exciting example is the Project CHANGE (Community-based Health Action Network to Generate trial participation and Eliminate disparities) program, a community-driven approach to increase lupus clinical trial participation among Black individuals with lupus, to ensure that those most burdened by the disease can benefit from new treatments. The FDA also has made this a priority with the release of draft guidance related to clinical trial diversity and diversity plans for clinical development.
A Time Of Great Promise And Progress
With the key facets of lupus research being addressed by dedicated partners with an emphasis on understanding and collaboration throughout the development continuum, it is a time like no other for those impacted by lupus.
About The Author:
An accomplished research scientist and organizational leader, Stacie Bell, Ph.D., came to Lupus Therapeutics with more than 25 years of experience in discovery research, clinical development, and patient engagement in the biopharmaceutical and nonprofit arenas. Prior to joining Lupus Therapeutics, she formed and served as CEO and president of the Global Nutrition Project and was previously the chief scientific and medical officer leading the research & medical affairs department at the National Psoriasis Foundation. Bell began her career as a graduate research associate in the Department of Biochemistry at Vanderbilt University School of Medicine in Nashville, TN, where she earned her Ph.D. in biochemistry. She graduated summa cum laude with a BS in chemistry from University of North Dakota.