Advancing Lupus Clinical Trials with Intelligent eCOA and Endpoint Solutions

Lupus or Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease manifesting in a wide range of symptoms, including joint pain, fatigue, rashes and organ damage, making it challenging to diagnose and monitor. The heterogeneous disease presentation and the fluctuating disease course make it particularly difficult to define reliable clinical outcomes and attribute changes to investigational treatments. To complicate even further, high placebo response rate has been repeatedly demonstrated in Lupus studies, making it harder to determine the true effects of a new drug. Overall, Lupus clinical trials face unique challenges that have historically made treatment development difficult and complex, slowing down the progress in solving significant unmet needs for SLE patients. 

Signant has invested substantial scientific, technical, and operational resources into developing comprehensive solutions specifically designed to address these challenges through a combination of endpoint quality strategies, innovative electronic clinical outcome assessment (eCOA) implementations, and advanced data analytics. 

Understanding the Lupus Assessment Landscape

The variety of Lupus manifestations make it particularly complex to fully capture disease activity, so researchers have adopted an array of COA measurements and composite indexes. Beyond the standard patient-reported outcomes (PROs) like SF-36 and FACIT-Fatigue, specialized clinician-reported outcomes (ClinROs) are widely adopted to support primary endpoints informing disease activity (SLEDAI and BILAG) or disease damage (SLICC, ACR). 

SLEDAI-2K and BILAG-2004 are the most common specific ClinROs despite the significant amount of time and necessary expertise to administer them correctly. The lengthy and interwoven nature of these instruments introduces intra-rater and inter-rater variability that can severely impact trial outcomes if not properly managed. 

Let’s consider BILAG-2004 for example. It captures disease activity across nine organ systems, encompassing 97 items. While it excels at providing detailed, granular assessment of disease activity across multiple organ systems, the relative complexity creates inherent variability risks especially in multicenter clinical trials where different clinicians with varying levels of experience must produce consistent, reliable measurements. 

In addition to the complexities inherent in these assessments, they’re commonly deployed on paper, creating opportunities for other data quality risks such as errors or unusable data.  

Improving Endpoint Data Quality in Lupus Clinical Trials

Signant’s Electronic BILAG and Intelligent eCOA

Developed with clinical thoughtfulness and input from one of the BILAG authors, Signant recently implemented a novel electronic version of BILAG, reimagining the assessment process to address the inherent challenges of the instrument. Signant’s electronic BILAG implementation incorporates several intelligent features that address longstanding concerns about adoption, administration, and interpretation of the paper-based assessment. These include:

• Visually simplified, pre-set completion workflows, enabling raters to more easily focus on only the active manifestations and navigate the assessment at the desired pace, while ensuring no missed items or data loss
• Structured and guided completion to prevent inconsistent reports
• Automatic logic-error checks
• Automated scoring validation, eliminating errors and reducing workloads for raters
• On-screen guidance derived from the BILAG glossary to standardize and simplify administration
• Composite approach, where clinical and laboratory results are both captured organically and independently
• Detailed reports to keep track of eligibility calculations, participant status, visit details, DCFs, compliance rates, and more

Comprehensive Clinical Ratings Quality Strategy

Properly trained raters are a critical factor in trial outcomes, especially for lupus clinical trials which rely on complex assessments to measure primary endpoints. Signant's approach to rater training for lupus trials focuses on standardizing assessment administration and scoring technique to ensure accuracy and consistency across sites and raters. A robust, effective training program should include:

• Rigorous rater training - Our training and qualification methodology follows a structured process including rater experience surveys, expertise verification, comprehensive training, certification exams, and ongoing performance management throughout the study lifecycle.
• Placebo response mitigation - Signant addresses the two major components affecting placebo response in RCTs: unintentional augmentation through site personnel interactions and patient expectations about study participation and treatment. Training targets both investigators/site staff and patients to establish appropriate expectations and communication approaches.

Protocol-Specific Trial Data Analytics to Enhance Endpoint Reliability

A third pillar to a comprehensive endpoint quality strategy for lupus trials, sponsors can incorporate real-time statistical monitoring of trial data to increase their reliability. Signant's PureSignal Analytics, our blinded data analytics solution, has been successfully applied in lupus trials to:

• Tailor algorithms to protocol-specific study endpoints and data quality indicators
• Verify appropriate patient inclusion/exclusion based on a trial’s eligibility requirements
• Monitor ClinRO data for inconsistencies or variability across sites and raters
• Proactively identify data quality concerns early (which typically affect 20-30% of trial data)
• Provide visualizations and analytics to identify areas that require intervention

Two recent case examples – in which centralized statistical monitoring identified non-random patterns in lupus trial data – highlight the value of a robust in-trial data analytics strategy:

1. Screening instability - Analytics identified that subjects with more than 3-point SLEDAI changes between screening and baseline had significantly lower end-of-treatment change than stable subjects.
2. Flare identification inconsistencies - The system detected that flares were sometimes recorded despite SLEDAI improvement, while a 3-point SLEDAI increase only resulted in flare recording 43% of the time.

The Path to Higher Quality Lupus Trials

By combining electronic assessment innovations, rater training, placebo response mitigation, and sophisticated data analytics, Signant has developed a comprehensive approach to addressing the most challenging aspects of lupus clinical trials that have contributed to inconclusive results. For pharmaceutical companies conducting SLE research, these advancements offer a path to more reliable endpoints, reduced data variability, and ultimately, more efficient and successful trials.

As lupus treatment development continues to evolve, implementing these evidence-generation strategies may prove essential for identifying true treatment effects and advancing much-needed therapies for this complex autoimmune condition.

About the Authors

Manuela Bossi, PhD is Associate Director, Digital Health Sciences at Signant Health, where she provides scientific expertise across various therapeutic areas. She earned her PhD from University College London, gaining extensive experience in clinical research and the development of digital treatments for a childhood condition. Over years at Signant, Dr. Bossi has supported commercial, product and operational teams, particularly in clinical trials for epilepsy/seizure disorders, oncology, immunology and dermatology. Along these, she has played a key role in the design and development of complex eDiaries.

Anthony T. Everhart, MD, FACP, is the internal medicine leader at Signant. Dr. Everhart is board-certified in internal medicine and a fellow of the American College of Physicians with over 23 years of experience in the practice of medicine and over 12 years of experience in clinical development. Prior to joining Signant, Dr. Everhart held positions of Vice President, Medical Affairs and Vice President, Medical Informatics at Chiltern and Covance, and consulted independently in the areas of medical monitoring, medical data review, data analytics, and physician adoption of technology. He has worked in all phases of clinical development in numerous therapeutic areas including allergy & immunology, cardiovascular, hematology & oncology, infectious disease & HIV, neurology, ophthalmology, psychiatry, respiratory, and rheumatology.