Data Quality Challenges in Systemic Lupus Erythematosus Trials: How Can This Be Optimized?

Lexy Kelley,Marilyn C Pike

doi:10.1007/s11926-012-0261-7

Abstract

Major scientific advances in basic science, pharmacology, and translational medicine have allowed the discovery of new molecular targets whose manipulation by new chemical entities has led to treatments for inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. Development of new agents for systemic lupus erythematosus (SLE) has lagged, however, because the protean manifestations of SLE present challenges for measuring therapeutic effects in a consistent manner. Composite end points combining several Disease Activity Indices (DAIs) are being used in ongoing global studies, but the uniform application of these complex DAIs across large numbers of clinical sites has proven difficult. We describe herein approaches that are being utilized to facilitate collection, review, and analysis of the clinical measures utilizing independent central adjudication committees.

Highlights

Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide array of clinical and laboratory manifestations that can affect every body system [1,2,3]
The development of reproducible composite primary end points such as ACR20, 50, and 70 and DAS28-CRP and others for the measurement of changes in rheumatoid arthritis activity leads to more interpretable trial end points and a revolution in the development of drugs for treatment of this disease compared with 20 years ago [54, 56]
By studying the differential responsiveness of patients with different phenotypes and genotypes to the new rheumatoid arthritis therapies that target specific immunologic pathways, it will be possible to develop a better understanding of the pathogenesis and genetics of this disease

Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease with a wide array of clinical and laboratory manifestations that can affect every body system [1,2,3]. The placebo effect was examined using multiple outcome measures including the SRI-4, SRI-5, and a stringent end point similar to the BICLA, which did not, allow a responder to have even one B flare These end points were compared with BOLD study protocol criteria minimally defined by either a ≥drop of one BILAG grade or a SLEDAI ≥4-point reduction from baseline but anchored by the investigators’ simple intent-to-treat–based determination, whether there was clinically significant improvement, no significant change, or clinically significant flare. Centralized adjudication committees (CACs) have been used successfully to analyze clinical end points that are not solely composed of objective laboratory data and are subject to variable and/or biased interpretation These adjudication committees are different from data monitoring committees ( known as data safety monitoring committees or DMCs), which are a group of individuals established for large, randomized, multicenter trials in which a treatment is intended to reduce mortality or major cardiovascular events, recurrence of cancer, or other life-threatening events [39]. (5) Cranial nerve disorder (6) Lupus headache (7) CVA (8) Vasculitis (9) Arthritis (10) Myositis (11) Urinary casts (12) Hematuria (13) Proteinuria >0.5 g/24 h, new or recent onset (14) Pyuria >5 WBC/hpf, excluding infection (15) (New) rash (16) Alopecia (17) Mucosal ulcers (18) Pleurisy (19) Pericarditis (20) Low complement (21) Increased DNA binding (22) Fever (23) Thrombocytopenia (24) Leukopenia

88. Active urinary sediment and supporting laboratory value

Conclusions

Findings

39. FDA guidance for clinical trial sponsors