Clinical trial outcomes for SLE: what we have and what we need

Abstract

The paradigm of drug approval in SLE currently relies on successful large phase III randomised controlled trials and a set of primary, secondary and additional end points. Taken together, these outcomes offer a nuanced understanding of the efficacy and safety of the investigational agent. In this review, we thoroughly examine the main outcomes used in SLE trials and highlight unmet requirements as well as potential venues for future trial design in SLE. Disease activity indices can be broadly categorised into global-specific and organ-specific indices, in particular for skin, joints and kidneys, but there is no universal consensus about their use in clinical trials. Because each of these instruments has its own intrinsic strengths and weaknesses, the assessment of treatment response has progressed from relying solely on one individual disease activity index to using composite responder definitions. Those are typically measured from the trial baseline to the end point assessment date and may be combined with the need to taper and maintain glucocorticoids (GCs) within prespecified ranges. Remission and low disease activity are two critical states in the perspective of 'Treat-to-Target' trials, but are not fully recognised by regulators. While significant progress has been made in clinical trial outcomes for SLE, there is a clear need for continued innovation. Addressing these challenges will require collaboration between researchers, clinicians, patients as well as with regulatory agencies to refine existing outcome measures, incorporate meaningful and ethnically diverse patient perspectives, foster relevant digital opportunities and explore new therapeutic avenues, including early use of investigational agents. By doing so, we can advance our ability to manage SLE effectively and safely and improve the lives of those living with this complex and impactful autoimmune disease.

Keywords: autoimmune diseases; clinical trial; disease activity; systemic lupus erythematosus.

Figure 1

The Physician Global Assessment (PGA) as recommended by the PGA International Standardisation COnsensus in SLE consortium. (A) The PGA graph, consisting of a 0–3 visual analogue scale (VAS) with anchored values. (B) The correct way to score the PGA, by putting a vertical tick on the 0–3 VAS as a continuous measure with one decimal (eg, 1.4 on a 0–3 scale). The PGA scale ranges from 0=‘no disease activity’ to 3=‘most severe disease activity’. Values ≥0.5 but ≤1 refer to mild disease activity; values >1 but ≤2 refer to moderate disease activity and values >2 up to 3 refer to severe disease activity. The PGA should be scored by experienced physicians, preferably by the same rater at each visit.

Figure 2

Combination of disease activity indices to obtain SRI-4 and BICLA response indices. BICLA, BILAG-based Combined Lupus Assessment; BILAG, British Isles Lupus Assessment Group; PGA, Physician Global Assessment; SLEDAI-2K, SLE Disease Activity Index 2000; SRI-4, SLE Responder Index-4.