Belimumab for treating active autoantibody-positive systemic lupus erythematosus: an evidence review group perspective of a NICE single technology appraisal

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (GSK) of Benlysta (Belimumab), as part of the Single Technology Appraisal (STA) process, to submit evidence for its clinical and cost-effectiveness for the review and possible extension of a previously conditionally approved intravenous (IV) formulation of belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarizes the company submission (CS), presents the ERG’s critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the National Institute for Health and Care Excellence appraisal committee.

This appraisal is different to the previous appraisal in three ways:
(1). This appraisal expands its definition of ‘high disease activity’.
(2). In TA397, belimumab was approved with a managed access arrangement (MAA) for adults only. This appraisal includes people aged five years or more.
(3). The original appraisal included an intravenous (IV) formulation only. The current appraisal also includes a new subcutaneous (SC) formulation in the form of a pre-filled pen.

The company was required to collect real-world data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR), including on the efficacy, safety and effect on health-related quality of life of belimumab versus rituximab. This appraisal looks at these data and additional clinical trial evidence presented in the company’s updated submission to address uncertainties identified during the original appraisal. The ERG identified three major concerns with the evidence presented on the clinical effectiveness in the current submission, namely: short follow-up in the main comparative trials (BLISS-SC, BLISS-52 and BLISS-76), using the propensity score-matching (PSM) analysis in calibrating the cost-effectiveness model can severely bias the results in favour of belimumab and BILAG-BR data are not suitable for a comparison of belimumab with rituximab.

The main issue in the economic analysis was the uncertainty about long-term disease activity progression and resulting organ damage. The company’s approach of calibrating modelled organ damage to longer term data analysed using the PSM analysis was methodologically inappropriate. The final analysis comparing belimumab with standard treatment for the IV formulation resulted in an incremental cost-effectiveness ratio of £12,335 per QALY gained and £30,278 per QALY gained in the company's and ERG's base-case analyses respectively. For the SC formulation the final analysis resulted in £8,480 per QALY gained and £29,313 per QALY gained in the company's and ERG's base-case analyses respectively. NICE recommended belimumab in both IV and SC formulations as an option as add-on treatment for active autoantibody-positive systemic lupus erythematosus in the HDA-2 subgroup.

Key points for decision makers
•The comparison with rituximab was made difficult because data collected to make a comparison between belimumab and rituximab, were unsuitable for this comparison. Further NHS England recommended that patients be prescribed belimumab prior to rituximab, which made it an inappropriate comparator.
•The ICER of belimumab compared with standard treatment ranged between £8,480 and £68,909 with different model assumptions.
•The largest uncertainty in this population was in the long-term comparative effectiveness, and indeed disease activity progression and resulting accumulation of organ damage. Further data should be collected on this.