Etelcalcetide for Treating Secondary Hyperparathyroidism: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The manufacturer of the calcimimetic drug etelcalcetide was invited to make an evidence submission as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) programme. Within this submission, they reported evidence on the clinical and cost effectiveness of etelcalcetide for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) on haemodialysis. The Southampton Health Technology Assessments Centre (SHTAC), part of the Wessex Institute at the University of Southampton, was the independent Evidence Review Group (ERG) commissioned to appraise the company's submission. This article describes the ERG's review and critique of the company's submission and summarises the NICE Appraisal Committee's subsequent guidance (issued in June 2017). The clinical-effectiveness evidence submitted by the company consisted of two double-blind, randomised controlled trials (RCTs) comparing etelcalcetide with placebo, one RCT comparing etelcalcetide with cinacalcet, two single-arm extension studies of the above trials, and one single-arm study evaluating the effect of switching from cinacalcet to etelcalcetide. No study specifically examined the population specified in the NICE appraisal scope: patients refractory to standard therapy with phosphate binders and vitamin D (PBVD). None of these trials were designed to collect long-term efficacy data for outcomes such as mortality, bone fractures, cardiovascular events, or parathyroidectomies. Instead, biomarker data from the trials were mapped to long-term outcomes by an assumed linear relationship between the trial outcome, reduction of parathyroid hormone (PTH) by > 30%, and the log-hazard ratios for the occurrence of clinical events derived from a large, long-term RCT of cinacalcet (the EVOLVE trial). After submission of a confidential Patient Access Scheme (PAS) discount reducing etelcalcetide drug costs, the incremental cost-effectiveness ratio (ICER) for etelcalcetide versus cinacalcet was £14,778 per quality-adjusted life-year (QALY) gained in the company's base case. While this value is lower than the NICE threshold range of £20,000 and £30,000 per QALY gained, it was the opinion of the ERG that the ICER was highly uncertain due to efficacy data limitations for etelcalcetide, inadequate synthesis of clinical-effectiveness evidence, and strong assumptions connecting short-term biomarker data with long-term clinical outcomes. The ERG produced an alternative base case for etelcalcetide versus cinacalcet, with an ICER of £22,400 per QALY gained, also subject to uncertainty. The NICE Appraisal Committee recommended etelcalcetide as an option for the treatment of SHPT in adults with CKD only if treatment with a calcimimetic is indicated and cinacalcet is not suitable, subject to the company's provision of the agreed PAS discount.