Systematic literature reviews (SLRs) play an essential role in health technology assessment (HTA), providing the basis for the evidence presented in a technology appraisal submission. Methodologically flawed SLRs and/or non-transparent reporting of SLRs can raise suspicion and influence an appraiser’s confidence in the evidence to support the clinical and cost-effectiveness case.
Our client required an HTA-ready SLR to compare the efficacy and safety of first-in-class inclisiran to other lipid-lowering therapies (LLTs) in lowering LDL-C in patients who have not achieved sufficient lowering with statins, are statin-intolerant, or where statins are contraindicated. The purpose of the SLR was to inform a network meta-analysis (NMA), as well as subsequent HTA in various jurisdictions including NICE in England.
As a key area of interest in public health, the evidence base in hypercholesterolaemia is extensive. On assimilation of this large data set, it became clear that there was considerable between-trial heterogeneity in terms of population disease characteristics, trial design/inclusion criteria, study treatment regimens, and outcome definitions. To ensure meaningful and usable data synthesis, whilst considering external validity, Tolley addressed these issues in a number of ways, including but not limited to:
- Clinical expert input was sought to address the heterogeneity in trial design and disease demographics of trial participants. Whilst experts confirmed this was representative of the heterogeneity of the hypercholesterolaemia patient population seen in clinical practice, they advised in ways to ensure the identification of sufficient robust RCT data, most comparable to the participant population of the inclisiran trials.
- The definition and reporting of statin regimens as high, low, or medium-intensity was variable across trials and therefore, under expert clinical guidance, the NICE clinical guideline definitions were used to judge individual trial statin regimens. European and US guidelines were considered but clinical experts suggested NICE guidelines would have the widest consistent applicability to clinical practice.
- A protocol amendment was made to restrict the inclusion of SLRs to those published in 2015 onwards with the rationale that this would allow published SLRs on the most recent comparators alirocumab and evolocumab to be captured, as well as the most recent and up-to-date SLRs on the more well established hypercholesterolaemia agents, ezetimibe and statins.
The data synthesised in this SLR was used to perform an NMA comparing inclisiran to relevant comparators in lowering LDL-C in patients with hypercholesterolaemia at increased cardiovascular risk, taking maximum tolerated dose statins.[1]
Tolley also supported with the NICE health technology assessment for inclisiran by producing the appendix containing the detail of the SLR performed, which provided support to the submission. In 2021, inclisiran received a positive recommendation from NICE for the treatment of primary hypercholesterolaemia or mixed dyslipidaemia, with a history of cardiovascular events, and insufficient LDL-C control despite maximum tolerated LLT (TA733).[2]
1. Burnett, H., et al., Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis. Curr Med Res Opin, 2022. 38(5): p. 777-784.
2. National institude for Health and Care Excellence (NICE). Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia (TA733). 2021; Available from: https://www.nice.org.uk/guidance/ta733/chapter/1-Recommendations.