Comparative effectiveness and safety, and health-related quality of life of haemophilia A treatments: two systematic reviews
Haemophilia-A (HA) is a congenital x‐linked bleeding disorder caused by a deficiency of blood coagulation factor VIII (FVIII), occurring in approximately one in every 5000 male live births. HA is currently without a cure and therefore requires life-long monitoring and treatment of potentially life‐threatening bleeding events. Existing treatments for the management of this disorder include the use of plasma‐derived factor concentrates, recombinant factor concentrates, and more recently, monoclonal antibodies (e.g. emicizumab). Individuals primarily utilize treatment either as on-demand (i.e. episodic treatment after a bleeding event has occurred), prophylactically (i.e. preventative treatment provided at regular intervals), or a combination of both.
Although effective at reducing bleeding rates, prophylactic treatment requires 2-3x weekly administration which can become quite burdensome, decreasing the overall quality of life for individuals with moderate to severe HA. Currently, novel HA gene therapies are being investigated in early- and late-stage clinical trials with the potential to address the unmet needs of the HA population.
A large scale systematic literature review (SLR) project, comprised of four individual SLRs across the areas of clinical efficacy and safety, health-related quality of life (HRQoL), economic evaluation, and cost/cost resource use for current, novel, and developing treatments within the HA population, was commenced in August of 2019. The preliminary results for the clinical and HRQoL SLRs were presented by Medlior’s industry partner on February 5-7, 2020, at the European Association of Haemophilia and Allied Disorders (EAHAD) in The Hague, Netherlands.
In collaboration with our industry partner, Medlior developed and executed individual, comprehensive search strategies for the Clinical and HRQoL SLRs. Searches were executed across multiple databases, clinical trial registries, and conferences resulting in combined 36,791 citations. After duplicates/triplicates were removed, 18,338 and 8,379 citations underwent title/abstract review in duplicate for the clinical and HRQoL SLRs, respectively utilizing the DistillerSR platform. Following title and abstract screening, the Medlior study team performed a full-text review of 730 publications for the Clinical SLR and 536 publications for the HRQoL SLR. In total, 184 citations were included for the Clinical SLR and 94 publications were included for the HRQoL SLR.
Using filtering functions within DistillerSR, citations were further categorized by study design to provide a better understanding of the landscape of evidence in the HA population. The Clinical SLR studies were categorized by randomized control trial (RCT) evidence and non-randomized comparative trial evidence. Similarly, studies in the HRQoL SLR were categorized as comparative and non-comparative trial-based evidence and non-interventional (observational) evidence.
The preliminary results for these SLRs highlighted considerable heterogeneity across study designs, treatments, and outcomes being reported in the HA population. Trials included in the Clinical SLR showed that very little head-to-head drug comparisons are available. Rather, treatment strategies (i.e. on-demand vs prophylactic or once-weekly vs twice-weekly administration schedules) are the focus of the current evidence. Breakdown of the study designs within HRQoL SLR showed that the majority of quality of life evidence in the HA population is at the observational level. Finally, substantial heterogeneity was seen among the HRQoL measurement tools utilized across the studies that were captured.
To conclude, preliminary results from two comprehensive SLRs on the clinical efficacy/safety and HRQoL evidence for the management of people with HA, showed a substantial volume of evidence in these areas. However, variation in treatment/treatment strategies and outcomes assessed underscore the challenges associated with synthesizing a large body of diverse evidence. Finally, no comparative evidence for novel gene therapies was identified at the time our search was conducted.