During 2017–2018 SBU has been one of many stakeholders involved in the CoreHEM initiative. The aim of the project was to determine a core set of outcomes to evaluate efficacy, safety, comparative effectiveness, and value for hemophilia gene therapy. The coreHEM project was jointly led by the Green Park Collaborative (GPC), the National Hemophilia Foundation (NHF) and McMaster University.
Following is a short summery from the original final report:
Hemophilia is an inherited bleeding disorder, caused by a deficiency of coagulation factor VIII (hemophilia A) and IX (hemophilia B). Currently, the gold standard of treatment is lifelong recurrent intravenous injection of the missing protein, either to prevent or treat bleeds, which is burdensome and heavily impacts a patient’s life. Existing therapies control the disorder, but they are far from ideal. The disorder, and treating it, continues to impose a heavy toll on quality of life. People living with hemophilia may have bleeding into the joints, soft tissue and muscles. This bleeding can cause short-term problems, such as intense pain usually and severely limiting activity, and long-term complications such as chronic pain, joint destruction, and eventually disability. For people with severe hemophilia, keeping up with the treatment regimen and avoiding bleeding episodes dominates daily routines and decisions for work and school schedules, travel, selection of recreational activities, and other issues of everyday life. Existing therapies control the disorder, but they are far from ideal. The disorder, and treating it, continues to impose a heavy toll on quality of life.
In 2011 SBU published a HTA-report on treatment of Hemophilia A and B and von Willebrand Disease
Gene therapy and hemophilia
Recent gene therapy trials in hemophilia have reported promising results, demonstrating that gene therapy could yield a long-term functional “cure” by changing or replacing the missing and abnormal genes.
Gene therapy would be life-changing for patients, relieving them of many of the daily burdens and limitations they currently endure. Phase 3 trials of gene therapy are beginning. This new treatment technology has the potential to change the landscape of hemophilia management. Therefore, we are at an opportune time to establish the standards for collecting and reporting on relevant, well-specified outcomes that are important to patients. Outcomes associated with a functional “cure” may be different than the outcomes used to assess the current standard of care.
The aim of the coreHEM project was to determine a core set of outcomes to evaluate efficacy, safety, comparative effectiveness, and value for hemophilia gene therapy. A core outcome set is a minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. CoreHEM was conducted between May and November 2017, and the data analysis completed on December 20th, 2017. The project used a modified Delphi consensus process that was adapted from the COMET Initiative approach. It utilized a multi-stakeholder collaborative process that included patients and patient advocates, clinicians, hemophilia researchers, US and international payers and HTA groups, representatives from government organizations, and life science companies with hemophilia gene therapy in development.
The initial list of candidate outcomes included 48 outcomes, from which six core outcomes were identified as crucial for evaluating the effectiveness of gene therapy: frequency of bleeds, factor activity level, duration of expression, chronic pain, mental health status, utilization of the healthcare system (direct costs). During the process, the group agreed to separately list core outcomes and relevant adverse events, as the latter would be required for regulatory purposes. The adverse events that were voted as important by the group were liver toxicity, short-term immune response to FVIII/FIX, immune response to gene therapy (cytotoxic), and thrombosis in the short-term adverse events domain, development of other disorders, vector integration into the host genome, and duration of vector neutralizing response in the long-term adverse events domain, and cause of death in the mortality domain. Two additional outcomes (duration/frequency/type of physical activity/sport/play, feeling of physical health/general health perception) were rated highly important. They did however not reach the threshold for inclusion in the core set.
|Core Outcome Set||– Frequency of bleeds
– Factor activity level
– Duration of expression
– Chronic pain
– Mental health status
– Utilization of healthcare system (direct costs)
|Additional Outcomes||– Duration/frequency/type of physical activity/sport/play
– Physical health/general health perception
|Adverse events||Short-Term||– Liver toxicity
– Short-term immune response to FVIII/FIX
– Immune response to gene therapy (cytotoxic)
|Long-Term||– Development of other disorders
– Vector integration into host genome
– Duration of vector-neutralizing response
|Mortality||– Cause of death|
Figure 1. Three groups of outcomes selected by coreHEM Delphi voting. Definitions for the core outcomes, additional outcomes and adverse events are provided in Appendix 14 in the final report.
Final report: “coreHEM: Developing Comparative Effectiveness Outcomes for Gene Therapy in Hemophilia,” details the methods, results, and impact identified by the initiative, as well as the final core outcome set, and preliminary work on measurements and instruments identified for those outcomes. http://www.cmtpnet.org/resource-center/view/corehem-COS/
Journal article: “Core outcome set for gene therapy in haemophilia: Results of the coreHEM multistakeholder project.” (Iorio A, Skinner MW, Clearfield E,et al.; for the coreHEM panel. Core outcome set for gene therapy in haemophilia: Results of the coreHEM multistakeholder project. Haemophilia. 2018;00:1–6. https://doi.org/10.1111/hae.13504)