Challenges for HTA Submissions Concerning Conditions Lacking Established Treatment Pathways

During health technology assessment (HTA) submissions, the manufacturer must specify the decision problem that their evidence submission is addressing. This involves defining the scope of the appraisal, including the population and possible subgroups, comparators, outcomes of interest, equality issues, and innovation. Whilst some HTA bodies such as the National Institute for Health and Care Excellence (NICE) in England pre-specify the scope of the evaluation, others, such as the Scottish Medicines Council (SMC), require the manufacturer to define their own decision problem. This can be particularly challenging in diseases where the therapeutic pathway is not well defined, for example in rare diseases or where treatment depends on a number of patient characteristics (health, age, prior treatment etc.). However, choosing the correct comparator(s) is key to HTA success; a common reason for failure with the SMC is not choosing the most appropriate comparator. Furthermore, the sequencing of treatments in the treatment pathway can have profound effects on the cost-effectiveness of therapies, and therefore in the absence of established pathways, manufacturers must establish these carefully and perform appropriate sensitivity analyses as required. We have explored how the lack of a well-defined treatment pathway can result in challenges for defining and addressing the HTA decision problem using examples from recent HTA submissions for treatments in orphan oncology, neuropathic pain, and scleroderma, in England, Scotland, and France. Factors such as collaboration with payers and clinicians and analysis of real world evidence are often used and we will summarise how different methods used to determine treatment pathways have been used by manufacturers with different HTA agencies to demonstrate areas of similarity and difference between countries.