In a rare disease context, the uncertainties around evidence can be particularly high. Small patient populations can constrain the feasibility of large-scale recruitment into clinical trials, registries and other sources of real-world evidence are often limited, and established practices in terms of clinical management can be poorly evidenced or highly heterogeneous. The challenges that these limitations may present in terms of meeting HTA evidence requirements for positive reimbursement are among NICE’s motivations for assessing selected interventions under its highly specialised treatment (HST) programme.
Generating evidence for HTA submissions and appraisals in a rare disease area can also require a more fundamental series of questions to be addressed. The selection of clinical endpoints, patient-reported outcomes and model approaches that are most appropriate for informing a robust and holistic assessment of relative cost-effectiveness is an important consideration across all assessments. In prevalent conditions, however, these considerations have often been addressed and reasoned in the same or similar therapeutic areas previously, providing a source of clarity around methodological preferences and, over longer timescales, setting standards for study design and data collection. In oncology indications, for example, there are well-established precedents for using partitioned survival or Markov model approaches, which also tend to be catered for by progression-free and overall survival endpoints collected in clinical studies. Although it is important that optimal approaches are not based on historical acceptability alone, this typically shifts the burden of evidence towards whether a divergence from established methods is warranted, rather than devising and validating a do novo model structure.
In rare diseases, there may be multiple clinical endpoints and modelling options available, and often no existing submissions from which to determine decision-maker and stakeholder preferences around model design. This can present a large risk, as considerations around endpoint selection are fundamental to the design of ITCs, evidence generation activities and model health states, potentially limiting the extent to which substantial changes are feasible if underlying choices are contested during the later stages of HTA review. Close engagement with HTA bodies, clinical experts and patient representatives from an early stage to establish an appropriate agreed approach, therefore, is crucial for de-risking the potential for underlying decisions to dominate discussions as a critical area of uncertainty.
A valuable but often neglected step at this early stage is to conduct early cost-effectiveness modelling to inform strategic decisions. Early modelling is most often used to provide early estimates of Economically Justifiable Price (EJP); the maximum list price that can be charged for a new intervention, while cost effectiveness results remain within the willingness to pay (WTP) threshold. The calculation of an EJP provides critical input to market access strategy before HTA negotiations begin, and can be used to inform go, no-go decisions. Early cost-effectiveness models can fulfil several additional objectives, however, especially in rare diseases where data is sparse, there are few precedents to inform model approach, and value messaging around unmet needs are unique to the treatment and disease area. Early models also allow companies to stress-test assumptions, explore structural options, and align with stakeholders on an optimal strategy for developing a robust body of evidence for HTA. Incorporating metrics such as the Expected Value of Perfect Information (EVPI) analysis can identify specific uncertainties that are most influential on cost-effectiveness conclusions, allowing evidence generation activities to be focused on priority areas of uncertainty.
Rare diseases often present evidence challenges, but also provide opportunities for positive and meaningful advances not only to the patients and carers immediately affected but also to HTA methods and processes as a whole. Drawing on the oncology example, the accumulation of evidence from previous appraisals can drive a tendency for new treatments to default to the same or similar methods rather in preference to methods that may better demonstrate clinical and cost-effectiveness value claims specific to the technology being considered. For submitting companies, exercising caution around novel methods is an understandable approach given potential risks around acceptability and challenges triangulating results against existing comparator evidence. Where no such precedent exists, there is potentially greater opportunity to approach evidence in a way that considers the immediate decision problem on its own merits, and an important role in shaping evidence generation to support ongoing development in the disease area.
To achieve HTA success in rare diseases, the Tolley team has addressed these challenges by:
• Engaging early with clinical experts and NICE to map out clinical outcome measures and identify the most appropriate tools for decision-making and longer-term evidence generation
• Exploring the validity of generic and disease-specific patient-reported outcome measures, with additional data generation activities to strengthen evidence
• Conducting early evidence needs and gap analyses
• Developing early economic models to establish an economically justifiable price range and identify sensitivity to key uncertainties
• Designing and conducting evidence generation exercises to address priority evidence gaps, including structured expert elicitation exercises and carer impact studies
• Conducting multi-stakeholder panel meetings involving clinicians, payer experts, patient and carer representatives and other key opinion leaders to incorporate perspectives from all stakeholder groups
• Establishing a differentiation between directly-observed clinical results and expected longer-term outcomes, to reduce the influence of uncertainties as a main driver of cost-effectiveness results
• Promoting a collaborative relationship with NICE and the EAG to identify solutions and scenario testing around remaining uncertainties
Addressing evidence needs effectively ahead of submission to HTA bodies can drastically reduce the number of uncertainties to resolve at the committee stage, which can avoid delays in reimbursement decisions and ultimately help to achieve the best outcomes for patients and companies. That’s why we emphasise the importance of evidence planning as part of our ‘one and done’ approach in all HTA submissions.