Rare Diseases: The Challenges of Demonstrating Value in an Oprhan Setting 

Stuart Mealing

Director of Pharmaceutical Consulting, YHEC

Securing reimbursement for therapies targeting rare diseases relies on a compelling demonstration of their value. However, the unique challenges inherent in rare disease research often make robust evidence generation an uphill battle. Drawing on his extensive experience in this complex landscape, Director of Pharmaceutical Consulting, Stuart Mealing, offers insightful perspectives on the hurdles and strategies for effectively showcasing the value of these vital interventions.

Tell us a bit about yourself and your role.
I am the Director of Pharmaceutical Consulting at YHEC. Alongside my role at YHEC, I am also a committee member for the Highly Specialised Technology pathway at NICE (the National Institute for Health and Care Excellence) – a process that is tailored to evaluate technologies for very rare conditions. I am an author on over 70 peer-reviewed publications, many of which are focused on rare diseases.

Can you briefly explain why demonstrating value in rare diseases is so challenging?
The core of the problem is that payers (especially national HTA agencies) often expect a level of evidence comparable to that of non-rare disease areas. However, generating this level of robust evidence in rare disease is inherently challenging due to several factors.

Firstly, the small number of affected individuals limits the feasibility of large-scale, randomised controlled trials, which are typically considered the gold standard for demonstrating efficacy and value. Recruiting enough patients can be a major hurdle. Furthermore, randomisation and blinding of randomised controlled trials may not be realistic. For example, it may not be possible to blind a gene therapy, such as CAR-T cell therapy.

Secondly, the heterogeneity of rare conditions can make it difficult to show consistent treatment effects across a diverse patient population. The variability in disease presentation and progression can obscure the true impact of an intervention.

Thirdly, the lack of established natural history data makes it harder to determine if observed improvements are directly attributable to the treatment or simply reflect the natural course of the disease. Without a clear understanding of how the disease progresses without the intervention, assessing value becomes complex.

Finally, the high cost of developing treatments for small patient populations often clashes with traditional value assessment models that may not adequately account for the unique challenges and the significant unmet need in rare diseases. This can lead to difficulties in demonstrating cost effectiveness using standard metrics.

What strategies could help in establishing the value of an intervention for a rare disease?
Demonstrating the value of a rare disease intervention requires a proactive and multifaceted approach. Early and thorough planning is essential: preparation for market access is far more important in the rare disease space because of the probable lack of evidence.

A crucial step involves establishing the key aspects of value for the intervention and assessing the challenges in demonstrating each of these. This forms the bedrock of a coherent evidence generation plan. Where possible, seek early advice from health economists or payers and design a cohesive project, spanning from the initial clinical trials to reimbursement. This integrated approach enables efficient collection and validation of data that will be needed at all stages.

Proactive engagement with reimbursement agencies is also key, particularly where the evidence base relies on an unconventional approach. While each agency will have a gold-standard methodology, they may be willing to engage with emerging methodologies and endpoints where they are truly required and have been appropriately validated.

Can you outline the importance of appropriate evidence validation?
Validation of the evidence will often underpin the perception of its quality, regardless of the results generated. Wherever possible, evidence should be validated in a structured manner using robust elicitation methods. Validation likely assumes a bigger role in the rare disease landscape (compared with non-rare diseases) because a substantial portion of the evidence may be novel, tailored to the condition, and not applicable to other decision problems. Therefore, building and maintaining strong, respectful relationships with stakeholders is essential. As previously discussed, it is also important to proactively engage with stakeholders if you’re using novel or unconventional endpoints/methods to ensure that these are acceptable.

What else should be considered while preparing the submission?
To provide the decision maker with sufficient context, it is helpful to characterise the disease’s unmet needs and summarise the potential impact of the new intervention. Remember – all payers have the same underlying considerations when making a decision: (1) how certain are they in their decision, and (2) are they comfortable accepting non-standard evidence sources?

Well-planned, well-structured, and forward-looking sensitivity analysis should be used to examine parts of the evidence package, particularly the evidence that is used for economic modelling. Ideally, any sensitivity and scenario analyses will be detailed in early protocols to ensure that adequate data are collected to support them. This ensures that these analyses can be integrated as core features in the model, rather than giving the impression of being an afterthought.

What are the key considerations for the project team?
For a project team navigating the complexities of reimbursement for a rare disease intervention, maintaining a holistic perspective on the evidence generation process is important. While each component of the evidence package is important, it only represents one facet of the overall value proposition. When generating clinical evidence, it can be hard to remember that this is just a starting point and not the totality of the evidence. Similarly, the economic model does not provide the whole story. Reimbursement agencies can forget this as easily as anyone else involved in the process. All evidence should be conceptualised and considered fully at initiation to ensure a coherent understanding of value. Ultimately, each piece of evidence is a tool to aid in decision making, but the totality of the evidence package is the true medium through which the intervention’s value proposition is conveyed.

What is YHEC's approach to this type of work?
YHEC has considerable expertise across the entire lifecycle of rare disease therapies, from providing early-stage advice and engaging with key opinion leaders and other important stakeholders, through to engaging with reimbursement agencies and preparing health technology assessment submissions. Collecting first-hand accounts of the disease and new therapies through patient-reported outcomes is also a valuable strategy for demonstrating value in rare diseases. For more information on this topic, please view our dedicated blog post by our in-house expert, Andria Joseph.

Contact us

Contact the YHEC team for more information and to find out how we can support evidence generation and health technology assessment in rare diseases.