1. The Multi-Domain Revolution: When One Size Doesn’t Fit All

The traditional approach to clinical endpoints has been rigid: define one primary measure of success and apply it uniformly to all patients. But rare diseases don’t necessarily follow these rules. The heterogeneity of many genetic orphan diseases means a child might show improvement in mobility while another has gains in vision or respiratory function.

Enter the multi-domain, responder-based endpoint: a flexible approach that allows patients to demonstrate meaningful improvement in any of several clinically relevant areas. Instead of forcing every patient through the same narrow measure of success, this method recognises that clinical benefit can manifest in multiple ways.

This is nothing new; multi-domain endpoints have been utilised across a range of therapeutic areas, from cardiovascular to neuromuscular indications. From a clinical perspective, this approach makes sense, especially in the context of diseases where symptoms are heterogeneous. But what happens when the symptoms are not only heterogeneous, but also misunderstood? Or when there is no validated, gold-standard multi-domain metric?

When it comes to these situations, payers are also in the dark. The good news is that manufacturers have the opportunity to work with the clinical community to define these metrics. However, the clinical point of view is not the only one that matters here; payers should get the chance to provide input into what these endpoints should cover, or what the hierarchy should be. No manufacturer wants to find themselves with a primary endpoint measuring behavioural changes, only to find payers place more value on cognitive improvements.

The challenges don’t stop at choosing a scale. In the absence of a recognised benchmark, payers will scrutinise what degree of change on that scale constitutes real clinical benefit. It falls to the manufacturer to set that threshold, taking national requirements into account. For instance, French authorities usually expect a two-point advantage over the control arm, not merely an improvement from baseline.

This is especially relevant in cases where there is not a gold standard scale for a disease, as is usually the case for orphan conditions with no treatment available. Beyond considering payers’ feedback, manufacturers should work together with their medical teams to build consensus on new scales and domains and educate payers on the clinical meaning behind point-based improvements. This leads us to our second strategy.

2. A Picture Worth a Thousand Data Points: The Power of Visual Evidence

The progressive and heterogeneous nature of many orphan diseases can sometimes make an improvement on paper difficult to understand for payers. Increasingly, payers want tangible outcomes, evidence of improvement that they could easily explain to the family of a patient. For example, a parent is not going to get excited about the fact that a new innovative therapy may result in a “three-point improvement” in motor skills, measured through a scale known by a series of letters and dashes. They will, however, feel optimistic if they know that their child will now be able to hold a pencil and write their name. 

Sometimes, the most compelling evidence isn’t found in spreadsheets or statistical analyses, it’s captured on video. Take an already-launched groundbreaking gene therapy for inherited blindness. While visual field tests provided important clinical data, it was the dramatic footage of treated patients navigating obstacle courses that truly demonstrated the treatment’s life-changing impact. 

This multimedia approach to evidence isn’t just emotionally compelling; it’s becoming increasingly accepted by health technology assessment agencies worldwide. Videos have been successfully used not only during clinical evaluation but also in price negotiations (even with bodies like the GKV-SV), fundamentally shifting how payers perceive treatment value. 

3. Thinking Beyond the Trial: Designing Endpoints for the Real World

We get it: demonstrating value through clinical trial outcomes and multimedia may not be enough. Despite teams’ efforts, payers may be reluctant to accept the claims of efficacy for an innovative treatment, citing uncertainties in long-term efficacy and safety. This may translate into P&MA conditions that don’t fully reflect the value developers see in their products. This is where outcomes-based agreements come in. We would be naïve to refer to these types of agreements as “innovative”, given they have been around for several years. However, they remain underutilised, but not for lack of trying.

Payers cite two key issues when it comes to outcomes-based agreements: burdensome tracking of patients and difficulty designing an agreement linked to subjective efficacy endpoints. In the case of orphan drugs, the first issue does not apply. The second, however, is more prominent than in non-orphan drugs, and can remain a major hurdle for developers and payers alike.

Here’s where many orphan drug developers make a common mistake: they treat clinical trial endpoints and post-launch reimbursement as separate challenges and don’t consider whether the selected endpoints will be a good fit for an outcomes-based agreement, should they need one. If these endpoints can’t be reliably measured in routine clinical practice, a strategy that could be banking on a payment by results collapses.

The solution is deceptively simple. Design trial endpoints with real-world accountability in mind from day one. This means selecting measures that are objective, easily trackable in routine care, and clinically meaningful to both physicians and patients.