What does payer-informed evidence generation for rare disease therapies look like?

Rare disease therapies are in a moment of transition. The Food and Drug Administration (FDA) increasingly accepting data from alternative clinical trial designs (e.g., single-arm, decentralized, with external control arms using natural history, trials incorporating surrogate endpoints). Although randomized, placebo-controlled clinical trials remain the industry gold standard, this flexibility has enabled rare disease therapy manufacturers to commercialize dozens of products

But regulatory approval is one part of patient access. Payers must accept the therapy and its body of evidence in order for the treatment to reach EVERY PATIENT POSSIBLE. Payers—as well as pharmacy benefit managers and value assessment bodies—often demand that rare disease therapies have an evidence base that is as robust as those of common conditions, seeking a level of certainty that clinical development programs for rare diseases may be unable to provide.

Current evidence standard vs. rare disease reality

Adequately powered randomized controlled trials are frequently infeasible in rare and ultra-rare populations. Small and geographically dispersed patient populations, ethical constraints on placebo-controlled arms, and a lack of validated endpoints and natural history data all complicate traditional trial design.

Payers may seek to address these evidence gaps by requesting that manufacturers conduct HEOR, natural history studies, indirect treatment comparisons, total cost-of-care analyses, cost-offset analyses, longitudinal data, or other data. However, small, geographically dispersed patient populations, disease heterogeneity, low physician awareness, a lack of physicians specializing in rare and ultra-rare diseases, a limited diagnostic toolbox, and a lack of validated biomarkers make it difficult to generate this type of evidence.

For payers, this translates into continued uncertainty at launch. A therapy may have FDA approval, but payers are frequently tasked with making coverage determinations without head-to-head comparative data, long-term evidence of sustained benefits, or population-level effectiveness data they would expect from manufacturers of therapies for more common conditions.

Providing payers with the evidence they need to feel comfortable offering coverage is not a task for any single stakeholder. Meaningful access in the rare disease sector requires sustained input from manufacturers, clinicians, regulators, and patient advocates alike. For example:

• Manufacturers can design robust long-term and real-world outcomes-based and economic evidence generation studies;
• Clinicians can contribute data from routine patient care through registries, and help interpret outcomes;
• Regulators can provide guidance on appropriate evidence generation strategies, continued development of alternative regulatory approval mechanisms and pilot programs as well as continued collaboration with manufacturers and researchers on validation of various biomarkers; and
• Patient advocates can help define meaningful outcomes and support patient-centered evidence collection over the course of a product’s lifecycle.

What payers value in rare and ultra-rare disease therapies

Before a therapy can reach payer plan sponsors and their respective pharmacy and therapeutics committees,’ stakeholders look for a distinct set of evidentiary signals when trial data alone cannot answer their questions. There are several key considerations:

• Durability of effect over time: Evidence that a therapeutic benefit persists beyond the trial window, typically demonstrated through registries and long-term follow-up data rather than the trial itself.
• Patient-reported outcomes (PROs) and functional status: Measures that capture how patients feel and function day to day, complementing biomarker data with evidence of real-world benefit. While PROs are increasingly incorporated into clinical trials, payers may view these data cautiously when instruments are not well validated, consistently administered, or clearly linked to outcomes that inform coverage decisions. Robust, validated measures that demonstrate a meaningful relationship between treatment and patient functioning can therefore strengthen their utility.
• The robustness of post-launch data: Manufacturers’ commitment to generating and sharing relevant post-launch evidence, including longer-term clinical outcomes and real-world data, and engaging with payers as evidence matures. Where appropriate, this may also include outcomes-based or value-based arrangements that allow coverage decisions to evolve as additional evidence becomes available.
• Industry openness to data sharing: While generally controversial and not widely acceptable as a strategy, data sharing can provide for the aggregation of vital clinical data, lower costs and cut out redundancies, create a shared bank of knowledge, reduce the limitations of small patient populations dispersed across vast geographies, and further enhance drug research efforts.

How we can help

As payers take on a larger role in determining whether therapies for rare and ultra-rare conditions reach the patients who need them, successful market access increasingly depends on evidence-generation strategies built with payer relevance in mind from the outset. Avalere Health partners with life sciences companies to design and implement real-world evidence-generation strategies that meet payer requirements and expectations and support payer engagement and value communication – approaches that translate rare disease evidence into durable coverage and reimbursement decisions. Connect with us to learn more.