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Successful Applications of Real-World Data and Real-World Evidence in Rare Disease Programs

Clinical trials for ultra-rare diseases can be particularly challenging to mount due to small, geographically-dispersed patient populations. For such trials, the US Food and Drug Administration (FDA) may allow the use of credible real-world data (RWD) and real-world evidence (RWE) in lieu of data collected in a Phase 3 trial. However, acceptance of that data depends on a sponsor’s understanding of the FDA criteria for historical control groups, study data standards, and clinical meaningfulness.

In this article, we review two case studies involving the successful use of RWD or RWE in advancing the clinical development of treatments for rare diseases.

Case Study 1: Using RWD and RWE to support an ultra-rare orphan drug program

Recently, Premier Consulting was engaged by a sponsor who had developed a potential treatment for an ultra-rare, life-threatening congenital disease. The treatment had been granted breakthrough therapy designation, but FDA approval would ultimately rest on the sponsor’s ability to demonstrate clinically meaningful improvement. Observational data that had been collected demonstrated extremely promising safety and efficacy potential, and a recently-published natural history study had detailed palliative care and symptom management for this disease. The main endpoint for clinically meaningful improvement in this population was a patient-specific qualify of life (QoL) endpoint.

As is common with rare and ultra-rare diseases, the data collected globally by individual physicians as part of their normal daily practice was not necessarily collected in a consistent fashion across practices. During its first meeting with the FDA, the sponsor:

  • Presented data by subject to the FDA in order to underscore changes over time within an individual patient. The agency requested that data be further standardized and presented by primary functional endpoint.
  • Outlined the existence of a natural history dataset that was published in the literature. The agency encouraged further review of the data for potential reference as a historical control.

The FDA also granted a second meeting for review. During that meeting, the sponsor presented data by endpoint, which complemented the data package and indicated the benefits of treatment outweighed the risks. Thus, the sponsor was able to satisfy regulatory requirements without conducting a Phase 3 trial.

Case Study 2: Applying RWE analytics in a rare pediatric disorder[1]

Alagille syndrome (ALGS) is a rare genetic disorder in children that causes cholestasis, xanthomas, and severe debilitating pruritis and may eventually require liver transplantation. Transplant-free survival is 24-41% at age 18.5 years. Maralixibat (LIVMARLI®), an ileal bile acid transporter inhibitor, was recently approved by the FDA for the treatment of cholestatic pruritis in patients with ALGS aged one year and older. While it had been shown that maralixibat interrupts bile acid recirculation and significantly improves pruritis, it was not known whether it impacts transplant-free survival.

The Global Alagille Alliance (GALA) Study is a registry that has 100 clinicians from 38 countries contributing data on patients with ALGS across a broad spectrum of data areas. GALA was designed to enhance understanding of ALGS and its impact, with the objective of paving the way for better treatment outcomes, management, and QoL. To determine whether maralixibat impacts transplant-free survival, scientifically-selected data from GALA was used as a comparator for the treated subjects in the clinical study to evaluate the time to first clinical event. Criteria used for choosing the comparison cohort included:

  • Key inclusion and exclusion criteria
  • Demographic characteristics
  • Disease characteristics
  • Index time for the relevant clinical events

To ensure that clearly-outlined statistical methods were applied to analyzing these data, the sponsor had to:

  • Clarify endpoint definitions
  • Outline rigorous sensitivity analyses around key assumptions to assess the consistency of conclusions
  • Check subgroup analyses and adjust for covariates of relevant factors

Across all analyses, patients treated with maralixibat showed significant improvements in event-free survival, lending evidence for potential consideration by regulators and supporting the need for further research in this area.

Key Takeaway

RWD and RWE play an important role in rare diseases, where capturing relevant data to support drug development is challenging. As the FDA and other regulatory bodies increasingly embrace the concept of utilizing RWD and RWE to fill critical information gaps, sponsors may benefit from early engagement with regulators to discuss the inclusion of these data in their development plans.

To learn more about using RWD and RWE in rare disease programs, read our guide on Using Real-World Data and Real-World Evidence to Support Rare Disease Programs.


[1] Hansen, et al. Presentation, European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2022.