WASHINGTON, DC—Real-world data and real-world evidence play an integral role in the approval of drugs and devices to manage rare disease, according to a group of experts who spoke at the National Organization for Rare Disorders’ Rare Disease and Orphan Products Breakthrough Summit.

The session, which was moderated by John Concato, MD, MS, MPH, an associate director for Real World Evidence Analytics, highlighted case studies of medical product approvals, numerous US Food and Drug Administration (FDA) center efforts and investigative projects, and underlying principles and terminology.

Zhenzhen Xu, senior mathematical statistician for the FDA, shared her insight on the use of real-world data and evidence in regulatory settings primarily from a statistical and clinical perspective.

Xu said the 3 major roles real-world data and evidence play in the regulatory approval process include supporting direct treatment comparisons by either meeting a historical benchmark or serving as a comparator arm. They also can help isolate the treatment effect of each component in a combination therapy or help establish the natural history of a disease.

Xu said a heterogenous disease course, lack of comparability between external controls and the study population, and unclear treatment effect size of the investigational product may make the use of real-world evidence and real-world data challenging.

She said that from a statistical perspective there may be biases like confounding selection or temporal results.

Advancing Oncology Treatment

Donna Rivera, PharmD, MSc, associate director of pharmacoepidemiology in the FDA’s Oncology Center of Excellence explored the use and effectiveness of real-world data within oncology research.

“We tend to think about how to use real-world data when there seem to be feasibility challenges, ethical concerns, and questionable equipoise in the context of conducting a clinical trial. So where those may be applicable are in areas such as rare biases pediatric, areas of significant unmet medical need, molecular subgroups, and underrepresented populations to advance health equity,” she said.

Dr. Rivera discussed the accelerated approval of alpelisib to treat PIK3CA-related overgrowth spectrum (PROS). Patients 2 years of age or older with severe PROS manifestations who require systematic therapy are eligible for alpelisib, she said.

Rivera said a single-arm clinical study was conducted with patients treated as part of an expanded access program (EAP) for compassionate use. Patients were from 7 studies in the US, Australia, France, Spain, and Ireland. PROS had no currently approved available treatment and it was found in about 14 people per one million.

The trial data was collected from radiographic images and medical charges of participating EAP sites. Subject objectives and endpoints, data collecting and research techniques, a statistical analysis methodology, and instructions for patient enrollment, treatment, and monitoring were all predetermined for the study, Rivera said.

Rivera identified response at week 24 as the study’s primary endpoint. She noted that factors that supported the decision included the predefined plan, rare diseases, no approved therapies, and objective outcome validation.

Supporting Medical Device Authorizations

Felipe Aguel, PhD, deputy director of the office of clinical evidence and analysis in the FDA’s Center for Devices and Radiological Health explored the promotion of real-world evidence as it relates to rare disease.

He discussed published real-world evidence guidance for medical devices and expressed a commitment to update it. He noted that he and his colleagues collected and published 90 publicly available illustrative examples of real-world evidence used in regulatory submissions from 2012 to 2019. He said they provided internal training on real-world evidence and published a statistical standard for leveraging data from sources beyond prospective research studies.

He also highlighted real-world evidence used for market authorization of medical devices indicated for rare diseases, such as the Minimally Invasive Deformity Correction (MID-C) Systems, Tether Vertebral Body Tethering System, SEEKER System, and the Enlite Neonatal TREC Kit.

Real-World Rare Disease Research

Ann McMahon, deputy director of science of the Office of Pediatric Therapeutics in the Office of the Commissioner at the FDA, presented findings from a rare disease study on congenital cytomegalovirus disease (cCMV), which she said is linked with serious health issues such as hearing loss. There are no FDA-approved therapies to manage cCMV, but some experts advise using antiviral treatment for select infants.

With that in mind, McMahon said, researchers set out to evaluate knowledge gaps that affect the development of antivirals for cCMV management.

“We identified infants with a diagnosis code for cCMV in FDA’s Sentinel database and assessed baseline disease severity, antiviral treatment, safety events, and hearing loss. We found that antiviral treatment does not fully align with current recommendations, safety events were infrequent and more children developed hearing loss over time, irrespective of treatment,” she continued.

Limitations of the study included the use of claims data, which contributed to a large number of patients being identified for the study and may have even led to some misclassification, she said.


FDA plenary panel: real world data/real world results. Presented at: National Organization for Rare Disorders’ Rare Disease and Orphan Products Breakthrough Summit; October 18, 2022; Washington, DC.