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Brooks et al. Rare Dis Orphan Drugs J 2024;3:15 https://dx.doi.org/10.20517/rdodj.2023.27 Page 9 of 14

As a follow-up, RDCRN, via NCATS, participated in the ERICA 3rd General Assembly. The European Rare
Disease Research Coordination and Support Action consortium (ERICA) is an organization in which all 24
European Reference Networks (ERNs) participate. Such meetings provide opportunities to share knowledge
with individual ERNs. Through knowledge sharing and engagement with stakeholders in the rare disease
domain, the RDCRN and European investigators will continue to have follow-up conversations on topics of
common interest.

Medical cost of rare diseases
Our mission of advancing rare diseases research cannot be met without an increased understanding of the
patient journey within our healthcare systems (HCS). Due to the large number of individual rare diseases
affecting a small patient population, fragmented across different healthcare systems, understanding the
medical needs of patients is a difficult task. In 2021, NCATS, along with external collaborators (Eversana™,
Oregon Health & Science University (OHSU), Sanford Health (Sanford), a large Midwestern integrated
HCS, and a health insurer in Australia), set out to quantify rare disease prevalence and the direct medical
costs of 14 representative rare diseases in 4 different HCS databases. This came to be known as the IDeaS
[4]
(Impact of Rare Diseases on Patients and Healthcare Systems) Initiative .

The IDeaS pilot study found that (1) ICD coding makes it difficult to count RD patients, which likely results
in inaccurate estimation of their true economic impact; (2) direct medical costs of rare diseases per patient
were estimated to be three to five times higher than age-matched controls; and (3) preliminary evidence
shows that diagnostic journeys are prolonged, which may result in progressive, irreversible, and costly
disease complications. Yearly direct medical costs are estimated to be around $400 billion in the U.S., on par
with cancer and heart disease expenditures. The results of this study suggest that RDs have a major impact
on patients and our healthcare system.

The legacy of the IDeaS study is the demonstration of the feasibility of gathering valuable information on
the prevalence, cost, and natural history of rare diseases. Data science approaches in rare disease research
face challenges, such as a general lack of individual diagnostic codes, thus leaving patients invisible to the
healthcare system, fragmented care due to a lack of general knowledge about RDs, and individually small
patient populations, decreasing statistical power for analyses. The results of this study suggest innovative
AI/ML tools that take these challenges into account will be necessary to speed rare disease knowledge, time
to diagnosis, and treatment.

Thus, following the publication of the pilot study, NCATS DRDRI has allocated funding through a contract
mechanism to further develop this methodology in a differing HCS context and a wider set of rare diseases.
This next iteration of the IDeaS initiative intends to use the results of the initial pilot study to inform
methods for clinical decision support tools to alert clinicians to possible cases of rare diseases. We hope to
identify utilization patterns prior to accurate diagnosis and estimate costs of medical care during the
diagnostic odyssey, with the larger goal of using this information to inform the development of approaches
to diagnose and identify rare disease patients sooner, while improving overall patient care management.

Clinical trial readiness, diagnostic odyssey, and scientific conference grants
The clinical trial readiness (CTR) grants support projects focused on obtaining the data needed to enable
efficient and effective movement of candidate therapeutics or diagnostics toward clinical trials, and to
increase their likelihood of success by the development and testing of rigorous biomarkers and clinical
outcome measures, or by better delineating the presentation and course of a rare disease to facilitate
upcoming clinical trial design. Given that only a small percentage of the thousands of rare diseases have an
approved therapy, the intent of this funding opportunity is to focus on projects that would help move more