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rare diseases closer to a clinical trial and provide valuable data to increase the likelihood of that clinical trial
to succeed. The first CTR grant was awarded in 2019, and the program remains active in funding projects to
this day. Through September 2023, there have been 42 awards made to a variety of rare diseases. A full
listing of funded research can be found in NIH RePORTER under opportunity numbers PAR-18-952,
PAR-18-953, PAR-22-100, PAR-22-101, PAR-23-159, and PAR-23-160.

The diagnostic odyssey funding opportunity is intended to support clinical projects to accelerate the
identification and accurate diagnosis of rare disease patients. The focus is on diagnostic approaches that
combine machine-assisted analysis, genomic sequencing, and clinical evaluation. Importantly, successful
strategies must be suitable for implementation at the primary or secondary care facilities by front-line
healthcare providers, and readily integrated into their standard clinical care workflow.

These diagnostic odyssey awards come in two phases. In the first phase, researchers develop a strategy for
using their proposed approach to make faster diagnoses and test that strategy in a real-world setting. If that
milestone is achieved, researchers will get access to a second phase of funding to test their approach in a
different healthcare setting which presents novel challenges or obstacles. The program awarded three
research projects in 2022, each of which is exploring a different approach to speed up the timeline for a
correct rare disease diagnosis. A listing of this program’s funded research can be found in NIH RePORTER
under opportunity number RFA-TR-21-008.

Additionally, NCATS participates in NIH support for conferences and scientific meetings. DRDRI
specifically has an interest in conferences identifying research opportunities for rare diseases, and those
including the active participation of relevant patient support groups in the meeting planning. While all
allowable costs are considered, NCATS is particularly interested in supporting trainees, students, fellows,
and young investigators to attend conferences, and participate in the meetings via poster presentations or
short talks. A focus on ensuring a diverse representation among invited speakers is also an important
consideration. There are three due dates per year for grant applications, and requests from intramural NIH
investigators are also allowed. These scientific conferences can often make a difference and move a rare
disease field forward by bringing together key individuals, such as researchers, clinicians, patients, families,
patient advocacy groups, and early-stage investigators, to name a few. The latest developments and research
results are shared with a robust exchange of information in multiple directions. These meetings are also a
great way to energize the community and inspire those involved to continue helping the patients.

“Many diseases as a time” projects
As noted above, current estimates are that the number of rare diseases with a known molecular basis is
estimated to be greater than 10,000 , although this number can vary depending on the extent of lumping
[1,2]
vs. splitting of different genetic disease subtypes. Regardless, this is a large number, and is likely to increase
given the expanded use of whole-genome sequencing for rare disease diagnosis. The sheer number of
diseases, as well as the fact that the majority of these diseases have a prevalence of approximately 1/million
people , present significant practical challenges from a commercial development standpoint (see also ).
[12]
[13]
However, based on knowledge of the molecular basis of many rare diseases, it is possible to develop a
rational therapeutic strategy for many of them, regardless of prevalence. Given this reality, there is clearly a
need for a fundamentally different approach to rare disease clinical trials and therapeutics development.

Shared molecular etiologies basket trials
While there are thousands of different rare diseases, the number of underlying pathogenic mechanisms, or
molecular etiologies, is far less. Moreover, many of these are, in principle, therapeutically actionable.