Notice of Intent to Publish a Funding Opportunity Announcement for Diagnostic Centers of Excellence (U01 - Clinical Trial Not Allowed)

Key Dates

• June 6, 2023 - Data Management Coordinating Center for Diagnostic Centers of Excellence (U2C Clinical Trial Not Allowed). See NOFO RFA-NS-22-051
• July 22, 2023 - Limited Competition for the Continuation of Clinical Sites for the Undiagnosed Diseases Network (U01 Clinical Trial Not Allowed). See NOFO RFA-NS-23-004

National Institute of Neurological Disorders and Stroke (NINDS)

The National Institute of Neurological Disorders and Stroke, in partnership with other NIH Institutes and Centers (ICs), intend to publish a Notice of Funding Opportunity (NOFO) to solicit applications for clinical sites that will provide expert diagnostic services for undiagnosed diseases across the nation. The clinical sites known as Diagnostic Centers of Excellence (DCoEs) will partner with the Undiagnosed Diseases Network (UDN) to sustain some of the key research activities currently performed by the Phase II UDN Clinical sites (see:RFA-RM-17-019) and facilitate its transition to a larger network that serves diverse undiagnosed patient populations. The DCoEs will establish collaborations and efficient processes with the Data Management and Coordinating Center (DMCC; see:RFA-NS-22-051); enroll and evaluate new participants; and foster scientific discovery. .

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. 

The NOFO is expected to be published in September 2023 with an expected application due date in November 2023.

This NOFO will utilize the U01, Research Project Cooperative Agreement, activity code. Details of the planned NOFO are provided below.

Background

Undiagnosed diseases are defined as long-standing symptoms or elusive medical conditions that have not been diagnosed despite extensive clinical evaluation. Undiagnosed diseases are often due to rare conditions and can include: 1) previously described diseases that are not recognized due to very low incidence or prevalence; 2) yet-to-be-described disorders that have not been previously documented; and 3) rare variations of more common diseases. These conditions and the lack of a diagnosis present difficult problems for patients, their families, and physicians resulting in a high emotional, physical, and financial burden to patients who may spend many years seeking a diagnosis and path to treatment. Diagnoses in these difficult cases require teams of clinicians and scientists with a wide variety of special expertise. Scientific advances springing from these diagnoses require an organized approach to testing, data analysis, and validation in patients with similar rare conditions or in model organisms.

In 2008, the NIH established an intramural Undiagnosed Diseases Program (UDP) to aid individuals plagued by longstanding medical conditions that elude medical diagnosis. Using a team science approach, comprehensive clinical phenotyping and cutting-edge diagnostic and genomic technologies, the UDP was successful in ending the “diagnostic odyssey” for many individuals with rare, challenging, and difficult-to-diagnose diseases. Based on the success of the UDP, the NIH Common Fund announced in 2012 an expansion of the UDP to form a nation-wide network - the Undiagnosed Diseases Network (UDN) - composed of the NIH UDP and extramural Clinical Sites. Phase I (FY2013-2017) of the UDN included seven Clinical Sites including the UDP, a Coordinating Center, and Core Laboratories to facilitate diagnoses (genome sequencing, testing variants in model organisms, metabolomics, and a biorepository). In Phase II (FY2018-2022), the number of Clinical Sites was expanded to twelve.

Over the past decade, the UDN has been very successful in achieving its objectives. Notably, through team science and collaboration, UDN investigators have provided difficult diagnoses for more than 650 individuals and discovered hundreds of novel disease-associated genes and genomic variants, including the identification of new diseases and syndromes. Together, the UDN has built an international reputation for advancing disease research while establishing exemplary clinical practices for undiagnosed diseases.

The UDN transitioned from the Common Fund in July 2023 and is currently administered by 17 different NIH Institutes and Centers along with the NIH Office of the Director. To have a broader impact on the clinical practice of undiagnosed diseases in the United States (US), the NIH envisions the UDN evolving into a larger, more diverse, self-sustained network that, with public and private partners, can provide expert diagnostic services for undiagnosed patients across the nation and foster scientific discovery. Leveraging the knowledge gained from the Phase I/II UDN (also see: Manual of Operations), the Phase III Network consists of a Data Management and Coordinating Center (DMCC), highly qualified and collaborative clinical sites including the UDP [referred to as Diagnostic Centers of Excellence (DCoEs)], patients with undiagnosed diseases (referred to as “participants” in this NOFO), family members, patient advocacy groups, the NIH and other stakeholders including external funding providers and/or resource providers (e.g., research cores administered by the DMCC).

The overarching goals of the UDN in Phase III include:

1. Continuing the proven success of the UDN in improving the clinical evaluation of difficult-to-diagnose patients using a collaborative team approach and investigating and validating promising new diagnostic technologies.
2. Facilitating research into the etiology of undiagnosed diseases by collecting and sharing standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and documentation of environmental exposures.
3. Promoting a broader integrated and collaborative community across multiple Clinical Sites and among laboratory and clinical investigators prepared to investigate the genetic, pathophysiologic, cell biologic, and molecular mechanisms underpinning these difficult-to-diagnose conditions.

Purpose and Research Objectives

The NIH intends to solicit proposals from highly qualified clinical sites in the US to join the Phase III Network as DCoEs through a U01 Cooperative Agreement award. Awarded DCoEs will have access to DMCC resources and infrastructure including high-quality phenotypic and genotypic data and collaboration with highly skilled physicians, researchers, and bioinformaticians. Successful applicants will demonstrate that they have the appropriate expertise, resources and infrastructure needed to conduct advanced diagnostic evaluations at their site and propose a research plan that meets the following Phase III priorities:

1. Scale clinical capacity to engage more participants across the US by increasing diagnostic efficiencies and incorporating community and third-party payer support for patient services. To achieve this goal, DCoEs are expected to:
   • Provide a plan to enroll an achievable number of participants based on the site’s experience, outreach capabilities, community needs, and budget. Awarded DCoEs are expected to work with the DMCC to develop an enrollment plan that utilizes a tiered evaluation approach and is based on the specific diagnostic needs of each participant (e.g., Tier 1: initial screening/record review; Tier 2: telemedicine visits; Tier 3: comprehensive on-site clinical evaluations for a subset of participants; Tier 4: research activities) with plans to scale up enrollment as diagnostic efficiencies are established.
   • Work closely with the DMCC and other DCoEs to improve the efficiency and cost-effectiveness of the clinical evaluation (e.g., Artificial Intelligence (AI)/machine learning and other innovative tools for record review and data analysis, tiered evaluation strategies and remote visits as described above, etc.), while still providing a comprehensive and expeditious clinical evaluation of participants.
   • Although DCoEs are encouraged to enroll and evaluate participants with disorders in any clinical specialty, applicants have the option to specialize in one or more areas of clinical practice including but not limited to pediatrics, neurology, ophthalmology, cardiology, gastroenterology, immunology, metabolism, environmentally-linked or infectious diseases, etc.
   • Seek reimbursement when possible from non-NIH sources for patient services, for example, by billing insurance, utilizing support from their institutions, outside partnerships, foundations, or private donors.
   • Collaborate with the DMCC and other DCoEs to incorporate health economics approaches into network operations and establish additional outside funding partnerships including institutional and philanthropic support, and private donations to support the expansion and sustainability of the UDN in Phase III.
2. Expand access to the UDN for individuals and groups who historically have not benefited from modern diagnostic investigations due to racial, ethnic, socioeconomic, geographic, sex/gender, language barriers or other systemic reasons.  To achieve this goal, DCoEs are expected to:
   • Collaborate with the DMCC to recruit and enroll individuals from populations defined by the NIH to experience health disparities in the US.
   • Partner with community collaborators that serve populations defined by the NIH to experience health disparities, including but not limited to academic institutions, local healthcare systems and hospitals, state and local public health agencies, community-based organizations, faith-based organizations, and rural or urban community health centers including those that serve economically disadvantaged individuals. At least one of the partnerships must be a community healthcare organization that provides services for economically disadvantaged individuals who are under/uninsured. Applicants are expected to establish cooperative and mutually beneficial partnerships with the community collaborators beyond simply providing patient referrals to the DCoE (e.g., opportunities for the community collaborators to partner with the DCoE in the clinical evaluation, gain clinical and research expertise in undiagnosed diseases, engage fully in UDN activities, and participate in DCoE decisions that impact the partnership) and provide appropriate reimbursement for research performed by the community collaborator. Note: the partnerships with community collaborators may also comprise a component of the applicant’s Plan for Enhancing Diverse Perspectives (PEDP), as described below.
   • Prioritize NIH funds to cover the patient costs of under/uninsured participants along with research studies that facilitate a diagnosis.
3. In addition to continuing the fruitful genomic approaches established in Phase I/II of the UDN, Phase III DCoEs are expected to propose and develop innovative strategies to investigate other potential causal factors in undiagnosed diseases such as environmental insults, infectious, oncologic, immunologic, or complex genetic disorders.
4. Ensure that participants consistently receive a high-quality experience, for example, by collaborating with the DMCC to survey and incorporate input from patients, caregivers and family members into the practice of the UDN.

Additional information

Successful applicants will be required to use a single-IRB managed by the NIH UDP that is consistent with NIH’s Single IRB Policy as described in NOT-OD-16-094 to ethically review Network-wide protocols involving human subjects research.

Plan for Enhancing Diverse Perspectives (PEDP)

• This initiative will require a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310. The partnerships with community collaborators (described above) may comprise a component of the PEDP.
• Prospective applicants are encouraged to view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

Data Sharing under this Initiative

NIH expects that the project datasets (phenotypic, genomic, environmental, covariates, and other relevant data and metadata) will be widely shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information in compliance with local, international, and federal regulations. Recipients must comply with the NIH Data Management and Sharing Policy and the NIH Genomic Data Sharing Policy. Working with the DMCC, controlled-access data must be registered in dbGaP and deposited into the AnVIL. 

Network Governance

Network governance is the same as described in RFA-NS-22-051, and will be managed by the Steering Committee, with advice from an External Advisory Committee. 

Funding Information

Public/State Controlled Institution of Higher Education
Private Institution of Higher Education
Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education)
Small Business
For-Profit Organization (Other than Small Business)
State Government
Indian/Native American Tribal Government (Federally Recognized)
County governments
Public housing authorities/Indian housing authorities
Indian/Native American Tribally Designated Organization (Native American tribal organizations (other than Federally recognized tribal governments)
U.S. Territory or Possession
Indian/Native American Tribal Government (Other than Federally Recognized)
Regional Organization
Eligible Agencies of the Federal Government

Applications are not being solicited at this time. 

Inquiries

Please direct all inquiries to:

Argenia Doss

National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-6369
Email: argenia.doss@mail.nih.gov

Laura Mamounas

National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: mamounal@ninds.nih.gov