Implementation Research to Improve Case Finding, Cascade Screening, and Treatment for Familial Hypercholesterolemia (FH) (R61/R33 Clinical Trial Required) | RFA HL 22 006

Opportunity Information: Apply for RFA HL 22 006

Implementation Research to Improve Case Finding, Cascade Screening, and Treatment for Familial Hypercholesterolemia (FH) (R61/R33 Clinical Trial Required) is a milestone-driven NIH grant opportunity (Funding Opportunity Number RFA-HL-22-006) that supports single-site clinical trials focused on improving how health systems identify, screen, and treat people with familial hypercholesterolemia. FH is a common inherited condition that leads to very high LDL cholesterol and substantially elevated risk of early cardiovascular disease, yet it is widely underdiagnosed and undertreated. This FOA is designed to move beyond discovery and instead test practical, real-world approaches that can be implemented at scale in clinical settings to find affected individuals earlier, reach their family members more systematically, and ensure evidence-based treatment leads to better health outcomes.

A central theme of the announcement is implementation at the population level, especially around two related processes: case finding (detecting likely FH in the general patient population) and cascade screening (systematically identifying and contacting blood relatives of a person diagnosed with FH, sometimes called an index case, based on inherited risk patterns). Applications are expected to directly address barriers that prevent these processes from working well in routine care. Those barriers can include gaps in clinical workflows, lack of coordination between specialties, difficulties communicating genetic risk to families, limited follow-through on referrals, privacy and consent challenges, and inequities in access to lipid testing, genetic services, and medications. The intent is not just to describe obstacles, but to test interventions that measurably improve performance along the screening and treatment pathway.

The FOA also explicitly encourages the use of implementation science methods to evaluate cascade screening programs as they operate in real health care environments. Projects are expected to generate evidence on practical outcomes such as uptake (how many eligible patients and relatives actually complete screening), feasibility (how workable the approach is within a clinical setting), cost-effectiveness (what resources are required relative to health gains), and scalability (whether the model can be expanded beyond the initial site or integrated across systems). This emphasis signals that NIH is looking for studies that produce actionable, decision-ready information for health systems, payers, and public health stakeholders, not only clinical efficacy results.

Another major component is the development or improvement of machine learning algorithms and data-mining approaches that leverage electronic health records to detect individuals at high risk for FH. Many patients with FH can be flagged through patterns already present in EHRs, such as very high LDL levels, early heart disease, family history indicators, or prior lipid-lowering therapy patterns. The FOA supports work that improves how these tools are built and used in practice, including algorithm performance, integration into clinical decision support, and how outputs trigger workflows for confirmatory testing, family outreach, and initiation or intensification of treatment. In other words, the goal is not just better prediction on paper, but better identification that actually translates into more diagnoses and improved patient management.

Treatment optimization and health outcomes are the final pillar. FH management often requires early and intensive lipid-lowering therapy, potentially including high-intensity statins, ezetimibe, PCSK9 inhibitors, or other agents depending on patient needs and access. This funding opportunity supports clinical trials that test strategies to improve initiation, adherence, intensification, and long-term control of LDL cholesterol, as well as downstream outcomes tied to cardiovascular risk. Projects may focus on improving care pathways, addressing medication access barriers, tailoring interventions to patient preferences, or redesigning follow-up processes to keep patients and relatives engaged over time.

The funding mechanism is the R61/R33 phased innovation award, which is structured around clear milestones. The R61 phase typically supports early, milestone-driven development and initial testing needed to prove that the approach is workable and positioned for success. If predefined milestones are met, the project can transition to the R33 phase for expanded implementation and evaluation. Because this FOA requires a clinical trial, applicants should be prepared to propose rigorous trial designs appropriate for implementation research, often involving pragmatic elements, workflow-based interventions, and outcomes that capture both implementation performance and clinical impact.

Eligibility is broad and includes many types of U.S.-based organizations: state, county, city, and special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; Native American tribal governments (federally recognized); tribal organizations (other than federally recognized tribal governments); public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status; for-profit organizations other than small businesses; and small businesses. The FOA also highlights additional eligible applicants such as Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Hispanic-serving Institutions, Historically Black Colleges and Universities, Tribally Controlled Colleges and Universities, faith-based or community-based organizations, regional organizations, eligible federal agencies, and U.S. territories or possessions. Foreign institutions are not eligible to apply, and foreign components are not allowed under NIH policy for this FOA, although non-domestic components of U.S. organizations may be eligible if they meet NIH requirements.

Administratively, the opportunity is offered by the National Institutes of Health under a discretionary grant program, with activity in the health category and CFDA numbers listed as 93.233, 93.837, 93.838, 93.839, and 93.840. The original closing date in the source information is 2021-05-07, and the creation date is 2020-04-16, which is useful context for applicants looking up the archived FOA or related reissued announcements. Overall, the opportunity is aimed at accelerating practical, evidence-based approaches that help health systems find FH cases earlier, systematically reach at-risk relatives through cascade screening, use EHR-based analytics to improve detection, and close treatment gaps so that identified patients and families achieve better cardiovascular outcomes.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Implementation Research to Improve Case Finding, Cascade Screening, and Treatment for Familial Hypercholesterolemia (FH) (R61/R33 Clinical Trial Required)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.233, 93.837, 93.838, 93.839, 93.840.
• This funding opportunity was created on 2020-04-16.
• Applicants must submit their applications by 2021-05-07. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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