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NIH Autoimmune Disease Research Efforts

NIH OVERVIEW AND ORGANIZATIONAL STRUCTURE

Analyzing autoimmune disease research efforts at the National Institutes of Health (NIH) begins with an understanding of the funding, administrative structure, and authorities of NIH and its constituent parts. For more than 130 years, NIH has been the federal agency primarily responsible for sponsoring and conducting basic, clinical, and translational research (CRS, 2021); research training; and health information and dissemination in the United States. The agency is one of the 11 operating divisions in the U.S. Department of Health and Human Services (HHS).¹ The stated mission of NIH is to “seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability” (NIH, 2017a). From its origin as the single-room Laboratory of Hygiene in 1887, the agency now executes its missions and goals through the Office of the Director (OD) and 27 Institutes and Centers (ICs) that focus on different areas of biomedical research (CRS, 2019). Appendix E includes the full list of the ICs and their missions.

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¹ The other 11 operating divisions are: Administration for Children and Families, Administration for Community Living, Agency for Healthcare Research and Quality, Agency for Toxic Substances and Disease Registry, Center for Faith-Based and Neighborhood Partnerships, Centers for Disease Control and Prevention, Centers for Medicare & Medicaid Services, Food and Drug Administration, Health Resources and Services Administration, Indian Health Service, and Substance Abuse and Mental Health Services Administration (see HHS, 2022).

The OD sets policy and coordinates the programs and activities of all NIH components. Legislation in 2006 and 2016 resulted in a number of changes at NIH (CRS, 2019). The NIH Reform Act of 2006,² which implemented many recommendations from a National Academies of Sciences, Engineering, and Medicine report that reviewed the structure and organization of NIH, strengthened the OD to perform strategic planning, created a standardized reporting system, and provided funding (Common Fund) for NIH-wide initiatives (CRS, 2019; NRC, 2003). The Act also required an integrated biennial report of NIH research activities. In response to the Act, the OD established the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI) in 2006 (DPCPSI, 2021). DPCPSI oversees a number of program Offices that coordinate research activities on specific topics that previously reported to the Director of NIH (DPCPSI, 2021). DPCPSI identifies and assists NIH in responding to emerging scientific opportunities, develops resources for the support of portfolio analyses and priority setting, and supports strategic planning, progress monitoring, evaluation, and reporting (CRS, 2019; DPCPSI, 2021).

More recently, the 21st Century Cures Act³ directed the NIH Director to develop an NIH-wide strategic plan to expedite IC collaboration, provide guidance on investments made by NIH, and “leverage scientific opportunity, and advance biomedicine.” The first NIH-wide strategic plan covered fiscal year (FY) 2016 to 2020, and the most recent plan covers FY 2021 to 2025 (NIH, 2021d).⁴ The Act also changed guidance on reporting on NIH research activities from the earlier mandated biennial report to a triennial report, the most recent of which covered FY 2016 to 2018.⁵

Congress annually appropriates funds for NIH overall and the ICs specifically, and sometimes Congress qualifies funds with specific requirements or instructions (NIH, 2021e). For example, Congress has required NIH to establish research programs, provided funding for research on specific topics, and mandated that NIH create research centers or institutes.

Today, NIH is the primary source of public funding for biomedical research in the United States with an annual discretionary budget authority of $40.3 billion⁶ for FY 2020 (NIH, 2020a; Viergever and Hendriks, 2016). Among federal agencies, NIH had the highest amount of discretionary funds in FY 2020 (Figure 5-1). Table 5-1 provides the trend in NIH appropriations from FY 2008 to 2020.

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²National Institutes of Health Reform Act of 2006, Public Law 109-482, 109th Cong. (January 15, 2007).

³21st Century Cures Act, Public Law 114-225, 109th Cong. (December 13, 2016).

⁴ Available at: https://www.nih.gov/about-nih/nih-wide-strategic-plan, accessed November 29, 2021.

⁵ Available at: https://dpcpsi.nih.gov/oepr/nih-triennial-report, accessed November 29, 2021.

⁶ This includes $80 million for Superfund Research activities (NIH, 2020a).

TABLE 5-1 NIH Appropriations (FY 2008–2020)

NOTE: FY, Fiscal Year.

SOURCES: NIH, 2010, 2020b.

Funding for NIH Institutes and Centers

NIH funding goes primarily to the ICs to support research conducted through both extramural grants and intramural research projects (NIH, 2020a). Extramural grants account for greater than 80 percent of NIH’s funding, while intramural support accounts for about 11 percent of NIH funding (NIH, 2020a, 2021d, 2021e). In 2020, NIH awarded approximately 50,000 competitive grants to approximately 300,000 researchers (NIH, 2020a, 2021e).

NIH ICs have different missions that guide their activities, and may focus, for example, on a specific disease, organ system, life stage, field of science, or training or technology. The ICs also include the NIH Clinical Center, the National Library of Medicine, and the Center for Scientific Review (CSR).

ICs plan and manage their own research programs in coordination with the OD (NIH, 2021a, 2021e). ICs engage in strategic planning to set priorities and plan activities (NIH, 2015, 2021e). Figure 5-2 presents FY 2020 congressional appropriations for the ICs and OD. The variation in the level of appropriation is notable, with the National Cancer Institute (NCI) receiving the largest amount of funding and the Fogarty International Center receiving the smallest. The level of IC appropriation

correlates with the level of research, training, and other activities that the ICs that engage in these activities can support.

NIH RESEARCH PROCESS

Extramural Research Funding

At NIH, 24 of the 27 ICs fund the extramural research program (NIH Central Resource for Grants and Funding Information, 2020), which supports research across the United States and beyond (NIH, 2021d). Extramural research can be categorized generally as “unsolicited” investigator-initiated research or “solicited” targeted research (NIH Office of Extramural Research, 2021). Most applications submitted to NIH for research or research training, including fellowships, are investigator initiated (NIH Office of Extramural Research, 2021). Investigator-initiated opportunities may be attractive to new investigators owing to the freedom to create an application to pursue any area of science NIH supports without waiting for a particular funding announcement. Moreover, new investigators pursuing investigator-initiated research opportunities receive a higher pay line than established investigators, whereas there is no pay differential for new investigators pursuing solicited research opportunities (NIAID, 2016). All applications are submitted in response to Funding Opportunity Announcements (FOAs), which are publicly available documents in which NIH describes its intentions to make discretionary awards for which it selects the awardees and/or the amounts of funding via a competitive process.⁷ FOAs can range from an NIH-wide umbrella announcement that channels investigator-initiated research applications, to a single IC’s announcement to solicit applications for a clearly defined scientific area in order to fulfill specific objectives⁸ (NIH Office of Extramural Research, 2021). CSR is the entry point for all NIH grant, fellowship, and cooperative agreement applications (CSR, 2021; Hodge, 2021).

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⁷ Non-discretionary awards, which are uncommon, are made to specific recipients, in accordance with statutory, eligibility, and compliance requirements. The award amount could be determined specifically or by formula (NIH Office of Extramural Research, 2021).

⁸ The most common FOA types are as follows. Program Announcements (PAs) are statements about a new or ongoing activity or program that may also invite applications for grant support. Requests for applications (RFAs) solicit grant or cooperative agreement applications in a well-defined scientific area to accomplish specific program objectives. Parent Announcements are omnibus announcements that enable applicants to submit investigator-initiated applications. Notices of Special Interest (NOSI) highlight a topic of interest and direct applicants to one or more FOAs (often Parent Announcements) to submit applications for the initiative (NIH Office of Extramural Research, 2021).

CSR’s Division of Receipt and Referral reviews grant applications for completeness and compliance with NIH policies and makes two referral assignments for each application (Hodge, 2021; NIH). The first assignment is to one or more NIH ICs for potential funding based on guidelines that each IC provides to CSR for assignment purposes, and these guidelines may include shared interests among different ICs (Hodge, 2021). The ICs’ assignment guidelines are not available to the public (Hodge, 2021). The second assignment is to either a CSR review group, the case for 75 percent of applications, or to IC review groups associated with solicited FOAs (Murrin, 2019).

CSR scientific review groups, also called study sections, review the applications for scientific merit (CSR, 2020). Information on each study section, including its reviewers, topics covered, and overlap with related study sections, is available on the NIH website.⁹

There are two kinds of CSR study sections, chartered and special emphasis panels (CSR, 2020). Chartered, also called standing or recurring, study sections review most investigator-initiated research applications; the sections consist of members who are “primarily non-federal scientists with expertise in consist of scientific disciplines and current research areas” (NIH, 2018).

Special emphasis panels perform reviews when the subject matter does not match up with a study section, when assigning a project to an appropriate study section might create a conflict of interest, or in the case of certain types of applications such as fellowships, Small Business Innovation Research, and Small Business Technology Transfer Research applications (CSR, 2020; Hodge, 2021; NIH, 2013). A special emphasis panel consists of temporary members whom CSR recruits based on expertise needed for each meeting.

CSR assigns each application to a Scientific Review Officer (SRO) (NIH, 2013). An SRO is an extramural staff scientist who is the designated federal official responsible for ensuring an application meets peer-review requirements and for managing the review process (NIH, 2018; NIMH, 2021). The two-stage review process involves evaluation by a panel of primarily non-federal scientists, and approval by the IC Advisory Council/Board and the IC Director (NIH, 2018, 2019a).

In the first stage of review, assigned reviewers provide their preliminary assessments and critiques to the SRO, who uses them to plan and frame the session with the fully convened study section (CSR, 2020; NIH, 2018). The section chair and the SRO partner to run the study section review meeting (NIH, 2018). At the meeting, the assigned reviewers present a critique of the application, and members then discuss the application

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⁹ Available at https://public.csr.nih.gov/StudySections (accessed November 19, 2021).

in depth (Hodge, 2021; NIH, 2013, 2018). The members each provide a final overall impact score (Hodge, 2021; NIH, 2013, 2018).

In the second stage of review, the Advisory Council or Board of the assigned IC, comprising “both scientific and public representatives selected for their expertise, interest, or activity in matters related to health and disease,” makes funding recommendations based on the results of the study section’s review and the IC’s programs and priorities (Hodge, 2021; NIH, 2013, 2018) The directors of the ICs make the final funding decisions (NIH, 2018). Figure 5-3 depicts an overview of the process. Chapter 6 discusses CSR study sections that review applications that focus on autoimmune diseases.

The ICs use a similar process to review grant applications submitted in response to solicited FOAs, but they convene ad hoc special emphasis panels with expertise appropriate for each separate FOA (NIAID, 2020).

NIH uses a broad range of activity codes to categorize funding mechanisms for research activities. Extramural research activities are typically grants, contracts, or cooperative agreements (NIH, 2019b). Investigator-initiated research project grants, so-called R01 grants, are considered the traditional grant mechanism and constitute the largest single type of support NIH provides (NIH, 2021g). For the purpose of this study, the committee was also interested in fellowships, research career programs, training programs, and cooperative agreements. Table 5-2 provides a brief description of these grants.

Intramural Research Funding

The NIH Intramural Research Program (IRP) supports research conducted on the NIH campuses, and 23 of the 27 ICs have an intramural component (IRP, 2021a; NIH, 2017b). Priority setting for intramural research projects is based on prior investigator success and innovative ideas, often in collaboration with investigators in other ICs or with extramural researchers.

The IRP budget supports more than 1,200 principal investigators and 4,000 postdoctoral fellows who conduct basic, translational, and clinical research (IRP, 2021b, 2021c). IRP principal investigators receive a review of their work every 4 years, and the external reviews are primarily retrospective (IRP, 2021a; Kastner, 2021; Rider, 2021). The IRP approach represents NIH’s commitment to individual researchers rather than individual projects, as is the case with extramural investigators, providing support for high-risk, high-reward projects not easily funded by R01 projects and for long-term studies requiring stable funding.

TABLE 5-2 Select NIH Grant Types

SOURCE: NIH, 2019b.

NIH Initiatives

NIH supports a number of specific initiatives. Initiatives originate in multiple ways, which include externally through congressional mandates, congressional language that is not a mandate, or direction from the Executive Branch (e.g., via HHS) as well as internally from the NIH OD, IC leadership and staff, or internal coordinating bodies. Directions from Congress or the Executive Branch are announced publicly, have specific goals, and may or may not have set-aside funding to support the goals. ICs may propose their own initiatives with or without dedicated funding. NIH initiatives may also derive from and be coupled with private-sector initiatives, with variable sharing of funds. Examples of the latter include large registries or clinical care consortia created by advocacy groups, strengthened in structure and resources by NIH or NIH-sponsored research, that pharmaceutical companies can use.

Select NIH Autoimmune Disease Research Efforts

The previous discussion provided a brief overview of NIH funding and the process for awarding grants. The next section focuses more specifically on autoimmune disease research activities. For the purpose of this report and the timeframe available to the committee to conduct its work, the committee chose to limit its review to the OD and 13 NIH ICs—the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Arthritis and Musculoskeletal Diseases (NIAMS), National Institute on Neurological Disorders and Stroke (NINDS), National Heart, Lung, and Blood Institute (NHLBI), NCI, National Eye Institute (NEI), National Institute of Dental and Craniofacial Research (NIDCR), National Institute of General Medical Sciences (NIGMS), National Institute of Environmental Health Sciences (NIEHS), Eunice Kennedy Schriver National Institute of Child Health and Human Development (NICHD), National Human Genome Research Institute (NHGRI), and National Center for Advancing Translational Sciences (NCATS)—that supported the majority of autoimmune disease research through intramural and extramural programs in FY 2020 based on the total amount of funding (see Figure 5-4).¹⁰Table 5-3 presents the general mission statements of the select NIH ICs. The committee notes that of these, the general mission of six Institutes focus on diseases, and six focus on organ systems or anatomy.

These ICs have different missions, favor different funding mechanism priorities, and focus on different autoimmune diseases. While they offer more detailed disease-specific interests in their website-searchable databases (Table 5-3), their reporting formats are not standardized, nor do they indicate how they choose diseases. Some listed diseases are common, such as rheumatoid arthritis, a focus of NIAMS, and some are exceedingly rare, such as autoimmune encephalitis, a focus of NINDS. Other diseases are lethal, such as vasculitis and systemic lupus erythematosus (SLE), which are areas of focus for NIAMS and NIDDK, while others are not lethal but cause life disruption treatable with today’s technologies, such as Hashimoto’s thyroiditis and Graves’ disease, a focus of NIDDK. The complexity and diversity in the group of autoimmune diseases has contributed to how research and other efforts to understand the diseases are dispersed across NIH ICs, which in turn may lead to siloing of efforts if there are no systematic attempts to coordinate activities across NIH. Yet another perspective can be seen when considering a disease such as Sjögren’s disease.

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¹⁰ The committee notes that many investigators funded by NIH also receive support from philanthropy, industry, and other private-sector sources. The committee did not seek to quantify or outline the relative contributions of these other sectors.

Sjögren’s disease is a prototypical, multisystemic autoimmune disease. Its manifestations include mucosal and ocular abnormalities, arthritis, respiratory and renal failure, multiple autoantibodies, cytopenias, neuropathy, maternal autoantibody-induced neonatal disease, and lymphadenopathy and lymphoma. Because it involves so many organ systems, Sjögren’s disease does not have “a home” in NIH; NIAMS, NIAID, NEI, NINDS, NHLBI, NCI, NICHD, and NIDCR all can legitimately claim primary interest in grants focusing on this disease.

In an effort to categorize the autoimmune diseases relevant to the ICs in Table 5-3, the committee had to gather information from a variety of sources since such information was not readily available from a sole source. The committee relied on presentations by invited speakers from the ICs during the committee’s information-gathering public sessions, publicly available information on the ICs’ websites, and committee members’ expert knowledge. The categorization of the ICs in Table 5-3, based on their mission statements and other publicly available information, reveals the broad and sometimes overlapping missions and focus areas

as they pertain to autoimmune diseases research. While there is some evidence of attempts to coordinate funding and research efforts among the ICs, it was difficult for the committee to assess how effective these efforts were, as discussed later in this chapter. Table 5-3 summarizes the autoimmune disease research focus of each IC, which range from basic to translational and clinical research.

Strategic Planning for Autoimmune Disease Research at NIH

ICs engage in a strategic process to set research priorities. In an effort to understand whether and how the various ICs prioritize autoimmune diseases as part of their overarching institutional plans and vision planning, the committee reviewed the strategic plans for the 13 ICs that funded most of the autoimmune diseases work in FY 2020. The strategic plans offer insights into what the ICs consider to be the most pressing issues that they can tackle within their mission and vision, as well as those issues that will hold the most promise for advancing their respective fields. Complicating the committee’s review of the strategic plans was the fact that there is no standardized approach and timeline by which the ICs release their reports (Table 5-4). Some ICs, such as NCI, release plans as part of the annual budget planning process to the President and Congress. Other Institutes—NIAMS, NIDDK, and NIGMS—release 5-year plans, while others—NHGRI, NIEHS, and NICHD—release reports periodically at intervals of 6 to 10 years. The committee found information about past reports to assess the frequency of the strategic planning process for some of the ICs, including NIAID, NHLBI, and NEI. This lack of standardization across ICs and consistency in the release of strategic plans for individual ICs has important implications since it may pose an obstacle for ICs in coordinating their strategic planning efforts, and subsequently, their funding and research efforts for autoimmune diseases. While the timeframe covered by some of the strategic plans overlap, the plans are at various stages of implementation.

Regarding the process for strategic planning, not all the ICs document their approach, so the committee was unable to fully evaluate how the ICs identified scientific and programmatic priorities outlined in the strategic plans. Some of the ICs, as discussed in the section below, go through a detailed process spanning 1 to 2 years that includes issuing a Request for Information (RFI) to solicit stakeholder feedback on their proposed themes or areas of focus. Broad and varied stakeholder input is essential for comprehensively surveying the field and ensuring that the priorities identified reflect what a variety of stakeholder groups consider as the most pressing issues.

TABLE 5-3 Missions and Autoimmune Diseases of Focus of Select NIH ICs

TABLE 5-4 Recent Strategic Plans Available from NIH ICs that Fund Autoimmune Disease Research

^a The plan offers 10 bold predictions of what might be realized in human genomics by 2030 (Green et al., 2020).

^b Based on schedule of previous plan.

NOTE: FY, Fiscal Year; IC, Institutes and Centers; NCATS, National Center for Advancing Translational Sciences; NCI, National Cancer Institute; NEI, National Eye Institute; NHGRI, National Human Genome Research Institute; NHLBI, National Heart, Lung, and Blood Institute; NIAID, National Institute of Allergy and Infectious Diseases; NIAMS, National Institute of Arthritis and Musculoskeletal and Skin Diseases; NICHD, Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIDCR, National Institute of Dental and Craniofacial Research; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NIEHS, National Institute of Environmental Health Sciences; NIGMS, National Institute of General Medical Sciences; NINDS, National Institute on Neurological Disorders and Stroke.

SOURCE: Green et al., 2020; NCATS, 2016; NCI, 2021a; NEI, 2021b; NHLBI, 2016; NIAID, 2021b; NIAMS, 2020b; NICHD, 2019; NIDCR, 2020; NIDDK, 2021b; NIEHS, 2018; NIGMS, 2021; NINDS, 2020.

The various strategic plans reference autoimmune diseases and issues of autoimmunity to varying degrees or not at all, as the discussion below notes for each individual IC. The Institutes that funded the most autoimmune diseases research and whose missions and focus align directly with autoimmune diseases—NIAMS, NIDDK, and NIAID—were more likely to mention the autoimmune diseases in their strategic plan. NIEHS, which is not a major funder of autoimmune diseases research, made mention of autoimmune diseases in its recent plan (FY 2018 to 2023) (NIEHS, 2018).

NIAMS

The current NIAMS strategic plan covers FY 2020 to 2024 and includes a section on scientific objectives that are disease and tissue specific, one of which is to advance and speed systemic rheumatic and autoimmune diseases research, and crosscutting themes of focus for NIAMS. The crosscutting scientific themes NIAMS identified acknowledge that most of the scientific challenges and opportunities transcend a single disease area or organ (NIAMS, 2020b). The four themes identified are all relevant to autoimmune diseases:

• “Precision medicine for arthritis and musculoskeletal and skin diseases” (NIAMS, 2020b). This involves, but is not limited to, leveraging new technologies and computational tools to improve knowledge of the molecular basis of health and disease.
• “Shared mechanisms in health and among diseases.” Focus areas include immunity and inflammation and the effects of environmental exposures.
• “Patient-centric approaches to health and disease.” Capturing patient-reported perspectives using tools such as the Patient-Reported Outcomes Measurement Information System (PROMIS®) as part of the research process.
• “Health and disease in diverse populations.” Promoting the relevance of NIAMS-funded research in groups that have been historically underrepresented in biomedical research in order to effect health equity for all populations.

The report also identifies aspirations or thematic issues that are germane to multiple diseases or conditions at NIAMS and those that hold the most promise for the future given the NIAMS portfolio (NIAMS, 2020b). The two most relevant for autoimmune diseases are:

• “Biomarkers will guide the choice of the most effective therapy for each individual rheumatoid arthritis patient […and]
• “Preventive therapy will delay the onset of autoimmune diseases like lupus and rheumatoid arthritis” (NIAMS, 2020b).

Independently of its IC-specific strategic plans, NIAMS published the Action Plan for Lupus Research in 2015, intending that it supplement ongoing long-term plans as well as the work of the Lupus Federal Working Group (LFWG) and the Autoimmune Diseases Coordinating Committee (ADCC) (NIAMS, 2015). More information on these organizations appears later in this chapter.

NIDDK

NIDDK established a Working Group of Council, consisting of 44 external scientists and patient advocates to provide input during the strategic planning process for its most recent strategic plan, which the Institute published in December 2021 (NIDDK, 2021b, 2021c). It issued an RFI in 2020 to seek input from different stakeholders, “including the scientific research community; patients and caregivers; health care providers and health advocacy organizations; scientific and professional organizations; federal agencies; and other stakeholders, including interested members of the public,” on the thematic considerations for the 5-year strategic plan (NIDDK, 2021b). After developing a draft strategic plan, NIDDK issued another RFI for the period August 10–31, 2021, to elicit feedback on the draft.

The strategic plan includes four major goals:

• “Advance understanding of biological pathways and environmental contributors to health and disease […and]
• Advance pivotal clinical studies and trials for prevention, treatment, and cures in diverse populations […and]
• Advance research to disseminate and implement evidence-based prevention strategies and treatments in clinics and community settings, to improve the health of more people, more rapidly and more effectively […and]
• Advance stakeholder engagement — including patients and other participants as true partners in research” (NIDDK, 2021c).

NIAID

The most recent NIAID-wide strategic plan is from 2017, and development of a new one is not yet scheduled.¹¹ The budget and planning page of NIAID’s website¹² does include strategic plans for various diseases and conditions and research areas, such as COVID-19, hepatitis B, tickborne disease research, vaccine adjuvants, and tuberculosis (NIAID, 2021b). NIAID’s last published strategic plan (NIAID, 2017) outlined the Institute’s then-current research priorities to inform its future decision making. The plan identified four scientific areas of focus, one of which is “allergy, immunology, and immune-mediated diseases,” including autoimmune disease. For this specific area, it emphasizes applying understanding of the human immune system in continuing to support immunology research that provides preclinical information that is crucial to

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¹¹ Personal communication. Susan Cooper, M.Sc., Director, Office of Program Planning, Operations, and Scientific Information, NIAID, September 7, 2021.

¹² Available at https://www.niaid.nih.gov/about/budget-planning.

developing new strategies to diagnose, treat, and prevent infectious and immune-mediated diseases. Another area of emphasis involves supporting clinical trial networks committed to treating and preventing allergic and autoimmune diseases and to preventing graft rejection. A third and final area of emphasis identified for this scientific area involves determining the precise mechanisms of human immune regulation (NIAID, 2017).

NINDS

NINDS organized its FY 2021 to 2026 strategic plan by focus areas that are not disease specific (NINDS, 2020). The four areas are:

• “Science: Support and perform rigorous and important neuroscience research.
• Training and Diversity: Fund and conduct neuroscience research training and career development programs to ensure a vibrant, talented, and diverse neuroscience workforce.
• Communications: Promote dynamic communication and diverse stakeholder engagement to accelerate scientific progress and reduce the burden of neurological disorders.
• Workforce Culture: Create and sustain a supportive work culture for the NINDS workforce that becomes the model for biomedical research and the neuroscience community” (NINDS, 2020).

While the strategic plan does not mention specific autoimmune diseases, NINDS seeks to advance research on the basic science and mechanisms of nervous system function in order to advance efforts to prevent and treat neurological disorders. In addition, NINDS will support the development and validation of biomarkers and outcome measures that are required to enable better and targeted therapeutic options for patients. The strategic plan also indicates as part of its science focus that is has a goal of supporting work to prevent neurological disorders and advance health equity (NINDS, 2020).

As part of its crosscutting strategies, the plan indicates NINDS’s intention to rely primarily on investigator-initiated research for its funded portfolio, but notes that productive collaborations and partnerships are essential as scientific advances highlight intersections between the interests of NINDS and other organizations (NINDS, 2020).

NHLBI

The most recent strategic plan available for NHLBI is from 2016 (NHLBI, 2016). This report is organized according to 4 goals, 8 strategic

objectives, 132 research priorities, and 12 critical challenges, the latter of which the strategic plan defines as obstacles to scientific progress, which when overcome, will result in significant impact. The report’s fifth strategic objective—developing and optimizing new diagnostic and therapeutic strategies to prevent, treat, and cure heart, lung, blood, and sleep diseases—states that one of its critical challenges is to understand the immune system from a systems biology perspective as a means of designing more efficacious treatment strategies for chronic inflammatory and autoimmune heart, lung, blood, and sleep diseases. This critical challenge was the only explicit reference to autoimmune diseases in the strategic plan. The critical challenges, along with a set of compelling questions, constitute NHLBI’s strategic research priorities (NHLBI, 2016).

The NHLBI plan mentions that investigator-initiated projects will continue to be the Institute’s primary focus, but it also acknowledges the importance of NHLBI-solicited research initiatives supported by new FOAs and that the plan’s strategic research priorities will shape the development of future FOAs and other activities (NHLBI, 2016).

NEI

On November 1, 2021, NEI released a strategic plan for 2021 to 2025 (NEI, 2021b). This strategic plan is the ninth comprehensive plan for the Institute since it was established; the plan prior to the current plan was published in August 2012. The new plan has seven areas of emphasis within three research domains: “1) Visual system in health and diseases; 2) Capitalizing on emerging fields; and 3) Preventing vision loss and enhancing wellbeing” (NEI, 2021b). One of the focus areas within the first research domain is “immune system and eye health” (NEI, 2021b), which will address how NEI can develop crosscutting program priorities and overarching goals for ocular immunology, infection, and inflammation biology. As part of this goal, NEI’s focus is to support research that develops targeted therapeutics for ocular immune-related diseases and improve imaging, biomarkers, and data analytics to support precision medicine for immune-mediated eye diseases, among other research goals. As with some of the other ICs, NEI points to how it leverages partnerships both within and outside of NIH to advance its mission and research priorities (NEI, 2021b).

NIEHS

The most recent version of the NIEHS strategic plan spans the years 2018 to 2023 and is organized around three themes:

• “Advancing environmental health sciences
• Promoting translation – data to knowledge to action
• Enhancing environmental health sciences through stewardship and support” (NIEHS, 2018).

Inflammation effects that result in autoimmune disorders is one major area of research interest identified for the first theme. In addition, NIEHS’s goals for advancing environmental health sciences include supporting research on the effects of the environment on biological systems and processes, which may have implications for many diseases, including autoimmune diseases (NIEHS, 2018).

NHGRI

NHGRI released its current strategic plan in 2020, following versions it issued in 2003 and 2011 (Green et al., 2020). In the plan, NHGRI identified four interrelated strategic areas that are at “the forefront of genomics” or are opportunities for human genomics in the next decade (Green et al., 2020). These areas are not disease specific, but overarching principles for genomics research that fall into the categories of:

• “Guiding principles and values for human genomics
• Sustaining and improving a robust foundation for genomics
• Breaking down barriers that impede progress in genomics
• Compelling genomics research projects in biomedicine” (Green et al., 2020).

While NHGRI funds and conducts some research on autoimmune diseases, its strategic vision does not mention them specifically (Green et al., 2020). It is conceivable that some of the details identified in the broad categories delineated above may have implications for several diseases, including autoimmune diseases.

NCI

NCI releases an institutional plan and budget annually for submission to the President and Congress. A summary document of the most current version, for FY 2023 (NCI, 2021a), highlights four focus areas: (1) clinical trials, (2) computer-based drug design, (3) precision prevention, and (4) tumor dynamics. The first highlighted area of the FY 2023 plan could have implications for autoimmune disease research in that a focus on expanding telemedicine into clinical trials could increase access to autoimmune disease trials in underserved communities. Similarly for

the third highlighted area, a focus on precision-medicine approaches to prevention could aid in developing personalized prevention approaches for autoimmune diseases based on genetics, family history, environmental exposures, and behaviors.

The FY 2022 summary document (NCI, 2021b) highlighted four focus areas including “cancer drug resistance, molecular diagnostics for cancer treatment, obesity and cancer, and cancer survivorship.” The FY 2021 plan summary (NCI, 2019a) identified three opportunities in cancer research: “the immune system and microbiome, artificial intelligence, and implementation science.” The FY 2021 plan’s first area of research, which focuses on harnessing the immune system in the development of immunotherapies, may have implications for individuals with autoimmune diseases, as trials for existing immunotherapies have excluded these individuals (NCI, 2019b).

NIGMS

NIGMS released its current strategic plan in 2021. True to NIGMS’s mission, which is crosscutting in nature to support biomedical research in general, the plan (NIGMS, 2021) is organized around five goals that include sustaining support for investigator-initiated research and investing in developing a skilled and diverse biomedical research workforce. NIGMS has supported some autoimmune diseases-focused research, so its goals may have relevance for the field of autoimmune diseases.

NIDCR

NIDCR released an RFI in August 2019 to solicit stakeholder input for its 2020 to 2025 strategic plan, but decided to postpone the plan release following the retirement of the former director in December 2019 and pending the installation of a new director who would provide new leadership and direction for the Institute (NIDCR, 2021b). The FY 2021–2026 strategic plan will be organized around five priority areas, all of which could potentially have a bearing on autoimmune diseases, such as SLE and Sjögren’s disease, that involve dental, oral, and craniofacial (DOC) diseases (NIDCR, 2021b). These include:

• “Advancing cross-disciplinary fundamental research in the biomedical, behavioral, social, and environmental sciences and driving translation toward early diagnosis, prevention, and treatment of DOC diseases and conditions across the lifespan.
• Developing more precise and individualized ways of managing and preventing DOC diseases.

• Accelerating research translation and the uptake of new discoveries into oral and general healthcare practices that reduce health inequities and disparities and improve oral health outcomes for individuals and communities worldwide.
• Nurture future generations of DOC researchers and oral health professional scholars who can address existing and emerging challenges driven by personalized and public health needs and a continually evolving landscape of science and technology advances.
• Expanding existing partnerships and create new ones to advance the NIDCR research enterprise and increase its reach and impact” (NIDCR, 2021b).

NICHD

NICHD’s most recent strategic plan is for the year 2020, having released its previous two strategic plans in 2000 and 2012. The report is organized around five themes, which include an emphasis on understanding the biological basis of development; promoting gynecologic, andrologic, and reproductive health; promoting healthy pregnancies and lifelong wellness; improving the health of children and adolescents as they transition into adulthood; and safe, effective therapies and devices for pregnant women, children, and individuals with disabilities. While the strategic plan does not focus on specific diseases or conditions, the plan mentions how the results from NICHD-funded researchers working with maternal mouse models that showed the persistence of fetal cells post-delivery could offer insight into diseases that affect women, including autoimmune diseases (NICHD, 2019).

NCATS

NCATS was established in 2011 and has published a strategic plan from 2016 (NCATS, 2016). The Center’s research is not disease specific but rather focuses on disease commonalities and the translational process. The NCATS strategic plan is organized around four strategies, and the first, and most relevant for autoimmune diseases, is to conduct and support innovative research to reveal fundamental scientific and operational principles of translational science to drive the development and dissemination of novel medical interventions. Among several objectives listed to support this strategy are (1) “to identify biological commonalities among diseases and use insight into shared mechanisms and pathways to test and treat multiple human diseases and conditions” (NCATS, 2016), and (2) to “drive development of medical interventions for rare diseases that

lack safe and effective treatments” (NCATS, 2016). The plan also points out obstacles that can limit the progress of translational science such as a lack of data interoperability; “a shortage of qualified biomarkers to diagnose disease and measure treatment response”; and “inadequate development and measurement of appropriate clinical outcome measures or endpoints, including patient-reported outcomes.” While no diseases are named in the plan, translational science research could benefit the field of autoimmune diseases (NCATS, 2016).

In summary, the committee notes the inherent difficulty in assessing the priorities of the ICs as it pertains to autoimmune diseases (as discussed earlier in this chapter). While ICs develop their strategic plans independently, on different schedules, and focus on broad thematic issues, there are sufficient commonalities in the themes and priority areas highlighted across the strategic plans that the committee reviewed to indicate that the process could benefit from a concerted effort. For example, some of the ICs, such as NIAMS and NEI, highlighted the development of biomarkers that will aid in the delivery of precision medicine. NIAID, NIAMS, and NIEHS all prioritized additional research on the basic science and mechanisms of the human immune system, and NIAMS also mentions the importance of understanding the effects of environmental exposures, which is a shared goal with NIEHS. Beyond scientific issues, a few of the ICs, such as NIDDK and NIAMS, highlight other priority areas such as the importance of the patient as partner in the research process, and NIAMS and NCATS call for the use of patient-reported outcomes in research. Better coordination in strategic planning and priority setting efforts across the ICs could enable the ICs to harness their expertise and resources effectively to address the pressing issues in autoimmune diseases research.

CONGRESSIONAL ACTIONS AND NIH AUTOIMMUNE DISEASE RESEARCH

On numerous occasions, Congress has issued mandates pertaining to autoimmune disease research at NIH. Constituents, advocacy groups, and other stakeholders who request congressional action on autoimmune diseases research have contributed greatly to such action, often through organized advocacy efforts (Autoimmune Association, 2021; Keenan, 2020). These mandates provide direction and in some cases funding for specific activities NIH-wide or at the IC level. This section provides an illustrative selection of specific mandates.

The National Institutes of Health Revitalization Act of 1993¹³ directed multiple ICs to pursue research on specific autoimmune diseases. The

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¹³National Institutes of Health Revitalization Act of 1993, Public Law 103-43, 103rd Cong., 1st sess. (June 10, 1993).

Act tasked NIAMS to develop a plan to expand research into etiology, prevention, diagnosis, treatment, and rehabilitation of arthritis affecting children; to establish a disease center for this purpose; and to make recommendations for expanding funding for such research. The Act encouraged NIAID to collaborate with external entities to research chronic fatigue syndrome, issue research grants to study it, establish an extramural study section to review related research, appoint experts on the disease to appropriate NIH advisory committees and boards, and report on NIH’s work and priorities involving the disease. The Act also enabled NEI to issue grants to support a variety of basic and clinical research on diabetes and the eye and to improve patient care. Furthermore, the Act directed NINDS to conduct and support research on multiple sclerosis, particularly the effects of genetics and hormonal changes on disease progression. Congress did not include appropriations language for these efforts.

One directive that has been renewed over many years is the Special Statutory Funding Program for Type 1 Diabetes Research, or Special Diabetes Program, a special appropriation for research on type 1 diabetes that NIDDK administers on behalf of the HHS Secretary in collaboration with multiple ICs and the Centers for Disease Control and Prevention (CDC) and with input from the Diabetes Mellitus Interagency Coordinating Committee. Begun in 1998, the Special Diabetes Program established collaborative research consortia and clinical trials networks dedicated to preventing, treating, and curing type 1 diabetes. Annual funding for the program has grown over time from $30 million to the current level of $150 million.¹⁴

The Children’s Health Act of 2000¹⁵ called for the NIH Director to “expand, intensify, and coordinate research and other activities involving autoimmune diseases among the institutes.” It also requested establishing an Autoimmune Diseases Coordinating Committee (ADCC) to coordinate activities across NIH and with other federal health programs. Its members would include representatives of germane NIH ICs, federal departments, and agencies, including CDC and the Food and Drug Administration (FDA). The ADCC was to create a plan for “conducting and supporting a broad range of research and education activities relating to biomedical, psychosocial, and rehabilitative issues, including studies of the disproportionate impact of such diseases on women.” It was to determine NIH priorities for autoimmune diseases, which would “reflect input from a broad range of scientists, patients, and advocacy groups.” Planning was to include research to identify the reasons for the incidence and prevalence

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¹⁴Consolidated Appropriations Act, 2021, Public Law 116-260, 116th Cong. 2nd sess. (December 27, 2020).

¹⁵Children’s Health Act of 2000, Public Law 106-310, 106th Cong. 2nd sess. (October 17, 2000).

of the diseases; basic research of causes; epidemiologic studies on disease frequency and progression, including disparities among sexes and racial and ethnic groups; improvement of screening techniques; and clinical research to develop treatments. The ADCC was also to plan information and education programs for the public and medical community. The ADCC would issue reports to Congress on autoimmune disease-related activities conducted or supported by NIH and the cost of NIH activities for each disease, and would identify appropriate future projects for consideration by NIH or other research entities. Congress authorized appropriations for FY 2001 through 2005, but the language did not include amounts.

The Children’s Health Act of 2000 also asked NIAMS and NIAID to expand and intensify programs for research and other activities involving juvenile arthritis and related conditions. Congress authorized NIAMS and NIAID to be appropriated “such sums as may be necessary” for FY 2001 through FY 2005. In addition, the Act directed NIDDK to conduct or support long-term epidemiology studies in those who have or who are at risk for type 1 diabetes in order examine the causes, characteristics, and complications of the disease, and to undertake an effort to support regional clinical research centers for preventing, detecting, treating, and curing juvenile arthritis and related conditions. NIH was to join HHS in a national effort to increase “research and development of prevention strategies, including consideration of vaccine development, coupled with appropriate ability to evaluate the effectiveness of such strategies in large clinical trials of children and young adults.” NIDDK was to be appropriated sums for FY 2001 through 2005, but the Act did not specify what those sums should be.

Another statute Congress passed in 2000 was the Public Health Improvement Act,¹⁶ which included directives to extend and intensify the study of SLE and charged NIAMS with coordinating with other ICs doing work related to SLE. NIAMS was asked to conduct or support research to include investigating the reasons for the preponderance of SLE in women, including African American women; basic research on disease causes; epidemiologic studies to examine disease progression, its frequency, and difference between sexes and racial and ethnic groups; development of improved diagnostic techniques; and clinical research to develop and evaluate new treatments. The Act also directed NIAMS to develop information and education programs for the health care community and the public. It was authorized appropriations for FY 2001 through 2003, but the Act did not specify sums.

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¹⁶Public Health Improvement Act, Public Law 106-505, 106th Cong., 2nd sess. (November 13, 2000).

Congress enacted the Rare Diseases Act of 2002¹⁷ with the intent of increasing the study of rare diseases and disorders—“defined as those affecting fewer than 200,000 individuals in the United States”—and the Act includes Crohn’s disease as an example of a rare disease. NIH created the Office of Rare Diseases in 1993, but it lacked statutory authorization, so the Act requested that NIH establish the Office within the OD. The Act directed the Office to recommend a varied research and educational agenda and to promote coordination and cooperation across the NIH ICs and those they supported, and, in collaboration with directors of other ICs, it was enabled to make cooperative agreements and to award grants to regional centers of excellence on rare diseases. Other duties specified for the Office included promoting the establishment of an information clearinghouse on rare and genetic diseases for the public and medical community, liaising with national and international organizations, reporting biennially on the activities that had and should occur, and reporting annually to Congress. The Office was appropriated “such sums as already have been appropriated for FY 2002, and $4,000,000 for each of the FY 2003 through 2006” for the purpose of cooperative agreements or grants for the regional centers of excellence for rare diseases.

Congress enacted the Pancreatic Islet Cell Transplantation Act of 2004¹⁸ to “increase the supply of pancreatic islet cells for research, to provide for better coordination of Federal efforts and information on islet cell transplantation.” Annual reports prepared by the NIDDK-led Diabetes Mellitus Interagency Coordinating Committee were directed to evaluate the federal activities and programs related to pancreatic islet transplantation and research, recommend legislation to increase the supply of pancreas tissue for islet cell transplantation, and address the adequacy of federal funding. The Act did not provide funding authorization or appropriation amounts.

The American Recovery and Reinvestment Act of 2009¹⁹ was a fiscal stimulus package developed in response to the Great Recession. Of the money appropriated to NIH, $7,400,000,000 was transferred to the ICs and the Common Fund,²⁰ in proportion to the appropriations otherwise made to them for FY 2009. The funds were to be used to “support additional scientific research,” and money was to be consolidated with and used for

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¹⁷Rare Diseases Act of 2002, Public Law 107-280, 107th Cong., 2nd sess. (November 6, 2002).

¹⁸Pancreatic Islet Cell Transplantation Act of 2004, Public Law 108-362, 108th Cong., 2nd sess. (October 25, 2004).

¹⁹American Recovery and Reinvestment Act of 2009, Public Law 111–5, 111th Cong., 1st sess. (February 17, 2009).

²⁰ Not included among the recipients were the National Institutes of Health–Buildings and Facilities, the Center for Scientific Review, the Center for Information Technology, the Clinical Center, and the Global Fund for HIV/AIDS, Tuberculosis and Malaria.

“the same purposes as the appropriation or fund to which [it] was transferred.” In addition, $1,800,000,000 was appropriated to NIH for repair, renovation, and construction of non-federal and NIH facilities and for instrumentation and research equipment.

The 21st Century Cures Act,²¹ enacted in 2016 to expedite the discovery, development, and delivery of new treatment and cures, appropriated $4.8 billion to biomedical research. While autoimmune disease research was not specifically named in the Act, the crosscutting nature of autoimmune disease research could enable it to benefit from the funding designated for NIH initiatives such as the NIH Beau Biden Cancer Moonshot, the Brain Research Through Advancing Innovative Neurotechnologies^® (BRAIN) Initiative, and the Precision Medicine Initiative. In addition, funding was directed to the Next Generation of Researchers Initiative to help support new researchers, sustain research careers, and promote growth, stability, and diversity of the biomedical research workforce.

In 2018, the National Clinical Care Commission Act²² established an HHS Commission, which included NIH as a member, to evaluate and make recommendations on how to better leverage and coordinate federal programs related to as many as two metabolic or autoimmune diseases with insulin-related etiology. In making its recommendations, the Act instructed the Commission to consider preventing and reducing the diseases and complications, “gaps in Federal efforts to support clinicians in providing integrated high-quality care,” “improvement in and improved coordination of Federal education and awareness activities related to the prevention and treatment of the diseases,” methods for dissemination of educational materials, and opportunities for consolidating overlap in federal programs related to the diseases. The Commission was to submit an operating plan, which could include a budget for the Commission’s activities, and a final report to the HHS Secretary and Congress, and it decided to focus on type 1 and type 2 diabetes. Congress did not appropriate funds for the Commission’s operation, and an HHS Joint Funding Agreement supported the Commission’s activities (National Clinical Care Commission, 2018).

Relevant Bills or Resolutions That Did Not Pass

There have been congressional actions directed to NIH autoimmune disease research efforts that Congress did not pass into law. One example is a bill that members of Congress submitted twice—the NIH Office of

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²¹21st Century Cures Act, Public Law 114-255, 114th Cong., 2nd sess. (December 13, 2016).

²²National Clinical Care Commission Act, Public Law 115-80, 115th Cong., 1st sess. (November 2, 2017).

Autoimmune Diseases Acts of 1998²³ and 1999²⁴—which called for establishing an Office of Autoimmune Diseases in the NIH OD. The 1999 bill (see Appendix F) was introduced by then Senator Joseph Biden. According to that proposed bill, the Director of the Office, consulting with the ADCC, was to recommend an agenda for autoimmune disease research across the ICs. The Director of the Office was also to promote coordination and cooperation among the ICs involved in autoimmune disease research and those supported by their research; promote NIH allocation of resources for such research; annually report on the research, including identifying projects that should be conducted or supported; and serve as the principal advisor to HHS, NIH, CDC, and FDA and other agencies regarding autoimmune diseases. The 1999 bill authorized a FY 2000 appropriation of $950,000 (20 percent more than that of the 1998 bill) as well as “such sums necessary for fiscal years 2001 and 2002.” While both bills required establishing or operating the ADCC, and the ADCC had been formed by the time of the 1999 bill, the establishment and duties of the ADCC were not required by statute until The Children’s Health Act of 2000. In the 2000 Act, the ADCC was directed to carry out certain duties that had been outlined for the proposed NIH Office of Autoimmune Diseases.

Other select examples of congressional action are the Scleroderma Research and Awareness Act (Congresses of 2009–2010, 2011–2012, and 2013–2014)^25,26,27 requesting the director of NIAMS to “expand, intensify, and coordinate” research of the disease; the Psoriasis and Psoriatic Arthritis Research, Cure, and Care Act of 2007,²⁸ 2009,²⁹ and 2011,³⁰ which encouraged the Director of NIH to “explore the development of a virtual Center of Excellence for Collaborative Discovery in Psoriasis and Comorbid Research or some other mechanism through which public and private

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²³NIH Office of Autoimmune Diseases Act of 1998, HR 4873, 105th Cong., 2nd sess., Congressional Record 144, no. 150, daily ed. (October 20, 1998); H 11695.

²⁴NIH Office of Autoimmune Diseases Act of 1999, S 1897, 106th Cong., 1st sess., Congressional Record 145, no. 157, daily ed. (November 9, 1999); S 14407.

²⁵Scleroderma Research and Awareness Act of 2010, HR 2408, 111th Cong., 1st sess., Congressional Record 155, no. 74, daily ed. (May 14, 2009); H 5664.

²⁶Scleroderma Research and Awareness Act of 2011, HR 1672, 112th Cong., 1st sess., Congressional Record 157, no. 57, daily ed. (May 2, 2011); H 2933.

²⁷Scleroderma Research and Awareness Act, S 1239, 113th Cong., 1st session, Congressional Record 159, no. 94, daily ed. (June 27, 2013) S 5498.

²⁸Psoriasis and Psoriatic Arthritis Research, Cure, and Care Act of 2007, HR 1188, 110th Cong., 1st sess., Congressional Record 153, no. 30, daily ed. (February 16, 2007); H 1895.

²⁹Psoriasis and Psoriatic Arthritis Research, Cure, and Care Act of 2009, HR 930, 111th Cong., 1st sess., Congressional Record 155, no. 27, daily ed. (February 10, 2009); H 1156.

³⁰Psoriasis and Psoriatic Arthritis Research, Cure, and Care Act of 2011, S 1107, 112th Cong., 1st sess., Congressional Record 157, no. 74, daily ed. (May 26, 2011); S 3427.

sector findings regarding psoriasis and its comorbid conditions can be regularly shared and leveraged”; the Prevention, Awareness, and Research of Autoimmune Disease Act of 2006³¹ (as well as during the 2003–2004 Congress³²), which required NIEHS to award grants to research environmental triggers of autoimmune diseases in genetically predisposed people; and the Women’s Autoimmune Diseases Research and Prevention Act (Congresses of 2001–2002³³ and 2003–2004³⁴), which directed the ADCC to include research on the causes of autoimmune diseases in women, particularly genetic, hormonal, and environmental factors; development of information and education programs on risk factors, including hormonal and environmental factors; and community outreach to historically underserved populations of women in its plan for NIH activities.

CURRENT COORDINATION OF AUTOIMMUNE DISEASE RESEARCH AT NIH

Role and Function of the Autoimmune Diseases Coordinating Committee

NIH established the ADCC in 1998 in response to congressional interest in the autoimmune diseases and the need to coordinate activities across the ICs and with other federal health programs and activities for autoimmune diseases (ADCC, 2000).³⁵ The inaugural ADCC membership consisted of representatives of the ICs that are engaged in autoimmune diseases research, and members from other federal departments and agencies that focus on autoimmune diseases, such as CDC, Veterans Administration, and FDA.³⁶ In addition, although Congress did not require it, the ADCC extended membership invitations to advocacy

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³¹Prevention, Awareness, and Research of Autoimmune Disease Act of 2006, HR 6214, 109th Cong., 2nd sess., Congressional Record 152, no. 123, daily ed. (September 27, 2006); H 7674.

³²Prevention, Awareness, and Research of Autoimmune Disease Act, HR 3359, 108th Cong., 1st sess., Congressional Record 149, no. 148, daily ed. (October 21, 2003); H 9811.

³³Women’s Autoimmune Diseases Research and Prevention Act, HR 5104, 107th Cong., 2nd sess., Congressional Record 148, no. 93, daily ed. (July 11, 2002); H 4552.

³⁴Women’s Autoimmune Diseases Research and Prevention Act, HR 370, 108th Cong., 1st sess., Congressional Record 149, no. 14, daily ed. (January 27, 2003); H 170.

³⁵Children’s Health Act of 2000, Public Law 106–310, 106th Cong. (October, 17, 2000), H.R. 4365. Departments of Labor, Health and Human Services, And Education, And Related Agencies Appropriation Bill, 1998, HR 105-205, 105th Cong., 1st sess. (July 25, 1997).

Departments of Labor, Health and Human Services, And Education And Related Agencies Appropriation Bill, 1998, 105th Cong., 1st sess. (July 24, 1997): Senate Report 105-58.

³⁶Children’s Health Act of 2000, Public Law 106–310, 106th Cong., 2nd sess. (October, 17, 2000), H.R. 4365.

groups and representatives from private autoimmune disease organizations.³⁷ The current membership of the ADCC remains similar, and the membership of advocacy groups has only continued to grow, providing these stakeholders with a greater voice (NIAID, 2021a). NIAID is the current chair of the ADCC.

In the first 2 years of its existence, the ADCC had several major accomplishments, as documented in its first report released in 2000 (ADCC, 2000). The committee analyzed information on autoimmune diseases research funding and research at NIH and established multi-IC collaborative working groups for autoimmune diseases. The ADCC was also instrumental in enhancing coordination and facilitating private and public partnerships for autoimmune disease research both within the ICs and with private disease organizations. In FY 1999, NIH “committed more than $393 million” to support autoimmune disease research (ADCC, 2000). A congressional conference report³⁸ stated that NIAID was being appropriated more funding for FY 1999 than the House and Senate had requested, urged NIAID to expand autoimmune disease research, and pointed to the ADCC to provide greater coordination and focus for such research, which likely facilitated the ADCC’s charge.

The ADCC released reports in 2000, 2002, and 2005, each with a different focus and purpose. The ADCC’s initial report summarized the state of autoimmune disease research and funding at NIH and identified the major challenges facing autoimmune diseases research (ADCC, 2000):

1. “Development of a mechanism-based, conceptual understanding of autoimmune disease;
2. Translation of this knowledge into new, broadly applicable strategies for treatment and prevention of multiple diseases; and
3. Development of sensitive tools for early and definitive diagnosis, disease staging, and identification of at-risk individuals.”

The subsequent ADCC report in 2002 (ADCC, 2002) was an autoimmune diseases research plan that had been requested by Congress, and it was informed by an expert panel that identified priority areas for autoimmune diseases research and considerations for implementing the research plan. The research plan had four major areas of emphasis:

• “reducing the burden of disease;
• enhancing understanding of disease etiology;

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³⁷ Personal communication. Ellen Goldmuntz, MD, PhD, Section Chief, Rheumatologic Autoimmune Disease Section, NAID. August 11, 2021.

³⁸Omnibus Consolidated and Emergency Supplemental Appropriations Act, 1999. Public Law 105-277, 105th Cong. (October 21, 1998). Conference Report 105-825 to accompany H.R. 4328.

• improving diagnosis, treatment, and prevention;
• increasing training, education; and
• information dissemination activities.”

The report underscored the importance of leveraging scientific and clinical knowledge to inform multiple autoimmune diseases and coordinating efforts to efficiently utilize available resources in both federal and private agencies, among others (ADCC, 2002). The report also called for Congress to appropriate additional funds in support of research in autoimmunity. Congress authorized funding for developing the ADCC research plan through amendments to the Children’s Health Act of 2000 (ADCC, 2002). A resolution submitted in the House in 2004³⁹ called for increase in appropriations to carry out the autoimmune diseases research. The committee, however, was unable to find additional information on appropriations for the research plan or its implementation.

The final ADCC report published in 2005 summarized progress made since the publication of the research plan in 2002 and pointed to funded and soon-to-be funded activities that signify NIH’s commitment to making progress in the areas identified in the research plan and encouraged continued investments in those areas. The ADCC reports ceased after the NIH Reform Act of 2006, which consolidated all the disparate reports required by law from NIH ICs in one comprehensive biennial report to Congress. As of FY 2016, NIH has further consolidated biennial reporting into a triennial report (ADCC, 2005).

The amount of NIH reporting to Congress on autoimmune diseases has changed over time. The ADCC reports ran 33 to 145 pages. In the NIH biennial reports for the years FY 2006 to 2009, the autoimmune disease section, which included type 1 diabetes, ran 14 to 19 pages, and in the reports for FY 2010 to 2013, including a new section on type 1 diabetes, autoimmune disease reporting ran 9 to 12 pages. For the FY 2014 to 2015 report, including a new diabetes section that intermixed type 1 and type 2 diabetes, autoimmune disease reporting ran 17 pages. In the most recent report, the first triennial report for the period FY 2016 to 2018, after including the section combining type 1 and type 2 diabetes, the content on autoimmune disease totaled 21 pages. The field of autoimmune disease research at NIH has expanded over time, yet the amount of reporting

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³⁹Expressing the sense of the House of Representatives with respect to the level of funding provided to the National Institutes of Health for carrying out the Autoimmune Diseases Research Plan H.Res.610, 108th Cong. 2nd sess. (April 28, 2004).

to Congress on NIH activities and priorities in the field appears to have diminished.⁴⁰

While the ADCC continues to be active to date, the committee was unable to identify information from publicly available sources to indicate the extent to which the ADCC’s activities contribute to research and funding priorities at NIH. The agenda for the last ADCC public meeting held in May 2020 focused on celiac disease, a topic the group pursued after congressional language addressed concerns about the disease, and featured invited speakers who addressed research gaps and opportunities and unmet needs according to patients (ADCC, 2020). As a follow-up to this meeting, “NIH plans to develop a Research, Condition, and Disease Category (RCDC) report for celiac disease within the NIH Research Portfolio Online Reporting Tools (RePORT) website” (NIH, 2021c). Establishing a celiac disease RCDC category will make all NIH-funded projects related to celiac disease available in a publicly accessible format. In addition, in FY 2021, NIAID is “developing a Notice of Special Interest to encourage investigator-initiated celiac disease research.” The ADCC is now using the process it used for celiac disease to explore other gaps and topics of interest to the community.⁴¹ An earlier public meeting held in April 2019 introduced the Accelerating Medicines Partnerships (AMP), a collaborative initiative for autoimmune diseases sponsored by NIAMS, NIAID, and other non-NIH partners (ADCC, 2019). Currently, the IC representatives on the ADCC convene regularly to review shared priorities and activities, but information about these meetings is not available to the public, so the committee is unable to report on the scope of current ADCC activities.⁴²

Since its establishment, the ADCC has played a role in coordinating research activities for autoimmune diseases across the ICs and with non-NIH external partners. Based on the review of available public information about the ADCC, and interviews with NIAID representatives, the committee notes that the ADCC functions as a convener of ICs and external partners and provides a forum for ICs to share information and coordinate their activities on autoimmune disease research. Outside of ADCC meetings, ICs may decide to develop or support collaborative research activities influenced in part by their participation in ADCC meetings, but this was difficult to assess from public documents. Currently, the ADCC

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⁴⁰ The committee is aware that information on autoimmune diseases may appear in the biennial and triennial reports in sections other than the autoimmune disease and diabetes sections. The intention was to estimate the clearly indicated content on autoimmune disease in the reports.

⁴¹ Personal communication. Ellen Goldmuntz, MD, PhD, Section Chief, Rheumatologic Autoimmune Disease Section, NAID. August 11, 2021.

⁴² Personal communication. Ellen Goldmuntz, MD, PhD, Section Chief, Rheumatologic Autoimmune Disease Section, NAID. May 11, 2021.

has no dedicated funding or staff; NIH staff who support ADCC operations do so as part of their general work responsibilities.

Other Modes of Coordination and Collaboration

The committee investigated other mechanisms by which NIH coordinates and collaborates on autoimmune disease research, both across NIH and external to NIH. For example, NIH established the Center for Human Immunology, Autoimmunity, and Inflammation as an NIH-wide “intramural initiative designed to study the human immune system” (NIH, 2012). Originally, its operation was supported jointly by several ICs, and this coordination and collaboration resulted in a study on human response to influenza vaccine that was collectively useful.⁴³ However, the Center could not sustain this funding model, partly because of difficulties in reaching agreement on projects that could yield benefit to all contributors, and eventually the Center was placed in NIAID.

NIH and FDA created the intramural NIH–FDA Immunology Interest Group in the 1990s as a part of an effort to foster interaction among scientists across both NIH and FDA, then located on the Bethesda campus.⁴⁴ It is one of the largest of such NIH groups and has led to offshoot groups. Speakers invited from within and outside NIH deliver weekly video seminars that anyone can view, and a large and active Listserv of some 1,500 listees further encourages collaboration. The Immunology Interest Group connects trainees and younger investigators with more established investigators across NIH and external experts, with a major vehicle being an annual workshop internal to NIH and FDA where approximately 400 attendees present abstracts and posters on active and unpublished work. The workshop, which the ICs jointly support, includes talks by intramural and extramural investigators who interact with trainees.

At the request of Congress, NIH established the NIAMS-led Lupus Federal Working Group (LFWG) in 2003 to facilitate collaboration on SLE “among NIH components, other federal agencies, voluntary and professional organizations, and industry groups with an interest in lupus” (NIAMS, 2019). With the help of LFWG and others, NIAMS published The Future Directions of Lupus Research in 2007, intended to guide the U.S. investment in SLE research (NIAMS, 2020a) and a follow-up Action Plan

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⁴³ Personal communication. Daniel Kastner, MD, PhD, Scientific Director, Division of Intramural Research Head, Inflammatory Disease Section, National Human Genome Research Institute, NIH, August 30, 2021.

⁴⁴ Personal communication. Pamela L. Schwartzberg, M.D., Ph.D, Chief, Cell Signaling and Immunity Section, NIAID; Senior Investigator, NHGRI, NIH, September 3, 2021.

for Lupus Research in 2015 (NIAMS, 2020a).⁴⁵ The latter was intended to “inform priority-setting processes among all lupus-related organizations” (NIAMS, 2015, 2020a) but not to dictate approaches to research or to compete with NIAMS’s strategic plans.⁴⁶ In addition to inviting experts to deliver talks, LFWG meetings serve as a forum for hearing patient concerns and disseminating information among members.

The National Institutes of Health Reform Act of 2006⁴⁷ directed NIH to establish DPCPSI, which sits within the NIH OD (DPCPSI, 2021). One of the Division’s responsibilities is to coordinate the research and activities of the various Offices that operate within the OD, such as the Office of AIDS Research and the Office of Research on Women’s Health (ORWH) (DPCPSI, 2021). The missions of these Offices vary, but in general they serve to enhance and promote the research of focus by coordinating and integrating activities across NIH’s intramural and extramural activities, as well as to stimulate and support research, disseminate research results, educate the public, and foster the development of a workforce for the field (OBSSR, 2021; ORWH, 2021b; SGMRO, 2021). Establishing an office requires having a research focus that cuts across most NIH ICs, with the office addressing concerns, particularly roadblocks, that the ICs share.⁴⁸ For example, NIH-funded researchers were inconsistent in the ways they recorded sex in clinical and animal trials, and while it was unlikely that a single IC would undertake advancing the policies and tools to capture these data in a uniform manner, it was appropriate for ORWH to do so. Similarly, ORWH initiated the Building Interdisciplinary Research Careers in Women’s Health program, a career development program, which “connects junior faculty to senior faculty with a shared interest in women’s health and sex differences research” (ORWH, 2021a). DPCPSI’s budget funds the activities of the NIH Offices and their staffs. Although the Offices can fund research, most can only do so by collaborating with one or more ICs. Each Office has a coordinating committee of IC representatives that serves as a primary coordinating hub to identify areas of need, gather consensus, and identify funding opportunities. The Offices release strategic plans, and the NIH triennial report to Congress describes Office activities.

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⁴⁵ Available at https://www.niams.nih.gov/about/working-groups/lupus-federal/action-plan (accessed December 6, 2021).

⁴⁶ Personal communication. Marie Mancini, PhD, Program Director, Systemic Autoimmune Diseases Biology, Division of Extramural Research, NIAMS, NIH, September 7, 2021.

⁴⁷ PL 109-482.

⁴⁸ Personal communication. James M. Anderson, M.D., Ph.D., DPCPSI Director, September 7, 2021.

Opportunities for IC Collaboration During the CSR Review Process

Independent of the efforts of the ADCC to coordinate autoimmune disease research activities, ICs can take steps among themselves to coordinate their research interests. The CSR review process, as noted earlier, presents an opportunity for ICs to collaborate on research activities, including collaborating on research funding for autoimmune diseases. CSR reviews all unsolicited grant applications and assigns them the appropriate IC for funding according to guidelines the ICs provide (Hodge, 2021). Those guidelines direct CSR on how to address grant applications that tackle areas of shared interest for multiple ICs. ICs may also “bid” to be part of grants that they have an interest in, which offers an opportunity for ICs to collaborate on studies that can leverage their mutual expertise and resources.⁴⁹ Since the committee did not have further access to materials governing this process or additional details on the process, it is unclear how well this process works and the frequency with which ICs bid on and collaborate on projects.

Major NIH Initiatives Involving Collaboration

A number of recent and ongoing initiatives provide evidence of collaboration on autoimmune disease research across ICs as well as including other federal agencies and external organizations and researchers. Institute representatives, during their meetings with the committee, along with information on IC websites, highlighted the major initiatives below.

Collaborations Among ICs

Clinical Islet Transplant (CIT) Consortium.⁵⁰Type 1 diabetes (CIT Consortium, 2021).

• Collaborators include:
  • NIDDK
  • NIAID
  • Principal investigators and research centers in the United States and Sweden
• Description: “The CIT Consortium is a network of clinical centers and a data coordinating center established in 2004 to conduct

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⁴⁹ According to multiple NIH speakers who spoke at the committee’s public information-gathering sessions (Goldmuntz, 2020; Hodge, 2021; McNamara, 2021).

⁵⁰ Website available at https://www.citisletstudy.org/what.html (accessed December 2, 2021).

studies of islet transplantation in patients with type 1 diabetes. Studies conducted by the CIT Consortium focus on improving the safety and long-term success of methods for transplanting islets, the insulin-producing cells of the pancreas, in people whose own islets have been destroyed by the autoimmune process that characterizes type 1 diabetes.”

Principal areas of focus include:

• “improving the isolation and viability of islets
• reducing complications of the islet transplant procedure, (e.g., bleeding and clotting in the blood vessels of the liver)
• reducing the side effects of immunosuppression
• achieving good blood sugar control without hypoglycemia
• following the fate of islets after transplantation and determining why donor islets sometimes fail
• evaluating new ways to safely prevent immune rejection of donor tissues.”

Autoantigens and Neoantigens Function in the Etiology and Pathophysiology of Type 1 Diabetes. Type 1 diabetes (NIH et al., 2021d).

• Collaborators include:
  • NIDDK
  • NIAID
• Description: The purpose of this initiative is to characterize the “function of neoepitopes and neoantigens in type 1 diabetes. This includes the function that post-translational modifications might have in the humoral and cell mediated autoimmune responses and overall in the etiology and pathophysiology of type 1 diabetes.”

Autoimmune Centers of Excellence (ACEs).^51,52 SLE, type 1 diabetes, inflammatory bowel disease, multiple sclerosis, pemphigus vulgaris, psoriasis, scleroderma, rheumatoid arthritis, and Sjögren’s disease (ACE, 2020).

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⁵¹ Website available at https://www.autoimmunitycenters.org/mission.php (accessed December 2, 2021).

⁵²Autoimmunity Centers of Excellence Progress Report 2021 is available at https://www.autoimmunitycenters.org/ACE%20Public%20Progress%20Report%20Jan-31-2022%20DAIT.pdf (accessed March 3, 2022).

• Collaborators include:
  • NIAID
  • NIDDK
  • NIH ORWH
  • Clinical research sites and principal investigators
• Description: “ACEs conduct collaborative basic and clinical research on autoimmune diseases. Close interaction between clinicians and basic researchers accelerates the discovery, development, and translation of therapies for autoimmune diseases from the lab to use in the clinic.” The principal areas of focus include:
  • Encouraging and enabling collaborative research—“across scientific disciplines, across medical specialties, and between basic and clinical scientists—in the search for effective treatments for autoimmune diseases”
  • Evaluating the safety and efficacy of treatment strategies for autoimmune diseases
  • Exploring the immune mechanisms underlying the agents evaluated in these ACE clinical trials.

Office of Rare Diseases Research.⁵³ A rare disease is defined as “a condition that affects fewer than 200,000 people in the United States,” which includes some autoimmune diseases (NCATS, 2021b).

• Collaborators include:
  • The Office sits in NCATS but is NIH-wide (NCATS, 2021a)
• Description: This Office facilitates and coordinates NIH-wide activities that involve research for a broad range of rare diseases, including autoimmune diseases. Duties of the Office include:
  • Developing and maintaining a centralized database on rare diseases.
  • Coordinating and providing liaison with organizations worldwide concerned with rare diseases research and orphan products development.
  • Advising the Office of the Director on matters related to NIH-sponsored research involving rare diseases.
  • Responding to information and policy requests about rare diseases.

___________________

⁵³ Website available at https://ncats.nih.gov/about/center/org/ordr (accessed December 2, 2021).

Collaborations Among ICs and External Agencies, Organizations, and Industry

Myasthenia Gravis Rare Disease Network (MGNet).⁵⁴Myasthenia gravis and its subtypes (Rare Diseases Clinical Research Network, 2021).

• Collaborators include:
  • NCATS
  • NINDS
  • Myasthenia Gravis Foundation of America
  • Industry (not named)
  • Academic medical centers
• Description: The “Myasthenia Gravis Rare Disease Network serves as a centralized, international consortium for physicians, scientists, patient advocacy groups, as well as industry partners to develop resources and implement ideas to enhance discovery, treatment, and advocacy for the patient community. The immediate goals of MGNet are to further define how patients respond to conventional treatments over time, evaluate a novel drug for therapy of some forms of MG, find biological markers of the disease (biomarkers), and encourage new scientists to engage in research on MG.”

Accelerating Medicines Partnership® (AMP®) Program including Autoimmune and Immune-Mediated Diseases (AMP® AIM).⁵⁵Rheumatoid arthritis, SLE, psoriatic spectrum diseases, and Sjögren’s disease (NIAMS, 2021a; NIH, 2021b).

• Collaborators include:
  • NIAMS
  • NIAID
  • NIDCR (NIH et al., 2021a)
  • ORWH
  • FDA (NIH, 2021b)
  • European Medicines Agency
  • Multiple biopharmaceutical and life science companies
  • Multiple nonprofit organizations
• Description: The purpose of the AMP® and AMP® AIM program is to establish disease teams that will focus on autoimmune and immune-mediated diseases, including rheumatoid arthritis,

___________________

⁵⁴ Website available at https://www.rarediseasesnetwork.org/mgnet (accessed December 2, 2021).

⁵⁵ The AMP® AIM program expands and builds upon the AMP® RA/SLE program.

SLE, psoriatic spectrum diseases, and Sjögren’s disease, with the goal of developing a thorough understanding of the cellular and molecular disease pathways and identifying novel targets for intervention.

Immune Tolerance Network (ITN).⁵⁶Type 1 diabetes, SLE, multiple sclerosis (Immune Tolerance Network, 2021).

• Collaborators include:
  • NIAID
  • NIDDK
  • The Juvenile Diabetes Research Foundation
  • Clinical sites and investigators worldwide
• Description: ITN’s purpose is “to advance the clinical application of immune tolerance by performing high-quality clinical trials of emerging therapeutics integrated with mechanism-based research. In particular, [they] aim to establish new tolerance therapeutics, develop a better understanding of the mechanisms of immune function and disease pathogenesis, [and] identify new biomarkers of tolerance and disease.” ITN conducts research on organ and cellular transplantation, autoimmune diseases, allergy, asthma, and type 1 diabetes. ITN collaborates with academic, government, and industry leaders to develop and fund cutting-edge immune tolerance research.

Environmental Determinants of Diabetes in the Young (TEDDY) Study.⁵⁷Type 1 diabetes (TEDDY Study Group, 2008).

• Collaborators include:
  • NIDDK
  • NIAID
  • NICHD
  • NIEHS
  • CDC
  • Juvenile Diabetes Research Foundation
  • Clinical centers in the United States and Germany, Sweden, and Finland
• Description: The long-term goal of the TEDDY study—an observational study that enrolled 8,668 participants with a 2025 estimated completion date—“is the identification of infectious

___________________

⁵⁶ Website available at https://www.immunetolerance.org (accessed December 2, 2021).

⁵⁷ Website available at https://teddy.epi.usf.edu (accessed December 2, 2021).

agents, dietary factors, or other environmental agents, including psychosocial factors which trigger [type 1 diabetes] in genetically susceptible individuals or which protect against the disease. Identification of such factors will lead to a better understanding of disease pathogenesis and result in new strategies to prevent, delay, or reverse [type 1 diabetes].” (Clinicaltrials.gov, 2021).

Type 1 Diabetes Trial Net (TrialNet).⁵⁸Type 1 diabetes (TrialNet, 2018).

• Collaborators include:
  • NIDDK
  • NIAID (ADCC, 2005)
  • NICHD (NIH et al., 2021e)
  • National Center for Complementary and Alternative Medicine (NIH, 2021e)
  • Juvenile Diabetes Research Foundation (TrialNet, 2018)
  • American Diabetes Association
  • Helmsley Charitable Trust
  • International network of researchers
• Description: TrialNet is an international network of researchers exploring ways to prevent, delay, and reverse the progression of type 1 diabetes (TrialNet, 2018). TrialNet was established in response to the Surgeon General’s Report Healthy People 2000, which identified diabetes as a national health objective for the nation. In response to the report, Congress created the Diabetes Research Working Group to develop a plan for diabetes research. One of the group’s recommendations was to conduct additional research studies and clinical trials on type 1 diabetes prevention.

SUMMARY

NIH is the primary funding agency for biomedical research, including autoimmune disease research. In 2020, NIH spent more than $1 billion on autoimmune disease research. Currently, 12 of 24 ICs provide the majority of funding to support extramural investigator-initiated autoimmune disease research, and 11 of 24 ICs provide funding to support intramural autoimmune disease research programs. Each IC has a different mission, and often has different research priorities and focuses on different autoimmune diseases than the other ICs. The autoimmune disease research focus of each IC ranges across basic, translational, and clinical research, and sometimes ICs have overlapping missions in autoimmune disease

___________________

⁵⁸ Website available at https://www.trialnet.org (accessed December 2, 2021).

research. These overlapping missions could impede the coordination of autoimmune disease research programs.

The committee identified evidence of attempts to coordinate funding and research efforts, but it was difficult for the committee to assess the effectiveness of these efforts. While the ADCC continues to be active to date, the committee was unable to determine the extent to which the ADCC’s activities contribute to setting research and funding priorities for autoimmune disease research at NIH. The lack of standardization of the process of strategic planning across ICs and consistency in the release of strategic plans by individual ICs has important implications, since it may pose an obstacle for ICs in coordinating their strategic planning efforts, and subsequently, their funding and research efforts for autoimmune diseases.

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