Purpose

The overarching purpose of this Funding Opportunity Announcement (FOA) is to promote the discovery of strong candidate biomarkers and endpoints for pain that can be used to facilitate the development of non-opioid pain therapeutics from discovery through Phase II clinical trials. Specifically, the focus of this FOA is on the identification and initial biological, analytical and clinical validation of pain biomarkers, biomarker signatures, and/or endpoints. Although research supported by this FOA can include animal studies, it must also include preliminary human validation research using carefully standardized human samples or human clinical studies. The goal of this initiative is to deliver candidate biomarkers, biomarker signatures, and/or endpoints that are ready for advanced clinical and analytical validation research.

Background

This FOA is part of the NIH HEAL (Helping to End Addiction Long-term) Initiative an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis.

More than 25 million Americans suffer from chronic pain, a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an overreliance on opioids for chronic pain despite their poor ability to improve function. This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative treatment options are thus critically needed.

The challenges facing the development of non-opioid alternative pain medications include: a lack of reliable measures of pain biology and perception, a difficult regulatory path with high safety and labeling hurdles, poor predictive power of preclinical models, and a paucity of validated targets. In addition, patient populations are heterogeneous across multiple pain conditions, with high variability in individual responses to intervention.

One potential solution toward accelerating the discovery and development of alternative pain therapies is the use of objective biomarkers and endpoints that could define pathophysiologic subsets of pain, evaluate target engagement of a therapeutic and predict analgesic efficacy of new therapeutics. Unfortunately, there are very few validated biomarkers available that provide the information described above. Therefore, the goal of this FOA is to promote the discovery of promising candidate biomarkers, biomarker signatures and endpoints for pain indications that will withstand rigorous validation and ultimately provide the tools necessary for the development of non-opioid therapeutics for the treatment of pain conditions.

Public Law 115-141, the Consolidated Appropriations Act of 2018 (signed March 23, 2018) includes a requirement that grantees from for-profit applicant organizations must provide a 50% match and/or in-kind contribution of all federally awarded dollars under the grant award (direct costs, as well as facilities and administrative costs) for research related to opioid addiction, development of opioid alternatives, pain management and addiction treatment.

Matching Requirement: A grantee from a for-profit organization funded under this funding opportunity announcement must match funds or provide documented in-kind contributions at a rate of not less than 50% of the total-Federally awarded amount, as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018.The applicant will be required to demonstrate that matching funds and/or in-kind contributions are committed or available at the time of, and for the duration of, the award. Applications must identify the source and amount of funds proposed to meet the matching requirement and how the value for in-kind contributions was determined. All matching funds and/or in-kind contributions must be used for the portion of allowable project costs not paid by Federal funds under the grant award. NIH will not be the recipient, nor serve as a pass-through entity, of any such matching funds and/or in-kind contributions required under this announcement. See 45 CFR 75.306 for additional details.

Biomarker and Endpoint Development

A biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions. A biomarker signature is a combination of multiple variables to yield a patient-specific indicator of normal biological processes or responses to an exposure or intervention including therapeutic interventions. Biomarker modalities are diverse, and can include genetic, protein, cellular, metabolomic, imaging, behavioral, and physiologic endpoints.

An endpoint is an outcome or event used to objectively measure the effect of a therapeutic or other intervention being studied. A precise definition of an endpoint typically specifies the type of assessments made, the timing of those assessments, the assessment tools used, and possibly other details, as applicable, such as how multiple assessments within an individual are to be combined.

The biomarker and endpoint development process begins with the Discovery phase, where initial identification and preliminary proof of concept studies of the potential biomarker and endpoint are conducted. The samples used must be from sources that are carefully standardized and annotated. Biomarker and endpoint detection technology is also developed during the Discovery phase. The identification of biomarkers and endpoints that reflect altered pain modulation and sensitivity; altered brain, spinal cord, or nerve function; altered behavior; and phenotypic characteristics of pain conditions are as important as metabolomic, proteomic and genomic indicators of pain. The biomarker and endpoint discovery phase also includes preliminary validation studies, such as initial analytical validation of the detection method along with studies designed to correlate modulation of the biomarker or endpoint with disease pathology, target engagement or response to an intervention. This funding opportunity supports the Discovery Phase.

The next phase of biomarker and endpoint development is the Validation phase, where analytical validation of the assay or detection technology is completed, along with increasingly rigorous clinical validation studies. The degree of evidence required to provide the necessary confidence in biomarker or endpoint validation depends upon the context of use for the biomarker or endpoint. As the context of use moves from research to accepted utility in clinical practice (i.e., as a diagnostic or predictor of therapeutic response), the required degree of validation evidence is increased and must include prospective, multi-site validation data. Note that the scope of this FOA includes initial analytical validation, and early clinical validation. It does not include the extensive validation activities described above, such as prospective, multi-site clinical studies. For other funding opportunities supporting analytical and clinical validation, please see PAR-18-548, PAR-18-549, PAR-18-550 and PAR-18-664.

Phased Award Mechanism and Transition to R33

This funding opportunity uses a R61/R33 Phased Innovation Award mechanism. The R61 phase will support proof of concept studies including activities such as sample collection, biomarker or endpoint identification, biomarker or endpoint detection method development, preliminary analytical validation of the detection method and correlational studies to define the association between the biomarker or endpoint with disease pathology, target engagement or response to an intervention. Examples of activities supported in the R33 phase can include more extensive analytical and/or biological validation and must include at least initial validation research using human samples or measures from human subjects. Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed milestones. The milestones should be clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the R61 phase. Milestones could address, for example, 1) The desired magnitude and reliability of the association between the biomarker or endpoint and disease pathophysiology, target engagement or responses to an intervention in preliminary animal studies or studies with human samples, 2) Desired precision, accuracy and dynamic range of the biomarker/endpoint detection method, and/or 3) Feasibility of biomarker/endpoint measurement.

Research Objectives

Applications to this FOA must propose a research plan designed to discover a biomarker, biomarker signature or endpoint that that will inform the diagnosis, prognosis, or development of non-opioid therapies for pain. The biomarker or endpoint should reflect pain pathophysiology, target engagement of a therapeutic intervention or response to a therapeutic intervention. Biomarker or endpoint discovery includes activities such as biomarker or endpoint identification, detection method development, analytical validation of the detection method and preliminary clinical validation using standardized samples or measures from human subjects. A separate FOA will be made available for later stage, multi-center validation studies.

The definitions of the terms analytical validation, clinical validation and context of use are provided below for the purposes of this FOA:

• Analytical Validation: Establishing that the performance characteristics of a measurement are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include sample collection and standardization procedures). Although the goal of analytical validation is to ensure a rigorous clinical conclusion, the level of analytical rigor that is necessary depends upon the characteristics of the biomarker, the detection technology, the type of clinical question (exploratory/informational) or its intended use as a biomarker (diagnostic, predictive, pharmacodynamic, etc.). Analytical validation establishes the measurement's technical performance, but does not validate the usefulness of the measurement.

• Clinical Validation: Establishing that the biomarker acceptably identifies, measures or predicts the concept of interest.

• Context of Use (COU): A statement that fully and clearly describes the way the biomarker is to be used and the biomarker-related purpose of the use. Considerations involved in defining the COU can include: biomarker modality and method of detection, clinical population characteristics, unmet need for the new biomarker and type of biomarker (response prediction, stratification, prognostic, diagnostic, target engagement, etc). Context of use statements are discussed extensively in the following link: https://fnih.org/sites/default/files/final/pdf/Evidentiary%20Criteria%20Framework%20Final%20Version%20Oct%2020%202016.pdf

Use of the BEST (Biomarkers, EndpointS, and Other Tools Resource) standardized biomarker definitions (https://www.ncbi.nlm.nih.gov/books/NBK338448/) is required for all studies.

Entry Criteria

• Biological rationale:Projects should be supported by a cogent biological rationale supporting the candidate biomarker, biomarker signature, or endpoint as well as a discussion regarding its unmet need. The biological rationale should include rigorously obtained evidence that the proposed biomarker, biomarker signature, or endpoint concept may be an indicator of normal biological processes, potential susceptibility or risk, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.

• Relevance for pain therapeutic development: Projects should address the relevance of the candidate biomarker, biomarker signature, or endpoint for pain therapy development or clinical practice.

Project Characteristics

The biomarker, biomarker signature, or endpoint must be focused on a pain condition.

Examples of pain biomarker, biomarker signature, or endpoint Discovery studies and activities that are responsive to this FOA include but are not limited to:

• Identification of biomarkers or signatures of the transition from acute to chronic pain
• Identification of biomarkers or signatures indicating alternations in reward systems that are indicative of the affective components of pain
• Identification of biomarkers or signatures for longitudinal characterization and prognosis of persistent pain or chronic pain
• Identification of a pain biomarker or signature in individuals with different vulnerabilities to opioid use disorder (OUD)
• Development of biomarkers in animal models of pain that could be measured in humans
• Identification and initial validation of a potential pain biomarker
• Identification and procurement of sample sources necessary for biomarker discovery and assurance of source standardization and annotation
• Identification and validation of objective pain endpoints
• Comprehensive set of biomarker discovery studies designed to identify a set of mechanistic markers associated with diverse pain conditions, including identification of combined biomarkers that form a signature for the selected pain condition
• Bioinformatics and/or statistical approaches to support biomarker identification
• Development and analytical validation of biomarker detection or measurement technology. The goal for analytical validation should be that the biomarker measurement meets FDA analytical performance criteria (https://www.fda.gov/downloads/drugs/guidances/ucm368107.pdf) within the scope of the intended Context of Use
• Analysis and resolution of pre-analytical variables included in the detection technology or biomarker measurement technology
• Proof of concept studies using human tissue, biofluids or imaging samples to confirm biomarker identification obtained using animal tissue sources
• Preliminary clinical validation studies to confirm biomarker identification

Analytical Validation can include the following metrics, with use of FDA guidance standards appropriate for the context of use:

• Accuracy
• Precision
• Analytical sensitivity
• Analytical specificity including interfering substances
• Reportable range of test results for the test system
• Reference intervals (range of normal values) with controls and calibrators
• Harmonization of analytical performance if the assay or method of detection is to be performed in multiple laboratories
• Establishment of appropriate quality control and improvement procedures
• Any other performance characteristic required for test performance with determination of calibration and control procedures.

Preliminary Clinical Validation can include the following metric with use of FDA guidance standards appropriate for the context of use:

• Demonstration of association of the result of the biomarker assay with a clinical endpoint (e.g., response to a therapeutic, target engagement, pain pathophysiology or clinical manifestation) in samples or data from patients that have been exposed to a uniform intervention or that have or will develop a disease or disorder

Examples of studies that are not responsive to this FOA

• Natural history studies aimed at understanding disease pathophysiology, genetic, or epigenetic mechanisms in the absence of biomarker identification, development of detection technology and early validation
• Biomarker identification or validation based only on animal data without confirmation using human tissue sources or preliminary clinical validation
• Use of non-standardized sample sources
• Large, prospective design clinical validation studies
• Prospective design clinical utility studies
• Therapeutic target validation and development
• Preclinical animal studies without a transition to studies involving human samples or data
• Development of candidate therapeutics
• Biomarker discovery outside non-addictive therapeutic options to pain conditions

Considerations for clinical trials

This FOA supports the discovery of biomarkers that indicate pharmacodynamic responses to pain therapeutics, that predict an efficacy or safety response to a pain therapeutic or that can be used to monitor a therapeutic response to a pain therapeutic.Thus while the studies outlined in an application may be defined as clinical trials, and may make measurements in patients on specific therapies, they should not seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, and/or clinical intervention and management.

Studies focused on examining biomarker clinical validation and evaluation of utility in clinical practice of biomarkers may be more appropriate for PAR-18-664. Prospective applicants are encouraged to discuss project suitability for this FOA with the NINDS Scientific/Research Contact listed in the Agency Contacts section below.

NIH Institute and Center Interests and Guidance

National Cancer Institute (NCI)

The National Cancer Institute (NCI) is interested in biomarker discovery and validation projects in the area of treatment related pain conditions, most notably, chemotherapy induced peripheral neuropathy, aromatase inhibitor arthralgias, and radiation induced pain conditions. In addition, biomarker discovery and validation projects are sought for disease related pain conditions, such as metastatic bone pain, painful conditions arising from cancers of the pancreas, brain, and head and neck.

National Eye Institute (NEI)

The NEI is interested in applications targeting the understanding of, and potential therapy for, ocular pain. Ocular surface disease, and particularly dry eye disease, presents a currently unmet need despite clear clinical significance. Therefore, NEI encourages applications in this area including, but not limited to, clinical trial work on drug candidates (novel or repositioned) and ocular drug delivery platforms. Biomarker identification and validation in the pursuit of non-opioid analgesics for corneal pain is especially encouraged.

National Heart, Lung, and Blood Institute (NHLBI)

The National Heart, Lung, and Blood Institute (NHLBI) encourages applications that identify and develop candidate biomarkers, biomarker signatures or endpoints for acute or chronic pain in children, adolescents and adults with sickle cell disease.

National Institute on Aging (NIA)

The National Institute on Aging (NIA) encourages applications that identify and develop candidate biomarkers, biomarker signatures or endpoints for acute or chronic pain in midlife or older age, particularly in older adults with neurodegenerative diseases or multiple morbidities.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

It will be useful to incorporate coexisting behavioral aspects such as chronic alcohol use/abuse in pain biomarkers discovery as chronic pain does not exist in isolation. Individual differences exist in people susceptible to comorbid chronic pain and alcohol-misuse in terms of pain sensitivity, tolerance and withdrawal mechanisms. Developing and validating biomarkers/biomarker signatures that can be used to subgroup individuals and to predict those who are likely to respond specifically to different treatments is critically needed. These biomarkers should be validated as diagnostic markers for comorbid alcohol abuse in various pain and emotional dysregulation conditions and used to develop new treatments and monitor clinical outcomes.

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIAMS has interests related to the discovery and preliminary validation of candidate biomarkers, biomarker signatures or endpoints with focus on areas such as pain related back pain that includes both lower and upper regions, osteoarthritis, other chronic MSK diseases/disorders, post-operative total joint replacement pain, chronic rheumatic and skin diseases and other diseases/conditions within the mission of NIAMS.

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

The mission of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating engineering with the physical and life sciences to advance basic research and medical care. One way that this is achieved is through the support of research and development of new biomedical imaging and bioengineering tools and technologies to improve the prevention, detection, treatment, and monitoring of disease. Among the topics of special interest is the development of new in vitro platforms for biomarker discovery in human tissues.

NIBIB will only support applications proposing early-stage clinical trials through Phase I, first-in-human, safety, feasibility, or other small clinical trials that inform the early-stage technology development in the submitted application. NIBIB will not support applications proposing Phase II, III, IV or pivotal clinical trials, or trials in which the primary outcome is efficacy, effectiveness, or a post-market concern.

National Institute for Child Health and Development (NICHD)

The National Institute for Child Health and Development (NICHD) will support research on the following biomarker research: 1) Development of biomarkers identifiable using biological materials obtained through non-invasive methods: saliva, sweat, urine/stool, hair, and the placenta/fetal membranes after delivery, 2) Biomarkers for pregnant women whose fetuses may be undergoing invasive procedures (e.g., fetal surgery, 3) Identification and validation of pain biomarkers for individuals who cannot verbalize their pain including infants, critically ill and severely injured children and children with substantial neurocognitive delay and/or compromise, 4) Identification of biomarkers in children with chronic as well as acute pain conditions, 4) Identification, discovery, and validation (for clinical applicability) biomarkers and endpoints that have therapeutic potentials for treating pediatric or obstetric pain, 5) Identification of biomarkers for gynecologic pain syndromes including chronic pelvic pain, dysmenorrhea, and vulvodynia, 6) Identification and validation of biomarkers specifically relevant to individuals with neuromuscular conditions, neuropathic pain, musculoskeletal pain, or pain generated by spinal cord injury or amputation, 7) Validation of biomarkers that detect change due to non-pharmacologic interventions such as physical therapy, acupuncture, or other integrative medicine approaches.

National Institute of Dental and Craniofacial Research (NIDCR)

NIDCR is interested in identification and initial biological, analytical and clinical validation of pain biomarkers, biomarker signatures, and endpoints for painful disorders of the orofacial region including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain, and other conditions. Investigators are encouraged to contact NIDCR program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

The NIDDK encourages applications that identify and develop candidate biomarkers, biomarker signatures or endpoints for acute or chronic pain in children, adolescents, and adults with diabetic neuropathy; pancreatitis, irritable bowel syndrome, and other gastrointestinal diseases; and kidney and lower urinary tract symptoms.

National Institute on Drug Abuse (NIDA)

NIDA is interested in research topics identified in this FOA under acute or persistent pain conditions, especially where such markers might inform the better use or non-use of opioids. NIDA is also interested in pain biomarkers in people in acute or persistent pain who have, or who are vulnerable to, substance use disorders.

National Institute of Neurological Disorders and Stroke (NINDS)

The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. NINDS is dedicated to achieving this mission bysupporting and performing basic, translational, and clinical neuroscience research through grants-in-aid, contracts, scientific meetings, and through research in its own laboratories, and clinics.

NINDS is interested in the discovery and development of robust, fit for purpose biomarkers, biomarker signatures and endpoints that will facilitate the development of non-addictive therapeutics for pain related to disorders within the mission of NINDS.

National Institute of Nursing Research (NINR)

The mission of the National Institute of Nursing Research (NINR) is to promote and improve the health of individuals, families, and communities. To achieve this mission, NINR supports and conducts clinical and basic research and research training on health and illness, research that spans and integrates the behavioral and biological sciences, and that develops the scientific basis for clinical practice.

NINR is interested in biomarkers for the assessment of pain that can improve clinical diagnoses. Areas of specific interest include but are not limited to:

• Biomarkers as objective indicators of the sensory characteristics, e.g., pain severity, intensity, and the temporal patterns of pain

• Biomarker composites of the immune, metabolic, neuroendocrine systems that inform evaluation of the chronic pain experience

• Biomarkers to assess chronic pain reduction/exacerbation that align with patient-reported outcomes

National Library of Medicine (NLM)

The National Library of Medicine supports research into new methods and approaches in the areas of biomedical informatics and data science, including modeling, visualization, analysis, organization and curation of biomedical data, information and knowledge. For this FOA, NLM is interested in novel informatics, computational and statistical methods that can benefit the discovery phase or prepare for validation phase activities, such as approaches that will (1) enhance the process of biomarker and endpoint detection; (2) validate detection methods, (3) automate the assignment of metadata or annotations to research data; (4) generate appropriate synthetic data to balance data gaps or bias in data sets.

Office of Behavioral and Social Sciences Research (OBSSR)

While the Office of Behavioral and Social Sciences Research (OBSSR) does not accept assignment nor manage NIH grants, the Office does provide co-funding support to NIH Institutes and Centers for grants that may come in under this announcement and that meet the mission of OBSSR. Of specific interest to OBSSR are applications that utilize behavioral outcomes as clinical manifestations for the clinical validity of the biomarkers.

Office of Research on Women’s Health (ORWH)

The Office of Research on Women’s Health (ORWH) is part of the Office of the Director of NIH and works in partnership with the 27 NIH Institutes and Centers to ensure that women's health research is part of the scientific framework at the NIH, and throughout the scientific community.

Opioids, both illegal (e.g., heroin, illicitly manufactured synthetic opioids) and legal (e.g., oxycodone, hydrocodone) are drugs that reduce the body’s perception of pain. Given the higher prevalence of pain disorders in females and their greater sensitivity to pain, there is a crucial need to recruit women into pain and opioid-related clinical research in sufficient numbers to determine sex-specific responses as well as sex differences in opioid use, misuse, and overdose. It is critical to address sex influences in basic science research on pain neurobiology and pathology, and in translational, interdisciplinary, behavioral, clinical, and/or health services research relevant to women's health, and, where appropriate, the use of both sexes to better understand the influence of sex as a variable on health and disease.

Integrating the purposeful accounting for sex as a biological variable (SABV) in biomedical research on pain, from the most basic to the clinical and applied efforts, will fill gaps in our knowledge, will inform more effective, personalized approaches to control pain acquisition, tolerance and effect pain resolution for women and men.

National Center for Complementary and Integrative Health (NCCIH)

The National Center for Complementary and Integrative Health (NCCIH) will support research on the discovery of biomarkers, biological signatures for clinical endpoints, and preliminary clinical validation of biomarkers for acute or chronic pain conditions, including chronic low back pain, that are treated with complementary and integrative health approaches. Examples of complementary and integrative health approaches include, but are not restricted to, acupuncture, manual therapy, meditation, hypnosis, yoga, Tai Chi, music interventions, light therapy, other psycho-behavioral or device approaches, herbal products, dietary supplements, special diets, probiotics, or a combination of any of these therapies with each other or with conventional pharmacological therapies.

Investigators are encouraged to form collaborations with individuals knowledgeable in bioinformatics, statistical analysis, detection technology development and analytical validation, tissue source standardization, pain biology and physiology, clinical experience appropriate for the type of biomarker, as well as those familiar with the ultimate goal of a successful project for this FOA, which is to have a robust candidate biomarker or endpoint that is ready for a rigorous prospective clinical validation process that is appropriate for the Context of Use of that biomarker or endpoint.

Leveraging Existing Research Resources

Applicants are strongly encouraged to leverage existing research resources for their studies whenever possible. Such resources may include tissue, cellular, or DNA samples from NINDS BioSEND (https://www.biosend.org/) or other existing biospecimen, imaging and data repositories. The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources from NINDS funded studies that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. Leveraging the resources and support from pain advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged. Studies are also encouraged that leverage the resources of ongoing clinical trials supported through other Federal or private funds.

Project Milestones

A project timeline including milestones is a required component of the application (see Section IV.2). Milestones are quantitative goals that can be used for go/no-go decision making as the project advances from the R61 to the R33 phase, and therefore should have quantitative criteria associated with them. All milestones should be useful as a measure of progress toward the overall goal of the project. A list of activities planned for each phase are not considered milestones because they do not provide decision-making goals. Milestones will provide clear indicators of a project's continued success or emergent difficulties. Progress toward achievement of milestones will be evaluated by NIH Program Staff, and funding for the project may be discontinued if milestones are not met. Some examples of goals that could be addressed in milestones for this FOA are presented in Section I, Phase Award Mechanism and Transition to R33.

The NIH Program Official will contact the applicant to discuss the proposed milestones prior to the award. The Program Official and Project Scientist will discuss with the Program Director(s)/Principal Investigator(s) any recommended changes to the research plan or suggestions from peer reviewers, and the plan will be revised as appropriate prior to the award.

Pre-Application Consultation

Applicants are strongly encouraged to consult with NIH Scientific/Research Staff early on during the planning for an application. This early contact will provide an opportunity to discuss and clarify NINDS policies and guidelines, including the scope of project relative to the NINDS mission and intent of this FOA. These discussions also provide important information on how to develop an appropriate timeline and milestone plan, which are subject to peer review under this program.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

Applications should include an Intellectual property (IP) strategy. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials.

• Applicants should describe the IP landscape surrounding their biomarker, biomarker signature or endpoint and its measurement. Applicants should describe any known constraints that could impede biomarker or endpoint development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar biomarkers that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program. If the applicant proposes using an agent(s) whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should include a letter (see letter of support) from any entities owning the IP indicating there will not be any limitations imposed on the studies or the project which would impede achieving the goals of the funding program.

• If patents pertinent to the biomarker being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable.

• Applicants should discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved.

All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims:

Within the Specific Aims section, include headers titled R61 Phase Specific Aims and R33 Phase Specific Aims. Under each header, state the specific objectives of the efforts. Briefly provide the context for the proposed set of studies, with an emphasis on the biological research rationale for the biomarker or endpoint, along with a cogent argument outlining its importance and unmet need. In addition, the major objectives of the proposed study should be stated, including the technical questions to be answered to further develop and validate the biomarker or endpoint.

Research Strategy:

The Research Strategy Section should include the following sections:

1. Rationale and Unmet Need

• Define the pain condition to be addressed and the unmet need for therapeutics in the specific area.

• Provide a strong biological rationale that supports the scheme for discovery of the putative biomarker, biomarker signature or endpoints.

• Describe the possible methods of detection for the biomarker, biomarker signature or endpoints and address the feasibility of this method of detection for use in Phase II and Phase III clinical trials.

• Define the intended clinical context of use for the biomarker, biomarker signature, or endpoint and its detection method. Include information on characteristics of the sample (i.e., specimen, image, EEG, behavioral or physiological endpoint) to be used for the measurement and how the measurement result will be used.

• If applicable, provide a comparison to other biomarker or endpoint approaches for the specified pain condition, discussing the advantages of the proposed biomarker approach and addressing the unmet need for a biomarker.

• Describe the potential for the proposed studies to significantly advance translational medicine in the pain indication area described.

• Address the probability for the biomarker, biomarker signature, endpoint and its detection method to be broadly adopted by the health care community for use in treatment or prevention.

2. Preliminary Data

• Provide a clear outline of the preliminary data supporting the biological rationale for the discovery scheme of the new biomarker, biomarker signature, or endpoint. Describe the overall strengths, weaknesses, and rigor of the preliminary data.

• Provide any existing natural history data that is relevant to the biomarker, biomarker signature, or endpoint discovery scheme.

• Provide data addressing the feasibility and utility of any existing detection method or biomarker that is related to the proposed discovery scheme.

• Provide the preliminary rationale for Context of Use.

3. Approach - address each of the items below.

Plans to obtain standardized samples and to assure a rigorous experimental design for sample collection, plans for bioinformatic and/or statistical analysis or deconvolution of data leading to initial biomarker identification, plans for initial proof of concept and validation, and plans for development and validation of the detection technology. Examples of activities comprising the above plans could include but are not limited to:

• Plan to ensure appropriate standardization of samples and data that are used in the biomarker or endpoint identification and early validation process

• Bioinformatics and statistical designs for analysis or deconvolution of sample data and refinement of biomarker identity

• Plans to obtain proof of concept for biomarker, biomarker signature or endpoint using clinical samples or measures

• Biomarker detection methodology development and validation approach

• Plan for resolution of pre-analytic variables in detection method

• Plan for evaluation of (i) Accuracy, (ii) Precision, (iii) Analytical sensitivity, (iv) Analytical specificity including interfering substances, (v) Reportable range of test results for the test system, (vi) Reference intervals (normal values) with controls and calibrators, (vii) Harmonization of analytical performance if the assay is to be performed in multiple laboratories, (viii) Establishment of appropriate quality control and improvement procedures, (ix) Any other performance characteristic required for test performance with determination of calibration and control procedures

• If biomarker identification and initial proof of concept are based on animal data, outline the approach for translation to human pathophysiology, target engagement or prediction of response to an intervention

• Approach for initial clinical validation of the biomarker or endpoint

• Plan for refinement and development of biomarker or endpoint or for the context of use

4. Timeline and Proposed Milestones (required)

• Transition from the R61 to the R33 phase is contingent upon the successful completion of one set of proposed milestones. The specific milestone(s) proposed in the application will depend on the goals of the application and the accomplishments necessary in the R61 phase for advancement into the R33 phase. Milestones and timelines must be provided under a separate, specific heading at the end of the Research Strategy Section, and will be evaluated as part of the scientific and technical merit of the R61/R33 application.

• Milestones should be proposed for completion at the end of the R61 phase. Quantitative milestones are required to provide clear indicators of a project's feasibility, continued progress or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of the R33 phase.

• Please see Project Milestones section above for guidance in writing Go-No Go, quantitative milestones.

• Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal. Indicate when it is anticipated that essential components of the project will be completed. The proposed timeline with specific milestones should be clearly delineated and should appear as the last element of the Research Strategy section.

• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

Team Management Plan:

• Applicants are strongly encouraged to form multidisciplinary teams that consist of bioinformatics and statistical experts, technical experts with experience relevant for the detection method, clinical scientists, clinicians with drug development experience, regulatory experts, statisticians, and other academic/industry experts relevant to the therapeutic modality. Describe the team's ability to design the details of the plans and experiments, and to execute the research strategy.

• Describe how the team will work together (e.g., data generation, reporting of data and integrated review across teams with various disciplines, decision-making, etc.) over the course of the project (and include letters of support below). This description should include an outline of roles and responsibilities for each team member.

Letters of Support:

• Applicants should include letters of support from consultants, contractors, and collaborators.

• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.

• If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.

• If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) will be needed and in place once the project is funded. This letter should come from a high official within the private entity who has authority to speak on these issues.

• If an application plans to utilize the infrastructure or resources of existing projects, whether funded by the NINDS, other governmental or non-governmental entities, letters of support detailing the terms of collaboration and data sharing must be included.

• If utilization of extant samples is proposed as a component of the study, letters of support or approval for use of those samples should be included.

• For-profit applicants must include a letter(s) of support confirming that the required secured cost matching (cash; in-kind commitments such as salary, consultant costs, equipment) is available and confirm that the essential personnel have the authority within the organization to allocate resources.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions: All instructions in the SF424 (R&R) Application Guide must be followed. Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy. Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials. For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed. For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable.

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research. Specific to this FOA How likely is it that the plans for cost matching will be adequate?

Not Applicable eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267 Diane St. Germain, RN, MS
National Cancer Institute )NCI)
Telephone: 240-276-7082
Email: dstgermain@mail.nih.gov

Houmam Araj, PhD
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: Houmam.Araj@nih.gov

Harvey Luksenburg, M.D.
National Hearth, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0080
Email:luksenburgh@nhlbi.nih.gov

Coryse St. Hillaire-Clarke, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-827-6944
Email: coryse.sthillaire-clarke@nih.gov

Soundar Regunathan, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-1192
Email: regunathans@mail.nih.gov

Charles Washabaugh, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5055
Email: washabac@mail.nih.gov

Tatjana Atanasijevic, PhD
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301 451 6873
Email: atanasijevict@mail.nih.gov

Susan Marden PhD RN
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6838
Email: mardens@mail.nih.gov

Yolanda F. Vallejo, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4655
Email: yolanda.vallejo@nih.gov

Teresa L.Z. Jones, MD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-435-2996
Email: Teresa.jones@nih.gov?

Yu (Woody) Lin, MD, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1318
Email: ylin1@nida.nih.gov

Mary Ann Pelleymounter, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: mary.pelleymounter@nih.gov

Julia Bachman, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: Julia.Bachman@nih.gov

Michelle R.J. Hamlet, Ph.D.
National Institute of Nursing Research (NINR)
Telephone: 301-496-9623
Email: Michelle.hamlet@nih.gov

Hua-Chuan Sim, MD
National Library of Medicine (NLM)
Telephone: 301-594-4882
Email: simh@mail.nlm.nih.gov

Jane C. Atkinson, DDS
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-827-6031
Email: jatkinso@mail.nih.gov

Wen G. Chen, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-451-3989
Email: Chenw@mail.nih.gov

Rajeev K. Agarwal, Ph.D.
Office of Research on Women's Health (ORWH)
Telephone: 301-402-1770
Email: Rajeev.Agarwal@nih.gov

Joseph Rudolph, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-408-9098
Email: josephru@mail.nih.gov Tijuanna DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@mail.nih.gov Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.