Participating Organization(s)
National Institutes of Health (NIH)
Components of Participating Organizations
National Institute of Neurological Disorders and Stroke (NINDS)?

National Cancer Institute (NCI)
National Eye Institute (NEI)
National Heart, Lung, and Blood Institute (NHLBI)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute on Drug Abuse (NIDA)
National Institute of Nursing Research (NINR)
National Library of Medicine (NLM)
National Center for Complementary and Integrative Health (NCCIH)

Office of Behavioral and Social Sciences Research (OBSSR)

Office of Research on Women’s Health (ORWH)

Funding Opportunity Title
Analytical and/or Clinical Validation of a Candidate Biomarker for Pain (R61/R33 Clinical Trial Optional)
Activity Code
R61/R33 Exploratory/Developmental  Phased Award
Announcement Type
New
Related Notices
Funding Opportunity Announcement (FOA) Number
RFA-NS-18-046
Companion Funding Opportunity
RFA-NS-18-041, R61/R33 Discovery of Pain Biomarkers FOA
Catalog of Federal Domestic Assistance (CFDA) Number(s)
93.393, 93.399, 93.867, 93.837, 93.838, 93.839, 93.233, 93.840, 93.847, 93.866, 93.273, 93.846, 93.286, 93.865, 93.121, 93.279, 93.853, 93.361, 93.879, 93.213, 93.313
Funding Opportunity Purpose
The overarching purpose of this Funding Opportunity Announcement (FOA) is to promote the validation 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 advanced analytical and clinical validation of pain biomarkers, biomarker signatures, and/or endpoints using retrospective and/or prospective methods. It is assumed that: 1) a candidate biomarker has already been identified, 2) assay technology has already been developed, and 3) a working hypothesis regarding Context of Use is in place. Research supported by this FOA will ultimately demonstrate that biomarker or endpoint change is reliably correlated with variables such as clinical outcome, pathophysiologic subsets of pain, therapeutic target engagement or response to a pain therapeutic; in addition, biomarker response will demonstrate specificity to the pain condition or therapeutic as demonstrated at multiple clinical sites. The goal of this FOA is to facilitate the advancement of robust and reliable biomarkers, biomarker signatures and endpoints of pain to application in clinical trials (Phase II clinical trials and beyond) and in the spectrum of clinical practice. 

Posted Date
September 19, 2018
Open Date (Earliest Submission Date)
October 27, 2018
Letter of Intent Due Date(s)
30 days prior to the application due date
Application Due Date(s)
November 27, 2018; March 7, 2019; November 25, 2019; March 12, 2020 by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)
November 27, 2018; March 7, 2019; November 25, 2019; March 12, 2020 by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Scientific Merit Review
February 2019, June 2019, February 2020, June 2020
Advisory Council Review
May 2019, August 2019, May 2020, August 2020
Earliest Start Date
July 2019
Expiration Date
March 13, 2020
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
  4. Table of Contents

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to promote the validation 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 advanced analytical and clinical validation of pain biomarkers, biomarker signatures, and/or endpoints using retrospective and/or prospective methods. It is assumed that: 1) a candidate biomarker has already been identified, 2) assay technology has already been developed, and 3) a working hypothesis regarding Context of Use is in place. Research supported by this FOA will ultimately demonstrate that biomarker or endpoint change is reliably correlated with variables such as clinical outcome, pathophysiologic subsets of pain, therapeutic target engagement or response to a pain therapeutic; in addition, biomarker response will demonstrate specificity to the pain condition or therapeutic as demonstrated at multiple clinical sites. The goal of this FOA is to facilitate the advancement of robust and reliable biomarkers, biomarker signatures and endpoints of pain to application in clinical trials (Phase II clinical trials and beyond) and in the spectrum of clinical practice. 

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 difficult to manage. In recent decades, there has been an overreliance on the prescription of opioids for chronic pain, contributing 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 validation of promising candidate biomarkers, biomarker signatures and endpoints for pain indications that will ultimately provide the tools necessary for the development of non-opioid therapeutics for the treatment of pain conditions.

Biomarker 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 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 function, 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 does not support the Discovery Phase.  For funding opportunities that support the Discovery of Biomarkers and Endpoints for Pain, please see RFA-NS-18-041.

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. This funding opportunity supports the Validation Phase.

Phased Award Mechanism and Transition to R33

This funding opportunity uses a R61/R33 Phased Innovation Award mechanism. The R61 phase will support analytical validation studies, including resolution of pre-analytic confounding variables and standardization or harmonization of assays or equipment across testing sites.  The R61 phase may also support correlational studies to further define the association between the biomarker or endpoint with disease pathology, target engagement or response to an intervention. Activities supported in the R33 phase can include more extensive analytical validation across multiple sites. In addition, the R33 phase should include extensive, multi-site retrospective and/or prospective clinical studies designed to define and optimize biomarker or endpoint sensitivity and specificity consistent with the finalized Context of Use for the biomarker, biomarker signature or endpoint.

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 precision, accuracy and dynamic range of the biomarker/endpoint detection method, 2) Desired magnitude and reliability of the association between the biomarker or endpoint and disease pathophysiology, target engagement or responses to an intervention in preliminary studies with human samples or human subjects, 3) Desired magnitude of initial sensitivity and specificity for the biomarker, and 4) Desired stage of development for final Context of Use and degree of validation evidence required for the Context of Use.

Research Objectives

Applications to this FOA must include a research plan designed to validate a biomarker, biomarker signature or endpoint that that will inform the diagnosis, response to a therapeutic or evidence of target engagement of a non-addictive therapeutic 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 validation includes activities such as analytical validation of the detection method and extensive clinical validation using retrospective and prospective clinical studies of human subjects.

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

  1. 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.
  2.  Clinical Validation: Establishing that the biomarker acceptably identifies, measures or predicts the concept of interest.
  3.  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

  • Applicants should have an identified biomarker, biomarker signature or endpoint with a working hypothesis regarding Context of Use.
  • The method of detection for the biomarker, biomarker signature or endpoint should be developed, although it is understood that further optimization may occur during the validation process. Applications are not limited by biomarker type or modality, and may include validation of prognostic, predictive, monitoring, diagnostic, risk, or response biomarkers using molecular, physiological, behavioral or neuroimaging data.
  • Plans for management of pre-analytic variables, such as standardization of biofluid or tissue sample collection, harmonization of instrumentation and image collection procedures across imaging centers, etc. must be in use as further sample or data collection continues in the validation process.
  • S?upporting Data: Applications should include data from rigorously designed studies demonstrating that the candidate biomarker identifies, measures or predicts the concept of interest. If available, the application should also include data addressing initial analytical validation of the detection method. 
  • Biological rationale: Projects should be based on a cogent biological rationale supporting the candidate biomarker, biomarker signature, or endpoint as well as a discussion regarding its unmet need in the field of pain therapeutic development within the context of the specific pain condition. The biological rationale should be supported by rigorously obtained evidence that the proposed biomarker, biomarker signature, or endpoint concept may be an indicator of pain biology or pain perception, 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 therapy development in which relief of pain is a primary outcome or clinical practice for pain indications.
 

Project Characteristics

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

  • A disease, such as cancer, arthritis, or neuropathy
  • A symptom complex, such as low back pain and headache
  • A treatment-related condition, such as post-operative pain?

 Examples of pain biomarker, biomarker signature, or endpoint validation studies and activities that would be appropriate under this FOA include but are not limited to:

  • Analytical validation of detection methods where the biomarker is likely to be used as a tool in the diagnosis and treatment of pain conditions.
  • Analytical and clinical validation of tissue/biofluid, imaging, physiological or behavioral biomarkers of pain conditions.
  • Analytical and clinical validation of biomarkers involving clinical intervention such as pharmacodynamic/response biomarkers, predictive biomarkers, safety biomarkers, or monitoring biomarkers.
  • Analytical and clinical validation of biomarkers that do not involve clinical intervention such as diagnostic, prognostic, or susceptibility/risk biomarkers.
  • Studies focused on improving standardization or harmonization of assays among laboratories for use in clinical trials.
  • Continued analysis and resolution of pre-analytical variables included in the detection technology or biomarker measurement technology as part of the analytical validation process.
  • Validation studies performed at multiple testing sites to establish analytical and clinical validation of biomarkers, biomarker signatures or endpoints.
  • Clinical validation studies of the biomarker, with the goal of establishing robust correlations between biomarker and disease or therapeutic response.
  • Rigorous evaluation of the specificity and sensitivity of the biomarker, biomarker signature or endpoint in populations appropriate for the Context of Use.
  • Refinement of the Context of Use
  • Retrospective, well controlled, multi-site clinical studies using meta-analysis or multiple independent studies
  • Prospective, well controlled, multi-site clinical studies
  • Studies to characterize patient cohorts with biomarkers that will be used to stratify patients or determine inclusion/exclusion criteria in clinical trials
  • Studies designed to provide a data package suitable for US Food and Drug Administration (FDA) biomarker qualification or approval
 

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 (normal values) with controls and calibrators
  • Harmonization of analytical performance if the assay 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.
 

 Clinical Validation can include the following metrics 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., survival, response, disease presence or absence) in samples or data from patients that have been exposed to a uniform intervention or that have or will develop a disease or disorder 
  • Definition of the sensitivity and specificity of the assay result within the context of the defined clinical endpoint and clinical population 
  • Estimation of the prevalence of the marker within subjects or patients for the intended clinical context 
  • Establishment of an appropriate cut-off or threshold for the assay using appropriate statistical analysis
 

Data obtained after completion of this FOA should be appropriate for use as a component of the package required for FDA qualification or approval of the biomarker.

Qualification of Biomarkers: If biomarker qualification is the intent of the application, applicants are encouraged to collect the clinical data needed to apply to the FDA for qualification of biomarkers intended to be used in the regulatory review process.  Researchers are encouraged to initiate the qualification process with the FDA prior to submitting an application to this FOA (if biomarker qualification is the intent of the application).  A plan to obtain advice from the FDA on the development of the biomarker should be included in the application, if applicable.  The FDA provides additional information about the Drug Development Tools Biomarker Qualification Program on its website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm.

Examples of studies that are not responsive  for this FOA

  • Natural history studies aimed only at exploring disease pathophysiology, genetic or epigenetic mechanisms rather than focused on biomarker, biomarker signature or endpoint development for use in the development of non-addictive therapeutic options for the treatment of pain
  • Studies on biomarkers that are not clinically relevant to pain
  • Applications that propose animal studies 
  • Studies focused on biomarker identification and discovery for pain conditions (Please see companion FOA, RFA-NS-18-041, instead) 
  • Applications that solely focus on creating or maintaining patient registries 
  • Therapeutic target identification
  • Development or clinical testing of candidate therapeutics
  • Clinical intervention studies other than those necessary to validate biomarkers
  • Applications that request support for infrastructure to establish new clinical trial networks are beyond the scope of this FOA
 

Considerations for clinical trials

This FOA supports the validation 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. While the studies outlined in an application to this FOA may be defined as clinical trials, they should not seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, and/or clinical intervention and management.

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 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, 5) Identification, discovery, and validation (for clinical applicability) biomarkers and endpoints that have therapeutic potentials for treating pediatric or obstetric pain, 6) Identification of biomarkers for gynecologic pain syndromes including chronic pelvic pain, dysmenorrhea, and vulvodynia, 7) 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, 8) 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 analytical and clinical validation of pain biomarkers, biomarker signatures, and/or 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 for biomarkers, biomarker signatures and end-points for pain conditions within the mission of NIDDK.  Topics of special interest are: 1) Biomarkers for diabetic neuropathy that measure the disease processes related to pain in the peripheral and central nervous systems; 2)  Biomarkers for diseases of the digestive system including, but not limited to:  functional gastrointestinal and motility disorders such as gastroparesis and irritable bowel syndrome;  inflammatory bowel disease;  hepatobiliary diseases such as PSC, PBC and biliary dyskinesia;  and exocrine pancreatic diseases such chronic pancreatitis; 3) Biomarkers for urologic chronic pelvic pain syndromes including Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome; 4) Biomarkers for pain in urinary stone disease and post-ureteroscopy stent-associated pain; and 5) Biomarkers for processes, diseases and mechanisms related to pain in end-stage renal disease (ESRD) patients treated with hemodialysis or kidney transplantation.

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.  To achieve this mission, NINDS is dedicated to achieving this mission by supporting 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. For more information on receiving samples from NINDS BioSEND, please see: https://www.biosend.org/mta_receiving.html. For more information on banking samples with NINDS BioSEND, please see: https://www.biosend.org/apply_to_bank.html.

 Leveraging the resources and support from pain advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are encouraged. Studies that leverage the resources of ongoing clinical trials supported through Federal clinical networks or private funds are particularly encouraged. 

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 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 NIH policies and guidelines, including the scope of the project relative to the NIH mission and intent of this FOA. These discussions also provide important information and guidance on how to develop an appropriate timeline and milestone plan, which are subject to peer review under this program.

See Section VIII. Other Information for award authorities and regulations.

Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
New
Resubmission
Revision

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Clinical Trial?
Optional: Accepting applications that either propose or do not propose clinical trial(s)

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards
Issuing IC and partner components intend to issue 8-10 awards in 2019. Awards issued under this FOA are part of funds set aside to support the HEAL (Helping to End Addiction Long-term) initiative.
Award Budget
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period
The R61 phase can be from 1-3 years and the R33 phase can be 1-4 years, with a total project duration of no more than 5 years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

1. Eligible Applicants

Eligible Organizations

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)

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply


Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.


Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Required Registrations

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.
  • 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.

Eligible Individuals (Program Director/Principal Investigator)
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.

3. Additional Information on Eligibility

 

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

 

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

  • Descriptive title of proposed activity
  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
  • Names of other key personnel
  • Participating institution(s)
  • Number and title of this funding opportunity

The letter of intent should be sent to:

Mary Ann Pelleymounter, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-451-4551
Fax: 301-219-9346
Email: mary.pelleymounter@nih.gov

Page Limitations
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed

Instructions for Application Submission
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.
SF424(R&R) Cover
All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations
All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Other Project Information
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.

SF424(R&R) Senior/Key Person Profile
All instructions in the SF424 (R&R) Application Guide must be followed.

 

All instructions in the SF424 (R&R) Application Guide must be followed.

Cost Matching Requirement for For-profit Applicants

Cost matching or documented in-kind contributions is required for for-profit organizations responding to this FOA.  The for-profit awardee is required to match funds or provide at least a 50% matching of funds or documented in-kind contributions at a rate of not less than 50% of the for the total-Federally awarded amount (direct costs, as well as facilities and administrative costs), as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018.   

Federal funds may not be used as a source of matching funds. Generally, cost matching requirements may not be met from the following sources:

a) Costs borne by another Federal grant or sub award;

b) Costs or contributions toward cost sharing on another Federal grant, a Federal procurement contract, or any other award of Federal funds;

c) Cost of services or property financed by income earned by contractors under a contract from the recipient (or sub recipient);

(d) Program income; and

(e) Patient incentives.

The for-profit organization 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. Applicants must submit budgets that clearly document the total costs, the source and amount of matching funds, and how valuation was determined in the case of in-kind contributions, as well as the Federal and Institutional (non-Federal) components of the budget. 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.

Budget Justification: All for-profit applicants must document the matching (non-Federal) component and the federal (non-matching) component in the total project budget. That is, the requested budget plus the cost-matching budget must be detailed in tabular format to document the cost-matching (non-Federal) component and the federal (non-cost matching) component. The amount of matching is subject to adjustment based on total allowable costs incurred.  All costs and contributions used to satisfy the matching requirement must be documented by the recipient, including how the value for in-kind contributions was determined, and are subject to audit. The cost matching requirement is not negotiable for for-profit organizations.

R&R Subaward Budget
All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement
All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Research Plan
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 and the Context of Use should be stated, including the technical questions to be answered to validate the biomarker or endpoint relative to the intended Context of Use.

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 and justifies the biomarker, biomarker signature, or endpoint, along with the proposed analytical and clinical validation scheme.
  • Define the intended clinical Context of Use for the biomarker, biomarker signature, or endpoint and provide a rationale for the Context of Use.
  • Describe the method of detection for the biomarker, biomarker signature or endpoints and address the feasibility of this method of detection for eventual use in Phase II and Phase III clinical trials across multiple clinical testing sites.
  • Provide 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 pain in the context of 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 or by the clinical research community for use in clinical trials. 

?2. Supporting Data

  • Provide a clear outline of the data supporting an argument that the biomarker has been identified along with the existing evidence that it measures the clinical concept of interest.
  • Provide preliminary validation data demonstrating that the candidate biomarker identifies, measures or predicts the concept of interest.
  • Provide information about the types of specimens that the assay or detection method utilizes (e.g., fresh frozen or formalin--fixed tissue, serum or plasma or the same types of detail applicable to neuroimaging, behavioral or physiological measures), including standardization data (variables that were standardized, Ns per variable, resolution of pre-analytic variables, etc.).
  • Summarize the data supporting the feasibility of the biomarkers use in a clinical setting.
  • Discuss whether any of the analytical validation metrics listed in Section I above have been analyzed or completed; if so, provide the metrics.
  • Describe the current status of biomarker clinical validation relative to the clinical validation metrics described in Section I.

3. Approach - address the items below, as appropriate.

Plans to further refine the scientific understanding of the biomarker (its association with disease, clinical outcome or therapeutic target), its assay or method of detection, and its performance (dose response/specificity and sensitivity of response and temporal relationship of response to magnitude of biomarker change), including but not limited to:

  • Plan to assure standardized and representative clinical sample and data (imaging, physiological or behavioral) collection
  • Carefully detailed plan to complete analytical validation of the assay or method of detection, or evidence that this has already been completed
  • 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
  • Plan for further optimization and analytical validation of the biomarker detection method, including establishing threshold or cut-off for assay
  • Feasibility and readiness of the methods for measuring biofluid, tissue, imaging, behavioral, or physiological biomarkers for implementation and clinical testing across multiple sites
  • Plan to systematically extend the understanding of the association between the biomarker and the disease, clinical outcome or therapeutic target using retrospective and/or prospective multi-site clinical designs
  • 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, across multiple sites
  • Plans to extend and refine the Context of Use
  • Plan to evaluate the performance of the biomarker in a clinical setting (sensitivity and specificity of biomarker response, quantitative nature of biomarker response relative to dose, time of intervention or progression of disease, etc.) across multiple sites
  • Plan to validate the performance of the biomarker against an established measurement of pain.
  • Without duplicating data in the PHS Human Subjects and Clinical Trials Information form, provide the statistical design and analysis plans for validation activities, including plans to ensure that the study is scientifically rigorous, adequately powered for multi-site designs, appropriate randomization plans are in place to minimize bias, and that reporting is transparent.
  • Plans to address regulatory requirements needed to get the biomarker and its assay into clinical trials within its intended clinical context
  • If FDA qualification of the biomarker is under consideration, plans for FDA interactions should be described in this section.

 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 clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the R61 phase.
  • Milestones should be proposed for 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.
  •  
  • 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.
  • For clinical trial applications, applicants should include a timeline.
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 with expertise in the specified pain condition, clinicians with drug development and/or biomarker experience, regulatory experts, 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 designated 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 NIH, 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. 

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

  • All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
  • If patent protection is being sought, investigators should explain how data will be shared after filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.

Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Human Subjects and Clinical Trials Information
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:

While the studies outlined in an application to this FOA may be defined as clinical trials, they should not seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, and/or clinical intervention and management.

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form
All instructions in the SF424 (R&R) Application Guide must be followed.

 

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials
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.
In addition, the Scientific Review Officer (SRO) will accept regulatory meeting minutes and transcripts, patents, and late-breaking data not to exceed 2 pages and not later than 30 calendar days prior to the peer review meeting.

1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

This FOA supports the validation of analytical methods for biomarker, biomarker signature or endpoint measurements, including evaluation of the assay, its performance characteristics, and the optimal conditions that will generate reproducibility and accuracy consistent with FDA guidelines that are fit for the purpose of the assay.  This FOA also supports multi-site clinical validation of candidate biomarkers using retrospective and/or prospective methods or evaluation studies, with the goal of establishing robust correlations between the biomarker, biomarker signature or endpoint and the pain condition or therapeutic response to a treatment for pain.

Therefore, the potential of the proposed project to provide robust validation of a biomarker assay or method of detection, and to demonstrate that biomarker, biomarker signature or endpoint change is reliably correlated with variables such as clinical outcome, pain progression, pain onset/severity, therapeutic target engagement or response to a therapeutic is essential and will be emphasized in assessing the overall merit of the applications. It is important that the application provides evidence of unmet medical need, is supported by a strong biological rationale, includes a carefully designed plan for analytical validation of the detection technology as well as advanced clinical validation of the biomarker, biomarker signature or endpoint itself and considers feasibility in a clinical setting across multiple sites. 

In addition, for applications involving clinical trials

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Overall Impact
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).
Scored Review Criteria
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?

Further criteria specific to this opportunity: What is the potential of the candidate biomarker, biomarker signature, or endpoint to address an unmet medical need in the specified pain condition? 2) What is the strength of the biological rationale for the biomarker, biomarker signature, or endpoint? 3) What are the strength and rigor of the data supporting the rationale? 4) What is the feasibility of measurement of the biomarker, biomarker signature, or endpoint from a clinical perspective? 5) How carefully have the investigators considered the phenotype, physiology, and feasibility of measurement of the targeted clinical population in the design of their biomarker, biomarker signature, or endpoint measurement? 6) Has the investigator carefully considered plans to obtain and refine Context of Use? 7) What is the overall potential for the proposed studies to significantly advance biomarkers, endpoints, and translational medicine in the field of pain indication described?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

 

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?

Further criteria specific to this opportunity: 1) Are the investigators knowledgeable and experienced about the biological target and/or disease biology? 2) Do the investigators have sufficient expertise in the target biology, pain condition, clinical phenotype, bioinformatics, detection technology, etc. in order to design and implement a robust validation plan for the biomarker, biomarker signature, or endpoint? 3) Will the team be able to manage a multi-site analytical and/or clinical validation process for the biomarker, biomarker signature, or endpoint and/or its assay? 4) Are the roles of each collaborator carefully defined in the research plan?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

 

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?

Further criteria specific to this opportunity: 

While novelty is important, does novelty of the biomarker come at the cost of feasibility in a clinical setting?   

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

 

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?

Further criteria specific to this opportunity: 1) Have the investigators outlined a systematic approach to gaining further scientific understanding of the biomarker, biomarker signature or endpoint and its relationship to disease, response to therapeutic intervention or therapeutic target? 2) Are the plans to further optimize and validate the biomarker detection method appropriate? 3) Does the application include a plan to ensure that samples and data used for analytical validation of the assay will continue to be collected in a standardized and representative fashion? 4) Does the application include a carefully detailed plan for analytical validation of the assay or detection method or provide evidence that this has already been done?  5) How well optimized and ready for implementation in a multi-site study are the methods for measuring biofluid, tissue, imaging, behavioral or physiological biomarkers?  6) Have the investigators outlined a systematic approach to evaluating the performance of the biomarker in a clinical setting? 7) Is the proposed statistical analysis appropriate for the experimental design and the quantitative characteristics of the endpoints?  8) How well does the application describe plans to ensure that the study is scientifically rigorous, adequately powered for a multi-site design, appropriate randomization plans are in place to minimize bias, and that reporting is transparent?  9) Is there a plan to assure standardized and representative clinical sample and data (imaging, physiological or behavioral) collection? 10) Has the applicant thoughtfully considered the potential to produce a biomarker, biomarker signature or endpoint method of detection that will be feasible to implement and will meaningfully translate to human biology? 11) Will the biomarker be sufficiently validated at the end of this project to enable its use in clinical trials or clinical practice for its Context of Use? 12) Does the validation plan include comparison to an established measurement of pain?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable:


Study Design


Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?


Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?


Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?


Data Management and Statistical Analysis


Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?  

 

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?

In addition, for applications involving clinical trials:

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed? Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate? If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial? If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Additional Review Criteria
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.
Milestones and Timelines

 Are the milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions at the R61/R33 transition point? Does the set of milestones allow the  evaluation of progress in the R61 phase and will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the R33 phase and achieve its end goals within the timeline of this grant mechanism? If a criterion is not to be used for go/no-go decisions, is it justifiable? Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?

Specific to applications involving clinical trials

 Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

 

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.

Additional Review Considerations
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.
Intellectual Property

 1) Does the application outline any known constraints that could impede biomarker, biomarker signature, or endpoint development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar biomarkers or endpoints that are under patent protection and/or on the market, etc.) and how these issues could be addressed while achieving the goals of this program? 2) Does the applicant outline the IP landscape of their biomarker or endpoint and/or its method of detection? 3) If applicable, how strong is the applicant's IP portfolio/position (pertinent to the proposed project), and to what extent does the applicant have a reasonable strategy to protect its IP going forward? 4) If the applicant has filed patents pertinent to the biomarker or endpoint and/or its method of detection, do they provide details about those patents? 5) If IP will be shared among co-investigators, does the applicant provide details about the plans for IP sharing?

 

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?

2. Review and Selection Process 

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

  • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

  • Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. 

 ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/ 

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.  Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

 Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE). 

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements.  FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award.  An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS.  The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award
Not Applicable

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final Research Performance Progress Report (F-RPPR), invention statement, and the expenditure data portion of the Federal Financial Report, including Federal and non-Federal share for cost matching, are required for closeout of an award, as described in the NIH Grants Policy Statement.

Special award condition specific to this FOA: A grantee from a for-profit organization funded under this 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. See 45 CFR 75.306 for additional details. Matching funds must be non-Federal funds set aside for this project and are available from the source(s) identified in the application, as committed to by the recipient. Cost matching will be evaluated by the awarding office to ensure that this requirement is being met. Compliance with the matching requirement must be verified on an annual basis and must be documented in the annual and final FFR.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts
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

Scientific/Research Contact(s)
Ann M. O’Mara, PhD, RN, FAAN
National Cancer Institute (NCI)
Telephone: 301-496-8541
Email: omaraa@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

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

Victoria Smith, PhD 
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779 
Email: victoria.smith@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

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

Peer Review Contact(s)
Joseph Rudolph, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-408-9098
Email: josephru@mail.nih.gov
Financial/Grants Management Contact(s)
Tijuanna DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations
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.


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