The overarching purpose of this Funding Opportunity Announcement (FOA) is to promote the discovery of strong candidate biomarkers and endpoints for pain that can be used to facilitate the development of non-opioid pain therapeutics from discovery through Phase II clinical trials. Specifically, the focus of this FOA is on the identification and initial biological, analytical and clinical validation of pain biomarkers, biomarker signatures, and/or endpoints. Although research supported by this FOA can include animal studies, it must also include preliminary human validation research using carefully standardized human samples or human clinical studies. The goal of this initiative is to deliver candidate biomarkers, biomarker signatures, and/or endpoints that are ready for advanced clinical and analytical validation research.
This FOA is part of the NIH HEAL (Helping to End Addiction Long-term) Initiative—an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis.
More than 25 million Americans suffer from chronic pain, a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an overreliance on opioids for chronic pain despite their poor ability to improve function. This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative treatment options are thus critically needed.
The challenges facing the development of non-opioid alternative pain medications include: a lack of reliable measures of pain biology and perception, a difficult regulatory path with high safety and labeling hurdles, poor predictive power of preclinical models, and a paucity of validated targets. In addition, patient populations are heterogeneous across multiple pain conditions, with high variability in individual responses to intervention.
One potential solution toward accelerating the discovery and development of alternative pain therapies is the use of objective biomarkers and endpoints that could define pathophysiologic subsets of pain, evaluate target engagement of a therapeutic and predict analgesic efficacy of new therapeutics. Unfortunately, there are very few validated biomarkers available that provide the information described above. Therefore, the goal of this FOA is to promote the discovery of promising candidate biomarkers, biomarker signatures and endpoints for pain indications that will withstand rigorous validation and ultimately provide the tools necessary for the development of non-opioid therapeutics for the treatment of pain conditions.
Public Law 115-141, the Consolidated Appropriations Act of 2018 (signed March 23, 2018) includes a requirement that grantees from for-profit applicant organizations must provide a 50% match and/or in-kind contribution of all federally awarded dollars under the grant award (direct costs, as well as facilities and administrative costs) for research related to opioid addiction, development of opioid alternatives, pain management and addiction treatment.
Matching Requirement: A grantee from a for-profit organization funded under this funding opportunity announcement must match funds or provide documented in-kind contributions at a rate of not less than 50% of the total-Federally awarded amount, as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018.The applicant will be required to demonstrate that matching funds and/or in-kind contributions are committed or available at the time of, and for the duration of, the award. Applications must identify the source and amount of funds proposed to meet the matching requirement and how the value for in-kind contributions was determined. All matching funds and/or in-kind contributions must be used for the portion of allowable project costs not paid by Federal funds under the grant award. NIH will not be the recipient, nor serve as a pass-through entity, of any such matching funds and/or in-kind contributions required under this announcement. See 45 CFR 75.306 for additional details.
Biomarker and Endpoint Development
A biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions. A biomarker signature is a combination of multiple variables to yield a patient-specific indicator of normal biological processes or responses to an exposure or intervention including therapeutic interventions. Biomarker modalities are diverse, and can include genetic, protein, cellular, metabolomic, imaging, behavioral, and physiologic endpoints.
An endpoint is an outcome or event used to objectively measure the effect of a therapeutic or other intervention being studied. A precise definition of an endpoint typically specifies the type of assessments made, the timing of those assessments, the assessment tools used, and possibly other details, as applicable, such as how multiple assessments within an individual are to be combined.
The biomarker and endpoint development process begins with the Discovery phase, where initial identification and preliminary proof of concept studies of the potential biomarker and endpoint are conducted. The samples used must be from sources that are carefully standardized and annotated. Biomarker and endpoint detection technology is also developed during the Discovery phase. The identification of biomarkers and endpoints that reflect altered pain modulation and sensitivity; altered brain, spinal cord, or nerve function; altered behavior; and phenotypic characteristics of pain conditions are as important as metabolomic, proteomic and genomic indicators of pain. The biomarker and endpoint discovery phase also includes preliminary validation studies, such as initial analytical validation of the detection method along with studies designed to correlate modulation of the biomarker or endpoint with disease pathology, target engagement or response to an intervention. This funding opportunity supports the Discovery Phase.
The next phase of biomarker and endpoint development is the Validation phase, where analytical validation of the assay or detection technology is completed, along with increasingly rigorous clinical validation studies. The degree of evidence required to provide the necessary confidence in biomarker or endpoint validation depends upon the context of use for the biomarker or endpoint. As the context of use moves from research to accepted utility in clinical practice (i.e., as a diagnostic or predictor of therapeutic response), the required degree of validation evidence is increased and must include prospective, multi-site validation data. Note that the scope of this FOA includes initial analytical validation, and early clinical validation. It does not include the extensive validation activities described above, such as prospective, multi-site clinical studies. For other funding opportunities supporting analytical and clinical validation, please see PAR-18-548, PAR-18-549, PAR-18-550 and PAR-18-664.
Phased Award Mechanism and Transition to R33
This funding opportunity uses a R61/R33 Phased Innovation Award mechanism. The R61 phase will support proof of concept studies including activities such as sample collection, biomarker or endpoint identification, biomarker or endpoint detection method development, preliminary analytical validation of the detection method and correlational studies to define the association between the biomarker or endpoint with disease pathology, target engagement or response to an intervention. Examples of activities supported in the R33 phase can include more extensive analytical and/or biological validation and must include at least initial validation research using human samples or measures from human subjects. Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed milestones. The milestones should be clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the R61 phase. Milestones could address, for example, 1) The desired magnitude and reliability of the association between the biomarker or endpoint and disease pathophysiology, target engagement or responses to an intervention in preliminary animal studies or studies with human samples, 2) Desired precision, accuracy and dynamic range of the biomarker/endpoint detection method, and/or 3) Feasibility of biomarker/endpoint measurement.
Applications to this FOA must propose a research plan designed to discover a biomarker, biomarker signature or endpoint that that will inform the diagnosis, prognosis, or development of non-opioid therapies for pain. The biomarker or endpoint should reflect pain pathophysiology, target engagement of a therapeutic intervention or response to a therapeutic intervention. Biomarker or endpoint discovery includes activities such as biomarker or endpoint identification, detection method development, analytical validation of the detection method and preliminary clinical validation using standardized samples or measures from human subjects. A separate FOA will be made available for later stage, multi-center validation studies.
The definitions of the terms analytical validation, clinical validation and context of use are provided below for the purposes of this FOA:
- Analytical Validation: Establishing that the performance characteristics of a measurement are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include sample collection and standardization procedures). Although the goal of analytical validation is to ensure a rigorous clinical conclusion, the level of analytical rigor that is necessary depends upon the characteristics of the biomarker, the detection technology, the type of clinical question (exploratory/informational) or its intended use as a biomarker (diagnostic, predictive, pharmacodynamic, etc.). Analytical validation establishes the measurement’s technical performance, but does not validate the usefulness of the measurement.
- Clinical Validation: Establishing that the biomarker acceptably identifies, measures or predicts the concept of interest.
- Context of Use (COU): A statement that fully and clearly describes the way the biomarker is to be used and the biomarker-related purpose of the use. Considerations involved in defining the COU can include: biomarker modality and method of detection, clinical population characteristics, unmet need for the new biomarker and type of biomarker (response prediction, stratification, prognostic, diagnostic, target engagement, etc). Context of use statements are discussed extensively in the following link: https://fnih.org/sites/default/files/final/pdf/Evidentiary%20Criteria%20Framework%20Final%20Version%20Oct%2020%202016.pdf
Use of the BEST (Biomarkers, EndpointS, and Other Tools Resource) standardized biomarker definitions (https://www.ncbi.nlm.nih.gov/books/NBK338448/) is required for all studies.
- Biological rationale:Projects should be supported by a cogent biological rationale supporting the candidate biomarker, biomarker signature, or endpoint as well as a discussion regarding its unmet need. The biological rationale should include rigorously obtained evidence that the proposed biomarker, biomarker signature, or endpoint concept may be an indicator of normal biological processes, potential susceptibility or risk, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.
- Relevance for pain therapeutic development: Projects should address the relevance of the candidate biomarker, biomarker signature, or endpoint for pain therapy development or clinical practice.
The biomarker, biomarker signature, or endpoint must be focused on a pain condition.
Examples of pain biomarker, biomarker signature, or endpoint Discovery studies and activities that are responsive to this FOA include but are not limited to:
- Identification of biomarkers or signatures of the transition from acute to chronic pain
- Identification of biomarkers or signatures indicating alternations in reward systems that are indicative of the affective components of pain
- Identification of biomarkers or signatures for longitudinal characterization and prognosis of persistent pain or chronic pain
- Identification of a pain biomarker or signature in individuals with different vulnerabilities to opioid use disorder (OUD)
- Development of biomarkers in animal models of pain that could be measured in humans
- Identification and initial validation of a potential pain biomarker
- Identification and procurement of sample sources necessary for biomarker discovery and assurance of source standardization and annotation
- Identification and validation of objective pain endpoints
- Comprehensive set of biomarker discovery studies designed to identify a set of mechanistic markers associated with diverse pain conditions, including identification of combined biomarkers that form a “signature” for the selected pain condition
- Bioinformatics and/or statistical approaches to support biomarker identification
- Development and analytical validation of biomarker detection or measurement technology. The goal for analytical validation should be that the biomarker measurement meetsFDA analytical performance criteria (https://www.fda.gov/downloads/drugs/guidances/ucm368107.pdf) within the scope of the intended Context of Use
- Analysis and resolution of pre-analytical variables included in the detection technology or biomarker measurement technology
- Proof of concept studies using human tissue, biofluids or imaging samples to confirm biomarker identification obtained using animal tissue sources
- Preliminary clinical validation studies to confirm biomarker identification
Analytical Validation can include the following metrics, with use of FDA guidance standards appropriate for the context of use:
- Analytical sensitivity
- Analytical specificity including interfering substances
- Reportable range of test results for the test system
- Reference intervals (range of normal values) with controls and calibrators
- Harmonization of analytical performance if the assay or method of detection is to be performed in multiple laboratories
- Establishment of appropriate quality control and improvement procedures
- Any other performance characteristic required for test performance with determination of calibration and control procedures.
Preliminary Clinical Validation can include the following metric with use of FDA guidance standards appropriate for the context of use:
- Demonstration of association of the result of the biomarker assay with a clinical endpoint (e.g., response to a therapeutic, target engagement, pain pathophysiology or clinical manifestation) in samples or data from patients that have been exposed to a uniform intervention or that have or will develop a disease or disorder
Examples of studies that are not responsive to this FOA
- Natural history studies aimed at understanding disease pathophysiology, genetic, or epigenetic mechanisms in the absence of biomarker identification, development of detection technology and early validation
- Biomarker identification or validation based only on animal data without confirmation using human tissue sources or preliminary clinical validation
- Use of non-standardized sample sources
- Large, prospective design clinical validation studies
- Prospective design clinical utility studies
- Therapeutic target validation and development
- Preclinical animal studies without a transition to studies involving human samples or data
- Development of candidate therapeutics
- Biomarker discovery outside non-addictive therapeutic options to pain conditions
Considerations for clinical trials
This FOA supports the discovery of biomarkers that indicate pharmacodynamic responses to pain therapeutics, that predict an efficacy or safety response to a pain therapeutic or that can be used to monitor a therapeutic response to a pain therapeutic.Thus while the studies outlined in an application may be defined as clinical trials, and may make measurements in patients on specific therapies, they should not seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, and/or clinical intervention and management.
Studies focused on examining biomarker clinical validation and evaluation of utility in clinical practice of biomarkers may be more appropriate for PAR-18-664. Prospective applicants are encouraged to discuss project suitability for this FOA with the NINDS Scientific/Research Contact listed in the Agency Contacts section below.
NIH Institute and Center Interests and Guidance
National Cancer Institute (NCI). 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). 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). 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). NIA encourages applications that identify and develop candidate biomarkers, biomarker signatures or endpoints for acute or chronic pain in midlife or older age, particularly in older adults with neurodegenerative diseases or multiple morbidities.
National Institute on Alcohol Abuse and Alcoholism (NIAAA). It will be useful to incorporate coexisting behavioral aspects such as chronic alcohol use/abuse in pain biomarkers discovery as chronic pain does not exist in isolation. Individual differences exist in people susceptible to comorbid chronic pain and alcohol-misuse in terms of pain sensitivity, tolerance and withdrawal mechanisms. Developing and validating biomarkers/biomarker signatures that can be used to subgroup individuals and to predict those who are likely to respond specifically to different treatments is critically needed. These biomarkers should be validated as diagnostic markers for comorbid alcohol abuse in various pain and emotional dysregulation conditions and used to develop new treatments and monitor clinical outcomes.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). NIAMS has interests related to the discovery and preliminary validation of candidate biomarkers, biomarker signatures or endpoints with focus on areas such as pain related back pain that includes both lower and upper regions, osteoarthritis, other chronic MSK diseases/disorders, post-operative total joint replacement pain, chronic rheumatic and skin diseases and other diseases/conditions within the mission of NIAMS.
National Institute of Biomedical Imaging and Bioengineering (NIBIB). The mission of NIBIB is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating engineering with the physical and life sciences to advance basic research and medical care. One way that this is achieved is through the support of research and development of new biomedical imaging and bioengineering tools and technologies to improve the prevention, detection, treatment, and monitoring of disease. Among the topics of special interest is the development of new in vitro platforms for biomarker discovery in human tissues. NIBIB will only support applications proposing early-stage clinical trials through Phase I, first-in-human, safety, feasibility, or other small clinical trials that inform the early-stage technology development in the submitted application. NIBIB will not support applications proposing Phase II, III, IV or pivotal clinical trials, or trials in which the primary outcome is efficacy, effectiveness, or a post-market concern.
National Institute for Child Health and Development (NICHD). NICHD will support research on the following biomarker research: 1) Development of biomarkers identifiable using biological materials obtained through non-invasive methods: saliva, sweat, urine/stool, hair, and the placenta/fetal membranes after delivery, 2) Biomarkers for pregnant women whose fetuses may be undergoing invasive procedures (e.g., fetal surgery, 3) Identification and validation of pain biomarkers for individuals who cannot verbalize their pain including infants, critically ill and severely injured children and children with substantial neurocognitive delay and/or compromise, 4) Identification of biomarkers in children with chronic as well as acute pain conditions, 4) Identification, discovery, and validation (for clinical applicability) biomarkers and endpoints that have therapeutic potentials for treating pediatric or obstetric pain, 5) Identification of biomarkers for gynecologic pain syndromes including chronic pelvic pain, dysmenorrhea, and vulvodynia, 6) Identification and validation of biomarkers specifically relevant to individuals with neuromuscular conditions, neuropathic pain, musculoskeletal pain, or pain generated by spinal cord injury or amputation, 7) Validation of biomarkers that detect change due to non-pharmacologic interventions such as physical therapy, acupuncture, or other integrative medicine approaches.
National Institute of Dental and Craniofacial Research (NIDCR). NIDCR is interested in identification and initial biological, analytical and clinical validation of pain biomarkers, biomarker signatures, and endpoints for painful disorders of the orofacial region including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain, and other conditions. Investigators are encouraged to contact NIDCR program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NIDDK encourages applications that identify and develop candidate biomarkers, biomarker signatures or endpoints for acute or chronic pain in children, adolescents, and adults with diabetic neuropathy; pancreatitis, irritable bowel syndrome, and other gastrointestinal diseases; and kidney and lower urinary tract symptoms.
National Institute on Drug Abuse (NIDA). NIDA is interested in research topics identified in this FOA under acute or persistent pain conditions, especially where such markers might inform the better use or non-use of opioids. NIDA is also interested in pain biomarkers in people in acute or persistent pain who have, or who are vulnerable to, substance use disorders.
National Institute of Neurological Disorders and Stroke (NINDS). The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. NINDS is dedicated to achieving this mission bysupporting and performing basic, translational, and clinical neuroscience research through grants-in-aid, contracts, scientific meetings, and through research in its own laboratories, and clinics. NINDS is interested in the discovery and development of robust, fit for purpose biomarkers, biomarker signatures and endpoints that will facilitate the development of non-addictive therapeutics for pain related to disorders within the mission of NINDS.
National Institute of Nursing Research (NINR). The mission of 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). NLM 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). 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). 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). NCCIH will support research on the discovery of biomarkers, biological signatures for clinical endpoints, and preliminary clinical validation of biomarkers for acute or chronic pain conditions, including chronic low back pain, that are treated with complementary and integrative health approaches. Examples of complementary and integrative health approaches include, but are not restricted to, acupuncture, manual therapy, meditation, hypnosis, yoga, Tai Chi, music interventions, light therapy, other psycho-behavioral or device approaches, herbal products, dietary supplements, special diets, probiotics, or a combination of any of these therapies with each other or with conventional pharmacological therapies. Investigators are encouraged to form collaborations with individuals knowledgeable in bioinformatics, statistical analysis, detection technology development and analytical validation, tissue source standardization, pain biology and physiology, clinical experience appropriate for the type of biomarker, as well as those familiar with the ultimate goal of a successful project for this FOA, which is to have a robust candidate biomarker or endpoint that is ready for a rigorous prospective clinical validation process that is appropriate for the Context of Use of that biomarker or endpoint.
Leveraging Existing Research Resources
Applicants are strongly encouraged to leverage existing research resources for their studies whenever possible. Such resources may include tissue, cellular, or DNA samples from NINDS BioSEND (https://www.biosend.org/) or other existing biospecimen, imaging and data repositories. The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources from NINDS funded studies that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. Leveraging the resources and support from pain advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged. Studies are also encouraged that leverage the resources of ongoing clinical trials supported through other Federal or private funds.
A project timeline including milestones is a required component of the application (see Section IV.2). Milestones are quantitative goals that can be used for go/no-go decision making as the project advances from the R61 to the R33 phase, and therefore should have quantitative criteria associated with them. All milestones should be useful as a measure of progress toward the overall goal of the project. A list of activities planned for each phase are not considered milestones because they do not provide decision-making goals. Milestones will provide clear indicators of a project’s continued success or emergent difficulties. Progress toward achievement of milestones will be evaluated by NIH Program Staff, and funding for the project may be discontinued if milestones are not met. Some examples of goals that could be addressed in milestones for this FOA are presented in Section I, Phase Award Mechanism and Transition to R33.
The NIH Program Official will contact the applicant to discuss the proposed milestones prior to the award. The Program Official and Project Scientist will discuss with the Program Director(s)/Principal Investigator(s) any recommended changes to the research plan or suggestions from peer reviewers, and the plan will be revised as appropriate prior to the award.
Applicants are strongly encouraged to consult with NIH Scientific/Research Staff early on during the planning for an application. This early contact will provide an opportunity to discuss and clarify NINDS policies and guidelines, including the scope of project relative to the NINDS mission and intent of this FOA. These discussions also provide important information on how to develop an appropriate timeline and milestone plan, which are subject to peer review under this program.
Deadlines: November 27, 2018; March 7, 2019; November 25, 2019; March 12, 2020 (letters of intent are due 30 days prior to deadline)
Filed Under: Funding Opportunities