Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

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.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

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 NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

The National Institutes of Health (NIH) intends to support the development of innovative quantitative measures involving myofascial tissues for pain management involving research participants using a two-phase grant funding mechanism. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://heal.nih.gov/ This notice of funding opportunity (NOFO) seeks research applications that will develop quantitative measures to facilitate the development of future biomarkers of myofascial tissues and assess their abilities to detect changes in myofascial tissues across a variety of pain management interventions, manipulations, or therapies. Promising quantitative measures may be based on minimally invasive imaging technologies, electrophysiological recordings, integration of multiparametric imaging and electrophysiology approaches, or their integration with other markers (e.g., immune factors, genomic markers, physiological factors) through multiscale modeling or machine learning analysis. The first phase, funded by the R61, will provide funding for up to 3 years to develop quantitative measures that can differentiate abnormal myofascial tissue from healthy tissues using cross-sectional correlations with clinical signs/symptoms. In addition, the R61 phase should include planning activities for the R33 phase. The second phase, funded under the R33, will support studies to assess the ability of the quantitative measures developed in the R61 phase to detect changes to myofascial tissues across a variety of pain interventions in rigorous, longitudinal clinical studies. The combined R61/R33 cannot exceed 5 years. Transition from the R61 to the R33 phase of the award will be administratively reviewed and will be determined based on successful completion of Transition Milestones that need to be clearly specified in the R61 phase application.

Diversity

In addition to scientific diversity, applicants should strive to incorporate diversity in their team development plan. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. Despite tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from diverse backgrounds, including those that are underrepresented in the biomedical, clinical, behavioral, and social sciences. Please refer to Notice of NIH's Interest in Diversity NOT-OD-20-031 for more details.

Background

Myofascial pain pain originating from muscles and/or associated soft tissues such as fascia is likely an important component of many severe and chronic pain conditions. In addition to chronic musculoskeletal disorders, there are a number of understudied chronic pain conditions in which myofascial tissues have been implicated, including temporomandibular disorders, headache, cancer-related pain, pelvic pain, pediatric pain, and diffuse pain disorders (e.g., Sickle Cell Disease Pain). Like most painful situations, myofascial pain can be managed with existing non-opioid therapies and non-pharmacologic treatments. However, evidence on which treatments are effective for myofascial pain is limited, and patients often receive treatments that are not based on high-quality scientific evidence. In addition, clinicians would like guidance on how to manage this type of pain. The field of musculoskeletal pain has largely focused on the skeletal system (bones, joints, intervertebral discs) and central nervous system (brain and spinal cord) components. The contribution of myofascial tissues, especially fascia, and the interactions of fascia, muscles, and peripheral nerves are understudied and remain mostly unknown. Many chronic musculoskeletal pain patients do not respond to surgery (targeting joint and other skeletal pathology) or develop significant side effects from pharmacotherapy including non-opioid and opioid analgesics (targeting the nervous system). In addition, it has been suggested that the patients persistent pain may be in part due to ineffective treatment of the myofascial pain component of their pain. Therefore, there is a strong need to address the contributions of myofascial tissues and their interactions with the neural and immune systems that may contribute to chronic pain, as the myofascial tissues are among the last unturned stones of all the tissue types involved in musculoskeletal pain. Specifically, identifying and developing quantitative measures involving myofascial tissues are critical for future biomarker development. Developing these measures may also lead to more effective pain management strategies through a variety of therapeutic approaches and shed light on the transition from acute to chronic pain.

Ideal biomarkers for pain management are objective measurements that are noninvasive or minimally invasive, as well as capable of monitoring the responses to and predicting the clinical outcomes of a given treatment. In the field of pain, developing such biomarkers has been challenging for two reasons: first, pain is a symptom rather than a disease; and second, pathophysiological mechanisms leading to pain are complex, heterogeneous, and still poorly understood. Nevertheless, some biomarkers have proven useful in managing some types of pain, for example pain resulting from small fiber neuropathies. For many types of pain, however, developing useful biomarkers has been difficult. This is especially true for musculoskeletal pain involving the back, neck, craniofacial complex, shoulders, hips, abdomen, pelvic floor, and extremities. For many years, structural imaging (X-rays, computed tomography [CT], magnetic resonance imaging [MRI]) of hard tissues (bones, cartilage, intervertebral discs) was the main tool to guide treatment decisions, including surgery. Over time, it became apparent that these biomarkers lacked sensitivity and specificity. Meanwhile, imaging and other objective measurements of soft tissues including muscles, and especially connective tissues or fasciae, lag far behind, and until recently, these tissues were not even considered as musculoskeletal pain biomarker candidates.

In parallel with the growing awareness of the limitations of single tissue-specific biomarkers, there has been an increasing appreciation of the neuroplastic, psychological and genetic components of pain. This led to the recognition that musculoskeletal pain is a complex, multifactorial biopsychosocial phenomenon that needs a systems approach integrating multiple types of assessment to guide both diagnosis and treatment.

One component that remains to be integrated into musculoskeletal pain models is the myofascial unit, including muscles and associated connective tissues, nerves, blood vessels and lymphatics. Recent studies in animals and humans have demonstrated that the perimuscular fascia is richly innervated with small-diameter fibers whose receptive fields increase in the presence of inflammation. In response to these studies, myofascial tissues are now receiving long-overdue attention as possible pain generators. Since the 1960s, the clinical literature has included descriptions of myofascial pain syndrome, which is currently diagnosed based on signs and symptoms, including tender and indurated nodules termed myofascial trigger points, which are detected by palpation. Myofascial pain can affect both males and females and often presents in individuals with a sedentary lifestyle combined with intermittent repetitive physical exertion. It may be focal and episodic in nature and include both active and latent phases. During the active phase, the patient complains of spontaneous pain that limits the range of motion and has localized, tender indurated foci within myofascial tissues. Palpation of these nodules reproduces the patient’s pattern of local and/or radiating pain. During the latent phase, focal palpable nodules are present and may be tender to palpation but without spontaneous pain. The latent phase also includes myofascial dysfunction, including soft tissue stiffness and reduced range of motion (not associated with pain) in the affected area. There is currently no physiological explanation for these clinical findings, nor are there quantitative measurements to differentiate active versus latent phases. Thus, it remains unclear how a patient may transition from a painless latent state to a painful and often disabling active state. Quantifying the myofascial tissue abnormalities in both latent and active states and in comparison to a healthy state is a critical prerequisite to develop clinically useful biomarkers and to optimize effective management for this prevalent and often debilitating problem. This constellation of symptoms is distinct from but may partially overlap with-- those of fibromyalgia, as patients with diffuse nociplastic pain syndromes (e.g. fibromyalgia, sickle cell chronic pain) can develop palpable myofascial trigger points.

Due to the lack of methods to objectively evaluate myofascial tissues, no quantitative measures currently exist to study myofascial tissue pathophysiology or to test the effects of treatments. It is in this context that HEAL supported the 2020 workshop on Quantitative Evaluation of Myofascial Tissues: Potential Impact on Musculoskeletal Pain Research, which demonstrated that this situation is ripe for change. Several key consensus themes emerged from this workshop, pointing to a unique and transformative research opportunity for HEAL to combat the challenges of pain management and opioid addiction. Current hypotheses discussed at the workshop on the pathophysiology underlying myofascial pain syndrome include:

For the active painful phase

• Motor endplate and or/ muscle spindle sensitization causing areas of focal persistent muscular contraction, local ischemia, acidosis and metabolic dysfunction
• Activation of nociceptors, especially within the heavily innervated perimuscular fascia
• Neurogenic inflammation and release of inflammatory cytokines in the myofascial milieu (muscle and/or fascia)

For the latent non-painful phase

• Chronic inflammation and fibrosis of the myofascial unit that may also involve peripheral nerves and muscle spindles
• Muscle atrophy, fatty infiltration, and fibrosis, causing motor weakness, abnormal (increased or decreased) muscle length and chronic muscle metabolic dysfunction
• Abnormal proprioception involving deep sensory mechanoreceptors within myofascial tissues
• Chronic segmental sensory, motor, and/or sympathetic dysfunction

The workshop outlined some specific state-of-the-art imaging technologies with some preliminary data on myofascial tissues, multiple types of technologies (e.g., imaging, electrophysiology, metabolic measurements) that have been used in musculoskeletal tissues but not yet applied to myofascial pain, and finally technologies used in other tissues (e.g., brain, liver) that could be applied to musculoskeletal tissues. There is an opportunity to harness these technologies for the development of quantitative measures of myofascial pain through a multidisciplinary approach. Since a substantial proportion of patients with non-specific musculoskeletal pain, including cancer-related pain, temporomandibular pain, and/or headache and migraine may have myofascial contributions, research on myofascial pain will potentially greatly enhance therapeutic development in all of these areas. The video recordings (Day 1and Day 2), executive summary, and detailed summary of the workshop can be found here: https://www.nccih.nih.gov/news/events/nih-heal-initiative-workshop-on-myofascial-pain. Investigating the contributions from myofascial tissues, in the context of their therapeutic potential, and identifying potential future biomarkers that can predict pain treatment responses and outcomes remain urgent unmet needs as we strive to end the opioid addiction and pain management crises in this country.

The purpose of this reissue is to identify additional measures that could inform future biomarker development from a broader range of pain conditions and pain populations, as well as support the development of new technological approaches that have the highest potential to address this unmet clinical need. The reissue of this NOFO will continue to fill a significant research gap within the HEAL pain research portfolio as well as the entire NIH pain research portfolio because myofascial pain continues to be an understudied area that has significant health and economic impacts. This NOFO also complements the ongoing HEAL Back Pain Consortium (BACPAC) Research Program, which focuses on an integrative approach to low-back pain yet does not include a myofascial tissue component, which remains a black box within the current back pain models. This NOFO intends to increase knowledge about other important pain conditions involving myofascial tissues, such as temporomandibular disorders, chronic neck and/or shoulder pain, and headache. Most importantly, by supporting the development of promising quantitative measures of myofascial tissue, this NOFO aims to accelerate and enhance the development of predictive biomarkers that can guide our choices of effective pain management and reduce opioid addiction long term.

HEAL Initiative

This NOFO is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://heal.nih.gov/.

The NIH HEAL Initiative will require a high level of coordination and sharing between investigators. It is expected that NIH HEAL Initiative awardees will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings, including an annual HEAL Investigators Meeting, as well as other activities.

Engaging People with Lived Experience and Other Collaborators:

People with lived experience (e.g., patients, patient advocates, caregivers, families, community leaders) have important insights that can improve meaningful outcomes, uptake of research findings, and health equity across the continuum of research from basic through implementation studies. The perspectives of other relevant collaborators (e.g., health service providers, payors, public health agencies, community-based organizations, biotech, pharma) can further improve research impact. The NIH HEAL initiative strongly encourages applicants to specify their plan for meaningful engagement of people with lived experience and other collaborators in the research process. Meaningful engagement will vary with the focus of the research but should at minimum ensure that researchers are connecting with relevant collaborators and incorporating their perspectives throughout the conception, implementation, and dissemination of the research. Meaningful engagement should address what the researchers will learn and how the people with lived experience and/or collaborators will benefit from the partnership. To promote health equity, as is relevant for the research proposed, it is recommended that at least two people with lived experience from populations who experience health disparities should be meaningfully engaged in these efforts (see NIH’s Notice of Interest in Diversity for more information: NOT-OD-20-031).

See this resource for more information in engaging people with lived experience: https://aspe.hhs.gov/lived-experience).

Clinical Trial Accrual Policy:

This NOFO will support applications that include a series of milestones for completion of the clinical trial and provide contingency plans to proactively confront potential delays or disturbances in attaining the milestones. Continuation of the award is conditional upon satisfactory progress, availability of funds, and scientific priorities of the HEAL Initiative. If, at any time, recruitment falls significantly below the projected milestones for recruitment, NIH will consider ending support and negotiating an orderly phase-out of the award. NIH retains the option of periodic external peer review of progress. NIH program staff will closely monitor progress at all stages for milestones, accrual, and safety.

Research Objectives and Requirements

This NOFO aims to achieve two major objectives using the R61/R33 phased approach.

Objective 1 (R61 Phase): Observational Studies and Planning for the R33 Phase (up to three years)

The primary objective of the R61 phase is to identify and develop quantitative measures for research participants that can differentiate abnormal myofascial tissues from healthy tissues in observational study designs and through cross-sectional correlations with clinical signs/symptoms. In addition, the investigators should include efforts directed towards the team building and planning for the R33 phase clinical trial during this first phase.

Potential quantitative technologies for developing such quantitative measures include, but are not restricted to:

1) Structural imaging (e.g., magnetic resonance [MR], ultrasound), addressing improved spatial resolution needed to visualize micro-structures such as muscle spindles that may be involved in myofascial pain

2) Functional assessments (e.g., elastography) to quantify soft tissue mobility and biomechanical properties (e.g., stiffness, viscosity, shear plane mobility)

3) Quantitative evaluation of tissue metabolism, perfusion, oxygenation, and fatty infiltration (e.g., positron emission tomography [PET], optical, photoacoustic, or MR spectroscopic imaging or electrophysiological measurements of muscle, sensory, motor, and autonomic peripheral activity)

4) Multimodal, multiparametric, and multiscale approaches integrating different types of measurements, including dynamic changes of tissue targets

Of particular interest to this reissue are non-proton (e.g., Sodium, Phosphorus, etc.) and multi nuclear MR imaging and spectroscopy, Molecular imaging (e.g., CEST MRI, pH measurements), whole body imaging, nerve imaging, thermal imaging, and measurements of brain-to-muscle communication.

No preliminary data are required for the R61 phase. However, feasibility may be demonstrated through literature citations or preliminary data in animal studies or human subject studies. Investigators may choose one type of technology or multiple types of technologies described above to develop the quantitative measures to assess the "myofascial unit," which includes muscles and associated connective tissues, nerves, blood vessels, and lymphatics. Thresholds or metrics for the quantitative measures should be hypothesized and described to distinguish healthy versus diseased tissue states with a reasonable degree of fidelity.

For the R61 phase, combining expertise in minimally invasive imaging technology, quantitative analysis and/or computational modeling, and myofascial pain will be strongly encouraged. The R61 phase should also include a brief plan to extend the investigator team with additional expertise in clinical trials and nonpharmacologic or integrative pain management and develop a clinical study protocol for the R33 phase. For example, in a collaborative team pain experts and clinicians may help define clinical criteria for myofascial pain; technology developers may facilitate the development and testing of objective quantitative measurements associated with different clinical conditions of myofascial pain, including patient reported outcomes; and interventionists may be important for the proper design and analysis of the R33 phase.

Objective 2 (R33 Phase): Interventional Studies

The primary objective of the R33 phase is to build on the quantitative measures identified and developed in the R61 phase to test their abilities to detect changes in myofascial tissues undergoing one or more pain management intervention(s) or manipulation(s) in randomized, controlled longitudinal studies of patients with pain. Additionally, changes in patient-reported outcomes in response to existing and putative treatments to relieve myofascial pain are of particular interest. Specifically, identified quantitative measures developed in the R61 phase should be measured at baseline and during and after treatments to measure changes in response to interventions. In addition, baseline measures should be evaluated for their ability to identify or predict patients who are more likely to have pain relief or better pain relief and other favorable effects after the intervention. Also, clinical pain measures should be assessed before (at baseline) and after the interventions.

The sensitivity and specificity of putative quantitative measures should be assessed during the R33 phase.

Current empirical treatment of myofascial pain includes acupuncture or dry needling, targeted injections (e.g., lidocaine, glucose or saline solutions), and manual therapies, while additional putative treatment may include drugs and devices, or other non-pharmacologic approaches. For the reissue of this NOFO, applicants must propose a rigorous, longitudinal clinical study using an intervention, manipulation, or therapy that is currently used clinically to treat pain conditions involving myofascial tissues to test the effects of the intervention on the quantitative measure(s) developed in the R61 phase.. Investigators are encouraged (but not limited) to choose one (or more) of the following treatments or therapies for the R33 study:

1. Physical force-based manipulations, such as manual therapies (e.g., massage therapy, soft tissue mobilization, strain-counterstrain techniques, joint mobilization, muscle energy techniques, high-velocity/low-amplitude thrusting, spinal manipulation, osteopathic manipulation, gua sha) and stretching-based physical activities (e.g., yoga, tai chi, dance therapy)
2. Thermotherapies (e.g., heating or cooling/cryotherapy)
3. Dry needling or acupuncture
4. Targeted injection therapies (e.g., lidocaine injection therapy)
5. Other local tissue manipulations

If another intervention, manipulation, or therapy not listed above is chosen, the application should describe evidence supporting the relevance of the intervention’s effect on the myofascial unit and how this therapy or intervention will produce measurable changes that can be measured using the proposed quantitative assessment developed in the R61 phase. Applicants are not expected to provide efficacy data to justify the choice of the intervention/treatment for the R33 phase.

R61 to R33 Transition Criteria and Process

Investigators are expected to describe a set of Transition Criteria in the form of quantitative milestones (please see Section IV.2 Research Plan for detailed instructions) that will allow for a definitive assessment of whether the R61 phase provides sufficient evidence to support the R33 phase of this two-phase award.

Key evidence in the Transition Criteria should include thresholds for the quantitative measures in the R61 phase to differentiate different states related to myofascial pain (e.g., healthy, latent, and active states). If multiple thresholds are proposed, prioritization should be provided to determine which measure(s) would be moved forward into the R33 for further development. Alternatively, the threshold of a composite measure may be described and proposed for R33 phase development if multidimensional measures are assessed in the R61 phase. Quantitative milestones must include specific thresholds. Preferred metrics include effect sizes (e.g., Cohen’s d >0.5), average area under the curve (e.g., AUC or ROC of 0.7), or other metrics of classification accuracy (e.g., sensitivity and specificity metrics of 70%).

Progress under the R61 phase will be administratively reviewed by the HEAL program team. Funding for and transition to the R33 phase are contingent on the following: 1) meeting the Transition Criteria approved by NIH prior to the initial R61 award, 2) NIH HEAL approval of the planned R33 research activities and investigator team, 3) the availability of funds, and 4) Relevance of the proposed project to program priorities. If a device or a drug is proposed in the R33 phase, investigators must communicate with the U.S. Food and Drug Administration (FDA) prior to the R33 award for determination about whether the R33 trial will need to be conducted under an Investigational New Drug (IND) application or Investigational Device Exemption (IDE).

Scope and Priorities

This NOFO supports the identification and development of objective quantitative measures of myofascial tissues. Both phases must include appropriate human subject research. Animal model studies are not allowed in response to this NOFO.

All applications must include quantitative assessments of at least one component of the myofascial unit in both the R61 and R33 phase studies using minimally invasive or non-invasive technologies. If an application does not include any quantitative assessment of the myofascial component, it would be deemed non-responsive to this NOFO.

Highly invasive technologies and biomarkers will be deprioritized. The R61/R33 award is primarily intended to stimulate the development and adaptation of innovative imaging technologies and similar quantitative assessment methods to differentiate between healthy and diseased states of myofascial tissues involved in pain in human subjects. Consequently, strong applications are expected to propose a well-conceived plan for up to 3 years of funding that focuses on research activities developing these technologies and quantitative assessment methods in the R61 phase. The description of the R33 phase may be brief and should specify the intended interventions and clinical pain population to be studied to test the biomarkers developed in the R61 phase. Note, the R33 phase research plan may be modified based on the outcomes of the R61 study and will need approval from the HEAL program team.

Research applications submitted under this NOFO are likely to cover a large group of pain conditions involving myofascial tissues. The following pain conditions will be prioritized in this reissue:

• Temporomandibular disorders
• Cancer Pain
• Headache
• Pelvic pain
• Diffuse pain (e.g., Fibromyalgia, Sickle cell disease pain)
• Pain in special populations (e.g., children, persons with physical and intellectual disabilities, hypermobility disorders, physically or mentally disabled, dementia patients, women of reproductive age, pregnant and lactating individuals, and health disparity populations [i.e. racial/ethnic groups, sexual and gender minorities, underserved rural and socioeconomically disadvantaged populations, people with limited English proficiency], etc.)

Non-responsiveness criteria:

• An application not proposing a quantitative assessment of at least one component of the myofascial unit will not be responsive to the NOFO
• An application that fails to include a specified intervention, manipulation, or therapy in the R33, or without an R33 section will be deemed not responsive to this NOFO

Consultation With NIH

Applicants are encouraged to consult with NIH Scientific Contacts listed in the NOFO before they begin developing their applications (see Section VII, Agency Contacts). This early contact will provide an opportunity to clarify whether the research topic is a fit with the NOFO’s purpose and priorities.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

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)

Local 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)

Federal Governments

• 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) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

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.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. 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 SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

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, per 2.3.7.4 Submission of Resubmission Application. 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 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. 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 notice of funding opportunity 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.

Letter of Intent

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:

Jessica McKlveen, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Email: [email protected]

Page Limitations

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this NOFO.

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, with the following additional instructions:

Other Attachments: The following attachments must be included in the application:

A document outlining quantitative milestones ( Milestones Document") as Other Attachments for the R61-to-R33 Transition Criteria.

The document should specify the threshold(s) to be used to differentiate healthy from diseased myofascial units in a chosen clinical pain population using the proposed technological measures. These quantitative milestones will need to explicitly detail a set of objective and quantitative measures that will be achieved during the R61 phase of the award as well as provide a list of proposed aims for the R33 phase. Each milestone in the Milestones Document should reference at least one of the study’s specific aims; the milestones document should also include a Gannt chart of the study timeline and clearly reference the month(s) and year that each milestone is expected to be completed.

If an enumerated milestone is describing a clinical milestone (i.e., subject recruitment/retention), the milestone should include the following Success Criteria: A clearly defined success measure or condition with details about how this measure/condition will be reached. For example, a recruitment milestone must describe how the recruitment and retention of any clinical cohort(s) and control cohort(s) used in the study are defined by a set of quantifiable metrics (e.g. 90% of a proposed cohort of subjects in each group have completed the specified diagnostic tests by the specified milestone deadline). Please also include metrics related to missing data or study dropouts, as well as subject number and characteristics in the described study (e.g. healthy subjects, specific patient population, age, gender, etc.)

All enumerated milestones should include sufficient justification that the success criteria are objective, quantifiable, and achievable in the timeframe described in the study timeline. They should also include a description of a clear decision rule that will be used to prioritize the outcome measures if more than one is proposed, as well as how contradictory changes in multiple measures will be handled.

All enumerated milestones should also include a brief justification or rationale for the measure(s) used to assess each primary outcome with references if available. This section may include justification for the number of subjects used per study, statistical analysis used and assumptions, rules for inclusion/exclusion of subjects or data, or randomization/blinding details.

A Data Management and Sharing plan must be included in Other attachments. NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing.?Consistent with the HEAL Initiative Public Access and Data Sharing Policy (https://heal.nih.gov/about/public-access-data), all applications, regardless of the amount of direct costs requested for any one year, are required to include a Data Management and Sharing Plan outlining how scientific data and any accompanying metadata will be managed and shared. The plan should describe data types, file formats, submission timelines, and standards used in collecting or processing the data. Data generated by HEAL Initiative-funded projects must be submitted to study-appropriate domain-specific or generalist repositories in consultation with the HEAL Data Stewardship Group to ensure the data is accessible via the HEAL Initiative Data Ecosystem. Guidelines for complying with the HEAL Public Access and Data Sharing Policy can be found at https://heal.nih.gov/data/complying-heal-data-sharing-policy. Resources and tools to assist with data related activities can be found at https://www.healdatafair.org/.

To maximize discoverability and value of HEAL datasets and studies, and facilitate data integration and collaboration, applications submitted in response to this FOA are strongly encouraged to incorporate standards and resources where applicable:

Applicants are encouraged to ensure that data collected by the study conform to Findable, Accessible, Interoperable, and Reusable (FAIR) principles.

Applicants are specifically encouraged to incorporate into their planning, an alignment with the guidelines, principles and recommendations developed by the HEAL Data Ecosystem, including but not limited to preparing data to store in selected specified repositories, applying minimal metadata standards, use of core HEAL Clinical Data Elements (CDEs, https://heal.nih.gov/data/common-data-elements), and other necessary requirements to prepare data to connect to the HEAL Data Ecosystem.

All new HEAL clinical pain studies are required to submit their case-report forms/questionnaires to the HEAL Clinical Data Elements (CDE) Program. The program will create the CDE files containing standardized variable names, responses, coding, and other information. The program will also format the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C 794 (d)), which require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities. HEAL Initiative clinical studies that are using copyrighted questionaries are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program.

To the extent possible, HEAL awardees are expected to integrate broad data sharing consent language into their informed consent forms and align study consent language with data access and re-use requirements as defined by repository HEAL investigators select to store their HEAL data long-term.

The NIH notices referenced below provide additional NIH guidance that should be considered in developing a strong data management and sharing plan. The list is instructive but not comprehensive.

Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014)

NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016).

NIH encourages the use of data standards including the PhenX Toolkit (www.phenxtoolkit.org) (for example, see NOT-DA-12-008, NOT-MH-15-009)

Data should be organized according to a standard model that is widely accepted within the field. An example for the clinical research studies would be the OMOP Common Data Model, which has also been successfully adapted for use with observational (including survey) studies more generally. In addition, the HL7 FHIR (Fast Healthcare Interoperability Resources) standard (NOT-OD-19-122) may facilitate the flow of data with EHR-based datasets, tools, and applications.

NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards, as they are applicable (NOT-OD-20-146). Use of the USCDI can complement the FHIR standard and enable researchers to leverage structured EHR data for research and enable discovery. In addition to USCDI, OMOP, and FHIR standards for enhanced interoperability, investigators and data centers should align their data collection and management practices with recommended guidance emerging from the HEAL CDE and Data Ecosystem programs.

Awardees conducting research that includes collection of genomic data should incorporate requirements under the NIH Genomic Data Sharing Policy (NOT-OD-14-124, NOT-OD-15-086).

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

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 should include brief descriptions of both the R61 phase and R33 phase as well as the transition criteria.

Research Strategy section should provide diagrams and describe the study designs as well as analytic plans for the R61 phase and the R33 phase separately. This section should also provide quantitative details of the R61 to R33 Transition Criteria as well as timeline for completing the R61 and the R33 phases. It is anticipated that the R61 study should be completed within 32 months post award to allow for a timely submission of transition request to the R33 phase.

R61 phase: (up to 3 years)

The R61 Phase may choose to study the myofascial unit in one of the following clinical populations:

• Temporomandibular disorders
• Cancer Pain
• Headache
• Pelvic pain
• Diffuse pain (e.g., Sickle cell disease pain)
• Chronic Low Back Pain
• Musculoskeletal pain conditions (e.g., shoulder, neck, arm, leg pain)
• Pain in special populations (e.g., children, persons with physical and intellectual disabilities, physically or mentally disabled, dementia patients, women of reproductive age, pregnant and lactating individuals, and health disparity populations [i.e. racial/ethnic groups, sexual and gender minorities, underserved rural and socioeconomically disadvantaged populations, people with limited English proficiency], etc.)

If another pain condition not listed above is chosen, the application should describe evidence supporting the relevance of the myofascial unit in such a pain condition.

The R61 phase may choose to employ one or multiple of the following technologies with minimal invasiveness to develop quantitative measures or integrate these measures with other markers (e.g., immune factors, genomic markers, physiological factors) through multiscale modeling or machine learning analysis to differentiate healthy from diseased myofascial units in the chosen clinical pain condition:

1) Structural imaging (e.g., MR, ultrasound), addressing improved spatial resolution needed to visualize microstructures such as muscle spindles that may be involved in myofascial pain

2) Functional assessments (e.g., elastography) to quantify soft tissue mobility and biomechanical properties (e.g., stiffness, viscosity, shear plane mobility)

3) Quantitative evaluation of tissue metabolism, perfusion, oxygenation, and fatty infiltration (e.g., PET, optical, photoacoustic, or MR spectroscopic imaging or electrophysiological measurements of muscle, sensory, motor, and autonomic peripheral activity)

4) Multimodal, multiparametric, and multiscale approaches integrating different types of measurements, including dynamic changes of tissue targets

Of particular interest to this reissue are non-proton (e.g., Sodium, Phosphorus, etc.) and multi nuclear MR imaging and spectroscopy, molecular imaging based on a wide range of modalities and approaches (e.g., optical and nuclear imaging, CEST MRIetc.), whole body imaging, nerve imaging, thermal imaging, and measurements of brain-to-muscle communication.

The R61 phase must also include a plan to develop a detailed research study and clinical study protocol with appropriate expertise for the R33 phase for the HEAL program team to review and approve.

R61-to-R33 Transition Criteria:

In the research strategy section, tThe R61-to-R33 transition criteria ( Milestones") must contain:

1) brief descriptions on the threshold(s) defined to differentiate healthy from diseased myofascial units in a chosen clinical pain population using the proposed technological measures. Preferred metrics include effect sizes (e.g., Cohen’s d >0.5), average area under the curve (e.g., AUC or ROC of 0.7), or other metrics of classification accuracy (e.g., sensitivity and specificity metrics of 70%).

2) A recruitment milestone defined by a set of quantifiable metrics (e.g. 90% of a proposed cohort of subjects in each group have completed the specified diagnostic tests by the specified milestone deadline).

3) Metrics related to missing data or study dropouts, as well as subject number and characteristics in the described study (e.g. healthy subjects, specific patient population, age, gender, etc.)

Additional details about the transition criteria must be provided as a document in the Other Attachments section, as described in the Other Project Information above.

R33 phase: (R61/R33 combined cannot exceed 5 years)

The R33 phase should be brief and must describe a rigorous, longitudinal clinical study using an intervention or therapy that may relieve pain. The chosen intervention should produce measurable changes of the myofascial tissue that will allow for the quantitative assessment of measures developed in the R61 phase. Investigators are encouraged (but not limited) to choose one (or more) of the following treatments or therapies for the R33 study, along with an appropriate control group (minimally a time control group) to conduct a randomized clinical trial.

1. Physical force-based manipulations, such as manual therapies (e.g., massage therapy, soft tissue mobilization, strain-counterstrain techniques, joint mobilization, muscle energy techniques, high-velocity/low-amplitude thrusting, spinal manipulation, osteopathic manipulation, gua sha) and stretching-based physical activities (e.g., yoga, tai chi, dance therapy)
2. Thermotherapies (e.g., heating, or cooling/cryotherapy)
3. Dry needling or acupuncture
4. Targeted injection therapies (e.g., lidocaine injection therapy)
5. Other local tissue manipulations

If another intervention, manipulation, or therapy not listed above is chosen, the application should describe evidence supporting the relevance of the intervention’s effect on the myofascial unit and how this therapy or intervention will produce measurable changes that can be measured using the proposed quantitative assessment developed in the R61 phase. Applicants are not expected to provide efficacy data to justify the choice of the intervention/treatment for the R33 phase.

The quantitative measure(s) developed in the R61 phase should be assessed in the R33 phase at baseline and at the end of the intervention as well as at a specified frequency during the intervention to monitor the ability of such measure(s) to assess responses to the intervention. An appropriate clinical pain assessment should also be performed at baseline and at the end of the intervention to assess the ability of the R61 quantitative measure(s) to predict clinical outcomes of the chosen intervention. The R33 phase should also propose to calculate the sensitivity and specificity of the R61 quantitative measures to monitor the treatment response and predict the clinical outcomes.

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.

HEAL Public Access and Data Sharing Policy:

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing and immediate access to publications (https://heal.nih.gov/about/public-access-data). Guidelines for complying with the HEAL Public Access and Data Sharing Policy can be found at https://heal.nih.gov/data/complying-heal-data-sharing-policy. Resources and tools to assist with data related activities can be found at https://www.healdatafair.org/. For more detail and specific data sharing requirements, see Section 4. Other plans.

Publications resulting from NIH HEAL Initiative funded studies must be immediately publicly available upon publication.

• For manuscripts published in journals that are not immediately open access, authors should arrange with journals in advance to pay for immediate open access.
• Costs to ensure manuscripts are immediately publicly available upon publication should be included in budget requests.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

The HEAL Initiative has additional requirements that must be addressed in the Data management and Sharing plan. All HEAL-generated data must be shared through the HEAL Initiative Data Ecosystem following HEAL’s compliance guidance (https://heal.nih.gov/data/complying-heal-data-sharing-policy). Specifically, HEAL applicants must include:

• Plans to submit data and metadata (and code, if applicable) to a HEAL-Compliant data repository (https://www.healdatafair.org/resources/guidance/selection) and follow requirements of the selected repository.
• Plans to register your study with the HEAL platform within one year of award (https://heal.github.io/platform-documentation/study-registration/).
• Plans to submit HEAL-defined study-level metadata within one year of award (https://github.com/HEAL/heal-metadata-schemas/blob/main/for-investigators-how-to/study-level-metadata-fields/study-metadata-schema-for-humans.pdf) and https://heal.github.io/platform-documentation/slmd_submission/).
• HEAL pain clinical studies must include plan to use HEAL core Common Data Elements (https://heal.nih.gov/data/common-data-elements). HEAL Initiative clinical studies that are using copyrighted questionaries are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials.
• To the extent possible, all other (non-pain) HEAL studies conducting clinical trials or research involving human subjects are expected to use questionnaires by the HEAL Clinical Data Elements (CDE) Program (https://heal.nih.gov/data/common-data-elements) if applicable and relevant to their research.
• Studies using CDEs, regardless of whether they are part of the HEAL repository, will be required to report which questionnaires are being used.
• To the extent possible, HEAL awardees are expected to integrate broad data sharing consent language into their informed consent forms.

HEAL has developed additional details and resources to fulfill these requirements (https://www.healdatafair.org/resources/road-map).

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

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined 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.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). 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.

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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier 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.

In order to expedite review, applicants are requested to notify the NCCIH Referral Office by email at [email protected] when the application has been submitted. Please include the NOFO number and title, PD/PI name, and title of the application.

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.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following: This NOFO is primarily focused on developing and/or adapting innovative technologies to assess the myofascial units in appropriate clinical pain populations for diagnostic purpose as proposed in the R61 phase. Secondarily, the R33 phase must describe an intervention, manipulation, or therapy relevant to the myofascial unit. The chosen intervention is intended to test whether the technological measures developed in the R61 phase can detect specific changes to myofascial tissue after a given intervention. The priority of this NOFO is the technological development in the R61 phase and the ability of the proposed technology or method to differentiate the healthy from diseased states of myofascial tissues in a chosen painful condition.

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.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCCIH 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 will receive a written critique.

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.

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

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 submitted in response to this NOFO. 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.

Section VI. Award Administration Information

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO 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 and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient 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, Recipients, and Activities, including of note, but not limited to:

• Federal wide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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. 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 NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

HEAL Data Sharing Requirements

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing. All HEAL Initiative award recipients, regardless of the amount of direct costs requested for any one year, are required to comply with the HEAL Public Access and Data Sharing Policy. HEAL award recipients must following all requirements and timelines developed through the HEAL Initiative Data Ecosystem, as described in HEAL’s compliance guidance (See Already Funded section: https://heal.nih.gov/data/complying-heal-data-sharing-policy):

1. Select a HEAL Compliant data repository (https://www.healdatafair.org/resources/guidance/selection)

• Data generated by HEAL Initiative-funded projects must be submitted to study-appropriate, HEAL-compliant, data repositories to ensure the data is accessible via the HEAL Initiative Data Ecosystem.
• Some repositories require use of specific data dictionaries or structured data elements, so knowing your repository’s requirements up front can help reduce the burden of preparing data for submission.
• HEAL-funded awardees must follow requirements for selected repository

2. Within one year of award, register your study with the HEAL platform

• This process will connect the Platform to information about your study and data, including metadata, and identify the selected repository. HEAL requests initial submission within one year of award, with annual updates, and to be updated in accordance with any release of study data.

3. Within one year of award, submit HEAL-specific study-level metadata.

• Some of the required study-level metadata will be auto-populated as part of the registration process.

4. Submit data and metadata (and code, if applicable) to HEAL-Compliant repository

• At the completion of the study and/or when prepared to make the final data deposits in the repositor(ies) of choice, ensure your study registration (https://heal.github.io/platform-documentation/study-registration/) is complete.
• The NIH HEAL Initiative expects data used in publications to be submitted to repositories at the time of or prior to publication, and no later than the end of the project period.

5. Additional Requirements for HEAL Initiative studies conducting clinical research or research involving human subjects.

These studies must meet the following additional requirements

• HEAL Initiative trials that are required to register in clinicaltrials.gov should reference support from and inclusion in the HEAL Initiative by including the standardized terms the HEAL Initiative (https://heal.nih.gov/) in the Study Description Section.
• All new HEAL clinical pain studies are required to use core questionnaires required by the HEAL Clinical Data Elements (CDE) Program Outside of the core questionnaires, studies should select questionnaires from among the repository of supplemental questionnaires that are already being used by other HEAL clinical pain studies. The program has created the CDE files containing standardized variable names, responses, coding, and other information for all of these questionnaires The program has also formatted the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C 794 (d); https://www.govinfo.gov/content/pkg/USCODE-2011-title29/html/USCODE-2011-title29-chap16-subchapV-sec794d.htm) which require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities.
  • Studies that wish to use questionnaires not already included in the HEAL CDE repository should consult with their program official and the HEAL CDE team. New questionnaires will be considered for inclusion in the repository on a case-by-case basis and only when appropriate justification is provided.
  • HEAL Initiative clinical studies that are using copyrighted questionaries are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program (https://heal.nih.gov/data/common-data-elements).
• To the extent possible, all other (non-pain) HEAL studies conducting clinical trials or research involving human subject are expected to use questionnaires by the HEAL Clinical Data Elements (CDE) Program if applicable and relevant to their research.
• To the extent possible, HEAL awardees are expected to integrate broad data sharing consent language into their informed consent forms.

Additional details, resources, and tools to assist with data related activities can be found at https://www.healdatafair.org/.

All data collected as part of the NIH HEAL Initiative are so collected under a Certificate of Confidentiality and entitled to the protections thereof. Institutions who receive Data and/or Materials from this award for performance of activities under this award are required to use the Data and/or Materials only as outlined by the NIH HEAL Initiative, in a manner that is consistent with applicable state and federal laws and regulations, including any informed consent requirements and the terms of the institution’s NIH funding, including NOT-OD-17-109 and 42 U.S.C. 241(d). Failure to adhere to this criterion may result in enforcement actions.

4. Reporting

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

Report and ensure immediate public access to HEAL-funded publications:

Publications resulting from NIH HEAL Initiative funded studies must be immediately publicly available upon publication.

• For manuscripts published in journals that are not immediately open access, authors should arrange with journals in advance to pay for immediate open access
• Costs to ensure manuscripts are immediately publicly available upon publication should be included in budget requests

Prior to publication, HEAL expects investigators to alert their program officers of upcoming manuscripts to ensure coordination of communication and outreach efforts.

Award recipients and their collaborators are required to acknowledge HEAL Initiative support by referencing in the acknowledgement sections of any relevant publication:

This research was supported by the National Institutes of Health through the NIH HEAL Initiative (https://heal.nih.gov/) under award number [include specific grant/contract/award number; with NIH grant number(s) in this format: R01GM987654].

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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients 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 the threshold. 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 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Alex Tuttle, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-496-2583
Email: [email protected]

Brennan Parmelee Streck, PhD, RN, MPH
National Cancer Institute (NCI)
Telephone: 301-357-0516
Email: [email protected]

Elena K Gorodetsky, M.D., Ph.D.
Office of Research on Women's Health (ORWH)
Phone: (301) 594-9004
E-mail: [email protected]

David A Thomas, Ph.D.
Office of Research on Women's Health (ORWH)
Phone: 301-435-1313
E-mail: [email protected]

Devon Oskvig, Ph.D.
National Institute on Aging (NIA)
Phone: (301) 496-9350
E-mail: [email protected]

Guoying Liu
NIBIB - NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING
Phone: (301) 594-5220
E-mail: [email protected]

Helena H. Ahn, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-3207
Email: [email protected]

Dena Fischer
NIDCR
Phone: (301)-594-4876
Email: [email protected]

Rebecca Lenzi, PhD
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phone: 301-402-2446
E-mail: [email protected]

Michael L. Oshinsky, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
Email: [email protected]

Jessica McKlveen, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Email: [email protected]

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: [email protected]

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: [email protected]

Kathleen Moy
National Institute on Aging (NIA)
Phone: 301.827.2856
E-mail: [email protected]

Mutema Nyankale
NIBIB - NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING
Phone: (301) 827-6317
E-mail: [email protected]

Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: [email protected]

Diana Rutberg
NIDCR
Phone: (301)-594-4798
Email: [email protected]

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Tel: (301) 594-7760
Email: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Section VIII. Other Information

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.

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 and 2 CFR Part 200.