Purpose

The purpose of this FOA is to solicit applications to develop, test and deploy novel analytic tools, technologies and/or methods (TTM) that will improve our understanding of mechanisms of cLBP and to improve the diagnosis, treatment and prevention of recurrences of cLBP. New mechanistic TTM will contribute to the development an integrated model of cLBP. Improved understanding of mechanisms of back pain is expected to lead to the development of novel therapies directed at these mechanisms. The TTM may also enable sub-phenotyping of patients with cLBP and evaluation and prediction of likelihood of treatment response. Application responding to this RFA may be design-directed, developmental, discovery-driven, or hypothesis-driven, including, for example, repurposing of existing established methods used in other conditions to new application to cLBP.

Awards made through this FOA will support an initial milestone-driven UH2 (Exploratory) funding period, with possible rapid transition to the UH3 (Implementation) funding period for a large validation project. UH3s will be awarded after administrative review of eligible UH2s that have met quantifiable scientific milestones and feasibility requirements necessary for the UH3, depending on the availability of funds. The UH2/UH3 projects must be submitted as part of a single application.

As members of the BACPAC Research Program, funded projects. The TTM research and development will run in parallel and will synergize with projects supported in the BACPAC Mechanistic Research Centers, the Data Integration, Algorithm Development and Operations Management Center and the Phase 2 Clinical trials. Successful analytic TTM are expected to lead to BACPAC Phase 2 Clinical Trials and in multimodal, sequential, adaptive clinical studies in stratified patient populations. TTM are expected to improve the diagnosis, treatment and prevention of recurrences of cLBP and/or to be useful for defining different mechanisms of in different patients and contribute to the development of algorithms for individualized treatment plans. Technology Research Sites will interface with the Interdisciplinary Mechanistic Research Centers, and the Systems Biology and Informatics Core for data integration and modeling. Together the Sites, Centers and Core will explore linkages between specific structural, dynamic, cellular or molecular abnormalities to specific patient-reported symptoms and function.

Background and Objectives of the ?BACPAC Research Program

NIH has identified a set of research priorities reflecting urgent unmet needs across the lifespan along with areas of promising scientific opportunity in order to develop concrete strategies capable of providing rapid and durable solutions to the opioid crisis. This includes an improved understanding of the biological underpinnings of chronic pain, discovery, development and testing of new non-addictive pain treatments. The Federal Pain Research Strategy is a long-term strategic plan to guide the federal agencies and departments that support pain research and to advance the science to better understand pain and improve pain care. Overall, the priorities cover basic through clinical, dissemination, and implementation research to support the translation of scientific discoveries into clinical practice and improve the lives of people with pain. The strategy includes several priority recommendations regarding the evaluation of efficacy, safety and interactions of novel drugs and non-pharmacologic treatments for pain. https://iprcc.nih.gov/Federal-Pain-Research-Strategy/Overview.

Back pain is one of the most common forms of chronic pain among adults worldwide. According to National Health Interview Survey data, 20% of adults in the United States reported frequent back pain and 28% of adults experienced low back pain that lasted a whole day or more during the past three months. Out of all 291 conditions included in the Global Burden of Disease 2010 Study, low back pain ranked highest in terms of years lived with disability. Back pain is over-represented among women and in people with low socioeconomic status. Children are also affected, a recent study indicated that the prevalence of low back pain in adolescents increases with age and reaches the levels observed in adults by age 18. There are disparities in the treatment of pain between whites and racial/ethnic minorities. BACPAC will aim to study low back pain in patients from diverse ethnic, racial, and socioeconomic groups and across the lifespan including adolescence.

In 2013, the NIH Pain Consortium established a Steering Committee for a Research Task Force (RTF) on Research Standards for cLBP. The RTF made recommendations for the use of a standardized consistent use of a definition of cLBP, a minimum dataset, and reporting outcomes. The RTF also made future research recommendations. They concluded that greater consistency in reporting should facilitate comparisons among studies and the development of disease phenotypes. https://www.ncbi.nlm.nih.gov/pubmed/24787228.

Despite the pipeline for new pharmacologic treatments for back pain which includes agents targeting inflammation, peripheral pain transmission or amplification, central sensitization, and descending modulation, there are currently no consistently effective and durable pharmacologic interventions for cLBP that work. This is also the case for non-pharmacologic interventions such as exercise, multidisciplinary rehabilitation, acupuncture, cognitive behavioral therapy (CBT), and mind-body practices. Clearly, more rigorous studies are needed that better integrate different modalities, and development of individualized treatment plans. In addition, a better means of identifying sources of pain in different individuals is a crucial need as is the need for patient stratification and improved outcomes measures.

Disease heterogeneity, lack of informative data for the management of patients with cLBP and the challenges of identifying the source of pain, assessing treatment response and disease modification necessitate the formation of a clinical program to undertake sequential, adaptive clinical trial design approaches to evaluate the safety and efficacy of targeted interventions. A translational research program can provide comprehensive information about patient phenotypes to stratify patient populations, and the use of predictive and monitoring algorithms will enhance the efficiency of trials as compared to single interventional approaches in large, heterogeneous patient populations. Clinical trials with novel designs that are paired with advanced diagnostic, imaging and robust outcome assessments and fully integrated mechanistic studies are needed to provide preliminary evidence of clinical effect and to design and launch efficacy trials.

The goal of the BACPAC Research Program is to probe the biomedical and biopsychosocial mechanisms of LBP using interdisciplinary methods and innovative technologies so that novel individualized targeted treatments can be developed, tested and combined for an integrated approach to treat cLBP. This highly collaborative research program will conduct research to deliver an integrated model of cLBP and patient-based algorithms to facilitate the identification of treatments tailored to the individual patient. The BACPAC Research Program will generate new knowledge regarding phenotypes, endotypes, mechanisms, diagnostics, trial outcomes, and therapeutic responsiveness. Data generated regarding disease phenotypes, endotypes, and treatment responses will be used to develop and test diagnostic, predictive and treatment algorithms and in multi-stage, adaptive study designs that may have the potential to determine the best therapeutic response of individual patients. BACPAC will aim to study low back pain in patients from diverse ethnic, racial, and socioeconomic groups and across the lifespan including adolescence.

This study is part of the 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 will bolster 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://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.

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.

Components of the BACPAC Research Program

The BACPAC Research Program consists of four primary components that will work collaboratively to achieve the overarching goals:

• A Data Integration, Algorithm Development and Operations Management Center (DAC). This Center will guide and coordinate all activities of the consortium and ensure communications, interactions, synergies and accountability. It will manage a core as a Consortium-wide registry, including patient reported outcomes and preferences. The DAC will include the BACPAC Systems Biology and Bioinformatics Group (SBG) to provide system level analysis for BACPAC generated multidimensional datasets to produce an integrated model of LBP. Using data from clinical studies across the Consortium, this Center will develop patient-centered algorithms for prediction of optimized therapeutic interventions.

• Interdisciplinary Mechanistic Research Centers (MRC) that will conduct translational research leading to further characterization of low back pain mechanisms and improved phenotyping of patients with chronic low back pain in clinical cohorts. Centers might conduct exploratory trials or innovative design clinical studies to obtain data for deep patient phenotyping or test new technologies.

• Technology Research Sites (Tech Sites) that will conduct technology development and deployment.

The Interdisciplinary Mechanistic Research Centers and the Technology Sites will interface with the SBG for the first level of research data integration and modeling. Together the Centers, Sites and Group will explore linkages between specific structural, dynamic, cellular or molecular abnormalities to specific patient-reported symptoms and function.

• Phase 2 Clinical Trials (Phase 2CT). The goal of the Phase 2 CTs will be to test the safety and efficacy of non-addictive therapies for cLBP. These trials will be conducted in two phases. A planning phase (UG3) to be carried out collaboratively within the BACPAC Consortium in consultation with the Early Phase Pain Investigation Clinical Network: EPPIC-Net (formerly known as the Clinical Trial Network for Pain Research, CTNPR) (https://grants.nih.gov/grants/guide/notice-files/NOT-NS-18-058.html, https://grants.nih.gov/grants/guide/notice-files/NOT-NS-18-069.html, https://grants.nih.gov/grants/guide/notice-files/NOT-NS-18-057.html).

The trial implementation phase (UH3) may be conducted within the EPPIC-Net Clinical Trial environment using the EPPIC-Net Trial Hubs, Clinical Coordinating Center (CCC) and Data Coordinating Center (DCC) infrastructure, services, operating and cost standards. Innovative trial designs will be used to test new non-addictive drugs, biologics, devices and complementary medicine approaches to relieve pain and improve physical function.

In addition to the component-specific projects, the BACPAC will conduct:

• A Collaborative Clinical Project to test at least one specific translational or clinical hypothesis on low back pain that builds on strengths of participating center(s) and engage other members of the BACPAC Research Program after award.
• Pilot Studies to be conducted either by the individual Centers, Sites or by the Consortium.
• Ancillary Studies linked to the trials to understand biological and biopsychosocial effects of the therapies or other aspects of the disease or treatment, to identify potential biomarkers and test new outcome instruments.

To manage the support for these projects, the DAC will establish a Funds Management Unit.

The Funds Management Unit (FMU) will administer after award, on behalf of the entire BACPAC Research Program, two funds: the Collaborative Clinical Fund for support of the Collaborative Clinical Projects and the Collaborative Research Fund for support of the Pilot and Ancillary Studies Projects and additional studies required for achieving the aims of the BACPAC Research Agenda.

BACPAC Governance Structure

The success of the BACPAC Research Program will require collaboration, cooperation, and extensive data and resource sharing among its component parts. It will also demand a commitment by all members to use common data, protocols and standards agreed upon by the Consortium. Therefore, participation in the BACPAC governance committees is an important responsibility. The governance structure will be finalized with the participant investigators and institutions after awards are made for the Mechanistic Centers, Technology Sites, Phase 2 Trials and the DAC.

The composition of the various committees and the meeting frequency are described in the Table below. These committees will include:

The BACPAC Steering Committee (BACPAC SC) will function as the governing body for the BACPAC Research Program. The BACPAC SC will have primary responsibility for developing a research agenda for the BACPAC Research Program to ensure that the work of the consortium leads to an integrated model of low back pain and to the development, testing and validation of patient-based diagnostic and treatment algorithms.

The BACPAC SC will:

• Provide scientific leadership for the BACPAC Research Program.
• Promote and ensure synergy, collaboration, and sharing of data and resources across the BACPAC components and among members.
• Formulate the BACPAC Research Program Agenda and approve the Collaborative Projects.
• Coordinate the BACPAC scientific agenda with EPPIC-Net and other funded components of the HEAL initiative.
• Disseminate information about the activities of the BACPAC Consortium.
• Report to the NIH and to the BACPAC Advisory Board appointed by NIAMS/NIH.

The BACPAC SC will establish Functional Working Groups to build synergies and facilitate interactions around specific research activities such as: 1) Mechanistic Research, 2) Systems Biology and Bioinformatics, 3) Technology Development Standards; and 4) Patient Reported Outcomes and Preferences.

The BACPAC Executive Committee (BACPAC EC) will direct the day-to-day administration and operations of the BACPAC Research Program. The BACPAC EC will be responsible for operationalizing the Research Agenda approved by the BACPAC SC. The EC will carry out a broad range of technical, operational and management functions to support the implementation of the BACPAC Research Program Agenda and for the day-to-day monitoring and coordination of BACPAC research projects.

The BACPAC EC will:

• Develop and execute a plan to implement the research priorities of the BACPAC Research Agenda.
• Coordinate the SC, Functional Working Groups, and Clinical Management Committee activities and deliverables.
• Disseminate the SC approved research plans, protocols and other relevant information to all BACPAC participating investigators and functional entities.
• Oversee planning of the collaborative project.
• Ensure the work of the Consortium is progressing along the agreed upon timelines and policies.

The BACPAC Clinical Management Committee (BACPAC CMC) will lead the development of a plan for BACPAC clinical common data and protocol elements for approval by the BACPAC SC.

The BACPAC CMC will:

• Develop a BACPAC Clinical Consensus Plan for a) cLBP case definition, b) a minimum dataset to be obtained in all participants, and c) outcomes measures that will be used across all projects. The Consensus Plan will be reviewed and approved by the SC.
• Serve as the Clinical Expert Group for the DAC activities around Clinical Registry, Data Integration and Coordination, and for the Phase 2CTs.
• Serve as the Clinical Expert Group for the DAC activities around Algorithm Development, Testing, and Validation to ensure algorithms are developed in the relevant clinical context.
• Design the Collaborative Clinical BACPAC Study in collaboration with the DAC Adaptive Design Expert Group.

An External Scientific Advisory Board (ESAG) will be constituted by NIH to provide advice and recommendations on research priorities, specific projects/analyses, project transition and future directions.

Membership and meeting frequency for the SC, EC, CMC and the ESAG are outlined in the table entitled "BACPAC Governance Committees". BACPAC SC meetings may include other ad hoc participants, such as research team members from the MRCs, Tech Sites or Phase 2CT. The Chair or Co-Chairs of the BACPAC SC will be selected by NIAMS for the first year of award. The SC members will nominate candidates for Chair or Co-Chairs for NIAMS/NIH approval in years 2-5.

Table: BACPAC Governance Committees

Timeline

The first year of the program will include significant planning activities during which limited funds will be available to awardees for all four FOAs. In this year, the Steering Committee will be established, the consortium will develop the clinical protocols, standard operating procedures, staff training plans, recruitment plans, electronic health record standardization, safety standards, and regulatory processes, identify biospecimen types and amounts to be collected, and develop biospecimen collection and storage protocols if needed. A systems biology analysis plan and an integrated clinical data analysis plan will be developed. The planning year will be followed by up to four additional years (duration varies across awards) of higher funding levels, during which the study will be implemented. It is anticipated that patient enrollment for the Collaborative Clinical Project and for the Implementation Phase of the Phase 2CTs to begin in Fall 2020, immediately after the planning year. In Fall 2021, an assessment will be performed to determine whether the rate of patient enrollment and retention is adequate to meet the assumptions of the power analysis. In the event of lower than expected enrollment or poor retention of patients, the BACPAC Steering Committee will make recommendations to NIH to either increase enrollment or terminate the study. NIH will make the final determination.

Technology Research Sites

Research Objectives

Technology Research Sites will support projects to develop, integrate, optimize, validate, translate promising tools, technologies and/or methods (TTM) that will lead to new understanding of the mechanisms of low back pain and identification of new targets for intervention and to improve the diagnosis, treatment and prevention of recurrences of cLBP. The TTM will contribute to a model of low back pain that integrates information about how mechanisms, operating in different tissues, result in pain and abnormal function. TTMs may also be developed for establishing patient phenotypes in whom different mechanisms are the drivers of the pain, which will contribute to the development of an algorithm for individualized treatments.

TTM that are successfully developed might be deployed in the clinical trials supported by BACPAC, including Phase 2 CTs and/or the Consortium wide multimodal adaptive trial. The TTM will enable and synergize with other integrated approaches and novel analytics for the discovery of disease mechanisms, sub-phenotyping of patients with chronic low back pain, identification of new targets for intervention and for evaluation and prediction of likelihood of treatment response. When applicable, rapid, scalable, and non- or minimally invasive TTM that will contribute to improved diagnosis, treatment and prevention of recurrences of cLBP are preferred. Technology Research Sites will interface with the Interdisciplinary Mechanistic Research Centers and the SBG for data integration and modeling. Together the Sites, Centers and Core will explore linkages between specific structural, dynamic, cellular or molecular abnormalities to specific patient-reported symptoms and function.

Applications in response to this FOA may propose a project from one of the following four categories that are at different technology development phases:

(I) Exploratory Research for Technology Development: Projects developing novel TTM to improve understanding, diagnosis, treatment and prevention of chronic low back pain. This is high risk, preliminary research that, if successful, should lead to a preliminary demonstration of feasibility, or to differentiate possible technical approaches to determine the one most likely to be successful. Experimental results from the exploratory project should serve as a foundation for next stage of development. The Project should identify and address a significant unmet clinical/research need or an emerging opportunity in LBP. It is expected that projects in this category generally will not have preliminary data.

(II) Focused Technology Research and Development: Projects are characterized by innovative research and development, addressing unmet technical challenges that are associated with the early stage development that lead to create an effective TTM for low back pain research. Well characterized physiological, psychological systems and standard experimental approaches in pain research are appropriate as model systems to evaluate and demonstrate performance of the technology. Project aims should be closely associated with technical milestones that represent meaningful benchmarks for the performance of the technology. Projects in this category generally have preliminary data demonstrating feasibility of the approach but may still have some elements of risk.

(III) Iterative Technology Research and Development: Projects are characterized primarily by the close coupling of the technology development with the application of emerging technologies to biomedical projects that serve as test-beds. Technologies are at a stage in which they can be tested in research for continued development and improvement.

(IV) Research and Development for Technology Optimization: Projects are characterized by refinement of existing technologies with high clinical impact on cLBP and making them transferrable to other research and clinical sites participating in the BACPAC Mechanistic Network and Clinical Trial sites. Projects in this category can demonstrate the utility of an available TTM from other research field for a novel use in cLBP research, or repurpose a drug, biologic or device developed or approved for a completely different indication for the treatment of cLBP.

Applications responding to this RFA may be design-directed, developmental, discovery-driven, or hypothesis-driven, and can develop and/or test TTM for facilitating the discovery of mechanisms of disease in cLBP, although studies may use other cohorts with acute LBP provided the results are directly applicable to the understanding of cLBP. Areas of interest include, but are not limited to, the following:

• TTM to develop and facilitate a better understanding of LBP mechanisms to enable phenotyping and sub-phenotyping, and evaluation and prediction of likelihood of treatment response.
• Sensor-driven, implantable devices to target peripheral pain pathways, or to monitor/track cellular and molecular changes, alterations in either structure or function of tissues and organs involved in cLBP.
• Wearable technologies to record patient reported outcomes.
• Modeling and development of in vitro, three-dimensional human tissue system that mimics in vivo tissue architecture and physiological conditions to facilitate and accurately monitor key organ-level functions of chronic low back pain.
• Clinical non-invasive or minimally invasive assessment and/or imaging tools to precisely locate pain-related neural circuits. This personalization will inform development and use of next-generation neurotherapeutic devices by identifying targets for intervention.
• Wearable technologies to target peripheral and central pathways involved in cLBP and to counter decreases in physical function and disability to inform or provide clinical treatment.
• A clinical trial may be proposed. If so it should be planned to be conducted in a phased way with planning and implementation phases.

The following are non-responsive to this RFA and will not be reviewed:

• Biomarker discovery or validation
• Development of new drugs
• Research involving the use of animal models is not excluded; however, any proposed animal model(s) must be highly relevant to human conditions and the demonstrated application to humans must be included in the specific aims of the proposed project(s).
• Technology development focused on metastatic bone disease or chronic low back pain due to acute or chronic infection or acute trauma.

Awards made through this FOA will support an initial milestone-driven UH2 (Exploratory) funding period of up to 2 years, with possible transition to the UH3 (Implementation) funding period for a large validation project. UH3s will be awarded after administrative review of eligible UH2s that have met quantifiable scientific milestones and feasibility requirements necessary for the UH3, depending on the availability of funds. The UH2/UH3 projects must be submitted as part of a single application. Applicants and recipients of UH2 funding should note that the UH2 award does not guarantee subsequent UH3 funding for implementation of the technology project.

UH2/UH3 Phase Innovation Award Approach

The application must clearly identify the significant unmet clinical/research need, or an emerging opportunity to develop, integrate, optimize, validate, translate or otherwise accelerate the adoption of promising tools, technologies and/or methods (TTM) that will lead to new understanding of the mechanisms of cLBP diagnosis. Specific aims and research approach should be clearly organized into two phases: UH2 and UH3.

The UH2 phase research plan must include clear, quantitative scientific milestones for making go/no-go decisions for transition to the UH3 phase. Awardees will develop, refine and finalize their research plans in collaboration with the BACPAC SC, DAC, MRCs and other Tech Sites. Tech Sites will use common standards and protocol elements as approved by the BACPAC SC in conjunction with NIH project scientists and other NIH staff assigned to the projects. Only those projects that successfully meet the scientific milestones and feasibility requirements will be considered for transition to the implementation phase (UH3). UH3 projects are expected to be conducted collaboratively with other components of the BACPAC Research Program.

It is recognized that applications in response to this FOA may propose projects at different development phases. Therefore, applicants have the flexibility to customize their UH2/UH3 objectives based on their development roadmaps, as long as the objectives are appropriate for and consistent with the development phases and stated program goals.

UH2 Exploratory Phase:

The objective is to develop new or adapt/improve existing TTM for use in clinical research of chronic low back pain. At the end of the UH2 phase, applicants will need to demonstrate proof-of-concept of a novel TTM based on a working prototype, analytical and/or clinical performance for cLBP, as well as its feasibility and suitability for the next stage development.

UH3 Implementation Phase:

The UH3 phase must include plans to optimize the TTM developed in its UH2 phase if needed, and to validate its clinical usefulness. For those applications including the optional clinical trials component, the trials should be proposed and conducted in UH3 phase.

Expected outcomes for UH3 phase include but not limited to:

• Completion of validation, adaptation, translation, and optimization steps required to test the performance of the TTM;
• Demonstration of performance, effectiveness, and promise of the TTM for mechanistic and/or clinical utility;
• Ongoing effective collaborations and synergies with other components of the BACPAC consortium, including Interdisciplinary Mechanistic Research Centers, and the Systems Biology and Informatics Core for data integration and modeling;
• Completion of regulatory requirements and approvals and deployment for clinical research use.

Milestones and UH2/UH3 Transition:

Applications must include well-defined milestones for the planning phase (UH2) and annual milestones for the implementation phase (UH3). Prior to a pending award, the PD/PI and NIH will negotiate a final list of milestones for each year of support. The proposed milestones for the UH3 phase may be revised during the award period in coordination with the BACPAC SC and NIH staff as activities in the UH2 phase progress.

At the completion of the research objectives for a UH2 or the UH2 funding period, whichever comes first, the applicant will submit a transition request for the UH3 phase. The request should include:

• Details on the successful completion of the quantitative scientific milestones of the UH2 phase.
• Demonstration of collaborative work, project synergies and interactions with other components of BACPAC,
• A detailed research plan describing the goals, objectives, approaches, milestones and deliverables of the proposed implementation phase, approved by the BACPAC SC.
• A description of how the Tech Site will work collaboratively with other components of the BACPAC Consortium and contribute to advancing the goals of the Consortium.
• A demonstration that all the regulatory and other requirements have been met.
• An intellectual property plan, if applicable.
• A demonstration of compliance with the BACPAC Data Sharing and Resource Sharing Plans.

The UH2 to UH3 transition request will undergo an NIH administrative review. It is anticipated that not all funded UH2 projects will transition to the UH3 stage. Prospective applicants should note that funding of the UH2 stage of the UH2/UH3 Phase Innovation cooperative agreement does not guarantee support of the UH3 project. UH3 Tech Site investigators are expected to work collaboratively with other components of the BACPAC Consortium.

Criteria for evaluation of the UH2 transition to UH3 will include the following:

• Successful completion of the UH2 milestones.
• Feasibility to apply the Tech Site’s TTM to ongoing and planned research projects and trials in the BACPAC Consortium.
• Available patient populations and statistical design considerations.
• Potential for meeting the goals of BACPAC Research Program, including contributions to collaborative activities.
• Availability of funds.

Researchers uncertain as to whether their intended TTM development project meets the requirements of this FOA are strongly encouraged to contact the Scientific/Research Contact listed below.

Pre-Application Webinar

NIAMS will hold a pre-application informational webinar for this FOA. Date, time, and other details will be posted at NIAMS website.

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)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Applicant organizations

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

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

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

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

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

For grantees from a for-profit organization, this FOA does require cost sharing, as defined in the NIH Grants Policy Statement. More information on cost matching requirements is in Section IV.2 R&R or Modular Budget.

3. Additional Information on Eligibility

Number of Applications

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

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

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

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:

Robyn Bent, M.S.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
One Democracy Plaza, Suite 800
Bethesda, MD 20892
Telephone: 301-594-5055
Email: [email protected]

Other Attachments:

1. Applications must include an Intellectual Property (IP) Strategy. Applicants are encouraged to prepare this attachment section in consultation with their institution's technology transfer officials. The section should be labeled "Intellectual Property Strategy. pdf" and may not exceed 3 pages. Please include the Attachment even if IP issues are not a consideration for the project. Indicate: IP issues are not applicable, and explain why. PLEASE include the Attachment even if IP issues are not a consideration for the project. Indicate: IP issues are not applicable and explain why.

This section should describe a dissemination plan that involves patent protection and commercialization:

• Describe the IP landscape surrounding their model system. Applicants should describe any known constraints that could impede sharing of their model system (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar model systems that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program.
• Include a letter from any entity who has ownership of the IP indicating whether they will provide the technology, if there are any limitations on the studies that can be performed with that technology, agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.
• If patents pertinent to the technology being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated US Patent and Trademark Office links, if applicable.
• Describe future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions
• State how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved, consistent with achieving the goals of the BACPAC Research Program.

2. Applicants may propose one or more concepts for future Pilot Research Projects and Ancillary Studies.

Present a brief description of the goals, significance and feasibility for each of the proposed concepts, indicating whether it will be associated with one or more or the components of the BACPAC Research Consortium. Details on the technical approach and a detailed budget should not be included. Each concept description should not exceed one page. Concepts may propose exploring a research question or applying the applicants analytic or technology in a different experimental model, system or population elsewhere in the BACPAC research Program sites and Centers.

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

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

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

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

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

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

(d) Program income; and

(e) Patient incentives.

The For-profit organization will be required to demonstrate that matching funds and/or in-kind contributions are committed or available at the time of, and for the duration of, the award. Applicants must submit budgets that clearly document the total costs, the source and amount of matching funds, and how valuation was determined in the case of in-kind contributions, as well as the Federal and Institutional (non-Federal) components of the budget. All matching funds and/or in-kind contributions must be used for the portion of allowable project costs not paid by Federal funds under the grant award. NIH will not be the recipient, nor serve as a pass-through entity, of any such matching funds and/or in-kind contributions required under this announcement. See 45 CFR 75.306 for additional details.

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

Applicants should budget for two annual two-day, in-person investigator meetings, and should budget to allow up to 4 persons from the investigator team to attend. (The expenses of the meeting room rental will be covered separately.)

The release of funds will be milestone-driven, according to milestones pre-specified in the Notice of Award.

For applications proposing a clinical trial:

• The applicants should include a full budget for all of the activities related to the planning and implementation of the clinical trial. However, some or all of the clinical coordination, data management, and clinical site operations may be subcontracted out to EPPIC-Net. Applicants are instructed to review the EPPIC-Net FOAs to understand what functions they provide. The decision will be made at the time of the UH3 award, and budgets will be adjusted accordingly.
• Costs at the clinical sites must include a trial infrastructure component that includes salary support for the PD/PI and study coordinator only.
• Trial costs should be budgeted on a per-subject or per-procedure basis. Applicants should provide a breakdown of the total per subject costs as part of the budget justification and should indicate how the cost for an item or procedure was determined. These costs should be calculated and presented taking into consideration that NIAMS anticipates that enrollment and follow-up for the proposed Phase 2 trials should be completed within 24 months after the opening date of enrollment.
• Costs for collection, analysis, shipping, and/or storage of biospecimens during the study should be included as a separate item in the budget. Specimens collected beyond that needed for the study or remaining at the close of study will be stored in the NIH EPPIC-NET Biorepository. Costs for shipping to the repository should be included in the budget. Costs for long-term storage in the EPPIC-NET repository will be covered through HEAL funds.
• Costs to support the DSMB will be covered by the NIAMS.
• If some trial costs are to be borne by sources other than NIH, these contributions must be presented in detail in the budget justification. These costs borne by third parties do not constitute cost-sharing as defined in the current NIH Grants Policy Statement and should not be presented as part of the requested budget.

Applicants should clearly indicate which technology developmental category that the project falls into.

To determine the appropriate category for technology development, applicants may wish to review information at https://www.nigms.nih.gov/about/overview/BBCB/biomedicaltechnology/Pages/technologydevelopment.aspx

Specific Aims : Applicants should address the scientific questions to be answered, provide the overall goal for the entire application, and indicated separately Specific Aims to be accomplished in the UH2 phase and those in the UH3 Phase. Specific aims should be scientifically appropriate for the distinct research phases of the project.

If a clinical trial is included, the goals of the clinical trial and the expected outcomes must be clearly and concisely presented. The primary and major secondary endpoints to be evaluated must be clearly stated. There should be a clear explanation of the importance of various endpoints.

Research Strategy: Within the single Research Strategy attachment, separate the information into the sections identified below. Applications will be assigned a single impact score. Organize the Research Strategy as described below.

1. Background and Significance :

Define the problem to be solved and the specific gaps in knowledge that the project will address.

Outline the main characteristics and applicability of the proposed TTM. Projects should be justified on the basis of a strong potential to improve the mechanistic knowledge, and/or advance the diagnosis, treatment and prevention of chronic low back pain, if successful. Explain and justify how the proposed TTM may contribute to an integrated model of cLBP, and to patient phenotyping and sub-phenotyping. Explain whether the proposed TTM will be sufficiently used by the BACPAC Research Sites and Centers or relevant research communities. Explain and justify the potential of the proposed TTM to offer immediate relief through treatment or lead to clinically actionable strategies that would reduce chronic low back pain.

If proposing a project involving a currently available TTM that was originally approved for other clinical conditions, provide an explanation of how adopting the TTM would substantially impact clinical research of chronic low back pain.

2. Innovation

Describe how the proposed TTM addresses the challenge in a new and creative way. Describe how the proposed TTM offers clear and significant improvement over what is currently available. If the proposed TTM is optimized or adopted from an established technology area, describe how it overcomes a significant/longstanding technical challenge.

3. Preliminary data

Projects falling into category I (Exploratory Research for Technology Development) need not have preliminary data; however, they may be included if available. Do not include links to websites . No animations (movies) are allowed in any documents.

Projects falling into Category II-IV (Focused Technology Research and Development, Iterative Technology Research and Development and Research and Development for Technology Optimization) should summarize preliminary data documenting the technology’s potential to achieve both analytical and clinical sensitivity and specificity comparable to currently used technology.

4. Approach

The Approach section should be sub-divided in two sections, describing activities to be completed during the UH2 Phase and the UH3 Phase. It is recognized that applications in response to this FOA may propose a project from different technology development phases, therefore, the research plan and approaches should be consistent with the technology development phase and stated program goals. All applications, regardless of stage category, should address plans for assessing potential clinical utility and feasibility.

The UH2 section should address the following areas, if applicable:

• Plans to develop new or adapt/improve existing TTM for the chronic low back pain.
• Plans to evaluate the feasibility of the TTM for diagnosis, treatment and prevention of chronic low back pain, and/or for understanding the underling mechanisms.
• Plans for replication/small scale validation studies to ensure quality of data and consistency of the experimental techniques.
• Potential clinical utility (its potential specificity, sensitivity, selectivity, and other key functional parameters).
• Strategies, pitfalls and alternative approaches.
• Specific performance milestones to be achieved during the UH2 phase, e.g., analytical and clinical specificity, selectivity, and sensitivity.
• Applications focused on the discovery of novel TTM should focus on the early and conceptual stages of project development.
• Describe how the TTM proposed can be used by other components of the consortium and the collaborative arrangements to implement them.
• Describe how the clinical and research data generated by the Tech Site will be shared with the Data Integration/ Registry component of the BACPAC DAC and the BACPAC Informatics/Systems Biology BACPA Core respectively.

The UH3 section should address the following areas, if applicable:

• Plans for optimizing the TTM for operability in a clinical setting.
• Plans to assess the validity of the TTM with clinical specimens or patients. (While it is not necessary in the UH2 phase to test the TTM in a patient cohort with chronic low back pain, data may be generated in the UH3 phase to show likelihood that it will be usable in clinical setting).
• Statistical justification for study design and approach (the number of subjects/samples needed and a clear scientific rationale for the range and types of subjects/samples to be used).
• Modifying approaches to accommodate the larger number of patients to be recruited and data to be managed.
• Specific performance specifications and milestones to be achieved during the UH3 phase.

In addition, for applications that involve clinical trials, either to be conducted in a phased fashion, or to be conducted elsewhere in the Research Program using the TTM under development to explore mechanisms of chronic low back pain, the following areas should be addressed, if applicable:

Note: Discuss the following without duplicating information collected in the PHS Human Subjects and Clinical Trials Information Form.

• Plans and scientific rationale for the proposed clinical trial. A discussion of the rationale/premise for the trial and how it supports the need for this clinical trial to test either the clinical functionality of the TTM, efficacy or effectiveness of an intervention that could lead to a change in diagnosis, treatment and prevention of chronic low back pain; the rationale/premise should be well supported by preliminary data, information in the literature or knowledge of biological mechanisms.
• Overall research rationale and design for the selection of patient cohorts and relevant controls.
• Description and justification for the selection of tissue acquisition and processing approach.
• Plans for patient phenotyping, including clinical, laboratory and other parameters.
• Strategies, pitfalls and alternative approaches to expedite IRB review and approval and for timely recruitment and tissue acquisition.
• Establish the methods of tissue and other specimen collections in patients and controls.
• Statistical justification for study design and approach (the number of subjects/samples needed and a clear scientific rationale for the range and types of subjects/samples to be used).
• Data management plans for the proposed analyses.
• Establish milestones and timelines to assess research progress.

Integration with BACPAC Research Program and Future Directions Statement:

Applicants should discuss a plan to interface with the Interdisciplinary Mechanistic Research Centers, and the Systems Biology and Informatics Core for data integration and modeling. It is recognized that applicants will NOT know in advance with whom they will be collaborating because the members of the BACPAC consortium will not be known before award; therefore, applicants should make reasonable assumptions as to the types of collaborations that will be available and build flexibility into their research plans. Also, applicants should prepare a future directions statement to address the potential of the proposed TTM for clinical use beyond the UH3 phase.

Transition Milestones to the UH3 Phase and Timeline:

Applicants should propose an overall plan for the progression from UH2 to the UH3. Applicants should state explicitly qualifiable transition milestones to the UH3 phase. This information must be provided under the heading, 'Transition Milestones to the UH3 Phase.' Examples of well-defined milestones are: results that support, reject, or are inconclusive regarding testing of their concept/hypothesis; appropriate objective performance targets; quantitative indicators for go/no go decision points such as an appropriate level of detection and coefficient of variation, or sensitivity and specificity; and timelines for assessing progress, including specific milestones for progressing from the UH2 to the UH3 funding periods. Additionally, applicants should address each of the items listed below:

• Define a timeline for the anticipated attainment of each milestone and the overall goal.
• Describe any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.
• Reviewers will be instructed to evaluate the appropriateness of these transition milestones. Program staff will use these applicant-defined and peer-reviewed criteria to determine if the UH3 will be awarded.

Letters of Support: Applicants are encouraged to include documentation of the commitment of any subcontractors, companies providing study agents or other resources for the project, consultants as well as service agreements for personnel or facilities. Letters of commitment must be co-signed by the business official of the collaborating center. Applicants are also encouraged to include a letter from the institution describing the relevant expertise, experience and accomplishments of the applicant organization in planning, coordinating and managing the technology development activities and functions provided for in the FOA, particularly with respect to chronic low back pain.

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

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan
Note that if an application is awarded, the NIAMS will organize an independent Data and Safety Monitoring Board or appoint an independent Safety Officer based on the risk and complexity of the trial. For more information about NIAMS requirements for Data and Safety Monitoring, please see: https://www.niams.nih.gov/grants-funding/conducting-clinical-research/data-safety-guidelines-policies).

Section 4 - Protocol Synopsis

4.2.a Narrative Study Description

As applicable, state how the following resources for clinical research will be utilized:

• NINDS Common Data Elements (https://www.commondataelements.ninds.nih.gov/#page=Default);
• NeuroQOL (http://www.healthmeasures.net/explore-measurement-systems/neuro-qol);
• NIH Toolbox (http://www.healthmeasures.net/explore-measurement-systems/nih-toolbox); and
• PROMIS (http://www.healthmeasures.net/explore-measurement-systems/promis).

4.4 Statistical Design and Power
Applicants should provide a Statistical Analysis Plan (SAP) including details on the analyses specified in the study protocol, including a description of how the statistical analysis of the primary, secondary and other endpoints will be performed, how the sample size was determined, study power, how missing data will be handled, plans for interim analyses for safety and futility, plans for recalculation of the sample size midway through the trial (if applicable), etc. If computer simulations were used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs), to choose between alternative outcome measures, or to determine sample size, accounting for the impact of noncompliance, missing data, subject eligibility criteria, etc., sufficient details about the simulations should be provided if the SAP. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

The final SAP will be developed with statistical guidance of the BACPAC DAC.

4.6 Will the study use an FDA-regulated intervention?

4.6.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status:

4.7 Dissemination Plan
UH2/UH3 applicants proposing a clinical trial must submit a plan for the dissemination of NIH-funded clinical trial information that will address how the expectations of the NIH Policy on the Dissemination of NIH-funded Clinical Trial Information will be met. Responsibility for adhering to this policy lies with the UH3/UH3 grantee institution.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-Related Attachments

The application must contain the following information, according to the instructions below, to provide evidence that the investigator(s) has planned a feasible clinical trial. The information provided here supports the Research Strategy and should not duplicate it. The following documents must be uploaded as separate pdf files with the names indicated below and appended with 1, 2, 3, etc., if needed.

1. Clinical Monitoring and Data Management Plan: The Clinical Monitoring and Data Management Plan is a required attachment and must use the filename "Clinical Monitoring and Data Management Plan.pdf." Applications lacking this attachment will be considered incomplete and will not be reviewed. Each Clinical Monitoring and Data Management Plan includes 2 parts: (A) The Clinical Monitoring Plan for the quality assurance of the proposed clinical trial through clinical data monitoring activities, and (B) the Data Management Plan for the quality controls proposed through data management activities.

Part A: The purpose of the Clinical Monitoring Plan is to verify that the clinical trial is being conducted, and documented in accordance with the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s):

• Describe the persons/entity responsible for conducting the clinical monitoring (e.g., contracted Clinical Research Associate, Data Coordinating Center, Independent study monitor from the Clinical Coordinating Center);
• Describe the frequency of planned monitoring activities (e.g., Study Initiation, Interim Visits, Study Close Out), locations where the monitoring will occur (e.g., participating clinical sites, data center, clinical coordinating center) and what data will be reviewed;
• Provide an overall description of the monitoring plan to ensure adherence to the protocol, adequate documentation of the consenting process, and the quality and consistency of the study intervention(s), including fidelity monitoring for behavioral interventions. Include methods to monitor study data collected and systems to record and manage exceptions and deviations. If applicable, describe monitoring of participating facilities, such as labs or pharmacies for adequate handling and storage of investigational product(s) and study specimens. Include a description to assure that the investigational product(s) accountability and reconciliation are performed adequately during and at the end of the trial per applicable regulatory requirements;
• Describe plans for handling any deficiencies that are uncovered and in cases of serious deficiencies the appropriate reporting to relevant authorities, including but not limited to the IRB of record, DSMB if one is assigned, FDA if applicable, institutional officials and the NIH.

Part B: The purpose of the Data Management Plan is to ensure that validated systems and controls are in place to assure the integrity of the clinical research data being collected for the proposed study:

• Describe methods and systems for data collection (e.g., Case Report Forms/CRFs), data entry, data verification and data validation. Describe the data query process and frequencies and any planned mitigation strategies in the event of noncompliance;
• Describe methods and systems to ensure data confidentiality and subject privacy;
• Describe process for locking the final trial datasets and the planned procedures on data access and sharing, as appropriate.
• The NIAMS requirements for clinical monitoring and data management for clinical trials as described above are in addition to the application's Data and Safety Monitoring Plan (DSMP) provided in section 3.3 of FORMS-E, which describes how research participant safety and data in the trial will be monitored by an independent monitoring and oversight entity.

2. Intervention Documents: The Intervention Documents attachment is required and must use the filename "Intervention Documents.pdf." Applications that lack an Intervention Document attachment will be considered incomplete and will not be reviewed. The Intervention Documents should include one of the following documents according to the type of intervention(s) to be used in the proposed clinical trial:

• Investigator's Brochure or Product Label/Package Insert (provide for trials in which the intervention is a device, drug, or a biologic): A compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects and provides information on the risk of the intervention;
• Intervention Monitoring Manual(s): (provide for trials in which the interventions are behavioral or social). A document that describes in detail the content and delivery of the intervention, the intervention manual should describe how to conduct the intervention, how to train the interventionists, how to monitor fidelity in delivering the intervention, and the rationale for the specified intervention.

3. Schedule of Events. The filename "Schedule of Events" should be used to name this attachment. Provide a schematic, table, or text description of the protocol-specified schedule of events for an individual study participant. It should capture each study visit/assessment time point and planned activity(ies) for each time point. Applications that lack a schedule of events attachment will be considered incomplete and will not be reviewed.

4. Clinical Trial Experience. The filename Clinical Trial Experience should be used to name this attachment. Provide a table detailing the characteristics of clinical trials or studies with longitudinal components in the last five years that demonstrate experience in conducting clinical trials of similar complexity in back pain or musculoskeletal chronic pain conditions. Applications that lack an Clinical Trial Experience attachment will be considered incomplete and will not be reviewed.

The table columns must include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

Column G: whether the trial(s) were completed on schedule or not

Column H: publication reference(s)?

There is no page limit for these attachments, but applicants should not include unnecessary information.

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

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

1. Criteria

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

For this particular announcement, note the following:

Technology Research Sites will support projects to develop, integrate, optimize, validate, translate or otherwise accelerate the adoption of promising tools, technologies and/or methods (TTM) that will lead to new understanding of the mechanisms of low back pain.

As a result, applications responding to this RFA may be design-directed, developmental, discovery-driven, or hypothesis-driven. Novelty is defined as TTM that have not been and/or are not used in clinical research of cLBP.

Reviewers need to take these into consideration and put emphasis on the potential of the TTM to significantly advance our knowledge in treatment/research of cLBP. Reviewers will assign a single impact score for the entire application, which includes both the UH2 and UH3 phases.

In addition, for applications involving clinical trials:

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

Significance

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

In addition, for applications involving clinical trials

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

Specific to the FOA:

Does the proposed TTM development have the potential to address a significant unmet need in cLBP research? Regardless of the inherent risk of the project, if continued development of the TTM is successful, would its availability improve the mechanistic knowledge, and/or advance the diagnosis, treatment and prevention of chronic low back pain? What are the potential and feasibility of the proposed TTM to be sufficiently used by BACPAC consortium or relevant research communities? Will the TTM contribute to an integrated model of cLBP? Will the TTM contribute to understanding subtypes of patients with cLBP?

Investigator(s)

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

Innovation

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

In addition, for applications involving clinical trials

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

Specific to the FOA:

Has the proposed TTM been used before in clinical research and/or diagnosis, treatment and prevention of cLBP? Does the project proposed to address the challenge in a new and creative way? Does the proposed TTM offer potential for clear and significant improvements over what is currently available? Does the proposed TTM overcome a significant/longstanding technical challenge if it is optimized or adopted from an established technology area?

Approach

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

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable?

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested?

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

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

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

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to the FOA:

Is the research plan consistent with the technology development phases and stated program goals?

For projects falling into category I (Exploratory Technology Research and Development): Does the application appropriately focus on exploratory research to determine technological feasibility rather than proposing hypothesis-driven, biomedical research? Are risks clearly addressed and alternative strategies described? If the project is intended to select the most appropriate technological approach among multiple alternatives, would completion of the proposed research plan be likely to result in sufficient preliminary data to make that determination? Would experimental results from the exploratory project serve as a foundation for the next stage of development? Does the application include an appropriate plan for assessing potential clinical utility and feasibility of the proposed TTM?

For projects falling into categories II-IV (Focused Technology Research and Development, Iterative Technology Research and Development, and Research and Development for Technology Optimization): Does the application appropriately focus on addressing technical challenges, testing, validation and optimization for utility in cLBP research? is the experimental approach reasonable with respect to known issues and concerns of technological feasibility? Will completion of the proposed research plan be likely to result in a functioning first instantiation of the TTM?

Does the application provide a future directions statement to appropriately address the potential of the proposed technology for clinical use beyond the UH3 project? Does the application provide a plan to interface with the Interdisciplinary Mechanistic Research Centers, and the Systems Biology and Informatics Core for data integration and modeling? What is the likelihood that the described technology will interface with BACPAC consortium?

In addition, for applications involving clinical trials:

?Does the application include a clearly presented schedule of events?

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

Environment

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

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Transition Milestones to the UH3 Phase

Is the overall plan for the progression from UH2 to the UH3 funding periods well thought out? Are milestones provided for the UH2 stage properly objective and quantitative whenever appropriate? Are these milestones well aligned with the specific aims of the Research Phases? How realistic are these milestones and associated timelines? Do the proposed milestones and timelines clearly identify benchmarks for successful completion of the UH2 stage? Are other critical go/no go decision points and timelines well defined and appropriate?

Specific to applications proposing clinical trials

Clinical Monitoring and Data Management Plan

Are the procedures for clinical data monitoring and data management activities adequate? Are standardized systems and controls in place for data monitoring to ensure data integrity and to assess the effect of the study intervention?

Intervention Documents
Reviewers will consider whether the intervention documents provided are acceptable in relation to the proposed research. For trials in which interventions are other than behavioral or social, is the Investigator's Brochure or Product Label/Package Insert acceptable? For trials in which the interventions are behavioral or social, is the Intervention Monitoring Manual acceptable?

Study Timeline

Specific to applications proposing clinical trials

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

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

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

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

Vertebrate Animals

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

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

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.