BACKGROUND:

The United States faces a crisis due to the high prevalence of chronic pain and associated opioid use disorder and overdose deaths. More than 25 million adults in the U.S. report experiencing pain every day. A major challenge in pain care is the lack of evidence-based best practices to prevent chronic pain from occurring after an acute pain episode. For most people, acute pain resolves over time as the injury or trauma heals. In many people however, acute pain from injury, surgery, or disease processes persists well beyond the initial insult (sometimes throughout life) and is often intractable. Chronic pain persists beyond recovery due to changes in the peripheral and central nervous systems. However, the mechanisms driving acute pain transition to a chronic state are poorly understood.

The ability to predict which patients are more likely to be susceptible versus resilient to the development of chronic pain is a crucial step towards the development of personalized prevention strategies to transform acute pain treatment approaches and reduce or prevent chronic pain. Toward this end, the NIH Common Fund supported Acute to Chronic Pain Signatures (A2CPS) Program aims to identify biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain after an acute pain event. Furthermore, if any of the predictive biomarkers identified through this program play a mechanistic role in the development of chronic pain, then the molecules, pathways, and/or brain circuits identified could serve as new potential therapeutic targets for reversing chronic pain or increasing patient resilience to chronic pain.

A2CPS is part of the multi-pronged HEAL (Helping to End Addiction Long-term) Initiative, an aggressive effort to speed scientific solutions to stem the national opioid public health crisis (https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative). HEAL will build on extensive, well-established NIH research to address the opioid crisis and provide safer therapies for people with pain. Funding for A2CPS will be from the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress.

Overall A2CPS Program Description: The A2CPS program will be funded as cooperative agreements through five linked FOAs. Awardees will work together as a consortium with strong communication and cooperation. The A2CPS program will support two longitudinal prospective studies on large cohorts of patients who experience acute pain from either a specific surgical procedure or a specific musculoskeletal trauma. The goal of the program is to identify candidate biomarkers and combine them into biosignatures predictive of the susceptibility or resilience to the development of chronic pain. The candidate biomarkers to be tested as primary outcomes in the two studies will be selected by a panel of external experts, consortium awardees, and NIH staff, who will consider the most promising biomarkers of transition or resilience to chronic pain based on current evidence. The size of each cohort is expected to be approximately 1800 patients, and the number of study biomarkers identified as primary study outcomes is expected to be approximately 40, based on an NIH power analysis calculation.

Overall, the A2CPS program will:

• establish a Clinical Coordinating Center (CCC) (RFA-RM-18-035) to support study design, efficiency, and quality; develop protocols and contracts; train clinical staff in study procedures; and develop, coordinate, and monitor study implementation at the consortium’s clinical sites. The CCC will lead the development of the clinical protocols in the planning year.
• support two Multisite Clinical Centers (MCCs) (RFA-RM-18-033 and RFA-RM-18-034), each of which will recruit one of the homogeneous pain cohorts at onset of an acute pain event; deliver, monitor, and record usual pain care including opioid and other analgesic use; assess patients for study-determined characteristics including detailed patient reported outcome’s (historical data such as previous surgeries, trauma, substance abuse, concurrent pain conditions, depression, somatization tendencies, support system, etc); perform brain imaging, sensory tests, and collect biospecimens at onset of acute pain and follow-up (time = 0, 3 months, and 6 months).
• support one or more Omics Data Generation Centers (ODGCs) (RFA-RM-18-032) with expertise and resources to generate a diverse set of omics data from the biospecimens collected. Biospecimens will be analyzed extensively by the ODGCs using high-throughput technologies that allow rapid identification of many different biological molecules from large numbers of samples. Because the majority of the potential circulating/tissue biomarkers in the literature at this time are from 4 categories: proteomics, lipidomics, metabolomics, and extracellular RNA, it is expected the ODGCs will have expertise in these areas. Applicants to this component will be required to set aside 20% of their budget in order to add in any compelling additional omics assays identified during the planning year.
• collect patient biospecimens sufficient for ODGC analysis. The ODGC will set aside 20% of the budget to have the flexibility to add assays as determined in the planning year. If added funds become available, collection of additional biospecimens for future analysis by novel or dramatically improved assays may also be considered during the planning year. There will be a transparent and rigorous biospecimen reporting structure in place as well as a process whereby PIs across the consortium can access biospecimens to perform tests. At the end of the study, all unused biospecimens will be submitted to an appropriate NIH repository .
• establish a Data Integration Resource Center (DIRC) (RFA-RM-18-031) to receive data from the CCC, MCCs, and ODGCs for coordination, standardization, collection, integration, and statistical analysis of the clinical, imaging, and omics data. The DIRC will make the A2CPS data available to the scientific community using resources obtained through the NIH Data Commons (https://commonfund.nih.gov/commons) to ensure the data will be FAIR (Findable, Accessible, Interoperable, and Reusable) and accessible via cloud based data storage and computing. The DIRC also will develop a virtual biospecimen repository, build a publicly accessible database/website, coordinate logistics, such as organizing PI meetings, and perform outreach activities.
• be governed by a Steering Committee of A2CPS investigators and NIH staff that will oversee development of consensus policies, protocols, and procedures for consortium-wide activities such as clinical coordination, data collection, and resource sharing.
• receive input on development and progress of the project from a panel of External Program Consultants (EPCs), a group of experts with broad, relevant expertise, who are independent of the awards.

Timeline: The first year of the program (estimated to be summer 2019-summer 2020) will be a planning year during which limited funds will be awarded to awardees for all five FOAs. In this year, the EPCs and 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. The consortium will assess and refine the statistical analysis plan (including power analysis) for each cohort. At the kick-off meeting or shortly thereafter, an expert panel, including consortium members, the EPCs, and outside experts will select approximately 40 evidence-based high value candidate biomarkers for primary study outcomes.

The planning year will be followed by up to three additional years (duration varies across awards) of higher funding levels, during which the study will be implemented. We anticipate patient enrollment to begin in summer 2020, immediately after the planning year. In July 2021 or at approximately 50% completion of 6 month phenotyping, a futility assessment will be performed to determine whether the rate of transition to chronic pain and patient retention is adequate to meet the assumptions of the power analysis. In the event of lower than expected transition or poor retention of patients, the A2CPS Steering Committee with the EPCs will make recommendations to NIH to either increase enrollment or terminate the study. NIH leadership will make the final determination. We expect enrollment to be complete by July 2022, and clinical assessments to be complete by January 2023. Data analysis and public archiving of the data for data mining efforts by the scientific community should be complete by February 2024.

FUNDING OPPORTUNITY:

The purpose of this FOA is to support one Multisite Clinical Center (MCC) to implement the enrollment and multimodal longitudinal assessment of a large cohort of patients with acute pain from a musculoskeletal trauma to identify biosignatures for resilience to and/or the transition from acute to chronic pain. ?Applications will be reviewed for responsiveness to this FOA. Applications deemed non-responsive to this FOA by NIH staff will be withdrawn without review. NIH staff do not anticipate that applications submitted to this FOA will be clinical trials given that there is no proposed intervention

UM1 mechanism. Awards made under this FOA will be through the UM1 mechanism for Research Projects with Complex Structure. This mechanism is for cooperative agreements to support large-scale research activities with complicated structures that cannot be appropriately categorized into an available single component activity code. The components represent a variety of supporting functions and are not independent of one another. Substantial federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of the award. The UM1 is typically reserved for high-priority research areas that require a significant level of involvement from NIH staff (oversight, coordination, or facilitation).

Key activities of the MCC will be to:

• communicate effectively with other consortium members (CCC, DIRC, ODGC) and NIH staff to achieve the overall goals of A2CPS. The MCCs are expected to work as a consortium with the CCC, ODGCs, and DIRC. Please see companion FOAs for these components to gain a better understanding of the responsibilities for each component.
• work with the consortium to assess and refine the power analysis for the consortium as a whole, to improve the likelihood of success.
• recruit and enroll patients with selected acute pain event.
• deliver, monitor, and record usual acute and long-term patient care including pain care.
• capture opioid use, including whether the patient is dependent on opioids at the 6 month assessment.
• capture injury details in the electronic health records.
• adapt electronic health records to align with A2CPS needs.
• phenotype patients for study-determined characteristics.
• perform study determined brain imaging and sensory tests at T=0, 3 months and 6 months.
• collect bio-specimens for study determined assays at T = 0, 3 months and 6 months.
• collect, store (on -site), and transfer biospecimens to ODGCs as needed.
• deposit patient assessment data and all primary data at the DIRC.

Applicants should plan to address the following items:

• Applicants should plan to develop a study enrolling approximately 1800 patients over a two-year period from a SINGLE specific type of musculoskeletal trauma (e.g. bone fracture event with expected 30% to 60% rate of transition from acute to chronic pain), and retain these patients for assessments at time = 0, 3 months, and 6 months post-trauma. In other words, all patients in the study must have experienced the same musculoskeletal trauma.
• Applicants should plan to provide justification for the selected musculoskeletal trauma with consideration of expected transition rate from acute to chronic pain based on the scientific literature and from their own preliminary data, if available.
• Applicants should plan to provide a power analysis that will accommodate identification of multiple individual biomarkers to create predictive biosignatures.
• Applicants should plan how the MCC will collaborate with the cross-consortium efforts.
• Applicants should consider partnering with existing groups or leverage existing resources to achieve the goals of A2CPS. This could include partnering with the National Center for Advancing Translational Sciences' Trial Innovation Network (www.trialinnovationnetwork.org) and/or Clinical and Translational Science Award (CTSA) awardees.
• Applicants should plan to propose and justify at least ten potential candidate biomarkers (to be included as part of the final set of around 40 primary outcomes to be tested) that they consider as the most compelling based on the scientific literature or from their own preliminary data.
• Applicants should plan to include steps they will take to avoid unconscious experimenter bias with respect to diagnosis of transition chronic pain?.
• Applicants should plan for the PDs/PIs and essential team members to travel domestically for four quarterly face to face meetings in year one of the program and for biannual meetings for the remainder of the funding period.

Informational Webinar. Prospective applicants are strongly encouraged to attend an informational webinar with NIH staff on September 6, 2018 from 2-4 PM EDT. Applicants also may contact NIH scientific staff and see the A2CPS FAQs (https://commonfund.nih.gov/pain/faq) for further information.

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, including the NIH Intramural Program

• 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

Applicant organizations

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

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

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

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

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

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

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

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

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

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:

Linda L. Porter, Ph.D.
National Institute on Neurological Disorders and Stroke (NINDS)
Telephone: 301-435-7572
Email: [email protected]:

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

with the following exceptions:

The UM1 mechanism requires that the research strategy consist of separate components describing supporting functions that are interdependent. For this specific FOA, the research strategy should consist of the following sub-sections with the indicated page limits, all sections are required:

• Overall Project Goals and Specific Aims: 2 page limit
• Research Management Plan (including intra-MCC communication, communication with other A2CPS components): 2 page limit
• Power analysis and cohort recruitment and enrollment: 6 page limit
• Clinical procedures, including capabilities and strategies for sample collections, electronic health record management, patient phenotyping, and sensory testing: 10 page limit
• CNS imaging capabilities and proposed strategy: 6 page limit
• Biospecimen collection, storage, and transfer capability and strategy: 2 page limit
• Plans for data deposition with DIRC: 2 page limit

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: The overall programmatic goal of the MCC is to implement the enrollment and multimodal longitudinal assessment of a large cohort of acute pain from a musculoskeletal trauma to identify biosignatures for resilience to and/or the transition from acute to chronic pain. Describe the goals of the MCC for the performance period of this project.

Research Strategy: The overall research strategy should be sure to address the following items:

• Applicants must provide a timeline and detailed quantitative annual milestones throughout the funding period. If selected for funding, applicants will work with NIH staff to develop more granular quarterly milestones for each year of funding.
• Applicants should provide a plan for enrolling approximately 1800 patients over a two-year period from a SINGLE specific type of musculoskeletal trauma (e.g. bone fracture event with expected 30% to 60% rate of transition from acute to chronic pain), and retain these patients for assessments at time = 0, 3 months, and 6 months post-trauma. In other words, all patients in the study must have experienced the same musculoskeletal trauma. A description of the homogeneity of the patient cohort and evidence of the MCC's ability to enroll this number of patients should be provided. We anticipate that enrollment will reflect the population of the US in terms of sex and ethnic diversity, take place across multiple sites, and use a central Institutional Review Board (IRB).
• Applicants should provide justification for the selected musculoskeletal trauma with consideration of expected transition rate from acute to chronic pain based on the scientific literature and from their own preliminary data, if available. The success of this project will depend in part on having a sufficiently high transition rate from acute to chronic pain.
• Applicants should describe their ability to manage and adapt their electronic health records for study needs, assess patient reported outcomes (including, but not limited to, historical data such as previous surgeries/injuries, trauma, substance abuse, concurrent pain conditions, depression, somatization tendencies, support system, etc.) , perform sensory testing (e.g. thermal, mechanical pain thresholds, conditioned descending modulation), perform CNS imaging (e.g. fMRI, RS-MRI with thermal stimulus, arterial spin labeling), and collect and store biospecimens.
• Applicants should provide a power analysis that will accommodate identification of multiple individual biomarkers to create predictive biosignatures.
• Applicants should describe how the MCC will collaborate with the cross-consortium efforts such as standardization of electronic health records, development of clinical protocols, safety standards, and biospecimen collection and storage protocols.
• Applicants should consider partnering with existing groups or leverage existing resources to achieve the goals of A2CPS. This could include partnering with the National Center for Advancing Translational Sciences' Trial Innovation Network (www.trialinnovationnetwork.org) and/or Clinical and Translational Science Award (CTSA) awardees.
• Applicants should propose and justify at least ten potential candidate biomarkers (to be included as part of the final set of around 40 primary outcomes to be tested) that they consider as the most compelling based on the scientific literature or from their own preliminary data. These candidate biomarkers could be in the areas of CNS imaging, patient reported outcomes, sensory testing, elements of the patient electronic health record, omics assays on biospecimens, or other well-justified areas. Examples of candidate biomarkers include patient reported psychosocial characteristics, targeted CNS changes, altered pain sensitivity and modulation, changes in the levels of a specific extracellular RNA species, protein, or metabolite, etc.
• A panel of external experts, consortium awardees, and NIH staff, will finalize the set of selected candidate biomarkers after the consortium kick-off meeting in August/September 2019. Therefore, applicants should provide evidence of their ability to shift effort and budget to support the final set of around 40 biomarker candidates and adapt to assessment of new and compelling candidate biomarkers.
• Applicants should describe steps they will take to avoid unconscious experimenter bias with respect to diagnosis of transition chronic pain.
• Applicants should plan for the PDs/PIs and essential team members to travel domestically for four quarterly face to face meetings in year one of the program and for biannual meetings for the remainder of the funding period.

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• A primary goal of the A2CPS program is to facilitate discoveries by the broad scientific community. Restrictive sharing practices and licensing terms for A2CPS-generated data and resources could substantially diminish their value and public benefit. Accordingly, awardees are expected to manage data, resources, protocols, and software in a way that achieves this goal.
• Applicants should indicate their willingness to abide by all data deposition, quality control metrics, standardization, metadata requirements, data and software release, and public copyright license policies developed by the A2CPS Steering Committee and approved by NIH staff. Sharing practices that hinder, prevent or block access to or use of A2CPS program data, tools, and resources for research purposes will not be considered acceptable. The development of policies, methods, and standards for such sharing is critically important. The NIH expects that the awardees, through the A2CPS Program Steering Committee, will develop such policies, methods, and standards in concert with the NIH. These policies, methods, and standards must remain consistent with NIH-wide policies on data and resource sharing.
• Specific Plan for Data Sharing. Consistent with achieving the goals of this program, the NIH expects that information such as collected data (e.g. clinical measures, brain images, patient reported outcomes, sensory testing, metabolomic, lipidomic, proteomic, etc.), technical protocols, and any other data or metadata collected under this FOA will be deposited in the DIRC.
• Data will be made available through the A2CPS portal as appropriate via the DIRC. The A2CPS portal will serve as the central access point for information regarding data, critical tools, protocols, and reagents developed by the A2CPS program. The A2CPS consortium will make the A2CPS data available to the scientific community using resources obtained through the NIH Data Commons (https://commonfund.nih.gov/commons) to ensure the data will be FAIR (Findable, Accessible, Interoperable, and Reusable) and accessible via cloud based data storage and computing.
• A2CPS data will also be deposited by the DIRC (or possibly other A2CPS grantees) in appropriate public or controlled-access data repositories. Applicants should identify such repositories and describe plans for deposition. For datatypes that lack suitable public repositories, applicants should indicate their willingness to identify an appropriate alternative solution consistent with achieving the goals of the program.
• Genomic Data Sharing Plan: If applicants propose to generate genomic data, they must indicate their willingness to abide by the NIH Genomic Data Sharing Policy (https://gds.nih.gov/) and should indicate their agreement to it in the data sharing plan.
• Specific Plan for Protocol and Reagent Sharing. As one of the primary goals of this program is to advance research through development, establishment, broad dissemination and use of community resources across the research community, NIH intends that protocols and reagents generated by the A2CPS program be broadly available and distributed at minimal cost, and without undue intellectual property constraints, so that they can be as widely used as possible for research purposes by the larger scientific community. For all applications and where otherwise applicable, the applicant should discuss plans for sharing and distribution of non-data resources that will be generated by the proposed project. Applicants are encouraged to use Research Resource Identifiers (RRIDs).
• The DIRC will work with all A2CPS program investigators to collect, curate, and disseminate information regarding reagents being developed by the program and to disseminate this information through the A2CPS Portal and other sources as appropriate and consistent with achieving the goals of the program.?
• Specific Plan for Sharing Software: A software dissemination plan, with appropriate timelines, is expected in applications proposing software development. There is no prescribed single license for software produced in this project. However, reviewers will be asked to evaluate the software sharing and dissemination plan based on its likely effectiveness. A dissemination plan guided by the following principles is thought to be the most effective:
  • The software should be freely available to biomedical researchers and educators in the non-profit sector, such as institutions of education, research institutions, and government laboratories.
  • The terms should also permit the dissemination and commercialization of enhanced or customized versions of the software, or incorporation of the software or pieces of it into other software packages.
  • To preserve utility to the community, the software should be transferable such that another individual or team can continue development in the event that the original investigators are unwilling or unable to do so.
  • The terms of software availability should include the ability of researchers outside the project and its collaborating projects to modify the source code and to share modifications with other colleagues. An applicant should take responsibility for creating the original and subsequent "official" versions of a piece of software.
  • Applicants are asked to propose a plan to manage and disseminate the improvements or customizations of their tools and resources by others. This proposal may include a plan to incorporate the enhancements into the "official" core software, may involve the creation of an infrastructure for plug-ins, or may describe some other solution.
  • Any software dissemination plans represent a commitment by the institution (and its subcontractors as applicable) to support and abide by the plan.

• Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds (NIH Research Tools Policy (http://grants.nih.gov/grants/intell-property_64FR72090.pdf) and other related NIH sharing policies at http://sharing.nih.gov).

Sharing within the A2CPS

The A2CPS program aims to maximize the benefits of sharing, while protecting the intellectual property of the data generators. Prepublication sharing of data within the consortium will allow collaboration across initiatives and further the progress of the A2CPS program towards its goals and objectives. Therefore, the A2CPS program requires that data, metadata, and resources generated from A2CPS funding be made available to other A2CPS members immediately upon being considered shareable . When A2CPS-generated material under embargo is shared within the A2CPS program, it will be considered confidential with the understanding that the information will not be used or disclosed by A2CPS members unless explicitly agreed upon by the originator of the data under mutually acceptable terms. That is, consortium members may not publish using material generated by other consortium members without a collaboration or other agreement, or until the material in question has been made available to the public. A2CPS investigators accessing embargoed material only available to members of the A2CPS must sign a non-disclosure form agreeing to these terms.

Prior to funding, NIH Program Staff may negotiate modifications to the Sharing Plan with the applicant.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for the A2CPS program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below. Awardee will retain custody of and have primary rights to the data and software developed under this award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

The PD(s)/PI(s) will have the primary responsibility for:

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Participating in group activities, including a Consortium-wide A2CPS Program Steering Committee and subcommittees as needed.
• The A2CPS Consortium will meet in person four times during the planning year, at least twice a year for subsequent years, and the A2CPS Program Steering Committee will recommend the frequency of other in-person and teleconference meetings as needed.
• Providing reports and data in a timely fashion as agreed upon by the A2CPS Program Steering Committee.
• Submitting all data as soon as they are collected to the A2CPS DIRC for quality control.
• Preparing abstracts, presentations and publications and collaborating Consortium-wide in making the public and professionals aware of the program.
• Assessing and disseminating data, protocols, and methods developed for or derived from the A2CPS program within and outside the Consortium.
• Adhering to policies regarding data sharing and publication established by the NIH and the A2CPS Program Steering Committee.
• Abiding by common definitions, protocols, and procedures, as chosen by majority vote of the A2CPS Program Steering Committee.
• Submitting periodic progress reports in a standard format, as agreed upon by the A2CPS Program Steering Committee and NIH A2CPS Working Group.
• Attending and participating in A2CPS Program Steering Committee meetings and accepting and implementing decisions by the NIH A2CPS Working Group, as appropriate.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The NIH A2CPS Working Group consists of NIH programmatic staff from multiple Institutes and Centers of the NIH as well as the Office of the Director.

The NIH Project Scientist(s) will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff will be to facilitate and not to direct the activities. The Project Scientist(s) will participate as members of the A2CPS Program Steering Committee and, the Project Scientists together will have a single vote. The Project Scientist(s) will have the following substantial involvement:

• Participating with the other A2CPS Program Steering Committee members in addressing issues that arise with A2CPS planning, operation, assessment, and data analysis. The Project Scientist(s) will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the awardees. The Project Scientist(s) will also help coordinate the efforts of the A2CPS Consortium with other groups conducting similar efforts.
• Attending all A2CPS Program Steering Committee meetings as a voting member, assisting in developing standard operating procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist(s) will be responsible for working with the grantees as needed to manage the logistic aspects of the A2CPS program.
• Reporting periodically on A2CPS progress to the Common Fund A2CPS Working Group and through it to the NIH Common Fund.
• Serving on subcommittees of the A2CPS Program Steering Committee as appropriate.
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.
• Participating in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through the program.
• Other NIH A2CPS Working Group staff may assist the awardee as designated by the Program Official.

Additionally, an agency Program Official or IC Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned Program Official may also serve as an NIH Working Group Project Scientist(s) to assist the awardee. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and Project Scientist will negotiate with the applicant and agree on a final set of approved milestones which will be specified in the Notice of Award. The NIH Program Official, in consultation with the Project Scientist and NIH A2CPS Working Group, will determine if the awardee has met the milestones required for each year of funding.

NIH reserves the right to withhold funding or curtail an award in the event of:

• Substantive changes in the project, or failure to make sufficient progress toward the work scope with which NIH concurred, or
• Ethical or conflict of interest issues.

Areas of Joint Responsibility include:

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to manage, assess, and disseminate the A2CPS program. The awardees and the Project Scientist(s) will meet in person with the A2CPS Program Steering Committee four times during the planning year, twice a year for subsequent years, and on conference calls as needed to share information on methodologies, analytical tools, and preliminary results. PDs/PIs, key co-investigators and pre- and post-doctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, are eligible to attend these meetings.

The A2CPS Program Steering Committee will serve as the main scientific body of the program. The A2CPS Program Steering Committee will be responsible for coordinating the activities being conducted by the program and is the committee through which the NIH A2CPS Working Group formally interacts with the A2CPS investigators. The A2CPS Program Steering Committee membership will include PD(s)/PI(s) of each A2CPS award, other staff as needed (ex-officio) and the NIH Project Scientist(s). The A2CPS Program Steering Committee may add additional members, and other government staff may attend the A2CPS Program Steering Committee meetings as desired. Each project will have one vote and the NIH Program Scientist(s) together will have one vote.

The A2CPS Program Steering Committee may establish subcommittees as needed to address particular issues, which will include representatives from the program and the NIH and possibly other experts. The A2CPS Program Steering Committee will have the overall responsibility of assessing and prioritizing the progress of the various subcommittees.

The A2CPS awardee agrees to work collaboratively to:

• Provide for secure, accurate and timely data submission.
• Participate in presenting and publishing new processes and substantive findings.
• Assess and disseminate A2CPS data and resources
• Participate in the governance of the A2CPS program as a member of the A2CPS Program Steering Committee.
• Interact with other relevant NIH activities, as needed, to promote synergy and consistency among similar projects.

External Program Consultants (EPCs):

• A group of EPCs will be responsible for reviewing and evaluating the progress of the entire A2CPS program. The EPCs, as appropriate and at the request of the NIH A2CPS Working Group, also will provide input to the NIH about the progress of the individual A2CPS projects in meeting their individual and Consortium goals and milestones. The EPCs will be comprised of 4-8 senior, non-federal experts who are not directly involved in the activities of the A2CPS program and who have relevant scientific expertise. NIH will appoint the EPCs and select one member as chair. The A2CPS POs, PSs, NIH A2CPS Working Group, and other NIH staff may attend the EPC meetings.
• The EPCs will meet at least once a year, in conjunction with a meeting of the A2CPS Program Steering Committee in the DC Metro area, to allow the EPCs to interact directly with the awardees, and by phone or email, at other times as needed.
• Annually, the EPCs will provide their individual assessments to the NIH of the progress of the A2CPS Consortium and, as necessary, will present recommendations regarding any changes to the A2CPS program. The assessments and recommendations will be provided, through the NIH A2CPS Working Group, to the Director of the Office of Strategic Coordination, NIH.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The three members will be: a designee of the A2CPS Program Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16. eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

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

Linda L. Porter, Ph.D.
National Institute on Neurological Disorders and Stroke (NINDS)
Telephone: 301-435-7572
Email: [email protected]:

Joseph Rudolph, Ph. D.
Center for Scientific Review (CSR)
Telephone: 301-408-9098
Email: [email protected]

Yvonne Talley
National Institute on Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-7432
Email: [email protected] 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.