It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Purpose

This Funding Opportunity Announcement (FOA) encourages UG3/UH3 phased cooperative research applications to conduct an efficient, large-scale pragmatic trial to evaluate the impact of, and strategies to best implement, acupuncture treatment of older adults (65 years and older) with chronic low back pain (CLBP). This FOA requires that the intervention under study be embedded into health care delivery system, real world settings. Awards made under this FOA will initially support a one-year milestone-driven planning phase (UG3), with possible transition to an implementation phase (UH3). UG3 projects that have met the scientific milestone and feasibility requirements may transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application, following the instructions described in this FOA.

This FOA is part of the NIH HEAL (Helping to End Addiction Long-term) Initiative - an aggressive trans-agency effort to speed scientific solutions to stem the national opioid public health crisis.

Trials must be conducted across two or more health care systems (HCS) and will become part of and work with the NIH HCS Research Collaboratory supported through the NIH Common Fund. (See https://commonfund.nih.gov/hcscollaboratory). The NIH HCS Research Collaboratory Program has established a CCC that is providing national leadership and technical expertise in all aspects of research with HCS. After awards are made by NIH, the CCC (http://rethinkingclinicaltrials.org/about-nih-collaboratory/) and the NIH will work with awardees from this FOA to facilitate the planning and rapid execution of high impact trials that conduct research studies with partnering health care delivery systems.

Background

Low back pain is an important US public health concern as it is commonly associated with high levels of disability and is one of the most common reasons for primary care visits. The prognosis for acute back pain is generally favorable, with many patients improving after one to three months. The predominant population effected by low back pain is the group with CLBP and have pain that lasts 3 months or longer. As the prevalence of chronic conditions increases with age, older adults (65 years and older) with CLBP are likely to also have other comorbid medical conditions. As older adults develop more chronic conditions, they are more likely to use healthcare services and suffer outcomes such as unnecessary hospitalizations, adverse drug reactions, declining functional status and mortality. The use of opioids for pain relief in older adults is therefore particularly concerning, in view of the complexity of their medical management. Successful non-pharmacologic pain management options for CLBP in older adults are critically needed. Such options must address not only pain symptoms, but also address patient levels of functioning to prevent or reduce subsequent disability.

In 2011, the Institute of Medicine (IOM) and the National Pain Strategy (NPS) recommended developing evidenced-based strategies for treatment of chronic pain that incorporates the biopsychosocial nature of the condition. The recent Centers of Disease Control (CDC) guideline for prescribing opioids for chronic pain states that "nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain" and has prompted research into nonpharmacological treatments for pain conditions.

In response to the U.S. opioid crisis, HHS is focused on preventing opioid addiction and providing more non-pharmacologic treatment options for chronic pain. AHRQ, CMS and NIH are collaborating in this effort. The Agency for Healthcare Research and Quality published a systematic review of noninvasive, nonpharmacological treatment for chronic pain in June 2018 (https://effectivehealthcare.ahrq.gov/sites/default/files/cer-209-evidence-summary-non-pharma-chronic-pain.pdf). This review included assessment of several nonpharmacological interventions, including exercise, acupuncture, spinal manipulation, and multidisciplinary rehabilitation that have been associated with modest benefits in CLBP. This review noted that acupuncture improved function and/or pain for at least one month after treatment ended for chronic low back pain.

Acupuncture efficacy trials data included in the review reported durable slight to moderate improvements in function and pain for CLBP patients that were <60 years of age. An acupuncture and chronic pain meta-analysis (Acupuncture for Chronic Pain: Update of an Individual Patient Data Meta-Analysis) reported results from an individual level patient data meta-analysis that found that acupuncture was effective for chronic pain with only minimal diminishing of effects one year after the treatment was complete. However, similar compelling data on the improvements in meaningful health outcomes of acupuncture for CLBP in older adults (65 or more years) are currently lacking; such studies are critically important for expanding non-opioid pain management options for older adults who frequently suffer with high levels of disease burden.

For health care policy makers or payers, such as the Center for Medicare & Medicaid Services (CMS), this evidence gap must be addressed to inform coverage determinations on nonpharmacologic interventions, including acupuncture, in older adults with CLBP. CMS is interested in generating evidence on promising items and services for Medicare patients and has several mechanisms to cover and pay for items and services in the context of a clinical study, including coverage with evidence development (CED) through a national coverage determination (NCD). CMS has published a guidance document for the Public, Industry and CMS staff, to help understand CMS implementation of CED through the NCD process (https://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=27 ). Section VI of this guidance document, entitled Requirements for CED under Section 1862(a)(1)(e), provides a list of general requirements for clinical studies that must be included (with occasional minor modifications) in the coverage determination. The guidance document relates that CMS would not anticipate approving a study that does not meet the listed requirements.

By addressing gaps in the literature on the benefits and harms of acupuncture in individuals 65 years and older, it is anticipated that evidence on improvements in health outcomes derived from this initiative would assist CMS in determining Medicare coverage for acupuncture in CLBP. To this end, applicants may wish to consider how their model would translate into the Medicare Fee for Service model of coverage and payment (e.g., sites where acupuncture is furnished, types of practitioners that can bill Medicare).

Additional language:

This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative 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.

Research Goals

This Funding Opportunity Announcement (FOA) encourages UG3/UH3 phased cooperative research applications to conduct an efficient, large-scale pragmatic trial or implementation science study to evaluate the impact of acupuncture treatment in people age 65 or older (Medicare population) with chronic low back pain (CLBP) in a way that is integrated into health care delivery, as there is insufficient evidence of the benefits in the Medicare age population. The largest U.S. study to date of acupuncture for CLBP was in patients up to age 65 with a median age 47 years ( 2009).

Awards made under this FOA will initially support a one-year, milestone-driven, planning phase (UG3), with possible transition to an implementation phase (UH3). UG3 projects that have met the scientific milestones and feasibility requirements may transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application, following the instructions described in this FOA. Trials must be conducted across two or more health care systems (HCS) and must be conducted as part of the NIH HCS Research Collaboratory. After awards are made by NIH and the NIH HCS Collaboratory Coordinating Center (http://rethinkingclinicaltrials.org/about-nih-collaboratory/) will work with awardees from this FOA to facilitate the planning and rapid execution of high impact trials that conduct research studies with partnering health care delivery systems.

For the purpose of this FOA, embedded pragmatic clinical trials are studies that are conducted within the health care delivery setting and are primarily designed to determine the effects of an intervention under the usual conditions in which it will be applied , which is in contrast with explanatory trials that are primarily designed to determine the effects of an intervention under ideal circumstances (http://www.bmj.com/content/350/bmj.h2147). "There are three key attributes of pragmatic clinical trials (PCTs): (1) an intent to inform decision-makers (patients, clinicians, administrators, and policy-makers), as opposed to elucidating a biological or social mechanism; (2) an intent to enroll a population relevant to the decision in practice and representative of the patients or populations and clinical settings for whom the decision is relevant; and (3) either an intent to (a) streamline procedures and data collection so that the trial can focus on adequate power for informing the clinical and policy decisions targeted by the trial or (b) measure a broad range of outcomes (http://rethinkingclinicaltrials.org/chapters/pragmatic-clinical-trial/what-is-a-pragmatic-clinical-trial-2/)."

Awards supported by this initiative will utilize the existing coordinating center of the NIH HCS Research Collaboratory. The overall goal of the NIH HCS Research Collaboratory program is to strengthen the national capacity to implement cost-effective large-scale research studies that engage health care delivery organizations and patients as research partners. The NIH HCS Research Collaboratory Program established a CCC led by Duke University in 2012 (http://rethinkingclinicaltrials.org/about-nih-collaboratory/), which is providing national leadership and technical expertise. Awardee(s) from this FOA will work with the NIH and CCC for both the planning and implementation of their pragmatic clinical trial or implementation study. All Projects must conduct research studies in partnership with at least two health care delivery systems, and work with the NIH and the CCC to ultimately make available data, tools, resources and lessons learned from Collaboratory research projects to facilitate a broadened base of research partnerships with HCS.

Embedded pragmatic clinical trials of acupuncture in older Americans with CLBP supported by this initiative will be expected to provide innovative approaches to address and overcome important barriers to research in the setting of HCS. Research conducted in partnership with health care systems is essential to strengthen the relevance of research results to real world health practice. Successful approaches and best practices established through this initiative should have a major impact on the management of CLBP in older adults in the US. (See http://commonfund.nih.gov/hcscollaboratory/).

Although the importance for biomedical research and strengthened partnerships with organizations that deliver health care is clear, many challenges exist, both cultural and practical. Many ethical and regulatory issues must be addressed to perform research in the health care delivery setting. Technical challenges to accessing and aggregating quality-controlled data from health care systems in understandable ways are not trivial. Research studies have frequently used endpoints that are not part of the normal evaluation of patients during a routine visit and interventions that are impractical in most care delivery settings. Education and engagement of providers and patients on the value of research in the care setting, and of researchers on the relevance of their work to health systems, are urgently needed for optimizing the care in all people. The NIH HCS Research Collaboratory program has created a broad framework to tackle some of these major challenges.

This UG3/UH3 will fund a one-year, milestone driven, start-up phase in preparation for a three-year randomized pragmatic clinical trial embedded delivery in two or more health care systems to assess the effectiveness of a minimum of 12 weeks of acupuncture treatment for addressing clinical significant changes in pain intensity, pain interference and/ or function in older Americans (age 65 or greater) with chronic low back pain (CLBP). Subject selection must be based on definition of chronic low back pain that will be consistent with definitions in guidelines and be sufficient to be amenable to improvement with an effective intervention. Acupuncture treatment should be compared to usual care or another known effective intervention for treatment of CLBP.

The proposed projects must address the following criteria:

Research studies must include the following:

(1) Must be done in a CLBP population that is 65 years or older, who meet guideline definition of CLBP. The project must enroll patients based on broad eligibility criteria to maximize diversity, and minimize intentional or unintentional exclusions based on risk, multi-morbidity, age, health literacy, demographics, or expected adherence.

(2) Must provide a minimum 12-week acupuncture intervention versus usual care or other intervention for chronic low back pain.

(3) Primary endpoint must be measured at 12 weeks, 6 months, and 12 months after randomization to treatment, with comparison to usual care, or other planned comparator arm. The study must be powered for primary endpoint assessment at 6 months. Important health outcomes to CLBP patients include improvements in pain and function, as noted in the systematic review.

(4) The project must leverage opportunities made available through integrated health care systems and use of outcomes that can be captured by passive follow-up by electronic health records, and with minimal need for adjudication. Augmentation of the electronic health record is allowable for patient reported data and outcomes, although this should be streamlined and collected only at necessary time points.

(5) Proposed analytic plans for projects that propose cluster-randomized trials must address adequacy of sample size and study power and employ analytic strategies relevant for such pragmatic trial designs. Applicants are strongly encouraged to consult Collaboratory Biostatistical Guidance documents (http://sites.duke.edu/rethinkingclinicaltrials/biostatistical-guidance-documents/) when developing pragmatic trial analytic plans.

(6) The project design must incorporate rigorous controls, prospectively identified, preferably by randomization. The design may incorporate novel randomization approaches, such as by cluster or timing of implementation. If another method is used to generate the comparison group, perhaps by staged assignment or staged implementation of the intervention, it should provide comparable rigor.

(7) Project must be done within at least two health care systems.

Research studies may include but are not limited to the following:

(1) Randomizing participants in the acupuncture arm to a maintenance phase for acupuncture versus no maintenance phase between 12 weeks and 24 weeks.

(2) Randomizing participants in the comparator arm to a maintenance phase or no maintenance.

(3) Collecting information from subjects on preference of interventions prior to, during and at end of study.

(4) Implementing cost-effective delivery methods for acupuncture such as group interventions with single provider versus other strategies.

(6) Including a cost-effectiveness evaluation.

(7) Evaluating different methods of implementing acupuncture into health care delivery to identify which is most efficient, cost-effective, and minimizes barriers.

Partnerships with health care delivery organizations will be critical in conducting this work. It is anticipated that the research will generally be performed with high volume electronically-supported integrated HCS to establish efficiencies. The HCS partnership must facilitate access to all data sources relevant to the project, which may include inpatient, outpatient, imaging, clinical laboratory, pharmacy and community data. Applicants, who may be from academic institutions or other organizations, must demonstrate experience in successful conduct of clinical or implementation research in partnerships with HCS. Applicants must identify at least two HCS as partners for the proposed Project. Applicants are encouraged to use as many health care systems as needed to assure that the results of the study are generalizable to the US population of patients age 65 or older who suffer from chronic low back pain.

These projects will be funded as phased awards with a one-year planning phase (UG3) and up to three-year implementation phase (UH3). Activities in both phases will depend on the specific study (e.g. disease domain, interventions, experimental design, randomization strategy and proposed outcome measures).

During the UG3 or planning phase activities will generally include, but are not limited to:

• Identify project staff that will participate in the Collaboratory Work Groups (see Section I.5 Additional Information http://rethinkingclinicaltrials.org/cores-and-working-groups/), which will develop guidelines and practices to be implemented across projects.
• Work with the Collaboratory to implement approved guidelines and practices for electronic data extraction and quality control methods and tools, as well as for electronic data sharing. In the planning phase, this will include developing and validating all electronic data methods and tools within the HCS needed for the Project (e.g. electronic health records, electronic methods for patient identification and outcomes assessment, patient reported data, biospecimens, images, high-throughput genomic data, family history data, data abstraction and survey instruments) and complete quality control testing at all sites.
• Assess adequacy and finalize clinically relevant outcome measures with other Collaboratory investigators. It is anticipated that successful applicants will work with other Collaboratory investigators and NIH to identify and harmonize common outcome measures (pain severity, pain interference, and pain functioning, as well as others). It is also anticipated that successful applicants will work with the CCC and NIH to develop metrics for resource utilization for planning and implementing Collaboratory pragmatic trials. If an award is made, NIH and CCC staff will work with the Program Directors/Principal Investigators to facilitate this aspect across Projects.
• Refine estimates of requirements with guidance from NIH and the CCC, for sample size, numbers of sites, site to site heterogeneity, and implementation timetable based on data derived from the partnering HCS.
• All studies must use at least two HCS for implementation.
• Develop detailed plans for site implementation, including site staff, method of identification, randomization (as applicable) and participant recruitment and acquisition and administration/implementation of the intervention if applicable.
• Address all ethical issues and issues related to human subject safety oversight for the Project, including development of informed consent documents or opt-out consent if applicable, and finalizing site of IRB review. Applicants must propose a consolidated or centralized IRB approach for trial oversight, to facilitate both appropriate and timely study implementation.
• Address all potential regulatory elements of the proposed trial (if applicable).
• Develop a detailed budget for conduct and completion of the Project, including preparation of a final study report.
• Finalize detailed plans for data coordination and quality control for the UH3 phase. It is not anticipated that the CCC will provide these functions for the acupuncture study. Data coordinating activities for individual Projects must be separately budgeted as part of the UH3 budget.

Project Implementation Phase (UH3): The objective of the up to three-year UH3 implementation phase is to actually conduct the Project in accordance with activities planned in the UG3 phase. Implementation activities will depend upon the study, but in general the following goals should be achieved:

• It is expected that the project will implement all aspects of the proposed pragmatic trial, including the identification and recruitment of proposed sample sizes of patients, practice sites, and clinicians, the execution of the intervention and its implementation, and the assessment of outcomes.
• The project is expected to provide complete assessment of all issues related to patient, clinician and site identification, and EHR tools used in these steps.
• The project is expected to provide definitive information about the execution of the intervention at all sites.
• The project is to provide detailed and definitive testing of the validity of methods used for monitoring and outcome assessment.

Milestones and UG3/UH3 Transition

Utilization of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. This FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to one year (UG3) and a full enrollment and clinical trial execution phase (UH3). Projects should include well-defined milestones for the planning phase (UG3) and annual milestones for the implementation phase (UH3). It is understood that the proposed milestones for the UH3 phase will be revised as activities in the UG3 phase progress. In the event of an award, the PD/PI, NIH staff and the Coordinating Center will negotiate a final list of milestones for each year of support.

At the completion of the UG3 planning phase, the applicant will be required to submit a detailed transition request for the UH3 implementation phase. UH3 transition requests will undergo an administrative review to determine whether the project will be awarded the implementation phase (UH3). All regulatory approvals should be obtained prior to the end of the UG3 award. Training of intervention providers, comparison group providers, or other resources should be planned at the start of the UH3 award to allow for the successful launch and execution of the proposed pragmatic trial in the UH3 phase. Prospective applicants should note that initial funding of the UG3/UH3 Phase Innovation cooperative agreement does not guarantee support of the UH3 Project implementation phase. Applicants should understand that transition to the UH3 phase of the project will occur only if an administrative review process recommends that the UG3 planning milestones have been successfully met, that the UH3 phase can proceed with confidence of success, and availability of funds. Continuation of the award is conditional upon satisfactory progress and subject to availability of funds. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NIH will consider ending support and negotiating an orderly phase-out of the award and retains, as an option, periodic external peer review of progress. NIH staff will closely monitor progress at all stages, milestones, accrual, and safety.

Types of Clinical Trials Not Responsive to this FOA

The following types of clinical trials are not responsive to this FOA and applications proposing such activities will be deemed non-responsive and not reviewed:

• Phase I (first-in-human) trials whether single or multi-site
• Single site trials
• Studies to understand the mechanism of the intervention
• Studies to assess initial feasibility of an intervention
• Drug or device safety trials
• Studies that propose to conduct studies in animals or in vitro studies
• Studies that do not propose a trial of acupuncture in humans
• Studies that proposes a sham or time and attention control

Additional Information

Governance: The awards funded under this FOA will be cooperative agreements (see Section VI.2 Cooperative Agreement Terms and Conditions of Award). Close interaction with the NIH staff and with the CCC will be required to accomplish the goals of this program.

HCS Research Collaboratory Work Groups have been established by the CCC and the NIH as the core collaborative activity of this program. The Work Groups provide a forum for discussion of challenges and solutions across projects. Harmonized and standardized policies and processes will be vetted in these groups. Work Groups have been established in the following areas: Electronic Health Records, Regulatory /Ethics, Biostatistics & Study Design, Health Care Systems Interactions, and Patient Reported Outcomes (http://rethinkingclinicaltrials.org/cores-and-working-groups/). Additional Work Groups may be identified as the HCS Research Collaboratory expands with this initiative and other new projects. Work Groups will comprise individuals from each of the Projects, the Coordinating Center, and staff from the NIH. PDs/PIs must identify study staff or investigators that will participate in Collaboratory Work Groups.

A Steering Committee has been established by the CCC to address issues that span all projects, provide input into the policies and processes of the HCS Collaboratory, and assist in dissemination of policies and processes that enable research in healthcare systems, involving their patients, and practitioners. At a minimum, the Steering Committee will have one representative from each of the Projects, one representative from each Work Group, one representative from the Coordinating Center, NIH Program Officers and Project Scientists for the CCC and Projects. All members are expected to actively participate in all Steering Committee activities. The combined vote of NIH membership may never exceed 40 percent.

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

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

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

• 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) 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active 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.

Key Personnel from the NIH Collaboratory Coordinating Center cannot be listed as Key Personnel on an application submitted in response to this FOA.

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

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).

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

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

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:

Martina Schmidt, Ph.D
Email: SchmidMa@mail.nih.gov
Telephone: 301-594-3456
Fax: 301-480-2419
Email: SchmidMa@mail.nih.gov

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

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

Facilities and Other Resources: The application should provide sufficient rationale for the proposed HCS(s) for the Project. Applicants should provide a description of successfully conducted clinical studies within the partnering HCS, and describe the infrastructure and expertise (e.g. clinical investigators, informaticists) to implement the proposed pragmatic trial within all proposed HCSs

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

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

Budgets for both phases (UG3/UH3) should be included; the UH3 budget will undergo reassessment during the UG3 planning phase.

The budget can include the cost of acupuncture personnel or acupuncture patient services, if the health care system does not currently reimburse for these services for eligible participants. If the health care system does provide reimbursement for these services, cooperative agreement funds may not be used to pay for the acupuncture or comparison group interventions/usual care. If funds are requested to support intervention staff, the budget justification must provide a description as to why the study cannot be done without these costs and how the intervention will be sustainable once the award is ended. Relevant CMS coverage pathways for certain services furnished in the context of a clinical study (e.g. CED) may be part of the budget justification.

The budget must include funds for collection of patient centered outcomes of pain severity, pain interference, and function at least monthly using a call-center or other direct to patient access for patient centered data collection unless it can be demonstrated that these outcomes are reliably available in HCS electronic health record. During the UG3 planning phase, the NIH may develop centralized resources to collect patient reported outcomes for HEAL Initiative pain studies, which would be utilized for the study supported under this FOA. If this occurs, the budget or subcontract for the patient reported data collection may be modified.

Minimum effort of personnel: The PD/PI must devote a minimum level of effort of 20% annually (2.4 -person months) to the project. There must be an appropriate mix of time allocated for senior and junior scientists to ensure the successful conduct of the study. Budgeted effort of other personnel must be appropriate to the needs of the project. The budget must include personnel at all participating HCS with expertise relevant to the project, which might include a health informatics expert, clinical investigators and staff with expertise in the administrative aspects of clinical trials oversight.

Applications should budget for study personnel to participate in each of the Work Groups.

Applications must budget for project PD(s)/PI(s) travel to attend two, one-and-a-half-day Health Care Systems Research Collaboratory program meetings in the first year, and an annual meeting in subsequent years in the greater Washington D.C. area

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:

To clearly distinguish between the two phases, applicants should specify separate UG3 and UH3 information in each subsection (Specific Aims and Research Strategy) of the PHS 398 Research Plan as appropriate. Activities in both phases will depend on the specific study (e.g. specific pain population, type of interventions, experimental design, randomization strategy and proposed outcome measures). In preparing the application, investigators should consider the fact that applications will be assigned a single impact score for both UG3 and UH3 phases.

Specific Aims: Applicants should address the scientific questions to be answered, what specifically will be done during the proposed funding periods and the impact of addressing the research question on public health. Specific aims should be scientifically appropriate for the distinct phases of the project. Include separate aims, within the designated page limit, for both the UG3 and UH3 phase, and clearly label them as UG3 specific aims and UH3 specific aims.

Research Strategy: Within the Research Strategy, applicants should first describe the UG3 Phase and then the UH3 Phase. The Research Strategy section should have a clear demarcation of the UG3 and UH3 phases of the application. It is not necessary to repeat background information or details of methods in the UH3 portion that were provided in the UG3 portion. The UH3 Phase must be described in sufficient detail to permit reviewers to assess significance and innovation of the proposed work and the strength of the experimental design. Address how the research question serves the goals of the overall Collaboratory program and addresses the urgent need for better pain management. Applications should describe details for the proposed pragmatic trial or implementation research study including projections for recruitment, attrition and effect size estimations. Investigators are encouraged to describe how the approaches, measures, design and outcomes proposed are pragmatic or utilize implementation research methods.

Applicants should provide full descriptions of how the acupuncture and any active comparison conditions (if applicable) will be integrated into the health care delivery. For example, will the acupuncture services be provided individually or in groups, will it be provided as part of primary care, physical therapy, or another part of the health care delivery? There should be a clear description of the minimal qualifications of the acupuncture providers and how they fit into the health care team, keeping in mind that the goal of this pragmatic trial is to have broad generalizability utilizing providers that are qualified and represent the range of providers that would implement the intervention if it were widely disseminated.

The application should describe the health care system partners, provide letters of support from the HCS included, and the investigative team's experience conducting pragmatic trials within health care systems. All studies must use at least two HCS for implementation. The application must provide a rationale for the HCS selected for the Project and provide a description of the infrastructure and expertise to implement the proposed pragmatic trial within all proposed HCS.

Both the UG3 and the UH3 phases of the Research Strategy must have a summary section which describes the proposed milestones (Go/ No-Go Criteria) that will allow for definitive assessment of whether the UG3 phase provides sufficient evidence to support the subsequent UH3 phase. For detailed instructions see: Section IV.2 Other Clinical Trial related attachments.

Collaboratory Work Groups are open to participation by individuals from all funded Projects, the CCC, and the NIH. Applicants should describe how project personnel would participate in the Collaboratory Work Groups (Electronic Health Records, Regulatory /Ethics, Biostatistics & Study Design, Health Care Systems Interactions, and Patient Reported Outcomes http://rethinkingclinicaltrials.org/cores-and-working-groups/). Applicants must describe their willingness to comply with policies, guidelines and practices developed by the Work Groups, and to work with the CCC in providing relevant information and materials.

Applicants must not propose work that duplicates efforts already funded or underway. Although novel theoretical approaches and methodologies may be needed, when possible applicants should leverage, adopt or adapt resources from ongoing NIH-supported efforts in informatics as well as other national efforts including but not limited to the many federal investments in the HMO Research Network, the CTSAs, REDCap, PROMIS, NIH Toolbox, Health Care Innovation Awards, DEcIDE, eMERGE, other networks, CERTs, SHARP, Vaccine Safety Datalink, the Sentinel Initiative

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

All applications, regardless of the amount of direct costs requested for any one year, must include a Data Sharing Plan. Applicants must provide a description of the resources that will be made broadly available including policies, practices, materials, and tools to facilitate collaboration, reuse, and replication of the project. Applications should provide descriptions of how privacy and confidentiality will be maintained. The plan must include a description of how data will be shared to allow for transparency and reproducibility of study findings (e.g. access to data, data enclave, or data repository).

Appendix:

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 with the following additional instructions:

If the application includes human subjects, it must include at least one human subjects study record for the activities of the UH3 project. If the UG3 will include any human subjects research a separate study record should be included for the UG3 human study(ies). As stated in the instructions, investigators must submit a study record for each clinical trial proposed in the application.

Section 2 - Study Population Characteristics

2.4 Inclusion of Women, Minorities, and Children
Describe the safeguards for vulnerable populations that may be participants in the research as appropriate (e.g., pregnant women, prisoners).

2.5 Recruitment and Retention Plan
Describe the following: 1) the planned recruitment methods including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants; Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP).

Applicants must provide strong evidence of the availability of appropriate institutional resources, and suitable patient populations. Documentation of availability of eligible subjects at clinic sites, presented in tabular format must be provided. The application must include relevant information that addresses the feasibility of recruiting participants who are eligible for the pragmatic trial implementation study. Specifically, applicants must provide evidence that each recruiting center in the study or trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the submitted protocol. For multisite applications, information must be provided for each participating site.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan
In addition to the NIH application requirements for a data and safety monitoring for clinical trials, Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.

Section 4 - Protocol Synopsis

4.7 Dissemination Plan
Describe how the investigators will facilitate and support timely publication and dissemination of results and developed tools as appropriate and consistent with achieving the goals of the program.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments
The following attachments must be included as a part of the cooperative agreement application. Attachments permit expansion of certain elements that cannot be appropriately described in the Research Strategy. All attachments listed below must be provided or the application will not be peer reviewed.

1. Clinical Trial Experience
Applicants must provide a detailed table listing the characteristics of trials that demonstrate Key Personnel experience in trial or implementation study coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf"", appended with 1, 2, 3, etc. as needed, and must not exceed 3 pages.
The table columns should include:

Column A: clinical trial or implementation study 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)

2. Planned Milestones for UG3 phase and planned milestones for UH3

Milestones must be provided as an attachment called "Milestones.pdf"", appended with 1, 2, 3, etc. as needed, and must not exceed 3 pages.

The milestone plan should describe the key milestones that need to be met for each phase of the application (UG3 and UH3) to ensure its success; the processes that will be used to reach the milestones; and a timetable identifying when each of these key milestones will be met.

All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. The research plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. Milestones should address overall recruitment and retention goals. The Terms and Conditions under this FOA will include a milestone plan that is mutually agreed upon by the investigators and NCCIH.

The milestones included in the attachment should be well described, quantifiable, and scientifically justified to allow an assessment of progress. For UG3 milestones, applicants should delineate what they propose to achieve in order to proceed to the UH3 phase. Funding for the UH3 phase is contingent on successfully meeting the UG3 milestones. The milestones should also include a timeline, a discussion of the suitability of the milestones for assessing success in the UG3 Phase, and a discussion of the implications of successful completion of these milestones for the proposed UH3 Phase. Annual milestones for the Project implementation (UH3) phase should also be included in the application, although it is understood that timelines and milestones for implementation in the UH3 phase that are proposed in the application will evolve as activities in the UG3 phase progress, if an Award is made.

Delayed Onset Study

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

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

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

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

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.

This initiative is not subject to intergovernmental review.

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.

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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.

Only the review criteria described below will be considered in the review process.

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

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

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

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

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?

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 this FOA:

Is the proposed pragmatic trial focused on acupuncture for pain management in subjects aged 65 years and older? How will successful approaches and best practices established through this initiative have a major influence on the management of CLBP in older adults in the US? Are clinical decision support tools for introduction of acupuncture for treatment of CLBP in HCS planned? How will the completion of the proposed pragmatic trial change the management of CLBP in in health care systems? Is there a strong likelihood that the UG3 planning activities and subsequent Project implementation in the UH3 phase achieve significant advances in the ability to perform acupuncture treatment for CLBP in HCS, if warranted?

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?

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

Specific to this FOA:

Do interdisciplinary teams include necessary expertise to conduct the trial? Do the PD(s)/PI(s) and key personnel have the necessary expertise in design and implementation of large-scale clinical studies within a HCS? For example, do they have expertise in using electronic health records for recruitment and outcomes assessment? Do the PD(s)/PI(s) have extensive experience in performing proposed Planning Phase activities, and do they have a track record of successful recruitment and retention in prior studies, investigative collaborations or partnerships with (within) health delivery organizations in conducting clinical studies within a HCS?

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?

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 this FOA:

Does the application challenge and seek to impact current conventional approaches to pain management studies by utilizing novel approaches or methodologies for a pragmatic trial or implementation research that will allow it to be successfully implemented in a HCS environment?

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?

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?

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 this FOA:

Will proposed planning activities (including plans for identifying a sufficiently large target patient population), allow for implementing the Project? Are the projections for recruitment, ongoing engagement, attrition and effect size estimations based on data in the proposed HCS or similar settings? Is the degree of pragmatic aspects of the approaches, measures, design and outcomes well justified for the design elements of the proposed study? Will the results provide relevant information and adequate data for other potential adopting HCS settings to determine applicability? Will rigorous controls be included in the design? Will broad but adequate eligibility criteria be used, as proposed? Can interventions be easily implemented? How will the approaches proposed overcome barriers to research in the HCS setting? Are the goals of the UG3 phase reasonable and if accomplished will they provide the basis for the proposed UH3 phase?

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?

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?

Specific to this FOA:

Does the application provide sufficient rationale for the HCS (s) selected for the Project? Has/have the HCS (s) successfully conducted clinical studies, such that there are sufficient infrastructure and expertise (e.g. clinical investigators, informaticists) to implement the proposed pragmatic trial within all proposed HCSs?

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.

Study Timeline

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

Milestones

Are the steps and milestones and expected completion dates clearly defined? Are the milestones feasible, well developed and quantifiable regarding specific goals and accomplishments for the UG3 and UH3 phases? Are the planned criteria for the UG3 milestones adequate to indicate readiness for UH3 phase? Are the UH3 milestones appropriate for the ensuring that the investigators will achieve UH3 phase study aims?

Resources and Data Sharing Plan The reviewers will comment on the appropriateness and adequacy of the proposed Resources and Data Sharing Plan to meet the goals of the HCS Research Collaboratory program.

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 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.

Not Applicable

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.

Not applicable

Not applicable.

Not applicable

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.

Not applicable.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

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

As part of the scientific peer review, all applications:

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Complementary and Integrative Health (NACCIH)l. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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

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

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

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

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

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

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

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

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

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this 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.

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

• Overseeing the overall budget, activities and performance of the Project. The PD(s)/PI(s) must devote a minimum level of effort of 2.4 person-months (20% full-time professional effort annually) o the project. If a project includes multiple PIs, the total annual PI effort must be at least 20%. The institution must obtain appropriate prior approval for any change in PI effort.
• Accepting the participatory and cooperative nature of the collaborative research process and complying with policies and practices developed by the NIH HCS Research Collaboratory governing structure.
• Sharing data, resources and software according to the approved sharing policies for the NIH HCS Research Collaboratory program.
• Participating in all meetings of the HCS Research Collaboratory Steering Committee. Identifying study team members with relevant expertise to participate in program-wide Work Groups and sub-committees (as appropriate).
• Cooperating with the NIH HCS Research Collaboratory Steering Committee, Collaboratory Coordinating Center, research partners, and NIH staff in the design and conduct of protocols, analysis of data, and reporting of results of research.
• Agreeing to accept close coordination, cooperation and management of the project with NIH, including those outlined below under "NIH Responsibilities."
• Submitting materials to the NIH Program Director, Coordinating Center, and/or Steering Committee as requested. This will include regular reports of accomplishments and roadblocks, conference and meeting summaries, and other reports as requested.
• Materials submitted will meet all subject and formatting requirements.
• Awardees will submit a detailed transition request for the UH3 Project implementation phase, outlining UG3 progress, how negotiated UG3 Milestones have been met, as well as detailed plans, budget and annual milestones for the UH3 implementation phase. Note that, funding of the UG3 Project planning phase cooperative agreement does not guarantee support of the UH3 Project implementation phase.
• Any of the above function may be performed by the applicant organization or by subcontract to the applicant organization.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

• The NIH Project Scientist will work with the PD(s)/PI(s) and the Steering Committee to ensure the objectives of the program are being met. The primary responsibility for the program resides with the awardee, although specific tasks and activities will be shared among the awardee and the NIH Project Scientist.
• NIH staff will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/PI(S) and his/her staff, periodic site visits for discussion with the awardees research team, observation of field data collection and management techniques, fiscal reviews, and other relevant stewardship activities.
• The NIH reserves the right to terminate or curtail the award (or an individual component of the award) in the event of inadequate progress or data reporting.
• Additional NIH staff may participate in all Work Groups, implementation teams and committees, including the Steering Committee, as appropriate. NIH may designate staff from other federal agencies to participate, if advantageous to facilitate the activities of the program.
• NIH staff will act as a resource and facilitator for activities of the awardee with non-NIH HCS researchers and other NIH, DHHS, or other federally-sponsored research networks that may be relevant to this effort.
• NIH staff will provide input, expert advice, and suggestions in the design, development, and coordination of the infrastructure development and implementation efforts.
• NIH staff will report periodically on progress of the program to the NIH Common Fund, NIH and Departmental leaders. NIH may also convene an external panel of experts to provide advice on program progress.
• NIH staff will conduct an administrative review of the UH3 transition request to determine whether the Project will transition to UH3 funding and be implemented. Criteria for transition to the UH3 phase used in the NIH administrative review include: successful achievement of the UG3 milestones, potential for successfully meeting the UH3 implementation phase plans and milestones, demonstrated ability of the team to work within the consortium arrangement, and the availability of funds.
• 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.

Areas of Joint Responsibility include:

• Ensuring that NIH HCS sites and investigators as well as NIH and other research partners fully comply with federal regulatory requirements. This includes but is not limited to those relating to human subjects protections, informed consent, and reporting of adverse events.
• Jointly developing appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health care provider organization patients, health care providers and other institutions involved in any Collaboratory research projects.
• Participating in the HCS Research Collaboratory Steering Committee to address issues that span all projects, provide input into the policies and processes of the HCS Research Collaboratory, and assist in dissemination of policies and processes that enable research in partnership with health care systems, their patients, and practitioners. At a minimum, the Steering Committee will be composed of one representative from each of the Projects, one representative from each Work Group, one representative from the CCC, the NIH Program Coordinator, and representatives from various NIH ICs and the Common Fund. The combined vote of NIH membership may never exceed 40% of the total committee membership.
• Participating in the HCS Research Collaboratory Work Groups that have been established as the core collaborative activity of this program. The Work Groups provide a forum for discussion of challenges and solutions across projects; harmonized and standardized policies and processes will be vetted in these groups. Work Groups have been established in the following areas: Electronic Health Records, Regulatory /Ethics, Biostatistics & Study Design, Health Care Systems Interactions, and Patient Reported Outcomes (http://rethinkingclinicaltrials.org/cores-and-working-groups/). Additional Work Groups may be identified as the HCS Research Collaboratory expands with new projects. Work Groups are open to participation by individuals from all funded Projects, the CCC, and the NIH.
• Awardees will work with other Collaboratory investigators and NIH to identify and harmonize common clinical outcome measures (such as measures of quality of life, physical function, pain or fatigue). NIH and CCC staff will work with the Principal Investigators to facilitate this aspect of Projects. The specific outcomes may be revised during the planning phase.
• Establishing and adherence by each Project Team (Project grantee, CCC grantee, and NIH staff) to a written plan of engagement, with timelines, to ensure timely delivery of the tested implementation plan.
• Working together with the CCC through all phases of the projects, including the implementation and close out, to assure all resources, materials, protocols, data, best practices, program policies, and lessons learned are disseminated broadly through the CCC, to inform researchers and health care systems engaged in research in health care settings.

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. It will have three members: a designee of the 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.

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

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

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)
Finding Help Online: 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 instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (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: support@grants.gov

Robin Boineau, M.D., M.A.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-435-6286
Email: robin.boineau@nih.gov

Basil Eldadah M.D. Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-6761
Email: eldadahb2@nia.nih.gov

Brett Hagman, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-0638
Email: brett.hagman@nih.gov

Shahnaz Khan, M.P.H
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phone: 301-451-9893
Email: Shahnaz.Khan@nih.gov

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: schmidma@mail.nih.gov

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: carows@mail.nih.gov

John Bladen
National Institute on Aging (NIA)
Telephone: 301-402-7730
Email: bladenj@nia.nih.gov

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: jfox@mail.nih.gov

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-7760
Email: edgertont@mail.nih.gov

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

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.