NIH-DOD-VA Pain Management Collaboratory – Pragmatic and/or Implementation Science Demonstration Projects ((UG3/UH3) Clinical Trial Required)

NIH-DOD-VA Pain Management Collaboratory – Pragmatic and/or Implementation Science Demonstration Projects ((UG3/UH3) Clinical Trial Required) is sponsored by National Center for Complementary and Integrative Health (NCCIH) / National Institutes of Health (NIH). This funding opportunity supports large-scale pragmatic clinical trials and/or implementation science demonstration projects on nonopioid approaches to pain management, including complementary and integrative approaches.

Expired RFA-AT-24-004: NIH-DoD-VA Pain Management Collaboratory Pragmatic and/or Implementation Science Demonstration Projects ((UG3/UH3) Clinical Trial Required) This notice has expired. Check the NIH Guide for active opportunities and notices. NIH-DoD-VA Pain Management Collaboratory Pragmatic and/or Implementation Science Demonstration Projects ((UG3/UH3) Clinical Trial Required) Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Department of Veterans Affairs ( VA ) Components of Participating Organizations National Center for Complementary and Integrative Health ( NCCIH ) National Institute of Nursing Research ( NINR ) All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers.

The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Division of Program Coordination, Planning and Strategic Initiatives, Office of Disease Prevention ( ODP ) Office of Behavioral and Social Sciences Research ( OBSSR ) Funding Opportunity Title NIH-DoD-VA Pain Management Collaboratory Pragmatic and/or Implementation Science Demonstration Projects ((UG3/UH3) Clinical Trial Required) UG3 / UH3 Exploratory/Developmental Phased Award Cooperative Agreement August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023.

See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 .

Notice of Funding Opportunity (NOFO) Number Companion Funding Opportunity Resource-Related Research Project (Cooperative Agreements) See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this NOFO is to solicit UG3/UH3 phased cooperative agreement research applications to conduct efficient, large-scale pragmatic clinical trial and/or implementation science Demonstration Projects within the infrastructure of the NIH-DoD-VA Pain Management Collaboratory (PMC) on nonpharmacologic approaches to pain management and other comorbid conditions in U.S. Veterans, military personnel, and their families.

The PMC established a Coordinating Center that provides national leadership and technical expertise for all aspects of health care system (HCS)-focused research including assistance to UG3/UH3 grant recipients.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO). Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review. Part 1. Overview Information Part 2.

Full Text of Announcement Section I. Notice of 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 Part 2.

Full Text of Announcement Section I. Notice of Funding Opportunity Description Since 2001, more than 2. 77 million U.S. troops have been deployed for Operation New Dawn, Operations Enduring Freedom (OEF) in Afghanistan and Iraqi Freedom (OIF) in Iraq.

The all-volunteer military experienced multiple redeployments to the war zone, extensive use of the reserve components of the military and National Guard, that also involved the deployment of women and parents of young children. Many of these deployed service members sustained severe injuries that in previous wars would have resulted in death.

Significant and continuing improvements in outer tactical vests (body armor) and helmets have saved lives. However, despite these improvements, many service members returning from these operations, and from other military operations, experienced pain, traumatic brain injuries (TBIs), symptoms of post-traumatic stress disorder (PTSD), suicidal thoughts or behaviors, substance abuse, and/or related comorbidities.

Studies report nearly 45% of active-duty service members and 50% of V eterans experience pain on a regular basis and there is significant overlap between chronic pain, PTSD, and persistent post-concussive symptoms. There is an ongoing challenge with pain among military and Veteran populations and an incomplete evidence base for effective pain management.

Opioid medications continue to be prescribed for the treatment of chronic pain, despite the association of chronic opioid use with the potential for misuse and they often fail to adequately control pain.

As a result, there continues to be a need for additional nonpharmacologic approaches to complement or replace pharmacological strategies for pain management and to reduce the needs and risks associated with excessive reliance on opioids. In June 2011, the Institute of Medicine (IOM) released a Consensus Report on "Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research" ( http://iom.

edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research. aspx ). The report notes that chronic pain affects an estimated 116 million American adults more than the total affected by heart disease, cancer, and diabetes combined.

Pain also costs the nation up to $635 billion each year in medical treatment and lost productivity.

The report notes that ideally, most patients with severe persistent pain would obtain pain care from an interdisciplinary team using an integrated approach that would target multiple dimensions of the chronic pain experience including disease management, reduction in pain severity, and improved functioning, emotional well-being, and health-related quality of life.

The NIH, U.S. Department of Defense (DoD), and U.S. Department of Veterans Affairs (VA) have been working individually and collaboratively to develop and improve pain management approaches for military personnel, Veterans, and their families.

In 2014, NCCIH partnered with the National Institute on Drug Abuse (NIDA) and VA to fund 13 grants to research military and Veteran health with a focus on nonpharmacologic approaches to pain and related conditions. This important partnership was expanded in 2017 to include the DoD and additional NIH agencies (NINDS, NIAAA, NICHD, ORWH, OBSSR, and NINR) to initiate the NIH-DoD-VA Pain Management Collaboratory (PMC).

The first wave of the Pain Management Collaboratory resulted in the support of 11 research projects focused on the development and testing of nonpharmacologic approaches to pain management ( RFA-AT-17-001 ) as well as a Coordinating Center ( RFA-AT-17-002 ). A twelfth research project was funded in FY22 ( RFA-AT-22-006 ).

Military and Veteran health care systems (HCS) and other HCS that provide services to military personnel, Veterans and their families are the targeted organizations for this program. Research conducted in partnership with eligible VA and DoD health care providers is essential for obtaining meaningful and relevant research results in real world health care delivery systems serving Veterans and service members.

Team-based care is increasingly recognized as fundamental to effective health care systems.

Defined as the interprofessional, multidisciplinary team approach to patient-centered care coordinated across a variety of systems, the National Academy of Medicine (formerly known as the Institute of Medicine) predicts team-based care models will cut down significantly on health care costs, estimating savings of $240 billion annually in national health care expenditures.

Despite the recognized and compelling need for research to identify and implement effective complementary nonpharmacologic approaches for pain management and comorbid conditions in military and Veteran populations, many challenges exist. Ethical and regulatory issues must be addressed to perform research in health care delivery settings.

Health care providers focus on providing the best treatment, based on current knowledge, whereas research typically focuses on studying which treatments work best in a precisely defined population. Further, research studies have frequently used endpoints that are not part of routine patient assessments of care and may support adoption of interventions that are challenging to implement in many health care delivery settings.

Multiple challenges remain in identifying the best strategies to successfully integrate evidence-based interventions within specific health care settings. Bridging the gap between research and practice is an important step in the direction of providing increased effective treatment options to patients.

The purpose of this NOFO is to solicit UG3/UH3 phased cooperative agreement research applications to conduct efficient, large-scale pragmatic clinical trial and/or implementation science Demonstration Projects within the infrastructure of the NIH-DoD-VA Pain Management Collaboratory on nonpharmacologic approaches to pain management and other comorbid conditions in U.S. military personnel, Veterans and their families.

The PMC established a Coordinating Center that provides national leadership and technical expertise for all aspects of HCS-focused research including assistance to UG3/UH3 grant recipients.

This new wave of the NIH-DoD-VA Pain Management Collaboratory awards solicited under the NOFO will: Support the design and execution of additional high-impact Demonstration Projects that will conduct pragmatic clinical trials focusing on effectiveness research, implementation research, or hybrid effectiveness-implementation research on nonpharmacologic approaches to pain management and comorbidities with patients in health care delivery systems that provide care to Veterans, military personnel, and their families Make available data, tools, best practices, and resources from these Demonstration Projects to facilitate a research partnership with health care delivery systems that provide care to Veterans, military personnel, and/or their families Demonstration Projects funded through this NOFO will be expected to work collaboratively with the Pain Management Collaboratory Coordinating Center (PMC3) and the other PMC projects funded under the previous waves of PMC trials as well as those funded under this NOFO.

This includes participation in PMC3 work groups, developing detailed plans for site implementation, determining resource needs, testing data extraction methods, developing plans for all aspects of ethical and regulatory oversight/protection of human subjects, and potentially integrating common data elements to increase the overall impact of findings.

Awards made under this NOFO will initially support a one-year milestone-driven research planning phase (UG3), with possible transition to a pragmatic trial and/or implementation science Demonstration Project research execution phase (UH3; 2-4 years). UG3 projects that have met the scientific milestone and feasibility requirements may transition to the UH3 phase following administrative review by the respective funding agency.

The UG3/UH3 application must be submitted as a single application, following the instructions described in this NOFO. All Demonstration Projects should address a research question important to the health of U.S. Veterans, military personnel, and their families that is focused on nonpharmacologic approaches to pain management and, if applicable, co-occurring conditions.

The Demonstration Project may provide a definitive test of the underlying question to assess intervention effectiveness or carry out implementation research (or hybrid effectiveness-implementation research).

Applications that include effectiveness research aims should be guided by the Pragmatic-Explanatory Continuum Indicator Summary 2 tool (PRECIS-2) and utilize more pragmatic approaches rather than explanatory when appropriate to address the proposed hypothesis (PRECIS-2 is described in https://www. bmj. com/content/350/bmj.

h2147 ). We define pragmatic trials as trials primarily designed to determine the effects of an intervention under the usual conditions in which it will be applied, in contrast with explanatory trials which are primarily designed to determine the effects of an intervention under ideal circumstances . Efficacy research involves strict limitations on who may participate to minimize error, bias, and confounding.

The emphasis on internal validity enhances confidence in interpreting positive results as indicating a causal relationship between the intervention(s) and outcome(s).

Effectiveness research is designed to test interventions of known efficacy in real-world settings with an emphasis on external validity, that is, whether the results can be applied to a definable group of patients in a particular clinical setting in routine practice (i.e., generalizability).

In effectiveness research, limitations on who may participate are minimized in order to maximize the likelihood that study participants and the population intended to benefit from the interventions are similar.

Dissemination research is the scientific study of targeted distribution of information and intervention materials to a specific public health or clinical practice audience, while implementation science is the scientific study of the use of strategies to adopt and integrate evidence-based health interventions into clinical and community settings to improve patient outcomes and benefit population health.

For the purposes of this NOFO, only effectiveness research, implementation science, and hybrid effectiveness-implementation trials will be responsive. Dissemination may be included as an aim, but applications that only propose dissemination research will be considered non-responsive.

The research question(s) proposed should be of major public health importance focusing on nonpharmacologic approaches to pain management and comorbid conditions in Veterans, military personnel, and their families and one that will engage partnership with health care delivery systems providing services to this population.

Although trials will be conducted in the VA and DoD health care systems, it is expected that many of the findings will be generalizable to practices across the broader health care community.

Types of nonpharmacologic approaches to study could include, but are not limited to, mindfulness/meditative interventions (e.g., mindfulness based stress reduction, meditation), movement based interventions (e.g., tai chi, yoga), manual therapies (e.g., spinal manipulation, massage, acupuncture), neuromodulation (e.g., electrical stimulation), and psychological and behavioral interventions (e.g., mindfulness-based cognitive behavioral therapy), or an integrative approach in which a complementary health approach is used in combination with standard care (e.g., cognitive behavioral therapy combined with standard pharmaceutical treatment).

Of special interest are effectiveness trials of approaches which have not yet been evaluated for effectiveness in the VA and/or DoD health care settings. Applicants are strongly encouraged to review the PMC website to avoid submitting a trial that overlaps significantly with other ongoing or completed PMC trials. The NIH RePORTER website at https://reporter.

nih. gov , the DoD Defense Technical Information Center website at https://discover. dtic.

mil , and the Patient-Centered Outcomes Research Institute website at https://www. pcori. org/ should also be reviewed to avoid submitting a trial that overlaps significantly with other on-going or completed trials testing methods to manage pain in U.S. Veterans, military personnel, and their families.

In addition, integrated models of multicomponent care that are delivered in different settings (e.g., pain care that could include collaborative care, care management, care delivered through tele-care, peer-coaches, or informal caregivers, etc.) will be of higher programmatic priority.

It is anticipated that the Demonstration Projects will generally be performed within large health care systems that utilize electronic health records to leverage data collection that occurs in health care delivery rather than requiring independent research data collection.

The HCS partnerships must be able to facilitate access to all data sources relevant to the project, which may include inpatient, outpatient, clinical laboratory, and pharmacy data. Applicants, who may be from academic institutions or other organizations, must have demonstrated success in conducting clinical research in partnerships with HCSs serving military or Veterans.

Interdisciplinary teams should include necessary expertise to conduct the trial such as military researchers on military-focused applications and VA researchers on Veteran-focused applications. Demonstration Project applicants should include and involve appropriate personnel, from health care systems providing care to these populations, and be able to document the commitment of the health care organization to the project.

For projects proposing effectiveness aims: Outcomes should include assessing pain and pain reduction, pain interference, ability to function in daily life, quality of life, and medication usage/reduction/discontinuation. Additional outcomes may focus on assessing conditions co-occurring with high frequency in this population.

There is also interest in obtaining objective sensor-based measures that provide data on people’s daily activities, to gain a better understanding of the relationship between ratings of pain with functional changes.

When testing effectiveness, projects are encouraged to enroll participants based on broad eligibility criteria to maximize diversity, with minimum exclusions based on risk, age, health literacy, comorbidities, or expected adherence. Studies should enroll from the target populations the interventions are intended to benefit, namely Veterans, active-duty service members, and their beneficiaries.

It is important that women are represented according to their proportion of the population being studied, preferably overrepresented, and include a comparative analysis of differential effects between men and women. Projects aimed at evaluating team-based care models should determine overall effectiveness of team-based care compared to conventional, non-team-based, primary care.

Secondary outcomes may assess differential benefits contributed by unique components of the team-based care package. Effective prevention and treatment of mental illness have the potential to reduce morbidity and mortality associated with intentional injury (i.e., suicide attempts and deaths, see reports from the Veterans Administration , the Department of Defense , and the National Action Alliance for Suicide Prevention ).

Lack of attention to the assessment of these outcomes has limited our understanding regarding the degree to which effective mental health interventions might offer prophylaxis.

Accordingly, where feasible and appropriate, this NOFO encourages the consideration of the NIMH recommendation that effectiveness research include assessment of suicidal behavior in order to advance understanding of how effective prevention and treatment of mental disorders might impact suicide relevant outcomes. In some cases, a stepped-wedge design may be the only practical way to generate the appropriate data.

Nevertheless, considering the practical, ethical, and analytical challenges as outlined by the NIH Pragmatic Trials Collaboratory , stepped-wedge designs should be avoided when another rigorous study design is feasible and will answer the study question. If proposed, a strong justification for a stepped-wedge design should be provided, including why an alternative design is not superior.

For projects proposing implementation science aims: Outcomes of implementation trials should focus on rigorous assessment of the strategies designed to increase uptake and adoption of evidence-based nonpharmacologic pain interventions. Investigators are encouraged to incorporate theories, models, and/or frameworks appropriate for implementation research when considering study hypotheses, measures, and outcomes.

When designing an application, applicants are also encouraged to utilize the extant literature on barriers to and facilitators of the implementation of practices to manage chronic pain and to consider the multi-level context and environment in which the proposed research will be conducted.

Specific Areas of Research Interest National Institute of Nursing Research ( NINR ) The National Institute of Nursing Research (NINR) supports research to solve pressing health challenges and inform practice and policy - optimizing health and advancing health equity into the future.

NINR discovers solutions to health challenges through the lenses of health equity, social determinants of health, population and community health, prevention and health promotion, and systems and models of care.

Drawing on the strengths of nursing’s holistic, contextualized perspective, core values, and broad reach, NINR funds multilevel and cross-sectoral research that examines the factors that impact health across the many settings in which nurses practice, including homes, schools, workplaces, clinics, justice settings, and the community. In the context of this NOFO, NINR's interests include, but are not limited to: 1.

Studies that examine multi-disciplinary, multi-level interventions or intervention bundles that focus on a holistic, contextualized approach to pain. 2. Studies focused on social needs affecting pain in Veterans, military service members, and their families.

3. Studies that address the interaction between social determinants of health and the implementation and response to the intervention or intervention bundle. 4.

Studies focused on advancing health equity and reducing disparities in rural, minority, low literacy, and other underserved populations, especially those that include engagement of members of the targeted population. 5. Studies that focus on nurse-led models of care that encompass the whole person, in the context of their lives and living conditions.

Research Planning Phase and Research Execution Phase These projects will be funded as phased awards with a one-year research planning phase (UG3) and a 2 4-year research execution phase (UH3). The UH3 budget will undergo reassessment during the UG3 planning phase. Activities in both phases will depend on the specific study (e.g., type of intervention, randomization strategy and proposed outcome measures).

During the UG3 or Research Planning Phase, activities should generally include, but are not limited to: Identify project staff who will participate in Work Groups of the NIH-DoD-VA Pain Management Collaboratory (see Additional Information below), which will develop and update policies and practices to be implemented across PMC projects.

Work with the NIH-DoD-VA Pain Management Collaboratory to comply with approved policies and practices for electronic data access extraction and sharing and develop quality control methods and tools.

This could include developing and validating all electronic data methods and tools within the HCSs needed for the Demonstration Project (e.g., Electronic Health Records (EHRs), electronic methods for patient identification and outcomes assessment, biospecimens, images, genomic data, family history, data abstraction and survey instruments) and complete quality control testing at all sites.

Assess adequacy and finalize clinically relevant outcome measures which may include adding measures that are common across Demonstration Projects. Identify additional implementation sites, if needed, in consultation with the NIH, DoD, VA, and the Pain Management Collaboratory Coordinating Center. Review of analytic plans and power calculations with biostatistics/design workgroup to optimize design and methods.

Develop detailed plans for site implementation, including determining need and role of site staff; method of participant identification, recruitment and acquisition; randomization (as applicable); and administration/implementation of the intervention, if applicable.

Address all ethical, human subject safety and oversight issues for the Demonstration Project, including development of informed consent documents or opt-out consent, if applicable, and finalizing single IRB review for trial oversight, in accordance with the Revised Common Rule, and other requirements needed for implementing a study in a Veteran or military facility.

Address all potential regulatory elements of the proposed trial (if applicable). Develop a detailed budget for conducting and completing the Demonstration Project, including preparation of a final study report. Develop detailed plans for data coordination and quality control, as these activities will not be provided by the PMC3.

Demonstration Project Research Execution Phase (UH3): The objective of the 2 4-year UH3 research execution phase is to conduct the effectiveness and/or implementation research within the NIH-DoD-VA Pain Management Collaboratory, in accordance with activities planned in the UG3 planning phase.

UH3 activities will depend upon the study, but in general the following goals should be achieved: Each Demonstration Project is expected to implement all aspects of the proposed trial as finalized during the UG3 Research Planning Phase. Each project is expected to provide complete assessment of all issues related to patient, clinician and site identification, and EHR tools used in these steps.

Each project is expected to provide definitive information about the execution of the intervention at all sites. Each project is to provide detailed and definitive testing of the validity of methods used for monitoring fidelity and outcome assessment. Each project is to provide all data coordination, cleaning, and analysis during the implementation of the trial.

Each project is expected to provide periodic reports to a Data and Safety Monitoring Board, which may require closed reports including unmasked data prepared by an independent statistician. Applicants who propose effectiveness aims should address one or more critical research questions to improve pain management for U.S. Veterans, military personnel, and their families.

The following list provides examples of some of the potential research questions that might be addressed by such pragmatic trials: Studies focusing on testing the timing, optimum components and overall benefit of an individualized integrated package of nonpharmacologic interventions such as mind-body therapies and other complementary health approaches; Evaluation of team-based, coordinated health care versus provider-driven models of health care delivery particularly in settings in which military personnel or Veterans normally receive care; Evaluation of sex and gender differences important for optimizing pain treatment; Evaluation of evidence-based, integrative interventions that improve pain and comorbidity outcomes in populations that experience health inequities, such as individuals that are socioeconomically disadvantaged, from medically underserved rural areas, and/or from racial and ethnic minority groups and/or sexual and gender minority groups who receive care in the VA and DoD health care systems; Assessment of the effectiveness of integrative pain management strategies to reduce the transition from acute to chronic pain, for example in the peri-operative period; Assessment of the effectiveness of integrative preventative strategies to prevent the development of chronic pain and/or the development of conditions that commonly co-occur with pain in high-risk individuals; Assessment of the effectiveness of complementary and integrative pain management strategies to facilitate health restoration, for example, post-operatively; Assessment of integrative pain management approaches and strategies to be implemented in outpatient transitions of care from DoD to VA; Studies evaluating the impact of behavioral approaches (e.g., motivational interviewing, meditation, mindfulness, yoga, tai chi, special diet) to conditions that are common co-morbidities with pain such as TBI, PTSD, sleep disturbance, and anxiety; Studies evaluating interventions comprised of multiple components (e.g., yoga plus mindfulness-based stress reduction) Studies to assess whether nonpharmacologic sleep treatments may improve both sleep and pain outcomes or studies to address whether treatment of sleep apnea results in improvements in chronic pain; Studies to test the value of technology-based tools for either self-monitoring or communication with providers; for example, studies could examine the value of a smart-phone application as an extension of a behavioral intervention for pain or test the value of technology-based collaborative interactions in a primary care environment.

Applicants who propose implementation science should address one or more critical research questions for implementing evidence-based pain management interventions for U.S. military personnel, Veterans, and their families.

The following list provides examples of some of the potential research questions that might be addressed by such trials: Studies to test the effect of system level innovations to improve implementation of established guidelines for nonpharmacologic approaches to pain management and comorbid conditions; Studies of the implementation of multiple evidence-based pain management practices within community or clinical settings to meet the needs of Veterans, U.S. military personnel and their families in diverse systems of care; Studies of the local adaptation of evidence-based practices in the context of implementation; Studies testing the effectiveness and cost-effectiveness of dissemination or implementation strategies for pain management to reduce health disparities and improve quality of care among rural, minority, low literacy and numeracy, and other underserved populations; Studies on reducing or stopping ("de-implementing") the use of clinical and community pain management practices that are ineffective, unproven, low-value, or harmful; Studies of influences on the creation, packaging, transmission, and reception of evidence-based nonpharmacologic pain management interventions; Studies that identify and test theories, models, and frameworks for dissemination and implementation (D&I) processes will be of higher programmatic priority.

Applicants who propose to evaluate team-based care models should address one or more critical research questions regarding comparative effectiveness in managing pain among U.S. military personnel, Veterans, and their families.

The following list provides examples of some of the potential research questions that might be addressed by such trials: Studies to determine overall effectiveness of team-based care compared to conventional, non-team-based, primary care.

Studies that include secondary outcomes to assess differential health benefits contributed by unique components of a team-based care package and the cost-effectiveness of the care package as a whole and of each component within the packaged compared to each other.

Identify mediators and/or moderators of positive outcomes associated with team-based care compared to conventional, non-team-based primary care (e.g., more efficient delivery of services, improved physician-patient communication and relationships, better treatment adherence, higher patient satisfaction).

Milestones and UG3/UH3 Transition Projects should include well-defined milestones for the research planning phase (UG3) and annual milestones for the research execution 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 and NIH staff will negotiate a final list of milestones for each year of support.

Prior to the completion of the UG3 research planning phase, the applicant will be required to submit a detailed transition request for the UH3 Demonstration Project research execution phase at least 60 days before the anticipated transition date. UH3 transition requests will undergo an administrative review by the respective funding agency to determine whether the Demonstration Project will be awarded the research execution phase (UH3).

Prospective applicants should note that initial funding of the UG3/UH3 cooperative agreement does not guarantee support of the UH3 Demonstration Project research execution phase. Successful completion of all UG3 milestones also does not guarantee transition to nor full support of the UH3 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, continued relevance to the funding agency, and availability of funds. Governance: The awards funded under this NOFO will be cooperative agreements (see Section VI.

2 Cooperative Agreement Terms and Conditions of Award). Participation in the Work Groups established by the Coordinating Center are a 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 are vetted in these groups.

Work Groups include: Stakeholder Engagement, Patient Resources, Ethical/Regulatory, Design/Biostatistics, Phenotype/Outcomes, Electronic Health Records, Implementation Science, and Data Sharing. Work Groups are comprised of individuals from the Demonstration Projects, the Coordinating Center, and staff from the NIH, DoD, and VA.

The Pain Management Collaboratory Coordinating Center has established a Steering Committee to address issues that span all projects, provide input into the policies and processes of the NIH-DoD-VA Pain Management Collaboratory, and assist in dissemination of policies and processes that enable research in health care systems serving the military and Veterans , involving their patients, and practitioners.

The Steering Committee includes at a minimum, one representative from each of the Demonstration Projects, one representative from each Work Group, one representative from the PMC Coordinating Center, Program Officers and Project Scientists from the NIH, DoD, and VA, and representatives from various NIH ICs, DoD, and the VA. All members are expected to actively participate in all Steering Committee activities.

The combined vote of NIH, DoD, and VA membership may never exceed 40 percent.

Types of Research Not Responsive to this NOFO The following types of research are not responsive to this NOFO and applications proposing such activities will be deemed non-responsive and will not be reviewed: Applications that do not include effectiveness research, dissemination and implementation trials, and/or hybrid effectiveness-implementation trials; Phase I (first-in-human) trials whether single or multi-site; See Section VIII.

Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer