HEAL Initiative: Pain Management Effectiveness Research Network: Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required)

HEAL Initiative: Pain Management Effectiveness Research Network: Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required) is sponsored by National Institute of Neurological Disorders and Stroke (NINDS), NIH. This NOFO will solicit applications for large-scale, multisite clinical trials that will inform clinicians about the efficacy or effectiveness of interventions or management strategies that reduce opioid use, improve functional outcomes, and reduce pain.

Expired RFA-NS-19-021: HEAL Initiative: Pain Management Effectiveness Research Network: Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Neurological Disorders and Stroke ( NINDS ) National Cancer Institute ( NCI ) National Eye Institute ( NEI ) National Institute on Aging ( NIA ) National Institute on Alcohol Abuse and Alcoholism ( NIAAA ) National Institute of Arthritis and Musculoskeletal and Skin Diseases ( NIAMS ) Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) National Institute on Drug Abuse ( NIDA ) National Institute of Dental and Craniofacial Research ( NIDCR ) National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) National Institute of Mental Health ( NIMH ) National Institute of Nursing Research ( NINR ) National Institute on Minority Health and Health Disparities ( NIMHD ) National Center for Complementary and Integrative Health ( NCCIH ) National Center for Advancing Translational Sciences ( NCATS ) 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.

Office of Behavioral and Social Sciences Research ( OBSSR ) Office of Research on Women’s Health ( ORWH ) Funding Opportunity Title HEAL Initiative: Pain Management Effectiveness Research Network: Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required) UG3 / UH3 Exploratory/Developmental Phased Award Cooperative Agreement January 21, 2020 - This RFA has been reissued as RFA-NS-20-028 .

January 2, 2019 - Notice of Change to Key Dates for RFA-NS-19-021. See Notice NOT-NS-19-028 . Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity See Section III.

3. Additional Information on Eligibility . Catalog of Federal Domestic Assistance (CFDA) Number(s) 93.

350; 93. 213; 93. 393; 93.

867; 93. 866; 93. 273; 93.

846; 93. 853; 83. 865; 83.

279; 93. 121; 93. 847; 93.

242; 93. 307; 93. 361 Funding Opportunity Purpose The purpose of this Funding Opportunity Announcement (FOA) is to solicit cooperative agreement applications that propose clinical trials to test the comparative effectiveness of existing therapies or effectiveness of existing or novel approaches for prevention and management of pain while reducing risk of addiction.

The studies must address questions within the mission and research interests of participating NIH Institutes and Centers and evaluate preventive strategies or interventions including medications, biologics, procedures, medical and assistive devices and technologies, diagnostic testing, behavioral change, rehabilitation strategies, complementary therapies, integrated approaches, and delivery system strategies in well controlled trials in specific pain conditions.

The overall goal is to inform clinicians about the effectiveness of interventions or management strategies that reduce opioid use that will improve functional outcomes and reduce pain across the continuum of acute to chronic pain associated with many types of diseases or conditions or pain presenting as a disease itself. Clinical trials will be conducted within the infrastructure of the HEAL Pain Effectiveness Research Network.

Open Date (Earliest Submission Date) New Date January 11, 2019 Letter of Intent Due Date(s) 30 days prior to the application due date. New Date February 11, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

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. AIDS Application Due Date(s) New Date February 11, 2019, by 5:00 PM local time of applicant organization All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates.

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. New Date February 12, 2019 per issuance of NOT-NS-19-028 .

(Original Expiration Date: February 2, 2019) Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide ,except where instructed to do otherwise (in this FOA or in a Notice from 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 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 Part 2. Full Text of Announcement Section I.

Funding Opportunity Description The purpose of this Funding Opportunity Announcement (FOA) is to solicit cooperative agreement applications that propose clinical trials to establish the comparative effectiveness of existing therapies or effectiveness of existing or novel approaches for prevention and management of pain while reducing risk of addiction.

The studies must address questions within the mission and research interests of participating NIH Institutes and Centers and evaluate strategies or interventions to prevent and/or manage specific pain conditions, including medications, biologics, procedures, medical and assistive devices and technologies, behavioral change, rehabilitation strategies,complementary therapies, integrated approaches, and delivery system strategies, through well-controlled trials.

The overall goal is to inform clinicians about the effectiveness of interventions or management strategies that reduce opioid use that will improve functional outcomes and reduce pain across the continuum of acute to chronic pain associated with many types of diseases or conditions or pain presenting as a disease itself.

To rapidly respond to this public health emergency, clinical trials will be conducted in the HEAL Pain Management Effectiveness Research Network (HEAL Pain ERN), which will be established through the infrastructure of the National Center for Advancing Translation Sciences (NCATS) Trial Innovation Network (TIN).

Trials will be implemented at the Clinical and Translation Science Award (CTSA) Program hubs, which each may contain multiple clinical sites at different institutions, and/or any other clinical sites selected by the investigator that is not affiliated with the CTSA program.

Awards made under this FOA will support a milestone-driven planning phase (UG3) for 1 year, with possible transition to a clinical trial implementation phase (UH3) of up to an additional four years. Only UG3 projects that meet the scientific milestones and feasibility requirements will 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 may NOT be used for applications that propose testing of interventions to establish initial efficacy of drugs, devices or biologics for approval by the Food and Drug Administration (FDA). This multisite effectiveness research consortium will be 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. This broad research effort seeks to improve pain care through understanding the development of chronic pain and by accelerating and improving the process of therapy development to more rapidly move discoveries into clinical practice to alleviate the burden of pain.

More information about the HEAL Initiative is available at: https://www. nih. gov/research-training/medical-research-initiatives/heal-initiative .

Public Law 115-141, the Consolidated Appropriations Act of 2018 (signed March 23, 2018) includes a requirement that grantees from for-profit applicant organizations must provide a 50% match and/or in-kind contribution of all federally awarded dollars under the grant award (direct costs, as well as facilities and administrative costs) for research related to opioid addiction, development of opioid alternatives, pain management and addiction treatment.

Matching Requirement: A grantee from a for-profit organization funded under this funding opportunity announcement must match funds or provide documented in-kind contributions at a rate of not less than 50% of the total-Federally awarded amount, as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018.

The applicant will be required to demonstrate that matching funds and/or in-kind contributions are committed or available at the time of, and for the duration of, the award. Applications must identify the source and amount of funds proposed to meet the matching requirement and how the value for in-kind contributions was determined.

All matching funds and/or in-kind contributions must be used for the portion of allowable project costs not paid by Federal funds under the grant award. NIH will not be the recipient, nor serve as a pass-through entity, of any such matching funds and/or in-kind contributions required under this announcement. See 45 CFR 75.

306 for additional details. The Nation faces a crisis of high prevalence of chronic pain and associated opioid use disorder and overdose deaths. More than 50 million adults in the U.S. have experienced chronic pain, and over 25 million report pain every day.

Nearly 20 million U.S. adults report high-impact chronic pain, which is defined as pain that interferes with their life. Many groups report a relatively high prevalence of chronic pain and high-impact chronic pain including women, older adults, previously but not currently employed adults, adults living in poverty, adults with public health insurance, and rural residents (2016 National Health Interview Survey data).

Reducing the burden of pain nationwide is a significant unmet need, and individuals need safe, non-addictive treatments to alleviate pain. Severe pain often is associated with diseases and chronic conditions such as diabetes, cancer, endometriosis, and sickle cell disease and it many persist as chronic pain following many surgical procedures or trauma.

Chronic pain conditions such as complex regional pain syndrome, migraine, and fibromyalgia are diseases themselves, and many chronic pain conditions co-occur in individuals.

The strength of evidence for the effectiveness of current strategies currently used to manage pain is often low to moderate (CDC Guideline for Prescribing Opioids for Chronic Pain, AHRQ Noninvasive, Nonpharmacological Treatment for Chronic Pain - A Systematic Review).

These strategies include some non-pharmacologic treatments for specific chronic pain conditions, long-term opioid therapy and different methods to initiate and titrate opioids, and comparisons of non-opioid and opioid drugs for pain management. More studies also are needed to inform evidence-based non-opioid treatments in the peri-operative setting.

Research Interests Specific to this FOA This FOA is soliciting applications for clinical effectiveness research for management of pain in ways that reduce the risk of addiction. Effectiveness research is defined as the conduct and synthesis of research comparing the benefits and harms of different interventions and strategies to prevent, treat and monitor pain conditions in real world settings.

The purpose of this research is to improve functional health outcomes by developing and disseminating evidence-based information to patients, clinicians, and other decision-makers, responding to their expressed needs, about which interventions are most effective for which patients under specific circumstances.

To provide this information, comparative effectiveness pain research must assess a comprehensive array of health-related outcomes for diverse patient populations and subgroups.

Defined interventions to be tested may include medications, biologics, procedures, medical and assistive devices and technologies, diagnostic testing, behavioral change, complementary approaches, rehabilitation strategies, integrated approaches, and deliver system strategies in well controlled trials. Therapies may be tested alone or in combination.

This research necessitates the development, expansion, and use of a variety of data sources and methods to assess comparative effectiveness and actively disseminate the results. Modified from Source: https://osp. od.

nih. gov/wp-content/uploads/FCCCER-Report-to-the-President-and-Congress-2009. pdf This FOA may NOT be used for applications that propose testing of interventions to establish initial efficacy of drugs, devices or biologics for approval by the FDA (see instead other opportunities such as EPPIC-Network below).

Applicants interested in conducting such trials are also encouraged to contact an NIH Program Official of the scientifically-appropriate NIH Institute or Center to discuss other FOAs for this purpose. Non-responsive applications will be withdrawn. Opportunities to Submit other Types of Pain Clinical Trials: For further information on these programs see: https://www.

painconsortium. nih. gov/Funding_Research/Funding_Opportunities The Early Phase Pain Investigation Clinical Network (EPPIC-Net) will provide infrastructure for the rapid design and performance of high-quality Phase 2 clinical trials to test promising novel therapeutics for pain.

This network will support exploratory clinical trials of investigational drugs and biologics, investigational devices, natural products, and surgical procedures for the treatment of pain. These trials may include deep phenotyping, validation of biomarkers and proof of mechanism, to support justification and provide the data for designing a future Phase 3 trial.

The specific pain conditions of interests for EPPIC -Net include well-defined conditions with high unmet therapeutic needs in patients across the lifespan.

The Pragmatic and Implementation Studies for the Management of Pain (PRISM) program will support studies to integrate interventions that have demonstrated efficacy into health care systems or implement health care system changes to improve adherence to evidence-based pain management guidelines.

PRISM encourages cooperative research applications to conduct efficient, large-scale pragmatic trial or implementation science study designs to improve pain management. The program requires that the intervention under study be embedded into health care delivery system, real world settings.

The pragmatic trial model collects most data needed for analysis of the research question as part of clinical care, and it is expected that this data will be obtained primarily through the electronic records of the health care system.

Studies needing to randomize participants individually, collect in-person measures for research purposes (such as specified clinical laboratory tests, observed studies of mobility or other measures of function) or deliver an intervention in a standardized fashion with fidelity monitoring should consider applying to the HEAL Pain ERN.

The NINDS-NHLBI-NCATS funded initiative, Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN) runs clinical studies in the prehospital setting and the emergency department. It includes academic hub sites, spoke hospitals, and EMS providers to support multicenter clinical studies on neurological emergencies, including the pre-hospital and emergency department treatment of acute pain.

Institute Specific Research Interests Many NIH Institutes, Centers and Offices (ICOs) share the goal to alleviate pain through support of clinical research to develop and evaluate interventions and approaches to alleviate pain across various pain conditions.

Participating NIH ICOs are interested in research to evaluate the effectiveness of pharmacological and non-pharmacological interventions to manage mission-relevant acute and chronic pain in ways that reduce the risk of addiction. Summaries of NIH ICO specific research questions that would be responsive to this FOA are outlined below.

Potential applicants are urged to contact NIH IC Program Staff (see Section VII) to ascertain whether proposed studies are responsive to their mission interests.

Patients in rural settings may lack access to efficacious, non-opioid methods to manage acute and chronic pain, despite the fact they are more likely than their urban counterparts to be older, have serious illnesses and disabilities, and need effective pain management therapies.

NCATS is interested in supporting research that establishes methods to translate efficacious non-opioid interventions for management of acute or chronic pain conditions into effective therapies that can be delivered successfully in rural settings.

The NCCIH is interested in supporting comparative effectiveness trials of mind and body approaches that have already demonstrated efficacy for specific pain conditions, such as low back pain, fibromyalgia, osteoarthritis and headache.

Types of mind and body approaches to study include, but are not limited to, passive body-based approaches (e.g. spinal manipulation, mobilization, massage, acupuncture), mind-based approaches (e.g. meditation, mindfulness techniques), active movement-based approaches (e.g. yoga, tai chi), or an integrative approach that involves more than one intervention (e.g. Mindfulness Based Stress Reduction).

NCCIH is particularly interested in applications utilizing innovative clinical trial designs such as sequential, multiple assignment, randomized trials (SMARTs) design to determine predictors of treatment response, treatment options at decision points, possible tailoring variables, or a sequence of treatment decision rules.

NCI is interested in clinical trials testing innovative and efficacious pharmacologic and non-pharmacologic approaches to treat or prevent acute and chronic cancer related pain syndromes caused by the disease or its treatment throughout the cancer trajectory (from diagnosis to survivorship and end of life).

Interests include trials that enhance understanding of the impact of differential pain outcomes on cancer treatment outcomes, other cancer treatment induced toxicities, functionality, health related quality of life, sleep and psychosocial issues. Further, studies examining the differential pain experience and response to pain treatment in diverse populations are of interest.

Examples of disease related pain syndromes include bone pain, visceral pain, and neuropathic pain (plexopathies, radiculopathies). Examples of treatment related pain syndromes include post-surgical phantom limb pain, radiation induced plexopathies, mucositis, aromatase inhibitors, and chemotherapy induced peripheral neuropathy.

The NEI encourages applications that propose clinical trials to establish the effectiveness of therapies or approaches for prevention or management of ocular pain. Ocular surface disease, and particularly dry eye disease, presents a currently unmet need despite clear clinical significance. NEI is also very interested in this area.

Contacting the NEI Program Officer prior to submission of the application is recommended. The chronic pain of sickle cell disease is a major source of decreased quality of life and is poorly responsive to current therapeutic modalities.

Trials that are of interest will evaluate the effectiveness of approaches that are informed by the bio-psychosocial model of pain management utilizing multi-disciplinary combinations of behavioral, pharmaceutical, interventional, and rehabilitative modalities to address the co-morbidities often present in patients with chronic pain associated with SCD.

While several studies have shown that the incidence of opioid addiction in SCD is low, the prolonged use of often high-dose daily oral opioid medications leads to dependence, risk of overdose, respiratory depression, immune dysfunction and hyperalgesia. Trials that evaluate the reduction or elimination of daily opioid use will also be of interest.

Examples of clinical trials that are of interest to NIA include studies that determine effective interventions for persistent pain in older adults in ways that maximize function, minimize pain’s interference with life, and/or mitigate pain treatment interactions with underlying aging processes, co-occurring conditions, and medications. Both pharmacologic and non-pharmacologic approaches are of interest.

Older adults with cognitive impairment, and other populations who may require more tailored behavioral therapeutic approaches, are of particular interest. Outcomes of interest include pain, functional measures, indicators of organ system function and disease, quality of life, subjective well-being, resource utilization, and cost-effectiveness.

Applicants proposing behavioral intervention research should note that, in addition to showing efficacy, issues of real-world training procedures, fidelity of delivery, and scalability should be addressed before proposing an effectiveness study through this FOA. NIA applicants considering a behavioral interventionare referred to the NIH Stage Model ( https://www. nia.

nih. gov/research/dbsr/stage-model-behavioral-intervention-development ) prior to proposing a (Stage IV) effectiveness study. NICHD is interested in research that includes the populations mentioned in the specific priorities below and which includes health disparity populations (i.e., diverse race/ethnicity, sexual and gender minorities, and underserved/low-resource communities) to the extent possible.

Effective methods to manage persistent pain of women with endometriosis, chronic pelvic pain, vulvodynia, and other gynecologic pain syndromes in ways that maximize function and minimize pain’s interference with life.

Innovative research methods such as adaptive (e.g. SMART) or multiphase optimization strategy (i.e. MOST) clinical trial designs to test the effectiveness of combined non-opioid pharmacological and non-pharmacological treatments, as well as behavioral and psychological interventions, for forms of acute or chronic pain in children, women of reproductive age, pregnant and lactating women.

Studies to address the weak evidence for the efficacy of different classes of analgesics to include acute and post-operative pain management in children, women of reproductive age, and pregnant and lactating women after minor and major surgical procedures.

Clinical trials testing existing pharmacotherapeutics to improve safety and effective treatment/management of pain (chronic or acute) in children and women during pregnancy and lactation. Dissemination and implementation projects aimed at inclusion of efficacious pharmacological and non-pharmacological pain interventions in children, women of reproductive age, and pregnant and lactating women in clinical settings.

NICHD’s National Center for Medical Rehabilitation Research (NCMRR) is interested in: Clinical effectiveness trials focused on rehabilitative interventions and strategies involving pharmaceutical, stimulation, and bioengineering approaches, exercise, motor training, occupational therapy and behavioral modifications for management of pain in individuals with physical disabilities.

Clinical trials in high priority research areas (https://www. nichd. nih.

gov/about/org/ncmrr) to include pediatric rehabilitation interventions that include the effects of maturation and the impact of early intervention. Rehabilitation prevention and treatment strategies for mitigating pain, a key secondary condition associated with physical impairments and disabilities are strongly encouraged.

NIDA is interested in research to evaluate the effectiveness of pain interventions that may prevent the initiation and progression or reduce the severity of opioid use disorders (OUDs) and overdose. There efforts include the evaluation of effectiveness of existing medications as well as studies of optimal behavioral treatments for pain management that can reduce the need for opioids to treat pain conditions (i.e., opioid-sparring).

NIDCR is interested in clinical trials aimed at reducing the burden of pain associated with acute and chronic oral and craniofacial diseases and conditions including temporomandibular joint disorders (TMD), trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain and other conditions.

Examples of research topics that would be appropriate to the NIDCR include: 1) Clinical research to address the weak evidence for the effectiveness of different classes of analgesics for acute pain management after dental procedures; 2) Clinical studies to test clinical tools and/or interventions designed to modify dental practitioner opioid prescribing behaviors, especially for adolescent and young adult patients; and 3) Clinical trials to test the effectiveness of non-opioid pharmacological, non-pharmacological treatments or a combination of these for management of oral and craniofacial pain conditions.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is interested in clinical trials testing effective interventions (both pharmacological and non-pharmacological) aimed at prevention and treatment of pain associated with acute and chronic diseases and disorders within our mission.

This includes but is not limited to painful diabetic neuropathy, Inflammatory Bowel Disease (IBD), pancreatitis, hepatitis, cholecystitis and choledocholithiasis, Irritable Bowel Syndrome (IBS), functional abdominal pain and other functional gastrointestinal disorders, urologic chronic pelvic pain syndrome, and kidney stone disease.

NIMH is interested in prevention and treatment intervention effectiveness trials that address acute or chronic pain and co-occurring mental health symptoms and disorders (e.g., depression, anxiety, post-traumatic stress disorder, suicide ideation and behaviors).

Responsive applications will include research to evaluate the effectiveness of pharmacologic, somatic, psychosocial (psychotherapeutic, behavioral), device-based, rehabilitative and combination interventions to prevent or treat co-occurring pain and mental health symptoms and disorders.

Effectiveness trial applications need to address: 1) the testing of hypotheses regarding moderators, mediators, and mechanisms of actions of these interventions; and 2) the use of service-ready scalable (including the use of technology) and sustainable approaches to improve delivery.

Consistent with the NIMH s, mechanism-based, Experimental Therapeutics approach, the goal is to support effectiveness trials that not only test the intervention effects on outcomes of interest, but also explicitly inform understanding regarding whether the intervention engages associated change mechanisms that were previously identified under more controlled, efficacy conditions.

This design will reconfirm the intervention targets and establish whether previously identified change mechanisms are operative in the effectiveness context (see NIMH web page on Clinical Trials). NIMH interest is limited to applications that focus in a substantial manner on the improvement of co-occurring pain and mental health outcomes.

Applications that target general health or global functioning are not considered responsive to this initiative. NIMHD’s mission is to lead, conduct and support scientific research to improve minority health and reduce health disparities.

Substantial literature suggests that diverse biological, psychological, and sociocultural mechanisms account for differences by race and ethnicity in the experience, epidemiology, and management of pain. A higher prevalence of risk factors for illness, such as lower socioeconomic status, poor health habits, and inadequate access to healthcare services, predispose rural populations and minority groups to a higher burden of pain.

Racial- and ethnic-based differences in the pain care experience have also been described, with there being substantial racial and ethnic disparities in the prevalence, management and treatment, progression and outcomes of pain-related conditions.

NIMHD is interested in applications that propose clinical trials that assess the effectiveness of interventions that reduce pain and disparities in pain management in health disparity populations. Secondary data analyses that identify factors contributing to disparities in pain and pain management in health disparity populations are also of interest.

NINDS is interested in research to prevent and treat acute and chronic nociceptive and neuropathic pain. Clinical trials designed to compare effectiveness of non-opioid analgesics and devices, either alone or in novel combinations, are of interest to NINDS. Disease areas of interest include migraine and other headaches, post-stroke pain syndromes, and others within the mission of NINDS.

NINDS is also interested in trials that test ways to manage pain with strategies that reduce opioid use in patients presenting to Emergency Departments (ED). Investigators interested in such trials should coordinate with the Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN).

NINR supports research that develops the scientific basis for clinical practice and is interested in clinical trials aimed at determining the effectiveness of non-pharmacologic approaches to reduce the severity of pain and to help individuals manage such pain. Proposed studies may focus on interventions that can be tested in one or across multiple diseases/conditions in diverse settings and populations and across the lifespan.

Topics of particular interest include behavioral approaches, e.g., exercise, diet, CBT, motivational incentives, to manage pain; biopsychosocial-centered approaches that emphasize self-management as care rather than cure of pain; studies that seek to optimize non-pharmacologic intervention timing, dosage and sustainability for pain management; and/or studies that assess effective contributions of family/caregivers in managing pain.

Outcomes of interest include quality of life, pain reduction, pain interference, and therapeutic reliance. Although the Office of Behavioral and Social Sciences (OBSSR) does not accept assignment of applications or administer awards, OBSSR does encourage applications relevant to the OBSSR mission and may provide co-funding support to ICs that do manage the awards.

OBSSR is specifically interested in studies that apply evidence-based approaches for behavioral change (e.g., provider prescribing practices, adherence to treatment and management recommendations for both the practitioner and patients, provider/patient communications and other topics) to improve outcomes that include reducing opioid use disorder, mitigating the transition from acute to chronic pain and enhancing effective management for those with persistent and chronic pain.

Additionally, approaches that include the identification of characteristics of individuals most likely to benefit from nonpharmacologic approaches for pain management are also of interest to OBSSR.

Although the Office of Research on Women’s Health (ORWH) does not accept assignment of applications or administer awards, it is expected that trials in the HEAL Pain ERN will recruit women in sufficient numbers to determine sex-specific responses as well as sex differences in trial outcomes. These comparisons have significant clinical relevance given the higher prevalence of pain in women.

Studies should, as appropriate, enroll both sexes to better understand the influence of sex as a variable. Overview of the HEAL Pain ERN Network Awardees will be required to conduct their studies through the NIH HEAL Pain Management Effectiveness Research Network (HEAL Pain ERN) which will have dedicated pain and clinical trial design expertise.

The HEAL Pain ERN will use the infrastructure of the NCATS Trial Innovation Network (TIN) ( www. trialinnovationnetwork. org ) to provide scientific guidance and coordination of the HEAL Pain ERN trials.

The TIN works with the broad consortium of Clinical and Translational Science Awards (CTSA) hubs ( https://ctsa. ncats. nih.

gov/ ) that each may contain multiple clinical sites at different institutions, to implement studies. Points of contact (POC) for the HEAL Pain ERN at the individual CTSA hubs will be posted on www. trialinnovationnetwork.

org . TIN dedicated pain and trial experts will participate on study teams of awarded UG3/UH3 projects during the planning and implementation phases and will provide clinical coordination center (CCC) services, data coordination center (DCC) services, recruitment and retention services, and biostatistical support.

The HEAL Pain Management Clinical Effectiveness Research Program Overview An expert Panel of External Program Consultants (EPCs) comprised of experts on pain and pain clinical trials will be established by NIH leadership. The role of the EPCs is to provide individual level advice to the NIH.

This group will assess the overall progress of the trials awarded through this FOA, including the collaborative interactions with the HEAL Pain ERN CCC, DCC, and biostatistics core, and make recommendations to NIH leadership about the overall program.

Dedicated pain experts and clinical trial experts from the HEAL Pain ERN CCC, DCC, and biostatistics core, NIH staff, and the awardees investigative team (PIs, biostatistician and study coordinator) will serve as the Clinical Trial Steering Committee, one for each trial, and will work collaboratively to plan and implement the trials.

A consortium of all the Clinical Trial Steering Committees across all funded trials defined here as the Program Steering Committee - will convene for a face-to-face kick off meeting during the planning year and subsequently by conference call. The individual Clinical Trial Steering Committees will meet regularly throughout the duration of the implementation phase of the trials.

Specific functions provided by the HEAL Pain ERN CCC, DCC and biostatistical core include but are not limited to: Developing the final study protocol with the study team investigators; Providing study design support, statistical analysis and interpretation of results for manuscripts and publications; Finalizing recruitment and retention plans with the site investigators before initiation of the trial; Developing associated trial documents, including the Manual of Procedure or Standard Operating Procedures; materials for site investigators, case report forms and training materials for study personnel with the study team; Training clinical site investigators and staff for the individual trials.

Training areas include, but are not limited to, regulatory requirements, Good Clinical Practice (GCP), adverse event reporting, human subject protections, informed consent, and NIH policies and procedures; Developing and maintaining a data management system for trial data collection and storage and adverse event reporting; Providing randomization support; Providing clinical operations and monitoring support including project management, to oversee