Full Summary – National Institutes of Health (NIH) Helping to End Addiction Long-Term (HEAL) Multi-Disciplinary Working Group (MDWG) Meeting

March 4, 2019

Ex Officio Members

• Rebecca Baker, Ph.D., Director, HEAL Initiative, Office of the Director, NIH
• Francis S. Collins, M.D., Ph.D., Director, NIH

Multi-Disciplinary Working Group

• Allan Basbaum, Ph.D., Professor and Chair, Department of Anatomy, University of California, San Francisco (by phone)
• Lynn DeBar, Ph.D., Senior Investigator, Kaiser Permanente Washington Health Research Institute; Affiliate Professor, Department of Psychiatry, University of Washington
• Eric Garland, Ph.D., Professor and Associate Dean for Research, University of Utah College of Social Work; Director, Center on Mindfulness and Integrative Health Intervention Development; Associate Director of Integrative Medicine-Supportive Oncology, Huntsman Cancer Institute
• Robert Gereau, Ph.D., Director, Washington University Pain Center, Washington University School of Medicine
• Patrice Harris, M.D., 2018–2019 President-Elect, American Medical Association
• Christian Heidbreder, Ph.D., Chief Scientific Officer, Indivior
• Sharon Henry, Ph.D., Professor of Physical Therapy Emerita, Department of Rehabilitation and Movement Science, University of Vermont
• Terry Jernigan, Ph.D., Professor of Cognitive Science, Psychiatry, and Radiology and Director, Center of Human Development, University of California, San Diego
• Hendrée Jones, Ph.D., Director, Horizons Program, and Professor, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill
• Richard Kuntz, M.D., Senior Vice President and Chief Medical and Scientific Officer, Medtronic
• Edward Nunes, M.D., Professor of Psychiatry, Columbia University Medical Center
• Judith Paice, Ph.D., RN, Director, Cancer Pain Program, Division of Hematology-Oncology, and Research Professor of Medicine, Northwestern University
• Wally Smith, M.D., Professor and Scientific Director, Virginia Commonwealth University Center on Health Disparities; Director, Adult Sickle Cell Program, and Florence Neal Cooper Smith Professor of Sickle Cell Disease, Virginia Commonwealth University
• Christin Veasley, Cofounder and Director, Chronic Pain Research Alliance
• Kenneth Verburg, Ph.D., Senior Vice President and Medicine Team Leader, Pfizer
• Constance Weisner, Dr.P.H., M.S.W., Senior Research Scientist, Kaiser Permanente Northern California Division of Research; Professor Emeritus, Department of Psychiatry, University of California, San Francisco

Speakers

• Jane Atkinson, D.D.S., Director, Trial Innovation Network, National Center for Advancing Translational Sciences (NCATS), NIH
• Walter J. Koroshetz, M.D., Director, National Institute of Neurological Disorders and Stroke (NINDS), NIH
• Jessica Hulsey Nickel, Founder, Addiction Policy Forum
• Joni L. Rutter, Ph.D., Deputy Director, NCATS
• David Shurtleff, Ph.D., Deputy Director, National Center for Complementary and Integrative Health (NCCIH), NIH
• Lawrence A. Tabak, D.D.S., Ph.D., Principal Deputy Director and Deputy Ethics Counselor, NIH
• Betty Tai, Ph.D., Director, Center for Clinical Trials Network, NIDA
• Amir Tamiz, Ph.D., Director, Division of Translational Research, NINDS
• Nora D. Volkow, M.D., Director, National Institute on Drug Abuse (NIDA), NIH
• Clinton Wright, M.D., Director, Division of Clinical Research, NINDS

Other Attendees

• Diana W. Bianchi, M.D., Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
• Robert H. Carter, M.D., Acting Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH
• Helene Langevin, M.D., C.M., Director, NCCIH
• Martha J. Somerman, D.D.S., Ph.D., Director, National Institute of Dental and Craniofacial Research, NIH

Rebecca Baker, Ph.D., Director, HEAL Initiative, Office of the Director, NIH

Dr. Baker, the designated federal official for the MDWG, opened the meeting at 8:30 a.m. The goal of the meeting was to introduce the aims of the HEAL Initiative to the MDWG members as the basis for future discussion about the plans for specific HEAL research studies.

Lawrence A. Tabak, D.D.S, Ph.D., Principal Deputy Director and Deputy Ethics Counselor, NIH

Dr. Tabak described the MDWG as a fact-finding body that can gather information, conduct research, analyze relevant issues, and draft position papers; any recommendations must go through an advisory council that is governed by the Federal Advisory Committee Act and that makes recommendations to the NIH Director. Dr. Tabak reviewed the ethical principles around conflict of interest and disclosure. He encouraged members to raise any questions or concerns about potential bias or conflict of interest, suggesting that the group err on the side of over-disclosure. If a real or perceived conflict arises, members who are special government employees will be excused from discussion of the matter; for other members, the MDWG will determine how to address the issue. Materials provided to the MDWG are strictly confidential.

Jessica Hulsey Nickel, Founder, Addiction Policy Forum

Ms. Nickel explained that the Addiction Policy Forum seeks not only to educate but to dispel myths and re-educate people about the science and evidence around addiction. Among the most pervasive myths are the notion that addiction is a moral failure and that it can be cured by a 28­day rehabilitation program. Better translating the science is key to ensuring that more people understand that addiction is a health condition that can be treated effectively with medication and other interventions. For example, the Forum translated some NIDA research into graphics (cartoons) and disseminated them to increase awareness and knowledge of addiction.

Ms. Nickel presented some of the real faces behind addiction and the stories of their surviving family members. Like those with cancer, diabetes, and other conditions, individuals and families facing addiction would like access to effective medications and individualized care from knowledgeable, reputable providers. They would like acknowledgement that addiction is a long-term condition that requires ongoing care. And they would like to eliminate the stigma around addiction that keeps people from seeking help. Ms. Nickel concluded by explaining that addiction is a health condition that affects the brain and describing how treatment and recovery work are key to addressing the stigma.

Christin Veasley, Cofounder and Director, Chronic Pain Research Alliance

Ms. Veasley emphasized pain is both a symptom and a disorder in itself. Chronic pain stems from numerous conditions, and individuals experience pain differently, leading to stigma, bias, and confusion about what pain is, even as scientific advances have legitimized chronic pain syndromes. Within the medical system, the workforce is insufficient to address chronic pain. People with chronic pain often do not have a medical home with team-based care, because there are so many types of pain conditions. There are no measures, markers, or diagnostics for pain. Despite an explosion of therapies, there is a lack of high-quality evidence about what works for whom and what risks are involved. There are few cost-benefit data on which to base recommendations for treatment.

Ms. Veasley outlined what patients hope to gain from new research:

• Objective measures, markers, and predictors
• Dynamic outcome measures that account for chronic pain complexity (e.g., defining improvement, better understanding what the visual analogue scale [VAS] measures, and incorporating function, sleep, and mood)
• Animal and human models that account for chronic pain complexity (e.g., taking multimorbidity and bidirectional impacts into account)
• Trials that account for complexity and individualization of pain (e.g., assessing individualized treatment, comorbidities, and synergistic effects and incorporating function, quality of life [QoL], and individualized goal-setting)
• Reverse translation and broad inclusion (e.g., listening to and learning from patients, including patients early and often, and valuing and respecting patients’ lived experience)

Ms. Veasley echoed the importance of knowledge translation, noting that it should not take nearly two decades to introduce evidence-based interventions into routine treatment. Including all stakeholders in groups like the MDWG can help reduce the knowledge translation gap.

Discussion

Dr. Collins pointed out that the perspectives of the presenters on addiction and chronic pain frame the intentions of the HEAL Initiative. Key points of discussion were the following:

Stigma

• More must be done in the field of implementation science to ensure that good evidence reaches the field and to overcome stigma that prevents people from asking for help. Lessons on overcoming stigma could be learned from the HIV/AIDS community.
• It is important to look through the lens of opioid use disorder (OUD) and chronic pain and to consider the possible unintended consequences of interventions (e.g., the effects of stigma).
• Engaging stakeholders, such as patients, in research design from the outset can help address stigma. Where possible, funding opportunity announcements (FOAs) should require stakeholder engagement, such as community advisory boards.
• Discrimination must be acknowledged and eradicated.
• Lack of understanding among payers and employers increases stigma (e.g., for people in workers compensation programs).

Education and Translation

• Most of the country lacks access to evidence-based treatment, so educating the clinical community is important, but the medical education curriculum is already packed.
• Payers (insurance providers) and employers also need education about effective interventions. Lack of understanding prevents health care providers from prescribing medications and prevents patients from receiving care.
• The FOAs promote rapid translation of knowledge, which is very important.
• Different audiences learn through different mechanisms, and the ability to absorb information is hampered during a crisis.
• A public education campaign may be of value to raise awareness about the issues.

Other Thoughts

• With so much overlap between pain and opioid use, there should be ways to address OUD and chronic pain together through research.
• Team-based care is effective for chronic pain, but without a sufficient workforce, infrastructure, and reimbursement system in place, it is difficult for providers to know what they can recommend that is available to their patients.

Introduction to the HEAL Initiative

Francis S. Collins, M.D., Ph.D., Director, NIH

Dr. Collins said that the HEAL Initiative seeks scientific solutions to the crises of OUD and chronic pain, recognizing they are interrelated. The initiative enjoys strong support from leaders across the Department of Health and Human Services (HHS), other federal departments, states, localities, and Congress. Beginning in 2018, Congress added $500 million per year to the NIH budget to address opioids and chronic pain. Because of the delay in passing the fiscal year (FY) 2018 budget, NIH was allowed to carry over some of its funding into FY 2019 and so has $850 million to be obligated in FY 2019. At present, 12 NIH Institutes and Centers (ICs) are leading 26 HEAL projects, with 20 collaborating NIH Institutes, Centers, and Offices (ICOs). More than 40 FOAs have been released for FY 2019.

The HEAL Initiative is organized according to six themes across two broad categories, and Dr. Collins gave some examples from each:

• Enhancing pain management
  • Preclinical research on pain
  • Clinical research on pain management
• Improving treatments for misuse and addiction
  • Expand therapeutic options
  • Develop new/improved prevention and treatment strategies
  • Optimize effective strategies
  • Enhance treatment for affected newborns

The governance structure includes an Executive Committee made up of the NIH IC directors supporting the HEAL Initiative. It will be informed by federal partners within HHS (e.g., the Centers for Medicare & Medicaid Services [CMS], the Substance Abuse and Mental Health Services Administration [SAMHSA], the Food and Drug Administration [FDA], the Centers for Disease Control and Prevention, the Office of the Assistant Secretary for Health, and the Office of the Surgeon General) and from other departments and agencies, including the Department of Justice and the Department of Veterans Affairs.

Senior NIH scientific and program staff from the 12 involved ICs will track the funded programs and their progress. They will work in teams aligned around the six themes of the Initiative. The MDWG will provide stakeholder expertise that will help NIH maintain a good balance of programs and act as a good steward of the resources. Dr. Collins said the MDWG’s insights will be particularly valuable for FOAs that are multidisciplinary and cross multiple ICs. At a future meeting, the MDWG might form subgroups on chronic pain and OUD.

The Executive Committee will also be informed by the HEAL Partnership Committee, which aims to develop public–private partnerships that can leverage the talent and resources of the private sector. The HEAL Partnership Committee (which includes three members of the MDWG) will develop a process for NIH to work with private partners to identify assets (e.g., compounds, devices, or knowledge) that could contribute to the initiative’s goals. The HEAL Partnership Forum provides another opportunity for open discussion with industry about the status of relevant work.

Improving Prevention and Treatment Strategies for Opioid Misuse and Addiction

Nora D. Volkow, M.D., Director, NIDA

Dr. Volkow said the HEAL Initiative provides NIH an opportunity to create new partnerships, build the evidence base, and translate knowledge into practice more quickly, which can not only improve health but also eliminate the stigma around OUD. The opioid crisis that began as a result of prescription opioids has transformed because of the availability of cheap heroin, fentanyl, and synthetic opioids. Now, OUD more frequently begins with heroin or fentanyl use, not prescription opioids. Patients who do not find effective treatment for chronic pain through the health care system might seek relief in the black market. Better prescribing practices remain fundamental, but there is a pressing need to prevent illicit substance use. Effective medications to treat OUD are underused because of stigma. The health care system lacks infrastructure to manage OUD. Retention in medication-assisted treatment remains poor.

Among the efforts to expand treatment options under the HEAL Initiative are research on stronger, longer-acting medications to treat OUD and devices to enhance the use of effective overdose-reversal therapies. To optimize use of effective treatment strategies, investigators are seeking ways to screen and identify patients at high risk of OUD. The HEAL Initiative will expand clinical trial networks (CTNs) to reach more rural areas and broaden an opioid registry to reach more diverse health care platforms. Working with partners in the criminal justice system, the HEAL Initiative will bring evidence-based treatments and interventions to more young adults and adolescents at risk. Other studies will address preventing OUD during the transition to adulthood, sleep disorders relevant to addiction, optimal length of OUD treatment, and effective, sustainable collaborative care models.

The HEALing Communities study will take a community-wide approach to prevention and treatment. The Advancing Clinical Trials in Neonatal Opiate Withdrawal Syndrome study seeks innovative ways to identify and treat newborns exposed to opiates. The HEALthy Brain and Child Development Study is an ambitious effort involving 10,000 subjects to assess how the environment affects those exposed to opiates.

Enhancing Pain Management

Walter J. Koroshetz, M.D., Director, NINDS

NINDS is focused on the biological underpinnings of chronic pain and accelerating discovery and preclinical development of new nonaddictive treatments by de-risking the process of research and development (R&D) across the pipeline, from discovery to market. In the short term, NINDS is funding research to establish the best pain management strategies for acute and chronic pain.

In the discovery phase, research aims to reveal biosignatures that will identify who will develop chronic pain after an acute event. Using phenotyping, genotyping, biomarkers, omics, and other techniques, researchers hope to pinpoint biomarkers that can play a role in preventing chronic pain and to learn who is at risk of OUD immediately and over time. Preclinical work is focusing on identifying new targets and validating them. With NCATS, NINDS is testing safe, effective, nonaddictive treatments using human cell-based screening platforms. Other efforts focus on new devices to deliver effective pain treatment.

The Early Phase Pain Investigation Clinical Network (EPPIC-Net) will facilitate early testing and lower the risks involved in R&D investment. NIH will invite external investigators (e.g., from pharmaceutical companies) to submit compounds and devices that it will consider for Phase II testing. The Back Pain Research Consortium supports research across the spectrum from discovery through clinical trials on the number-one major cause of disability.

The Comparative Effectiveness Research Network, a joint effort between NINDS and NCATS, will coordinate clinical research and raise the profile of pain treatment. Another study aims to develop an integrated approach to pain control for people undergoing hemodialysis, who frequently use high-dose prescription opioids for pain. Through the Pragmatic and Implementation Studies for Management of Pain to Reduce Opioid Prescribing (PRISM) effort, NINDS and NCCIH will look at real-world settings, incorporate nonpharmacological approaches, and work with CMS on Medicare coverage of treatment.

Discussion

The following key points arose:

Private-Sector Assets

• NIH believes that the private sector will bring forth compounds and devices that may have potential for addressing chronic pain and OUD but that have stalled in the R&D process. NIH will have more leeway than the makers to test the assets in different cohorts and for different indications.
• Devices often come from small biotech firms, many of which lack the resources to pursue Phase II trials.

Economics

• NIH should consider health equity issues from the outset. The real-world costs and barriers to treatment should be taken into account (e.g., the indirect costs and copays of seeing a physical therapist three times a week).
• Despite strong evidence for nonpharmacological interventions for chronic pain, CMS does not pay for them. CMS should clarify the threshold for evidence that would support a decision to pay for novel treatment. FDA should develop new outcome measures to assess effectiveness.
• Understanding community variables and real-world settings is important to changing reimbursement structures.

Other Topics

• The clinician workforce lacks sufficient personnel trained in the complex issues of addiction and chronic pain.
• Researchers’ language should focus on recovery and should frame treatment as a process of continuous recovery.
• Clinicians lack information about the use of cannabidiol and cannabis among patients with chronic pain.

Optimizing Retention, Duration, and Discontinuation of Medications for OUD

Betty Tai, Ph.D., Director, Center for Clinical Trials Network, NIDA

Asked how NIH should pursue research on the optimal length of OUD treatment, experts and stakeholders indicated that while medical treatment for OUD is highly effective, dropout and relapse rates are very high, making it difficult to assess the optimal length of treatment in safe, ethical ways. Therefore, NIDA proposes to study the factors affecting retention in treatment and discontinuation of treatment through a partially randomized clinical trial.

Phase 1 seeks to retain patients in medical treatment and reduce dropout rates, as measured by the number who remain in OUD medical treatment for 6 months. Phase 2 will assess how to discontinue treatment while minimizing the risk of relapse or other consequences by tapering off medications and using supportive counseling among patients who have decided to discontinue treatment. The consequences of relapse after discontinuing medication are dire, including fatal overdose (especially as a result of reduced tolerance), infection with HIV or other sexually transmitted infections, and engagement in the criminal justice system. Little is known about how to help patients who want to discontinue treatment. There is consensus in the field that successful discontinuation requires abstinence for 3 to 5 years, good social function, and good QoL. Dr. Tai said that it may be possible to assess the optimal duration of treatment by mining large databases.

Dr. Tai described the structure of both studies. Notably, patients will select their treatment arm—buprenorphine or extended-release naltrexone—because patients have strong preferences, and randomizing them may not support retention. Both arms involve some randomization to treatment as usual with or without intensive case management. In the discontinuation study, patients will either taper off their medication, transition to extended-release naltrexone, or discontinue medication; each group will undergo standard follow-up, either with or without additional relapse prevention tools. The study aims to identify relapses early and re-engage those patients. To speed up the timeline, the discontinuation study will recruit some patients from the same sites who are already doing well but did not participate in the retention study.

Discussion

Dr. Collins acknowledged that the design is challenging, but he hoped that it compensates for the inability to conduct fully randomized trials in this population. Dr. Tai provided more detail, noting, for example, ongoing discussion about developing a marker or using phenotyping to identify risk factors for relapse, the need to clarify definitions of what constitutes stability and good social function, and the role of case managers in learning what triggers relapse among individual patients. About 20 to 25 sites will participate in the study; the scope and capacity of the sites will dictate the pace of enrollment and ability to reach sufficient power.

Regarding trial design, a participant observed that some form of stratification of patients may improve the distribution of patients as they are randomized into the different treatment groups. Clustering may counter the potential placebo effect among subjects who know they are getting standard follow-up that is already known to be poor.

Behavioral Research to Improve Medication-Based Treatment for OUD (BRIM)

David Shurtleff, Ph.D., Deputy Director, NCCIH

Smoking cessation research has demonstrated that integrating pharmacotherapy with behavioral and social interventions addresses the primary and related issues better together than any intervention alone. Mindfulness-based interventions for substance abuse and pain management include efforts to promote cognitive control, enhance interoceptive awareness (e.g., recognition of cravings), restructure the reward system, decrease stress reactivity, reduce pain catastrophizing, increase psychologic flexibility, and enhance top-down modulation of ascending nociceptive input. Dr. Shurtleff drew the links between the cognitive process of mindfulness practices (e.g., meditation) and the function of neural networks that affect, for example, decision making and response to certain stimuli.

The BRIM program is studying the integration of behavioral and social interventions into medical treatment for OUD to increase adherence, prevent relapse, and improve abstinence. The program was launched in FY 2018, and researchers were asked to leverage funding provided to SAMHSA for state-targeted responses to the opioid crisis that take into account chronic pain, stress reduction, and interventions targeting individuals, families, health care providers, and communities. Studies funded so far include various approaches to mindfulness techniques, one focusing on pregnant women, and one using comprehensive cognitive behavioral therapy. The announcement of a new round of longer-term awards has attracted more ICOs and more applicants. The existing studies are eligible for funding to expand their efforts, increase the power of their studies, and recruit more subjects from under-represented populations.

Discussion

Key points of discussion follow:

Data Sharing

• The HEAL Initiative can advance more aggressive data sharing and open science practices. In some cases, research is linked to state databases, so it will be easy for state agencies to adopt the findings. Other efforts are building their own data coordination centers, which will require harmonization. Some states penalize those receiving public benefits for using drugs, so study participants must be protected.
• NIH’s data sharing policy committee is wrestling with the issue for all grantees.
• NIH should consider collecting common, critical data elements from funded initiatives to address long-term questions, such as variability in pain-sensitivity and pain-regulation phenotypes. NIH is investing in a data network to collect pain information from HEAL programs and potentially from pharmaceutical R&D trials with large data sets.

Trial Design

• The BRIM program includes a focus on retention, with the recognition that some nonpharmacological interventions must be introduced over a long time, and the benefits may take time to manifest, just as with medications.
• The behavioral interventions in the BRIM study were developed decades ago; newer cognitive and behavioral science techniques are not yet incorporated into large studies.
• Ultimately, BRIM aims to construct a self-care model that provides individuals with the tools to manage their own health in way that the health care system cannot, which may ultimately improve other health outcomes.

Preclinical Research in Pain Treatments: Discovery and Validation of Targets for Pain, Animal and Human-Based Screening Platforms

Walter J. Koroshetz, M.D., Director, NINDS

Dr. Koroshetz said NIH’s strength lies in discovering new targets; he reiterated that some new research will emphasize validation in various settings and species, followed by generalizability, with the goal of lowering the risk of adopting new targets into translational projects. Some interesting areas of research include new ways to design and interact with receptors that can be evaluated in silico. The Brain Research through Advancing Innovative Technologies Initiative is heavily invested in developing ways to turn cell types on and off, possibly through chemical measures. A recent study found a method for turning off neurons in the basal amygdala so that animals feel pain but do not respond to it, opening up new capacity to dissect the circuits.

Preclinical Screening Platform for Pain (PSPP)

Amir Tamiz, Ph.D., Director, Division of Translational Research, NINDS

The PSPP aims to accelerate discovery and preclinical development of nonaddictive pain treatments, de-risk assets so they can be made available for research quickly, and generate high-quality data using pain models to advance promising treatments into trials. NIH will incorporate industry-standard protocols and work with industry to generate robust data.

The PSPP will include a public database where all findings and protocols will be published. Dr. Tamiz anticipates the PSPP will have a catalytic impact on the field. Development began in 2018, and the platform is already testing some compounds. In 2023, NIH will evaluate the platform to see whether it achieved useful, meaningful milestones, then identify the next steps. Anyone can submit ideas for assets to evaluate through the PSPP.

Developing Drugs and Testing Platforms for Pain, Addiction, and Overdose

Joni L. Rutter, Ph.D., Deputy Director, NCATS

NCATS’ role in the HEAL Initiative includes intramural and extramural work, with a number of intramural collaborations. Some efforts are developing human-based platforms for testing treatments for pain, addiction, and overdose, and they range from simple, single cell-based assays to three-dimensional fabricated tissue models and multi-organ models. Other efforts are putting compounds through the preclinical regulatory requirements, with the goal of accelerating novel compounds toward testing. Some have developed new chemical structures to modulate novel targets, while others are combining artificial intelligence with synthetic chemicals to assess compounds better, faster, and more cheaply.

The NCATS in-house chemistry program can help assess compounds and conduct toxicology testing. NCATS can also help develop drugs for clinical testing by providing capability (such as pharmacokinetic or safety evaluation) or assisting with scaling up to a Good Manufacturing Practices (GMP) production facility.

Among the extramural opportunities is an FOA to support creation of tissue models/chips and another for developing innovative, specialized platforms to help solve the opioid crisis. Intramural collaboration does not include funding but enables investigators to use NCATS resources and expertise for free. It also allows investigators to fail fast, ensuring that work that proceeds to the next milestone has a high likelihood of success. Dr. Rutter pointed out that NCATS can create on-ramps into the product pipeline—as well as off-ramps—to get to approval and commercialization.

Discussion

Asked about the status of models in development, Dr. Koroshetz said that some models are specific to certain types of pain, and some types of pain may require more relevant models. For validation studies, he and his colleagues will try to match the asset to the best population and animal model to evaluate the asset and refine the model.

Models

• Models should account for sex as a biological variable, even at the cellular level. Some research is already demonstrating different pain responses between male and female cells.
• The field lacks models for centralized pain, which represents a huge gap that cuts across diseases. Centralized pain occurs with many diseases for which the pain was initially caused by nociceptive input and then transforms into chronic pain (e.g., fibromyalgia, irritable bowel syndrome, pelvic pain, and sickle cell disease).
• NCATS is supporting development of human cell models that can last as long as 60 days so that researchers can evaluate longer-term exposure to interventions.
• The field is beginning to realize that animal models may be measuring sensitization to input, not spontaneous pain.
• Some work on animal models aims to assess outcomes related to functional performance.
• Research should explore new territory in animal models, such as the use of marmosets, which have neurological components similar to humans.

Other Topics

• Working with industry may be a means to gather information from the preclinical and animal model data about products that failed clinical testing—information that is not in the public domain.
• The research community has indicated that focusing on validating endpoints that better predict human response can provide insights that allow for reverse engineering to develop new models. Biomarkers may help identify efficacy and predict validity.
• Some research is seeking new analgesics that are not addictive, looking at the potential use of cannabinoids, for example. NCATS may be able to help by providing researchers with tetrahydrocannabinol manufactured in a GMP setting and developing tests of the addictive, analgesic, and anti-inflammatory properties of the product.

EPPIC-Net

Clinton Wright, M.D., Director, NINDS Division of Clinical Research

EPPIC-Net will create an infrastructure that draws on existing expertise and facilitates learning and training, allowing for innovative trial design and iterative learning approaches to speed up research. EPPIC-Net will also establish a pool of well-phenotyped patient cohorts and incorporate biomarkers and endpoints that demonstrate target engagement or proof of principle.

EPPIC-Net will be similar to current CTNs but provide more flexibility and nimbleness to pave the way for more partnerships with industry researchers. It will include a data coordination center, a clinical coordination center, and specialized hubs and spokes set up around different pain conditions. The data coordination center will facilitate data sharing and allow programs to put their data in a repository that others can use.

Anyone can propose an asset for testing by completing an online template that enables NIH to screen the proposals. Selected assets will be reviewed independently, on a rolling cycle, according to traditional NIH review procedures. If the asset appears promising, NIH will solicit more information, and the asset will undergo extensive review and prioritization. NIH will then work with the asset holder to develop a study protocol and with the clinical coordination center to identify a site with the expertise to conduct the research. EPPIC-Net will store data and biosamples from trials or from industry partners that can be used by others.

Discussion

In response to Dr. Collins, Dr. Wright explained that some sites will likely have capacity to set up trials quickly for common pain conditions (e.g., back pain or diabetic neuropathy); for other conditions, EPPIC-Net will seek out new partners. Dr. Wright and Dr. Koroshetz clarified that NIH partners with FDA; asset holders can communicate with FDA when they face hurdles or bottlenecks. NIH will prioritize assets for which Phase I and safety research are already completed. NIH can learn from assets that failed testing and build on existing work for which more evidence is needed. Key points of discussion follow:

• EPPIC-Net will be set up to incorporate phenotype data. A trans-NIH discussion is needed about how pain conditions are phenotyped. Phenotype data are very important to understanding who will respond to treatment.
• NIH should let the field know that the HEAL Initiative offers an opportunity to prioritize assets focusing on pain or OUD and facilitate their inclusion in, for example, the NIH Blueprint for Neuroscience Research. NCATS can provide resources for early toxicology studies, manufacturing, and meaningful Phase I trials, among others. Such opportunities will be attractive to smaller companies that are working on high-risk discovery.
• At present, no reliable biomarkers have been identified for chronic pain, which represents a significant unmet need.
• The current FOA does not include genotyping, but it may be considered, as costs are coming down.
• One barrier to pain research is the problem of secondary data analysis. The lack of biomarkers and the use of limited outcomes measures (e.g., VAS) stymies advances. Imaging, such as functional magnetic resonance imaging correlated with pain, could elevate efforts, but it is expensive. In addition, pain may not be the same, neurobiologically, across individuals. It is possible that imaging could reveal categories related to prediction of pain.
• Some research is exploring what happens in the brain as individuals transition from acute to chronic pain. Work is underway to advance potential biomarkers and to refine imaging technology for use in clinical trial settings.
• Little is known about chronic pain when it is not triggered by an acute event. Because pain draws on neurological and musculoskeletal systems, dynamic imaging may yield understanding about the transition from acute to chronic pain.

Pain Management Effectiveness Research Network (Pain ERN)

Jane Atkinson, D.D.S., Director, Trial Innovation Network, NCATS

The Pain ERN, a trans-NIH initiative co-led by NINDS and NCATS, will compare the effectiveness of existing therapies or novel delivery approaches to prevent or manage pain while reducing the risk of addiction. It will strengthen and inform current clinical guidelines, address pain management across diverse communities, develop a suite of effective pain strategies for patients and providers, and improve patients’ and families’ QoL.

The Pain ERN will build on the infrastructure of the NCATS Clinical and Translational Science Awards (CTSA) program, allowing NIH to address multiple conditions through one network that has access to millions of patients. The NCATS Trial Innovation Network, part of the CTSA program, will provide clinical and biostatistical coordination and expertise in pain and support the development of recruitment and retention plans before trial launch to ensure stakeholders are engaged in advance and the trial goals are meaningful to participants.

NIH staff who oversee HEAL trials meet regularly to discuss standardization across CTNs using validated patient-reported clinical outcomes, common data elements, common data standards (e.g., Clinical Data Interchange Standards Consortium [CDISC]), and common adverse event coding. The Pain ERN studies will use CDISC data standards, which aligns with FDA’s needs. Data and biospecimens will be stored in the EPPIC-Net central data repository for public use.

Discussion

Dr. Atkinson said trial data are typically available about 5 to 6 years after the trial begins, which gave rise to the suggestion that some metadata, such as recruitment variables, could be made available sooner if doing so would not interfere with the integrity of the analysis. Investigators generally agree that they would like to maintain the confidentiality of their data for about a year to allow for publication before the data are shared broadly. (All NIH-funded research findings must be published in ClinicalTrials.gov within 1 year of the conclusion of data collection.)

New technology may help speed up patient recruitment and data collection—for example, by enabling oversight from a distance. Dr. Atkinson agreed but underscored the need to maintain the quality of the research processes and to avoid overwhelming the data and clinical coordination centers. She added that NIH can use electronic methods to identify which sites to visit and support web-based training of study personnel. Dr. Atkinson clarified that collecting biosamples is optional, but NCATS could consider asking sites to collect and submit DNA samples.

HEAL Application Logistics

Francis S. Collins, M.D., Ph.D., Director, NIH

Dr. Collins and Dr. Baker fielded several questions related to the logistics around the HEAL Initiative, addressing the following:

• NIH will use the conflict-of-interest disclosure process as the first step to determine who can serve as a peer reviewer for HEAL applications, and it is recognized that many in the field are likely to have some connection to an application, given the scope of the Initiative.
• In most cases, it is not yet known whether expiring FY 2018 FOAs will be reissued or extended. Applicants are encouraged to talk with NIH program officers about next steps and future opportunities. NINDS will reissue its FOA for EPPIC-Net.
• Paylines are not determined until all the applications have been submitted. NIH expects to obligate all of its $850 million in 2019, so the likelihood of funding may be higher than usual.
• NIH has the flexibility to select and fund high-quality components of an application to complement its portfolio.
• Reviewing bodies will determine whether to request revisions to applications.

Summary of Discussion

Francis S. Collins, M.D., Ph.D., Director, NIH

Dr. Collins hoped MDWG members would offer their input on the novel model of the working group. He outlined key points he gathered from the discussion of the five specific projects:

OUD Treatment Retention and Discontinuation

• The study design to enhance retention and discontinuation is a creative approach for a research question for which a purely randomized trial is not practical or ethical, and MDWG members supported the draft model. Cluster randomization was suggested for the follow-up after discontinuation, to get away from the influence of experts who think their method is best.
• The study will not wait 2 years to start Phase 2.

BRIM

• Adding behavioral intervention to medication could improve the ability for people to sustain treatment, because it helps with other aspects of addiction and because many have pain that will persist. Providing tools to manage pain and avoid relapse are key. Behavioral research entities are an important part of the project.
• Behavioral intervention is an important part of the HEAL Initiative.
• Maintaining behavioral interventions can be difficult and demanding.
• As applications are assessed, it may be appropriate to consider the role of new mind-body interventions beyond the well-known, longstanding approaches.
• The overarching goal of enhancing self-care is laudable.

Developing, Discovering, Validating, and Testing Pain Treatments

• Many questions arose about validating targets.
• Discussion included the utility of models for chronic pain, the need for models of centralized pain, and what kinds of models would be relevant.
• Research should go beyond looking at lessening pain to evaluating subject function.
• It is possible to learn more about animal models from failed industry projects.
• The potential role of cannabinoids should be explored.
• Research should ensure that new compounds are not addictive.

EPPIC-Net

• NIH hopes to achieve some early wins by prioritizing compounds that are ready for Phase II trials. It should also consider some that still need to go through Phase I or even earlier assessments.
• NIH should look for other ways to gather and assess promising compounds in the early stages of development, especially from companies that do not have the resources to push their discoveries forward (e.g., through the NIH Blueprint for Neuroscience Research and NCATS).
• EPPIC-Net should prepare for rapid enrollment of subjects with various pain syndromes and should consider how to convince people to enroll.
• Phenotyping is important and challenging. Genotyping may be a possibility, because the costs are coming down.
• Partnering with FDA is crucial so that progress does not stall in the late stages of development. FDA appears to be very motivated in this space.
• Thorny questions remain about assessing the outcomes of EPPIC-Net trials, such as whether any biomarkers are valid or better than VAS.

Pain ERN

• Biospecimens should be collected, even if there is no plan for testing them yet.
• The MDWG will strive to seek balance in the portfolio for this effort.
• NIH should look for mechanisms to accelerate findings without compromising the integrity of the research and opportunities to learn along the way, such as evaluating metadata.

General Issues

• Health equity should be front and center for all projects, not an afterthought.
• Reimbursement issues should be addressed; NIH should determine what evidence is needed to convince CMS to pay for interventions.
• Workforce training is needed, as the field lacks sufficient expertise in research and practice.
• OUD treatment alone is not enough; there must be support for ongoing recovery.
• Regarding data sharing, NIH should monitor research closely and push investigators to go beyond where NIH can.
• NIH must constantly avoid the tendency to separate OUD from chronic pain, as the two are clearly connected but involve separate teams and FOAs.
• Research should incorporate sex as a biological variable in clinical trials, animal studies, and even cell research.

Observations on the MDWG Process

Francis S. Collins, M.D., Ph.D., Director, NIH

Bridging the Pain and Addiction Communities

• The NIH Pain Consortium can be a forum for continued dialogue between experts in OUD and pain management. It meets annually and can be revised to incorporate different aspects of the HEAL Initiative. It may be appropriate to update the name of the consortium and ensure that it continues to focus on OUD and pain management.
• The HEAL Initiative is structured to support integration across fields, but it can be revised as needed.
• Once awards are made, NIH will convene the grantee community, providing another opportunity for cross-fertilization.
• NIH should keep tabs on federally funded research on the use of opioids for chronic noncancer pain and determine possible links to HEAL research. Comparisons of the utility of opioid vs. nonopioid treatment will likely come up in some HEAL studies.

Disseminating and Increasing Uptake of Findings

• NIH should consider the infrastructure for disseminating findings and how to shorten the time to uptake, possibly by mapping existing resources (e.g., medical societies and SAMHSA). The Executive Committee and its federal partners can begin thinking now about a unified mechanism for dissemination. Using multisite studies increases the chance that those sites will adopt what they studied. The American Medical Association and specialty societies have many mechanisms for disseminating findings, but reaching primary care providers remains challenging.
• Programs should keep in mind the roles of insurance companies and dental schools in education and outreach.
• NIH should identify experts in implementation science to ensure uptake of findings.
• Some work in the PRISM program includes real-world trials, which may inform uptake.
• NIH’s collaboration with the departments of Defense and Veterans Affairs may provide an opportunity to look more systematically at the implementation of new interventions.

Social and Economic Issues

• Socioeconomic aspects of disease are difficult but necessary to address. The HEALthy Brain and Child Development Study is one opportunity.
• Some of NIH’s funding goes to the Small Business Innovation Research and Small Business Technology Transfer programs, which may be a mechanism for reaching out to small companies that can address socioeconomic aspects, such as expanding access to shelter for homeless people so they can get treatment.
• The HEALing Community project offers an opportunity to evaluate how communities affect behavior. NIH’s Office of Behavioral and Social Sciences Research is involved in many of the FOAs. NIH must make sure the concepts are meaningfully integrated.
• Research should evaluate resilience at the community level and other positive factors that may protect against addiction and transition to chronic pain. Good social support is recognized as an important predictor of successful recovery, at every level of addiction.

Other Topics

• The HEAL Initiative will focus on long-term addiction, regardless of the cause.
• Some ICs will define common data elements and outcomes for their CTNs. Some will incorporate the CDISC standards for different pain elements.
• NIH should consider the sustainability of efforts once the funding ends.
• Private partners should be required to contribute something of value—such as data or assets from clinical failures—in exchange for NIH setting up a public infrastructure to support clinical trials for assets already deemed safe. The MDWG members on the HEAL Partnership Committee—Ms. Veasley, Dr. Verburg, and Dr. Paice—will report back to the MDWG in May about discussions.

Rebecca Baker, Ph.D., Director, HEAL Initiative, Office of the Director, NIH

Dr. Baker thanked the participants for their time and effort. The next MDWG meeting is scheduled for May 17, 2019, in Bethesda. Another meeting will take place in August 2019. Dr. Baker asked participants to let her know if they want to engage with NIH and HEAL in other ways or pursue different threads of conversation. The meeting adjourned at 3:58 p.m.

BRIM: Behavioral Research to Improve Medication-Based Treatment for OUD

CDISC: Clinical Data Interchange Standards Consortium

CMS: Centers for Medicare & Medicaid Services

CTN: clinical trial network

CTSA: Clinical and Translational Science Awards

EPPIC-Net: Early Phase Pain Investigation Clinical Network

FDA: U.S. Food and Drug Administration

FOA: funding opportunity announcement

FY: fiscal year

GMP: Good Manufacturing Practices

HEAL: Helping to End Addiction Long-Term

HHS: U.S. Department of Health and Human Services

ICs: Institutes and Centers

ICOs: Institutes, Centers, and Offices

MDWG: Multi-Disciplinary Working Group

NCATS: National Center for Advancing Translational Sciences

NCCIH: National Center for Complementary and Integrative Health

NIDA: National Institute on Drug Abuse

NIH: National Institutes of Health

NINDS: National Institute of Neurological Disorders and Stroke

OUD: opiate use disorder

Pain ERN: Pain Management Effectiveness Research Network

PRISM: Pragmatic and Implementation Studies for Management of Pain to Reduce Opioid Prescribing

PSPP: Preclinical Screening Platform for Pain

QoL: quality of life

R&D: research and development

SAMHSA: Substance Abuse and Mental Health Services Administration

VAS: visual analogue scale