IPRCC Meeting - 10/23/2017

NIH Campus
Building 31 Room 6C6 — 6th Floor
C Wing, Conference Room 6
Bethesda, MD
IPRCC Annual Meeting Agenda - October 23, 2017(pdf, 37 KB)

Federal Register Notice - August 28, 2017

Introduction

The October 23, 2017 meeting of the Interagency Pain Research Coordinating Committee (IPRCC) was convened at 8:30 a.m. in Building 31, Porter Neuroscience Center, 6th Floor, C Wing, on the National Institutes of Health (NIH) campus.

In accordance with Public Law 92-463, the meeting was open to the public. Walter Koroshetz, MD, Director, National Institute of Neurological Disorders and Stroke (NINDS), presided as chair.

In attendance were the following members of the IPRCC:

Federal Members: Walter Koroshetz, MD; Chester Buckenmaier, MD; Charles G. Helmick, III, MD; Sharon Hertz, MD; Richard Ricciardi, PhD, CRNP; Martha J. Somerman, DDS, PhD;

Scientific Members: Allan Basbaum, PhD, FRS; William Maixner, DDS, PhD; Judith Paice, PhD, RN, FAAN

Public Members: Penney Cowan; Christina Spellman, PhD; Cindy Steinberg; Catherine Underwood, MBA; Michael Pasternak, PhD

Ex-Officio Member: Nora Volkow, MD, PhD; David Shurtleff, Ph.D. taking over for Josephine P. Briggs, MD

Designated Federal Official: Linda L. Porter, PhD

Ad hoc IPRCC Members: Daniel B. Carr, MD; Jan Chambers; and Roger B. Fillingim, PhD

 

Welcome and Call to Order

Walter Koroshetz, MD, Director, NINDS and Chair, IPRCC

Dr. Koroshetz noted that there is activity across NIH and the federal government to devise a plan to develop new non-addictive pain treatments and address the opioid crisis in this country. Several reports related to this important topic will be addressed during the meeting.

Dr. Labosky will present a Common Fund (CF) proposal concept on acute-to-chronic-pain transition. The Common fund is set aside money allocated to the Office of the NIH Director, Dr. Francis Collins, which is used to support transformative research. Congressional language states that the NIH Pain Consortium must submit a pain research proposal each year for CF support.

The Federal Pain Research Strategy (FPRS) has been rolled out. Dr. Koroshetz thanked the IPRCC, the Office of Pain Policy, Dr. Basbaum and Dr. Porter (the co-chairs), and others who helped develop the strategy.

NIH is developing a public-private partnership, to pursue research that might yield non-addictive pain treatments and better ways to treat addiction. Dr. Koroshetz said that he and Dr. Volkow, and Dr. Collins will elaborate on that endeavor during today's meeting. 

Official approval of incoming IPRCC members, Daniel B. Carr, MD, Jan Chambers, and Roger B. Fillingim, PhD is expected soon. They were introduced as nominees last year and are joining us today as ad hoc members. Dr. Koroshetz thanked Allan Basbaum, William Maixner, and Penney Cowan, for staying on the committee during this transition.

Dr. Koroshetz highlighted recent science advances in pain research.  He noted that research to understand pain circuits is moving along at a rapid pace.

A study by Chen, et al.explored PD-L1 in dorsal root ganglion (DRG) cells. PD-L1 is a checkpoint inhibitor that when blocked in cancer patients, dramatically reverses some tumors. In this paper, they found that PD-L1 is produced by melanoma cells and DRG cells. In DRG cells of the sciatic nerve, PD-L1 turns down the pain signal. This finding shows how discoveries in the cancer field can help pain research.

A potential master switch that turns the gain up on pain is being explored.  A microRNA was discovered that regulates a whole suite of proteins. This microRNA was found to be associated with about 80% of all proteins that are switched on in some models of chronic pain. Peng, et al.2 knocked out the microRNA to determine if it might be modulated to switch pain signals on and off, turning pain intensity up and down, and scaling pain perception.

A paper by Jensen, et al.provides an example of a novel mechanism for pain mediation at the cellular level. There are substance P receptors on the surface of DRG cells that mediate pain signals. The study went beyond the role of receptors outside the cells and looked at their role in pain modulation when the receptor moves off the cell surface into endosomes. The results suggest that blocking endocytosis may decrease hyperalgesia in some models of pain.

 

Approval of the Minutes of the October 31st, 2016 IPRCC Meeting

Linda Porter, PhD, Director, NINDS Office of Pain Policy

The IPRCC considered and approved the October 31st, 2016 IPRCC meeting minutes with no corrections.

 

NIH COMMON FUND CONCEPT

A Research Plan for Understanding the Transition from Acute to Chronic Pain

Dr. Patricia Labosky, Office of Strategic Planning; Dr. Linda Porter, Office of Pain Policy

The NIH Common Fund is managed by the Office of Strategic Coordination/Division of Program Coordination, Planning, and Strategic Coordination/Office of the NIH Director. Common Fund programs address emerging scientific opportunities and pressing challenges in biomedical research that no single NIH Institute or Center can address. The CF functions as a “venture capital” space where high-risk, innovative endeavors with the potential for extraordinary impact can be supported. Programs are short-term (5-10 years), with deliverables intended to catalyze research across multiple biomedical research disciplines.

Dr. Labosky presented a concept for a CF proposal on pain. Nearly 26 million Americans report pain every day. Their sole treatment is often opioids. Deaths from opioid overdoses exceeded 33,000 in 2015 and are rising. Patients with chronic pain need safer and more effective treatments. There are no objective signatures of acute-to-chronic-pain transition. This study will enable identification of patients at risk for chronic pain by identifying a signature and may guide treatment to prevent chronic pain prevention.

Why is a trans-NIH program needed? Chronic pain is a symptom of many diseases and can be a disease itself. This project will involve scientists from diverse areas of research and will bring in advanced technologies.

The NIH recently hosted a cutting-edge science meeting series to address the opioid crisis. Some of the key themes of the meetings were directly relevant to the CF program. For instance, one theme was the need for standardized objective biomarkers and extensive patient phenotyping, which is an important gap in our understanding of the acute-to-chronic-pain transition.

The FPRS, a long-term strategic plan to enhance the federal pain research agenda, includes prioritized research recommendations. Some of the recommendations were used to develop this CF program, including, prospective studies on acute-to-chronic-pain transition and precision medicine approaches to prevent and treat chronic pain.

Proposed CF program:

1) Clinical trial

  • Recruit patients with time = 0 for an acute pain event with known incidence of transition to chronic pain.
  • Follow-up over 6 months to identify objective markers (psychosocial and psychophysical assessment, neuroimaging, and multi omic assays) in those who transition to chronic pain and those who recover.
  • Create a database for the community to use.

2) Parallel clinical study

  • Recruit patients with established chronic pain of more than one year.
  • Assess objective markers as in the transition cohort.

3) Data coordination and analysis center

  • Signatures predicting transition to chronic pain
  • Signatures defining established chronic pain
  • Signatures predicting efficacy of pain management strategies

Awardees would work together during an initial planning year. Everything would be standardized: pain management protocols, types/timeframe for sample/data collection, psychosocial assessments, imaging protocols, and sample collection protocols. A pilot study is being considered.

Discussion Points

  • Dr. Buckenmaier noted that for pain research, the DoD uses a program called PASTOR, which leverages NIH PROMIS instruments, and is taking biological samples from soldiers with acute pain. Comparison of these studies should prove valuable.
  • Dr. Maixner noted that NIDCR funded his 15-year study Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA), which uses a similar design. Their team could offer lessons learned.
  • Dr. Carr suggested rethinking our reliance upon randomized controlled trials and meta-analyses, in light of increasing interest in alternative means of data gathering (e.g., electronic health records). Dr. Labosky replied that electronic health records will be utilized.
  • Dr. Koroshetz emphasized the need for a pilot study on one cohort that would be highly informative to generalize findings to other populations. He asked what patient populations might be best for the studies. Dr. Hertz said some patient populations are known to be at risk for transition (e.g., post-surgical pain). Dr. Maixner said OPPERA identified ways to stratify patients by acute to chronic pain transition risk. Dr. Fillingim added that it is important to characterize the temporal dynamics of this transition and avoid the naïve view that there is an on/off switch; some people will have pain at some, but not all assessment time points.
  • Dr. Koroshetz stressed that the pilot should yield short term results. Dr. Maixner suggested that current international guidelines support the 6 months proposed follow-up as a time point to consider pain as chronic.
  • Dr. Spellman referred to Dr. McLean’s work in emergency medicine at UNC, looking at patients post automobile accident and victims of sexual assault.
  • Ms. Cowan suggested looking at lifestyles and family interventions. Dr. Maixner added that the community should generate surveys, tapping into exposures across a lifespan that can drive onset and persistence of pain.

 

THE FEDERAL PAIN RESEARCH STRATEGY

Dr. Linda Porter and Dr. Allan Basbaum, Co-Chairs FPRS Steering Committee

Overview

Dr. Porter described the development of the FPRS, an effort of the IPRCC and the NIH Office of Pain Policy to oversee development of a long-term (10-year timeframe) strategic plan to advance the federal pain research agenda. The strategy is relevant to the missions of all federal agencies and departments that support pain research. The FPRS final report(pdf, 982 KB) is now publicly available.

The federal pain research portfolio is large and complex. It requires coordination and strategic planning to ensure it moves forward efficiently. NIH is the biggest federal funder of pain research, although the other agencies and departments have important and unique niches.

The strategy fulfills the IPRCC's mandates to identify critical gaps in basic and clinical pain research and to make recommendations to ensure that the activities of NIH and other federal agencies are free of unnecessary duplication of effort. The FPRS completes the National Pain Strategy (NPS) section on pain research, in that it includes an agenda for developing physiological, clinical, behavioral, psychological, outcomes, and health services research.

The FPRS planning committee, which included the NIH Office of Pain Policy, members of the NIH Pain Consortium (a trans-NIH collaborative), and members of the IPRCC, assembled a diverse and balanced group of scientific experts, patient advocates, and federal representatives to identify and prioritize research recommendations.

There was oversight and feedback throughout the FPRS development process. The IPRCC helped to set up the steering committee, which gave the charge to a set of five working groups. The working groups were organized thematically based on the temporal continuum of pain (acute to chronic). The NINDS Office of Pain Policy also was a valuable resource during development.

The goal was to advance pain research and ultimately relieve the burden of pain. The working groups looked at the state of the science, current research, opportunities from other fields that are using advanced approaches and identified barriers and gaps holding back the field. Patient advocates served in the working groups to ensure that the needs of people with pain were represented. The product is a comprehensive set of prioritized research recommendations.

The working groups selected their most important priorities, and then ranked them; the top quartile is noted clearly in the report, and an appendix contains the top priorities recommended by all the working groups. The working groups also identified two additional measures within their respective groups:

  • Which of their individual group’s priorities would be the most impactful if moved forward
  • Which has the greatest near-term value (to be moved forward immediately)

Next Steps

The FPRS is a guidance document, not a mandate. It is a way to help the agencies and departments collaborate and provides justification for selected pain research priorities to assist with funding decisions.

The FPRS rollout is underway and will include use of distribution lists and websites to announce its release. At least two of the working groups plan to publish details from the FPRS two-year development process.

The FPRS has already been helpful in planning stages for initiatives. The FPRS is helping to support the public-private partnership and the CF proposal, and may serve for future benchmarks as to how pain research advances over the next 10 years.

Discussion Points

  • Dr. Basbaum emphasized that the details within the document are critical. Interesting topics discussed during the development process include the question of what makes an individual susceptible to acute-to-chronic-pain transition, or even the possibility that there is no transition (a person may be in a state of chronic pain from the moment the injury occurs). Are there resilience factors that allow people not to transition?
     
  • Dr. Maixner mentioned that the Center for Scientific Review is creating a pain-focused study section and has agreed to use an American Pain Society (APS) list of reviewers to serve on study sections where there is no pain expertise. Ms. Underwood added that the APS list has been used and is continuing to be updated. 

 

THE PAIN MANAGEMENT TASK FORCE – CARA

Intersection with IPRCC

Dr. Vanila Singh, Chief Medical Officer OASH

Dr. Singh described the objectives and establishment of the Pain Management Task Force called for in the Comprehensive Addiction and Recovery Act (CARA) of 2016.

Primary objectives of the task force:

  1. Review best-practice guidelines for prescribing pain medication and managing acute and chronic pain.
  2. Identify gaps and inconsistencies in the current guidelines.
  3. Identify how to best disseminate the findings of the advisory committee.  

The task force will sunset in July 2019. The nomination process for members was open August through September 2017. There was great interest in serving from experts around the country. According to statute, the not-to-exceed-30-member group must be diverse: prescribing physicians, pharmacists, dentists, pharmacy organizations, medical organizations, patient advocacy groups, veteran’s organizations, first responders, leaders in the mental health and addiction treatment communities, and representatives from state medical boards and hospital associations. Two thirds will be non-federal stakeholders. Federal partners will include HHS, NIH, CDC, SAMHSA, and perhaps the Indian Health Service.

It is an interagency task force, and one requirement is that the Secretary of HHS convene the meeting with DoD, Veterans Health Administration, and Office of National Drug Control Policy representatives. The first meeting will be January/February 2018. There will be sub-groups established, and it is expected that experts who are not task force members will attend meetings and express opinions. The application review process is underway.

Dr. Singh emphasized the importance of balancing the effects of opioid misuse and overuse deaths with appropriate pain management for patients.

Discussion Points

  • Dr. Singh clarified that the list of committee members will be released around mid-November.
     
  • Dr. Paice referred to one section of CARA that is of concern. Section 704 describes programs to prevent prescription drug abuse under Medicare that exempts hospice and long-term care facilities and identifies beneficiaries who are “at-risk” based on how much opioid they are prescribed. “At-risk” patients will be relegated to access only one prescriber and one pharmacy which will be devastating for some people, such as those with cancer or hemophilia, who would have to get a prescription, which would not be valid, from someone else.

 

UPDATES FROM IPRCC MEMBERS

FDA Risk Evaluation and Mitigation Strategy

Dr. Sharon Hertz, IPRCC FDA Representative

Dr. Hertz gave an update on the FDA opioid action plan, which focuses on policies aimed at reversing the opioid epidemic while still providing patients access to effective pain relief.

The FDA requires that drug manufactures develop risk evaluation mitigation strategies (REMS) to train prescribers on use of extended-release and long-acting (ER/LA) opioids. The FDA recently established a Blueprint to guide development of these continuing education courses. 400,000 health care providers took the REMS training, but not all of them fit the target population (i.e., ER/LA prescribers). It is difficult to evaluate the effect of education on the key outcomes, which include inappropriate prescribing, misuse and abuse, addiction, and unintentional overdose and death. An advisory committee that convened in May 2016 recommended that the FDA expand the program to include immediate-release opioids and include nurses and pharmacists in the target population.

Draft FDA Blueprint Revisions:

  • Broadens Blueprint to include information on pain management:
    • Principles of acute and chronic pain management
    • Non-pharmacologic treatment options
    • Pharmacologic treatment options (non-opioid analgesics and opioid analgesics)
    • Basic elements of addiction medicine and opioid use disorders (OUD)
  • Public comment period on the draft closed July 2017. More than 680 comments were received from:
    • Prescriber organizations
    • Continuing education providers
    • Pharmacy organizations
    • Industry
    • Patient organizations
    • Complementary medicine organizations
    • Federal agencies (CDC, NIH)
  • FDA will share the revision with federal agencies
  • Goal is to have a final revised Blueprint by late Fall

In December 2016, the FDA completed relabeling of all immediate-release opioids. A letter announced safety labeling changes, which included expanded warnings pertaining to risks of concomitant use of benzodiazepines and opioids for pain. Another letter announced updated methadone and buprenorphine labeling for OUD. Because the patient populations receiving prescriptions for pain or for OUD are not the same, the labels will not be the same. The risks of managing people with OUD and the risks with managing people with pain have different weights.

There are ten FDA approved abuse-deterrent opioid formulations. The FDA does considerable pre-market work to make them less appealing for abuse. The message conveyed in the community however, is that they are less addictive, which is inaccurate. The formulation changes only the ability to manipulate the products for use by routes other than the route intended. The FDA is using Advisory committees to get a better sense of unintended consequences of people managing to defeat abuse-deterrent characteristics. In July 2017, the FDA convened a public workshop (Data and Methods for Evaluating the Impact of Opioid Formulations with Properties Designed to Deter Abuse in the Post-market Setting) to discuss ways to improve the analysis and interpretation of existing data.

When the FDA labels an opioid as schedule II, the intent is that the reader will understand its meaning and appropriately use the medication. That step has not been successful. The FDA therefore, has been adding a progressively longer box warning and has sought input from the National Academies of Sciences to improve benefit-risk assessment. The FDA recently removed extended-release Opana (oxymorphone) from the market, because the population that was obtaining it illegally and abusing it, was being harmed by elements of the formulation.

The FDA is partnering with NIDA and pharma, to accelerate development (i.e., fast track, breakthrough therapy designation, and priority review) of new products. The first modified-release formulation of buprenorphine was approved last year, and there are two novel depot buprenorphine products under review.

Another element of the FDA’s action plan is the Opioid Policy Steering Committee (announced May 2017), established by the Commissioner to examine additional FDA regulatory and policy actions to combat the opioid crisis. The committee:

  • Is considering whether there are circumstances when FDA should mandate education for HCPs, and how to pursue this effort.
  • Issued a notice to solicit public input (FDA-2017-N-5608).
  • Is emphasizing means to evaluate rates of new cases of addiction.

Discussion Points

  • Dr. Paice said that health care providers need to know much more about the differences between the benzodiazepines and their unique risks. Dr. Hertz responded that needed detail hopefully will come out through thoughtful creation of these programs. It is difficult to anticipate the impact of labeling.  It may have no impact or unintended consequences.
     
  • Dr. Maixner suggested that REMS courses be an accreditation requirement. Dr. Hertz agreed, adding that FDA has authority to regulate industry, but cannot directly influence medical education accrediting bodies.
     
  • Ms. Steinberg asked about patient input into the crisis. Dr. Hertz said the FDA has patient and consumer representatives on advisory committees, as standard practice.
     
  • Ms. Steinberg said there is a lack of pain management curricula in medical schools. Ms. Cowan said we first need to educate current prescribers.

 

Systematic Review on Non-Pharmacological Treatments for Chronic Pain

Dr. Ric Ricciardi, IPRCC AHRQ Representative

Dr. Ricciardi reported that the AHRQ evidence-based practice center is doing additional sub-population analyses on their Systematic Review on Non-Pharmacological Treatments for Chronic Pain. He will share the link to the draft document when it is released for public viewing.

Dr. Ricciardi noted that AHRQ’s Academy for Integrating Behavioral Health and Primary Care developed the Integration Playbook as a guide to integrate behavioral health care in primary care and other ambulatory care settings, yielding a treasure chest of ways to assess pain, as well as best-practices for different organizations. Also, AHRQ did an environmental scan on medication-assisted treatments (MATs) for opioid addiction in rural primary care practices.

AHRQ is invested in clinical decisions support. Use of the electronic health record for systematic quality improvements in care is permanent. The second part of a contract, to develop clinical decisions support, will be on chronic pain management and opioid prescribing.

Discussion Points

  • Dr. Koroshetz asked if there are hospitals or healthcare systems using the clinical decisions support for pain? Dr. Ricciardi said it is in development. The process is to take best-practice guidelines, translate the text into artifacts, then the artifacts become different kinds of programming materials that can be used. He will keep the IPRCC updated regarding pilot testing.  
     
  • Dr. Carr asked how to factor in the differing durations of trials for different interventions. Dr. Ricciardi said there will be definitions based on IPRCC recommendations, regarding inclusion/exclusion criteria.
     
  • Ms. Cowan asked if AHRQ has considered the current Patient-Centered Outcomes Research Institute (PCORI) grants on treating pain with goal setting, tapering, and relaxation.
     
  • Dr. Ricciardi said the CDC is developing clinical decision support through its opioid prescribing guideline.

 

Joint Educational Program Curriculum and the West Virginia University

DoD/USUHS Collaboration

Dr. Chester Buckenmaier, IPRCC DoD Representative

Dr. Buckenmaier noted that the DoD has 9.6 million healthcare beneficiaries, and that the VA has nearly as many. He suggested that there is some reluctance to address opioid issues in the military. A cultural change needs to happen among providers and patients, and the key is education.

In 2009, the Joint Pain Education Project (JPEP) was established to provide training for opioid prescribers. JPEP is designed for primary care with goals to form a standardized curriculum with common language for the DoD and VA. The specific aim is to improve pain care transition between the DoD and VA. JPEP includes 31 modules with video adjuncts.  Each is structured to be delivered in 20-30 minutes.

Dr. Buckenmaier said that the defense and veterans pain rating scale (DVPRS) is the DoD activity he believes best summarizes what has to happen nationally. The DVPRS assesses the impact of pain on general activity, sleep, mood, and stress. As such, the DVPRS relies less on pain intensity for pain assessment than the frequently used 0-10 scale.  If zero pain intensity is the goal, then opioids are the best available option. We need to change the framework by which we are assessing pain and recognize that this is a bio-psychosocial problem. Some states are interested in adopting the DVPRS. The first state to incorporate this tool into its hospital system was West Virginia, which is at the front line of the opioid crisis.

Discussion Points

  • Dr. Koroshetz asked if there are pain treatment centers within the military system. Dr. Buckenmaier responded that there are integrated healthcare systems that evolved from the DoD pain management task force, but the funding for them is declining.

 

UPDATES ON THE NATIONAL PAIN STRATEGY

Implementation

Alicia Richmond-Scott, OASH

Ms. Richmond-Scott explained that some of the National Pain Strategy (NPS) implementation working groups have met. There are two agency representatives co-chairing each of the six working groups, which are based on NPS thematic areas (population research, service delivery and payment, disparities, prevention and care, professional education and training, and public education and communication).

The charge for the working groups is to achieve the NPS deliverables. The Office of the Assistant Secretary held an NPS stakeholder session to share updates on relevant activities in May 2017 and plan for another early next year. In November, OASH will solicit a list of new NPS activities across HHS and the VA and DoD.

Discussion Points

  • Ms. Steinberg asked whether OASH is collecting information on new initiatives or money allotted to start new activities or for ongoing activities. Ms. Richmond noted that the newly formed work groups may be doing relevant work with existing funds that are not yet identified.
     
  • Ms. Steinberg asked how more resources could be directed to the NPS. Dr. Porter said there were not resources set aside for NPS activities. The working groups are developing work plans. Once that plan is organized, it might be easier for them to request resources in future appropriations. NIH is working with other agencies to pursue resources for projects that align with NPS deliverables.
     
  • Dr. Maixner asked if there are mechanisms by which different agencies within HHS can be brought together to create resources? Dr. Porter said that would be done through the working groups. Ms. Richmond said it would depend on the specific deliverable, and that resource consolidation is a topic of discussion within the workgroups. 
     
  • Dr. Ricciardi suggested that AHRQ with its focus on implementation might have resources for relevant activities. An organization that has an evidence-based best-practice could make a nomination through the AHRQ website for that best-practice to be implemented. AHRQ looks at the evidence and feasibility and decides whether to put it on the list for a pilot study, or a full-scale implementation effort. Money is provided through a trust fund. Dr. Porter said that is an important point, because there are resources that can be targeted.
     
  • Dr. Koroshetz said that the NPS and FPRS provide the groundwork to respond to opportunities to address the opioid crisis, should resources become available.  In addition, promoting these strategies may help to identify people and organizations (e.g., medical schools, healthcare systems) who are in a position to contribute greatly to our efforts. 
     
  • Dr. Helmick added that the intent of the NPS included changing how people think about pain in the public arena. Building momentum in the public arena may affect those making decisions about pain care.

 

American Pain Society Research Awards for NPS Objectives

Catherine Underwood, CEO American Pain Society

The 2011 Institute of Medicine Report; Relieving Pain in America and the NPS missions are strategic goals of the American Pain Society (APS). In April 2016, the APS released a Request for Proposals to support pain research that aligned with the objectives of the National Pain Strategy. Three proposals were selected after peer review, for two-year awards.  All three proposals were focused on non-pharmacological approaches to pain management, spanning pediatric to geriatric populations.

One project will be led by Dr. Tonya Palermo at Seattle Children's Hospital. It focuses on research to develop, promote, and disseminate a free web-based, mobile app on pain self-management interventions for adolescents with chronic pain. The app will be tested in eight pediatric specialty care clinical sites. 

A second project will be led by Drs. Kathleen Sluka and Barbara Rakel at the University of Iowa. The Epic electronic health record data will be tapped to create algorithms for prescribing transcutaneous electric nerve stimulation (TENS) to adults with chronic musculoskeletal pain. They will evaluate the prescribing practices in three outpatient clinics at the University of Iowa Healthcare System. A primary outcome will be the effect on prescription practices for non-pharmacological and pharmacological treatments.

  • The third project will be led by Drs. Cary Reid and Dimitris Kiosses at Columbia University. They will evaluate the effects of eight-week emotion regulation self-management program in adults over 60 years of age who have chronic pain and negative emotions.  Over 50,000 adults with a wide range of cognitive functioning will be enrolled. The primary outcomes are reduction in pain intensity and pain-related disability.

Data from these projects will be presented at the APS 2019 Annual Scientific Meeting.  

Discussion Points

  • Dr. Maixner said this is an example of stakeholders providing technologies that will help with pain management and the opioid crisis.
     
  • Dr. Koroshetz asked about the resources to support these studies. Ms. Underwood replied that the APS was given a two million dollar, unrestricted donation from Pfizer to support research selected by APS.

National Health Interview Survey (NHIS): Mining the NHIS 2016 Data on Pain and Restructuring NHIS Pain Question Set

Dr. Chad Helmick, IPRCC Member, CDC

In October 2012 the Assistant Secretary for Health charged the IPRCC to create the NPS, and to include chronic pain objectives for Healthy People 2020, a program that outlines the HHS-created health objectives for the nation. The NPS was released in 2016 and inclusion of health objectives related to pain for Healthy People 2020 has progressed.

An expert work group proposed four developmental objectives for Healthy People 2020:

  • Decrease the prevalence of adults having high-impact chronic pain.
  • Increase public awareness and knowledge on pain.
  • Increase self-management of high-impact chronic pain.
  • Reduce the impact on family and significant others.

To collect data in support of the Healthy People 2020 pain objective, two high impact pain-related questions were added to the National Health Interview Survey (NHIS) for 2016 and 2017. It is a nationally-representative survey (35,000 people every year) of the civilian non-institutionalized population, and a standard survey to collect baseline data for measuring Healthy People 2020 objectives. The pain questions each used a six-month time frame to ask, “How often did you have pain?” and “How often did the pain limit your life or work activities?” The NPS definition of high impact chronic pain is pain on most days or every day, and pain related limitations in lifestyle.

The NHIS staff used the NPS definition of high-impact chronic pain.

The 2016 data analysis is being completed. Publication options are CDC’s Morbidity and Mortality Weekly Report (MMWR) (reviewed by major media), or through an academic journal (permits more detail but reaches a smaller audience).

The NHIS team is cutting questions from the survey to increase response rates but is excited about including pain questions as part of a rotating module every two years. However, they will use a three-month (not a six-month) time frame, because it is a previously-established international standard. They are also considering additional pain questions relating to:

  • Work limitations attributable to pain.
  • How has pain affected your family or significant others?
  • Pain self-management.
  • Questions that get at the anatomical site of pain.
  • Opioid use for pain.

Discussion Points

  • Dr. Spellman asked when they will have the 2016 data analyzed and available. Dr. Helmick responded that it would be quickly for MMWR and longer according to schedules for the journal article.  Ms. Steinberg encouraged both publications and for advance notice, so she could promote press attention. Dr. Helmick will spread the word within CDC, as well as the IPRCC.
     
  • Dr. Helmick was asked when Healthy People 2030 data is collected and noted that 2030 objectives should be finalized in 2019.
     
  • Dr. Fillingim asked if there has been discussion of looking at pain duration. Dr. Helmick said only the initial question of chronicity during three- and six-month time periods; but that is something he can discuss.
     
  • Ms. Steinberg mentioned that Dr. Richard Nahin has done creative epidemiological research with old data that might be cross-referenced with the new data. She emphasized that getting the data out will create public awareness. Dr. Shurtleff assured her that they will push that information out to the press to achieve public appreciation.
     
  • Dr. Maixner asked what kind of opioid-related questions will be included in the NHIS. Opioid use questions will be included concurrently with the pain questions, in either 2019 or 2020.
     
  • Dr. Porter reminded the committee of a previous presentation by Dr. Chris Jones on a pilot study contracted through Johns Hopkins University. The study reviewed payer coverage protocols for low back pain to determine what pharmacological and non-pharmacological treatments were covered.  It included a pharmacy, a state Medicaid, and one private insurer. They have expanded the study to look nationwide (13 state Medicaid systems, medicare, and private payers) to assess coverage more broadly. The study should be completed in another 3-4 months.

PUBLIC-PRIVATE PARTNERSHIP TO ADDRESS PAIN & THE OPIOID CRISIS

Introduction

Dr. Francis Collins, Director NIH

Dr. Collins described an NIH effort to accelerate treatment development for acute and chronic pain and to address the public health emergency of opioid addiction and overdose.

Opioid addiction has affected virtually all parts of the country, with alarming statistics on the number of people whose lives are being lost every day to overdose (now made much worse by fentanyl and carfentanil finding their way into the heroin supply). Dr. Collins emphasized that we also want to pay close attention to the fact that 25 million adults have pain every day in the US and need better pain care.  

Medication-Assisted Treatment is available and effective for Opioid Use Disorder but is drastically underutilized. We do not know how long treatment needs to continue to avoid relapse. We also are concerned about whether overdose reversal with Narcan is going to be sufficient in dealing with more potent opioids in particular fentanyl and carfentanil. Dr. Collins said it is unfortunate that we have such a limited repertoire of pain medicines and so rely on opioids. We need potent, non-addictive pain medicines. Moreover, we would like to speed up the process of developing and getting approval of safer treatments.

The three research areas that are particularly important in dealing with the crisis are addiction treatment, overdose reversal, and pain management.

Many research efforts have led to significant advances, which we can build upon:

  • Genetic studies of individuals with congenital inability to experience pain who have mutations in sodium channels (Nav1.7) have revealed potential targets for analgesics that might provide pain relief through mechanisms other than opioid receptors.
     
  • There are two means of binding morphine to the opioid receptor; one through G-protein signaling (leading to pain relief) and the other through β-arrestin (leading to respiratory depression, tolerance, and addiction). Can we identify agonists to this receptor which would activate the G-protein but not β-arrestin pathway?
     
  • Probuphine (version of buprenorphine) extends the duration of addiction medication action by months rather than days and may provide MAT that doesn't require daily administration.
     
  • The nasal spray version of naloxone has become the major source of overdose reversal.
     
  • Vivitrol (injectable form of naltrexone) allows an antagonist to be present for a month, assisting addiction recovery.

Dr. Collins stressed the need to build a strategy that both tackles the problem of pain, with safe and effective non-addictive medications, and provides solutions for addiction. We need a way to test these treatments with heightened efficiency, which will require a national research network.

Dr. Collins explained that in April he made the case to the heads of R&D of pharmaceutical companies that the opioid crisis necessitates an unprecedented level of partnership between public and private sectors. Industry agreed that it was a priority. That led to a series of science meetings with academia, industry, and government, to identify new approaches in which a partnership would speed the treatment development process. Following the meetings, another series of discussions in September with pharmaceutical companies (including support from PhRMA) were held, as well as a meeting with Governor Christie and pharmaceutical company CEOs in mid-September. Two partnership projects were designed:

1) Develop new formulations and combinations of medications to treat, reverse overdoses, and develop devices to prevent opioid misuse.

2) Accelerate development of new non-addictive pain therapies by advancing therapeutics in the current pipeline, establish a data sharing collaborative between industry groups, and determine objective measures to understand and predict responses to pain.

NIH and PhRMA jointly issued a request asking companies whether they would take part in a serious design phase of a work plan that would tackle these two projects. Thirty-three companies answered “yes.”

A discussion about next steps with representatives of those companies was held in October. Each company will choose which projects in which they want to take part. Information about what assets the companies can contribute is being collected. Together we will outline goals, milestones, and a specific budget. We aim for a detailed project plan in December.

Discussion Points

  • Dr. Maixner asked whether there are other ways we can bring pharma into this space. Dr. Collins said it was clear they already are substantially ratcheting up their interest. Dr. Janet Woodcock, representing the FDA, has indicated a willingness to reframe the drug-approval process, in terms of tolerance for any side effects. With tens of thousands of people dying from opioids every year, an alternative that gives somebody indigestion might not be so bad, if it is potent and non-addictive.
     
  • Dr. Buckenmaier asked whether there is room in this partnership for integrated health practices (modalities like massage, acupuncture, yoga, etc.). He added that, in his experience, there is no silver bullet solution to this problem. Dr. Collins said NIH is intensely interested in looking for those kinds of integrated solutions, and any future testing of ways to manage chronic pain will consider what all the modalities are and how they work in a given situation.
     
  • Ms. Steinberg asked about the chance of getting a Common Fund project for pain. Dr. Collins said the time is right. The particular CF project being formulated in this instance still has several steps to go through, however.

Addressing the Opioid Epidemic

Dr. Nora Volkow, Director NIDA

Dr. Volkow noted that in a crisis, people quickly become polarized. As a consequence of the opioid crisis, people are questioning the value of opioid medications for managing pain. Data suggest that when you repeatedly administer an opioid you rapidly become tolerant. There is evidence however, that for certain patients, opioids may be one of few effective options. All conventional opioid medications target mu opioid receptors. These medications are extraordinarily effective in mitigating pain because they inhibit brain signaling that is responsible for processing pain. There is a high concentration of mu opioid receptors in the nucleus accumbens, the brain’s main reward region. Drugs that activate the nucleus accumbens, including opioid agonists, are potentially addictive. The extent to which activation of this reward system is part of the analgesic effects of opioids, or the addictive properties of opioids, is unclear. Developing alternative opioid agonists, without reward and addictive potential is a great challenge.

The opioid crisis is due in part to over-prescribing of opioid medications. The estimate is that 6-8% of patients being treated with opioid medications are becoming addicted. For unknown reasons, a patient can be stable on a high dose of an opioid and then suddenly overdose. The process is not completely predictable.

There is a campaign to decrease opioid prescribing. Since 2010, there has been a significant decrease. However, CDC estimates that 64,000 people died from drug overdoses in 2016; 22% higher than 2015. The rise in heroin fatalities reflects two phenomena: Many individuals initiated prescription opioids for their abuse potential and rewarding effects, not to treat pain. People addicted to prescription opioids found it harder to get their medications and shifted to heroin. Import of heroin into the U.S. dramatically increased. Around 2013, synthetic opioids, fentanyl and carfentanil (50 and 5,000 times higher potency than heroin, respectively), began coming from China, and were used to lace heroin and prescription opioids.

There are three MAT medications for treating OUD.  Methadone is a full agonist that requires daily administration for which patients must travel to a clinic.  Buprenorphine is a partial agonist which a physician can prescribe typically 2-3 times a week. The patient can take it home, but it may not be sufficient to prevent withdrawal. Naltrexone (Vivitrol) is an extended release antagonist that is not needed daily.

MATs decrease opioid use and overdose deaths, criminal activity, and infectious disease. However, MAT is massively underutilized; and relapse rates are high, partially due to difficulty maintaining compliance.

Approximately 2.5 million people are addicted to opioids, 600,000 are engaged in care, and 300,000 are initiated on MAT. Failure to continue treatment results in relapse, with high risk for overdose. Less than 2% maintain continuous opioid abstinence.

Some relatively immediate solutions may include alternative formulations of medications that have been shown to be effective such as Vivitrol and Probuphine.  

Two new longer-duration formulations of extended-release buprenorphine may be available soon. Also, alternative models are being developed to allow patients to take buprenorphine home on a 30-90 day basis (e.g., a delivery device). Repurposing medications for OUD is an option for the public-private partnership. Companies may have compounds for which approval will be easier because there is already clinical and toxicity data. In parallel, groups are characterizing the neural circuitry properties associated with and changed by drug exposure, to develop targetable endophenotypes.

NIDA is interested in prospective studies of patients being treated with opioids. Can we achieve predictive biomarkers by studying patients who develop OUD?

Discussion Points

  • Dr. Maixner proposed broadening buprenorphine’s application to include trials with chronic pain, and to do likewise with other medications that target common neural mechanisms between chronic pain states and OUD. There is evidence that neuroplastic adaptations linked with acute-to-chronic transition and the conversion between drug experimentation and addiction, may be shared. The neurocircuitry and endophenotypes of addiction may be relevant to the neurobiology of pain.
     
  • Ms. Chambers asked if a special place needs to be carved out for people who have substance use disorder and chronic pain. Dr. Volkow said that treating a patient with severe pain and who has become addicted to their opioid medication is a great challenge. NIDA conducted a large clinical trial evaluating Suboxone on those patients to see whether we could control their craving, prevent withdrawal, and manage their pain with buprenorphine. At three years, 30% of patients were tapered off buprenorphine.
     
  • Ms. Cowan asked if, in the trial that managed addicted patients’ pain with buprenorphine, other pain management modalities were used. She said if you provide patients with all the other components of pain management, in addition to self-management, you might be able to taper them off more quickly. Dr. Volkow agreed that they should address the extent to which an integrated pain model facilitates weaning patients off buprenorphine.
     
  • Dr. Paice asked about people with a serious illness and substance use disorder, who now need treatment with opioids. Dr. Volkow said that part of the public-private partnership is a clinical research network that addresses those questions.
     
  • Dr. Carr thanked Dr. Volkow for her awareness that the crisis tends to polarize the community. Patients with chronic illness, particularly chronic pain, are victims of stigmatization. Dr. Volkow said the opioid crisis is very different from other substance use epidemics. There is a treatment that can be life-saving when used properly.

Addressing the Chronic Pain Crisis

Dr. Walter Koroshetz, Director NINDS

Dr. Koroshetz discussed plans for the public-private partnership.

NIH does research to develop new targets for pain medicines. If nobody prosecutes those targets to make commercial products, the patient never benefits. So, we are tied to industry to get medications out to patients. Every month there is a new target discovery, but the process for moving it to patients has been slow, filled with failures, and expensive. Hence, pharmaceutical companies have shied away from investing in this area.

Since there are different pain syndromes, with different biologies, it may be feasible to go after particular pain conditions in ways that are less entangled with the brain’s reward systems. Trying to separate this out pharmacologically is one approach. Another way is to target different circuits, preferentially, to reduce addictive properties.

Challenges to developing new pain therapeutics were identified with the pharmaceutical companies during the science meetings:

  • Regulatory: The FDA cannot approve a medication going into 22 million people if its risk is high. Instead of pursuing a drug to treat all pain conditions, we could develop treatments and conduct trials in subtypes of pain. The risk-benefit would be easier to assess. If the drug works, another population could then be tested. This way it is not immediately in widespread distribution.
     
  • Lack of predictive preclinical models: Can the current models be improved? Can preclinical experimentation algorithms be engineered to be more predictive?
     
  • Lack of biomarkers (measurements that can be made in the human that reflect that the drug is actually hitting its target and functioning properly): Companies are forced to go from the preclinical to clinical setting without knowing what is happening in the brain. An objective measure of nociception or experience of pain, would be transformative.

    Limited research resources: What we have for pain research pales in comparison to the big cancer and stroke centers.

Partnership interests include:

  • Data/information sharing on successful/failed drug development efforts.
  • Creating a clinical trial network to coordinate testing of novel treatments:
    • For specific pain conditions, to phenotype patients, develop biomarkers, and test therapies in those confined groups.
    • Industry has developed drugs that may work for pain, but then deprioritized them. These drugs could be recovered and tested in multiple pain conditions.
    • Test combination therapies.
  • Development of biomarkers:
    • To test whether a drug hits its target.
    • To stratify pain populations.
    • To better predict clinical outcomes in response to treatment.
    • To develop objective measures for actual pain sensation.
  • Re-engineering the preclinical platform to better predict efficacy of new treatments.
  • Applying new technologies to improve discovery of new targets.

 

Discussion Points

  • Dr. Maixner said there have been several large cohort studies done at university medical centers that speak to the ability of groups to assemble research projects. There are several networks that exist, that can be expanded.
  • Ms. Chambers asked if there is interest in biomechanical research? Dr. Volkow said Dr. Collins has reached out to see if we can generate a recommendation of potential partners.
  • Dr. Spellman noted that NIH may be poised to convene people who compete with each other for NIH grants where larger scale data is needed in multiple institutions.
     
  • Dr. Buckenmaier used the example of the VA/DOD Stepped Care model of integrated health that includes non-drugs plus medications. There is literature supporting the use of an integrated model for pain.

    Ms. Steinberg said self-management strategies and support networks is the way to actualize an integrated health program.

  • Dr. Fillingim said integrated and non-pharmacologic approaches certainly have biological effects. That is an opening for studying, and insisting on the study of, these treatments in combination with other pharmacotherapies.
     
  • Dr. Carr said there might be a bias against approving agents designed to be an incramental component of multimodal therapy, because if you are coadminister agents it is challenging to dissect out the effect of each one. Perhaps incentivize pharma to develop drugs that are designed to be one component of a multimodal ‘cocktail’. Also, we have assumed that nociception alone drives the pain experience, but the forgotten half of the pain equation has to do with stigma, isolation, and marginalization. Addressing isolation and dysphoria is effective; pharmacological ways to do that (involving oxytocin) are now under development. Such a broadened discussion will help accommodate integrated therapies, which indeed have biological effects.
     
  • Ms. Cowan said she supports multimodal therapy. However, in addition to passive therapy, patients must be taught to manage pain. That is how to maintain their wellness long term.
     
  • Dr. Fillingim asked if there is a goal to supplant the patient’s experience with a biomarker that does not require having to ask the patient how they feel? Dr. Koroshetz said it depends on at what level you can make your measurement. If you could measure microRNA-183, that would be tremendous for regulating pain in the DRG. There is ongoing fMRI work pursuing a pain signature that is separate from a nociceptive signal. That would help segment patient populations, and allow the generation of treatments that are likelier to succeed in one segment than another. In terms of integrated care, a problem arises when everyone has a different standard of care. One thing a community could do is assemble a group and say for this population this is the standard of care. Dr. Hertz commented that putting pharmacologic therapy into a multimodal model, creates an effect not due to the drug. There needs to be a more comprehensive look at the drug development program. Phase II has virtually disappeared in drug development. Fundamental elements that create a successful phase III study should not be skipped. Better exploratory work in phase II might entail having some in the context of multimodal management and some where the non-pharmacologic management is less.
     
  • Dr. Porter noted that in the Common Fund concept, the biomarker component will involve pursuing risk factors for acute-to-chronic transition. Patient-reported outcomes and bio-psychosocial screening tools will be important. Dr. Fillingim said, in clinical trials, it might be ideal to show that patients got better even if they did not know they got better.
     
  • Ms. Chambers remarked on social stigmatization. Many groups feel that 80% of pain is a psychological condition. Patients are marginalized by the interface with the healthcare system. Educating the public, the medical community, and patients on how significant this component is, is important. Dr. Maixner said that promoting the understanding of the lack of separation between mind and body, and the fact that there is a neurobiology that underlies pain, is important. Psychological interventions work on the same systems as endogenous opioids.

 

IPRCC WEBSITE

Dr. Leah Pogorzala, Office of Pain Policy NINDS

Dr. Pogorzala explained that NINDS and the Pain Consortium have revamped their websites and are working on making them even better. The IPRCC main page is the same although links within it have changed.

 

PUBLIC COMMENT PERIOD

Dr. Porter referred the committee to a written public comment: Protecting Access to Pain Relief Coalition sent in a three-page summary of major activities they are involved in.

 

ADJOURN

We certify that, to the best of our knowledge, the foregoing minutes are accurate and complete.
 
Linda Porter, PhD
Designated Federal Official
Interagency Pain Research Coordinating Committee
Director, Office of Pain Policy, National Institute of Neurological Disorders and Stroke
 
Walter Koroshetz, PhD
Chair Interagency Pain Research Coordinating Committee
Director, National Institute of Neurological Disorders and Stroke
 
These minutes have been formally approved by the committee.

 

___________________________________________________________________________________

Endnotes

 

[1] Osteen JD, et al. Selective Spider Toxins Reveal a Role for the Nav1.1 Channel in Mechanical PainNature. 2016 June 6;534(7608):494-9.

 

[2] Manglik A, et al. Structure-Based Discovery of Opioid Analgesics with Reduced Side EffectsNature. 2016 August 17;537(7619):185-190. 

 

[3] Ren W, et al. The Indirect Pathway of the Nucleus Accumbens Shell Amplifies Neuropathic PainNature Neuroscience. 2016 February;19(2):220-2.

 

[4] Von Korff, et al. United States National Pain Strategy for Population Research: Concepts, Definitions, and Pilot Data(link is external)Journal of Pain. 2016 October;17(10): 1068–80.

 

REFERENCES

1 Chen G, et al. PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1. Nat Neurosci. 2017 Jul;20(7):917-926.

2 Peng C, et al. miR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes. Science. 2017 Jun 16;356(6343):1168-1171.

3 Jensen DD, et al. Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Sci Transl Med. 2017 May 31;9(392).

IPRCC Meeting

October 23, 2017

 

8:30 a.m. CALL TO ORDER AND WELCOME

Welcome and Introduction of Committee Members

Highlighted Pain Research Advances

Dr. Walter Koroshetz, Director NINDS and Chair IPRCC

 

9:15 a.m. Approval of the Minutes of the October 31, 2017

IPRCC Meeting Dr. Linda Porter, Ph.D., Director Office of Pain Policy, NINDS and Designated Federal Official IPRCC

 

9:20 a.m. NIH COMMON FUND CONCEPT
A Research Plan for Understanding the Transition from Acute to Chronic Pain

Dr. Patricia Labosky, Office of Strategic Planning

Dr. Linda Porter, Director Office of Pain Policy

 

9:45 a.m. THE FEDERAL PAIN RESEARCH STRATEGY
Overview

Dr. Allan Basbaum, Co-Chair Federal Pain Research Strategy

Next Steps

Dr. Linda Porter, Co-Chair Federal Pain Research Strategy

 

10:35 a.m. BREAK

 

10:55 a.m. THE PAIN MANAGEMENT TASK FORCE – CARA
Intersection with IPRCC

Dr. Vanila Singh, Chief Medical Officer OASH

 

11:20 a.m. UPDATES FROM IPRCC MEMBERS
FDA Risk Evaluation and Mitigation Strategy

Dr. Sharon Hertz, IPRCC FDA Representative

 

11:40 a.m. Systematic Review on Non-Pharmacologic Treatments for Chronic Pain

Dr. Ric Ricciardi, IPRCC AHRQ Representative

 

11:50 a.m. Joint Educational Program Curriculum and the West Virginia University DoD/USUHS Collaboration

Dr. Chester Buckenmaier, IPRCC DoD Representative

 

12:10 p.m. LUNCH

 

1:30 p.m. UPDATES ON THE NATIONAL PAIN STRATEGY
1:40 p.m. Implementation

Alicia Richmond Scott, OASH

1:50 p.m. American Pain Society Research Awards for NPS Objectives

Catherine Underwood, CEO American Pain Society

2:10 p.m. National Health Interview Survey: Mining the NHIS 2016 Data on Pain and Restructuring NHIS Pain Question Set

Dr. Chad Helmick, IPRCC Member, CDC

 

2:30 p.m. PUBLIC-PRIVATE PARTNERSHIP TO ADDRESS PAIN & THE OPIOID CRISIS
Introduction

Dr. Francis Collins, Director NIH

2:45 p.m. Addressing the Opioid Epidemic

Dr. Nora Volkow, Director NIDA

3:15 p.m. Addressing the Chronic Pain Crisis

Dr. Walter Koroshetz, Director NINDS

 

3:45 p.m. IPRCC WEBSITE
Updated Website

Dr. Leah Pogorzala, Office of Pain Policy NINDS

 

3:50 p.m. PUBLIC COMMENT PERIOD

 

4:00 p.m. ADJOURNMENT

The October 23, 2017 meeting of the Interagency Pain Research Coordinating Committee (IPRCC) was convened at 8:30 a.m. in Building 31, Porter Neuroscience Center, 6th Floor, C Wing, on the National Institutes of Health (NIH) campus. In accordance with Public Law 92-463, the meeting was open to the public. Walter Koroshetz, MD, Director, National Institute of Neurological Disorders and Stroke (NINDS), presided as chair.

In attendance were the following members of the IPRCC:

Federal Members: Walter Koroshetz, MD; Chester Buckenmaier, MD; Charles G. Helmick, III, MD; Sharon Hertz, MD; Richard Ricciardi, PhD, CRNP; Martha J. Somerman, DDS, PhD;

Scientific Members: Allan Basbaum, PhD, FRS; William Maixner, DDS, PhD; Judith Paice, PhD, RN, FAAN

Public Members: Penney Cowan; Christina Spellman, PhD; Cindy Steinberg; Catherine Underwood, MBA; Michael Pasternak, PhD

Ex-Officio Member: Nora Volkow, MD, PhD; David Shurtleff, Ph.D. taking over for Josephine P. Briggs, MD

Designated Federal Official: Linda L. Porter, PhD

Ad hoc IPRCC Members: Daniel B. Carr, MD; Jan Chambers; and Roger B. Fillingim, PhD

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