DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NATIONAL ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES ADVISORY COUNCIL
MINUTES OF THE 96th MEETING
September 5th, 2018
9:00 a.m. to 3:00 p.m.
I. CALL TO ORDER
The 96th meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council (NAMSAC) was held on September 5, 2018, at the National Institutes of Health (NIH) Campus, Building 31, Conference Room 10. The meeting was chaired by Dr. Stephen I. Katz, Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Council members present:
Dr. Joan E. Bechtold, Professor, Orthopaedic Surgery, University of Minnesota
Dr. Jill P. Buyon, Director, Division of Rheumatology, Department of Medicine, New York University School of Medicine and Director, NYU Lupus Center
Ms. Magdalena Castro-Lewis, former Vice President for Programs, National Alliance for Hispanic Health (via teleconference)
Mr. Vincent Del Gaizo, Patient advocate and founding member and past Chair, Friends of the Childhood Arthritis and Rheumatology Research Alliance
Dr. Michael Econs, Glenn W. Irwin, Jr., Professor of Endocrinology and Metabolism; Director, Division of Endocrinology and Metabolism; Professor of Medicine and Medical and Molecular Genetics;
Indiana University School of Medicine
Dr. James Elbaor, Director, American Institute of Orthopaedics and Sports Medicine
Dr. Michael V. Holers, Professor, Department of Medicine, University of Colorado Denver School of Medicine
Dr. Judith A. James, Vice President of Clinical Affairs, Oklahoma Medical Research Foundation
Dr. Sundeep Khosla, Dr. Francis Chucker and Nathan Landow Research Professor; Director, Mayo Clinic CTSA/Center for Clinical and Translational Science; Dean for Clinical and Translational Science, Mayo Clinic College of Medicine
Dr. Ethan A. Lerner, Associate Professor of Dermatology, Massachusetts General Hospital
Ms. Rosemary J. Markoff, Co-Chair, Scleroderma Foundation National Advocacy Committee
Mr. William J. Mulvihill, The Mulvihill Advisory Group
Dr. Anthony Oro, Eugene and Gloria Bauer Professor of Dermatology and Associate Director, Center for Definitive and Curative Medicine, Stanford University
Dr. Amy Paller, Professor, Dermatology, Feinberg School of Medicine
Dr. Stephen J. Tapscott, Professor, Fred Hutchinson Cancer Research Center
Dr. Michael J. Yaszemski, Professor, Orthopaedic Surgery and Biomedical Engineering, Mayo Clinic
Staff and Guests
The following NIAMS staff and guests attended:
Dr. D. Lee Alekel
Dr. Laura Lewandowski
Dr. D.J. Bradshaw, Uniformed Services University of the Health Sciences
Dr. Aileen Chang, University of California, San Francisco (via videoconference)
Dr. Rodger Glass, Director, Fogarty International Center, NIH
Ms. Anna Hyde, Arthritis Foundation
Mr. Peter Herzog, Scleroderma Foundation
Dr. Evelyn Hsieh, Yale University (via videoconference)
Dr. David Jett, National Institute of Neurological Disorders and Stroke, NIH
Dr. Peter Kilmarx, Deputy Director, Fogarty International Center, NIH
Dr. Michael Lauer, Deputy Director for Extramural Research, NIH
Mr. Nate Robinson, IQ Solutions
Dr. Christine Sizemore, Fogarty International Center, NIH
Ms. Alexandra Yaszemski, Uniformed Services University of the Health Sciences
II. CONSIDERATION OF MINUTES
A motion was made, seconded, and passed to approve the minutes of the 95th NAMSAC meeting, held on June 12, 2018.
III. FUTURE COUNCIL MEETING DATES
Future Council meetings are currently planned for the following dates:
February 5, 2019
June 12, 2019
September 10, 2019
February 4, 2020
June 9, 2020
September 1, 2020
IV. DIRECTOR’S REPORT AND DISCUSSION
Dr. Katz reminded Council members that the open session of this NAMSAC meeting was being videocast and will be archived on the NIH website. The June Council meeting was viewed by 114 people in real time and by an additional 44 individuals at a later date. Council members were asked to encourage their colleagues to view the proceedings of this meeting online at the NIH Center for Information Technology’s VideoCasting and Podcasting website. He noted that beginning with the next Council meeting (February 5, 2019), the group will meet in the Natcher Conference Center because the entire sixth floor of Building 31 on the NIH Campus will be under renovation.
Dr. Katz thanked Mr. Seiden and Drs. Bechtold, Holers, Khosla, and Paller, whose terms on the Council are expiring. Because of uncertainties related to appointing new members whose terms would begin on October 1, they have been invited to remain on the council through a 180-day Administrative Extension. All five of these Council members have kindly agreed to extend their terms through March 2019.
Budget and Congressional Activities
Fiscal Year (FY) 2019 begins on October 1, 2018; although both the House and Senate Appropriations Committees are supportive of the NIH, it is likely that the year will begin under a Continuing Resolution (which typically means that the NIH will be able to continue to operate at, or slightly below, its current budget). Dr. Katz noted that there is a proposed $2 billion increase for the NIH from the Senate Committee. He reminded Council members that the Institute publishes its funding plan online, and will post its FY 2019 plan as soon as it is available (NIAMS’ 2018 funding plan is available here).
On August 23, 2018, NIH Director Dr. Francis Collins testified in front of the Senate Health, Education, Labor and Pensions Committee on the topic of “Prioritizing Cures: Science and Stewardship at the National Institutes of Health.” Senators asked questions about topics such as gene therapy, regenerative medicine, substance abuse, and the All of Us Research Program. Dr. Collins provided an opening statement on public-private partnerships and was accompanied by the following Institute Directors: Dr. Diana Bianchi (Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD]), Dr. Anthony Fauci (National Institute of Allergy and Infectious Diseases [NIAID]), Dr. Richard Hodes (National Institute on Aging [NIA]), and Dr. Norman Sharpless (National Cancer Institute [NCI]).
Overview of NIH and NIAMS Activities and Plans, Including Personnel Changes
Dr. Katz reviewed the meeting’s open session and thanked Dr. Bechtold for leading the Council Agenda Working Group, which also includes Drs. Holers, Econs, and James as well as Ms. Castro-Lewis and Mr. Mulvihill. Dr. James has agreed to lead this group after Dr. Bechtold leaves the Council.
- Dr. Susana Serrate-Sztein, NIAMS Associate Director for Strategic Initiatives, presented a concept clearance related to a back pain initiative.
- Dr. Roger Glass, Director of the Fogarty International Center (FIC), addressed the Council because the diseases within NIAMS’ mission affect people around the globe. Three researchers provided examples of activities that involve collaborations with scientists from outside the United States:
- Dr. Evelyn Hsieh, a K01 awardee from Yale’s Department of Rheumatology who specializes in osteoporosis in rural China
- Dr. Aileen Chang from the Department of Dermatology at the University of California, San Francisco, who works on Kaposi’s sarcoma and other diseases in Kenya
- Dr. Laura Lewandowski, a Clinical Fellow in NIAMS’ Systemic Autoimmunity Branch, who discussed her work on autoimmune diseases in cohorts from around the world.
- Dr. Michael Lauer, NIH Deputy Director for Extramural Research, described NIH’s plans for the Next Generation Researchers Initiative (NGRI), which prioritizes funding for R01-equivalent applications from early-stage investigators and investigators who are at risk of losing all NIH funding or who have only one active award. Dr. Katz noted that the NIAMS Supplements to Advance Research (STAR) program aligns closely with the priorities of the NGRI. The Institute has decided to reissue the STAR program with recommendations from the Council regarding the number of additional R01 awards that an investigator can hold and be eligible for one of these supplements.
- NIAMS Deputy Director Dr. Robert Carter discussed NIH-wide efforts to foster high-risk research that has the potential for large payoffs. Council members were briefed on an evaluation of the NIAMS Research Innovations for Scientific Knowledge (RISK) initiatives during the last Council meeting; the Institute has decided to renew the Funding Opportunity Announcements (FOAs) for 2 more years.
- Dr. David Jett, Director of the NIH Countermeasures Against Chemical Threats (CounterACT) Program, and Dr. Hung Tseng (Program Director, Extracellular Matrix Biology and Diseases Program, and Program Director, Skin Repair, Regeneration, and Pigmentation), NIAMS’ representative to the program, described this trans-NIH initiative. The goal of the CounterACT program is to develop new or improved medical countermeasures to prevent and treat acute and long-term conditions caused by chemical agents that may be released during a terrorist attack, an industrial accident, or a natural disaster.
- Ms. Cindy Caughman, Chief of NIAMS’ Scientific Planning, Policy, and Analysis Branch, provided an introduction to the Institute’s strategic planning process. Every 5 years, the NIAMS re-examines its priorities and the scientific opportunities on which the research community should be capitalizing. The Institute will collect input from researchers, the patient and advocacy communities, and anyone who is interested in the NIAMS mission areas. Council members will be provided with regular updates and will be asked to provide feedback at several points throughout the process.
The Pathways to Prevention Workshop on the Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention will take place at the end of October in the Masur Auditorium on the NIH Campus. Dr. Katz invited interested Council members who are unable to attend in person to view the proceedings via videocast. He also thanked Dr. Khosla and Dr. Faye Chen (Program Director, Rare Diseases and Integrated Physiology of Bone Program) for their work in developing this program. An update on the workshop will be provided during the February Council meeting.
Also during the February Council meeting, Dr. Katz will provide an update on the activities of two new working groups of the Advisory Committee to the NIH Director (ACD). The first follows up on a letter that Dr. Collins sent to all grantees in response to concerns that foreign entities have developed systematic programs to influence NIH peer review and divert U.S. biomedical technology and intellectual property. The working group is charged with providing recommendations on how to prevent undue foreign influence and how to work with grantee institutions on these issues while balancing recognition of the honorable and beneficial contributions of foreign nationals to U.S. biomedical science. The second will provide recommendations on what the NIH should be doing to nurture and encourage the application of machine learning and artificial intelligence to biomedical science (e.g., what the research and training needs are, how best to attract artificial intelligence and machine learning experts into biomedical science, etc.).
The NIH also is reexamining the role of the Recombinant DNA Advisory Committee (RAC), which was established in 1974 to provide advice on research that manipulates DNA; it later expanded its purview to clinical trials using gene transfer to treat diseases. In a plan published on August 17, 2018, for public comment, the NIH proposed that the RAC now focus only on new technologies such as gene editing and synthetic biology. Comments will be accepted through October 16, 2018.
Dr. Katz then reported on personnel changes at the NIH and NIAMS. At the NIH level:
- On August 31, Dr. Patricia A. Grady retired as Director of the National Institute of Nursing Research (NINR), a position she held for more than 23 years. Dr. Ann Cashion, NINR Scientific Director and Acting Deputy Director, will serve as the Acting Director of NINR while the NIH conducts a nationwide search to fill the position.
- Dr. Collins has appointed Dr. Helene Langevin as Director of the National Center for Complementary and Integrative Health (NCCIH). Dr. Langevin comes to NIH from the Osher Center for Integrative Medicine, jointly based at Brigham and Women’s Hospital and Harvard Medical School, where she served as Director of the Osher Center and Professor-in-Residence of Medicine at Harvard Medical School since 2012. Her research interests have focused on the role of connective tissue in low back pain and the mechanisms of acupuncture, manual, and movement-based therapies. Her more recent work has focused on the effects of stretching on inflammation resolution mechanisms within connective tissue. Dr. Langevin is expected to join NIH in November 2018.
At the NIAMS level:
- Mr. Erik Edgerton will join NIAMS in mid-September as its new Deputy Chief Grants Management Officer. Mr. Edgerton has spent the past three years at the NCI as a Supervisory Team Leader. Before that, he worked in the NIAMS Grants Management Branch from 2004 to 2015. Mr. Edgerton is a Certified Research Administrator and brings leadership experience and expertise in a variety of complex grant mechanisms, including Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR).
- Dr. Kristy Nicks has been named Program Director for the Bone Biology, Metabolic Bone Disorders, and Osteoporosis portfolio. Dr. Nicks has been at the NIAMS for almost 3 years as a contracted Senior Scientific Analyst. She received her Ph.D. in Physiology and Biophysics from the University of Arkansas for Medical Sciences. Dr. Nicks joined the NIAMS following her post-doctoral training with Dr. Khosla at the Mayo Clinic and has experience in musculoskeletal biology, endocrinology, osteoporosis, and disparities in bone health research.
- Dr. Ted Zheng has moved from NIAMS’ Review Branch and named Program Director on the Joint Biology and Diseases and Orthopaedics Team in the Institute’s Extramural Research Program. Dr. Zheng first joined the NIAMS as a Scientific Review Officer in 2012. Before that, he was Vice President of Yisheng U.S. Biopharma, Inc., where he oversaw work on vaccines for inflammatory diseases including rabies, Japanese encephalitis, hepatitis, and influenza. Dr. Zheng was an awardee of several SBIR grants on autoimmune diseases and served as an ad hoc reviewer for two NIH SBIR/STTR study sections.
- Dr. Yasuko Furumoto has joined the Institute as a Scientific Review Officer. Dr. Furumoto has considerable experience with NIH peer review, having served as a Scientific Review Officer for the NCI and the NIH Center for Scientific Review (CSR). She also is familiar with NIAMS-supported research, having served for many years in the Intramural Research Program’s Translational Immunology Section and Laboratory of Molecular and Immunogenetics before moving to the NCI.
The NIAMS continues to search for a Clinical Director for its Intramural Research Program. This physician-scientist will direct the NIAMS Program in Translational Research, which includes training and clinical care branches as well as multiple investigative laboratories and branches. Dr. Katz asked Council members to inform the NIAMS if they know of any qualified individuals who are interested in becoming prospective candidates.
Highlights of Selected Recent Scientific Advances
Dr. Katz described several scientific advances of interest to the Council:
- Dr. Tracy McGaha and colleagues at the University Health Network in Toronto explored whether it is possible to thwart lupus by preventing autoimmune reactions to apoptosis. Their findings in a mouse model suggest that a transcription factor called the aryl hydrocarbon receptor may hold the key to preventing autoimmunity-associated with apoptosis. Co-culturing immune cells from mice with apoptotic cells led to activation of the aryl hydrocarbon receptor, which reduced inflammation. In contrast, blocking the aryl hydrocarbon receptor caused a shift towards pro-inflammatory factors. These findings may lead to new therapeutic strategies targeting the aryl hydrocarbon receptor to treat or prevent the development of systemic lupus erythematosus (SLE) and possibly other autoimmune diseases (Nat Immunol. 2018 Jun;19(6):571-582. doi: 10.1038/s41590-018-0107-1. [Epub 2018 May 14] PMID: 29760532).
- A second lupus advance is from the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus (PROMISSE) study, led by Dr. Jane Salmon at the Hospital for Special Surgery. PROMISSE investigators (including Council member Dr. Jill Buyon) analyzed complement activation products in blood samples taken from participants at their monthly doctor visits. About 20% of the patients with lupus and/or antiphospholipid antibody syndrome developed pregnancy complications. The levels of complement activation products in patients with adverse pregnancy outcomes were elevated, as compared with those without adverse outcomes, as early as 12 to 15 weeks of pregnancy and remained high through 31 weeks. The increased levels of specific complement activation products identified in early pregnancy in this study appear to be highly predictive of adverse pregnancy outcomes, and can therefore help to identify a subset of at-risk patients for careful monitoring and for future intervention trials (Ann Rheum Dis. 2018 Apr;77(4):549-555. doi: 10.1136/annrheumdis-2017-212224. Epub 2018 Jan 25. PMID: 29371202).
- Former Council member Dr. Gary Firestein and his group at the University of California, San Diego, have been using epigenetic approaches to investigate the role of cells called fibroblast-like synoviocytes in rheumatoid arthritis (RA). The researchers used four cutting-edge technologies (ATAC-seq, ChIP-seq, RNA-seq, and whole-genome bisulfate sequencing) to create a high-resolution map of the epigenetic landscape of RA fibroblast-like synoviocytes. Using a novel algorithm, they integrated these diverse datasets to uncover RA-specific pathways and transcription factors. Unexpectedly, they discovered that a signaling pathway associated with Huntington’s disease (a fatal genetic brain disease) ranked top among RA pathways, above the many pathways already known to be relevant to RA. The researchers also showed that a protein involved in Huntington’s disease is present in RA fibroblast-like synoviocytes and plays a role in these cells’ invasion into cartilage. This overlap with Huntington’s disease suggests the possibility of new therapeutic targets and drugs for both conditions (Nat Commun. 2018 May 15; 9(1):1921. doi: 10.1038/s41467-018-04310-9. PMID: 29765031).
- From NIAMS’ Extramural Skin Biology and Diseases Program, Dr. Pierre Coulombe and his group at Johns Hopkins explored potential treatments for painful palmar-plantar keratoderma (PPK) which is associated with skin disorders such as pachyonychia congenital, a genetic condition caused by keratin mutations. Mice that are unable to express keratin 16 develop PPK and can be used as a model to study the disorder; Dr. Coulombe’s group showed that these mice exhibit sexual dimorphism. To ameliorate painful palmar-plantar skin thickening, male mice can be treated using the drug sulforaphane. However, females need a dual drug treatment, such as sulforaphane plus diarylpropionitrile—a drug that opposes estrogen-receptor beta—to effectively treat the condition. These results are exceedingly important for designing future PPK clinical trials (J Invest Dermatol. 2018 May; 138(5):1094-1100. doi: 10.1016/j.jid.2017.09.054. [Epub 2017 Dec 24] PMID: 29277538).
- Although several mouse models of atopic dermatitis (AD) are available, little is known about the basic mechanisms that lead to skin barrier defects and skin microbiome imbalances that characterize the condition. Researchers in the NIAMS Intramural Program’s Cutaneous Leukocyte Biology Section led by Dr. Keisuke (Chris) Nagao recently examined the skin of mice that lack Adam17 in the epidermis (called A17 mice) to determine the transcriptional similarity to human eczema. By comparing gene expression profiles between normal and eczematous skin from the A17 mouse, researchers identified differentially expressed genes important for skin barrier function and immunity, including the JAK signaling pathway, which is a potential therapeutic target in humans. In addition, when comparing the differential gene signature from the mouse model to a differential gene expression databases for human AD, the researchers confirmed the A17 model was more transcriptionally similar to human AD than other mouse models of AD (J Invest Dermatol. 2018 May 8. pii: S0022-202X(18)31957-2. doi: 10.1016/j.jid.2018.04.021. PMID: 29751002).
- A research team led by Drs. Michael Kyba and Rita Perlingeiro at the University of Minnesota injected mouse pluripotent stem cells straight into injured muscle, where the cells formed a tumor called a teratoma. The teratoma, which can develop into multiple mature tissues, served as an in vivo bioreactor, producing satellite cells that can form functional muscle with normal innervation and fatigability when implanted into injured muscle. Not only did the muscle stem cells isolated from the teratomas repopulate the mature muscle fibers of a damaged muscle, but they also repopulated the satellite cell population normally found in muscle itself (Cell Stem Cell. 2018 Jul 5;23(1):74-85.e6. doi: 10.1016/j.stem.2018.06.010. PMID: 29979993).
- Moderate to vigorous intensity aerobic activities such as running are well known for reducing cardiovascular events and overall mortality. However, running and other high-impact exercises have been thought to be detrimental to knee joints and consequentially make knee osteoarthritis (OA) worse. Using data from the Osteoarthritis Initiative (OAI), investigators at Baylor College of Medicine, under the leadership of Dr. Grace Lo, evaluated whether running is harmful in people with knee osteoarthritis. They have shown that running is not associated with worsening of knee OA symptoms, nor with changes to the knee structure. Instead, running can be a healthy way to manage osteoarthritis symptoms as it improves knee pain (Clin Rheumatol. 2018 May 4. doi: 10.1007/s10067-018-4121-3. [Epub ahead of print] PMID: 29728929).
Dr. Buyon explained that the PROMISSE study began roughly 15 years ago and resulted in a significant change in the way lupus patients are managed. PROMISSE results have reassured the community that many lupus patients can have good outcomes in terms of pregnancy. Through this effort, very specific risk markers for pregnancy outcomes were identified; this has changed the way patients who want to become pregnant are evaluated. The impetus for the study referenced by Dr. Katz in his Director’s Report was based on the finding that antiphospholipid antibodies activate complement in a mouse model. In humans, it is now possible to examine complement activation and angiogenic factors, particularly early in pregnancy, to predict with a great degree of certainty who will have an adverse pregnancy outcome. Also interesting is the fact that this complement activation is independent of lupus activity. Dr. Katz added that this study dispels the long-held assumption that lupus was exacerbated in pregnant women, particularly at the time of delivery.
Dr. Gayle Lester, NIAMS Acting Director of the Division of Extramural Research, provided additional information on the study by Dr. Lo using data from the OAI that Dr. Katz described in his Director’s Report. She noted that Dr. Lo was a NIAMS K awardee and has continued her research at Baylor using the OAI database and conducting ancillary studies with OAI cohort members. Dr. Lo is interested in how best to advise OA patients in terms of improving their mobility and reducing pain. The findings from Dr. Lo and colleagues will be helpful to many OA patients who had previously been advised not to run or engage in other vigorous exercise activities. She also explained that the OAI has been a valuable resource for investigators like Dr. Lo who can access data and collaborate with OAI investigators. The OAI is still following up on members of the original 4,800 subject cohort and is an extremely rich resource that is being widely used.
Dr. Katz asked NAMSAC members for feedback on the activities of the Council Agenda Working Group, which was formed in early 2017. The Working Group has been providing extremely thoughtful and useful suggestions and Dr. Katz has asked that the Working Group continue its activities under the leadership of Dr. James. He reminded Council members that the Working Group has been tasked with recommending agenda items that: (1) are important across the Institute’s mission areas, (2) can be broadly discussed, and (3) will provide some guidance regarding the operations of the NIAMS activities and mission. Recently, the Working Group has been discussing succession planning for the group, and Dr. Econs has been asked to join the Council Agenda Working Group. Dr. Katz described examples of other specific topics the Working Group has proposed focusing on, such as: strategic planning, the select pay process, eliminating health disparities/emphasizing diversity, workforce development, scientific partnerships, mentoring Council members, and balancing NIAMS priorities. Dr. Bechtold indicated that one of the goals of the Council Agenda Working Group is to identify topics to inform Council members so that they can most effectively assist the Institute in its endeavors. Dr. Holers acknowledged the strong and effective leadership Dr. Bechtold has brought to the Working Group, noting that the group has accomplished several of its original goals and continues to work to identify areas in which it can assist the Institute. Dr. Katz commented that the NIAMS looks forward to the Working Group’s continued engagement.
V. CONCEPT CLEARANCE
Dr. Serrate-Sztein introduced a concept on back pain that the NIAMS has been developing in collaboration with a large group of other Institutes for consideration as part of the NIH Helping to End Addition Long-term (HEAL) Initiative. HEAL an umbrella term used by the NIH to sponsor a number of initiatives, activities, announcements, meetings, FOAs, etc., as part of the scientific contribution to curb the public crisis associated with the opioid epidemic. The NIH embarked upon a year-long process to consult with the community through a series of meetings and solicitations to seek input to help define HEAL areas of priority, opportunities, and strategies. Additional information can be found on the NIH HEAL Initiative website. The site contains an up-to-date compilation of newly published FOAs. Two areas of scientific focus for NIH’s HEAL Initiative are to: (1) improve treatments for opioid misuse and addition, and (2) enhance pain management.
A group of Institutes led by the NIAMS has been working on the premise that chronic back pain is one of the leading contributors to the prevalence of chronic pain in adults, and therefore, any strategy to address chronic pain needs to include a focus on chronic back pain. The Back Pain Consortium (BACPAC) Research Program has been proposed as a patient-centric initiative using state-of-the-art approaches, strategies, and technologies to study patients with chronic back pain, and use that information to inform longitudinal studies and clinical trials. BACPAC will support studies to dissect the components and mechanisms of low back pain and integrate new information into algorithms to identify, prioritize and test new therapies targeted to specific mechanisms. If approved, BACPAC will be an FY 2019 initiative. Related FOAs will be posted to the NIH HEAL Initiative website; Dr. Katz indicated that Council members will be kept informed about BACPAC.
VI. GLOBAL HEALTH OPPORTUNITIES: OSTEOPOROSIS/LUPUS
Dr. Glass opened this session by noting that the diseases and conditions of interest to the NIAMS are extremely common around the world. He asked NAMSAC members to consider the following questions:
- Why should the NIAMS engage in an agenda for research in global health?
- What is the Institute currently doing in this regard?
- What are the conditions in the NIAMS portfolio that can best be studied in other settings with:
- Unique populations (e.g., genetic makeup, environmental exposures, infectious disease risk, other comorbidities, etc.)?
- Higher incidence of diseases and/or different presentations and outcomes?
- Outstanding investigators with novel ideas and treatments?
- Where can the NIAMS engage in clinical trials globally and what novel approaches to studying treatment are available (e.g., tele-dermatology and dermatopathology)?
When Dr. Collins assumed Directorship of the NIH, he indicated that expanding research in diseases affecting the developing world would be one of his priorities. Dr. Glass commented that taking recent medical advances to the developing world could provide unique opportunities, and getting people engaged early in their career and keeping them interested and funded can lead to tremendous scientific impact.
Global health is a strong interest on university campuses—roughly 10 years ago, the Consortium of Universities for Global Health (CUGH) was established to capitalize on university-level interest in global health. The Consortium’s mission is to support academic institutions and partners to improve the wellbeing of people and the planet through education, research, service, and advocacy. The CUGH supports universities as transforming forces in global health; at present, 172 universities participate in this initiative. Dr. Glass noted that all of the universities represented by NAMSAC members are either CUGH members or have global health programs.
Skin diseases, arthritis, and musculoskeletal diseases are not only extremely prevalent globally, they also permeate many of the other disease processes found globally (e.g., infectious diseases, fungal diseases, osteomyelitis, cancer, genetic disorders, etc.). Dr. Glass referred Council members to NIH’s World RePORT website, where users can review ongoing NIH-supported research throughout the world. There are three NIAMS grants in Brazil, one in Africa, and a few in China, but half of the world does not receive funding or support from the NIAMS for diseases in its purview. Roughly 98% of NIAMS extramural funds are allocated to U.S.-based institutions.
Dr. Glass emphasized the value of early career exposure to global health issues and its impact on the next generation of researchers, noting that in 1965, Dr. Katz worked in Uganda and one of his sons is now a global health expert. He commented that there are lessons that can be learned from treating patients in the developing world that can have significant benefit in the United States. For example, the simple treatment for diarrhea used in the United States today (oral rehydration therapy) came about from treating cholera patients in developing countries where intravenous therapies were not available.
FIC’s mission is to address global health challenges through innovative and collaborative programs for research and training, and to support and advance the NIH mission through global partnerships. Fogarty offers an International Clinical Research Scholars and Fellows Program as well as Career Development Awards for U.S. and foreign fellows. The Center also develops platforms for quality research in low- and middle-income countries (LMIC) to support ethics, research management, clinical trials sites, and to build centers of excellence and support research training between U.S. and LMIC universities. Fogarty also supports a Global Health Fellows and Scholars program that supports graduate/medical students, post-docs, and fellows.
Dr. Glass outlined FIC’s 2014-2019 strategic plan goals as follows:
- Build research capacity of individuals, institutions, and networks to meet future and evolving global health challenges.
- Stimulate innovation in the development and evaluation of technologies to address global health problems.
- Support research and research training in implementation science.
- Advance research on prevention and control of the dual burden of communicable and non-communicable diseases and disability.
- Build and strengthen partnerships to advance global health research and research capacity.
Dr. Glass introduced presentations by Drs. Hsieh, Chang and Lewandowski, three former Fogarty fellows who presented their work to the Council.
Building a Career in Global Rheumatology Research
Dr. Hsieh explained that her career in global health began during medical school when she was selected to participate in the Fogarty-Ellison Global Health Scholars Program, a program that uniquely emphasizes mentorship, development of a strong peer network, and hands-on research training. This program taught Dr. Hsieh to develop and implement studies, publish papers, write grant applications, and navigate complex international research landscapes. During her residency and fellowship, Dr. Hsieh developed a passion for rheumatology and aspired to become a pioneer in global rheumatology. She became interested in the burgeoning crisis of osteoporosis and factures worldwide, particularly in East Asia, and obtained two research grants to fund her doctoral dissertation on this project, including one from the Rheumatology Research Scientist Foundation, which focused on osteoporosis and HIV.
Dr. Hsieh explained that as patients with HIV are living longer with antiretroviral therapy, it has become increasingly apparent that chronic immune activation and antiretroviral exposure are linked to increased rates of fracture. Her mentor in China, Dr. Taisheng Li, Director of Infectious Diseases at Peking Union Medical College Hospital, is a Principal Investigator (PI) on a series of multicenter HIV clinical trials involving more than 20 hospitals across China. Leveraging the infrastructure and resources of this network, Dr. Hsieh and colleagues conducted a series of studies that sought to apply both biomedical and behavioral research methodologies to evaluate this problem among Chinese patients with HIV. This led to their involvement in an international collaborative paper focused on osteoporosis screening for this population and most recently, their work has focused on mechanistic roles of vitamin D and HIV-associated bone loss. These studies laid the foundation for Dr. Hsieh’s career development award from the FIC, which aims to establish a longitudinal cohort of Chinese patients with HIV and use mixed-methods approaches to risk stratify and identify strategies for bone loss in this population. The goals were accelerated by the opportunity to nest this study within a larger clinical trial through the China AIDS Clinical Trial Network. This trial will provide vitamin D versus placebo to a group of patients at the time of antiretroviral initiation and follow them for 1 year to evaluate the ability of vitamin D to mitigate bone loss compared to placebo. During the second year, all patients will receive vitamin D to further examine the relative impacts of early versus delayed supplementation on bone health. Dr. Hsieh has been in Beijing for the past year implementing the study and reported that four of six sites are currently recruiting, with the remaining two sites set to begin recruiting this month. Her group has obtained supplemental funding to hire a research coordinator to add trabecular bone score and high resolution peripheral quantitative computed tomography analyses to this study and to perform an evaluation of osteoporosis-related resources in regions of high HIV prevalence.
Dr. Hsieh explained that her work in HIV has led her to think critically about the drivers of bone loss in chronic immune activation and inflammation and to begin thinking about other models of inflammatory bone loss. To this end, she has developed a collaboration with Peking Union Medical College Hospital’s Rheumatology Department, which has built a series of rheumatic disease registries, including one for RA. Dr. Hsieh’s group has begun early collaborative work on RA-associated bone loss and hopes to ultimately establish a comparative platform for studying the immunologic drivers of bone loss in HIV and RA.
Dr. Hsieh highlighted the recently established Fogarty Global Health Scholars site in Lima, Peru, for which Dr. Hsieh and her long-time mentor, Dr. Patricia Garcia (past Chief of the Peruvian National Institutes of Health and former Minister of Health of Peru) will serve as co-mentors. They recently co-mentored a master’s student from the London School of Hygiene and Tropical Medicine and are looking forward to creating a novel training site that will focus on previously understudied areas in global health, including rheumatology and musculoskeletal diseases.
Global Health Dermatology
Dr. Chang explained that her interest in global health began during her senior year undergraduate work at Rutgers University, when she led a seminar on the topic. After her first year of medical school, she spent a summer in Beijing at Peking Union Medical College as a Sjogren’s Syndrome Foundation fellow. This experience provided her with her first exposure to health care outside of North America and international collaborations. While in medical school, Dr. Chang became interested in dermatology and met Dr. Carrie Kovarik, a dermatologist at the University of Pennsylvania who focuses on mobile telemedicine in Botswana. Dr. Kovarik supported Dr. Chang’s development of a program in Botswana on the use of mobile phones to improve education. Through this work, Dr. Chang had an opportunity to spend time in a dermatology clinic in Botswana. There, she experienced firsthand the significant relevance of dermatology to global health.
Her group in Botswana had a large number of referrals—many for complex cases. Dr. Chang learned the value of visual diagnostic skills in a limited resource setting, as well as the ability to carry out minimally invasive bedside procedures such as skin biopsies and skin scrapings. As she transitioned into residency, Dr. Chang’s interest in global health dermatology expanded. In Navajo Nation, she saw challenging patients and was impressed by primary care providers’ ability to manage complex conditions in a setting that has poor access to specialty care. In South India, she rotated at a dermatology residency program and saw a wide range of skin conditions that she had never before encountered. Then, back in Botswana, she served as the only dermatologist for the entire country for a 1-month period.
Following her residency, Dr. Chang moved to Uganda for her Fogarty year. Her research projects were centered on Kaposi sarcoma and involved the Infectious Disease Institute in Kampala, Uganda (which conducted the laboratory component of the project) and the Academic Model Providing Access to Healthcare (AMPATH) center in Eldoret, Kenya (which recruited patients). Dr. Chang is now working on a project related to scabies control. A single dose of ivermectin to entire island populations with endemic scabies has led to a dramatic and sustained decrease in scabies prevalence for over a decade. She is exploring whether this approach could be used in other scabies-prevalent settings such as refugee and migrant camps. Another project Dr. Chang is working on relates to wound care in Western Kenya. Dr. Chang is leading a randomized controlled trial evaluating the use of low-cost, locally made compression bandages on lymphedema from Kaposi sarcoma. The goal of this project is to evaluate the delivery of this intervention through home-based or community-based care, since the major barrier that remains to accessing this care is transportation costs to clinic. Dr. Chang concluded her remarks by noting that mentorship and funding support at critical points in her career have enabled her success, and she looks forward to supporting future global health dermatologists as they embark on their careers.
Pediatric Onset Systemic Lupus Erythematosus (SLE) in South Africa: Opportunities and Challenges
Dr. Lewandowski came to the NIH as a Fogarty fellow in 2014, with a strong interest in global health and rheumatology. She explained that SLE is associated with increased mortality in high-income countries and is more common/severe in African Americans/Afro-Europeans. The epidemiology of SLE in Africa is largely undetermined. The incidence of SLE in Africa is presumed to be low; however, recent studies challenge this theory. In the United States, children have higher disease activity, require more therapy, and accrue more organ damage than adults.
To determine whether SLE is more severe in pediatric patients in Africa than North America, Dr. Lewandowski’s team (based primarily out of Red Cross Hospital in Cape Town, South Africa) enrolled 100 children into a retrospective cohort of South African pediatric SLE patients. She and her colleagues conducted a chart review from onset of symptoms to enrollment. A subset of patients was followed to determine management and outcomes. For a North American comparative population, they used the Childhood Arthritis and Rheumatology Research Alliance’s (CARRA) lupus data, which includes roughly 1,000 well-described lupus patients.
Compared to the CARRA cohort, African patients were younger and had a shorter disease duration. With regard to the clinical symptoms of lupus, more organ involvement was observed in the South American patients, especially in terms of lupus nephritis and central nervous system involvement. Interestingly, African American North American patients were more like their white North American comparators than like the South African patients. South African children had more severe disease at presentation and worse outcomes. Dr. Lewandowski reported that 57% of South African children presented with catastrophic illnesses such as stroke, seizure, acute renal failure, and sudden onset blindness. Compared with 1% of CARRA patients, 15% of South African children required dialysis (fewer than 1% of the CARRA patients required a kidney transplant compared to 8% of South African children). She saw this even in patients that did not have barriers to care.
To further explore these issues, Dr. Lewandowski came back to the NIAMS and her mentor, Dr. Mariana Kaplan (Senior Investigator and Chief of the NIAMS Systemic Autoimmunity Branch and Acting Director of the NIAMS Lupus Clinical Trials Unit) to develop the International Multisite Assessment of Genetics and Inflammation in Early Onset Lupus (IMAGINE SLE). IMAGINE SLE has study sites in the United States, Canada, South Africa, and Mexico, and is sampling DNA, RNA, and plasma from early onset SLE patients and relatives. The researchers are using whole exome/genome sequencing to investigate rare genetic variants that have a large effect size on disease to help understand more about the pathogenesis of lupus. To date, 111 pediatric and 129 parental samples have been collected.
Dr. Katz commented that the NIAMS occasionally receives applications from abroad. Even after peer review, if the NIAMS wants to fund an application from outside of the United States, the Institute needs Council approval and the application must comprehensively describe the uniqueness associated with the study population. He commented that the presentations by Drs. Glass, Hsieh, Chang, and Lewandowski provide compelling arguments for why the NIAMS need to explore unique populations that could provide a dimension that could not otherwise be explored in the United States. He also explained that the NIAMS has a robust and successful program for its K awardees during their third year, and it may be possible to invite appropriate FIC K awardees to the NIAMS K awardee meeting.
Dr. Glass noted that the presentations by Drs. Chang and Lewandowski focused on rheumatologic and dermatologic diseases and that the NIAMS currently has no investments/grants in Africa. He pointed to the need to build a future based on the work of these researchers who are young and who are at institutions that have global health programs at foreign sites. Dr. Katz agreed with Dr. Glass, noting that the NIAMS looks forward to entertaining these types of applications when they are based on compelling science and hold promise for improving knowledge.
Dr. Khosla commented that he was struck by the data in lupus showing that disease manifestations were different in South Africans versus the African Americans in North America. He suggested that when the Council reviews applications from abroad, the extent that these applications can make comparative links to U.S. cohorts is very helpful.
Ms. Castro-Lewis asked if there are similar studies done in Hispanic communities and compared to the U.S. population in Latin American countries. Dr. Katz noted that Dr. Hsieh is working in Peru, where she was initially studying sexually transmitted diseases and HIV before adding osteoporosis to her work. Dr. Hsieh added that in Peru there are good researchers and productive research teams that perhaps have not been well harnessed.
Dr. Glass described the D43 program grant at FIC, which bridges U.S. and foreign universities such that over the course of 5 years, there is a training program for leadership and research on the proposed areas of study. He suggested that this is an effective way to build collaborations and partnerships for robust clinical trials.
VII. NEXT GENERATION RESEARCHERS INITIATIVE UPDATE
Dr. Lauer began his presentation by describing an article from a special issue of Nature titled “Young, Talented and Fed-Up” that was published in May 2016 that focused on the difficulties and stresses faced by young investigators. The article indicates that scientists who are starting laboratories report being under historically high pressure to publish, secure funding, and earn permanent positions yet have little time available for research (Nature. 2016 Oct 27;538(7626):446-449. doi: 10.1038/538446a. PMID: 27786221). Within an associated series of articles and survey data, it was pointed out that it is becoming increasingly difficult to secure funding and that success rates for funding have gone down. Dr. Lauer noted that there was a time when the success rate at the NIH was 60%. This has changed significantly over the last few decades; researchers are having much more difficulty getting funded now and the burden is falling most heavily on new faculty members. These may be some of the most innovative and ambitious people, but the current landscape is incentivizing them to be more conservative with regard to the types of projects they propose.
Dr. Lauer also referenced a July 2016 New York Times article that pointed out that the average age at which an NIH-funded researcher first achieves independence is now 42-43 years old, up from 35 years old in 1980. Effectively, this means that a researcher is an apprentice until middle age. Furthermore, those who already have funding have a much easier time getting additional funding compared with those who do not already have funding, so it is becoming increasingly difficult to break into the pool of NIH-funded researchers.
Dr. Lauer described an article published last year that examined the age distribution of PIs on Research Project Grants (RPGs) funded by the NIH (Proc Natl Acad Sci USA. 2017 Jun 20;114(25):6498-6503. doi: 10.1073/pnas.1609996114. PMID: 28584129). From 1990 through 2007, the proportion of early stage investigators declined from about 55% to just over 30%, leveling out in large part due to the implementation of the NIH Early-Stage Investigator policy. The proportion of late-stage investigators grew from well under 10% in 1990 to more than 20% in 2015, possibly due to the aging population and the end of mandatory retirement. The curve for mid-stage investigators initially increased from more than 35% to more than 50% between 1990 and 2005, but began declining with the payline crash of 2005-2006 and has continued with a downward trend of about 1% per year.
A 2015 paper resulting from a series of workshops exploring potential solutions to the stresses faced by the biomedical research community identified two core problems: (1) too many researchers vying for too few dollars, and (2) too many postdocs competing for too few positions (Elife. 2015 Jun 30;4:e09305. doi: 10.7554/eLife.09305. PMID: 26122792). Between 2003 and 2015, there has been a 10% increase in the number of NIH RPG awardees, but there has been a 50% increase in the number of RPG applicants over this time. Dr. Lauer reported that more recently, this discrepancy has started to plateau.
The ability to remain funded by the NIH is a challenge to investigators as well. Roughly 60% of investigators among who received their first R01 between 1996 and 2000 (during the doubling of the NIH budget) were still in the system. However, among those receiving a first R01 between 2006 and 2010 (after the doubling and during the “payline crash”), only about 50% were still in the system. A recent paper published by NIGMS investigators using data from across the NIH found that a smaller percentage of women than men are staying in the system beyond 5-6 years after receipt of first RPG.
A provision of the 21st Century Cures Act (passed by Congress in December 2016 with overwhelming bipartisan support) establishes the NGRI and states that “The Director of the National Institutes of Health shall…develop, modify, or prioritize policies, as needed…to promote opportunities for new researchers and earlier research independence, such as policies to increase opportunities for new researchers to receive funding…, and enhance workforce diversity.” Dr. Lauer referenced two recent reports:
- The Next Generation of Biomedical and Behavioral Science Researchers: Breaking Through, from the National Academies of Sciences, Engineering, and Medicine. The report includes recommendations for the NIH and for universities as well as comments on the structure of postdoctoral training. Of particular interest, there is an appendix that reviews reports issued on this topic in the last 25 years and identifies the status of the recommendations found in these reports. The report also includes a chapter explaining the landscape of funding for early career investigators.
- The U.S. Government Accountability Office report titled NIH Research: Action Needed to Ensure Workforce Diversity Strategic Goals are Achieved. This report highlights how the NIH is responding to the NGRI and in general, was complimentary of the NIH. The report calls on the NIH to develop quantitative metrics for assessing diversity and tracking them over time.
A subcommittee to the ACD is examining the NGRI and has been working since June 2017. The subcommittee released preliminary recommendations in June 2018 and plans to issue final recommendations in December. Among its recommendations, the subcommittee feels that the NIH should fund more early stage investigators, promote diversity, and closely monitor at-risk investigators who are conducting meritorious research. It is also considering other approaches to help further the goals of the NGRI (e.g., increasing the size of some Common Fund programs and/or K award programs). While it waits to receive final recommendations from the subcommittee, the NIH hopes to fund roughly 1,100 early stage investigators in FY 2018 (last year, the NIH funded a record high of 1,040 early stage investigators) and draw increasing attention to meritorious at-risk investigators.
Dr. Katz suggested that since the early 1990s, the NIH has set the bar for funding meritorious applications significantly higher. The NIAMS has a program that encourages K awardees to apply for R01s earlier in the process, and these applicants typically fare better than those applying for an R01 without previously having a K award. He also noted that in 2006, the success rate for a new investigator for a first, non-amended application was 6%, a finding that helped prompt the NIH to establish its NIH Early-Stage Investigator policy.
Dr. Oro asked how the NIH plans to fund more early stage investigators while keeping the payline the same and without a significant budget increase. Dr. Lauer acknowledged that this is a significant challenge and noted that the NIH budget overall has increased slightly in recent years. This activity has been flagged as a significant priority by lawmakers and Dr. Collins. The amount of money required to fund the planned 1,100 early stage investigators in 2018 represents approximately 3% of the NIH budget. Individual ICs will be asked to reprioritize their activities and initiatives to help accommodate funding of early stage investigators as well as retaining established investigators who propose high-quality research and are at risk for losing all funding. Dr. Lauer noted that NIH ICs have a variety of programs to target specific groups such as early stage investigators (e.g., NIAMS’ STAR program provides additional support for early career investigators to pursue innovative and high-risk research).
Dr. Katz acknowledged NIH’s gratitude toward Congress for the recent budget increases. However, now more so than ever, a significant amount of these increases is allocated to specific programs.
In response to a question from Dr. Tapscott, Dr. Lauer explained that the NIH has made some attempts to model what the workforce looks like, with assumptions built in to reflect the proportion of people who would be successful based on a set of accepted metrics, with the goal of assuring those who are successful (as reflected by these accepted metrics) are receiving stable funding over time. He noted that Dr. Bruce Weinberg, an economist at The Ohio State University who has been funded by the NIA, has shown that the rate of aging within the scientific workforce is higher than in the general workforce. This rate of aging substantially increased around 1995-1996, which coincided with the end of mandatory retirement, and he predicted that if there are no additional interventions, the instability in the scientific workforce will continue for at least another 10 years (Proc Natl Acad Sci USA. 2017 Apr 11;114(15):3879-3884. doi: 10.1073/pnas.1611748114. PMID: 28348239). Dr. Lauer explained that the critical time for a researcher is at the end of their first grant. The attrition rate for researchers who receive a second grant is fairly stable and predictable.
Dr. Buyon asked if the researcher dropout rate is related to tenure, noting that many institutions require a second R01 to stay on track for tenure. She also asked about NIH efforts to engage universities in discussing these types of issues. Dr. Katz noted that an NIH group comprised of senior leadership did engage university leaders on this topic and one major issue identified was that universities were not giving credit to those working on R01 grants and publishing papers, outside of the PI. This model has changed somewhat in recent years. Dr. Lauer referenced the Institute for Research on Innovation & Science, a network that has pulled together detailed personnel data on students and faculty linked to U.S. Census data to explore data related to career trajectories.
Dr. Khosla asked if there is an opportunity to create a category of grants that allow late stage investigators to partner with and mentor early stage investigators in a way that allows early stage investigators to take over a competing renewal to leverage the strengths of the late stage investigators without removing their funding while incentivizing late stage investigators to mentor and put succession plans in place. Dr. Lauer indicated that there has been substantial discussion about this type of approach.
VIII. NIH-WIDE HIGH RISK/HIGH REWARD PROGRAM
Dr. Carter presented a slide deck adapted from a presentation given by Dr. George Santangelo (Director, Office of Portfolio Analysis, DPCPSI) to the Advisory Committee to the Director titled “Analysis of NIH High-Risk, High-Reward (HRHR) Research.” The four NIH HRHR Common Fund Program awards include:
- Pioneer Awards: Available to investigators at all career levels and intended for innovative research with groundbreaking, high-impact approaches to broad areas of biomedical or behavioral sciences.
- New Innovator Awards: Available to early career investigators and intended for unique, innovative research that has not yet received an RPG or equivalent NIH grant.
- Transformative Research Awards: Given to individuals and teams of investigators at any career stage, for promoting promote cross-cutting, interdisciplinary approaches for unconventional research that could challenge existing paradigms.
- Early Independence Awards: Awarded to junior scientists who recently received a doctoral degree and provide the opportunity to bypass post-doctoral training and move immediately into independent research positions.
An analysis of NIH HRHR programs was conducted to determine how the productivity of these awards compares with NIH R01 awards. HRHR award outputs were analyzed using a variety of metrics. The research productivity of HRHRs and all NIH R01s from FY 2011-FY 2016 were assessed by measuring the following outputs: (1) publications, (2) influence of publications per the Relative Citation Ratio (RCR), (3) clinical impact (based on producing one or more clinical trials or guidelines, or at least one publication cited by a clinical trial or guideline with results), and (4) technological impact (based on producing one or more patents or at least one publication cited by a patent).
Results of the analysis indicate that HRHR awards fund highly productive research and are focused on projects that are of higher impact than traditional R01 awards. The currently available metrics suggest that HRHR awards equal or outperform NIH R01s. Dr. Carter explained that HRHR publications were found to be more influential, with higher mean and median RCRs, higher mean and median weighted RCRs per award, and a higher percentage of awards with at least one publication at or above the RCR 15th percentile. The analysis also found that a higher percentage of HRHR awards have had technological impact, but a lower percentage of HRHR awards have had clinical impact as compared to R01s (this finding is not surprising, given that HRHR awards are intended to support fundamental, transformative, paradigm-shifting ideas that generally require more time to advance to a clinical trial than most R01s).
Dr. Carter briefly reviewed a number of previously funded HRHR awards relevant to the NIAMS and noted that two new HRHR awards relevant to the Institute were recently awarded.
In response to a question from Dr. Econs about the per-publication cost associated with HRHR awards compared to R01s, Dr. Carter indicated that his suspicion is that the cost for the Pioneer and Transformative awards is higher than for a typical R01 award. He also clarified that the Transformative Awards are actually considered to be R01s, the other HRHR awards are unique types of funding mechanisms that have separate approaches for being reviewed.
Dr. Katz explained that almost all funding for HRHR awards comes from the Common Fund, not from within the IC budgets (except when ICs are asked to supplement). The total Common Fund budget is roughly $560 million; approximately one-third of it is allocated to these HRHR awards.
Dr. Oro asked if NIH Common Fund programs tend to attract younger, early stage investigators. Dr. Carter explained that the New Innovator and Early Independence awards specifically target these researchers, while the Pioneer awards are meant for more established investigators who have trans-NIH ideas that might be difficult to fund through a single IC.
V. NIH COUNTERMEASURES AGAINST CHEMICAL THREATS UPDATE
Dr. Jett explained that CounterACT is a Congressionally-mandated and funded program that is part of the overall biodefense effort that began at the NIH shortly after the events of September 11, 2001. The program focuses on chemical threats to national security and the development of better therapeutics for use during a chemical emergency, such as a terrorist attack or large-scale industrial accident. Although there is overlap with similar Department of Defense programs, the NIH CounterACT initiative focuses on the civilian population. The NIAMS has been a key partner in the program since its inception in 2006. CounterACT’s mission is to understand fundamental mechanisms of toxicity caused by chemical threat agents and the application of this knowledge to develop promising therapeutics for reducing mortality and morbidity caused by these agents. Specific goals of the program are to: (1) improve the nation’s medical response capabilities, (2) support cutting-edge research to improve the knowledge base, and (3) develop optimized lead compounds for transition to advanced development. Dr. Jett noted that positive outcomes for the program are creating a large science and technology knowledge base in the open literature, and developing a robust translational pipeline of optimized lead compounds ready for advanced development and FDA approval.
The program is funded by a special appropriation as a supplement to the NIH budget and has been stable since 2006 at roughly $46-50 million per year. IC funds are not used for this program. Development of the CounterACT program began in 2004 with a series of workshops and seed funding in the form of administrative supplements to garner interest before the first appropriation and funding grants in 2006. Over the years, FOAs have been published and in 2011, 5-year budget plans, instead of annual plans, were instituted. The program is currently in its second 5-year plan.
Dr. Jett explained that the Department of Homeland Security has an office that models the use of toxic chemicals in terrorism scenarios and develops a Chemical Threat Risk Assessment (CTRA) list that is updated every few years. He presented a slide showing the current list, which includes more than 190 chemical that the NIH is charged with studying. Through CounterACT, a method of categorizing these chemicals was developed based on their “toxidrome,” or mode of action and acute toxicity, thereby allowing the possibility of developing therapeutics that could be effective against more than just one of the chemical threats. Because the variety of chemicals on the CTRA can cause a host of acute effects, CounterACT features a cross-functioning team that includes participation from different NIH ICs that have the required expertise. Six ICs currently manage CounterACT grants and contracts (including the NIAMS) and the program receives scientific support from across all 27 NIH ICs (e.g., the NIAMS provides a wealth of knowledge on the effects of vesicant agents and wound healing).
Dr. Jett provided a high-level overview of the CounterACT program structure, which is designed to promote a progressive translational effort beginning with basic research through translational research, culminating in an optimized lead compound ready for advanced development funding through the Biomedical Advanced Research and Development Authority (BARDA), industry, or another entity. The program includes Research Centers of Excellence, U01 cooperative agreements, and R21 grants, as well as some SBIR grants.
Current funding announcements are designed to promote the progressive translational program structure beginning with exploratory R21 grants for target identification and screening, through lead identification and finally lead optimization, where the deliverable is an optimized lead compound that has met the requirements outlined in the FOA, which have been vetted with BARDA. This vetting increases the chances of a successful project garnering further support from that agency. All our grants are reviewed within the NIH CSR by a Special Emphasis Panel.
Dr. Jett highlighted some of the opportunities being pursued by the CounterACT program. These include enhancing its product development portfolio by providing assistance to potential applicants via webinars, and helping funded investigators meet milestones by offering mid-year web conferences that can be attended by the entire trans-NIH team. The program is also trying to increase its visibility through attendance at conferences and by establishing a greater presence in the civilian scientific peer-reviewed literature.
To date, CounterACT has produced six optimized lead compounds that have transitioned to multimillion dollar contracts with BARDA. Dr. Jett provided highlights of recent scientific advances related to antidotes for cyanide and nerve agents.
Following Dr. Jett’s presentation, Dr. Tseng briefed Council members on the NIH CounterACT Research Center of Excellence within the Environmental and Occupational Health Science Institute (EOHSI) at Rutgers University, which is focusing on mustard gasses. Dr. Tseng explained that this grant is the largest investment of the CounterACT program and one of the longest-running grants. The NIAMS has been managing this grant since it began, approximately 13 years ago. Dr. Tseng acknowledged Ms. Sheila Simmons and Mr. Andrew Jones of the NIAMS Grants Management Branch for their support. On the program side, Dr. Carl Baker provided support until his retirement, at which point Dr. Tseng began serving as Project Officer.
Dr. Tseng noted that the EOHSI was established in 1996 and already has a list of impressive achievement. In addition to the CounterACT Research Center of Excellence, the EOHSI houses an NIEHS Center of Excellence as well as other centers and training programs from the Department of Energy and U.S. Environmental Protection Agency. The EOHSI also has a strong program in skin toxicology research. The EOHSI was awarded its CounterACT grant based on its proposal to develop countermeasures against sulfur mustard gas, one of the first chemical warfare agents invented and used in World War I. Because the toxin is delivered in gas form, the body’s surface area and respiratory tract are most vulnerable. Most recent reports of its use come from Sudan, Syria, and Yemen.
Dr. Tseng described the EOHSI Center’s strategic plan, which is structured to achieve the goal of delivering countermeasures to BARDA and features the following activities:
- Identify FDA-approved medical products as well as new countermeasures for treating sulfur mustard injury.
- Formulate these drugs for optimal delivery to target organs.
- Develop drugs into successful Investigational New Drug (IND) applications.
- Elucidate mechanisms for sulfur mustard-induced toxicity for better countermeasure development.
- Develop rapid screening assays.
The Center has generated 144 publications and two patents (with more pending) since 2007. It has a dedicated education core that provides training from high-school students to medical residents, and offers masters and doctoral degrees. The Center has also organized seminars and workshops to inform the general public about issues related to chemical warfare and threats to the civilian population.
After briefly reviewing highlights of Center projects in the areas of skin, eye, and lung, Dr. Tseng described activities of the Center’s Pharmaceutical and Medicinal Chemistry Core (charged with developing new countermeasures) and its Pharmacology and Drug Development Core (which provides the interface between the Center and the FDA and pharmaceutical industry).
Dr. Jett opened the discussion session by noting that each year, a CounterACT Center hosts an annual meeting during which all program investigators convene with representatives from industry and other agencies to share information, provide updates on progress, and identify opportunities for collaboration. The next such meeting will be hosted by the EOHSI and will feature opening remarks by Dr. Katz.
Dr. Lerner asked about the status of effective deliverables coming out of the CounterACT program. Dr. Tseng referenced the countermeasures being developed at the EOHSI and noted that significant time is required to proceed through the regulatory process. Furthermore, it can be challenging to identify pharmaceutical companies that are willing to offer their existing products for this purpose. Dr. Jett noted that six products have transitioned into advanced development, some of which are poised to be approved by the FDA in the near future. Roughly 12 more products are expected to transition into advanced development in the next 2-3 years. He also reminded Council members of the program’s mission to increase the scientific and knowledge base.
VI. NIAMS STRATEGIC PLAN FY 2020-2024
Ms. Caughman described NIAMS’ efforts to update its current Long-Range Plan (available online here), which covers FY 2015-2019. The updated Plan will align with the NIH-Wide Strategic Plan and comply with the 21st Century Cures Act with regard to: (1) articulating scientific goals, objectives, and priorities; (2) serving as an efficient and effective steward of public resources; and (3) describing the scientific planning process. She explained that the purpose of the Institute’s Strategic Plan is to provide a broad scientific outline that describes current and emerging arthritis and musculoskeletal and skin research opportunities, communicate the Institute’s perspective, serve as a resource for all who are interested in NIAMS’ activities, and encourage the best investigator-initiated research ideas. In keeping with the 21st Century Cures Act, key to the development of the Plan will be emphasizing women and minorities and reducing health disparities. As with the existing Plan, the goal is to provide a document that will inform the Institute’s priority-setting process while enabling the NIAMS to adapt to the rapidly changing biomedical and behavioral sciences landscape.
The Institute will build on its existing Strategic Plan while refreshing disease- and tissue-specific topics in the areas of arthritis and rheumatic diseases, skin biology and diseases, bone biology and diseases, musculoskeletal biology and diseases, and muscle biology and diseases. The updated Strategic Plan will also identify cross-cutting topics that transcend these disease- and tissue-specific areas, and will continue to reflect the Institute’s commitments to reducing health disparities, supporting the next generation of biomedical and behavioral researchers, and disseminating research results.
Ms. Caughman presented a high-level overview of the Strategic Plan development process, which includes:
- Receiving input via a Request for Information (RFI) (September-October 2018)
- Listening sessions with the research community and NIAMS Coalition (November/December 2018)
- Five listening sessions will cover disease- and tissue-specific topics; others will address training and career development as well as perspectives from the NIAMS Coalition.
- An update to the NAMSAC (February 2019)
- Review by a NAMSAC working group (April-May 2019)
- Presentation to the NAMSAC with working group report (June 2019)
- Posting the draft plan and a subsequent RFI (June-July 2019)
- Presenting the final draft plan to the NAMSAC (September 2019)
- Obtaining NIH/HHS clearance and posting the final plan (September-October 2019)
The RFIs will be used to encourage input from all NIAMS stakeholders (including patient and advocacy organizations, professional societies, academic departments and individuals) over a 6-week period beginning in mid-September 2018. Specific feedback will be requested on: (1) research opportunities in found in the current plan that should be modified because of progress over past 5 years, (2) emerging research needs and opportunities that should be added, and (3) cross-cutting scientific themes or research-related themes common to all, or most, of the NIAMS mission. Dr. Katz noted that some Council members will be asked to participate in the working group that will be reviewing the draft plan.
VII. COMPARATIVE EVALUATION OF NIAMS AND NIAID IMMUNE-DERMATOLOGY EXTRAMURAL PROGRAMS
This portion of the meeting occurred during closed session.
VIII. BOARD OF SCIENTIFIC COUNSELORS REPORT
This portion of the meeting occurred during closed session.
IX. NIAMS: CURRENT AND FUTURE ROLES IN HEALTHY PEOPLE INITIATIVE
This portion of the meeting occurred during closed session.
X. SPECIAL ACTIONS
This portion of the meeting occurred during closed session.
IX. CONSIDERATION OF APPLICATIONS
In closed session, the Council reviewed and recommended a total of 844 primary and secondary applications. The total cost requested in year -01 for all applications was $321,739,574.
The 96th National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Meeting was adjourned at 3:00 p.m. Proceedings of the public portion of this meeting are recorded in this summary.
I hereby certify that, to the best of my knowledge, the foregoing summary and attachments are accurate and complete.
Stephen I. Katz, M.D., Ph.D.