Department of Health and Human Services
Public Health Service
National Arthritis and Musculoskeletal and Skin Diseases Advisory Council
Minutes of the 83rd Meeting
8:30 a.m. to 2:15 p.m.
CALL TO ORDER
The 83rd meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council (NAMSAC) was held on June 3, 2014, at the National Institutes of Health (NIH) Campus, Building 31, Conference Room 6. The meeting was chaired by Dr. Stephen Katz, Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Council members present
Dr. Lynda F. Bonewald
Dr. David R. Eyre
Dr. Gary S. Firestein
Dr. Sherine Gabriel
Ms. Michelle Hofhine
Dr. Gary A. Koretzky
Dr. Ted Mala
Dr. Katherine Mathews
Dr. Martha M. Murray
Dr. Grace Pavlath
Dr. Alice P. Pentland
Dr. Gwendolyn L. Powell Todd
Dr. Anthony E. Rankin
Dr. Christy I. Sandborg
Dr. Elizabeth Shane
Mr. Alexander Silver
Ms. Elizabeth Smith
Dr. Xiao-Jing Wang
Staff and Guests
The following NIAMS staff and guests attended:
Mr. Steven Austin
Dr. Carl Baker
Ms. Pamela Beheler
Ms. Susan Bettendorf
Ms. Elizabeth Bouras
Dr. Amanda Boyce
Dr. Stephanie Burrows
Ms. La’Tanya Burton
Dr. Robert Carter
Dr. Faye Chen
Dr. Ricardo Cibotti
Ms. Robin DiLiello
Ms. Theresa Do
Dr. Jonelle Drugan
Mr. Erik Edgerton
Ms. Elizabeth Elliott
Ms. Barbara Footer
Dr. Nancy Garrick
Ms. Gail Hamilton
Ms. Katie Joffee
Mr. Andrew Jones
Dr. Stephen Katz
Ms. Mary Beth Kester
Ms. Shahnaz Khan
Ms. Stephanie Kreider
Mr. Mark Langer
Dr. Gayle Lester
Dr. Helen Lin
Ms. Anita Linde
Ms. Mimi Lising
Ms. Leslie Littlejohn
Dr. Kan Ma
Dr. Marie Mancini
Dr. Su-Yau Mao
Dr. Kathryn Marron
Dr. Joan McGowan
Ms. Leslie McIntire
Dr. Laura K. Moen
Ms. Regina Mong
Ms. Melinda Nelson
Ms. Anna Nicholson
Dr. Glen Nuckolls
Dr. John O’Shea
Dr. James Panagis
Ms. Vivian Pham
Ms. Reaya Reuss
Ms. Trish Reynolds
Dr. Kathy Salaita
Dr. Susana Serrate-Sztein
Dr. William Sharrock
Ms. Sheila Simmons
Dr. Kentner Singleton
Ms. Allisen Stewart
Ms. Robyn Strachan
Ms. Yen Thach
Dr. Hung Tseng
Dr. Bernadette Tyree
Ms. Lisa Walker
Dr. Fei Wang
Dr. Yan Wang
Ms. Sara Rosario Wilson
Dr. James Witter
Dr. Xincheng Zheng
Mr. Michael Bykowski, Consolidated Solutions and Innovations
Ms. Sara Chang, Lupus Foundation of America
Mr. Dale Dirks, Health and Medicine Counsel of Washington
Mr. Jeff Domanski, National Institute of Biomedical Imaging and Bioengineering, NIH
Mr. Quardricos Driskell, National Psoriasis Foundation
Dr. Ellen Gadbois, Office of the Director, NIH
Ms. Patti Brandt Hansberger, Office of Legislative Policy and Analysis, NIH
Ms. Tracy Hart, Osteogenesis Imperfecta Foundation
Ms. Niva Haynes, American Academy of Dermatology
Ms. Kim Holmes, IQ Solutions
Ms. Leah Howard, National Psoriasis Foundation
Dr. Lynne Jones, Orthopaedic Research Society
Ms. Annie Kennedy, Muscular Dystrophy Association
Dr. David Murray, Office of Disease Prevention, NIH
Mr. Simit Pandya, American Academy of Orthopaedic Surgeons
Ms. Brittany Peterson, Health and Medicine Council of Washington
Mr. Nate Robinson, IQ Solutions
Ms. Kirstie Saltsman, IQ Solutions
Mr. Richard Taffet, Ehlers-Danlos National Foundation
CONSIDERATION OF MINUTES
A motion was made, seconded, and passed to accept with no changes the minutes of the 82nd NAMSAC meeting, held on February 11, 2014.
FUTURE COUNCIL MEETING DATES
Future Council meetings are currently planned for the following dates:
September 8, 2014
February 4, 2015
June 16, 2015
September 8, 2015
February 2, 2016
June 7, 2016
September 13, 2016
DIRECTOR'S REPORT AND DISCUSSION
Dr. Katz began his Director’s Report by welcoming participants and thanking Council members for their attendance and input. He noted that additional information on many of the items included in his Director’s Report can be found in the Shorttakes section of the NIAMS website.
Update on Budget and Congressional Activities
On March 4 2014, President Obama released his fiscal year (FY) 2015 budget request to Congress. Council members were advised that the President’s budget request is only a starting point for the FY2015 appropriations process and that changes are expected as that process continues. The amount requested for the NIH is $30.4 billion, an increase of approximately $211 million from the 2014 enacted budget. The amount requested for the NIAMS is $520.2 million, representing an increase of $851,000 above what it received this year.
Dr. Katz reminded Council members that as part of NIAMS’ commitment to transparency, the Institute’s funding plan for FY 2014 is available on its website. This year’s R01payline is higher than last year’s, at the 14th percentile for established investigators and at the 19th percentile for new and early stage investigators. The goal of this differential payline is to ensure equal success rates for new and established investigators who are applying for a new or Type 1 R01 grant. The Institute also reserves a small portion of each year’s budget for projects that address subjects of particular relevance to NIAMS’ scientific and health priorities, even if their assigned scores and percentile rankings would not qualify for funding under the current payline. This select pay process is described on the NIAMS website, and Council input is encouraged regarding any suggestions in this area. Dr. Katz presented a slide with a histogram showing the number of R01 applications and awards as well as R37s (which are R01-equivalent Method to Extend Research In Time [MERIT] Awards), for experienced, new, and early stage investigators in 2013. In addition to providing data for all R01 applicants regardless of career stage, the NIAMS also has posted separate graphs on applications and awards from established and new investigators. Dr. Katz reported that the NIH has updated its policy regarding resubmitted grant applications. Beginning on April 17 of this year, an applicant whose resubmission application (also known as the A1) is not funded may now submit the same idea as a new application (or A0) for the next appropriate due date. Previously, NIH’s policy specified that if an A1 application was not funded, any new A0 application had to be substantially different in content and scope.
As part of the regular appropriations process, NIH Director Dr. Francis Collins and a group of IC Directors appeared before the House and Senate Labor, Health and Human Services, and Education Appropriations Subcommittees. This year, Senator Barbara Mikulski (D-MD) also provided Dr. Collins with a unique opportunity to address the full Senate Appropriations Committee at a hearing titled "Driving Innovation Through Federal Investments." Dr. Collins chose to feature one of Dr. Raphaela Goldbach-Mansky’s (Section Head in the NIAMS Pediatric Translational Research Branch) patients, a young girl named Kayla who has been treated for neonatal onset multisystem inflammatory disease (NOMID) at the NIH Clinical Center since she was 1 year old. Dr. Katz showed a short video developed by NIAMS’ Communications Office featuring Kayla, her mother, and Dr. Goldbach-Mansky. The primary message of the video is that NIH’s goal is to conduct and support research that will save and improve people’s lives. The video also underscores the importance of studying rare diseases.
On May 6, at the request of the Scleroderma Foundation, NIAMS Deputy Director Dr. Robert Carter participated in an educational briefing for Congressional staff titled "Hope Through Medical Research: Advancing Our Scientific Understanding of Scleroderma and Related Autoimmune Diseases." Senators Elizabeth Warren (D-MA) and Kirsten Gillibrand (D-NY) sponsored the event. Dr. Carter also represented the NIAMS at two Hill briefings on the Accelerating Medicines Partnership (AMP), a public-private partnership between the NIH, the Foundation for the National Institutes of Health (FNIH), pharmaceutical companies, and health advocacy organizations.
Highlights of Selected Recent Scientific Advances
- A recent paper provides new insights into how rheumatoid factor and anti-citrullinated peptide antibodies (ACPAs) contribute to rheumatoid arthritis (RA). Dr. Jeremy Sokolove, Dr. William Robinson, and their teams at Stanford University School of Medicine characterized the sera from RA patients and divided the patients into groups based on whether they were positive for rheumatoid factor and ACPAs. Patients who were positive for both types of autoantibodies had more severe disease and significantly elevated circulating levels of inflammatory markers compared with patients who had neither or only one type of autoantibody. A follow-up experiment showed that rheumatoid factor enhances ACPAs’ ability to stimulate pro-inflammatory cytokine production by macrophages in vitro. More research is needed to understand how these findings can inform the treatment of patients with co-occurrence of rheumatoid factor and ACPAs (Arthritis Rheumatol. 2014 Apr;66(4):813-21. PMID: 24757134).
- Numerous studies have shown that moderate-to-vigorous levels of exercise improve pain and function for patients with knee osteoarthritis (OA); however, many who have OA cannot engage in even moderately intense physical activities. Using data from the Osteoarthritis Initiative (OAI), a research team led by Dr. Dorothy Dunlop at Northwestern University demonstrated that even light-intensity activities can preserve the health of people with knee OA. Individuals over age 45 who had or were at risk of developing knee OA were more than 30% less likely to develop arthritis-related disabilities if they spent more than 4 hours per day doing light activities (e.g., walking, housework), compared with those who engaged in these similar activities for less than 3 hours per day (BMJ. 2014 Apr 29;348:g2472. doi: 10.1136/bmj.g2472. PMID: 24782514).
- Dr. Stuart Warden and his research team at Indiana University explored whether bone benefits due to exercise during youth persist into aging. They examined the upper arm bones of more than 100 active and retired professional baseball players (specifically pitchers and catchers who specialize in overhand throwing). The humerus bone of their throwing arms had roughly 50% more bone mass, thickness, and overall size. Consistent with other studies, bone mass gradually declined after the players retired. However, the bone loss occurred mostly from the inside of the bone, whereas the size increase during the players’ active days was on the bone’s outer layer. The throwing arms continued to be approximately 30% larger than the non-throwing arms. The players who kept exercising after retiring from professional sports lost less bone mass from the inside of the humerus bone, and they continued to maintain more of the bone size and strength advantages than their inactive former colleagues (Proc Natl Acad Sci USA. 2014 Apr 8;111(14):5337-42. doi: 10.1073/pnas.1321605111. Epub 2014 Mar 24. PMID: 24706816).
- Council member Dr. David Eyre (of the Department of Orthopaedics and Sports Medicine at the University of Washington School of Medicine) and colleagues have done work to clarify how transforming growth factor beta (TGF-β) is liberated from the matrix during bone resorption and regulates new bone formation. Studying a mouse model of the brittle bone disease osteogenesis imperfecta (OI), the researchers determined that collagen, possibly in association with other matrix components, is important for maintaining a supply of TGF-β in bone and controlling its release. The bones of mice that contained collagen mutations similar to those that cause OI in humans showed cellular changes that indicated higher levels of TGF-β signaling. Treating the mice with an antibody that blocks TGF-β action restored the amount of bone and its structure to a nearly normal state. An antibody similar to the one used in these studies has already been tested in humans for use in diseases other than OI and has been found to be reasonably well tolerated. Therefore, it may be possible to test fairly soon whether TGF-β blocking is a useful therapeutic approach in OI. Dr. Eyre clarified that this work was carried out with a number of collaborators led by Dr. Brendon Lee at Baylor College of Medicine (Nat Med. 2014 May 4. doi: 10.1038/nm.3544. [Epub ahead of print] PMID: 2479323).
- Researchers led by Dr. Jacqueline Hecht at the University of Texas previously demonstrated that mutations cause a protein named COMP to remain trapped inside cartilage, where it provokes an inflammatory response that damages chondrocytes in pseudoachondroplasia (PSACH; a heritable disorder of the growth plate that results in disproportionate dwarfism, limb deformities, pain, early onset OA, and hyperextensible joints). More recent work by these researchers examined the effects of three U.S. Food and Drug Administration-approved drugs (lithium, phenylbutyric acid, and valproate) in a mouse model of PSACH. Although the drugs lessened the amount of COMP trapped in the cells and the associated chondrocyte damage due to inflammation, the drugs had significant side effects or did not improve the animals’ overall skeletal health. However, this study provides proof-of-concept that there may be an early treatment window during early childhood in which the chondrocytes of the growth plate can be rescued. If safer treatment options are developed, administering them during this window could permit skeletal growth to continue and may improve the quality of life for people with PSACH (J Bone Miner Res. 2014 May;29(5):1258-68. doi: 10.1002/jbmr.2139. PMID: 24194321).
- A protein called HLA-B*51 has been implicated in Behçet’s disease, but its role in Behçet’s pathogenesis remains a mystery. Dr. Mike Ombrello, along with former NIAMS Clinical Director Dr. Dan Kastner, other colleagues at the National Human Genome Research Institute (NHGRI), and several international collaborators, used a statistical approach to identify six amino acids that comprise HLA-B that independently influence a person’s risk of developing Behçet’s disease. When the investigators combined their findings with knowledge about the structure of the HLA-B and HLA-A proteins, they discovered that these amino acids influence communication between immune system components. Their findings are consistent with the inflammatory responses that characterize Behçet’s disease, but also explain other observations suggesting that altered immune reactions contribute to the condition (Proc Nat Acad Sci USA. 2014. In press).
- To better understand the factors that contribute to the progression of lung disease in scleroderma patients, Dr. Robert Lafyatis and his group at Boston University School of Medicine analyzed the gene expression of lung tissue in a prospective cohort of patients with scleroderma-related interstitial lung disease. The investigators found that the expression of certain genes, including interferon-regulated and TGF-β-regulated genes, correlated with changes detected by pulmonary tests that are routinely used by clinicians to monitor lung disease progression. The results could help clinicians to determine which scleroderma patients are most likely to progress to severe restrictive lung disease, and point to pathways that could be targets for the development of therapies that slow or halt disease progression (Arthritis & Rheumatol. 2014 Mar;66(3):714-25. doi: 10.1002/art.38288. PMID: 24574232).
- Dr. Bradley Olwin and colleagues at the University of Colorado, Boulder, built on previous studies suggesting that exposing aged muscle stem cells to a young environment improves their function by developing a cell culture model in which they could grow stem cells from aged mice on young muscle fibers. However, the young fibers failed to improve the aged cells’ regenerative abilities, as did injecting aged stem cells into the muscles of a young animal. The researchers discovered that, unlike the younger cells, the aged stem cells were unable to produce quiescent daughter cells. The expression of proteins that are critical to stem cell maturation following division was altered in the older cells (Nat Med. 2014 Mar;20(3):265-71. doi: 10.1038/nm.3465. Epub 2014 Feb 16. PMID: 24531379).
- Merkel cells in the skin are involved in sensing light touch. Together with nerve fibers, they organize into specialized structures called touch domes. Recent results from the laboratory of Dr. Ellen Lumpkin at Columbia University show that Merkel cells and the associated nerves work together, with each responsible for different aspects of touch perception. Whereas the Merkel cells contribute to the detection of a static, sustained pressure, the nerve endings provide the sensation of a dynamic change in pressure. This work could facilitate the development of treatments for conditions that impair sensory functions of the skin (Nature. 2014 Apr 6. doi: 10.1038/nature13250. [Epub ahead of print] PMID: 24717432).
Personnel Changes at the NIH
Dr. Katz reported that after 24 years of federal service, Dr. John Ruffin announced his retirement as Director of the National Institute on Minority Health and Health Disparities (NIMHD). Dr. Yvonne Maddox, Deputy Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), is serving as NIMHD’s Acting Director while the NIH engages in an ongoing search to identify Dr. Ruffin’s successor.
In the NIH Office of the Director, Dr. Robert Kaplan has moved from directing the NIH Office of Behavioral and Social Sciences Research (OBSSR) to the Agency for Healthcare Research and Quality (AHRQ), where he will serve as the Chief Science Officer and coordinate AHRQ interactions with federal agencies and other groups such as the Patient-Centered Outcomes Research Institute (PCORI). Dr. William T. Riley of the National Cancer Institute (NCI) has agreed to serve as Acting OBSSR Director.
Overview of NIH and NIAMS Activities and Plans
NIH wide, the Intramural Research Program (IRP) is developing a 10-year vision for how it can continue to use its valuable laboratory science expertise, clinical resources, and population-based programs to advance basic biomedical research and clinical applications. Council member Dr. Gary Koretzky (Dean of Weill Cornell Graduate School and Senior Associate Dean for Research at Weill Cornell Medical College) has been working closely with Dr. John O’Shea (Scientific Director of NIAMS’ Molecular Immunology and Inflammation Branch), Dr. Joseph Craft (Paul Beeson Professor of Medicine, Yale School of Medicine, and Chair of the NIAMS Board of Scientific Counselors), Dr. Katz, and other NIAMS staff to focus the Institute’s contribution to this effort.
Council members were encouraged to review a recent editorial in the Proceedings of the National Academy of Sciences that describes challenges facing the U.S. biomedical research enterprise. The authors’ assessment of the workforce and funding issues facing the academic research community, as well as recommendations to address them, is generating considerable discussion both at the NIH and in the wider community.
The NIH strives to ensure that all applicants are treated fairly by the peer review process. In response to research suggesting discrepancy in success rates for NIH R01 grant funding between white and African-American applicants, NIH’s Center for Scientific Review (CSR) is looking for rigorously constructed, well-designed, and creative proposals for: (1) new methods to detect bias in peer review, and (2) strategies to strengthen fairness and impartiality in peer review. Proposals are due at the end of the month.
With regard to NIAMS information dissemination efforts, several NIAMS staff members have spoken with various media outlets since the February Council meeting. Last month, Drs. Jim Witter (Health Scientist Administrator in the NIAMS Division of Skin and Rheumatic Diseases) and Gayle Lester (Health Scientist Administrator in the NIAMS Division of Musculoskeletal Diseases) joined colleagues from the National Center for Complementary and Alternative Medicine (NCCAM), National Institute on Aging (NIA), the Mayo Clinic, the Arthritis Foundation, and the American College of Rheumatology to answer questions about OA, RA, and gout during a Twitter chat. Ms. Liz Szabo, a medical reporter with USA Today, hosted the event, which reached more than 21 million Twitter users. Dr. Katz reported that the AMP also generated considerable media coverage in addition to the Capitol Hill events he described previously. In addition, Dr. Katz participated in a Washington Journal segment during which he highlighted ongoing research and recent advances.
Dr. Katz concluded his Director’s Report by highlighting two upcoming events:
- On June 9, 2014, Dr. O’Shea will receive the 2014 Ross Prize in Molecular Medicine, conferred by the Feinstein Institute for Medical Research’s peer-reviewed journal Molecular Medicine. The award will be given at the New York Academy of Sciences in Manhattan, followed by scientific presentations by Dr. O’Shea and other prominent researchers.
- On June 19, 2014, the NIH will hold a symposium to commemorate 10 years of achievement by the NIH Common Fund (which is used for trans-NIH activities). Dr. Katz will be participating at the meeting and helping to lead a session titled "Re-Engineering the Clinical Research Enterprise."
Council member Dr. Ted Mala, Director of the Traditional Healing Clinic at the South Central Foundation, asked whether Kayla (the young girl with NOMID featured in the video presented by Dr. Katz) needs to take medicine to treat her disease throughout her life. Dr. Katz indicated that the medicine anakinra is administered subcutaneously to Kayla every day. The drug was previously approved for the treatment of RA (although was not found to be very effective for RA). A similar anti IL-1 receptor drug, rilonacept, has been approved in Europe but not yet in America. Rilonacept is less painful to administer and can be administered less frequently.
Dr. Koretzky noted that there have been discussions throughout the extramural research community regarding whether NIH’s review and funding process is most appropriate (i.e., with a focus on projects rather than the investigators themselves). He asked whether NIH leadership has considered re-examining the approach for evaluating the productivity of investigators and their future potential. Dr. Katz explained that with the exception of training, the NIH is mandated to support research projects, and whatever it funds must fall under the umbrella of projects or programs. Council member Dr. Xiao-Jing Wang, Professor in the Department of Pathology at the University of Colorado, Denver, asked why work done by the Intramural Research Program does not necessarily have to fall under the umbrella of projects or programs and instead is funded based primarily on the investigators. She also asked if the productivity of extramural researchers could play more of a factor in terms of funding decisions made by the NIH. Dr. Katz reminded the group that the productivity of the investigators is always a component of the review (whether it is for proposed intramural or extramural research initiatives). Within the IRP, the investigators’ productivity generally does play a more prominent role, but there is still a programmatic focus.
DEVELOPING A STRATEGIC PLAN FOR PREVENTION RESEARCH AT NIH
Dr. Murray explained that the ODP recently finalized its Strategic Plan. Created in 1986, the ODP falls under the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI) within the NIH Office of the Director. He explained that from ODP’s perspective, prevention research encompasses both primary and secondary prevention. It includes research designed to promote health; prevent onset of disease, disorders, conditions, or injuries; and detect and prevent the progression of asymptomatic disease. Prevention research targets biology, behavior, factors in the social and physical environments, and health services. It informs and evaluates health-related policies and regulations.
ODP’s mission is to improve the public health by increasing the scope, quality, dissemination, and impact of prevention research supported by the NIH. ODP fulfills this mission by providing leadership for the development, coordination, and implementation of prevention research in collaboration with NIH ICs and other partners. ODP’s vision is that by 2018, it will extend its value as a resource to the NIH and the broader prevention research community, providing guidance in prevention research methodology, identifying gaps in existing evidence and facilitating the coordination of new activities to address those gaps, promoting quality improvements in the review of prevention research, and increasing the impact and visibility of prevention research. Building on this foundation, the ODP sought input from key stakeholders to refine its draft strategic priorities and to develop measurable objectives, activities, and timelines for each priority. The ODP organized the input around the draft strategic priorities. Subsequently, teams recommended refinements to the priorities and candidate objectives, tasks, benchmarks, and timelines.
ODP’s Strategic Plan was approved in January 2014 by NIH Director Dr. Francis Collins and includes 6 strategic priorities:
- Strategic Priority I: Systematically monitor NIH investments in prevention research and assess the progress and results of that research.
- Strategic Priority II: Identify prevention research areas for investment or expanded effort by the NIH.
- Strategic Priority III: Promote the use of the best available methods in prevention research and support the development of better methods.
- Strategic Priority IV: Promote collaborative prevention research projects and facilitate coordination of such projects across the NIH and with other public and private entities.
- Strategic Priority V: Identify and promote the use of effective evidence-based interventions.
- Strategic Priority VI: Increase the visibility of prevention research at the NIH and across the country.
Dr. Murray concluded his presentation by noting that ODP’s Strategic Plan can be reviewed online at http://prevention.nih.gov/aboutus/strategic_plan/default.aspx.
In response to a question from Dr. Carter, Dr. Murray noted that the design and analysis of group randomized trials is a strong interest of his and that he has used this expertise to help inform the progress of the NIH Collaboratory, particularly with respect to comparative effectiveness research. Five of the seven funded NIH Collaboratory projects are group randomized trials; Dr. Murray has helped these investigators fully understand the nuances and details related to these types of studies, which are widely used in prevention research. He has also worked with PCORI leadership regarding the development of materials for group randomized trials.
Dr. Mala asked about the relationship between the ODP and the Office of the Surgeon General’s National Prevention Council. Dr. Murray explained that the ODP is involved in the development of a national prevention strategy and serves as one of the NIH liaison groups to the National Prevention Council. The ODP works more closely with the Office of Disease Prevention and Health Promotion, which is a sister office to the Office of the Surgeon General and the Office of the Assistant Secretary for Health.
INTRAMURAL RESEARCH PROGRAM — LONG-RANGE PLAN
Dr. Katz explained that each NIH IC was charged by NIH Director Dr. Francis Collins with providing a vision for what the IRP will look like in 10 years, with a focus on current scientific opportunities, unique capabilities of the IRP, and how best to integrate the IRP and the NIH Clinical Center. He reminded Council members that in general across the NIH, 10% of ICs’ budgets are spent on the IRP. The NIAMS formed an IRP Long-Range Planning (IRP-LRP) Committee, Co-Chaired by Drs. Katz, Koretzky, and O’Shea. Committee members include intramural and extramural scientists representing the broad areas of NIAMS interest, NIAMS leadership, and IRP staff from other NIH ICs.
In March of this year, the NIAMS IRP-LRP Committee began its deliberations, with a report to be submitted to NIH Deputy Director for Intramural Research Dr. Michael Gottesman and NIH Principal Deputy Director Dr. Larry Tabak by July 31. Dr. Koretzky noted that there was significant input from both extramural and intramural communities that helped guide the work of the NIAMS IRP-LRP Committee. He asked his fellow Council members for additional input. He described the Committee’s approach. The Committee held an in-person meeting in April and developed a number of preliminary conclusions.
IC reports will be reviewed and merged into a single report by an ad hoc group of IC Directors in August. The final trans-NIH report will be submitted to a subcommittee of the Advisory Committee to the NIH Director (ACD) in September; the resulting draft ACD report will be submitted to Dr. Collins by the end of October this year. Dr. Koretzky concluded his remarks by expressing hope that the Committee will have completed its work and be able to present its final recommendations at an upcoming NAMSAC meeting.
Dr. O’Shea explained that concurrent with the work of the NIAMS IRP-LRP Committee, the Institute’s IRP faculty met to describe their respective visions of the IRP’s future. A number of useful themes emerged through these discussions that will also help guide the future direction of the NIAMS IRP.
Council member Dr. Lynda Bonewald, Lefkowitz Professor in the Department of Oral Biology at the University of Missouri-Kansas City School of Dentistry, suggested that the IRP-LRP Committee pay particular attention to projecting what NIAMS’ stakeholder community will look like in the future and assessing how the Institute can meet its needs moving forward. She noted that the prevalence of musculoskeletal diseases—already one of the costliest disease groups in the United States—will be increasing in the future. She also noted the importance of training in this area and expressed concern that without an increased emphasis in musculoskeletal diseases, the NIAMS IRP will not be responding to one of its core areas of interest moving forward.
Council member Dr. Sherine Gabriel, Dean of the Mayo Medical School, William J. and Charles H. Mayo Professor, and Professor of Medicine and Epidemiology at the Mayo Clinic, characterized the work of the NIAMS IRP-LRP Committee as a well-timed and outstanding effort. She asked for additional information regarding how training activities through the IRP differ from other NIH IC training efforts. Dr. Koretzky noted that historically, the NIH has been a place that has uniquely trained physician scientists. The NIAMS IRP-LRP Committee has discussed the possibility of collaborating with extramural institutions under an agreement whereby individuals are trained as clinicians locally at their extramural institutions and then come to the NIH for intensive scientific training. Other new models of training may be explored as well. Dr. Katz suggested that a future Council meeting include a presentation on the NIAMS’ internal scholars and fellowship programs. He also noted that although the NIAMS IRP should not attempt to cover the entire breadth of the Institute’s mission, it should address areas of importance that are not covered by a critical mass of researchers elsewhere. In response to Dr. Bonewald’s concerns regarding musculoskeletal diseases, Dr. Katz noted that there are strong bone biology and bone disease programs across the country, but there is a certain subset of musculoskeletal diseases that are not covered—focusing on this subset of diseases represents a significant opportunity for the NIAMS IRP.
Council member Dr. Gary Firestein, Professor in the Department of Medicine at the University of California, San Diego School of Medicine, suggested that the NIAMS IRP-LRP Committee consider exploring a few additional topics, including how informatics are organized within the NIAMS and expanding cross-disciplinary interactions beyond just disease groups and involving engineering and other disciplines. Dr. Koretzky noted that both of these topics were discussed at length during the Committee’s April face-to-face meeting. He suggested that there is some degree of “siloing” of information and infrastructure among NIH IRPs. There are a number of trans-NIH initiatives and other opportunities for creating economies of scale and informing the activities of ICs across the NIH. He noted that the Committee has encouraged Dr. O’Shea to reach out to IRP Scientific Directors and meet on a regular basis to strategically plan how best to leverage each others’ strengths and identify where expertise and infrastructure should reside.
Mr. Alex Silver, Chairman of the Jackson Gabriel Silver Foundation and a member of the Council, expressed strong support for the NIH IRP, explaining that it represents the single largest source of capital to address unmet medical needs. He indicated that foundations are being asked to reduce the level of risk associated with research to the point where commercial parties can become involved. From the rare disease perspective, there has been a shift in how research is funded such that foundations are now directly funding research (as opposed to the funding coming from universities and corporations).
Council member Dr. Christy Sandborg, Professor of Pediatrics at Stanford University, asked about the process that identifies and selects clinical areas to be pursued by the NIAMS IRP. Dr. O’Shea explained that the Institute looks for areas of scientific opportunity and strives to recruit experts who have expertise that is complementary to that which already exists within the NIAMS. He suggested that in the next 10 years, the NIAMS will likely focus more on RNA rather than just protein-coding genes, and likely will need to recruit expertise in this area. In general, the NIAMS looks to have basic science complementing the clinical science, and likewise the clinical work providing an opportunity for the basic scientists to translate their ideas.
Dr. Wang expressed support for the Committee’s recommendation to enhance intramural and extramural collaborations and asked how this might occur moving forward. Dr. Katz noted that the extramural research community has been enriched by being able to send patients and materials to the NIH for study and pointed to the work of Dr. Goldbach-Mansky as an example.
NIAMS 2nd ANNNUAL FORUM FOR CLINICAL MENTORED K AWARDEES
Dr. Mancini reminded Council members that the K08 and K23 awards are intended for individuals with clinical doctorate degrees (usually, but not always, M.D. degrees). The K08 supports those conducting research in a more basic translational manner while the K23 is specifically for mentored patient-oriented research careers. She defined patient-oriented research as research using human subjects or samples from human subjects in which the Principal Investigator (PI) has direct contact with the humans. The purpose of these awards is to provide support for a sustained period of protected time (3-5 years) for intensive research career development under the guidance of an experienced mentor or sponsor in the biomedical, behavioral, or clinical sciences leading to research independence. These awards require a 75% time commitment (50% for surgeons).
Dr. Mancini presented some additional background information and the results of an institute analysis of NIAMS K08 and K23 awardees from FY2001-2006. For this cohort, the average time from start of K award to receipt of R01 award was 5 years. No differences were observed between K awardees with M.D. degrees compared with those who have both M.D. and Ph.D. degrees. However, it was noted that the R01 success rate was higher for K08 awardees than it was for K23 awardees, and NIAMS staff are examining potential causes for this discrepancy. Dr. Mancini also presented data on the number of K awardees from this cohort who successfully received a subsequent R01 award based on disease area. K awardees working in the area of skin were most successful (60%), followed by rheumatology (35%) and musculoskeletal (15%).
Based on these and other data gathered in recent years, the NIAMS sponsored its first Annual Forum for Clinical Mentored K Awardees in December 2012. A second Forum was held in December 2013. The goals of the Forum were to: (1) discuss the challenges junior clinician-scientist investigators face in pursuing research independence, (2) provide networking opportunities for K awardees, (3) promote interactions with NIAMS extramural staff and leadership, and (4) enhance the Institute’s support of early stage clinician-scientists. Prior to the Forum, participants were asked to provide feedback regarding the obstacles facing clinician-scientists. Current K awardees were also asked to provide input on the challenges they see with regard to accessing NIH or university research resources. All Forum participants were also asked to address what the NIAMS, as well as the broader medical/scientific community, can do to: (1) help support the progression to independent clinician-scientist careers, and (2) encourage leveraging opportunities with industry and other federal partners.
The Second Annual Forum for Clinical Mentored K Awardees included third year K08 and K23 awardees, recent clinical mentored K award recipients who now have independent research careers, established investigators/mentors, and representatives from professional/voluntary organizations (including the American Society for Bone and Mineral Research, Orthopaedic Research Society, Rheumatology Research Foundation, and American College of Rheumatology [ACR]). The Forum featured an overview of K awardees’ research; breakout sessions that allowed for close interactions with NIAMS Grants Management staff, NIAMS Scientific Review Group members, Program Directors, and clinical staff; and group discussions on two large topics (how to make the most out of a K career development award and planning a successful transition to an R01). Dr. Mancini discussed a number of key messages that have been identified through the Forum:
- K awardees would benefit from an informational session(s) early in their award to discuss policy, other award options, etc. Dr. Mancini noted that on February 27, 2014, the NIAMS hosted its Orientation to Your Mentored Clinical K Award Webinar for first- and second-year mentored clinical K awardees and their mentors. The 2.5-hour webinar set the stage for awardees to establish a relationship with the NIH/NIAMS and featured a description of NIAMS extramural staff roles, a review of the main rules and policies of the award, and an opportunity for awardees to start networking with each other. A total of 51 individuals participated in the webinar.
- The Forum highlighted the importance and roles of mentors as well as the value of the mentoring team approach.
- The gap between K award "capped" salary and actual salary is a problem.
- Organizations committed to supporting research career development should consider a type of K award supplement and/or bridge funding. Some foundations are instituting these (e.g., ACR’s Rheumatology Research Foundation and the Orthopaedic Research and Education Foundation).
- Increased interactions among the NIAMS, K awardees, and mentors may provide needed encouragement and impetus.
Dr. Mancini concluded her remarks by indicating that the Third Annual Forum for Clinical Mentored K Awardees is scheduled for December 4-5, 2014. The NIAMS will also continue the Orientation to Your Mentored Clinical K Award Webinar for first-year K awardees.
Dr. Katz asked about the participants in the February 27, 2014, Orientation to Your Mentored Clinical K Award Webinar for first- and second-year mentored clinical K awardees and their mentors. Dr. Mancini reported that 13 of 18 invited first-year K awardees participated, as did 7 of 18 invited second-year K awardees. A total of 28 NIAMS staff participated. Of some concern, only 3 of 37 invited mentors participated in the webinar.
Dr. Koretzky asked if the NIAMS has looked at R01 renewal trends for K awardees. Dr. Mancini noted that she has not examined these data for this cohort of K awardees. Dr. Koretzky suggested that these trends may provide additional insight regarding why K awardees were or were not successful in obtaining an R01 renewal. He also asked about whether the NIAMS has considered some type of support for mentors, suggesting that if some small reward was included, it may incentivize some mentors to be more actively engaged. Dr. Katz noted that apart from the K24 award, which is specifically designed for mentors, there is no current mechanism for supporting mentors.
Dr. Bonewald commented that it would be interesting to know at what age K awardees who successfully receive an R01 award do so. She expressed concern that only 15% of K awardees focusing on musculoskeletal diseases are receiving R01s and suggested that mentors also be invited to attend the Annual Forum for Clinical Mentored K Awardees. Dr. Katz noted that the number of NIAMS K awardees focusing on musculoskeletal diseases who are applying for and receiving subsequent R01 awards is increasing. Dr. Mancini indicated that it appears that the vast majority of K awardees focusing on musculoskeletal diseases who either did not apply for an R01 or who applied and did not receive an R01 are still involved in the research enterprise in some fashion.
Council member Dr. Elizabeth Shane, Professor of Medicine and Vice Chair for Clinical and Epidemiological Research at Columbia University College of Physicians and Surgeons, asked if mentors could view the Orientation to Your Mentored Clinical K Award Webinar at different times other than when it was initially held. If so, this could increase the number of mentors who participate. Dr. McGowan explained that the Webinar is interactive and that participation in real time is preferred. The NIAMS is considering scheduling telephone calls with individual K awardees when they first receive their award, their mentor, and a NIAMS Program Director to help orient the awardees and their mentors. Dr. Shane expressed support for this suggestion.
Dr. Firestein suggested that the Institute consider funding sources in addition to R01 awards as metrics of K awardee success (e.g., some clinical investigators may be conducting commercially sponsored clinical trials). He also expressed concern about the capped salary and the fact that in rheumatology, an estimated 60-70% of trainees are women. Salary and gender disparities may be embedded into the system in this cohort of young investigators who are likely in the single digits percentile using the Association of American Medical Colleges scale. Dr. Katz noted that the dollar amount of the K award could be increased, but it would result in a lower success rate. This topic may be discussed at a future Council meeting.
ACCELERATING MEDICINES PARTNERSHIP
Dr. Carter explained that the AMP arose in light of the fact that the process associated with developing new medicines takes too long, costs too much, and fails too often. Despite recent advances in biomedical technologies, fewer new drugs are coming to market. Many late failures are due to non-efficacy. A new approach is needed to target the pathways that are critical to disease progression and potentially prevent late-stage efficacy failures.
In February of this year, NIH Director Dr. Francis Collins launched the AMP, which aims to distinguish targets of disease most likely to respond to new therapies. Partners have developed research plans and are sharing costs, expertise, and resources through an integrated governance structure that enables best-informed contributions from all participants. The NIH, industry, and non-profit organizations will invest a total of $230 million over the next 5 years on the following three pilot projects: (1) Alzheimer’s disease (led by the NIA), (2) type 2 diabetes (led by the National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]), and (3) RA/systemic lupus erythematosus (led by the NIAMS and the National Institute of Allergy and Infectious Diseases [NIAID]).
Dr. Carter noted that although the clinical picture has improved for both RA and lupus, there are still significant unmet needs (e.g., many patients respond only partially or not at all to treatment; there is a poor understanding of who to treat, when, and with what; and for some patients, there are still no therapies). Even though much is known about the cells and proteins that make up the immune system, little is known about the activation/damage in the tissues of humans or about the overall interaction between the immune system and the tissue cells in these diseases. The RA/lupus AMP partners will seek to understand what is happening in the tissues, what is happening at the individual cell level, and how is the immune system interacting with tissue cells leading to the pathways that cause disease. There are six industry RA/lupus AMP partners: AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Sanofi, and Takeda. Similarly, there are six non-profit RA/lupus AMP partners: Lupus Foundation of America, Alliance for Lupus Research, Lupus Research Institute, Rheumatology Research Foundation, Arthritis Foundation, and FNIH.
The first phase of this initiative will involve developing standardized methods of applying single-cell and other technologies to tissues and prove that models work (year 1). The second phase involves the development of disease-specific expression profiles of tissue cells (year 2). The final phase will involve stratifying patients by molecular mechanism based on the tissue and blood analyses (years 3-5). Dr. Carter described the AMP RA/lupus network structure and governance, noting that through the AMP, it is hoped to identify key regulators of disease progression, shared and disease-specific biological pathways, and a model for developing a systems-level understanding of disease. He also explained that industry and advocacy groups may be able to provide additional input into the process by participating in a Council working group, although the exact mechanism for doing so has not yet been fully developed. Dr. Carter concluded his remarks by outlining the AMP RA/lupus timeline. RFAs were posted in March of this year; applications were due on May 21. In late July/early August, proposed projects will be reviewed and summary statements will be reviewed in late August/early September. It is expected that the earliest projects will be funded by late September this year.
Dr. Koretzky asked how intellectual property issues will be addressed through the AMP. Dr. Carter indicated that these issues will be negotiated with the institutions at the time of award. Any data generated through funding by this mechanism will be in the public domain. However, it may be possible for an institution to take the publicly available information it developed through this project and create intellectual property (e.g., a biomarker) that would have commercial value. Dr. Katz indicated that NIH’s experience with other public-private partnerships (e.g., the OAI) will help inform discussions.
Dr. Gabriel asked how the AMP will be different from other previous attempts at accelerating the drug development process. Dr. Carter explained that the AMP as related to RA and lupus will be focusing on pathways that are active in the tissues, which is a departure from previous attempts. Dr. Firestein added that in the past, tissues and blood samples from very well phenotyped patients collected in a quality controlled manner suitable for "-omics" experiments were not available. Their availability today will lead to the generation of large amounts of data and is a significant departure from traditional drug development scenarios.
UPDATE ON NIAMS LONG-RANGE PLAN FY 2015-2019
Ms. Linde reminded the group that the NIAMS Long-Range Plan for FY 2015-2019 is meant to be a broad scientific outline designed to inform the Institute’s priority-setting process while enabling it to adapt to the rapidly changing biomedical and behavioral science landscapes, particularly in terms of encouraging the most promising investigator-initiated research ideas. Roughly 1 week before this NAMSAC meeting, Council members were provided a draft of the Plan for review before it is made publicly available for broader input. The Plan is used to communicate the Institute’s perspective and to serve as a resource for all who are interested in NIAMS’ activities. Ms. Linde emphasized that the NIAMS does not use its Long-Range Plan as a prescriptive document and understands that the science will continue to evolve during the next 5 years covered by the Plan.
Ms. Linde briefly reviewed the Long-Range Plan’s development process, noting that the Plan was first introduced to the Council during its September 10, 2013, meeting. From October 2013 through January 2014, 68 responses were received through an RFI. On November 6, 2013, more than 40 professional and voluntary organization representatives were briefed during the NIAMS Coalition Day. Additional input was generated in December 2013 through half-day listening sessions involving members of NIAMS’ core communities. Ms. Linde noted that the independent investigators and professional society representatives who attended the December 2013 Second Annual Forum for Clinical Mentored K Awardees also had an opportunity to discuss the Long-Range Plan with Institute leadership. Council members were again briefed on the Long-Range Plan at the February 11, 2014, NAMSAC meeting. The NIAMS will be soliciting more comments through an additional RFI in June-July of this year, and will be presenting the draft Long-Range Plan to the NIAMS Coalition in July. The final version of the Long-Range Plan will be presented to the Council at its September 8, 2014, meeting.
As with the previous Long-Range Plan, the Plan for FY 2015-2019 is organized around a series of disease- and tissue-specific topics (arthritis and rheumatic diseases, skin biology and diseases, bone biology and diseases, muscle biology and diseases, and musculoskeletal biology and diseases) as well as cross-cutting topics (health disparities, training and career development, and information dissemination). Ms. Linde commented that the input that the Institute receives in developing its Long-Range Plan help shapes NIAMS’ thinking regarding potential initiatives, partnerships, and select pay decisions. It is a critically important vehicle for the Institute to communicate with its constituency groups regarding its core interest areas and most promising scientific opportunities in the coming years.
Dr. McGowan acknowledged the efforts of the NIAMS Program Directors who helped shape the Long-Range Plan. She noted that the Long-Range Plan will drive the Institute’s strategic thinking over the next 5 years. It does not encompass all of NIAMS’ activities, but rather is a high-level summary of where it sees the science and its mission areas moving. Dr. Katz agreed, noting that Council members’ input will be incorporated into the next draft of the Institute’s Long-Range Plan.
Dr. Serrate-Sztein discussed the Institute’s steps for promoting funding stability and flexibility in research, which is an NIH-wide goal and was included as a discussion topic during the April 29, 2014 NIAMS Scientific Retreat. She noted that the Retreat focused entirely on science management issues this year. The NIH is working to provide flexible funding in an attempt to encourage investigators to try high-risk ideas and bring more innovative approaches to the currently funded portfolios. It is examining current and new funding mechanisms to provide this flexible funding. Examples of possible directions the NIH might take include extending funding periods to provide stability for investigators to engage in innovative, high-risk research as well as giving a greater emphasis to an investigator’s history of accomplishments during application review. NIH ICs will be given flexibility to implement whatever approaches their leadership feels will be most appropriate for their research communities.
At the NIAMS, the initial focus within the context of flexible funding is on early established investigators, or EEIs, defined as those who have renewed their first R01 (Type 2) application in the current fiscal year. The NIAMS is proposing to provide supplemental funding to EEIs through a new mechanism, the Supplements To Advance Research from Projects to Programs (STAR) Award. This supplemental award program is modeled after the MERIT award and will support activities that effectively allow EEIs to transition from a single, structured research project to multiple related projects with interconnected goals but with clearly distinct approaches and areas of focus. STAR awards would allow EEIs to explore new areas and high-risk ideas, expand and improve laboratory capacity, accelerate resource-intensive projects, mentor junior scientists, and have some degree of funding stability.
The Institute is proposing that the STAR award eligible cohort begin with PIs who received their first R01 in 2009 (this is when the NIH adopted its standard definition of a “new investigator”). The Type 2 R01 award must be the only NIH source of support (i.e., the EEI must be the PI), and the supplement must be activated in the second or third year of their renewed R01. Dr. Serrate-Sztein described options and considerations that the NIAMS might use to identify potential candidates and make STAR awards. Dr. Serrate-Sztein invited Council members to provide input on the proposed STAR Award, particularly with regard to eligibility criteria, funding levels, length of award, contents of the nomination essay, and program evaluation criteria. The details will be presented to the full Council at a future meeting.
Dr. Katz noted that the proposed STAR Award resulted from lengthy discussions among program staff and that a number of alternatives were considered (e.g., expanding the MERIT Award Program, supplementing or extending existing awards, etc.). He estimated that 5-7 individuals would be eligible for the STAR Award on an annual basis and underscored the fact that this proposed mechanism reflects the Institute’s commitment to flexibility, innovation, and stability. Council member Dr. Alice Pentland, James H. Sterner Professor and Chair in the Department of Dermatology at the University of Rochester School of Medicine and Dentistry, indicated that the NIAMS has targeted a talent pool that likely will provide innovation. The EEIs have enough of a track record to demonstrate productivity and supplementing their work would be an appropriate use of NIAMS resources.
Dr. Koretzky asked about the STAR Award eligibility criteria and whether a first percentile renewal would fare better than a 12th percentile renewal. Dr. Serrate-Sztein explained that anyone who received a Type 2 R01 would be eligible regardless of percentile.
Dr. Katz explained that out of the pool of EEIs beginning in 2004-2006, there were 81 such individuals. Of that pool 14 have Type 2 awards from their original R01. The idea behind the STAR Award is to provide these individuals with an opportunity to enhance and expand their work without having to apply for another R01.
Dr. Bonewald expressed some concern that the NIAMS may be restricting itself and missing an opportunity to supplement creative, productive researchers who already have their third R01 awards. Dr. Katz acknowledged that the Institute is intentionally restricting itself. By limiting eligible individuals using the criteria described by Dr. Serrate-Sztein, the Institute can readily estimate the approximate costs associated with the STAR Award Program and factor those costs into its budget. He reminded Council members that they will have significant input on the review and selection of STAR awardees.
Dr. Eyre asked if the STAR awards could be linked to some mechanism of matching funds from the EEI’s home institution and whether the award could be used for equipment. Dr. Katz indicated that matching funds may be a possibility, and that the award could be used for equipment. Council member Dr. Katherine Mathews, Professor in the Departments of Pediatrics and Neurology at the University of Iowa, expressed support for the concept of using this type of supplemental funding to help transform a project into a program. She suggested that this topic be included as a focal point in the nominee’s essay (i.e., asking EEIs to describe how the STAR Award would help them develop their research project into a program).
Dr. Serrate-Sztein asked Council members to submit any additional comments they have regarding the STAR Award after this NAMSAC meeting.
CONSIDERATION OF APPLICATIONS
In closed session, the Council reviewed a total of 761 applications requesting $812,128,121 in total costs and recommended 761 for $812,128,121 in total costs.
This portion of the meeting occurred during closed session.
FEDERAL COLLABORATION ON TISSUE ENGINEERING AND REGENERATIVE MEDICINE
This portion of the meeting occurred during closed session.
The 83rd National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Meeting was adjourned at 2:15 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.
Laura K. Moen, Ph.D.
Stephen I. Katz, M.D., Ph.D.