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Advisory Council Minutes
October 24, 2013
Department of Health and Human Services
Public Health Service
National Arthritis and Musculoskeletal and Skin Diseases Advisory Council
Minutes of the 80th Meeting
June 4, 2013
8:30 a.m. to 2:30 p.m.
CALL TO ORDER
The 80th meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council (NAMSAC) was held on June 4, 2013, at the National Institutes of Health (NIH) Campus, Building 31, Conference Room 6. The meeting was co-chaired by Dr. Stephen I. Katz, Director and Dr. Robert Carter, Deputy Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Council members present
Dr. Lynda F. Bonewald
Dr. Harry C. Dietz
Dr. David R. Eyre
Dr. Gary S. Firestein
Dr. Sherine E. Gabriel (via teleconference)
Ms. Michelle Hofhine
Dr. Ted Mala
Dr. Katherine Mathews
Dr. Martha M. Murray
Dr. Regis J. O’Keefe
Dr. Alice P. Pentland
Ms. Jean R. Pickford
Dr. E. Anthony Rankin
Dr. Elizabeth Shane
Ms. Elizabeth Smith
Mr. Bradley R. Stephenson
Dr. Julio L. Vergara
Dr. Xiao-Jing Wang
Staff and Guests
Mr. Steven Austin
Dr. Carl Baker
Ms. Pam Beheler
Ms. Susan Bettendorf
Ms. Elizabeth Bouras
Dr. Amanda Boyce
Mr. Gahan Breithaupt
Ms. Justine Buschman
Dr. Robert Carter
Mr. Kevin Cheezum
Dr. Faye Chen
Dr. Ricardo Cibotti
Mr. Richard Clark
Ms. Stephanie Craver
Ms. Alison Davis
Ms. Robin DiLiello
Ms. Theresa Do
Dr. Jonelle Drugan
Mr. Erik Edgerton
Ms. Elizabeth Elliott
Ms. Barbara Footer
Ms. Gerda Gallop-Goodman
Dr. Nancy Garrick
Ms. Gail Hamilton
Ms. Katie Joffee
Mr. Andrew Jones
Dr. Stephen I. Katz
Ms. Mary Beth Kester
Ms. Shahnaz Khan
Ms. Stephanie Kreider
Ms. Colleen Labbe
Mr. Mark Langer
Dr. Gayle Lester
Dr. Helen Lin
Ms. Anita Linde
Ms. Leslie Littlejohn
Dr. Kan Ma
Dr. Su-Yau Mao
Dr. Marie Mancini
Dr. Kathryn Marron
Dr. Joan McGowan
Ms. Leslie McIntire
Dr. Laura K. Moen
Ms. Clairisse Mullsteff
Ms. Anna Nicholson
Dr. Glen Nuckolls
Dr. James Panagis
Ms. Vivian Pham
Dr. Charles Rafferty
Ms. Trish Reynolds
Ms. Kathy Salaita
Dr. Susana Serrate-Sztein
Dr. William Sharrock
Ms. Sheila Simmons
Ms. Theresa Smith
Ms. Allisen Stewart
Ms. Robyn Strachan
Ms. Yen Thach
Dr. Hung Tseng
Dr. Antonella Nadia Tullio
Dr. Bernadette Tyree
Dr. Robert Walker
Dr. Fei Wang
Dr. Xibin Wang
Dr. Yan Wang
Dr. Chuck Washabaugh
Ms. Sara Rosario Wilson
Dr. James Witter
Dr. Xincheng Zheng
Dr. Andrea Baruchin, Foundation for the National Institutes of Health
Mr. Michael Bykowski, Consolidated Solutions and Innovations
Mr. Dane Christiansen, Health and Medicine Council of Washington
Ms. Sarah D’Orsie, America Academy of Physical Medicine and Rehabilitation
Ms. Ann Elderkin, American Society for Bone and Mineral Research
Dr. Maria Freire, Foundation for the National Institutes of Health
Ms. Patti Brandt Hansberger, Office of Legislative Policy and Analysis, NIH
Dr. V. Michael Holers, University of Colorado, Denver (via teleconference)
Ms. Leah Howard, National Psoriasis Foundation
Ms. Judith Mun, American Association of Colleges of Osteopathic Medicine
Dr. Richard Nakamura, Center for Scientific Review, NIH
Mr. Richie Taffet, Ehlers-Danlos National Foundation
Dr. Maria Vassileva, Foundation for the National Institutes of Health
Dr. Shimere Williams, Lewis-Burke Associates
CONSIDERATION OF MINUTES
A motion was made, seconded, and passed to accept with no changes the minutes of the 79th NAMSAC meeting, held on February 5, 2013.
FUTURE COUNCIL MEETING DATES
Future Council meetings are currently planned for the following dates:
September 10, 2013
February 11, 2014
June 3, 2014
September 8, 2014
February 4, 2015
June 16, 2015
September 8, 2015
ACTING DIRECTOR'S REPORT AND DISCUSSION
Dr. Katz thanked NIAMS Deputy Director Dr. Robert Carter, who had served as the Institute’s Acting Director while Dr. Katz was out on extended medical leave. Due to his recent absence in the weeks leading up to this meeting, Dr. Katz informed the Council that Dr. Carter would present the Acting Director’s Report.
Dr. Carter reminded the Council that these meetings serve two general purposes: (1) conveying information on NIAMS and NIH activities to the community, and (2) obtaining expert advice and guidance from Council members.
Personnel Changes at the NIAMS
Dr. Carter reported that Dr. Charles Rafferty has announced his intention to step down from his position as Chief of the Scientific Review Branch. Dr. Rafferty joined the NIAMS in 2009, and immediately became involved in review activities related to the American Recovery and Reinvestment Act (ARRA). Dr. Rafferty also led the Branch when the Institute was establishing its new Clinical Trials Standing Study Section. Dr. Carter acknowledged and thanked Dr. Rafferty for his efforts and noted that he has agreed to stay on for an interim period. Dr. Kathy Salaita has joined the Institute as the new Chief of the NIAMS Scientific Review Branch. She comes to the NIAMS from NIH’s Center for Scientific Review (CSR), where she held positions as a Referral Officer and as Acting Chief for the Healthcare Delivery and Methodology Integrated Review Group.
Update on NIH and NIAMS Activities
The NIH is taking formal steps to better quantify the value of biomedical research, not just from an economic standpoint, but also with an eye towards health benefits. NIH Director Dr. Francis Collins has charged the NIH Scientific Management Review Board (SMRB) with developing parameters and approaches for assessing and communicating the value of the work supported by the NIH, particularly in terms of improved health outcomes. Dr. Katz is a member of the SMRB’s Value of Biomedical Research Working Group. The SMRB will be addressing the challenges associated with directly connecting research dollars with tangible health outcomes and defining NIH’s contribution. More on this topic may be presented at future Council meetings.
Dr. Carter informed the Council that the SMRB’s Small Business Innovation Research and Small Business Technology Transfer (SBIR/STTR) Working Group issued preliminary recommendations about better ways for the NIH to leverage its SBIR/STTR programs. The Working Group determined that NIH’s SBIR/STTR programs are meeting their statutory objectives and are considered an asset. The group also suggested improvements to the program in terms of speeding up the application and funding process, emphasizing commercialization, and strengthening trans-NIH communication and collaborative efforts.
At the last Council meeting, Dr. Sally Rockey, NIH Deputy Director for Extramural Research, described some of NIH’s activities to address the future biomedical research workforce. Since then, the NIH has solicited grant applications for a handful of new programs. These include activities to interest undergraduate students from underrepresented backgrounds in research and enhance the training experiences of graduate students and fellows. The solicitations have closed, but Dr. Carter brought them to the Council’s attention because of the importance the NIAMS places on the training and workforce component of its mission. The Institute featured these solicitations in last month’s update to the professional societies, advocacy groups, and members of the research community. Additional information is available on the NIAMS Web site.
Highlights of Selected Recent Scientific Advances
- People complaining of knee pain often have symptoms of a torn meniscus in addition to the cartilage and bone changes that are associated with osteoarthritis. They have several treatment options, including having the torn part of the meniscus removed surgically before beginning physical therapy. They also can opt for physical therapy without an operation. Dr. Jeff Katz’s multisite, randomized controlled clinical trial, Meniscal Tear in Osteoarthritis Research (MeTeOR), recently reported that about two-thirds of the 350 enrolled participants with knee OA and symptomatic meniscal tears fared equally well 12 months after enrolling in the study, regardless of whether they had surgery first or they started physical therapy and avoided surgery altogether. Those participants who interrupted their initial round of physical therapy to have surgery because their symptoms were persisting or worsening, also improved during the study period. The results imply that surgery may provide more immediate relief (i.e., in the 3-6 month timeframe), but that physical therapy is also acceptable as the initial choice for some patients. If symptoms persist or worsen, surgery remains an option, as it was shown to be effective with few adverse events for many who were not responding well to physical therapy. Researchers are continuing to monitor MeTeOR Trial participants to answer the question of whether surgical removal of the meniscus puts patients at risk of more rapid progression of OA (N Engl J Med. 2013 Mar 18. [Epub ahead of print.] PMID: 23002201). Dr. Carter indicated that this work presents a major advance in understanding the options available to OA patients with meniscal symptoms. Council member Dr. Martha Murray, Associate Professor of Orthopaedic Surgery at Harvard Medical School, noted that this study did not stratify patients who felt disabled because of their meniscal tear. She commented that for those patients who are unable to walk or work due to the pain from their tear, physical therapy likely is not an option. Treatment should be based on each individual patient’s symptoms. Council member Dr. E. Anthony Rankin, Chief of Orthopaedic Surgery at Providence Hospital and Clinical Professor of Orthopaedic Surgery at Howard University, noted that patients need to be educated about their treatment options and expected outcomes.
- Research supported by two NIH Director’s Pioneer Awards is contributing to new insights into the role the immune system plays in skeletal muscle regeneration after injury. Repair and regeneration of muscle, as for other tissues, requires an influx of immune cells to remove debris. In muscle, the immune response also stimulates replacement of the lost muscle fibers. While previous studies have supported a model in which macrophages engulf debris and communicate with muscle progenitor cells, this latest work by Drs. Ajay Chawla and Thomas Rando shows that other immune cells contribute to muscle regeneration. The new data indicate that when eosinophils infiltrate injured muscle, they secrete the cytokines IL-4 and IL-13. These signaling molecules target muscle tissue cells called fibroadipogenic progenitors (FAPs). Once stimulated by IL-4 and IL-13, the FAPs replace macrophages as the major cell type that engulfs debris from damaged cells—they also promote the division and maturation of muscle satellite cells. The FAPs cause adipocytes, or fat cells,to form in the absence of the cytokines. This appears to contribute to the fatty infiltration of muscles in children who have muscular dystrophies (Cell. 2013 Apr 11;153(2):376-88. doi: 10.1016/j.cell.2013.02.053. PMID: 23582327).
- Brown fat has long been pursued as a potential agent for combating obesity. As the insulating tissue that helps infants regulate their body temperature, increasing the amount of brown fat could greatly increase a person’s basal metabolic rate. This could lead to weight loss and the associated health benefits. Evidence is mounting that strategies to increase brown fat in adult animals may exist. This includes two recent papers from NIAMS-funded investigators. A research team led by Dr. Michael Rudnicki demonstrated that, contrary to past literature, muscle satellite cells can become brown fat through a process that involves regulation of a transcription factor by micro-RNA. The authors stimulated brown fat development after muscle injury by targeting the micro-RNA in satellite cells with antisense oligonucleotides. The oligonucleotide treatment also reduced the amount of weight that animals gained after muscle injury when they were fed a high-fat diet (Cell Metab. 2013 Feb 5;17(2):210-24. doi: 10.1016/j.cmet.2013.01.004. PMID: 23395168). Another group, led by Dr. Shihuan Kuang, showed that inhibiting the protein myostatin can stimulate the conversion of white fat to a darker, metabolically active tissue called beige fat without going through muscle satellite cells. While not true brown fat, beige fat resembles brown fat with its energy burning properties. Although the exact mechanism remains unclear, myostatin inhibition activates expression of the gene for irisin, via a well-characterized signaling pathway. Dr. Carter noted that a great deal of attention has been given to developing products that inhibit myostatin and to finding compounds that act as exercise "mimetic" by activating this pathway (FASEB J. 2013 Jan 29. [Epub ahead of print] PMID: 23362117).
- Dr. Rita Perlingeiro and colleagues recently published a strategy that may lead to cell-based therapies for people who have muscular dystrophy. The researchers: (1) harvested donor cells from young, dystrophic mice which lacked the protein dystrophin and a related protein, utrophin; (2) converted the cells into stem cells capable of forming many different tissues; (3) delivered the gene for a utrophin fragment, which will compensate for the disease-causing mutation in the mice; (4) caused the stem cells to become muscle progenitor cells; and (5) transplanted the cells back into dystrophic mice, where the cells engrafted into muscle and restored function. There was no indication that the transplanted cells would form tumors in the donor mice, which has been a previous concern of cell therapies derived from stem cells (Nat Commun. 2013 Mar 5;4:1549. doi: 10.1038/ncomms2550. PMID: 23462992). Dr. Carter commented that although this laborious process is a long way from being replicated in humans, it does represent an exciting proof of concept that can combine gene therapy with de-differentiated and reprogrammed cells to correct disease in vivo.
- Existing lupus therapies globally suppress the patient’s immune system, which leads to various side effects and complications. In theory, localized drug delivery to immune cells should alleviate some of these challenges. A multidisciplinary collaboration between NIAMS grantee Dr. Joe Craft of Yale’s Department of Immunobiology and Dr. Tarek Fahmy from the Yale Department of Chemical and Environmental Engineering designed and tested a nanogel formulation that could deliver the immunosuppressive drug mycophenolic acid to specific cells. They used a lupus-prone mouse model to show that the delivery approach led to the preferential accumulation of mycophenolic acid in dendritic cells, which are involved in the immune dysfunction, inflammation, and organ damage that characterize the disease. This new drug delivery method improved the survival by 3 months when given prophylactically to the animals before they developed symptoms, and by 2 months when given to mice that already had serious kidney damage. Although further studies are needed before this nanogel strategy can be tested in humans, this research provides a promising starting point for lupus treatments and could be applied more broadly to other autoimmune conditions (J Clin Invest. 2013 Mar 1. pii: 65907. doi: 10.1172/JCI65907. [Epub ahead of print] PMID: 23454752).
- NIAMS Intramural Research Program investigators in the laboratories of Drs. John O’Shea (NIAMS Scientific Director and Chief of the Molecular Immunology and Inflammation Branch), Juan Rivera (NIAMS Deputy Scientific Director), and Vittorio Sartorelli (Senior Investigator in the Laboratory of Muscle Stem Cells and Gene Regulation) collaborated with colleagues at the National Cancer Institute (NCI) to discover a connection among certain autoimmune diseases, including multiple sclerosis, asthma, Crohn’s disease, celiac disease, and type 1 diabetes. Genome-wide association studies had repeatedly shown minor alterations in or around the BACH2 gene in DNA from patients with diverse autoimmune disorders. In this latest paper, the investigators report that the transcription factor Bach2 regulates the differentiation of CD4+ T-cells of the immune system and prevents inflammatory disease by controlling the balance between tolerance and immunity (Nature. 2013 June 27; 498(7455):506-10. Doi: 10.1038/nature12199. [Epub ahead of print] PMID: 23728300 ). Dr. O’Shea noted that this work provided the opportunity for NIAMS intramural scientists to perform chromatin immunoprecipitation sequencing (ChIP-seq) analysis to examine the genome-wide effects of BACH2.
Update on Budget and Congressional Activities
Dr. Carter explained that the NIH is operating under the Consolidated and Further Continuing Appropriations Act of 2013 (which President Obama signed into law on March 26, 2013) as well as the sequestration provisions of the Balanced Budget and Emergency Deficit Control Act. Combined, this legislation provides $29.15 billion for the NIH in fiscal year (FY) 2013. This is approximately 5.5 percent less than the FY 2012 level. The funding level for the NIAMS is $505 million, which is a decrease of approximately 5.7 percent from the FY 2012 budget. Dr. Carter noted that roughly 85 percent of the Institute’s budget is allocated to extramural grants, about 5 percent is for administration, and 10 percent supports the Intramural Research Program. Of the 85 percent that funds extramural grants, 78 percent is used for Research Project Grants (RPGs), most of which are investigator-initiated studies. The remaining extramural dollars support Centers, career awards, training awards, and conference grants. The current funding plan is available on the NIAMS website.
Dr. Carter indicated that the NIAMS is keeping its paylines for competing R01 applications consistent with last year’s, including a slightly higher payline for new investigators
Although the budget landscape for FY 2014 is still uncertain, the President’s FY 2014 budget request clearly signals the Administration’s support for NIH-funded biomedical research. The President’s proposed budget comes close to restoring NIH’s previous operating level and includes a slight increase for the NIAMS over FY 2012.
On May 15, Dr. Collins and some NIH Institute and Center (IC) Directors testified at a Senate Subcommittee hearing on the President’s FY 2014 budget. In his testimony, Dr. Collins featured some of the Common Fund initiatives and trans-NIH activities, such as plans for managing “Big Data” and the FY 2014 Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Dr. Carter noted that the members who were present were knowledgeable and supportive of NIH’s mission. Dr. Carter pointed to the importance of raising awareness of how the NIH operates, how it makes decisions, and the value of its accomplishments so that they can be communicated to Congress.
In this regard, in April, 24 staffers from the Senate Health, Education, Labor, and Pensions Committee (the Committee that authorizes the NIH) visited the NIH to learn about its mission, organizational structure, scientific advances, and initiatives. Dr. Katz participated in a panel discussion with the group on priority setting with Drs. Larry Tabak (NIH Principal Deputy Director), Harold Varmus (NCI Director), Tom Insel (National Institute of Mental Health Director), and Susan Shurin (National Heart, Lung, and Blood Institute Deputy Director). Staffers were enthusiastic about the NIH and asked for examples of exciting scientific breakthroughs that they could relay to their supervisors and constituents. They were particularly interested in learning how the NIH makes its funding decisions about research on particular diseases, tissues, or populations.
Dr. Katz spoke at a March 21 Congressional Briefing on psoriasis research that was hosted by Representative Jim Gerlach (R-PA). The National Psoriasis Foundation and the American Heart Association co-sponsored the briefing, which drew a significant number of staffers. Dr. Carter noted that as an Institute, the NIAMS embraces these types of opportunities to visit Capitol Hill to speak with members of Congress and their staff to make them aware of the progress and promise of NIAMS’ investments across the country.
The NIAMS Coalition Steering Committee also recently visited the NIH to learn more about the Institute and tour some of its intramural laboratories. Dr. Carter noted that the NIAMS appreciates opportunities to work with the Coalition and inform its member organizations about its activities. On May 21, Dr. Carter spoke with a broader cross-section of Coalition members via teleconference. Coalition Co-Chairs Kim Cantor of the Lupus Foundation of America and Sarah D’Orsie of the American Academy of Physical Medicine and Rehabilitation co-hosted the call, which included representatives from 20 NIAMS Coalition groups. The main topic of discussion was the NIH budget and priority setting, with a focus on the importance of supporting the best research and how funding decisions are made.
Before concluding his report, Dr. Carter noted that Dr. Collins has been trying to relay the impact that the current budget landscape is having on NIH’s stakeholders. He has been asking for the community’s stories and experiences. Joining several other NIH ICs, the NIAMS has shared Dr. Collins’ request through its Twitter feed.
In opening the discussion session, Dr. Carter asked Council members to share their thoughts on what their institutions are doing to adapt to limited resources and how the NIAMS can complement their efforts. Council member Dr. Lynda Bonewald, Lefkowitz Professor in the Department of Oral Biology at the University of Missouri-Kansas City School of Dentistry, noted that at its June Council meeting, the American Society for Bone and Mineral Research (ASBMR) will be discussing bridging funds for young and established investigators to keep these researchers active until funding levels can be restored. Dr. Carter noted that the NIAMS would be interested in working with the ASBMR. Dr. Bonewald indicated that the ASBMR is considering prioritizing based on how close applicants came to receiving funding. Dr. Carter commented that the Institute cannot release the names of applicants to the ASBMR, but it can make applicants aware of this.
Dr. Susana Serrate-Sztein, Director of the Division of Skin and Rheumatic Diseases, discussed a similar bridging effort in which the Institute has successfully worked with the American College of Rheumatology Research Foundation and the Arthritis Foundation to target transitioning junior investigators. Through this effort, individuals who have applied for NIH funding with competitive applications focused on rheumatic and related diseases that did not meet the funding level are made aware of the program and encouraged to contact the Foundations. The vast majority of investigators who received bridge funding through this program have subsequently received NIH awards.
Council member Dr. Harry Dietz III, Victor A. McKusick Professor of Medicine and Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, commented that since sequestration, the number of grant applications received by the National Marfan Foundation and the Scleroderma Research Foundation have increased dramatically. These organizations have been effective in alerting their donors to the nature of the situation and the possibility that key groups of investigators dedicated to their causes could be lost. Fortunately, these organizations have seen an increase in the amount of funds brought in, in parallel with the increase in applications. However, the groups cannot keep up with the overwhelming peer review needs associated with the increase in applications. Dr. Dietz suggested that it would be helpful to allow these types of organizations access to peer review information at the NIAMS (e.g., identifying applications that are just on the edge of funding) that could lead to natural partnerships. Dr. Dietz also suggested that private foundations and patient advocacy groups could be used to help supplement the amount that a funded grant receives. Dr. Carter indicated that the NIAMS cannot share specific review data with outside groups, but it can alert the applicants and suggest that they contact outside groups that are able/willing to provide assistance. Dr. Katz noted that these types of partnerships have worked well in the past.
Council member Dr. Regis O’Keefe, Chair of the Department of Orthopaedics and Rehabilitation at the University of Rochester Medical Center, noted that academic medical centers are facing not only a decrease in NIH funding, but also a reduction in revenue from hospital admissions. For example, at the University of Rochester approximately 50 percent of hospital profits are transferred to the medical school and used primarily for research purposes. With some hospitals anticipating lower profit margins in the future, this is having a direct impact on the research infrastructure. The University of Rochester Medical Center is responding by developing a strategic plan that is driven less by a growth strategy and more by considering what resources and intellectual infrastructure are present and trying to place people in programs in more creative ways to enhance research. Although this is a positive shift, there is concern that there are not enough funds available to recruit young investigators. The institution is also placing some of the hospital’s reserve funds into an endowment to support research. Dr. O’Keefe commented that the current budget landscape is pushing many academic medical centers to be more selective in the research they pursue.
Council member Dr. Elizabeth Shane, Professor of Medicine and Vice-Chair for Clinical and Epidemiological Research at Columbia University College of Physicians and Surgeons, noted that even those institutions that receive high levels of NIH funding are very concerned about the funding landscape. The Dean at Columbia University has developed a strategic plan focused on Centers of Excellence, which unfortunately led to competition from groups within the University to be selected as priorities for funding. The plan likely will lead Columbia to focus on building its strengths rather than trying to develop new areas of expertise.
Council member Dr. Sherine Gabriel, Dean of the Mayo Medical School, William J. and Charles H. May Professor, and Professor of Medicine and Epidemiology at the Mayo Clinic, commented that her institution is taking the centers approach as well. She noted that most academic medical centers are trying to consolidate capabilities and expertise in a few selected areas. At Mayo, Centers are now accountable to both research and practice, so they must demonstrate scientific value as well as value to improving the practice and improving health. She also underscored the concerns about trainees and young faculty. She asked about the possibility of partnering with industry to help move along some of the high-quality research that cannot currently by funded by the NIH. Dr. Katz noted that many foundations are heavily supported by industry, and there has been an increase in foundation support in the last 20 years, primarily due to new drugs being developed in certain areas.
Dr. Carter summarized the discussion to this point, noting the important role of foundations and patient advocacy groups as well as the need to support new investigators and trainees. Does the reorganization of medical institutions into centers change what the NIAMS does? How should the Institute react to these changes? Dr. Bonewald commented that the reason for setting up these centers is to make investigators more competitive and is a response not only to limited funding opportunities, but also to the emphasis on team-based science. Investigators who are part of a center will have better support in place compared to those who are not. Team-based science appears to be the way of the future. Dr. Dietz commented that although a team approach with developed infrastructure could make a grant more appealing in the review process, there should not be an a priori criterion that this infrastructure be in place. Rather, the best science should be rewarded, whether it comes from a large center or an individual.
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, cautioned that with institutions taking an area of emphasis approach, uncommon or rare diseases are at risk of being neglected.
Dr. Gary Firestein, Professor in the Department of Medicine at the University of California, San Diego, and a member of the Council, noted that other specialties overcame the challenges associated with team science long ago, particularly in the physical sciences such as physics and astronomy. He suggested that the lessons learned through these successes can offer important insights. He also noted that during the review process, it is important to identify who is creating silos and their own infrastructure versus those who are using shared infrastructure as a way to use research dollars more wisely.
FOUNDATION FOR THE NATIONAL INSTITUTES OF HEALTH UPDATE
Dr. Maria Freire, President and Executive Director of the Foundation for the National Institutes of Health (FNIH), provided an overview of the FNIH and described the two-fold purpose of the Foundation, which is to: (1) support the NIH in its mission; and (2) advance collaboration with biomedical researchers from universities, industry, government, and nonprofit organizations. The FNIH was created by Congress and became operational in 1996. The Foundation was formed as a 501(c)(3) nonprofit organization with an independent Board of Directors (the NIH Director and U.S. Food and Drug Administration [FDA] Commissioner are ex officio Board members). Since 1996, the FNIH has raised more than $700 million and has supported more than 400 projects (105 of which are currently active). These projects include research partnerships, scientific education/training efforts, conferences/events, and capital programs. Dr. Freire explained that 94 cents of every dollar spent by the FNIH directly supports these programs. The Foundation has held the coveted 4-star Charity Navigator rating for the past 7 years.
Dr. Freire presented a slide showing the members of the FNIH Board of Directors, and then reviewed the Foundation’s portfolio. Of the 105 active FNIH projects, the vast majority, 70 percent, are research projects. Of the $208 million FNIH raised for the NIH, almost $7.5 million supports research in the NIAMS portfolio.
Dr. Freire described key FNIH competencies in helping to build public-private partnerships, and their place on the discovery-pre-clinical-clinical pipeline. She then discussed specific FNIH-supported projects that fall within the NIAMS portfolio: the Osteoarthritis Biomarkers Project and the Bone Quality Project, both of which are under the auspices of the Biomarkers Consortium, and an FNIH-launched project, "Developing Endpoints for Clinical Trials in Community-Acquired Bacterial Pneumonia (CABP) and Acute Bacterial Skin and Skin Structure Infections (ABSSSI)."
Dr. Freire closed her presentation by thanking NIAMS staff involved with FNIH-supported projects, noting that their expertise has been invaluable in moving these initiatives forward and supporting the mission of the FNIH.
Dr. Katz opened the discussion session by acknowledging the valuable support that the FNIH has given to the Osteoarthritis Initiative (OAI) and to the NIH overall. Dr. Shane asked how the FNIH selects specific projects and about the distribution of funds to NIH ICs. Dr. Freire explained that the Foundation receives ideas from the NIH and from other, independent sources.
Dr. Bonewald asked for an update on the Sarcopenia Project, noting that sarcopenia lags behind OA in terms of definition and biomarkers. Dr. Maria Vassileva of the FNIH explained that the Sarcopenia Project is managed by the Metabolic Disorders Steering Committee at the FNIH. Dr. Glen Nuckolls, Health Scientist Administrator within the NIAMS Division of Musculoskeletal Diseases, is a member of the project team.
Council member Dr. David Eyre, of the Department of Orthopedics and Sports Medicine at the University of Washington School of Medicine, noted the importance of the Osteoarthritis Biomarkers Project and asked about how and when the data will be presented for publication. Dr. Joan McGowan, Director of the NIAMS Division of Musculoskeletal Diseases, explained that the findings will be published in peer-reviewed literature and noted that the OAI database, which is the resource for the Osteoarthritis Biomarkers Project, is available to the public.
In response to a question from Dr. Murray about the lack of FNIH-supported work in the pre-clinical area, Dr. Freire explained that the Foundation is sensitive not to move too far into the competitive space occupied by industry. The Foundation is in discussion with the NIH National Center for Advancing Translational Sciences to identify what projects the FNIH can support in this area. Dr. Freire also noted that this space is where much of the work on rare and neglected diseases needs to occur.
CSR UPDATE FOR NIAMS
CSR Director Dr. Richard Nakamura opened his presentation by quoting President Obama, who spoke at the 150th Anniversary of the National Academy of Sciences on April 29, 2013, and stated: "We’ve got to protect our rigorous peer review system and ensure that we only fund proposals that promise the biggest bang for taxpayer dollars…that’s what’s going to maintain our standards of scientific excellence for years to come." Dr. Nakamura reminded the group that CSR’s mission is to ensure that NIH grant applications receive fair, independent, expert, and timely reviews—free from inappropriate influences—so that the NIH can fund the most promising research. He noted that in 2012, the CSR reviewed 73.7 percent (1,718) of NIAMS grant applications.
Dr. Nakamura explained that the CSR is the focal point for initial review at the NIH. The CSR receives all NIH applications, refers them to NIH ICs and CSR scientific review groups, and reviews the majority of grant applications for scientific merit. In general, the Center reviews more basic and translational work, while the ICs review more complex and clinically oriented applications. Dr. Nakamura outlined the NIH peer review process, beginning with PIs submitting applications (either through their own initiative or in response to a funding announcement) that undergo peer review at CSR or within the ICs. The applications go to study sections and are ranked, after which they go through a process of percentiling (a normalization process that equilibrates the outputs of all study sections). The applications, with their scores, are reviewed by ICs and their Councils, at which point funding decisions are made, within the context of the strategic goals of the ICs and the scientific significance of the individual applications.
In any given year, the CSR receives approximately 85,000 applications and reviews about 58,000 of them, using 16,000 reviewers, 230 Scientific Review Officers, and almost 1,500 review meetings. Dr. Nakamura presented a slide showing a steady decline in grant success rates from a high of almost 40 percent in 1979 to less than 19 percent in 2012.
Dr. Nakamura discussed score compression, which has been taking place since 2009. He reminded the Council that in 2009, the CSR moved from a 100-500 scoring scale to a 1-9 point system, with a "1" being exceptionally strong with essentially no weaknesses and a "9" having few strengths and numerous major weaknesses. The CSR noted that a number of reviewers were incorrectly using the presence or lack of identified weaknesses as an indicator of the significance or strength of a given application. This was never the intent, and the CSR has changed the descriptors of the 1-9 scale and emphasized the overall impact of applications using the following five criteria: (1) significance, (2) investigator, (3) innovation, (4) approach, and (5) environment (weighted based on reviewer’s judgment). The CSR has clarified that to receive a high score (i.e., 1-3), the application must address a problem of high importance/interest in the field. The application may have some or no technical weaknesses. Dr. Nakamura also noted that many reviewers were hesitant to score applications worse than 5—the CSR has clarified that applications scoring 5 should denote good, medium-impact applications and that the entire spectrum of scoring should be used. Dr. Nakamura reported that these clarifications have improved the scoring of applications by reviewers.
Dr. Nakamura presented a slide showing the distribution of preliminary impact scores, noting that the peak for preliminary impact scores is between 3 and 4, 5 percent of scores coming out of initial review were "1s," and about 17 percent were "2s." Given that the award range is includes only about 10 percent of applications, this information gives program staff very little to work with. However, the distribution of scores for discussed applications showed a greater spread (e.g., applications in the 1-2 range represented about 15 percent of all applications).
Diversity and fairness are keys to CSR activities. In 2011, a paper by Ginter et al., showed that applications with strong priority scores were equally likely to be funded, regardless of race. However, African American applicants were 10 percentage points less likely to receive NIH research funding compared to Whites. These findings did not extend to Hispanic applicants or gender. Suggested explanations in the paper included the possibility of bias in the peer review system and cumulative disadvantage. These findings prompted NIH leadership to charge the Advisory Committee to the Director (ACD) to evaluate the NIH peer review system. The ACD has recommended the following: (1) establish a Peer Review Subcommittee (done); (2) provide more information for not discussed applications (done); (3) conduct text analysis of applications, summary statements, and discussion (in process); (4) evaluate anonymized applications to determine if the bias disappears when applicants and their institutions are not disclosed (in process); and (5) provide diversity awareness training to NIH staff (in process).
Dr. Nakamura explained that the CSR is continuing to work on increasing the representation of minority groups in its scientific review groups. Since 2011, there has been a 42 percent increase in African Americans and a 22 percent increase in Hispanics on CSR scientific review groups. Overall, under-represented minority reviewers have increased by 25 percent since 2011.
The CSR has also started an Early Career Reviewer Program to: (1) train qualified scientists without significant prior review experience so that they become effective reviewers, (2) help emerging researchers advance their careers by exposing them to the review experience, and (3) enrich the existing pool of NIH reviewers by including scientists from less research-intensive institutions as well as those from research-intensive institutions. To qualify as an early career reviewer, the individual may not have reviewed for the NIH beyond one mail review, must demonstrate scientific qualifications, and may not have an NIH R01 or equivalent funding. To date, 2,134 early career reviewers have been accepted into the program, with almost 700 having served on a study section. A total of 223 study sections have included early career reviewers on their rosters. Almost one-third of those in the program are under-represented minority scientists. Dr. Nakamura noted that in a survey of 142 early career reviewers, 98 percent found the experience to be useful, 90 percent reported being in a better position to write their own grants, and 97 percent would recommend the experience to a colleague. He added that early career reviewers are only allowed to participate in one review per year, have a reduced workload during the review, and provide only tertiary reviews.
The CSR is also advancing additional review platforms beyond face-to-face meetings in an effort to recruit reviewers and reduce travel. The CSR is using electronic review (e.g., telephone-assisted meetings, video-assisted discussions, Internet-assisted meetings, telepresence meetings) and is pursuing other types of face-to-face meetings (e.g., editorial board-style meetings).
Dr. Nakamura then shifted the discussion to explain why the NIH decided to move away from the A2 award. In 2008, it was noticed that the A2 applications had become the second-most popular form of award. The A0 decreased from more than 60 percent of awards down to 30 percent (lower than both the A1 and A2). Since 2008 when the A2 was eliminated, the A0 has rebounded back up to 50 percent. Dr. Nakamura added that there has been no significant difference in the length of time to receiving an A0 award between new and established investigators. Eliminating the A2 did not differentially affect any major subgroup that the CSR could identify. The major effect seemed to be the reduction of time to award.
Dr. Nakamura concluded his presentation by noting a number of challenges facing the CSR in the future:
- More effectively distributing applications across study sections
- Developing improved tools for applicants, for referral, and for review
- Providing better service to applicants and ICs
- Developing a science of peer review so that the quality of peer review can be continuously improved.
Council member Dr. Ted Mala, Director of the Traditional Healing Clinic at the South Central Foundation, suggested that the CSR work to improve the participation of American Indians and Native Hawaiians in scientific review groups. Dr. Nakamura agreed, noting that he is open to any suggestions in this regard. He noted that CSR Scientific Review Officers have been reminded that there are under-represented minority groups other than African Americans and Hispanics. The CSR is hoping to enroll more American Indians and Native Hawaiians into its Early Career Reviewer Program and asked Council members to forward the names of any suitable individuals.
Dr. Katz noted that when the overall NIH success rate was in the 23 percent range, the success rate for the 01 submission from new investigator applicants was only 6 percent—this was one of the motivating factors for eliminating the A2 application. Dr. Nakamura explained that the CSR Advisory Council has suggested that the Center conduct an experiment allowing some researchers to opt in to a "one application, all applications are new" review process in which the criteria for what constitutes a new application are loosened. The review committee will score the application, and the applicant cannot resubmit during this experiment. This would allow an investigator to come back with a different application after making changes in response to the reviewers’ comments, but the application would be treated as a new application. The CSR is seeking feedback on this approach.
Council member Dr. Firestein noted that the structure of study sections is going to become increasingly complex as a result of the shift toward multidisciplinary, team-based science. Dr. Nakamura agreed, noting that this has been an issue for as long as the CSR has been in existence, and welcomed the Council’s input on how the CSR can accommodate these changes. He noted that some have suggested that the editorial board-style review is a better approach in these instances because multiple forms of expertise can be called upon to cover different parts of an application.
Dr. Dietz pointed out that junior investigators are often learning grantsmanship in their first submission, and without the A2, they only have one opportunity to address the reviewers’ scientific concerns regarding their application. Dr. Nakamura noted that the NIH has considered a number of different possibilities and that some institutions are taking measures to ensure that the A0 application is the equivalent of an A1 application when it comes in for peer review. A study of what different institutions are doing with their PIs to ensure that they are more likely to succeed would be useful.
Dr. Pentland congratulated Dr. Nakamura for the success of CSR’s Early Career Reviewer Program and suggested that the only way that CSR’s "one application, all applications are new" experiment could work is if reviewers were changed so that reviewers did not have the possibility of seeing the same work from a PI in a subsequent application.
Dr. Serrate-Sztein noted the variability in scores across study sections and asked about the factors within a study section that affect reviewers’ voting and scoring behaviors. Dr. Nakamura indicated that study sections often develop their own culture in terms of what a reasonable spread of scores is, and it becomes difficult to move. A concerted educational effort is needed to shift reviewers’ behavior.
OVERVIEW OF THE NIAMS CENTERS EVALUATION WORKING GROUP REPORT
Dr. Carter reminded the group that during its September 2012 meeting, Council members were presented with the concept of the NIAMS Centers Program review along with the goals and vision for this evaluation. In February of this year, Dr. Carter presented the Council with an update. At this meeting, he presented the final report from the Centers Evaluation Working Group (CEWG).
Dr. Carter noted that Centers are used to support areas of research where progress would benefit from or even require integrated, synergistic groups of investigators. This synergy can be built at Centers through multidisciplinary research, shared resources, and cooperative technological innovation. He explained that the goal of the review was to design funding strategies to optimally support synergistic groups of investigators, based on the research needs and opportunities. Dr. Carter clarified that the review did not take into consideration the following: (1) the relative budget of the total Centers program (versus RPGs), (2) program project (P01) type projects, (3) the performance of any individual Center, or (4) clinical trials.
Beginning in October 2012, a series of listening sessions were held to poll the community on the needs and opportunities that apply to these types of groups of investigators. Various stakeholders (e.g., ASBMR, American College of Rheumatology, Orthopaedic Research Society, Clinical and Translational Science Award [CTSA] investigators, etc.) participated in these listening sessions. The Centers Evaluation Working Group met multiple times since October 2012 as well. A Request for Information was issued in November 2012 to solicit input from other organizations.
The CEWG undertook the task of integrating the themes expressed at the listening sessions and other inputs from the community into a coherent set of goals that would transform the current NIAMS Centers framework. In its report, the CEWG attempted to convey to NIAMS the needs and opportunities identified by investigators and patient groups within the NIAMS mission areas. A set of common, integrated goals emerged:
- Foster interdisciplinary science to promote innovation. Dr. Carter defined "interdisciplinary science" as bringing together different disciplines in a way that has not been done before to create a single, new, integrated approach to a problem.
- Facilitate sharing of research resources, particularly clinical material, which both basic and clinical researchers need to advance new hypotheses.
- Accommodate the research community’s need for shared clinical methodologies (e.g., trial planning, data analysis, etc.).
- Increase community awareness and use of shared resources.
- Foster mentorship and training within Centers.
- Rather than force projects to fit within current structures, create structures that are flexible enough to accommodate Centers that can best work within local institutions.
Dr. Carter emphasized that the intended outcome of the Centers Program is to understand disease in humans. Competition should be based on new approaches and new resources devoted towards understanding human disease. The CEWG made the following two overarching conclusions in its report:
- NIAMS Centers should support the conduct of interdisciplinary research, in which teams of investigators pool their expertise in different disciplines to create a new, integrated approach to solving a problem.
- NIAMS Centers should prioritize improving access to resources, with both the importance of the resource and the potential impact of providing access to that resource as criteria for judging significance in review.
Dr. Carter suggested that these conclusions represent significant changes from current practice. Instead of a Center that has several different projects with various degrees of relationships, there is one project supported by a set of cores that brings together investigators to develop something new. In this vision, the criteria for review of resources becomes not the institution’s strength, but the importance of the resource and the ability to make it more widely available.
CEWG member Dr. V. Michael Holers of the University of Colorado, Denver, commented that given the diverse background of the individuals involved in crafting the group’s report, there were many robust discussions and there was agreement on the topics included in the report and the conclusions made by the group. He acknowledged that the implementation and administrative aspects of building these mechanisms will be a challenge, but the CEWG members shared a high level of enthusiasm for the conclusions as presented in their final report.
Council member Dr. Pentland, also a CEWG member, agreed that the evaluation was a thoughtful and complete process, with ample time for Working Group members to express themselves. The group wants Centers to continue supporting pilot projects and agreed that technical development could be included in Centers’ applications. Council member Bradley Stephenson, an Attorney at Law and member of the Muscular Dystrophy Association’s National Task Force on Public Awareness (and a CEWG member), reiterated the message that the report’s findings came from the community and that there was strong participation on the part of all CEWG members in drafting its final report.
In response to a question, Dr. Carter noted that the NIAMS is working on approaches to assess Center productivity in the hopes of improving the ability to foster collaborations.
Dr. Firestein discussed how Centers interact with CTSAs, noting that there are ways to improve efficiency by using and leveraging existing CTSA resources to avoid duplicative efforts. He noted that often, Centers are required to have a core or service—these are very similar to what occurs within CTSAs. Rather than having a Center or CTSA create these cores or services from the ground up, he suggested that they supplement or augment specialized groups within existing infrastructure. Some of the other programs that exist within the CTSAs (e.g., training programs and pilot project programs) could be drawn upon by Centers as well.
Dr. Katz asked if the CEWG placed any importance on the geographic location of Centers during its discussions. Dr. Carter commented that the breadth of the community that has access to a Center is important, and that when forming interdisciplinary groups, if a key person is at a different institution, their inclusion should be supported. Council member Dr. Xiao-Jing Wang, Professor in the Department of Pathology at the University of Colorado, Denver, asked about mechanisms to help investigators at different Centers interact. Dr. Carter responded that the CEWG did not discuss this issue in depth.
Dr. Eyre asked if part of the purpose of the Centers Program was to catalyze the physical presence of institutes at academic medical centers that would focus on the mission of the NIAMS. He suggested that the program offers the long-term opportunity to build the mission of NIAMS through regional Centers. Dr. Carter agreed, noting that Centers receive benefits from being linked with an institution, just as institutions receive benefits from Centers to which they are linked. Having the flexibility to pull in people for technical development and pilot feasibility studies is an important component.
Dr. Katz thanked Dr. Holers and the Council members who served on the CEWG. Dr. Carter reported that in terms of next steps, a Request for Comments will be issued to solicit feedback on the report. The next opportunity for a new Centers announcement is expected in 2015.
NIAMS PLANNING ROUNDTABLES
Dr. McGowan reminded the Council that the NIAMS regularly holds roundtable discussions as part of its priority-planning process. Roundtable topics are developed by NIAMS Program Directors who obtain feedback at scientific meetings, from study sections, and by talking directly to investigators to identify topics of emerging importance to the Institute and its stakeholders. She and Dr. Serrate-Sztein briefly summarized the meetings for the Council members. Reports will be posted on the NIAMS website at a future date.
- Anabolic Therapies and Strategies to Regenerate the Musculoskeletal System
The Anabolic Therapies and Strategies to Regenerate the Musculoskeletal System Roundtable was held on April 3, 2013, and included experts from the bone, muscle, and cartilage research areas, as well as a patient advocate. Dr. McGowan reported that one of the overarching round table discussion themes centered around the need for an integrative, global view for developing anabolic therapies. Specific issues in this regard include considering other musculoskeletal tissues as well as the musculoskeletal system as a whole; considering tissues and systems outside of the musculoskeletal system; common and diverse pathways and their actions; combining anti-catabolic and anabolic approaches; and considering the complexity and heterogeneity of the tissues, pathways, developmental stages, and disease status. Additional topics discussed related to this theme were promoting effective collaborations between scientists from different fields (i.e., team science) and continuing to develop systems biology and bioinformatics resources, methodologies, and strategies to manage large data sets.
A second theme that arose from this round table was controlling specificity. Topics under this theme included the selective nature/restricted distribution of anabolic pathway components, controlling the local environment, limiting the duration of drug action, targeted delivery, limiting disease usage, and the stratification of patients and diseases.
The third major theme from this round table centered on future needs related to basic, translational, and clinical studies. Specific discussion points included new targets/therapies, a better mechanistic understanding and potential application to other tissues for existing targets, off-target effects and strategies to limit them, the need for surrogate markers, and the nature and identity of the in vivo source of stem and progenitor cells (specifically, how to control their maintenance, proliferation, and differentiation). Additional discussion points included a better understanding of the cross-talk between and among musculoskeletal and other tissues, the value of developmental biology and rare disease studies, and engaging the private sector with academic and government partners.
- Inflammation and Osteoarthritis
The Inflammation and Osteoarthritis Roundtable was held on April 30, 2013. This roundtable focused on recent advances in inflammation research to enhance understanding of the early process involved in the initiation and onset of osteoarthritis. Dr. McGowan noted that a large number of inflammation-related therapeutic targets and drug candidates have been validated in animal models. Roundtable participants identified a number of important needs and areas of opportunity:
- Stratifying the disease and identifying disease subsets (acute vs. chronic inflammation; stage of disease—early vs. middle vs. late).
- Developing new biomarkers to enable subsets to be identified, integrating clinical phenotype with molecular aspects.
- Identifying those patient populations that are most sensitive to interventions.
- Better defining the inflammatory targets, mediators, and cell sources.
- Defining and validating meaningful and feasible endpoints.
- Identifying a safe, accurate, reproducible non-contrast method of assessing synovitis/joint inflammation in a noninvasive manner.
- The need for improved animal models that better reflect human disease.
- Selecting the most promising drug candidates.
- Taking advantage of ongoing clinical trials for other diseases to look for effects on OA.
- Partnerships To Advance Therapies for Rheumatic Diseases in Children and Adults
Dr. Serrate-Sztein noted that at last year’s NIAMS Scientific Retreat, the Institute examined the factors that affect the ability and feasibility of establishing partnerships with segments of the private sector (both for profit and not for profit). This roundtable was organized as a follow-up to those discussions with the goal of engaging representatives from industry to explore opportunities for collaboration in the area of rheumatic diseases in children and adults. At the time that this roundtable was held, the Institute was already supporting two large database and registry projects: the Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA) and the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database (TETRAD).
Roundtable participants discussed the evaluation and reporting of safety data from the use of biologic and other disease-modifying drugs in rheumatoid arthritis in adults and children with rheumatic diseases. Dr. Serrate-Sztein noted that Dr. Janet Woodcock of FDA participated in the discussions. The roundtable also included lead investigators from CARRA and TETRAD as well as representatives from industry groups conducting research in this area. Dr. Serrate-Sztein explained that both CARRA and TETRAD were funded through the American Recovery and Reinvestment Act (ARRA), and both were tasked with creating an infrastructure for which there was a demonstrated need as well as a sustainability plan.
Roundtable participants also discussed in more general terms areas in which the NIAMS could interact with the private sector to study on rheumatic diseases. There was a sense that companies and investigators are now in a position to share large clinical data sets, and the Institute may be able to help facilitate these types of interactions as well as more general types of collaborations to help accelerate the translation of research findings. In general, the companies expressed an interest in working with the NIAMS and with investigators. The major limiting factors preventing these partnerships appear to be defining the goals and the timing and timeliness of the collaborations. Industry representatives expressed a desire to work with the NIAMS on improving outcome measures
Dr. Katz expressed enthusiasm that TETRAD is being considered by the FNIH, and indicated his hope that CARRA will be considered by the Foundation as well.
Dr. Firestein asked if industry representatives expressed an interest in providing resources to help build the infrastructure for shared resources such as CARRA and TETRAD, or whether their interest in participating was more contingent on these resources having been already developed. Dr. Serrate-Sztein commented that there was not a clear sense of industry’s position on this issue.
Dr. McGowan commented that some companies do not trust the rigor of NIH-conducted studies and have similar concerns about turning over data sets to academic investigators.
- Anabolic Therapies and Strategies to Regenerate the Musculoskeletal System
NIAMS EXTRAMURAL PROGRAM SCIENTIFIC RETREAT 2013
Dr. Serrate-Sztein provided highlights of the discussions from each of the three scientific sessions from this year’s Retreat.
Strategies for Successful Rare Disease Clinical Trials
Dr. Serrate-Sztein noted that this was identified as an area of interest and investment for the Institute during last year’s Retreat. This session was dedicated to discussing the challenges and developing strategies that the NIAMS and NIH can use to improve the likelihood of success for clinical trials of rare diseases. Retreat participants discussed two scenarios: (1) the single PI with late transition research funding, and (2) a network considering an FNIH study.
Following discussions and presentations, three main messages arose:
- It is essential to collect and disseminate the right information. Retreat participants indicated that the NIAMS can do a better job at providing information to the community about the resources that currently exist that may help them develop a clinical trial. Some NIH ICs are using creative approaches to help investigators develop their clinical trial applications.
- There are critical clinical trial design issues that require careful consideration. Furthermore, there are alternative study designs that may be preferable to the traditional randomized, controlled clinical trial for studying some rare diseases.
- Clinical trials for rare diseases need to be viewed as collaborative projects, both at the planning stage and at the execution stage. Involving patient voluntary organizations along with experts, clinical trialists, statisticians, etc., is crucial. Patient voluntary organization participation makes a tremendous difference, not only in terms of recruitment, but also study design.
The Circadian Cycle in NIAMS-Relevant Tissues
The purpose of this session was to inform NIAMS staff about this emerging area of investigation and to explore research opportunities relevant to diseases and tissues within the mission of the NIAMS. There has been a significant increase in the number of publications related to the circadian cycle, but diseases and tissues of interest to the NIAMS in this area are poorly represented in the published literature. Retreat participants agreed that the circadian rhythm is relevant to all of the tissues and diseases tied to the NIAMS mission. They discussed how best to encourage and facilitate collaborations between the large community of circadian rhythm investigators and researchers working in NIAMS mission areas.
Dr. Katz commented that this was one of the most interesting sessions held at a NIAMS Retreat. Council member Dr. Katherine Mathews, Professor in the Departments of Pediatrics and Neurology at the University of Iowa, attended the Retreat and noted that one of the take-away messages from this session was that biomarkers may be very sensitive to the time of day they are drawn.
Impact of the Functionalized Genome on NIAMS Diseases — Implications From ENCODE
Dr. McGowan noted that the Encyclopedia of DNA Elements (ENCODE) is an international public research consortium launched by the National Human Genome Research Institute (NHGRI) in September 2003. The goal of ENCODE was to build a comprehensive parts list of functional elements in the human genome, including elements that act at the protein and RNA levels, and regulatory elements that control cells and circumstances in which a gene is active. ENCODE has begun to transform the interpretation of genome-wide associated studies. The purpose of this Retreat session was to: (1) gain a better understanding of the opportunities enabled by ENCODE, and (2) discuss strategies to overcome challenges and facilitate leveraging of the ENCODE resources to advance NIAMS research.
Following presentations and discussion, Retreat participants identified the following potential follow-up activities:
- Generate genome-wide ENCODE-type data from cells and tissues that are directly relevant to rheumatic, skin, and musculoskeletal diseases.
- Integrate these data with the data and analytical resources produced by the original ENCODE investment as well as with data from NIAMS’ investment in genome-wide association studies.
- Stimulate active collaborations between investigators experienced in the study of NIAMS-specific diseases and tissues and investigators experienced in the genome-wide analysis of biochemical features such as DNase hypersensitivity, DNA methylation, histone modification, and bioinformatics experts.
Dr. McGowan noted that to ensure data are compatible with quality control and formatting standards established by ENCODE, involvement of NHGRI staff and investigators with direct experience in the ENCODE data pipeline will be valuable.
CONSIDERATION OF APPLICATIONS
The Council reviewed a total of 903 applications in closed session requesting $986,405,607 in total costs and recommended 903 for $986,405,607 in total costs.
This portion of the meeting occurred during closed session.
RARE DISEASES CLINICAL NETWORK UPDATE
This portion of the meeting occurred during closed session.
The 80th NAMSAC meeting was adjourned at 2:30 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.