Department of Health and Human Services
Public Health Service
National Arthritis and Musculoskeletal and Skin Diseases Advisory Council

Minutes of the 82nd Meeting
8:30 a.m. to 2:45 p.m.

January 2014 NIH Leadership Forum

Dr. Katz asked Council members for feedback regarding four potential changes that were considered at length during the January 2014 NIH Leadership Forum:

Discussion

Council member Dr. David Eyre of the Department of Orthopaedics and Sports Medicine at the University of Washington School of Medicine commented that his MERIT Award provided him with much-needed flexibility to be more creative while considering more innovative approaches and specific aims that are not usually possible in a typical R01 setting. Dr. Katz noted that NIAMS MERIT Awardees tend to perform very well on their subsequent applications.

Dr. Koretzky voiced concerns regarding the current funding climate, explaining that creativity and innovation often are not rewarded. The proposals that receive funding tend to be flawless, and flawless proposals often do not include innovative or creative next steps, which could leave them open to criticism. He suggested that the NIH move to a model whereby a subset of NIH or IC programs fund the scientists themselves rather than the projects. Dr. Koretzky continued, noting that the best predictor of future success is having had past success, including demonstrating past creativity and innovation. He agreed with Dr. Eyre’s comments about the MERIT Awards in terms of providing valuable flexibility to awardees, but reminded the group that these awards target only a very small number of investigators.

Dr. Koretzky also pointed to the need for a funding mechanism that would allow researchers to submit proposals highlighting what they have done, outlining the impact of their work, and providing a broad description of future plans without the need for delving into the minute details for these future plans. Dr. Katz indicated that this approach is very similar to that of the Howard Hughes Medical Institute. The challenge with adopting a new approach such as this is determining from where resources should be taken so that this type of mechanism can be funded and adopted. Dr. Koretzky suggested that many MERIT awardees would be willing to forgo their MERIT Award to participate in this type of mechanism. Dr. Katz explained that the NIAMS will include this topic in its next round of retreat discussions.

Council member Dr. Xiao-Jing Wang, Professor in the Department of Pathology at the University of Colorado, Denver, suggested that rather than revamping or removing the MERIT Award mechanism, that the format for competitive renewal be changed. Instead of reviewing the previous specific aims of a project, she recommended that the competitive renewal process involve consideration of what work has been done, what scientific achievements have been reached, and what the proposed new work involves. This change would involve a “bigger picture” view and depart from the renewal process focusing on whether a project’s specific aims have been met. Dr. Katz noted that such a change could also place greater emphasis on innovative, riskier ideas. He also explained that this type of process may require a more substantial time commitment on the part of the investigators because of the greater flexibility allowed to them.

Dr. Eyre suggested that elements of the MERIT Award system be built into the review process for R01 grants. He reminded the group that the mean lifetime (in the field) of an R01 Principal Investigator has been decreasing, which is detrimental to the infrastructure of medical research in terms of long-term productivity. Dr. Katz agreed and emphasized that this issue must be addressed. The NIH has begun moving in a direction that responds to these types of issues (e.g., the move to the A1 from the A2 to decrease the time it takes for an investigator to receive his or her first award).

Council member Dr. Lynda Bonewald, Lefkowitz Professor in the Department of Oral Biology at the University of Missouri-Kansas City School of Dentistry, agreed with the concept of incorporating elements of the MERIT review and pointed to the need to identify up-and-coming young investigators who have creative ideas. She also cautioned against fostering a sense of entitlement among more senior investigators. Council member Dr. Elizabeth Shane, Professor of Medicine and Vice-Chair for Clinical and Epidemiological Research at Columbia University College of Physicians and Surgeons, cautioned that in some areas, certain work is needed before high-risk, innovative projects should be considered (e.g., generating basic information for certain diseases to fill knowledge gaps). Dr. Katz agreed, explaining that certain types of clinical studies, whether they are interventional or observational, do not apply to this discussion. He also noted that discussion of this topic will continue at the June 3, 2014, Council meeting.

1. CALL TO ORDER

   The 82nd meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council (NAMSAC) was held on February 11, 2014, at the National Institutes of Health (NIH) Campus, Building 31, Conference Room 6. The meeting was chaired by Dr. Stephen I. Katz, Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

   Attendance

   Council members present

   Dr. Lynda F. Bonewald
   Dr. David R. Eyre
   Dr. Gary Firestein (via teleconference)
   Ms. Michelle Hofhine
   Dr. Gary A. Koretzky
   Dr. Ted Mala
   Dr. Katherine Mathews
   Dr. Martha M. Murray
   Dr. Grace Pavlath
   Ms. Alice P. Pentland
   Dr. Gwendolyn L. Powell Todd
   Dr. Christy I. Sandborg
   Dr. Elizabeth Shane
   Mr. Alexander Silver
   Dr. Xiao-Jing Wang

   Staff and Guests

   The following NIAMS staff and guests attended:

   Staff

   Ms. Alexandra Adams Ms. Marysheyla Alvarez Mr. Steven Austin Dr. Carl Baker Ms. Pamela Beheler Ms. Susan Bettendorf Ms. Elizabeth Bouras Dr. Amanda Boyce Mr. Gahan Breithaupt Ms. La’Tanya Burton Ms. Justine Buschman Dr. Robert Carter Dr. Faye Chen Dr. Ricardo Cibotti Mr. Richard Clark Ms. Barbara Cohn Ms. Robin DiLiello Dr. Jonelle Drugan Mr. Erik Edgerton Ms. Elizabeth Elliott Ms. Barbara Footer Dr. Nancy Garrick Ms. Valerie Green Ms. Gail Hamilton Mr. Andrew Jones Dr. Stephen Katz Ms. Shahnaz Khan Dr. Gayle Lester Dr. Helen Lin Ms. Anita Linde Ms. Mimi Lising 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. Clairisse Mullsteff Ms. Melinda Nelson Ms. Anna Nicholson Dr. Glen Nuckolls Dr. John O’Shea Dr. James Panagis Ms. Vivian Pham Ms. Kelli Reid Ms. Trish Reynolds Dr. Kathy Salaita Dr. Susana Serrate-Sztein Dr. William Sharrock Dr. Richard Siegel Ms. Sheila Simmons Dr. Kentner Singleton Ms. Theresa Smith Ms. Allisen Stewart Ms. Robyn Strachan Ms. Yen Thach Ms. Jamie Thompson Dr. Phil Tonkins Dr. Hung Tseng Dr. Fei Wang Dr. Yan Wang Dr. Chuck Washabaugh Ms. Sara Rosario Wilson Dr. Xincheng Zheng Dr. David Zielinski

   Guests

   Ms. Jessica Avery, Office of Science Policy, NIH
   Mr. Randy Beranek, National Psoriasis Foundation
   Mr. Michael Bykowski, Consolidated Solutions and Innovations
   Dr. Gail Cassell, Scientific Management Review Board, NIH/Eli Lilly and Company
   Ms. Sara Chang, Lupus Foundation of America
   Mr. Dane Christiansen, Marfan Foundation
   Mr. Richard Gelula, National Alopecia Areata Foundation
   Ms. Petra Harvey, Osteognesis Imperfecta Foundation
   Ms. Kim Holmes, IQ Solutions
   Ms. Leah Howard, National Psoriasis Foundation
   Ms. Mary Beth Huber, Osteogenesis Imperfecta Foundation
   Ms. Juanita Marner, Office of Science Policy, NIH
   Dr. Pamela McInnes, National Center for Advancing Translational Sciences, NIH
   Mr. Simit Pandya, American Academy of Orthopaedic Surgeons
   Dr. Andrew Robertson, National Psoriasis Foundation
   Mr. Nate Robinson, IQ Solutions
   Ms. Michelle Rodrigues, SRI International
   Ms. Kirstie Saltsman, IQ Solutions
   Mr. Richard Taffet, Ehlers-Danlos National Foundation
   Dr. Marina Volkov, Office of Science Policy, NIH

2. CONSIDERATION OF MINUTES

   A motion was made, seconded, and passed to accept with no changes the minutes of the 81st NAMSAC meeting, held on September 10, 2013.

3. FUTURE COUNCIL MEETING DATES

   Future Council meetings are currently planned for the following dates:

   June 3, 2014
   September 8, 2014
   February 4, 2015
   June 16, 2015
   September 8, 2015

4. DIRECTOR'S REPORT AND DISCUSSION

   Dr. Katz welcomed Council members, NIAMS staff, and guests, and opened his Director’s Report by introducing five ad hoc Council members:

   • Dr. Gary A. Koretzky, Dean of Weill Cornell Graduate School of Medical Sciences in New York, who has made numerous contributions to the understanding of signal transduction mechanisms in hematopoietic cells. Dr. Koretzky has served as the Chair of NIAMS’ Board of Scientific Counselors (BSC).
   • Dr. Grace Pavlath, Professor in the Department of Pharmacology at the Emory University School of Medicine. Dr. Pavlath has also served on the NIAMS BSC and her research focuses on cell signaling and the pathways that regulate muscle cell migration, muscle regeneration and fibrosis, and satellite cell function as well as the molecular defects that lead to oculopharyngeal muscular dystrophy.
   • Dr. Gwen Powell Todd, a professional educator and marketer who applies her leadership, teaching, and coaching expertise to the areas of business, education, healthcare, and community service. Dr. Powell Todd has also served on the NIAMS BSC and has been an active member of the Institute’s National Multicultural Outreach Initiative African American Work Group since its inception. She is also an advisor to the Cicatricial Alopecia Research Foundation.
   • Dr. Christy Sandborg, Professor of Pediatrics in the Division of Pediatric Rheumatology at Stanford University School of Medicine. Dr. Sandborg is a leader in pediatric rheumatology research and is committed to providing training and research opportunities to nurture and challenge future pediatric rheumatologists and subspecialists. Dr. Sandborg’s research encompasses the design of new models of care for children with complex chronic illness.
   • Mr. Alexander Silver, Co-Founding Partner of P2 Capital Partners, LLC, in New York City. Mr. Silver has been an active member in the NIAMS Coalition since 2010, and is the Founder and Chairman of the Jackson Gabriel Silver Foundation, a non-profit organization focused on epidermolysis bullosa (EB). The Foundation supports research at the University of Southern California that has produced a potential new drug treatment for EB. It exemplifies how advocates and scientists can provide hope for patients and their families by working together.

   Personnel Changes at the NIH and the NIAMS

   At the NIH level:

   • Dr. George Koob joined the NIH last month as the Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Dr. Koob formerly worked at the Scripps Research Institute.
   • Dr. Phillip Bourne as the first Associate Director for Data Sciences. Dr. Bourne comes to the NIH from the University of California, San Diego and will lead NIH’s Big Data Initiative.
   • A few weeks prior to this Council meeting, NIH Director Dr. Francis Collins announced that Dr. Hannah Valantine would be joining the NIH as its first Chief Officer for Scientific Workforce Diversity. Dr. Valantine, who served as Senior Associate Dean for Diversity and Leadership at Stanford School of Medicine and Professor of Cardiovascular Medicine at Stanford University Medical Center, will begin her new position in the spring. She will work closely with all NIH Institutes and Centers (ICs), with the grantee community, and with community stakeholders as the NIH moves forward in this important area.

   At the NIAMS level:

   • Dr. Mariana Kaplan has joined the Institute as Chief of the new Systemic Autoimmunity Branch within the NIAMS Intramural Research Program (IRP). Dr. Kaplan was Professor of Internal Medicine in the Division of Rheumatology, Department of Internal Medicine at the University of Michigan, where she held several NIH grants. Dr. Kaplan is a rheumatologist whose research primarily focuses on lupus. Dr. Katz reminded the group that the NIAMS IRP is featured in this month’s Shorttakes newsletter, which is available on the NIAMS website.
   • Dr. David Zielinski, current Chief of the Institute’s Science Policy and Planning Branch, has accepted the position of Associate Dean of Science on the Faculty of Arts and Sciences at Columbia University.
   • Dr. Stephanie Burrows has joined the Branch as a Science Policy Analyst—she comes to the NIAMS from the National Heart, Lung, and Blood Institute (NHLBI), where she worked on policy, planning, reporting, and legislative activities for almost 10 years. Dr. Burrows holds a Ph.D. in Biology from Massachusetts Institute of Technology and is NIAMS’ primary Science Policy Analyst for research and training activities related to its skin and rheumatic diseases portfolio.

   Update on Budget and Congressional Activities

   Dr. Katz reported that in FY 2013, the NIAMS funded 260 research project grants (RPGs), new and competing continuation applications for a success rate of 15.9%—a figure higher than last year’s rate of 15.6%. The overall NIH success rate for FY 2013 is estimated to be 16.8%. Dr. Katz noted that the Institute works extremely hard to be transparent with regard to its funding activities, and posts this information on the Institute’s website as soon as it becomes available.

   With regard to FY 2014, President Obama signed the Omnibus appropriations bill that will fund the Federal government for the remainder of FY 2014 on Friday, January 17. For the entire NIH, the FY 2014 budget will be $30.15 billion, approximately $1 billion above the 2014 post-sequester budget. The NIAMS FY 2014 budget will be $520 million, a $15 million increase over the Institute’s budget for FY 2013. This 2.7% increase is similar to what most other ICs received (Dr. Katz noted that last year, the NIAMS budget decreased by roughly 5.1%). The NIAMS has posted its interim funding plan on its website.

   Highlights of Selected Recent Scientific Advances

   • A study conducted by Dr. Dan Littman’s team at the New York University School of Medicine suggests that the microbiome plays an important role in rheumatoid arthritis. The researchers compared the gut microbiome of people with new-onset, untreated rheumatoid arthritis to that of healthy controls, patients with rheumatoid arthritis who were receiving treatment, and patients with psoriatic arthritis. They found that the bacterium Prevotella copri was more abundant in patients with new-onset, untreated rheumatoid arthritis than in the other groups, suggesting that the bacterium contributes to the development of the disease. More extensive studies are needed to determine whether P. copri can cause rheumatoid arthritis, but if so, therapies that target the bacterium could help to prevent the disease or delay its onset (Elife. 2013 Nov 5;2(0). pii: e01202. PMID: 24192039).
   • Skin lesions in people with atopic dermatitis are abundantly colonized by Staphylococcus aureus, whereas most healthy individuals do not harbor the bacterium. A research team led by Dr. Gabriel Núñez at the University of Michigan Medical School wanted to determine whether there is a mechanistic link between S. aureus colonization and the development of the disease. The team discovered that a toxin produced by the bacterium promotes the skin reaction seen in atopic dermatitis. Their results indicate that the toxin triggers the activation of mast cells, leading to inflammation. The findings also provide an impetus for further studies to determine whether inhibition of the bacterial toxin could benefit individuals who are susceptible to atopic dermatitis (Nature. 2013 Nov 21;503(7476):397-401. Epub 2013 Oct 30. PMID: 24172897).
   • Two recent advances have been made in the understanding of chronic itch, a very challenging symptom for patients and one for which there currently are no effective therapies. The first of the two studies, from Dr. Diana Bautista’s group at the University of California, Berkeley, focused on a signaling protein called thymic stromal lymphopoietin (TSLP), which is known to play a role in atopic dermatitis. TSLP is produced by keratinocytes and when injected into the skin of mice, it causes rapid and incessant scratching—a behavioral sign of itch. It has long been assumed that TSLP acts on the cells of the immune system; however, Dr. Bautista’s group demonstrated that TSLP released by keratinocytes acts directly on skin sensory neurons by binding to receptors expressed on the surface of the nerve cells. Although a considerable amount of research is focused on the immune system, these results suggest that therapies targeting the nervous system may be effective (Cell. 2013 Oct 10;155(2):285-95. Epub 2013 Oct 3. PMID: 24094650).
   • The second chronic itch study was conducted by Dr. Zhou-Feng Chen’s team at Washington University School of Medicine. The researchers created genetically modified mice that express an activated form of a protein called B-Raf in a specific group of sensory neurons. These mice develop chronic itch and represent a unique new resource for studying chronic itch and for testing treatments to control it (J Clin Invest. 2013 Oct 15. pii: 70528. [Epub ahead of print] PMID: 24216512.
   • Scleroderma is incredibly heterogeneous, resulting in a broad spectrum of disease severity. Determining prognosis is difficult because at present, there are no clinically useful biomarkers that predict which patients will progress to severe disease. Dr. Robert Lafyatis at the Boston University School of Medicine, collaborating with colleagues in Europe and the United States, found that high levels of a protein called CXCL4 correlates with the presence and progression of serious complications such as pulmonary fibrosis and pulmonary arterial hypertension. The levels of CXCL4 in circulation were significantly elevated in patients with scleroderma compared to healthy people and to patients with other autoimmune diseases such as lupus or ankylosing spondylitis, or in people with liver fibrosis. The findings suggest that CXCL4 holds promise both as a predictive biomarker to help clinicians identify patients that might benefit from aggressive therapy, and as a potential therapeutic target (N Engl J Med. 2013 Dec 18. [Epub ahead of print]. PMID: 24350901).
   • In another scleroderma-related advance, a research team led by Drs. Bert Vogelstein and Antony Rosen at the Johns Hopkins University School of Medicine has found evidence that scleroderma may actually be triggered by an immune response to cancer in some patients. Patients with autoantibodies to a protein called RPC1 are known to have a high incidence of cancer. Often, the onset of scleroderma occurs around the time of the cancer diagnosis. The researchers found that cancers from these patients had a mutation in the gene that codes for the RPC1 protein. The resulting mutant RPC1 protein triggered an immune response that targets not only mutant RPC1, but also the normal version, leading to scleroderma. The findings reveal a possible new direction for developing therapies for this subset of patients, namely strategies that focus on detecting, diagnosing, and treating the underlying cancer. The study also suggests the need for more research to explore the potential cancerous origins of other autoimmune diseases (Science. 2013 Dec 5. [Epub ahead of print]. PMID: 24310608).
   • Mouse studies conducted by Dr. Gerard Karsenty’s laboratory at Columbia University demonstrated that the bone-derived hormone osteocalcin is capable of crossing the blood-brain barrier, where it interacts with neurons to influence brain structure and the animals’ behavior. Furthermore, the researchers showed that maternal osteocalcin crosses the placenta during pregnancy, where it allows the brain to develop normally before the embryos are able to synthesize this hormone on their own. It is well understood that mice and humans differ in many details of metabolism and physiology, but these provocative findings provide a context for studies of osteocalcin function in humans (Cell. 2013 Sep 26;155(1):228-41. PMID: 24074871).
   • Work by Dr. Sundeep Khosla at the Mayo Clinic is showing that a common childhood injury could be indicative of poor bone health. Although previous research has not found a connection between forearm fractures in pediatric patients and bone health as measured by conventional DXA, this study included two unique features. Patients were grouped according to whether their injury was caused by mild trauma or from a more forceful impact and the researchers used an advanced imaging method called high-resolution peripheral quantitative computed tomography (HRpQCT) that assesses bone strength, bone quality, and bone structure. Compared with the children without fracture, the children in the mild trauma fracture group showed compromised bone strength and bone quality. In contrast, those children whose fractures occurred during a more forceful trauma did not show any significant differences in bone quality compared with their uninjured peers. These results suggest that children who break a bone after a mild trauma are at increased risk of future fractures and could benefit from dietary changes and physical activities to help them build stronger bones (Bone Miner Res. 2013 Aug 19. [Epub ahead of print]. PMID: 23959563).

   Update on NIH and NIAMS Activities and Plans

   Dr. Katz called Council members’ attention to a Nature commentary written by NIH Director Dr. Francis Collins and NIH Principal Deputy Director Dr. Larry Tabak (this article was sent to Council members in advance of the meeting). The commentary describes NIH plans to enhance the reproducibility of research and follows on from Dr. Tabak’s September 2013 presentation to the Council.

   During the week before this Council meeting, NIAMS Deputy Director Dr. Robert Carter, Dr. Susana Serrate-Sztein (Director of the NIAMS Division of Skin and Rheumatic Diseases), and Ms. Anita Linde (Director of the NIAMS Office of Science Policy, Planning, and Communications) participated in launching the Accelerating Medicines Partnership (AMP). Supported by a partnership between the NIH, the Foundation for the National Institutes of Health (FNIH), 10 pharmaceutical companies, and several advocacy organizations including the Lupus Foundation of America and the Rheumatology Research Foundation, AMP investigators will identify and validate promising biological pathways and targets in three disease areas: (1) Alzheimer’s disease, (2) diabetes, and (3) the autoimmune disorders rheumatoid arthritis and lupus. The AMP will begin with pilot projects lasting 3-5 years. For each pilot, scientists will develop research plans for characterizing biomarkers and selecting biological targets most likely to respond to new therapies.

   The NIAMS is involved in an FNIH Biomarkers Consortium effort to track the progression of osteoporosis more precisely and pave the way for more effective treatments. Dr. Joan McGowan (Director of the NIAMS Division of Musculoskeletal Diseases) has played a leading role in this activity, as has Dr. Gayle Lester (Director of NIAMS’ Clinical Osteoarthritis and Diagnostic Imaging Program), who is chairing the 3-year project.

   Also under Dr. McGowan’s leadership, the NIAMS—along with the National Institute on Aging (NIA) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)—is championing a potential NIH Common Fund initiative to encourage research into the mechanisms by which physical activity improves health.

   The Institute works closely with the NIAMS Coalition, which provides a forum through which professional and voluntary organizations can coordinate among themselves and with the NIAMS. In November 2013, more than 40 representatives from Coalition member organizations participated in the Institute’s Coalition Outreach and Education Meeting entitled “Creating Connections for Science.” The group received welcoming remarks by NIH Director Dr. Francis Collins, who emphasized the importance of the unique perspectives that patient advocates and professional societies bring to the NIH. Dr. Katz commented that the Institute greatly values the partnerships it has through the NIAMS Coalition and its members. He introduced a new Co-Chair of the NIAMS Coalition, Ms. Leah Howard from the National Psoriasis Foundation. Ms. Howard is taking the place of Ms. Kim Cantor from the Lupus Foundation of America, who has completed her 2-year term. Ms. Howard joins current NIAMS Coalition Co-Chair Ms. Sarah D’Orsie of the American Academy of Physical Medicine and Rehabilitation.

   The NIAMS continues to communicate with patients, health care and research professionals, and the general public through its social media presence. Dr. Katz acknowledged the efforts of Mr. Rich Clark, of NIAMS’ Office of Science Policy, Planning, and Communications OSPPC), and the other members of the Institute’s social media team. Recently, this group coordinated and participated in Twitter chats about the Patient-Reported Outcomes Measurement System (PROMIS) and the broader topic of arthritis.

   Building on the success of its 2013 efforts to ensure that the results of the Institute’s research investments and health messages reach all Americans, the NIAMS’ National Multicultural Outreach Initiative has reissued its series of health planners for 2014. Dr. Katz thanked Dr. Carter, Ms. Linde, and Ms. Mimi Lising (Writer/Editor in the NIAMS OSPPC) for their leadership in this effort. He also acknowledged the valuable input the Institute received from Council members, particularly Drs. Ted Mala, Director of the Traditional Healing Clinic at the South Central Foundation, and Gwen Powell Todd. Approximately 120,000 of these planners have been distributed.

   • Analysis of Review Group Outputs (ARGO): Dr. Katz commented that biomedical science is evolving rapidly, but the overall structure of NIH peer review study sections is not as agile. The NIH is considering ways to systematically evaluate the characteristics of study section “behavior” or “performance” to ensure that resources are directed towards the most compelling opportunities.
   • Maximizing Efficiencies of Core Facilities: Dr. Katz explained that there are many core facilities at academic medical centers; the question is how best to maximize them to develop innovative technologies. A national database of core facility resources is one strategy under consideration to enhance the utilization of core resources. At the next Council meeting, an update will be given on the NIAMS’ recent evaluation of its own centers program.
   • Changes to the NIH Biosketch: The Leadership Forum included discussion on potential changes to the biosketch section of grant applications. Although the details have not yet been worked out, approaches are being considered that will allow applicants to better describe their contributions to the field.
   • New Approaches to Supporting Innovative Science: Various ICs have developed new ideas for developing support for researchers who are at vulnerable stages in their career. Many fall out of the research enterprise because they are tied to a particular program and not given enough latitude.

5. SCIENTIFIC MANAGEMENT REVIEW BOARD (SMRB) RECOMMENDATIONS ON APPROACHES TO ASSESS THE VALUE OF BIOMEDICAL RESEARCH SUPPORTED BY NIH

   Dr. Gail Cassell, Chair of the NIH SMRB Working Group on Approaches to Assess the Value of Biomedical Research Supported by NIH, presented the Working Group’s findings and recommendations. She began by explaining that the NIH requested that the SMRB identify appropriate parameters and approaches for assessing and communicating the value of biomedical research supported by the NIH in July 2012.

   Dr. Cassell noted that the NIH is responsible for investing public funds in biomedical research and should use these funds effectively. There are increasing opportunities and expectations to improve assessment efforts, and the results of reliable assessments can be used to demonstrate accountability, enhance management, and increase public awareness. Furthermore, assessment results can improve priority-setting and decision-making processes at the NIH, but it is first necessary to ensure assessments are sound. Dr. Cassell highlighted two challenges associated with the assessment of biomedical research supported by the NIH: (1) proper attribution is very difficult due to time lag and the complexity of the biomedical research and public health enterprises; and (2) although some of what the NIH produces is easy to measure, these markers of progress do not begin to fully capture the wealth of NIH’s contributions to the world.

   In its deliberations, the SMRB Working Group on Approaches to Assess the Value of Biomedical Research Supported by NIH considered outputs and outcomes/goals in three categories of value: science, health, and broader societal impacts. Dr. Cassell presented the main findings and recommendations of the Working Group, which were developed over a one-year period. She began by describing the overarching findings and recommendations, and subsequently presented additional details concerning: the value of NIH knowledge and its application; multiple factors and contributors involved in determining NIH’s contributions to a given outcome; contributions and effects of many stakeholders; and the benefit of coordinating assessment efforts. Dr. Cassell also addressed the need for data collection and storage, varied methodologies for assessments, and clear communication with the appropriate audience.

   Dr. Cassell summarized the recommendations by stating that the NIH needs to be more rigorous in assessing the value of supported research. To do so, the ICs and NIH Offices should coordinate their assessment efforts and adopt a systematic, comprehensive, and strategic approach. This will help to produce a credible, representative snapshot of the overall value of NIH-funded research. She noted that the NIH needs better tools, techniques, and databases to conduct sound assessments and that the NIH should communicate the results of assessments to the public and help the public understand the biomedical research process.

   Discussion

   Dr. Katz opened the discussion session by noting that the SMRB spent a tremendous amount of time listening to renowned experts in this field—not just from within the United States, but also including experts from Singapore, England, and other parts of the world. Testimony from these experts indicated that there is no single best approach to assessing the value of biomedical research.

   Mr. Silver commented that this is an incredibly complex problem that, from a private sector perspective, would be approached through the use of case studies. He suggested that one or more case studies be developed from each of the categories of value considered by the SMRB in this effort (science, health, and broader societal impacts). The multiple constituencies that benefit from NIH-supported research would have tremendous interest in these case studies and in the larger goal of assessing the value of biomedical research supported by the NIH . He asked about how best to bring in the private sector, non-profit groups, and other stakeholders to assist in these efforts (especially in terms of defraying the costs associated with this work). Dr. Cassell indicated that the Working Group generally felt that case studies would be an effective approach and agreed that selecting powerful case studies in each of the categories would work. She also agreed that there is a need to involve stakeholders outside of the NIH.

   Dr. Katz commented that the final report clearly indicates that a multi-pronged approach is required. He also emphasized the importance of involving groups from outside of the NIH and pointed to the critical need for public-private partnerships to make the assessment of biomedical research supported by the NIH most effective and useful.

   Dr. Cassell noted that through expert testimony, the SMRB clearly heard that the NIH should be the driver of most biomedical research in the future, as it is today. Experts also indicated that there is a need to give more attention to how the NIH can best collaborate in a proactive, progressive manner with countries around the world. There are case studies showing that major investments made by multiple countries have successfully solved difficult problems and have been well worth the collective effort. She commented that developing case studies and involving groups from outside the NIH are important next steps.

   In response to a question regarding the formation of a trans-NIH committee on assessments, Dr. Cassell indicated that this group will develop consistent policies for how the assessment data would be collected, coordinated, and tracked while taking advantage of NIH’s Big Data initiative. The group will be focused more on data collection than on data assessment or analysis of value. Evaluation of the data will be conducted by an extramural body (although it is unclear as of yet which group will be asked to carry out the evaluation). Dr. Marina Volkov of NIH’s Office of Science Policy noted that the trans-NIH committee also will be involved with implementation, relying heavily on the advice and guidance from outside experts.

   Dr. Bonewald emphasized the need for objectivity with regard to developing approaches to assessing the value of biomedical research supported by the NIH and suggested that experts with no vested interest in the NIH or the United States be utilized in this effort. Dr. Cassell agreed with the need for objectivity, but noted that many countries benefit from NIH funding—finding experts with absolutely no vested interest in the United States and/or NIH may be difficult. Nevertheless, international expert input would be extremely helpful to the process.

6. COUNCIL OPERATING PROCEDURES

   Council Executive Secretary, Dr. Laura K. Moen (Director of the NIAMS Division of Extramural Research Activities), explained that on an annual basis, the Statement of Understanding between the Council and NIAMS is reviewed. She presented the Statement of Understanding, which describes the Council’s operating procedures.

   No Council members expressed any concerns or had any questions regarding the Statement of Understanding between the Council and the NIAMS. The Statement of Understanding for the Council’s operating procedures was accepted for the next year.

7. CONTEMPORARY CLINICAL TRIALS ISSUES FOR NIH

   Dr. Pamela McInnes, who was recently named Deputy Director of NIH’s National Center for Advancing Translational Sciences, explained that the trans-NIH Clinical Trials Working Group was formed as an outcome of discussions on NIH’s management of clinical trials during the September 2012 NIH Leadership Forum. These discussions were influenced by the National Cancer Institute’s (NCI) response to a 2010 Institute of Medicine (IOM) report titled A National Cancer Clinical Trials System for the 21st Century as well as information gathered as part of a requirement for the NIH to respond to a Congressional directive on the management of clinical trials. The Clinical Trials Working Group was charged with: (1) considering a range of issues and concerns related to NIH’s role in the stewardship, leadership, and management of clinical trials and clinical trial networks; (2) evaluating options for NIH actions; and (3) making recommendations to the NIH Director to enhance the quality and transparency of NIH-supported clinical trials.

   Dr. McInnes co-chaired the Clinical Trials Working Group with Dr. James Doroshow of NCI. The Working Group included representatives from every IC (Dr. McGowan represented the NIAMS) as well as numerous additional staff who provided technical support. The Working Group identified a series of guiding principles and best practices to lead its efforts. First, interventional clinical trials are complex and challenging. Second, there is no area closer to the NIH mission of improving the nation’s health. Third, trials must be conducted at the highest levels of reproducibility to generate the quality of knowledge capable of changing clinical practice, improving patient care, and developing new products. Dr. McInnes explained that the essential components of these guiding principles/best practices are the high quality of the science, up-to-date knowledge and training of investigators and study personnel, and effective systems to support and oversee any clinical trial.

   Early in the process, the Clinical Trials Working Group identified that network infrastructures were already receiving significant attention from all funding ICs, and so it focused its work primarily on the investigator-initiated clinical trials, an area for which some serious gaps were noted and for which support infrastructure is not always in place. Leadership from each IC was approached and asked to provide input on what they perceived as the most pressing issues related to the management and oversight of clinical trials. This input was gathered, analyzed, and categorized. Five subgroups were formed to address priority areas within the major topics that were identified:

   • Subgroup 1: Clinical trials acceptance policies, award mechanims, and funding decisions
   • Subgroup 2: Monitoring systems for accrual for clinical trials
   • Subgroup 3: Institutional review board (IRB) issues in multi-site trials
   • Subgroup 4: Publication and dissemination of clinical trial results
   • Subgroup 5: Good clinical practice (GCP) training for all clinical trials investigators and NIH staff managing clinical trials

   An additional topic identified by IC leadership related to independent safety and data quality oversight was referred to an NIH group that will address it in following up on an Office of the Inspector General report on data safety monitoring board-related issues. Dr. McInnes commented that even though this subject was not assigned to a specific subgroup, the Clinical Trials Working Group strongly endorsed the concept that independent safety and data quality oversight should be tailored commensurate with risk and is an essential element in the management of any clinical trial.

   Dr. McInnes then reviewed the Clinical Trials Working Group’s eight primary recommendations:

   • ICs should be encouraged to fully utilize their authorities to establish and apply research priorities in selecting specific clinical trial applications for review and award, and to determine that the investment rests on a robust scientific, regulatory, and operational foundation.
   • Peer review of clinical trial applications must be made more rigorous by ensuring that review panels include appropriate clinical trial experts as well as basic science experts to evaluate the rigor and validity of any preclinical data provided. Secondary review by Advisory Councils should ensure that clinical trials address important IC clinical research priorities.
   • ICs should be strongly encouraged to incorporate trial-specific language into Notices of Grant Award to establish timelines for startup, set feasibility milestones based on accrual, and specify expectations for downstream data-sharing and publication.
   • ICs need appropriate clinical trials monitoring systems and tools so that oversight of funded trials is in place, optimized, and permits the collection of essential data. Core elements should be standardized across the NIH to allow for inter-operability across IC systems to facilitate data pooling. Frequency of data collection should be tailored, but should be more frequent than annually, and cannot rely solely on the annual grant progress report.
   • Program Officers responsible for clinical trials have a critical stewardship role and need appropriate initial and continuing training on the fundamentals of conducting and monitoring clinical trials. ICs should have an administrative infrastructure with authority and accountability to empower Program Officers to implement warranted actions.
   • The NIH should strongly support streamlining IRB review of multi-site studies. This includes endorsing the Advanced Notice of Proposed Rulemaking for changes in 45 CFR Part 46; developing standard language that ICs can use as a term of award if mandating the use of a single IRB of record for multi-site studies; and developing and posting a public/Web-accessible toolbox for reliance agreements between institutions such that a single IRB can function as the IRB of record for multi-site clinical studies.
   • The NIH should adopt the position that dissemination of results is a requirement for successful completion of clinical trial funding.
   • All personnel involved in clinical trials research supported by NIH grants or contracts, as well as NIH staff overseeing or managing clinical trials, should receive documented GCP training.

   These recommendations were submitted to the NIH Steering Committee and IC Directors. Dr. McInnes indicated that the recommendations were very well received, and that a separate group is working on the implementation process.

   Discussion

   Dr. Katz asked about the Working Group’s recommendations with regard to the IC pre-approval process. Dr. McInnes explained that the Clinical Trials Working Group’s recommendation is to allow ICs the authority to grant approval for clinical trials prior to submission without necessarily being restricted by the $500,000 cap. Council members were reminded that pre-approval is required for applications of more than $500,000 and that the pre-approval process involves a review by a subgroup of Council members (NIAMS’ own Clinical Trials Working Group) working with NIAMS staff.

   Dr. Carter explained that it is difficult for Council members on the NIAMS Clinical Trials Working Group to evaluate an application during the pre-approval process because the information that can be provided to them is restricted. The NIAMS Clinical Trials Working Group only has access to the Letter of Intent associated with each application and therefore cannot conduct a scientific review or, in some cases, even form an educated opinion regarding whether the trial will make a difference in its field. Council member Dr. Alice Pentland, also a member of the NIAMS Clinical Trials Working Group, added that the Working Group usually only looks at one such application during its meetings. If all applications were presented to the Working Group, it would allow for making an easier determination of impact because the applications could be compared with each other. Dr. Katz commented that he hopes that as a result of the recommendations of the trans-NIH Clinical Trials Working Group, applications of less than $500,000 will be looked at in the same way (i.e., reviewed by the Council’s Clinical Trials Working Group and then by NIAMS study section) as those for more than $500,000.

   With regard to the recommendation on the dissemination of results, Dr. McInnes commented that large, important studies with negative outcomes still get published. Underpowered studies tend not to get published in traditional journals. It is hoped that the ClinicalTrials.gov system will be improved so that each study includes at least a summary of the study, explanation of the study design, inclusion and exclusion criteria, and the final outcome. Dr. Koretzky noted that studies that are not accepted for publication in peer-reviewed journals often are included in public databases where there is not as much scrutiny as there is with ClinicalTrials.gov and that the results could be misleading (e.g., if it is not made clear that a study was underpowered and therefore its results may not have answered the question being examined). Dr. McInnes agreed, noting that there have been some discussions about allowing comments to be added to some of these databases in the hopes that the community polices itself.

   Dr. Gary Firestein, Professor in the Department of Medicine at the University of California San Diego School of Medicine, asked whether the Clinical Trials Working Group discussed IRB over-reach—instances in which IRBs perform a scientific review rather than focusing on safety and risk. This is often a major impediment to study approval. Dr. Firestein noted that IRBs should be focusing on their primary charge, which is balancing safety and risk. Dr. McInnes explained that this issue was discussed, and that there does not appear to be a single, simple solution.

   Dr. Firestein also commented on issues that interfere with using trusted and reliable systems. Dr. Firestein serves as Chair of the University of California Clinical and Translational Science Awards (CTSA) Consortium and explained that within this system, there is a well-known and understood set of policies. There is a tension in that IRBs in many instances are unwilling to cede control to these types of systems. This issue will require NIH mandates or aggressive stances from institutional officials to keep IRBs focused on their primary mission. Dr. McInnes agreed that this is a challenge, particularly in certain states that present legal issues (e.g., Pennsylvania), but overall, significant progress is being made in overcoming these types of challenges. Dr. Katz suggested that the solution from NIH’s standpoint is to strongly encourage use of a single IRB.

   In response to a question from Dr. Mala about how NIH ICs can be brought up to the same level with regard to implementing the Clinical Trials Working Group recommendations, Dr. Katz explained that approaches range from using the Office of the NIH Director’s influence to NIH working groups such as the trans-NIH Clinical Trials Working Group that includes representation from all ICs. Dr. Katz also noted that the NIAMS is moving toward suggesting common IRBs for some studies to increase efficiency and reduce the time required before studies can begin. Dr. McGowan explained that an implementation committee has been formed and will follow up on the recommendations from the trans-NIH Clinical Trials Working Group.

8. UPDATE ON THE NIAMS LONG-RANGE PLAN

   Ms. Linde provided the Council with an update on the NIAMS Long-Range Plan for fiscal years 2015-2019, which applies to the extramural portion of the Institute’s research portfolio. The plan was initially developed through collaboration among NIAMS’ extramural scientific divisions and with considerable input from the outside community. She explained that the purpose of the NIAMS Long-Range Plan is to: (1) provide a broad scientific outline that describes current and emerging arthritis and musculoskeletal and skin research, (2) communicate the Institute’s perspective to its various constituencies and communities, (3) serve as a resource for all who are interested in NIAMS activities, and (4) encourage the best investigator-initiated research ideas. Ms. Linde emphasized that the Long-Range Plan is not intended to be prescriptive or restrictive in any way.

   The NIAMS Long-Range Plan for FY 2015-2019 will include the following five disease- and tissue-specific topics: (1) arthritis and rheumatic diseases, (2) skin biology and diseases (3) bone biology and diseases, (4) muscle biology and diseases, and (5) musculoskeletal biology and diseases. Additionally, the Plan will include cross-cutting topics in the areas of health disparities, training and career development, and information dissemination activities.

   Ms. Linde described the Plan’s development process to date, reminding Council members that they were briefed on the Plan initially during their September 2013 meeting. Between October 2013 and January 2014, 68 comments (from both individuals and organizations) were received in response to a Request for Information (RFI). This input is being incorporated in the Plan. In November 2013, the Plan’s development process was shared with the NIAMS Coalition and additional input was encouraged. A series of listening sessions that included 80 participants was held in December 2013. These listening sessions included broad segments of NIAMS’ research communities. Prior to taking part in the listening sessions, each participant canvassed their professional colleagues for additional feedback. Next steps include presenting the draft Long-Range Plan to the Council and NIAMS Coalition in June 2014, soliciting additional comments on the Plan through another RFI in the summer of 2014, and presenting the final plan to the Council and posting it to the NIAMS website in September 2014.

   Additional scientific resources being utilized to help shape the Long-Range Plan include NIAMS roundtable discussion topics, scientific planning retreat topics, and other NIH plans and trans-NIH processes (e.g., the NIH Health Disparities Strategic Plan, Muscular Dystrophy Coordinating Committee Action Plan, etc.).

   Dr. McGowan briefly described the focal points from the NIAMS listening sessions on musculoskeletal biology and diseases, bone biology and diseases, and muscle biology and diseases.

   Dr. Serrate-Sztein then described the major topics arising from the NIAMS listening sessions on skin biology and diseases as well arthritis and rheumatic diseases. She noted that there was remarkable agreement between both communities regarding the current status of the Plan and the areas identified for additional development and highlighted as emerging opportunities.

   Dr. Katz added that training was also identified as an additional topic that spanned many of these areas.

   Discussion

   Dr. Mala also asked whether the Long-Range Plan would be a dynamic document, such that emerging opportunities could be included in the future when they are identified. Dr. Katz explained that the Long-Range Plan is not a strategic plan and can evolve. The Plan represents a partnership with the Institute’s scientific communities that outlines where the NIAMS is, where it is going, and where important opportunities lie. It allows for the incorporation of emerging opportunities that have yet to be identified. Congress frequently requests copies of the Plan to help it gain a sense of the scope of the NIAMS and the crossover between the interests of the NIAMS and other NIH ICs.

9. ENHANCING REPRODUCIBILITY UPDATE FROM NIAMS

   Dr. Kathy Salaita, Chief of the NIAMS Scientific Review Branch, briefly updated the Council on the Institute’s participation in an NIH-wide effort to increase reproducibility and rigor in research. She explained that the exploratory clinical trials R21 funding announcement is expected to be re-issued this spring. The timing of this re-issue presents the NIAMS with an opportunity to incorporate a renewed focus on scientific rigor and reproducibility into the funding announcement. She explained that the clinical trials R21 review is done by the NIAMS’ chartered clinical trials study section, AMSC.

   If all goes as planned, the receipt date for the applications that will be submitted in response to the new funding announcement is in July 2014. These applications will be reviewed during the November 2014 AMSC Clinical Trials Study Section meeting and then reviewed by Council members during the January 2015 Council meeting. Reviewers attending the March AMSC meeting will be briefed regarding these upcoming changes and will receive formal training before the November review meeting. Dr. Salaita explained that the critique templates used to incorporate the elements from the funding announcement will be modified in a manner that does not add unnecessary burden to reviewers.

   The new expectations regarding scientific premise, rigor, and study design will be clearly communicated to the applicants through the funding announcement. In addition to the standard review criteria, applications will be evaluated from two perspectives:

   • The scientific rationale and premise of the study. Principal Investigators (PIs) will be asked to demonstrate that there is adequate scientific foundation to justify the proposed research. This justification can be provided through rigorous literature citations and if the PI has data, those data can be presented for review (Dr. Salaita reminded the group that R21 applicants are not required to present preliminary data). Data from other sources can also be submitted.
   • Evaluation of the study design. This will include methods, the plans for analysis, outcome measures, and the feasibility of the study design. Applications should include descriptions of the target populations, participant eligibility, and the proposed intervention.

   Dr. Salaita explained that the NIAMS does have plans in place for outreach to the scientific community to raise awareness of these upcoming changes.

   Discussion

   Dr. Shane asked if the Institute would be changing the page length of the R21 applications in response to the changes described by Dr. Salaita. Dr. Salaita indicated that the page length will not change, although different materials can be included in the appendices.

10. 2014 STATE OF THE NIAMS IRP

    Dr. O’Shea reported that despite sequestration and the government shutdown in 2013, last year was a successful one for the NIAMS IRP. He reviewed the high-level goals for the NIAMS IRP that were presented to the Council in 2007: (1) maintain the research infrastructure during “less than robust” growth, and (2) enhance clinical/translational research. Around that time, the NIAMS invested in next-generation gene sequencing technology, capabilities, and infrastructure. Dr. O’Shea commented that this investment has paid off handsomely, leading to the publication of a series of high-quality papers in prestigious peer-reviewed journals.

    As an example, he described recent work from the laboratory of Dr. Vittorio Sartorelli, Senior Investigator in the NIAMS Laboratory of Muscle Stem Cells and Gene Regulation. With the completion of the human genome, it was found that only 2% of the genome is genes. Although most of the genome is not composed of genes, 80% of it is active and most of the genome is transcribed. The current view is that a large portion of the genome is switches which contain most of the genetic susceptibility to disease. Gaps in current knowledge include determining how the 98% of the genome that is not made up of genes can inform the field about the acquisition of cell identity, and how all of the genomic switches are linked to cell signaling. Dr. Sartorelli and colleagues showed that enhancer RNA (eRNA) is important for allowing access of transcription factors to master regulators such as MyoD. In collaboration with Dr. Rafael Casellas, Chief of the NIAMS Laboratory of Molecular Immunogenetics, Dr. Sartorelli carried out work to identify what parts of the genome are interacting with one another by studying developmental changes in the enhancer landscape of broadly expressed genes.

    Other examples of recent work and accomplishments from within the NIAMS IRP include:

    • Work by Dr. Golnaz Vahedi, Research Fellow in the NIAMS Molecular Immunology and Inflammation Branch, and colleagues indicates that there is only about a 50% overlap in the creation of the roughly 20,000 active switches found in Th1 and Th2 cells, which are considered to be very similar. Furthermore, in comparing Th1 and Th2 cells to embryonic stem cells and macrophages, the researchers found only 90 shared switches, lending further evidence to the concept that the creation of these switches is very cell specific.
    • Investigators are continuing their work on superenhancers/stretch enhancers, which are large clusters of transcriptional enhancers that drive cell identity. In particular, NIAMS IRP researchers are trying to identify the most relevant T cell switches, determine how they are controlled, and understand how effective drugs influence superenhancers.
    • Dr. Markus Hafner, Group Leader of NIAMS’ Laboratory of Muscle Stem Cells and Gene Regulation, has developed a technique called PAR-CLIP to gain additional understanding of how RNA interacts with proteins—there are 3 billion nucleotides in the genome, 80% of which are being transcribed, and this work is beginning to shed light on their functions. The NIAMS is hoping to develop a genome editing core in partnership with the NCI and/or National Institute on Aging.
    • The NIAMS IRP is expanding its computational biology core by building up its whole exome/genome sequencing capacity (in collaboration with Merck) as well as its computational biology capabilities. These efforts are resulting in the discovery of new diseases. An example is sting-associated vasculopathy with onset in infancy (SAVI), discovered by Dr. Raphaela Goldbach-Mansky, Section Head of the NIAMS Pediatric Translational Research Branch.
    • Dr. Goldbach-Mansky has also developed a number of strategies for treating neonatal-onset multisystem inflammatory disease (NOMID), one of which led to the U.S. Food and Drug Administration’s approval of the drug anakinra for treating this disease.
    • To enhance clinical/translational research within the NIAMS IRP, the Institute created the NIAMS Scholars Program as well as a new training program in partnership with Children’s National Medical Center. The NIAMS has also been actively recruiting clinical faculty.
    • A number of NIAMS IRP researchers have been recognized for their work:
      • Dr. Goldbach-Mansky was inducted into the American Society for Clinical Investigation.
      • Dr. Alasdair Steven, Senior Investigator in the NIAMS Laboratory of Structural Biology Research, received the Eduard Kallenberg Medal.
      • Dr. O’Shea will be awarded the Ross Prize in Molecular Medicine.

    Dr. O’Shea explained that NIH Director Dr. Francis Collins has asked each Institute to develop a long-range plan for their IRP. Dr. Koretzky is chairing a subcommittee of the Board of Scientific Counselors (comprising scientists from within and outside of the NIH) to forecast what the IRP should look like in 10 years, and how it should reach these goals. The subcommittee is working to identify current and projected scientific opportunities, existing strengths and weaknesses, the unique capabilities of the IRP, potential long-term investments, leveraging resources across the IRP, training opportunities, and other issues that can enhance the IRP for the future.

11. SUMMARY OF K FORUM AND OTHER LISTENING SESSIONS

    Due to time constraints, this presentation was rescheduled for the next Council meeting.

12. CONSIDERATION OF APPLICATIONS

    In closed session, the Council reviewed a total of 820 applications in closed session requesting $943,308,686 in total costs and recommended 820 for $943,308,686 in total costs.

13. SPECIAL ACTIONS

    This portion of the meeting occurred during closed session.

14. NEW DEVELOPMENTS IN ARTHRITIS BIOLOGY

    This portion of the meeting occurred during closed session.

15. ADJOURNMENT

    The 82nd National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Meeting was adjourned at 2:45 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.