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

Minutes of the 87th Meeting
8:30 a.m. to 2:20 p.m.

September 8, 2015 Council Webcast

1. CALL TO ORDER

   The 87th meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council (NAMSAC) was held on September 8, 2015, 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. Joan E. Bechtold
   Dr. Sherine E. Gabriel
   Ms. Michelle Hofhine
   Dr. Michael V. Holers
   Dr. Sundeep Khosla
   Dr. Gary A. Koretzky
   Dr. Katherine Mathews
   Dr. Martha M. Murray
   Dr. Amy Paller
   Dr. Grace Pavlath
   Dr. Anthony E. Rankin
   Dr. Christy I. Sandborg
   Mr. Richard F. Seiden
   Dr. Elizabeth Shane (via teleconference)
   Mr. Alexander Silver (via teleconference)
   Ms. Elizabeth Smith
   Dr. Gwendolyn L. Powell Todd
   Dr. Xiao-Jing Wang

   Staff and Guests

   The following NIAMS staff and guests attended:

   Staff

   Ms. Alexandra Adams Dr. Lee Alekel Dr. Carl Baker Ms. Pamela Beheler Ms. Elizabeth Bouras Dr. Amanda Boyce Mr. Gahan Breithaupt Dr. Stephanie Burrows Ms. Justine Buschman Dr. Robert Carter Dr. Faye Chen Ms. Jennifer Chi Dr. Thomas Cheever Dr. Ricardo Cibotti Mr. Richard Clark Ms. Robin DiLiello Ms. Theresa Do Dr. Jonelle Drugan Ms. Barbara Footer Dr. Nancy Garrick Ms. Gail Hamilton Ms. Sara Hwang Ms. Aleisha James Dr. Chao Jiang Mr. Andrew Jones Dr. Stephen I. Katz Ms. Mary Beth Kester Ms. Shahnaz Khan Ms. Stephanie Kreider Mr. Mark Langer

   Dr. Gayle Lester Dr. Helen Lin Ms. Anita Linde Ms. Leslie Littlejohn Dr. Yin Liu Dr. Kan Ma Dr. Marie Mancini Dr. Su-Yau Mao Dr. Kathryn Marron Dr. Joan McGowan Ms. Leslie McIntire Dr. Laura K. Moen Ms. Anna Nicholson Dr. John O’Shea Dr. James Panagis Ms. Vivian Pham Ms. Reaya Reuss Ms. Trish Reynolds Dr. Kathy Salaita Dr. Susana Serrate-Sztein Ms. Allisen Stewart Ms. Yen Thach Dr. Phil Tonkins Dr. Hung Tseng Dr. Bernadette Tyree Dr. Fei Wang Dr. Xibin Wang Dr. Chuck Washabaugh Dr. James Witter Dr. Xincheng Zheng

   Guests

   Dr. Rebecca Baker, Office of Clinical Research and Bioethics Policy, Office of the Director, NIH
   Mr. Mark Beckwith, Nevus Outreach
   Ms. Laura Berkson, Office of Legislative Policy and Analysis, Office of the Director, NIH
   Mr. William Branson, Events Management Branch, Office of the Director, NIH
   Mr. Mike Bykowski, Consolidated Solutions and Innovations
   Mr. Jason Ezzelle, ICON
   Ms. Adrienne Hallett, Office of Legislative Policy and Analysis, Office of the Director, NIH
   Ms. Patti Brandt Hansberger, Office of Legislative Policy and Analysis, Office of the Director, NIH
   Dr. John Holden, Department of Veterans Affairs
   Ms. Mary Beth Huber, Osteogenesis Imperfecta Foundation
   Ms. Kim James, IQ Solutions
   Dr. Joseph Laakso, Endocrine Society
   Dr. Clifford Rosen, Maine Medical Center Research Institute (via teleconference)
   Ms. Kirstie Saltsman, IQ Solutions
   Mr. Taylor Scott, Nevus Outreach
   Ms. Ellen Seiden
   Ms. Kristin Stephenson, Muscular Dystrophy Association
   Mr. Joseph Stewart, Health and Medical Council of Washington
   Dr. Larry Tabak, NIH Principal Deputy Director
   Dr. Maria Vassileva, Social and Scientific Systems, Inc.
   Ms. Randi Williams, KAI Research, Inc.

2. CONSIDERATION OF MINUTES

   A motion was made, seconded, and passed to accept with one minor change (noted below) the minutes of the 86th NAMSAC meeting, held on June 16, 2015.

   • Dr. Laura K. Moen, NAMSAC Executive Secretary and Director of the NIAMS Division of Extramural Research Activities, agreed to amend the June 16, 2015, minutes to indicate that Council member Dr. Anthony Rankin, Chief of Orthopaedic Surgery at Providence Hospital and Clinical Professor of Orthopaedic Surgery at Howard University, participated by teleconference.

    

3. FUTURE COUNCIL MEETING DATES

   Future Council meetings are currently planned for the following dates:

   February 2, 2016
   June 7, 2016
   September 13, 2016
   January 25, 2017
   May 24, 2017
   September 6, 2017

4. DIRECTOR'S REPORT AND DISCUSSION

   Dr. Katz began the meeting by welcoming participants and thanking Council members for their attendance and input. He informed the Council that the public portion of this NAMSAC meeting was being videocast.

   Dr. Katz noted that the following NAMSAC members have completed their 4-year terms on the Council:

   • Ms. Michelle Hofhine, Vice President of Marketing at Accredited Home Care Services
   • Dr. Katherine Mathews, Professor in the Departments of Pediatrics and Neurology at the University of Iowa
   • Ms. Elizabeth Smith, a patient advocate
   • Dr. Xiao-Jing Wang, Professor in the Department of Pathology at the University of Colorado, Denver

   Dr. Katz thanked each for their exemplary service and many contributions to the Council’s deliberations. Dr. Katz also welcomed former Council member Dr. Clifford Rosen, Executive Director of the Maine Medical Center Research Institute and Chair of the NIAMS Arthritis and Musculoskeletal and Skin Diseases Clinical Trials (AMSC) study section. Dr. Rosen was invited to participate in this NAMSAC meeting via teleconference and provide comments on strategies for strengthening the Institute’s clinical trials portfolio.

   Update on Budget and Congressional Outreach Activities

   On October 1, 2015, the Federal Government is due to begin its new fiscal year (FY). It is expected that FY 2016 will begin with a Continuing Resolution. This means that the NIH will be able to continue operating at its FY 2015 budget level. In keeping with the Institute’s commitment to transparency, it will post its FY 2016 interim paylines as soon as they are available.

   Dr. Katz noted that the House and Senate are both interested in the NIH strategic planning and priority-setting process, including how select pay decisions are made. Congress has asked the NIH to develop a formal strategic plan as part of the FY 2015 appropriations bill. He reminded Council that the Institute reserves a small portion of each year’s budget for projects that address subjects of particular relevance to its scientific and health priorities, even if their assigned scores and percentile rankings would not qualify for funding under the current payline. There is no type of application process for this type of select funding. Instead, suggestions come from NIAMS staff, and Council members’ input in this area is welcome. Dr. Katz also noted that the NIAMS select pay process is described on the Institute’s website, along with other pertinent IC funding information.

   The NIAMS always appreciates opportunities to educate members of Congress about the NIH, the NIAMS, and the importance of the work being supported. Since the June NAMSAC meeting, Dr. Katz has participated in a series of courtesy visits organized by the American Academy of Dermatology Association (AADA). He and AADA President Dr. Mark Lebwohl spent a day on Capitol Hill meeting with Senators Richard Durbin (D-IL), Jack Reed (D-RI), and Bill Cassidy (R-LA), and with Representatives Charles Dent (R-PA) and Chuck Fleischmann (R-TN). Members were interested in how NIH-funded basic research contributes to new treatments, the costs of these new treatments, ways to speed the development process, and support for new investigators.

   Personnel Changes at the NIH and NIAMS

   At the NIH

   • Dr. Alan Guttmacher announced last month that he will retire as Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NICHD Deputy Director Dr. Catherine Spong will serve as the Acting Director while the NIH conducts a national search for a permanent replacement.
   • Dr. William Riley, who has been the Acting Director of NIH’s Office of Behavioral and Social Sciences Research (OBSSR) since May 2014, is now OBSSR’s permanent Director.

    

   At the NIAMS

   • Dr. Thomas Cheever recently joined the Institute as a Program Director within the Division of Musculoskeletal Diseases. Dr. Cheever is a Ph.D.-trained neuroscientist with a strong scientific background in neuromuscular biology and pathophysiology, spinal muscular atrophy, and muscular dystrophy. He will manage the Institute’s Muscle Disorders and Therapies Program. Before joining the NIAMS, Dr. Cheever was a Health Science Policy Analyst within the National Institute of Neurological Disorders and Stroke (NINDS).
   • Dr. Yin Liu has joined the NIAMS as a Scientific Review Officer. Dr. Liu comes from the NIAMS Intramural Research Program (IRP), where he served as a Staff Scientist in the Translational Autoinflammatory Disease Section. Before joining the IRP in 2010, Dr. Liu spent three years as a Staff Scientist with the National Cancer Institute’s (NCI) Experimental Immunology Branch.

    

   NIH-Wide and NIAMS Scientific Activities

   Dr. Katz asked for Council members’ input on NIAMS’ existing suite of clinical research initiatives and on new approaches the Institute could consider to encourage the clinical research community to submit ideas for high-quality, high-impact trials that are likely to change clinical practice. The current clinical trials pathway emerged when the NIAMS examined this issue 5 years ago. At that time, the Institute formed a dedicated study section for the review of applications submitted under these initiatives and established a working group of the Council to advise the Institute on the Letters of Request that investigators submit to the NIAMS in advance of their applications. Now, as part of its ongoing stewardship responsibilities, the NIAMS is re-examining its clinical trials strategy and soliciting input on:

   • Ways to improve the suite of Funding Opportunity Announcements (FOAs) to provide adequate opportunities for all types of clinical trials
   • The types of support necessary for the different stages of clinical trial implementation
   • Ways the Institute can improve the early review of a concept for a future clinical trial
   • Other ways to optimize NIAMS’ support of clinical trials.

   Also relevant to clinical research is the work that NIH Deputy Director for Science, Outreach, and Policy Dr. Kathy Hudson has been doing to update the Common Rule for the protection of human subjects in research. The current regulations (which have been in place since 1991) were developed at a time when research was predominantly conducted at universities, colleges, and medical institutions, and each study generally took place at a single site. The expansion of research into new scientific disciplines, such as genomics, along with an increase in multisite studies and significant advances in technology, highlight the need to update the regulatory framework. A more participatory model of research has also emerged, with individuals looking for more active engagement with the research enterprise. During the September 2014 NAMSAC meeting, Dr. Hudson described the Advanced Notice of Proposed Rulemaking that included key reforms to: (1) simplify consent documents, (2) calibrate oversight to level of risk, (3) increase privacy and security safeguards for research with biospecimens and data, (4) facilitate broad participation in research, and (5) streamline Institutional Review Board (IRB) review. The Department of Health and Human Services (HHS) addressed the input it received and published an updated proposal in the form of a Notice of Proposed Rulemaking. The updated Common Rule would apply to all clinical trials, regardless of funding source, if they are conducted at a U.S. institution that receives funding for research involving human participants from a Common Rule agency. Dr. Katz asked Council members and their respective institutions/professional societies to provide any comments within the next 90 days.

   Dr. Katz noted that the NIH is continuing to incorporate public feedback into its plans for the President’s Precision Medicine Initiative, a national research cohort of one million or more volunteers. This summer, the NIH continued its series of workshops and launched several other outreach activities to shape the cohort of volunteers who will share their genetic data, biological samples, diet/lifestyle information, and electronic health records so that researchers can put precision medicine into large-scale practice.

   The NIAMS has had a long-standing commitment to engaging patient communities and other members of the public in its activities. On October 27, 2015, it will host an Outreach and Education Day for members of the NIAMS Coalition, an independent consortium of national professional and voluntary organizations that are committed to raising awareness about NIAMS-funded research. These biennial meetings provide a forum for Coalition members to share best practices for connecting science to the public while gaining a better understanding of how the NIH operates. The Institute recently joined a few of its Coalition partners, NIH’s National Center for Complementary and Integrative Health (NCCIH), and the Centers for Disease Control and Prevention (CDC) for a Twitter chat about arthritis. The ABC Network’s Chief Health and Medical Editor Dr. Richard Besser hosted the event, which was estimated to reach more than 600,000 Twitter accounts.

   Anyone interested in NIAMS activities can subscribe to the monthly NIAMS Update. The August issue featured a guest letter by Dr. Janine Clayton, Director of NIH’s Office of Research on Women’s Health. Dr. Clayton emphasized the new NIH policy on the inclusion of sex analyses in preclinical research. Beginning in the fall of 2016, scientists will account for the possible role of sex as a biological variable in any vertebrate animal and human studies they propose. Council members were encouraged to review the list of frequently asked questions that the Office of Extramural Research has developed to guide applicants.

   In celebration of Hispanic Heritage Month, the NIAMS has refreshed its Spanish language portal. The new site features quick and easy navigation tools to help Spanish-speaking individuals identify and locate NIAMS health topics. It also includes landing pages that provide all information on a given topic in one place. Additional enhancements include improved access to NIAMS’ Spanish-language health information and related federal resources, information on participating in clinical research studies, and responsive design that makes the site easier to read on mobile devices.

   The Institute is also improving the digital accessibility of information for American Indians and Alaska Natives. On behalf of the Trans-NIH American Indian/Alaska Native Health Communications and Information Work Group, the NIAMS has launched a quarterly e-newsletter titled Honoring Health: Resources for American Indians and Alaska Natives. The inaugural issue features healthy aging, with content from the NIA.

   Highlights of Selected Recent Scientific Advances

   • Council member Dr. Grace Pavlath (Senior Vice President and Scientific Program Director at the Muscular Dystrophy Association as well as Professor in the Department of Pharmacology at Emory University School of Medicine) and colleagues recently uncovered some of the ways repair and maintenance properties of muscle satellite cells vary with the types of skeletal muscles where the cells reside. In contrast with limb muscle satellite cells that cycle between active and inactive states, depending on whether the muscle has recently been stressed, the investigators determined that nasal pharyngeal satellite cells are nearly always in their active form and regularly fuse with muscle fibers. Unlike in limb skeletal muscles, continuous satellite cell fusion in the pharyngeal muscles appears necessary for fiber maintenance. This discovery provides insight into swallowing problems associated with aging and dystrophies (Stem Cells. 2015 Jul 14. doi: 10.1002/stem.2098. [Epub ahead of print] PMID: 26178867).
   • NIAMS grantee Dr. Roberto Caricchio and colleagues at Temple University School of Medicine built on findings that DNA/protein complexes can induce lupus-like disease in animal models and determined that interactions between the bacterial protein curli and fragments of bacterial DNA trigger the production of molecules known to play a role in lupus pathology. The researchers showed that these curli-DNA complexes, which are present in biofilms of many types of commonly occurring bacteria, can accelerate lupus pathology in lupus-prone mice and can even provoke autoimmunity in normal, control mice. The finding that biofilm components trigger immune responses suggests that strategies to address underlying functions—instead of, or in addition to, treatments that suppress autoimmunity—may also benefit lupus patients (Immunity. 2015 Jun 16;42(6):1171-84. doi: 10.1016/j.immuni.2015.06.002. PMID: 26084027).
   • In a multicenter study, Dr. Frank Roemer of Boston University School of Medicine and colleagues compared the x-rays and MRIs from more than 350 people in the Osteoarthritis Initiative who developed osteoarthritis (OA) and an equal number of participants who did not develop OA. They identified several MRI features that preceded radiographic OA by 1 or 2 years. Major risk factors included effusion synovitis and other signs of inflammation, bone marrow lesions at various locations in the leg bones, and medial meniscal damage. At that point, cartilage damage (long considered the pathogenic hallmark of OA) was not associated with an increased risk of subsequent radiographic OA. Having 5 or 6 of the structural changes that were considered statistically meaningful risk factors dramatically increases a person’s risk of developing OA within 1 or 2 years. Each of these, individually or in combination, could be viewed as a candidate target for OA interventions, moving the field beyond the hyaline cartilage targets that have been the focus of many years of research (Arthritis Rheumatol. 2015 May;67(8):2085-96. doi: 10.1002/art.39176. PMID: 25940308).
   • A research team led by Dr. Stephen Messier at Wake Forest School of Medicine found that weight loss does not appear to slow the joint degeneration that characterizes knee OA, although patients report feeling and moving better. As part of the Intensive Diet and Exercise for Arthritis (IDEA) Study, the investigators measured joint space narrowing by x-ray and several of the same parameters examined by Dr. Roemer and colleagues noted above. Despite the previously reported improvements in pain and function, the investigators could not detect significant improvements in knee joint structure. This held true regardless of whether participants were assigned to a diet only, diet and exercise, or exercise only group, showing that weight loss and exercise should continue to be important components of OA treatment strategies. However, the mechanism for these improvements remains unclear, and the lack of a correlation between clinical and structural changes in knee OA related to exercise and weight loss has significance with regard to clinical trials if improvements in pain, function, and structure are required for proof of efficacy (Osteoarthritis Cartilage. 2015 Jul;23(7):1090-8. doi: 10.1016/j.joca.2015.03.034. Epub 2015 Apr 15. PMID: 25887362).
   • NIAMS K23 awardee Dr. Veena Ranganath from the University of California, Los Angeles and an international team of researchers surveyed and examined a subset of patients who were participating in the Treatment of Early Aggressive Rheumatoid Arthritis Trial, a study of the effectiveness of different treatment options for patients with rheumatoid arthritis (RA). The investigators compared the extent to which a patient’s symptoms were in remission with MRI findings of the patient’s wrist. Despite being a small study of 118 participants, Dr. Ranganath’s team observed ongoing evidence of damage as seen on MRI, even though patients were clinically in remission. This suggests that clinicians should think carefully before stopping or scaling back on therapy for patients whose symptoms appear to be in remission, at least until more data about the risks and benefits of withdrawing or continuing these therapies long-term have been collected (Arthritis Care Res. 2015 Jul;67(7):929-39. doi: 10.1002/acr.22541. PMID: 25581612).
   • A recent publication by a team of investigators including NIAMS grantees Drs. Craig McDonald (University of California, Davis), Eric Hoffman (Children’s National Medical Center, Washington, DC), and Lee Sweeney (University of Florida) describes the identification of 44 proteins that could potentially serve as biomarkers because they are present in significantly different amounts between Duchenne muscular dystrophy (DMD) patients and age-matched controls. Plotting a protein’s concentration with patient age resulted in 4 different patterns. Of the 44 proteins identified, 18 were elevated in young patients as compared with their age-matched controls, then fell to near normal levels as patients matured. Another 15 of the potential biomarkers did not change concentration with age but were present at significantly lower amounts in DMD patients than in normal controls. Of the remaining proteins, concentrations of 6 were significantly elevated in DMD patients at most ages, and 5 were found at comparable levels in young patients and controls, but differed significantly later in life. Some of these proteins might provide better methods for monitoring the effectiveness of new therapies, lead to better patient stratification in future clinical trials, and lend additional support to new therapeutic approaches being pursued (Proc Natl Acad Sci USA. 2015 Jun 9;112(23):7153-8. doi: 10.1073/pnas.1507719112. Epub 2015 May 26. PMID: 26039989).
   • A group led by Dr. Robert Lafyatis of Boston University Medical Center examined whether the expression of molecular markers of disease-related scarring of the skin could be used to monitor patient response to an experimental compound that inhibits TGF-beta signaling. In both clinical and molecular evaluations, these patients showed profound decreases in skin scarring and in TGF-beta expression. The results strongly indicate not only that molecular profiles can serve as biomarkers of therapeutic efficacy, but also that targeting the TGF-beta in these patients is an effective strategy to block scarring. The discovery that TGF-beta inhibition reduces scar formation also may provide a major advance for scarring-mediated organ dysfunction common to many other diseases including lung fibrosis, kidney fibrosis, and cardiac fibrosis that occurs after heart attacks and during heart failure (J Clin Invest. 2015 Jul 1;125(7):2795-807. doi: 10.1172/JCI77958. Epub 2015 Jun 22. PMID: 26098215).

   Discussion

   To open the discussion session, Dr. Katz asked Dr. Pavlath for any additional comments on her study of nasopharyngeal muscles and the need for satellite or stem cells. Dr. Pavlath indicated that this work emphasizes the fact that satellite cell biology is different in different muscles, and that the field should not focus only on studies that examine limb muscles. She also noted that the group’s followup studies are using animal models of disease to see how those cells are affected.

   Dr. Mathews commented that the MRI work in DMD described by Dr. Katz is extremely promising; the protein and urine biomarkers will require significant work, but it is hoped that a biomarker related to disease progression can be identified.

   Dr. Katz explained that all of the NIAMS-funded clinical studies featured in his Director’s Report address pressing research questions that could dramatically improve patient care. That is, ultimately, NIAMS’ goal for every project in its clinical research portfolio, but the process for meeting this goal varies with every question. Council members were reminded of his request for input regarding the Institute’s efforts to identify and support the most impactful clinical studies to improve the lives of people affected by diseases and conditions within its mission.

   Council Member Discussion about NIAMS Existing Clinical Trials Initiatives

   The NIAMS clinical trials study section, AMSC, was formed as a result of the NIAMS interest in improving the evaluation of clinical trials to provide better information for funding decisions and brings together clinical trialists, investigators, biologists, and statisticians. Dr. Rosen noted that AMSC has successfully added review of observational studies and planning grants and that may open up opportunities for other investigators.

   Dr. Katz noted that the Institute has begun the process of rotating members on the Clinical Trials Study Section. He also explained that part of the Institute’s concept clearance process has always involved the submission of ideas from the scientific community, followed by examination from a working group of the Council. Clinical trials are extremely expensive to conduct; as a result, the NIAMS and other NIH ICs review and evaluate them very carefully to determine not only whether these applications are well done, but also whether the work they represent will make a difference in clinical practice.

   Council member Dr. Elizabeth Shane, Professor of Medicine and Vice Chair for Clinical and Epidemiological Research at Columbia University College of Physicians and Surgeons, suggested that the clinical research community is not fully aware of the steps that the Institute and its Clinical Trials Study Section have taken to identify the best and most impactful clinical studies. Finding a way to convey the Study Section’s work, progress, and successes to the community would be helpful. Council member Alexander Silver, Chairman of the Jackson Gabriel Silver Foundation agreed, adding that developing a simple way to make this work accessible to the community in a format that is easy to digest would be of great value. Dr. Katz commented that the Institute has focused several issues of its monthly newsletters on the way it has approached its review of clinical trials. Additional methods for disseminating this information may be pursued.

   Dr. Sundeep Khosla, Professor of Medicine and Professor of Physiology at the Mayo Clinic and a member of the Council, reminded the group that NIH’s definition of a clinical trial is fairly unequivocal when some behavioral or pharmaceutical interventions are involved. He described a scenario in which a modest-sized R01 application that may involve basic or mouse studies is followed by an application for a human study with some intervention to better understand underlying mechanisms. Using NIH’s definition, this would be considered as a clinical trial grant, but its purpose is very different than that of a phase II or III clinical trial. He asked if the investigators of these types of studies, which build team science and should be encouraged, should go through a pre-approval process, or apply for a planning grant, or whether there are more effective mechanisms. He also asked if these applications should be reviewed by the AMSC and if there are other processes in place to ensure that these types of studies are not overlooked. Dr. Shane indicated that she shares some of these concerns, particularly from the perspective of a clinical investigator and conducting mechanistic science.

   Dr. Serrate-Sztein explained that the NIH has expanded its definition of a clinical trial. Protocols that involve an intervention in humans in order to study a mechanism are now included as part of that definition. If NIH’s definition of a clinical trial is applied to mechanistic studies, it introduces a number of regulatory requirements (e.g., human subject concerns, safety issues, etc.), but they are somewhat different for mechanistic trials compared with traditional intervention studies that, for example, are looking for a clinical outcome. Dr. Khosla opined that traditional intervention studies and mechanistic studies are fundamentally different and should not be reviewed using the same approach. He noted that the regulatory requirements are less of a concern compared with the way in which the Institute reviews the applications.

   Dr. Carter reminded the group that the new NIH definition of a clinical trial includes language indicating that the trial not only include an intervention, but that the intervention have an effect on a health-related outcome. It may be possible that the Institute could differentiate between trials that have health-related outcomes and those that have mechanistic outcomes while still keeping with NIH’s definition. Dr. Rosen indicated that the AMSC is well positioned to review studies of the type described by Dr. Khosla. He also suggested that the charge and the work of the AMSC could be publicized at some of the specialty meetings. Dr. Shane suggested that Study Section members with expertise in different areas could write short perspective pieces for their fields’ primary journals that explain the Study Section to their particular constituencies.

   Council member Dr. Gary Koretzky, Dean of Weill Cornell Graduate School and Senior Associate Dean for Research at Weill Cornell Medical College applauded the NIAMS for the careful thought that went into the AMSC. He suggested that the number of grants described by Dr. Khosla that are submitted to the Institute will be increasing because investigators who are conducting basic mechanistic studies are being strongly encouraged to push their research to examine the question of whether or not their findings will affect humans.

   Council member Dr. Sherine Gabriel, Dean of Rutgers Robert Wood Johnson Medical School, noted that observational studies can inform post-interventional or post-marketing efforts and asked if the NIAMS has given thought to these types of studies (which can feed back to, and inform, future clinical trials). Dr. Katz indicated that the Institute does consider these.

   Dr. Khosla commented that the AMSC is ideally suited to review the interventional clinical trial, for which a planning grant is required, large amounts of money are involved, and the Institute must be certain it is funding the best projects. In his opinion, the purely human studies with small numbers of subjects involving an intervention to examine underlying mechanisms in humans could also go to the AMSC. However, a planning grant for these types of studies may not be appropriate. The truly translational studies that involve basic and human studies may or may not belong in the AMSC, and it is not clear that the basic study sections have the necessary expertise. Those grants are particularly challenging in terms of review. Dr. Rosen suggested that the R21 mechanism could be utilized more frequently for proof of concept-type applications, and that the Study Section is well suited for reviewing these.

5. MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITY IN HUMANS: AN NIH COMMON FUND PROGRAM

   Dr. McGowan, Director of the Division of Musculoskeletal Diseases, provided a brief background on the NIH Common Fund. Common Fund programs address important challenges that are of high priority for the NIH overall, have an opportunity for impact, and are expected to benefit biomedical research in a broad manner. Common Fund programs are limited to a maximum of 10 years and deliverables from these programs are designed to catalyze change via new biological paradigms, datasets, technologies, research/training methods, etc. These initiatives must also be sufficiently complex that a coordinated, trans-NIH effort is necessary.

   Both the public and the scientific community have been interested in physical activity, defined by the CDC as “Any bodily movement produced by the contraction of skeletal muscle that increases energy expenditure above a basal level.” A review of the NIH physical activity research portfolio indicated that there has been much attention given to enhancing the performance of muscles (e.g., athletic performance) as well as the effect of different types of physical activity on the health outcomes of particular mission areas of the individual ICs (e.g., the effect of physical activity on depression, cardiovascular disease, cancer, etc.). Many questions remain however. For example:

   • What are the cellular and circulating molecules that transduce the benefits of physical activity within and among tissues?
   • What are the primary mechanisms that affect all tissues/organs in response to physical activity?
   • If some cancers are prevented by physical activity, what are the mechanisms?

    

   The goal of the 2016 Common Fund initiative titled "The Molecular Transducers of Physical Activity in Humans" (MoTrPAC) is to discover the molecules and pathways responsible for physical activity’s benefits for human health. Dr. McGowan explained that the exploitation of the molecular mechanisms for the many well-documented health benefits of physical activity is hindered by a lack of knowledge about the signaling molecules that are altered by physical activity and communicate its effect among cells, tissues, and organs.

   The MoTrPAC effort is being led by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the NIAMS. A working group, including representatives from 14 ICs and 3 Offices from the NIH Office of the Director, has been formed to coordinate the initiative’s activities. Dr. McGowan described the genesis of this Common Fund initiative, beginning with discussions on exercise and muscle from a 2010 Fall NIAMS Roundtable. The Common Fund proposal was approved in 2013.

   A series of webinars led to a 2014 meeting titled "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits." Presentations and discussions at this meeting emphasized the: (1) challenges imposed by both the integrative and the intermittent nature of physical activity, (2) tremendous discovery potential of applying "-omics" technologies to understand inter-organ crosstalk and biological networking systems during physical activity, and (3) need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human physical activity trials. A white paper based on the discussions and presentations from the webinars and the meeting was developed and published in the July 2015 issue of Cell Metabolism.

   On June 11, 2015, the NIH issued a press release indicating that the Molecular Transducers of Physical Activity in Humans Program was moving forward. The initiative is being funded at approximately $170 million for 6 years (FY 2016-2021). Goals of the project are to: (1) map the molecular changes that occur after physical activity in humans, and (2) place all of the information into a user-friendly database that any researcher can access to develop hypotheses about how physical activity improves or preserves health. The map of molecular transducers will be developed as part of this effort, and samples will be made available to investigators for additional study. Samples will include different types of tissues from both child and adult subjects.

   FOAs related to this initiative will be issued soon. Additional information can be found online at Molecular Transducers.

   Discussion

   Dr. Katz remarked that the NIAMS enthusiastically supports and participates in many trans-NIH programs. He noted that the scientific community is well-positioned to take advantage of a coordinated effort in this area. Dr. Katz emphasized that an enormous amount of effort has gone into the development of this initiative.

   Dr. Rosen congratulated Dr. McGowan and the Institute, adding that there is a tremendous need for this work. He anticipates that the response from the research community will be overwhelming. Dr. Shane echoed Dr. Rosen’s comments, indicating that there will likely be a significant influx of grant applications to this exciting and timely initiative. Dr. Katz indicated that the Institute will keep the Council informed on the progress of this initiative.

6. THE NIH ACTION PLAN FOR LUPUS RESEARCH

   Ms. Anita Linde, Director of the NIAMS Office of Science Policy, Planning and Communications (OSPPC) reminded Council members that the Institute is leading the Action Plan for Lupus Research as the convener of the Lupus Federal Working Group, on behalf of the entire NIH. Roughly 1 year ago, the Congressional Lupus Caucus wrote to the NIH and asked that it develop the Action Plan for Lupus Research to guide the agency’s investment in the disease over the coming years. The Plan builds on an earlier research plan that the NIH put forth in 2007.

   Once finalized, the Plan will provide a broad outline that the scientific community can use in considering future opportunities for lupus research across the basic, translational, and clinical research arenas. The Plan will also be used to communicate NIH’s perspective about lupus and what it sees as the needs and opportunities going forward. It is hoped that the Plan will serve as a useful resource for all constituencies and communities that are interested in propelling lupus research forward in the future as well as a framework to encourage the best investigator-initiated research ideas.

   Ms. Linde provided an overview of the participatory process that has taken place in the last several months as the Plan has been developed. Steps in this process have included substantive input from both internal NIH scientific experts in autoimmunity and lupus as well as considerable feedback from the broader extramural community. A Request for Information (RFI) was issued at the outset of this process to assist in building the framework for the new Action Plan. Additionally, a webinar was held this spring with more than 60 individuals from the scientific community to obtain additional input. Based on their feedback, the draft Action Plan was developed (the draft Plan is currently available on the NIAMS website for review and comment). Additionally, significant input has been obtained from many NIH ICs. It is anticipated that the final Action Plan will be delivered to the Congressional Lupus Caucus later this year. Throughout the process, the NIAMS has been providing regular updates to the Congressional Lupus Caucus, the NAMSAC, and the Lupus Federal Working Group.

   Based on the webinar discussions and comments on the draft Plan, a revised Action Plan was drafted (organized according to the key topics discussed during the webinar) and a period of public comment is ongoing to provide feedback on the revised Plan. The Plan will be finalized once the second period for public comment is closed. The NIAMS will provide an update on the Plan to the Lupus Federal Working Group in October 2015. Dr. Serrate-Sztein thanked and acknowledged the NIAMS staff members who have played crucial roles in the Plan’s development.

   Discussion

   Dr. Holers asked about prioritization of efforts, noting that the draft Action Plan outlines opportunities, but does not prescribe a path moving forward. Dr. Katz explained that each of the groups that provided feedback on the Plan has its own set of priorities. The Institute itself does not set priorities for these groups; rather, it is left to the community to set priorities based on the science.

7. DEVELOPING THE NIH-WIDE STRATEGIC PLAN AND THE FY16 NATIONAL CHILDREN’S STUDY REDIRECTION PLAN

   Principal Deputy Director Dr. Larry Tabak reminded Council members that Consolidated and Further Continuing Appropriations Act of 2015 (H.R. 83), enacted December 16, 2014, mandates that the NIH shall submit to Congress an NIH-wide 5-year scientific Strategic Plan no later than 1 year after enactment. Additionally, the pending 21st Century Cures Act includes a discussion about what the Strategic Plan should include (e.g., ensuring that rare and pediatric diseases remain a priority, maintaining the biomedical research workforce, etc.). The Strategic Plan should be a living document that will help guide the NIH in fulfilling its mission over the next 5 years, articulate approaches and opportunities that are forward-looking and inspirational, and identify major trans-NIH themes that will advance biomedical research. The Plan should not describe all of the important current and future NIH activities, nor should it address the priorities of the individual Institutes, Centers, and Offices (ICOs), because each ICO has its own strategic plan (and each will be referenced in the NIH Strategic Plan).

   Dr. Tabak presented an overview of the Strategic Plan’s framework, including:

   • An overview that articulates the mission of the NIH while attempting to capture the unique climate of today’s biomedical research tempered with the constraints facing the community in the face of lost purchasing power over the last decade.
   • A series of areas of opportunity that apply across biomedicine, highlighted by the interconnectivity and the continuous nature of fundamental science, health promotion/disease prevention, and treatments/cures. For each area of opportunity, the Strategic Plan will include a description of emerging, highlight specific examples of recent breakthroughs, align with the larger HHS Strategic Plan, and emphasize the unique role of the NIH within HHS.
   • Unifying principles that explain how the NIH sets priorities and how it enhances stewardship of the public funds with which it is entrusted. For each of these, the Strategic Plan will include a description of the current status and/or emerging opportunities, highlight specific examples of recent breakthroughs, and align them with the HHS Strategic Plan.

   RFIs and webinars have been used to solicit public feedback on the NIH Strategic Plan. Roughly 1,000 individuals have been engaged through these approaches. Dr. Tabak is presenting the Plan to the National Advisory Councils of 21 NIH ICOs. He has heard broad feedback in terms of emphasizing implementation science, interdisciplinary science, peer review, workforce training, the need for systems approaches, more explicit inclusion of behavioral and social sciences, and patient partnerships. He has also received specific feedback on promoting the use of big data and emphasizing population health.

   Discussion

   Dr. Koretzky asked if the Strategic Plan would include information on increasing the impact of public-private partnerships. Dr. Tabak indicated that this will be included under the section on stewardship. The Plan also notes that the NIH needs new partners, particularly in the private sector. He cited the Accelerating Medicines Partnership, with which the NIAMS is engaged, as an example.

   Dr. Katz asked about concerns that some diseases are referenced in the Plan while others are not, and how the NIH Strategic Plan addresses common diseases versus rare diseases. Dr. Tabak noted that there is a paucity of descriptions regarding specific diseases or conditions in the Plan, although examples of research progress that mention specific diseases and conditions are included. The document in no way will attempt to reflect the myriad of diseases and conditions that the NIH deals with (these discussions are included in the strategic plans of specific NIH ICs). In this document, the NIH is attempting to articulate overarching principles that hopefully apply to the decision-making required to support all diseases and all conditions. Efforts will be made to reach some balance in the types of examples referenced in the Plan and to make specific reference to the importance of supporting research on rare diseases and conditions.

   Dr. Khosla asked about the balance between the NIH historically setting priorities and allocating funds versus the perception that more of these activities are being legislated. He offered the example of funding at the NIA, where non-Alzheimer’s R01 applications are funded at the 8th percentile and Alzheimer’s applications are funded at the 16th-17th percentile. Dr. Tabak explained that there have been moments in history during which certain diseases and conditions have come to the forefront, largely because of scientific needs and opportunities as well as public health burden, catalyzed by stakeholder interest which in turn translates into Congressional interest. Dr. Katz reminded the group that there was a Congressional allocation for Alzheimer’s research that enabled the percentile scores at the NIA referenced by Dr. Khosla.

   Dr. Koretzky emphasized the importance of highlighting the stewardship and workforce issues described by Dr. Tabak and suggested that workforce issues should be a central part of the Strategic Plan. He also pointed to the need for the NIH to maintain its flexibility to respond to important scientific advances and needs that arise. Dr. Tabak agreed, indicating that there is near universal agreement on the need to stabilize the biomedical research workforce, with a particular emphasis on the physician scientist pool.

   In closing the discussion session, Dr. Katz acknowledged the important contributions of Mary Beth Kester, Health Science Policy Analyst within the OSPPC, in representing NIAMS’ interests as the Institute’s liaison to the NIH Strategic Plan Working Group.

8. FY16 NATIONAL CHILDREN’S STUDY (NCS) REDIRECTION

   Dr. Tabak noted that a number of NIAMS staff—Drs. Serrate-Sztein and Marie Mancini (Program Officer in the Division of Skin and Rheumatic Diseases) in particular—have played important roles in helping with the reconfiguration of the NCS. He reminded Council members that the Children’s Health Act of 2000 authorized the NCS. A pilot study was launched in 2009, but the larger, main study was never initiated. The Institute of Medicine (IOM) reviewed the study and identified a number of concerns about the design, management, and oversight structure as well as the cost. Dr. Collins convened a working group of the ACD that found that the NCS, as outlined, was not feasible. As a result, Dr. Collins determined that the NCS should be discontinued at the end of 2014. This provided the NIH with an opportunity to develop a set of initiatives for FY 2015. At that time, it was unclear whether the funds would be available for ongoing commitments or if this was the only year these funds would be available. Therefore, in planning the FY 2015 initiatives, the assumption was made that funding would be for 1 year only and as a result, a series of initiatives were awarded in full with no out-year commitments).

   Three main initiatives were funded at a total of approximately $144 million: (1) developing tools that would enhance studies of environmental influences of pediatric diseases, (2) studying the influence of environment on in utero development with the goal of identifying the "seeds" of future diseases and conditions, and (3) expanding the examination of environmental influences on later child development by leveraging extant programs.

   The overarching goal of the FY 2016 plan is to take advantage of existing studies by leveraging extant cohorts to investigate the longitudinal impact of prenatal, perinatal, and postnatal environmental exposures on pediatric health outcomes that have a high public health impact. The plan is to support multiple synergistic longitudinal studies by using extant cohorts, representing variable environmental exposures, sharing standardized research questions, and focusing on four key pediatric outcomes. A series of core elements that will be addressed across all studies is envisioned and includes demographics, typical early development, epigenetic influences on early childhood development, and environmental factors. Focus areas that are specific to critical pediatric conditions/outcomes include upper and lower airway disease; obesity; pre-, peri-, and postnatal outcomes; and neurodevelopment.

   The NIH is working to ensure that recruitment plans are robust enough to address racial and ethnic minority health issues and that there is a balance between characterization of environmental factors and health-related endpoints. Dr. Tabak explained that studies may leverage additional features. Examples include: (1) utilizing existing tissue banks collected across pregnancy and data sets by funding additional analyses; (2) serving as a test bed for validating new technologies, tools, and approaches for environmental and pediatric monitoring; (3) using systems approaches to develop multi-variable models to predict disease development; and (4) recruiting women during subsequent pregnancies to compare outcomes of first and second children.

   Dr. Tabak described an additional opportunity that has arisen as a result of the reconfiguration of the NCS: creating an Institutional Development Award (IDeA) States National Pediatric Clinical Research Network that would address access gaps for rural children through a national network for pediatric research embedded at IDeA locations. The Network would link existing IDeA state centers with experts in clinical trials located around the country.

   Dr. Tabak concluded his remarks by noting that RFAs are expected to be issued in January 2016, with council review of applications taking place in late September 2016.

   Discussion

   Council member Dr. Christy Sandborg, Professor of Pediatrics at Stanford University, asked about the number of existing biorepositories as part of these efforts, noting that in the State of California, every baby born has blood specimens that are saved and used for research. Dr. Tabak explained that there will be a restricted number of these biorepositories that are available, and that there are a fair number of NIH-supported studies collecting specimens. If the NIH recommends the use of existing sample repositories, it would not preclude the collection of new materials going forward.

   Dr. Khosla noted that an IOM report on the Clinical and Translational Science Awards (CTSAs) emphasized pediatric and child health. Within the CTSA Consortium, each CTSA site is being asked to develop infrastructure for pediatric studies and establish collaborations across the network. He asked about the degree to which the efforts described by Dr. Tabak will tie into the existing CTSA network, which has an infrastructure funded by NIH that could facilitate some of this work. Dr. Tabak explained that to the extent that a CTSA has already launched a pediatric cohort of some type, it would make sense to try to leverage this infrastructure and compete for these funds. Another model that has been discussed by stakeholders is for those who have trials or studies in a particular area banding together to create a synthetic cohort from among existing trials in that area. These approaches are not mutually exclusive, and any and all groups that have ongoing children’s studies or studies of mothers are being encouraged to apply.

   Council member Dr. Joan Bechtold, Professor of Orthopaedic Surgery at the University of Minnesota, asked if there is a way or a need to formally include the reproducibility of research in this effort as well as in the work related to the NIH Strategic Plan described by Dr. Tabak earlier in the meeting. He noted that this issue has been discussed in the context of both of these projects, and the desire is for investigators to make the best case for the most important questions they want to answer. Researchers will not be dissuaded from approaching the NIH with this type of work.

9. 21ST CENTURY CURES ACT

   Ms. Adrienne Hallett, NIH Associate Director for Legislative Policy and Analysis explained that the 21st Century Cures Act represents a collective effort of the House Energy and Commerce Committee to put forward an effort to accelerate the discovery, development, and delivery of treatments and cures for diseases. The Act is a high priority for the Committee’s Chair, Representative Fred Upton (R-MI). The bill has passed the House and is currently being considered by the Senate.

   The version of the bill that passed in the House establishes Innovation funding allocations to include: (1) an Accelerating Advancement Program, (2) additional funding for early stage investigators, (3) funding for high risk/high-reward research, and (4) intramural research funding at no more than 10 percent of the total amount per year. Other authorized uses of these funds include research project awards, individual research awards, the Small Business Innovation Research program, and the development of an Innovation Fund strategic plan.

   The 21st Century Cures Act carries with it a number of additional provisions. For example, it:

   • Reauthorizes the NIH
   • Requires the development of an NIH Strategic Plan (the efforts described earlier by Dr. Tabak would fulfill this requirement)
   • Establishes 5-year renewable terms for IC Directors
   • Requires the creation of an Innovation Prizes Program that has an external board and is a public-private venture
   • Requires the NIH to implement measures to reduce administrative burdens among researchers
   • Requires each IC Director to support high-risk, high-reward research
   • Includes a Sense of the Congress that participation in or sponsorship of conferences is essential to NIH’s mission
   • Authorizes a capstone award
   • Establishes a new loan repayment program (LRP) that provides researchers with up to $50,000 per year and provides for inflationary increases
   • Raises the cap of other NIH LRPs to $50,000 per year and provides for inflationary increases
   • Exempts NIH research from the Paperwork Reduction Act requirements
   • Establishes a Lyme Disease and Other Tick-Borne Diseases Working Group.

    

   Looking forward, Ms. Hallett explained that Rep. Upton is very eager to get the 21st Century Cures Act enacted by year’s end. The Senate appears to be on a somewhat slower timeline, with a draft expected in the next few months and final action anticipated early next year.

   Discussion

   Dr. Katz asked about the intent of the capstone provision in the bill. Ms. Hallett explained that the Capstone Award is intended to support senior scientists and facilitate the transition or conclusion of research programs. The duration of the award can be determined by the NIH.

   Dr. Martha Murray, Associated Professor of Orthopaedic Surgery at Harvard Medical School, asked if the funds allocated to the NIH through the 21st Century Cures Act would be divided among the ICs at the same percentages as current funding from Congress. Ms. Hallett explained that the legislation does not speak to how the $1.7 billion in funding would be allocated among the ICs, leaving it to NIH to develop an allocation plan.

10. CONCEPT CLEARANCE FOR FY 2017 SCIENTIFIC INITIATIVES

    Dr. Katz explained that although the majority of the NIAMS budget supports investigator-initiated research projects that are reviewed through the NIH Center for Scientific Review (CSR), the Institute regularly scans the scientific landscape for areas or activities that are ripe for investment but are not being pursued through the regular, unsolicited grant application process. He reminded Council members that each September, they are briefed in general terms on the Institute’s initiatives that may be developed for funding in the fiscal year two years from now. These initiatives are developed through internal NIAMS discussions, often with significant input from the extramural community.

    Drs. Serrate-Sztein and McGowan briefly described the following new initiatives:

    • NIAMS Initiative for New Investigators: The goal of this initiative is to design a NIAMS Small Grant Program for New Investigators to develop preliminary data for their first R01 application.
    • Accelerating Research on the Intervertebral Disc (ARID) Revision Awards: The purpose of this initiative is to encourage applications to develop new research directions to accelerate basic research on intervertebral disc biology and the factors that lead to degeneration.
    • Building Complex 3-Dimensional in Vitro Models of Human Musculoskeletal and Skin Tissue: This initiative intends to facilitate the building of complex 3-dimensional human musculoskeletal and skin tissue models.
    • NHANES Collaboration for Osteoporosis Data to Support Healthy People 2020: This initiative, in collaboration with the National Center for Health Statistics (NCHS)/Centers for Disease Control and Prevention (CDC), would partially support the NHANES bone mineral density assessments during 2017-18 to provide data for an analysis of the Healthy People 2020 osteoporosis objective (reduce the proportion of adults with osteoporosis).
    • Core Centers for Clinical Research (CCCR): The ultimate goal of this initiative is to address existing and future clinical research needs at the institutional, local and national level.

    Concepts for Possible Re-Issue:

    • Ancillary Studies to Large Clinical Projects
    • Centers of Research Translation (CORT)
    • NIAMS Rheumatic Diseases Research Resource-Based Centers

    Discussion

    Dr. Shane voiced strong support for the NIAMS Initiative for New Investigators. She reminded the group that during the last NAMSAC meeting, the Institute indicated that it was considering sun-setting the R03 program and developing a small grant program for clinical K awardees during the last few years of their award so that they could generate additional preliminary data to assist in securing their first R01. She suggested that K awardees be made aware of this initiative early on in their awards so that they can plan accordingly.

    With regard to the Building Complex 3-Dimensional in Vitro Models of Human Musculoskeletal and Skin Tissue initiative, Dr. Khosla indicated that the Defense Advanced Research Projects Agency (DARPA) and NIH recently funded a number of related projects. He asked if the Institute feels that additional projects in the musculoskeletal disease area are warranted. Dr. McGowan explained that the Institute is seeking to leverage advances made in previously funded projects on microphysiologic systems and bring them into NIAMS’ mission areas so that its tissues and diseases processes of interest are better represented with this technology.

    Dr. Sandborg asked whether investigational R01-type projects are associated with the CCCR initiative, or if only core activities apply. Dr. Katz explained that all of the Institute’s clinical activities are undergoing transition. This initiative is intended to focus on the needs of the community; this initiative may supplant the current P60 program.

11. BOARD OF SCIENTIFIC COUNSELORS REPORT

    This portion of the meeting occurred during closed session.

12. CONSIDERATION OF APPLICATIONS

    In closed session, the Council reviewed a total of 740 applications in closed session requesting $941,782,467 in total costs and recommended 740 applications for $941,782,467 in total costs. Forty applications were considered by early concurrence.

13. SPECIAL ACTIONS

    This portion of the meeting occurred during closed session.

14. PATIENT REPORTED OUTCOMES RESEARCH

    This portion of the meeting occurred during closed session.

15. ADJOURNMENT

    The 87th National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Meeting was adjourned at 2:20 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.