Department of Health and Human Services
Public Health Service
National Arthritis and Musculoskeletal and Skin Diseases Advisory Council
Minutes of the 88th Meeting
8:30 a.m. to 2:25 p.m.
CALL TO ORDER
The 88th meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council (NAMSAC) was held on February 2, 2016, at the National Institutes of Health (NIH) Campus, Building 31, Conference Room 6. The meeting was chaired by Dr. Stephen Katz, Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Council members present
Dr. Joan E. Bechtold
Ms. Magdalena Castro-Lewis
Dr. Sherine E. Gabriel
Dr. Michael V. Holers
Dr. Sundeep Khosla
Dr. Gary A. Koretzky
Dr. Ethan Lerner
Mr. William Mulvihill
Dr. Martha M. Murray
Dr. Amy Paller
Dr. Anthony E. Rankin
Dr. Christy I. Sandborg
Mr. Richard F. Seiden
Dr. Elizabeth Shane
Mr. Alexander Silver
Dr. Stephen J. Tapscott
Dr. Gwendolyn L. Powell Todd
Staff and Guests
The following NIAMS staff and guests attended:
Dr. Lee Alekel
Mr. Steve Austin
Dr. Carl Baker
Ms. Pamela Beheler
Ms. Elizabeth Bouras
Dr. Amanda Boyce
Dr. Stephanie Burrows
Ms. Justine Buschman
Dr. Robert Carter
Dr. Faye Chen
Ms. Jennifer Chi
Dr. Thomas Cheever
Dr. Ricardo Cibotti
Ms. Robin DiLiello
Ms. Theresa Do
Dr. Jonelle Drugan
Ms. Elizabeth Elliott
Ms. Barbara Footer
Ms. Gail Hamilton
Ms. Aleisha James
Dr. Chao Jiang
Ms. Katie Joffee
Mr. Andrew Jones
Dr. Stephen Katz
Ms. Mary Beth Kester
Ms. Shahnaz Khan
Ms. Stephanie Kreider
Mr. Mark Langer
Dr. Gayle Lester
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. Melinda Nelson
Dr. John O’Shea
Dr. James Panagis
Ms. Vivian Pham
Mr. Robert Pines
Mr. James Powell
Ms. Reaya Reuss
Ms. Trish Reynolds
Dr. Kathy Salaita
Dr. Susana Serrate-Sztein
Dr. Richard Siegel
Ms. Sheila Simmons
Ms. Robyn Strachan
Ms. Yen Thach
Dr. Hung Tseng
Ms. Christine Tsui
Dr. Bernadette Tyree
Dr. Fei Wang
Dr. Yan Wang
Dr. Chuck Washabaugh
Dr. James Witter
Dr. Xincheng Zheng
Dr. Josephine Briggs, Director, National Center for Complementary and Integrative Health, NIH
Mr. Mike Bykowski, Consolidated Solutions and Innovations
Ms. Kim Cantor, Lupus Foundation of America
Ms. Petra Harvey, Osteogenesis Imperfecta Foundation
Ms. Kim James, IQ Solutions
Mr. Blake McDonald, American Acadamy of Dermatology Association
Dr. Lynn Mirigian, American Society for Bone and Mineral Research
Ms. Anita Roach, Lupus Foundation of America
Mr. Nate Robinson, IQ Solutions
Mr. Taylor Scott, Nevus Outreach, Inc.
Ms. Kristin Stephenson, Muscular Dystrophy Association
Ms. Randi Williams, KAI Research, Inc.
CONSIDERATION OF MINUTES
A motion was made, seconded, and passed to approve the minutes of the 87th NAMSAC meeting, held on September 8, 2015.
FUTURE COUNCIL MEETING DATES
Future Council meetings are currently planned for the following dates:
June 7, 2016
September 13, 2016
January 25, 2017
June 21, 2017
September 6, 2017
DIRECTOR'S REPORT AND DISCUSSION
Dr. Katz reminded Council members that the public portion of this NAMSAC meeting was being videocast. Almost 150 people viewed the September NAMSAC meeting, either live or afterward.
Dr. Katz introduced the following four new Council members:
- Ms. Magdalena Castro-Lewis is an active member of the NIAMS Multicultural Outreach Initiative Hispanic/Latino Work Group. She is the former Vice President for Programs at the National Alliance for Hispanic Health and has extensive experience with developing culturally and linguistically appropriate health education materials and forming national and community-based partnerships to improve the health of Hispanic families.
- Dr. Ethan Lerner is an Associate Professor of Dermatology at Harvard Medical School and an Associate Biologist in Dermatology at Massachusetts General Hospital. Dr. Lerner’s research focuses on understanding the mechanisms that underlie the itch sensation in order to develop effective anti-itch therapies. He has published more than 100 peer-reviewed articles and has served on various advisory committees.
- Mr. William Mulvihill is a Special Advisor to the President of the University of Cincinnati and Executive Director of the University of Cincinnati Presidential Bicentennial Commission. Mr. Mulvihill currently serves as Trustee Emeritus of the Arthritis Foundation in Atlanta, and is on the board of directors for the Alliance for Lupus Research in New York.
- Dr. Stephen Tapscott is a muscle biologist who runs a laboratory at the Fred Hutchinson Cancer Research Center. His work focuses on epigenetics and gene transcription in normal muscle development and disease. Dr. Tapscott serves on various national and international advisory panels and is credited with more than 150 peer-reviewed articles, books chapters, and other publications.
Personnel Changes at the NIH and NIAMS
This fall, Dr. Thomas Insel stepped down as Director of the National Institute of Mental Health (NIMH) to join Google Life Sciences, where he will lead a new effort focusing on mental health.
Also in the fall, the NIH welcomed Dr. Michael Lauer as the new Deputy Director for Extramural Research. Dr. Lauer has worked at the NIH since 2007, when he became a Division Director at the National Heart, Lung, and Blood Institute (NHLBI). Dr. Lauer is continuing the NIH Office of Extramural Research’s commitment to communication and transparency, and is building upon Dr. Sally Rockey’s tradition of blogging to better connect extramural researchers with the NIH. His weekly blog posts can be viewed by subscribing to the "Open Mike Blog at the NIH" (the search term "Open Mike Blog at the NIH" will take users directly to Dr. Lauer’s blog).
At the NIAMS, Dr. James Panagis will retire from the Commissioned Corps and the NIH after 34 years of federal service on February 29. Dr. Panagis came to the NIAMS from the Agency for Health Care Policy and Research (AHCPR), now known as the Agency for Healthcare Quality and Research (AHRQ), in 1995. Since then, in addition to leading the Institute’s Orthopaedic Research Program, Dr. Panagis has represented the Institute on countless trans-NIH and interagency committees, including the earliest stages of the NIH Bioengineering Consortium. He also served as the NIAMS liaison to the American Academy of Orthopaedic Surgeons (AAOS) and has been actively involved in the American AAOS Clinician Scientist Development Program. He participated in the Department of Defense’s (DoD) Peer Review Orthopaedic Research Program, and was a practicing hand surgeon at the Walter Reed National Military Medical Center through 2012. Dr. Katz read excerpts from some letters received from the AAOS and the Orthopaedic Research and Education Foundation (OREF) acknowledging his contributions to the orthopaedics community.
With Dr. Panagis’ departure, Dr. Charles Washabaugh, the Scientific Review Officer who leads the NIAMS Arthritis and Musculoskeletal and Skin Diseases Clinical Trial Review Committee, will leave the Scientific Review Branch to join the Division of Musculoskeletal Diseases as a Program Officer. Dr. Washabaugh joined the NIAMS in 2006 from the University of Pittsburgh, where he conducted research on muscle development and regeneration. As a Program Officer, Dr. Washabaugh will administer a portfolio that comprises a portion of the Institute’s orthopaedics research.
Ms. Anna Nicholson has moved from the NIAMS Clinical Management Team to direct the National Institute of Dental and Craniofacial Research’s (NIDCR) Office of Clinical Trials and Operations Management. In her eight years at the NIAMS, Ms. Nicholson contributed significantly toward the development and implementation of the Institute’s current clinical research policies and procedures. She also provided operational and management support for the extramural clinical trials funded by the NIAMS. Ms. Shahnaz Khan will help oversee NIAMS’ clinical portfolio while the team recruits another clinical research manager.
Dr. Kristy Nicks has joined the Division of Musculoskeletal Diseases from Dr. Sundeep Khosla’s research team at the Mayo Clinic’s Center for Clinical and Translational Science (Dr. Khosla is a Council member and Dr. Francis Chucker and Nathan Landow Research Professor, Director of the Mayo Clinic Center for Clinical and Translational Science, and Dean for Clinical and Translational Science at the Mayo Clinic College of Medicine). Dr. Nicks will be assisting the Division’s Program Directors while the Institute prepares to launch the NIH Common Fund’s Molecular Transducers of Physical Activities Consortium later this year.
NIH and NIAMS Budget and Congressional and Outreach Activities
On December 18, President Obama signed the fiscal year (FY) 2016 Omnibus Bill into law. This bill boosts the NIH budget by $2 billion over FY 2015 levels. The increase for the NIAMS is $20.4 million, or 3.9%. This is the most encouraging budget outcome in 12 years. Dr. Katz noted that the NIAMS applauds the bipartisan support for the NIH and biomedical research that made this increase possible, and particularly thanks the House and Senate leadership. This budget increase comes at a particularly good time to take advantage of significant opportunities to improve human health, powered by dramatic advances in scientific knowledge and technological innovation. Specifically, the additional funds will allow the NIAMS to: (1) increase its investments in physicians who have an interest in pursuing patient-oriented academic research careers through K awards, (2) increase its investments in training programs, and (3) continue to promote innovative research. The Institute’s initial funding plan and paylines for FY 2016 are posted on the NIAMS website.
The FY 2016 budget increase required considerable effort from many groups—patients, advocates, scientists, colleagues in the public and private sectors—all of whom successfully made the case for biomedical research. In particular, Dr. Katz recognized the significant efforts of NIH Director Dr. Francis Collins in helping the NIH obtain the FY 2016 increase. Dr. Katz noted that the NIAMS always welcomes opportunities to educate the Congress about what the NIH does and how the Nation’s research investments accelerate medical progress. On January 13, Dr. Katz and NHLBI Director Dr. Gary Gibbons spoke about recent advances and emerging opportunities in Marfan Syndrome research. The event featured former Baylor basketball standout Isaiah Austin and another patient, Owen Gray. Both described how Marfan Syndrome has changed their lives. The briefing also included remarks by Representatives Bill Flores (R-FL), Steve Israel (D-NY), and Chris Van Hollen (D-MD).
In October, Dr. Katz spoke at the Scleroderma Foundation’s Congressional briefing on recent progress and future research opportunities in scleroderma and other fibrotic diseases. Senator Debbie Stabenow (D-MI) also spoke at the briefing where she, along with Senators Kirsten Gillibrand (D-NY) and Roy Blunt (R-MO) were honored with awards.
Dr. Katz acknowledged Mr. Robert Riggs, CEO of the Scleroderma Foundation, as the new Co-Chair of the NIAMS Coalition. Mr. Riggs, Ms. Mary Wheatley of the Rheumatology Research Foundation, and Ms. Leah Howard from the National Psoriasis Foundation—along with other members of the NIAMS Coalition Steering Committee—were instrumental in planning the fifth biennial Coalition Outreach and Education Day. More than 50 Coalition members, representing 42 different organizations, attended. The presentations included a talk by Ms. Mary Woolley, President of Research!America, about how the organization educates non-scientists about medical research. Dr. Katz noted that Coalition members, the American public, and elected representatives all share an interest in many of the same topics discussed during NAMSAC meetings (e.g., the NIH and NIAMS budgets, how the Institute invests the money entrusted to it, and research results that have emerged from the work the NIAMS supports).
Highlights of Selected Recent Scientific Advances
- A paper from Dr. Michael Rudnicki’s laboratory at the University of Ottawa describes the paradigm-changing discovery that the genetic defect that causes Duchenne muscular dystrophy directly affects muscle stem cells. The investigators reported that normal muscle stem cells express the dystrophin protein. They went on to determine that muscle stem cells lacking dystrophin have a reduced ability to activate and proliferate. Although the dystrophic fibers contain more stem cells, they produce far fewer muscle progenitor cells that can move to the next phase of muscle repair. The discovery that dystrophin is present in present in muscle stem cells could explain some of the pathophysiology of Duchenne muscular dystrophy, particularly the increased muscle fibrosis seen in later stages of the disease. It also sheds light on the functions of different parts of the dystrophin protein, and may cause investigators to rethink gene therapy strategies (Nat Med. 2015 Nov 16. doi: 10.1038/nm.3990. [Epub ahead of print] PMID: 26569381).
- A group of researchers that includes Dr. Lou Kunkel of Boston Children’s Hospital were working with golden retrievers that have the canine equivalent of muscular dystrophy and found one dog that appeared to have escaped the disease, even though it lacked dystrophin. The dog had a near-normal lifespan and fathered several litters of pups (which is unheard of for dogs with muscular dystrophy); one of those pups was also spared of muscular dystrophy. The unaffected dogs had a mutation that increased levels of a protein called Jagged1. Because Jagged1 is unrelated to dystrophin or any of its associated proteins, this discovery points to a previously unrecognized cellular pathway that compensates for the loss of dystrophin and significantly diminishes disease severity. The researchers now have a collaborative research agreement with Pfizer to screen for drugs that may upregulate Jagged1 in people (Cells. 2015 Nov 19;163(5):1204-13. doi: 10.1016/j.cell.2015.10.049. Epub 2015 Nov 12. PMID: 26582133).
- As part of a project that involves growing bone cells on the International Space Station (ISS) to understand how bone responds to physical stresses, Dr. Paola Divieti Pajevic and her team at Harvard Medical School tested a new osteocyte line in an earth-based rotating wall bioreactor that simulates the nearly complete absence of gravity. Under these conditions, the cells adopted a three-dimensional configuration instead of the flat layers seen in dishes. They also produced more of the anti-bone building protein sclerostin and proteins such as RANK-ligand that stimulate bone resorption by osteoclasts. Dr. Pajevich and her team are analyzing results from experiments conducted in space to determine whether these findings held true on the ISS (J Biol Chem. 2015 Jul 3;290(27):16744-58. doi: 10.1074/jbc.M114.628313. Epub 2015 May 7, PMID: 25953900).
- A team of researchers led by Dr. Roberto Pacifici from Emory University School of Medicine report on the discovery of a potential target for bone loss caused by hyperparathyroidism. Parathyroid hormone (PTH) is a major regulator of calcium metabolism and bone homeostasis. In addition to acting on bone cells directly, PTH influences the behavior of T cells that contribute to these actions. The researchers showed that IL-17A plays a critical role in mediating PTH-induced bone loss in hyperparathyroidism. They identified two molecules—the calcium channel blocker drug diltiazem and an anti-human IL-17A antibody in clinical testing—that can prevent bone loss in a mouse model of hyperparathyroidism. Although the results suggest two non-surgical alternatives for preventing bone loss in hyperparathyroidism, more clinical work is needed before the compounds can be used in this patient population (Cell Metab. 2015 Nov 3;22(5):799-810. doi: 10.1016/j.cmet.2015.09.012. Epub 2015 Oct 8. PMID: 26456334).
- Dr. Edward Botchwey, a NIAMS grantee at the Georgia Institute of Technology who received the 2009 Presidential Early Career Award for Scientists and Engineers, is leading a team of investigators who are developing a strategy to use inflammatory molecules to promote the blood vessel development that appears to be essential for wound healing. Their paper describes how the researchers engineered drug-eluting, gel-based implants that can release exogenous stromal cell derived factor-1alpha, a protein that recruits immune cells to build webs of blood vessels. Dr. Botchwey’s group demonstrated that the protein enhances recruitment of pro-regeneration immune cells, facilitates the initial formation of arteries, and enhances blood vessel network formation (Biomaterials. 2015 Oct 23;77:280-290. doi: 10.1016/j.biomaterials.2015.10.045. [Epub ahead of print] PMID: 26613543).
- Previous work by Dr. Angela Christiano at Columbia University showed that the drugs tofacitinib and ruxolitinib (which inhibit JAK-STAT signaling) caused rapid hair regrowth in alopecia areata patients and mouse models. The mice in her study grew more hair when the drugs were applied to the skin than when given systemically. In recent experiments in normal mice, her research team found that when used topically, the inhibitors triggered hair follicle transition from a dormant, resting state into their active phase. These studies were extended to humans through the use of model systems in which human hair follicles were cultured in vitro or where human skin was grafted onto mice. In both models, inhibition of the JAK-STAT pathway stimulated hair shaft growth (Sci Adv. 2015 Oct 23;1(9):e1500973. eCollection 2015 Oct. PMID: 26601320).
- Dr. Richard Siegel’s team in the NIAMS Intramural Autoimmunity Branch participated in a collaborative research study to characterize the genetic causes of early onset systemic autoinflammatory diseases. When the investigators screened and sequenced genes from six unrelated families, they found that they affected members in each family harbored a mutation in the TNFAIP3 gene, which encodes an NFκB regulatory protein called A20 (Nat Genet. 2015 Dec 7. doi: 101038/ng.3459. [Epub ahead of print] PMID: 26642243). NIAMS Scientific Director Dr. John O’Shea provided additional details on this work later in the meeting.
- Antiphospholipid syndrome (APS) is an inflammatory autoimmune disease that was first described in association with systemic lupus erythematosus. APS is characterized by the presence of antiphospholipid antibodies, which stimulate the formation of undesirable blood clots by activating the endothelial cells lining the blood vessels, platelets, and circulating monocytes. Recent work by Dr. Jason Knight of the University of Michigan has shown that antiphospholipid antibodies also stimulate the release of protein-chromatin complexes called neutrophil extracellular traps (NETs) by neutrophils and that circulating NETs contribute to thrombotic events in APS (Arthritis Rheumatol. 2015 Nov;67(11):2990-3003. doi: 10.1002/art.39247. PMID: 26097119).
- Pregnancy loss and thrombosis are common features of people who have APS and in lupus patients who also have antiphospholipid antibodies. The NIAMS has made a long-term investment in the multicenter Predictors of Pregnancy Outcome: biomarkers in antiphospholipid antibody Syndrome and Systemic lupus Erythematosus (PROMISSE) study, launched by Dr. Jane Salmon at the Hospital for Special Surgery in New York and her colleagues. When the study began, it was unclear what patient characteristics or disease signs or symptoms were associated with poor pregnancy outcomes. Recently, PROMISSE has shown that most women who have lupus can expect a good pregnancy outcome if their disease is inactive (Ann Intern Med. 2015 Aug 4;163(3):153-63. doi: 10.7326/M14-2235. PMID: 26098843). The investigators also identified molecules in the women’s blood that indicate a higher risk for serious complications (Am J Obstet Gynecol. 2016 Jan;214(1):108.e1-108.e14. doi: 10.1016/j.agog.2015.09.066. Epub 2015 Sep 29. PMID: 26432463). PROMISSE investigators have also confirmed that lupus anticoagulant is the only antiphospholipid that is associated with poor pregnancy outcomes after the first trimester in antiphospholipid antibody-positive women (Lupus Science& Medicine. 2016;3:e000131. doi: 10.1136/lupus-2015-000131). The ability to identify these women, in the first few weeks of pregnancy or before they become pregnant, who are at extremely high risk of miscarriage, premature delivery, or other serious complications will enable providers to tailor assessment, reproductive counseling, and treatment for women with lupus.
Overview of NIH and NIAMS Activities and Plans
Dr. Katz explained that the Institute remains committed to improving the health of patients with rheumatic, musculoskeletal, and skin diseases by funding investigator-initiated clinical studies, such as PROMISSE, that lead to better patient outcomes. To that end, the NIAMS has implemented a suite of funding opportunities designed to support a broad spectrum of clinical studies. During a discussion at the September NAMSAC of ways to strengthen the impact of NIAMS clinical trials, several Council members recommended that the Institute adjust its policy to allow funding of R01 applications that, while primarily intended to answer basic and preclinical research questions about disease mechanisms, also contain a clinical research aim. In follow-up to that discussion, NIAMS Deputy Director Dr. Katz asked Dr. Robert Carter lead an internal working group to develop a strategy to address this recommendation—Dr. Carter provided an update on the working group’s efforts later in the meeting.
Dr. Katz noted that revisions to the Common Rule that provides for the protection of human research participants are being considered. The proposed changes, which were included in a Notice of Proposed Rulemaking (NPRM), focus on privacy issues and informed consent. The comment period on the NPRM has closed. Dr. Katz noted that there were a large number of responses. The Office for Human Research Protections is reviewing the feedback to determine what changes need to be made. The community is also undertaking its own efforts to update clinical trial conduct and reporting. Dr. Katz called Council members’ attention to a proposed policy from the International Committee of Medical Journal Editors to require clinical investigators who wish to publish in participating journals to: (1) articulate their data sharing policies before starting their studies, and (2) commit to sharing all of their data, not just an aggregate summary, within six months of publication. This is a clear change and something that the research community has been looking towards for some time.
During the last NAMSAC meeting, Council members heard from NIH Principal Director Dr. Lawrence Tabak about NIH’s plans to redirect funds from the National Children’s Study (NCS), which closed in December 2014, into other projects. Since then, the NIH has funded the Validation of Pediatric Patient Reported Outcomes in Chronic Diseases Consortium (PEPR). PEPR’s main, long-term goal is to conduct robust clinical validation studies of child patient-reported outcomes and to examine the impact of environmental stressors on children’s symptoms and quality of life. It will involve the use of pediatric self-report and parent proxy instruments developed through the NIH Common Fund’s Patient Reported Outcomes Measurement Information System (PROMIS) initiative.
The NIH released its Strategic Plan in December. The Plan has four interdependent objectives that will help guide NIH’s priorities over the next five years: (1) advance opportunities in biomedical research, (2) set priorities, (3) excel as a federal science agency by managing for results, and (4) enhance scientific stewardship. The Plan is designed to complement the strategic and long-range plans of the various Institutes, Centers, and NIH Offices, each one having its own Congressionally-mandated mission. The NIH Strategic Plan features a handful of NIAMS-led trans-NIH activities as examples that support its objectives (e.g., PROMIS and the Accelerating Medicines Partnership [AMP]).
The Muscular Dystrophy Coordinating Committee, which is led by the NIH and chaired by Dr. Katz, published an updated Action Plan for the Muscular Dystrophies. The Action Plan outlines priority areas for advancing research, improving diagnosis and treatment, and reducing the personal and societal impacts of all types of muscular dystrophy. The NIH published its Action Plan for Lupus Research last month. As the convener of the Lupus Federal Working Group, the NIAMS has been leading NIH’s efforts to refresh this Plan at the request of Congress. Dr. Katz thanked staff in the Office of Science Policy, Planning, and Communications and in the Division of Skin and Rheumatic Diseases for their dedicated efforts in surveying the scientific landscape and incorporating public comments into this document.
Developing and sustaining the biomedical workforce, particularly clinician scientists, is a high priority throughout the NIAMS and NIH. A few years ago, the NIAMS began holding a forum for clinical and patient-oriented investigators who are in the third year of their K08 and K23 career development awards. Many in the community have indicated that the K-to-R01 transition is a particularly vulnerable period in the career timeline of clinician scientists. The long-term goal is to leverage the Institute’s investment in early stage clinician scientists by encouraging and enabling K08 and K23 awardees to continue performing research in their chosen fields.
The NIH has also been looking at the challenges facing physician scientists. In response to recommendations from a working group of the Advisory Committee to the NIH Director (ACD), the NIH revised its policy regarding salary support for K08 and K23 recipients. An increase in salary support will take place across the NIH for K08 and K23 awardees beginning in 2017; however, the NIAMS budgeted for this increase and is implementing it this year for all clinical K awardees. In addition, applicants will be allowed to request up to $30,000 for their research (the previous amount had been capped at $20,000).
Within the IRP, Dr. Oliver Duverger, Staff Scientist in the Developmental Skin Biology Section, was 1 of 13 winners of the 2015 Federation of American Societies for Experimental Biology’s BioArt Competition. Dr. Duverger’s winning electron micrograph displays the lattice structure of tooth enamel—it was the only submission from the NIH to win an award. Dr. Katz also congratulated Dr. Mariana Kaplan, who was honored by the Lupus Foundation of America with the Evelyn V. Hess Award for her work on the role of the innate immune system in the development of premature atherosclerosis in lupus. Dr. Kaplan is Chief of the IRP’s Systemic Autoimmunity Branch and is currently investigating the role of abnormal neutrophils and NETs in systemic autoimmunity.
Dr. Katz noted that lupus is one of several diseases in the NIAMS mission that disproportionately affects members of racial and ethnic minority groups. The Institute is proud to serve as a reliable source of research-based health information for people of all backgrounds. In fact, a surge in visits to the NIAMS website and the Spanish-language portal was observed following singer Selena Gomez’s announcement regarding her treatment for lupus. Many of the Institute’s health information dissemination efforts for underserved minorities are coordinated through its National Multicultural Outreach Initiative, which has involved several current and former Council members over the years.
As more Americans of all races and ethnicities seek health information through social media, the NIAMS continues to partner with a range of organizations on Twitter Chats. For example, the NIAMS acknowledged World Psoriasis Day by holding a Twitter Chat with the NHLBI, the National Psoriasis Foundation, and the American Academy of Dermatology.
In closing, Dr. Katz reminded Council members that many of the materials discussed during his Director’s Report are available on the NIAMS website. Additionally, Council members should be receiving the NIAMS Update, a monthly digest produced by the Office of Science Policy, Planning, and Communications. Among other items, the Update links to news about NIH activities and recent findings from NIH-funded research, patient-oriented publications and products, and Funding Opportunities and Announcements (FOAs).
Council member Dr. Grace Pavlath, Senior Vice President and Scientific Program Director at the Muscular Dystrophy Association and Professor in the Department of Pharmacology at Emory University School of Medicine, expressed great enthusiasm for PEPR, particularly with regard to the opportunity it presents for the funded groups to collaborate. Her group has already identified a series of potential new collaborative directions and will be incorporating PROMIS tools into fields where they have not previously been used.
Dr. Tapscott commented that the two muscular dystrophy studies Dr. Katz highlighted in his Director’s Report (led by Drs. Rudnicki and Kunkel) serve as good examples to illustrate how the research being conducted by various groups in this field is coming together, leading to the development of molecular models that will provide new opportunities for therapy. The NIAMS should be credited with helping to move these advances forward.
On behalf of the orthopaedic community, Council member Dr. Anthony Rankin, Chief of Orthopaedic Surgery at Providence Hospital, thanked Dr. Panagis for his years of service to the field. Council member Dr. Joan Bechtold, Professor of Orthopaedic Surgery at the University of Minnesota, echoed those comments.
PRECISION MEDICINE INITIATIVE
Dr. Josephine Briggs, Director of the National Center for Complementary and Integrative Health (NCCIH), is leading the President’s Precision Medicine Initiative (PMI) Cohort Program until a permanent Director is recruited. Dr. Briggs began by reminding the group that the NIAMS and NCCIH have a long-standing history of partnering on a number of trans-NIH initiatives (e.g., PROMIS). PMI’s mission is to enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized therapies. The vision of the PMI includes recruiting roughly 1 million people into a large, big data venture that will permit the development of more individualized therapies. Public engagement and privacy are two major issues that will influence the success of the PMI.
Dr. Briggs offered examples to illustrate why researchers are optimistic that therapies can be more effectively targeted, noting that genetic markers have enabled much more effective therapies. Zelboraf™ is targeted to the 60% of metastatic melanoma patients whose cancer contains a V600E mutation in the BRAF gene and has been shown to double the survival rates in this group. Kalydeco™ has been shown to be effective in treating a small subset of cystic fibrosis patients. The drug is targeted to mutations responsible for 5% of all CF cases, and is the first CF therapy to treat the underlying cause of the disease rather than just treating symptoms.
In addition to the development of newer, targeted therapies, another component of precision medicine involves understanding the genomic variants that influence the metabolism or effectiveness of drugs. There is already some evidence supporting the use of genomic tools to target therapies. Information extracted from electronic health records (EHRs) can be combined with genetic information to crowdsource which treatment works/does not work for which patient.
The PMI is tapping into the powerful capabilities of genomics, EHRs, an active and engaged participant base, technologies, and the ability to manage increasingly large datasets. Central to the vision of the PMI is the notion that a stronger effort is needed to engage the participants in research studies, with the goal of having a large number of individuals truly engaged in the clinical research process. Through a model of "partnership replacing paternalism," the PMI aims to have a user-centered approach that puts the participant first. Participants will be engaged in design and oversight, push new consent models, and will have their data shared with them (i.e., not just donating their data to the research endeavor or the health care system).
Another driving factor for the PMI relates to the advances that have been made with regard to DNA sequencing power. Dr. Briggs noted that the human genome can now be sequenced in less than a day for around $1,000-$5,000. The feasibility of whole-exome or whole-genome sequencing of 1,000,000 Americans is more realistic now than it has ever been. Dr. Katz commented that the PMI is not solely based on genetic/genomic studies. Dr. Briggs agreed, noting that in addition to the genetic component, another significant focus of the PMI is to accrue a population that truly reflects the diversity of America and to collect data on social and environmental determinants of health.
Mobile health devices represent another technological advance that the PMI aims to exploit. Mobile devices can now track increasing amounts of health information—for example, blood pressure and pulse rate—and can connect with devices such as inhalers and spirometers. Dr. Briggs commented that mobile devices are well distributed across the population, and that it is reasonable to hope that mobile devices can help link participants to the PMI effort. More research is needed to identify the most effective ways of engaging participants through their mobile devices.
The PMI will also use EHRs, which offer unique tools for research and data mining. Despite their utility and increasing adoption, however, they can be fraught with errors. The Federal Government’s Office of the National Coordinator for Healthcare Information Technology (ONCHIT) is responsible for setting many of the standards for EHR use (e.g., standards for how data are transmitted between providers or between a provider and a patient) in partnership with the Centers for Medicare and Medicaid Services (CMS). The new momentum behind the PMI (including the President’s enthusiasm for this initiative) has enhanced partnerships between ONCHIT, CMS, and other federal agencies that have an interest in the PMI. Patients have a right to their EHR data, and the administration has strong interest in seeing increased access for patients to their own medical records in formats that are useful. Dr. Briggs explained that the technology developed for the national Blue Button program promises to allow patients to download the information from their EHR. In the next few years, it is anticipated that the structure for movement of data will improve significantly and that patients will have a much stronger ability to access their medical records and send them, with their permission, for research use.
Dr. Briggs presented the PMI timeline, beginning with its launch by the President in January 2015 and the March 2015 establishment of the NIH ACD PMI Working Group. The core concept behind the PMI is to assemble a cohort of 1,000,000 or more people that will broadly reflect the diversity of the United States (it will not attempt to be statistically representative). There will be a strong focus on groups that are often under-represented in NIH research. The PMI will include a longitudinal cohort with continuing interactions. Cohort members will, from the beginning, asked about their willingness to be contacted again for secondary studies. Two recruitment approaches have been recommended: (1) through a direct volunteer portal (i.e., any individual can sign up), and (2) through large healthcare provider organizations (many of which have highly effective, integrated EHRs). Dr. Briggs noted that from the onset of the PMI, the President has been enthusiastic about the concept that anyone, anywhere in America who wants to enroll in the PMI should be able to do so.
Dr. Briggs introduced the following PMI core values:
- Participation is open to interested individuals.
- The PMI represents the rich diversity of America.
- Participants are partners in all phases of the cohort program.
- Participants have access to study information and data about themselves.
- Data can be accessed broadly for research purposes.
- The initiative adheres to the PMI privacy principles and forthcoming security framework.
- The PMI is a catalyst for progressive research programs and policies.
The initial core data set, as envisioned by the ACD, will be centrally collected and stored in a coordinating center or biobank, align with other large data sets when possible, and leverage existing data standards and common data models when possible. Data sources will include self-report measures, baseline health exams, structured clinical data from EHRs, biospecimens (blood and urine samples), and mobile health data. Information will flow in from both health provider organization volunteers and their records as well as from direct volunteers (with the direct volunteers instructing their providers to provide their health records). To make this effort as cost-effective and streamlined as possible, a goal is to make the initial PMI cohort as simple and practical as possible.
Dr. Briggs presented a flow chart depicting the governance of the PMI and showed how the main PMI components will interact. In terms of projected PMI enrollments, roughly 79,000 participants are expected to enroll this year, leading to an eventual enrollment of approximately 1,098,000 participants in 2019. A number of funding announcements related to the PMI have already been published. Responses to Requests for Applications (RFAs) related to the biobank, coordinating center, five to seven health provider organizations, and a technology center are due in the next week. The FY 2016 budget for the PMI is $215 million, including a $200 million appropriation to the NIH, $10 million to the U.S. Food and Drug Administration (FDA), and $5 million to the ONCHIT. The PMI budget will increase to $230 million in FY 2017, after that, the core support of the cohort will be flat, and it is hoped that additional funds can be identified and secured to support specific scientific studies.
Council member Mr. Alex Silver, Chairman of the Jackson Gabriel Silver Foundation, characterized the PMI as an ambitious and much-needed project. He commented that the keystone of the PMI appears to be recruitment and asked about how the PMI leadership group is approaching this issue. Dr. Briggs explained that the value of participation to those enrolled in the PMI is a critical component, and is one of the reasons why there is a significant emphasis on a pilot enrollment phase. It is hoped that feeding information back to participants will help them to build a sense of membership in something that is of broader benefit. Additionally, the provision of information back to participants is of potential value to them. The PMI will be seeking to learn about what type of information will help keep participants engaged. Participants will not be paid for enrolling in the PMI, so developing methods of engagement is particularly important to this effort.
Mr. Silver also asked about what measures are being taken to keep the data secure. Dr. Briggs noted that the White House convened a panel of security experts to develop a document on PMI security principles; the PMI will be using almost the highest level of government security possible, including a set of standards to ensure that data are as secure as possible. PMI data will be made available to researchers in a data enclave (as opposed to a direct export to researchers’ computers) that will allow for monitoring the uses of the data. Under this model, it will be possible to take action against any user who tries to manipulate the data in an unauthorized manner. Mr. Silver noted that in some cases, patients do not always report the full extent of their health information (e.g., many smokers will not admit to their doctor that they smoke). Dr. Briggs commented that research indicates that people are often more honest to a computer than they are in a face-to-face interview, and that the White House has developed a set of PMI privacy principles that will be used to safeguard the privacy of participants’ data.
Dr. Katz asked about how often PMI participants will be contacted and asked to provide data. Dr. Briggs noted that a PMI pilot project is seeking to identify the impact of asking for data over different time intervals (e.g., once per month, once every 6 months, once per year, etc.). Participants will be asked about their preferences for being contacted.
Dr. Khosla asked about the extent to which the PMI will be able to obtain good, usable information from EHRs without human intervention and whether any PMI pilot projects are exploring this issue. Dr. Briggs indicated that previously published work suggests that over time, it will be possible to identify which phenotypes can be effectively extracted from EHRs. At the NIH Clinical Center, the phenotyping capacity of the hospital can be effectively utilized for some of the ancillary studies built on top of the PMI. During the early stages of the PMI, a simple physical evaluation will be carried out on each participant.
Council member Dr. Gwendolyn Powell Todd, a patient, health advocate, and educator, expressed enthusiasm that the PMI will reflect the diverse nature of the U.S. population and asked if there is a target level of participation for various ethnic and racial groups. She also noted that some groups may not be overly enthusiastic about participating in research studies, and asked about strategies for including these populations. Dr. Briggs commented that having the diversity that would truly make the PMI cohort reflective of the U.S. population (in terms of both socioeconomic and racial/ethnic diversity) will require special recruitment efforts. PMI outreach efforts to participants in different groups will need to take into account the needs and concerns of each of these populations. The PMI healthcare provider organization solicitation asks the organizations to provide information regarding their capabilities for reaching underserved communities. And, one of the first tasks of the PMI Steering Committee will be to establish enrollment benchmarks so that progress toward enrollment objectives can be measured. PMI’s communication contractor will be asked to develop strategies for reaching targeted populations.
Council Member Mr. Richard Seiden, an Attorney at Foley and Lardner LLP, applauded Dr. Briggs and the NIH for developing the PMI. From the patient advocate’s perspective, he suggested that organizations such as Kaiser could serve as a beneficial source of information on patients. Dr. Briggs noted that Kaiser is an active contributor to the Health Care System Collaboratory and has a long history of being active in clinical research. Dr. Briggs, who also leads the Health Care System Collaboratory, noted the need for those in the research enterprise to place higher value on the partnerships that have been developed with major healthcare organizations, particularly with respect to their research operations. Many healthcare organizations are committed to the concept of a learning healthcare system, being a part of that research, and contributing to the overall effort. The PMI has received Letters of Intent from 45 health provider organizations proposing to submit applications.
Council member Dr. Sherine Gabriel, Dean of Rutgers Robert Wood Johnson Medical School, asked about laboratory testing and how the PMI will ensure that it can obtain accurate and standardized testing results across the cohort. Dr. Briggs noted that the centralized biobank will store all samples and will conduct the laboratory analyses after careful piloting using laboratory methods that have been fully vetted.
INTRAMURAL RESEARCH PROGRAM OVERVIEW
Dr. Katz reminded the group that on an annual basis, Council members are provided with an update on the activities of the NIAMS IRP. Dr. O’Shea opened his remarks by noting that the IRP represents NIAMS’ single largest investment. The IRP includes 25 faculty (including tenured faculty, tenure-track faculty, assistant clinical investigators, staff scientists, clinicians, and one contractor who is an orthopaedic surgeon). The IRP also has 20 clinical faculty (including scholars), Cores, and a training and outreach group. The IRP is reviewed annually by the NAMSAC as well as the Board of Scientific Counselors.
Dr. O’Shea echoed Dr. Katz’s earlier comments congratulating Dr. Kaplan for her receipt of the Evelyn V. Hess Award. Dr. Kaplan has been studying the pathogenesis of lupus for many years and is a leader in exploring how neutrophils and their products (NETs) contribute to lupus (and how that is related to the induction of interferons, which also are important for lupus pathogenesis). She has a paper coming out in Nature Medicine showing that lupus neutrophils use mitochondrial reactive oxygen species (ROS) to synthesize NETs, which are enriched in oxidized mitochondrial DNA, as a way of inducing interferons. Lupus neutrophils create NETs, and use of a mitochondrial ROS scavenger prevents this process. This finding may have potential for rapid translation.
Dr. Kaplan also has a strong interest in conducting clinical trials and has joined Dr. Sarfaraz Hasni, Staff Clinician in the NIAMS office of the Clinical Director as part of the IRP’s team conducting lupus clinical trials. Dr. O’Shea updated Council members on the status of IRP’s lupus clinical trials: one has been completely enrolled, another trial on PPAR-gamma agonists has started, and the IRP is attempting to begin a trial examining the use of tofacitinib (a JAK inhibitor) in lupus (with a focus on documenting the safety of using this drug in patients with lupus).
Dr. Peter Grayson, a recently appointed Assistant Clinical Investigator in the IRP’s Systemic Autoimmunity Branch, is working on vasculitis and has been studying gene expression in an effort to understand how it relates to the different types of vasculitis. He recently published a paper showing that a granulocyte signature was associated with antineutrophil cytoplasmic antibodies-associated vasculitis and correlated with disease activity. This finding intersects with work by Dr. Kaplan, who has been studying low density granulocytes associated with lupus, offering an opportunity for collaboration between the two investigators. Dr. Grayson has also been using resources available at the NIH Clinical Center to obtain images showing the effects of vasculitis therapy.
Dr. O’Shea explained that most of the cocaine found in the United States is contaminated with levamisole, a drug used to treat parasitic worm infections in humans and animals. Levamisole is cheaper than cocaine and difficult to detect. The drug carries with it a number of potentially dangerous side effects. Dr. Grayson has been studying levamisole-induced vasculitis. Interestingly, patients exhibit significant vasculitis without internal organ involvement that resolves if the patients stop using contaminated cocaine. Dr. Grayson was able to show that levamisole induces a unique form of cell-death known as NETosis and that this is mediated by neutrophil muscarinic receptors. This work was conducted in collaboration with the National Institute on Drug Abuse (NIDA).
In another collaboration, Dr. Grayson worked with Dr. Dan Kastner, Adjunct Investigator in the Office of the Clinical Director, who identified a new genetic cause of vasculitis that is a deficiency of adenosine deaminase 2 (ADA2). Dr. Grayson recognized that ADA2 is also associated with NETosis and was able to make the connection between ADA2 and adenosine-mediated regulation of NET formation.
Dr. Mike Ombrello, Assistant Clinical Investigator in the Office of the Clinical Director, has been trying to gain a better understanding of childhood arthritis and has launched an international effort to conduct a genome-wide association study on this condition. It is believed that childhood arthritis is an autoimmune disease with multiple autoinflammatory components. Dr. Ombrello is resequencing to look for rare variants. Dr. O’Shea commented that overall, the IRP has an impressive number of rheumatologists who are interested in pediatric rheumatology, which is of particular interest to the NIAMS because of the genetic components and the opportunities for additional study that they represent.
Roughly one year ago, the IRP recruited Dr. Andrew Mammen, Principal Investigator in the Laboratory of Muscle Stem Cells and Gene Regulation, a neurologist whose primary interest is myositis. Dr. Mammen discovered a new form of myopathy—myopathy associated with use of statin drugs. In a letter to the New England Journal of Medicine, Dr. Mammen showed that this form of myopathy can be treated with intravenous immunoglobulin. More recently, he identified another type of myopathy in scleroderma, fibrosing myositis, that is associated with increased mortality. Dr. Mammen is now a tenure-track investigator at the NIAMS. In addition to his duties with the Institute, Dr. Mammen sees myositis patients at Johns Hopkins. This partnership allows Dr. Mammen to use the basic translational and clinical aspects of the NIH while still benefitting from direct patient interactions at Johns Hopkins.
Dr. Daniella Schwartz, Clinical Fellow in IRP’s Rheumatology Fellowship and Training Branch, has been studying early onset retinal vasculitis, which she found is a result of mutations of A20, a molecule in the NFκB pathway that negatively regulates signals by pro-inflammatory cytokines. Dr. Kastner worked with Dr. Schwartz to successfully demonstrate that these patients can be effectively treated with anakinra.
NIAMS IRP researchers began studying a transcription factor called Bach2, which is referred to as a guardian transcription factor because it acts in B cells and T cells. In T cells, it represses effector transition. Regulatory T cells that are supposed to be controlling the immune response, gene expression in those T cells in mice that do not have Bach2, effector genes are massively upregulated. ChipSeq analysis was used to determine that Bach2 binds to roughly half of all the genes that are dysregulated. This work was extended to further determine that Bach2 has a super enhancer. In trying to characterize the role of super enhancers in T cells, IRP investigators found that drugs like tofacitinib preferentially act on portions of the genes that have super enhancer architecture. Dr. O’Shea described a patient from the United Kingdom who suffered from colitis and infections since childhood. She was found to have hypogammaglobulinemia. After sequencing, a mutation of Bach2 was found. Additional patients with similar clinical presentation and Bach2 mutations have since been identified. It appears that having just one mutant allele in Bach2 may lead to disease. GWAS studies in these patients often identify loci that have super enhancers; NIAMS IRP researchers have found that genes that have super enhancer architecture are more likely to cause problems when there is only one mutant allele.
Dr. O’Shea provided additional examples of work done by NIAMS IRP investigators and recent accomplishments of the IRP overall. These included:
- Dr. Michael Ward, Chief of the Clinical Trials and Outcomes Branch, in the area of spondylitis and the most effective treatments for these disorders.
- Dr. Rafael Casellas, Chief of the Laboratory of Molecular Immunogenetics, who has been using next-generation sequencing technology to study how the genome is organized in B cells.
- Work by Dr. O’Shea to understand the accessibility of the entire genome to examine the relatedness of the different types of innate cells, adapter cells, and their precursors.
- Dr. Vittorio Sartorelli, Senior Investigator in the Laboratory of Muscle Stem Cells and Gene Regulation, who is studying epigenetic regulation in muscle stem cells and the role of sensors of metabolic changes in muscle stem cells.
- In response to the recent Ebola crisis, NIAMS IRP nurses and staff, including Dr. Paul Plotz, Scientist Emeritus in the Office of the Director, volunteered to travel to Africa and help conduct trials.
- The IRP’s Training Branch has been conducting an extremely successful summer program.
Looking ahead to 2016 activities, Dr. O’Shea noted that a number of IRP staff will be presenting their work to the BSC. The IRP will also be holding a Spring Colloquium and will be initiating a search to identify one or more tenure-track clinical investigators.
Council member Dr. Gary Koretzky, Dean of Weill Cornell Graduate School and Senior Associate Dean for Research at Weill Cornell Medical College, noted that roughly 18 months ago, each Institute was mandated to review their respective IRPs and make recommendations to the NIH Office of the Director. He asked if there have been any new NIH-wide initiatives identified as a result of this work, or if there have been any new directions identified for the NIAMS IRP. Dr. O’Shea explained that a long-term NIH IRP plan has been reviewed by Dr. Collins and the ACD and that there have been no significant changes identified. However, this effort helped identify the need to recruit a new clinical investigator within the NIAMS IRP, and helped identify the need to improve the way resources are used across the NIH and to improve diversity on the NIH Campus.
Dr. Katz added that each Institute developed an IRP long-range plan; one focus of the NIAMS plan was on how it can most effectively utilize the Clinical Center and its IRP. The ACD also issued a trans-NIH IRP long-range plan. Although the ACD plan provided strong recommendations with regard to trans-NIH initiatives, recruitment of staff, utilization of staff and responsibilities of staff positions, and oversight by the BSC, Dr. Katz characterized the plan as somewhat disappointing because it does not fully incorporate input from the Institutes and their respective Advisory Councils. Dr. O’Shea added that the exercise of generating the NIAMS long-range plan was useful to the Institute in that it provided an opportunity for faculty to provide feedback on their thoughts regarding the future of the Institute. Dr. Katz noted that this activity also provided an opportunity for NIAMS leadership to consider how the overall clinical program might be revitalized.
CORE CENTERS FOR CLINICAL RESEARCH CONCEPT DISCUSSION
Dr. Susana Serrate-Sztein (Director of the NIAMS Division of Skin and Rheumatic Diseases) presented an update on NIAMS’ efforts to renew and reshape its Core Centers program. She described the Institute’s process for reviewing the CCCR, starting with a review of the Centers program in 2013 under Dr. Carter’s leadership. In close consultation with the community, the Centers Evaluation Working Group was formed and developed a key report that established principles for the NIAMS to consider in restructuring its Centers program. The principles that emerged from that report emphasize: (1) trying to capture the most important opportunities to advance the science within the Institute’s mission, (2) providing flexibility in research activities and scientific scope, and (3) ensuring that the Centers serve as a resource for the entire community. In response to this report, the NIAMS has reformulated its Centers program, now referred to as the Core Centers for Clinical Research (CCCR). To help guide this work, the NIAMS established a CCCR Working Group. And, to ensure the broadest input possible was received, the Institute issued an RFI and carefully reviewed the responses. Three RFAs have been issued, in the areas of skin, musculoskeletal disease, and rheumatic diseases. The Institute has also restructured its Centers of Research Translation (CORT) program.
Consistent with input received in response to the RFI and with the prevailing thoughts of the CCCR Working Group, the CCCR is designed to be flexible, foster innovation, and address the most pressing needs of the NIAMS clinical research community. Center design and focus should consider existing and projected gaps in knowledge, as well as the breadth of concepts that can be meaningfully addressed including feasibility, adaptability, and adoptability. A Center’s emphasis can be on synergy and integration within each Center. The Centers will individually and cooperatively foster the training of future clinical researchers. Stakeholder (e.g. community, patients, researchers, etc.) involvement at all levels, from conceptualization to implementation, is encouraged.
In terms of structure, Centers will include one or more mission-focused Methodology Research Core(s) and a small Administrative Unit. The Methodology Research Cores are expected to provide expertise and support for the development and implementation of clinical projects within the NIAMS mission. The Methodology Research Cores can be theme-focused (i.e., pharmacoepidemiology, alternative trial designs, big data analysis). In the past, Centers’ Methodology Cores included activities related to clinical research but did not have a particular focus. It will be up to the investigators to present the theme, the rationale behind the theme, align the resources that would be available to foster the theme, and to explain how advancing the theme advances the field of clinical research for that particular disease or group of diseases.
It is expected that the new CCCR program will include a pilot and feasibility (P&F) program, which will provide protected environments for junior clinical researchers. P&F projects may be proposed if they are: (1) consistent with the clinical research definition and goals of the FOA, (2) are an initial proof-of-concept study, and/or (3) enhance the premise of a future clinical research project. P&F projects can be used to develop new methodologies or adopt and adapt innovative methodologies/metrics from other fields. Centers’ applications should include their approach for soliciting, reviewing, and administering their P&F programs.
Dr. Katz thanked Dr. Serrate-Sztein, Dr. Carter, and other NIAMS staff involved in this work. He also expressed his appreciation to those former and current Council members who served on the Working Group (which was chaired by Dr. Carter), as well as those Council members who participated in the listening sessions held with various professional organizations. Council members who served on the working group included Drs. Michael Holers (Professor in the Department of Medicine at the University of Colorado School of Medicine) and Christy Sandborg (Professor of Pediatrics at Stanford University). Dr. Katz noted that plans to reformulate the Institute’s Centers program proceeded in concert with NIAMS Scientific Review Officers as well as those who will be conducting the peer review of applications.
Dr. Holers indicated that there were some initial concerns regarding the potential for a disconnect between the quality of the methodologic cores and the scientific review of the proposed science. He asked how the approach described by Dr. Serrate-Sztein addresses this concern. Dr. Serrate-Sztein explained that the process envisioned by the Institute is one in which the Centers would not have to define their P&F projects up front but instead propose the process they intend to use to solicit, review, prioritize, and select these projects. This approach appears to be working well in other funding mechanisms.
Dr. Koretzky asked if there have been any discussions regarding renewals (e.g., the expectation to be renewed, what is expected after five years, etc.). Dr. Serrate-Sztein noted that it is not realistic to establish concrete outputs based on actual changes in clinical practice. However, Centers should be accountable to the metrics that they establish for themselves initially, and the advisory committees within each Center should be engaged in discussing changes in outputs or metrics. Centers selected for funding are responsible for identifying milestones and outputs; this information should be included as part of any progress report they submit. Dr. Koretzky emphasized the importance of defining measures of success and expectations, both on the part of the Centers as well as for the NIAMS.
Dr. Khosla noted that there are clear synergies and overlaps between the CCCR and CTSA programs—moving forward, these could be identified in future FOAs. He also commented that the CCCR program is well-suited for encouraging team-based science approaches, which is an area of focus across institutions.
Dr. Lerner asked about what, if any, consideration was given to existing contract research organizations (CROs) using this mechanism. Dr. Serrate-Sztein indicated that CROs would not be excluded from applying, provided that they do more than just deliver a service to clinical trials, projects, or other activities. The CCCR is conceived as a set of resources to serve research, primarily clinical research, but if the CRO brings innovation or proposes new technologies, they would not be excluded from competition. Dr. Katz agreed, emphasizing that part of the CCCR program’s goal is to develop new methodologies that can be adopted by other groups.
Dr. Gabriel expressed enthusiasm regarding NIAMS’ efforts to reshape its Centers program and commented that Centers should be pushed to specify modest, reasonable steps related to achieving clinical care goals that can be met. Dr. Sandborg asked about how the Methodology Cores can be used more broadly, and suggested that their effects upon other groups’ research could be included as a metric of success. Dr. Serrate-Sztein agreed, noting that the Institute places an emphasis on disseminating information related to resources created by the Centers.
UPDATE ON RA/LUPUS AMP PROGRAM
Dr. Katz noted that the RA/Lupus AMP program has been in existence for almost one and a half years and has benefitted greatly from leadership by Dr. Holers. Dr. Holers explained that the program was established in response to the high attrition rate associated with late-stage drug development. Much of this attrition is due to efficacy problems in late-phase development. This important issue is of great interest not only to industry, but to the scientific community in general. For a number of years, federal leaders (including Dr. Collins) have been engaged in discussions in an effort to identify ways to address this problem.
Established in 2014, the goal of the AMP is to increase the number of new diagnostics and therapies for patients and reduce the time and cost associated with developing them. A novel aspect of the program is partnership between the NIH, industry, and non-profit organizations. AMP partners develop project plans through which costs, expertise, and resources are shared. A new, integrated governance structure is used that enables the best-informed contributions from all participants. The total budget for AMP is $230 million over the next 5 years, with $41.6 million allocated for RA/lupus (with half of this amount coming from the NIH and half coming from industry).
Dr. Holers explained that all data generated (including processed/analyzed data) by the AMP is expected to be: (1) deposited in a rapid and timely way into a repository that is accessible for use by the broad biomedical community; and (2) available to all qualified investigators, consistent with applicable laws, regulations, and policies and unencumbered by any intellectual property claims. It is anticipated that the AMP will be generating large datasets that will be publicly available; this is a new way of conducting science for many of the involved parties, but is consistent with the emerging themes and goals of the NIH and the research community.
Dr. Holers presented the list of RA/Lupus AMP program participants and pointed out that the RA/Lupus AMP investigators are senior-level investigators, all of whom have proposed novel, interesting, and important methodologies and approaches. One of the challenges with this program has been to sort through the investigators’ proposals to identify the best candidates to move forward. Two technologies, CyTOF and RNASeq, have been selected for use in the AMP primary projects (the projects with the highest funding priority). These technologies will be used to analyze specimens from kidney and synovial biopsies. The RA/Lupus AMP leadership is continuing to consider ways in which additional proposed technologies might be incorporated.
The research phases, as originally envisioned, include a UH2 (exploratory) funding period for research phase 0 and phase 1, as well as a UH3 (implementation) funding period for research phase 2. Currently, the group is transitioning between phase 0 and phase 1. A total of 33 sites and subsites are involved in the RA/Lupus AMP. Dr. Holers reviewed progress to date in the following areas:
- Leadership and organization
- Communication and collaboration
- Research Plans and Operations
- Technology Assessments and Data Management
Dr. Holers reviewed the strengths and opportunities associated with the RA/Lupus AMP, noting that RA and lupus are important problems and that the RA/Lupus AMP represents a novel approach for the NIH and industry that features academic-industry collaborations on a global scale for a common project. The RA/Lupus AMP includes a strong clinical and scientific team made up of highly dedicated Principal Investigators and expert Working Group Chairs/Co-Chairs. It is hoped that AMP-developed cutting-edge approaches for sample processing will be applicable across the wide range of NIAMS diseases. Clinical and biospecimen databases, built on freeware, improve the potential for sharing information within and outside the RA/Lupus AMP. Many of the technology advances associated with this work have been developed in other fields but are now being applied to RA and lupus. This disease study model can be adapted to other disease areas where a similar NIH-industry collaboration would provide benefit.
There are substantial challenges associated with this effort as well. These relate to network complexity and size (e.g., varied expectations of the investigative group, staged budgeting that imposes limitations and uncertainties); the nature of public/private partnerships (balancing public data access with the current realities of academic career development, the new role of industry partners in setting goals and evaluating projects); and practical challenges such as starting a novel, complex network that requires very large time investments for implementation/operational issues with uneven distribution of infrastructure/organization work by investigators.
In concluding his remarks, Dr. Holers presented a list of five-year deliverables, suggesting that a successful RA/Lupus AMP program will yield the following in 2019:
- High quality, comprehensive, integrated datasets in the public domain.
- Identification of new molecules and pathway targets for drug development.
- Validated and disseminated SOPs/protocols.
- Single cell assays that can be rapidly applied to other NIAMS diseases.
- Coordinating Center/consortium/infrastructure for future NIAMS program project grants, initiatives, clinical trials, and industry partnerships.
- New data analysis and systems biology approaches and algorithms.
- Sustainability, including the potential for new industry partnerships in RA/Lupus and other diseases.
Dr. Katz thanked Dr. Holers for his presentation, noting that it effectively captured the promise and challenges of the program. He asked Dr. Holers to comment on utilization of the IRP in this effort. Dr. Holers explained that there has been involvement from the NIAMS IRP in terms of working with one of the datasets; the program appreciates the support of those IRP investigators and looks forward to continuing to interact with them.
Council member Dr. Amy Paller, a Professor of Dermatology at Feinberg University School of Medicine, suggested that the RA/Lupus AMP will contribute greatly to an increased understanding of these diseases. She asked if the program is limited to the study of RA and lupus in adults, and if so, whether there has been consideration given to extending these efforts into the pediatric population. Dr. Holers explained that at present, the RA/Lupus AMP is limited to adults, he noted some challenges associated with bringing the pediatric population into this work (e.g., the difficulty in obtaining biopsies in children), but acknowledged that it is a logical extension of the program.
Dr. Koretzky suggested that inter-site validation of emerging technologies may be a significant challenge. He asked how the RA/Lupus AMP is managing this issue. Dr. Holers explained that a blinded process is being used. Samples have been aggregated and distributed to multiple sites, which are generating data. It is expected that intra-site validation will be stronger than inter-site validation. Slightly different but useful answers are anticipated from these different technologies.
Mr. Mulvihill commented that the RA/Lupus AMP carries with it additional non-science benefits, for example, demonstrating the benefit of showing competing organizations how to collaborate in a public-private partnership. He indicated that this work should not be limited to a five-year window if progress is being made, given the opportunities to extend these partnerships. Dr. Carter noted that through the RA/Lupus AMP, the NIAMS is trying to effect change with regard to how research in these disease areas is conducted. On a larger scale, this effort is trying to change the practice of medicine in these diseases. Dr. Carter thanked Dr. Holers for his efforts in leading this work.
R01 WITH HUMAN MECHANISTIC STUDIES: CONTINUATION OF SEPTEMBER 2015 COUNCIL DISCUSSION
Dr. Katz emphasized that the Institute takes Council discussions very seriously. He reminded the group that during the last NAMSAC meeting, Council members discussed the R01 with multiple aspects/aims, one of which may be clinical research. Dr. Carter noted that several years ago, the NIAMS undertook a process similar to that used in reformulating its Centers program to also examine the Institute’s clinical trials process. This work was initiated with an eye towards ensuring that the clinical trials funded by the NIAMS are impactful. One of the changes that resulted from this effort was that the Institute established its own separate study section to review and evaluate clinical trials with the appropriate disease expertise, methodology expertise, and input from a patient representative. This approach has been very successful. To ensure that the applications that include clinical trials are seen by this study section, the NIAMS instituted a policy that it will not accept applications for clinical trial through the parent R01 mechanism (because these trials are not reviewed by the NIAMS Clinical Trials study section).
During the last Council meeting, there was a lengthy discussion about the study section and the clinical trials process at the NIAMS. During these deliberations, the concept of the hybrid R01 (an R01 application that includes both basic and translational components) was discussed. Dr. Carter noted that one of the most effective ways to study human biology is to determine the effects of an intervention on mechanisms of interest in humans. At the NIH, any intervention in humans intended to study a health-related outcome is considered to be a clinical trial. Therefore, the types of mechanistic applications discussed during the last NAMSAC meeting were not allowed under the Institute’s policy. However, during discussions in September, it was noted that this policy penalizes NIAMS investigators by not allowing them to submit applications with translational aims.
NIAMS Division Directors met following the last NAMSAC meeting to revise the policy, and per a recent communication sent to Council members, the Institute will now allow R01 applications with a clinical aim, but whose primary objective is mechanistic, to go through the parent R01. The Institute anticipates receiving applications for which it is unclear whether the primary objective is mechanistic or clinical. All investigators applying for an R01 that includes a clinical trial will be asked to discuss their application with the appropriate NIAMS Program Officer before submitting their application. This policy will be extended to the parent R21 as well. The Institute will ensure that decisions are harmonized across the NIAMS and will put procedures in place to facilitate these decisions.
Council member Dr. Elizabeth Shane, Professor of Medicine and Vice-Chair for Clinical and Epidemiological Research at Columbia University College of Physicians and Surgeons, applauded the Institute for taking this action. She noted that the Institute’s revised policy will be extremely helpful to those conducting basic research who want to translate it into humans.
Dr. Khosla echoed Dr. Shane’s comments, thanking NIAMS leadership for thinking through this issue and addressing the concerns raised by the Council during its last meeting.
COUNCIL OPERATING PROCEDURES
NAMSAC Executive Secretary Dr. Laura K. Moen, Director of NIAMS’ Division of Extramural Research Activities, presented the annual Statement of Understanding between the Council and the Institute. The Statement of Understanding identifies topics that will be brought to the Council’s attention (e.g., special actions, appeals, special review of investigators who are receiving more than $1 million in direct costs in awards, etc.).
Council members unanimously approved the Council Operating Procedures.
CONSIDERATION OF APPLICATIONS
In closed session, the Council reviewed a total of 796 applications requesting $1,067,485,703 in total costs and recommended 796 for $1,067,485,703 in total costs.
This portion of the meeting occurred during closed session.
OSTEOPOROSIS AND METABOLIC BONE DISEASES UDPATE
This portion of the meeting occurred during closed session.
The 88th National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Meeting was adjourned at 2:25 p.m. Proceedings of the public portion of this meeting are recorded in this summary.
I hereby certify that, to the best of my knowledge, the foregoing summary and attachments are accurate and complete.
Laura K. Moen, Ph.D.
Stephen I. Katz, M.D., Ph.D.