Department of Health and Human Services
Public Health Service
National Arthritis and Musculoskeletal and Skin Diseases Advisory Council
Minutes of the 75th Meeting
8:30 a.m. to 3:00 p.m.
This portion of the meeting occurred during closed session.
CALL TO ORDER
The 75th meeting of the National Arthritis and Musculoskeletal and Skin Diseases (NAMS) Advisory Council was held on September 27, 2011, at the National Institutes of Health (NIH) Campus, Building 31, Conference Room 6. The meeting was chaired by Dr. Stephen Katz, Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Council members present
Dr. Lynda F. Bonewald
Dr. S. Wright Caughman
Dr. Leslie J. Crofford
Dr. Harry C. Dietz III
Dr. David R. Eyre
Dr. Gary S. Firestein
Dr. Linda Griffith
Dr. John H. Klippel
Dr. Henry M. Kronenberg
Dr. Ted Mala
Dr. Regis J. O’Keefe
Dr. Alice P. Pentland
Ms. Jean R. Pickford
Mr. Bradley R. Stephenson, J.D. (via teleconference)
Dr. H. Lee Sweeney
Dr. Julio L. Vergara (via teleconference)
NIAMS Staff in Attendance
Mr. Steve Austin
Dr. Carl Baker
Mr. Eric Bernhard-Gove
Dr. Michael Bloom
Dr. Eric Brown
Dr. Amanda Boyce
Mr. Gahan Breithaupt
Dr. Branden Brough
Ms. Justine Buschman
Ms. Nazia Cheema
Dr. Faye Chen
Dr. Ricardo Cibotti
Mr. Richard Clark
Ms. Barbara Cohn
Ms. Stephanie Craver
Ms. Theresa Do
Dr. Jonelle Drugan
Mr. Erik Edgerton
Ms. Elizabeth Elliott
Ms. Sharon Fair
Ms. Cheryl Fleming
Ms. Barbara Footer
Ms. Kaitaia Fu
Dr. Nancy Garrick
Ms. Gerda Gallop-Goodman
Ms. Gail Hamilton
Ms. Katie Joffee
Mr. Andrew Jones
Ms. Shahnaz Khan
Mr. Mark Langer
Dr. Gayle Lester
Dr. Helen Lin
Ms. Anita Linde
Ms. Mimi Lising
Ms. Leslie Littlejohn
Dr. Kan Ma
Dr. Marie Mancini
Dr. Kathryn Marron
Ms. Melanie Martinez
Dr. Joan McGowan
Ms. Leslie McIntire
Dr. Laura K. Moen
Ms. Melinda Nelson
Ms. Anna Nicholson
Dr. Glen Nuckolls
Dr. James Panagis
Ms. Vivian Pham
Dr. Charles Rafferty
Dr. Mahendra Rao
Ms. Natalie Reyes
Ms. Trish Reynolds
Dr. Louise Rosenbaum
Dr. Susana Serrate-Sztein
Dr. William Sharrock
Ms. Sheila Simmons
Ms. Robyn Strachan
Ms. Yen Thach
Ms. Jamie Thompson
Dr. William P. Tonkins, Jr.
Dr. Hung Tseng
Dr. Bernadette Tyree
Dr. Fei Wang
Dr. Xibin Wang
Dr. Chuck Washabaugh
Ms. Sara Rosario Wilson
Other Federal Staff
Ms. Judy Dulovich, Office of the Director, NIH
Ms. Rhonda Edwards, Office of the Director, NIH
Ms. Mary Beth Kester, National Institute of Biomedical Imaging and Bioengineering, NIH
Dr. Rajiv Kumar, Center for Scientific Review, NIH
Dr. Michael Lauer, National Heart, Lung, and Blood Institute, NIH
Ms. Esther Weiss, Office of the Director, NIH
Members of the Public
Ms. Courtney Brandenburg, Lupus Foundation of America
Mr. Frederick Chen, KAI Research, Inc.
Ms. Karen Chesbrough, Foundation for Physical Therapy
Ms. Rachael Crockett, Foundation for Physical Therapy
Ms. Celeste Crouse, KAI Research, Inc.
Ms. Ann Elderkin, The American Society for Bone and Mineral Research
Ms. Niva Haynes, National Psoriasis Foundation
Ms. Kimberly McGraw, IQ Solutions, Inc.
Ms. Nancy Moy, SRI International
Mr. Ted Shoneck, Tunnell Government Services, Inc.
Mr. Richie Taffet, Ehlers-Danlos National Foundation
CONSIDERATION OF MINUTES
A motion was made, seconded, and passed to accept with no changes the minutes of the 74th NAMS Advisory Council meeting, held on June 14, 2011.
FUTURE COUNCIL MEETING DATES
Future Council meetings are currently planned for the following dates:
January 31, 2012
June 5, 2012
September 11, 2012
February 5, 2013
June 4, 2013
September 10, 2013
DIRECTOR'S REPORT AND DISCUSSION
Dr. Katz welcomed Council members, NIAMS and other federal staff, and members of the public to the 75th NAMS Advisory Council meeting. He mentioned two sources of information available to the public for those who want to keep up with ongoing changes and activities of the Institute: ShortTakes, which is only available online, provides information about initiatives and activities on Capitol Hill, at the U.S. Department of Health and Human Services, and at the NIH, and his Director’s Column, which contains updates, personnel changes, and outreach efforts at the NIH and the NIAMS.
Dr. Katz noted that his Director’s Column this month focuses on the 10th anniversary of the NIAMS Community Health Center (CHC). The CHC, which is an extension of the NIAMS Intramural Research Program, is a medical and health information center that provides health care services to those affected by arthritis, lupus, and other rheumatic diseases. In addition, the CHC serves as a venue for community-based research, public education, and training for NIH clinical fellows.
With more than 2,000 patients enrolled to date in the CHC’s Natural History of Rheumatic Diseases in Minority Communities protocol, the CHC has been the source for a number of articles on research findings that have been published in peer-reviewed journals. Dr. Katz announced that the NIAMS will be hosting a celebration on September 28th for the CHC’s 10th anniversary, during which NIH Director Dr. Francis Collins would be acknowledging the community that made the Center possible. On a final note, the Center will be moving from downtown Washington to the Glenmont area of nearby Silver Spring, Maryland.
Dr. Katz thanked those in attendance for being at this meeting, including those attending via teleconference: Mr. Bradley R. Stephenson (attorney and member of the Muscular Dystrophy Association National Task Force on Public Awareness) and Dr. Julio L. Vergara (Distinguished Professor in the Department of Physiology at the University of California, Los Angeles School of Medicine). Neither Ms. Karen Evans (Chair, Lupus Foundation of America) nor Ms. Ann Kunkel (University of Kansas Medical Center) was able to attend. Dr. Katz acknowledged the four departing Council members, who would receive framed certificates in recognition for their service: Ms. Ann Kunkel, Dr. S. Wright Caughman (Executive Vice President of Health Affairs, CEO of the Woodruff Health Sciences Center, and Chairman of Emory Health Care at Emory University), Dr. John H. Klippel (President and CEO of the Arthritis Foundation), and Dr. H. Lee Sweeney (William Maul Measey Professor and Chair, Department of Physiology, University of Pennsylvania School of Medicine).
Personnel Changes at the NIH/NIAMS
At the NIH level, Dr. Jeremy M. Berg stepped down as head of the National Institute of General Medical Sciences (NIGMS). The next Director, who was recruited from a nationwide search, is going through the required approval process, could not be named. In the meantime, Dr. Judith H. Greenberg is serving as the Acting Director.
On August 31, 2011, after nearly 20 years of federal service, Dr. Vivian Pinn retired from her position as Director of the NIH Office of Research on Women’s Health (ORWH). Dr. Katz reminisced over the warm and collegial relationship he shared with Dr. Pinn over their mutual commitment to reducing the burden of autoimmune diseases, which disproportionately affect women. Dr. Janine Austin Clayton, Deputy Director of ORWH, has been appointed Acting Director.
At the end of September, 2011, Dr. Toni Scarpa will retire as Director of the Center for Scientific Review (CSR). Dr. Katz mentioned that Dr. Scarpa helped the NIH design and implement the first major changes to the NIH in the 65 years of the peer review period. These changes included shorter applications, realigned review criteria and summary statement formats, a limit on the number of times an application could be resubmitted, and a continuous application submission program for peer reviewers. Dr. Scarpa was viewed as a very good steward of public resources, and he implemented a number of cost-cutting measures. In particular, he was recognized for saving an estimated $35 million a year by instituting the use of non-refundable airline tickets, electronic review platforms, and the paperless distribution of review materials. Dr. Richard Nakamura, most recently the Scientific Director of the National Institute of Mental Health (NIMH), will serve as the Acting Director of CSR.
On September 30, Dr. Barbara Alving will step down as Director of the National Center for Research Resources (NCRR). Dr. Louise Ramm, the current Deputy Director of NCRR, will become the Acting Director while the NIH implements the redistribution of NCRR programs to other ICs..
Dr. Katz noted that the administration of the Clinical and Translational Science Awards (CTSAs) is scheduled to move from NCRR to the proposed National Center for Advancing Translational Sciences (NCATS) this fall. To facilitate the transition, the NIH decided to delay the release of its next CTSA funding opportunity announcement until June 2012. Institutions that received those awards in 2008 and planned to apply this fall will get administrative extensions. The CTSA/NCATS Integration Working Group, which was chaired by Dr. Katz, endeavored to align the goals of the CTSA and the NCATS while reducing the difficulties associated with the changes.
Dr. Mahendra Rao will be the Director of the new NIH Intramural Research Center for Regenerative Medicine (NIH-CRM). The NIH-CRM, a Common Fund program that is administered by the NIAMS, will build upon existing stem cell research to advance translational studies, and ultimately, cell-based therapies in the NIH Clinical Center. It will also serve as a resource for the extramural community. Dr. Rao, who gave an address later in the meeting, is internationally renowned for his work with human embryonic stem cells. He received his M.D. from Bombay University in India, his Ph.D. from the California Institute of Technology, and postdoctoral training at Case Western Reserve University. He has also worked at the NIH before, as chief of the Neurosciences Section of the National Institute on Aging’s Intramural Research Program. Dr. Rao’s intramural lab will be housed jointly in the NIAMS and the National Institute for Neurological Disorders and Stroke (NINDS).
Dr. Katz congratulated Dr. Joan McGowan, Director of the NIAMS Division of Musculoskeletal Diseases (DMD), who was presented with the Shirley Hohl Service Award from the American Society for Bone and Mineral Research (ASBMR) September 19, 2011. This award, one of the highest awards given by ASBMR, goes to an individual whose activities represent the dedicated and unselfish devotion in service to the Society and its missions and goals. He noted that Dr. McGowan’s leadership as the DMD Director has provided a strong foundation for the NIAMS bone biology and diseases research portfolio. A respected member of the NIH community, Dr. McGowan has served as a long-standing co-chair, with Dr. Katz, of the Federal Working Group on Bone Diseases, and a contributor to the Women’s Health Initiative. Dr. Katz praised her leadership in both of these roles and for overseeing the completion of the Surgeon General’s Report on Bone Health and Osteoporosis as senior scientific editor.
Update on Budget and Congressional Activities
Dr. Katz remarked that the impact of the recently passed Budget Control Act remains unclear, but that there will be a continuing resolution up until November 18, 2011. . The proposed caps on discretionary spending may result in spending cuts to the NIH, and the NIH leadership is actively engaged in planning for operating with reduced budgets.
Earlier this month, Dr. Katz participated in a Congressional briefing that was organized by NIAMS Coalition members to commemorate the 25th anniversary of the Institute. Dr. Katz gave special thanks to Coalition members and leaders who put the event together. Sponsored by Representative Bill Young (R-FL), the event acknowledged the dedicated service of Representative Michael Burgess (TX), an obstetrician from Texas, Representative Anna Eshoo (CA), Senate Labor-HHS Appropriations Subcommittee Chairman Tom Harkin (IA), and former Representative and Research!America chairman John Porter. The event, which was attended by Congressional and NIAMS staff, researchers, patients, and advocates – notably Ann Elderkin [of ASBMR]. Dr. Katz noted that it was an excellent opportunity to recognize members of Congress for their support over the years and to demonstrate the importance of continued funding for research to reduce the burden of bone, joint, muscle, and skin diseases.
Highlights of Selected Recent Scientific Advances
Although the NIH covers many common chronic diseases, many others within the NIH’s mission affect relatively small portions of the population. In addition, the impact of individual gene variance is thought to be relatively small. Therefore, the NIAMS recognizes the importance of international collaborations in getting large enough patient cohorts to obtain statistically significant results.
- A recent study of one such disease, ankylosing spondylitis (AS), comprising the efforts of investigators around the world, including the Wellcome Trust Case Control Consortium and Dr. Michael Ward from the NIAMS Intramural Research Program. The study revealed that the gene ERAP-1, which encodes an enzyme involved in antigen processing, is associated with AS only in patients that are positive for HLA-B27. This gene-gene interaction points to a possible key mechanism by which HLA-B27 contributes to the development of AS through the aberrant processing of antigens by ERAP-1, which leads to the enzymatic cleavage of a particular peptide that fits into the HLA-B27 groove (Nat Genet. 2011 Aug 10;43(8):761-767. doi: 10.1038/ng.873. PMID: 21743469).
- At the University of Pennsylvania, Dr. Tejvir Khurana determined that the interleukin-15 receptor alpha (IL-15Ra), a protein that regulates immune cells, also plays an important role in determining endurance by affecting the characteristics of fast muscle fibers. Although most of the research was done on mice, the researchers also examined the IL-15Ra gene in humans and found that Olympic-level endurance athletes exhibit a higher frequency of certain IL-15Ra genetic variations than others, underscoring the relevance of animal studies to human health and disease. (J Clin Invest. 2011 Aug 1;121(8):3120-32. doi: 10.1172/JCI44945. Epub 2011 Jul 18. PMID: 21765213).
- A team of intramural scientists at the NIAMS, led by Dr. Maria Morasso, in collaboration with researchers at the National Cancer Institute (NCI), have discovered that the deletion of the gene Distal-less 3 (Dlx3) in mice is associated with the development of a type of skin inflammation that involves the cell signaling molecule interleukin-17 (IL-17). Keratinocytes in mice lacking Dlx3 were found to proliferate faster and differentiate abnormally. The mice also showed compromised skin barrier function and an inflammatory response, characterized by the infiltration of the epidermis by white blood cells that produce IL-17. This discovery helps elucidate the complex network of cell signaling molecules in the skin’s barrier function and its disruption. (Proc Natl Acad Sci USA. 2011 Jul 12;108(28):11566-11571. Epub 2011 Jun 27. PMID: 21709238).
- A research team led by Dr. John Varga from the Northwestern University Feinberg School of Medicine has found a potential mechanism for scleroderma pathogenesis. Wnt10b, a molecule that regulates cell behavior, is found in high concentrations in the skin of scleroderma patients. Dr. Varga’s team studied a mouse genetically engineered to overproduce Wnt10b in adipose tissue, where it is not usually found. They showed that the mouse adipose tissue was replaced by fibrotic tissue, a reasonable model of what takes place in scleroderma patients. Based on this finding, the researchers proposed that Wnt10b has the ability to convert fat cells into muscle-like cells that produce excessive amounts of connective tissue proteins and cause the fibrosis seen in scleroderma. (Arthritis Rheum. 2011 Jun;63(6):1707-17. doi: 10.1002/art. 30312. PMID: 21370225).
- Dr. Elena Tourkina and colleagues at the Medical University of South Carolina found fibrocytes in lung tissue samples from systemic scleroderma patients with interstitial lung disease but not in samples from healthy control subjects. This suggests that fibrocytes are derived from blood and not from fibroblasts. Levels of calveolin-1, a cell membrane protein that appears to regulate fibrosis, were significantly reduced in fibrotic lung tissue. (Fibrogenesis Tissue Repair. 2011 Jul 1;4(1):15. [Epub ahead of print] PMID: 21722364).
- Long-term studies by Dr. Michael Brenner of Harvard Medical School and colleagues have examined synovial fibroblasts, already identified as a major source of proinflammatory factors in the joints of rheumatoid arthritis (RA) patients. In 2007, the investigators found that in mouse models, cadherin-11 maintains a tissue culture in RA joints, contributes to synovial inflammation, and mediates cartilage degradation. They found, in addition, that inhibiting cadherin-11 in arthritic mice reduced disease activity. A recent study by the team examined the specific mechanisms of cadherin-11 on joint tissue inflammation in RA patients. They uncovered multiple pathways through which cadherin-11 augments production of the pro-inflammatory factor interleukin-6 (IL-6). These findings support the dual role of cadherin-11 in RA joints: it maintains structural stability through connections between synovial fibroblasts and it contributes to the production of molecular mediators that drive inflammation and bone erosion. (Proc Natl Acad Sci USA. 2011 May 17;108(20):8402-7. Epub 2011 May 2. PMID: 21536877).
- A very recent study by Drs. Michael Zuscik and Randy Rosier at the University of Rochester found that human parathyroid hormone, already approved to treat osteoporosis in older women, restored cartilage in mouse joints that resembled the knees of post-traumatic osteoarthritis patients. After a month of treatment, the mice receiving parathyroid hormone had nearly a third more cartilage than the control mice. This study is a classic example of how clinical observation can provoke basic research; the investigators designed their animal studies after their colleagues noted the reduction in arthritis pain in osteoarthritis patients taking parathyroid hormone medication for osteoporosis. These findings suggest a major breakthrough in the treatment of arthritis pain in humans. (Sci Transl Med. 2011 Sep 21;3(101):101ra93. doi: 10.1126. PMID: 21937758).
- Dr. Bradley Olwin of the University of Colorado, Boulder, recently tested the hypothesis that developing bones secrete molecules that may affect muscle development. He found that muscle is present, but greatly reduced, in mice that lack the bone-derived protein called Indian hedgehog. This finding suggests that bone communicates with muscle via Indian hedgehog, which is at least partially responsible for muscle development. (Dev Biol. 2011 Aug 15;356(2):486-95. Epub 2011 Jun 13. PMID: 21683695).
NIH/NIAMS Activities and Plans for the Future
Last month the U.S. Department of Health and Human Services issued a final rule in the Federal Register that revised the Financial Conflict of Interest (FCOI) regulations for grant recipients and contractors. The new rule requires that researchers funded by the Public Health Service (PHS) must report income from outside sources that exceeds $5,000 and relates to the investigator’s institutional responsibilities. This is true regardless of whether the income or its source directly relates to the federally-funded project. Certain payments are exempt, such as income from seminars or lectures at universities or medical schools, and service to federal, state, and local governments. However, the rule has been broadened to include equity interests in non-publically-traded entities.
Institutions will have the added but important responsibility of determining whether significant financial interests that are disclosed by investigators relate to research funded by the PHS and, therefore, constitute FCOIs. When institutions determine that they do, the institutions will become responsible for ensuring that the public has access to information about investigators’ significant financial interests. In addition, institutions will be required to train investigators about the new policies.
Dr. Katz mentioned a website, "Dollars for Docs," on which pharmaceutical companies voluntarily list their contributions to college funds, household buildings, and the like. In 2013, this reporting will become compulsory, and specific payments, such as speaking fees, research fees, and department fees will have to be itemized, in the interest of transparency.
The U.S. government is also considering changes to the so-called Common Rule, the regulations governing the ethics, safety, and oversight of human research. Dr. Katz noted that the government is accepting public input through October 27 and encouraged those present to provide input. He noted that one of the proposed changes would allow institutional review boards (IRBs) to focus more on high-risk studies and less on those with minimal risk of potential harms.
Dr. Katz announced an NIH funding opportunity through the Director’s Transformative Research Awards program, which is supported through the Common Fund. The NIH is currently soliciting applications for these awards, which provide a unique opportunity for investigators to receive up to $25 million a year for large projects with minimal preliminary data. The awards are intended to support basic, translational, and clinical projects in any area within the NIH mission. The only requirement is that the impact is expected to be truly transformative, not simply high impact. The application deadline is January 12, 2012, with letters of intent due on December 12, 2011.
Dr. Katz announced that the Advisory Committee to the NIH Director’s Working Group on the Future Biomedical Research Workforce is soliciting input from the extramural community. The Working Group has identified several issues it plans to consider when it develops a model of a future biomedical research workforce. The group is currently seeking input from students, postdoctoral fellows, scientists, scientific societies, NIH grant institutions, and the general public. Dr. Katz asked that meeting attendees share the link and encourage their colleagues to participate in this process.
Another workforce-related issue that Dr. Katz brought up was the finding published last month in the journal Science that black investigators are 10 percent less likely than white investigators to receive a new research project grant, even when education, institution, and other factors that influence the likelihood of success are controlled. The study, commissioned by the NIH with assistance from the National Science Foundation, also found that black, Hispanic, and Asian investigators were less likely to resubmit unfunded applications. Dr. Katz stated that these results are worrisome, and that the underlying causes for these discrepancies must be identified and rectified.
He assured meeting attendees that the NIH is committed to addressing inequalities. To do so, the NIH is working to increase the number of early career investigators, including those from underrepresented populations, to participate in the peer review process, which is thought to enhance one’s chances for funding. In addition, the NIH is examining the grant review process for bias and developing interventions to ensure that all applicants are reviewed fairly.
Continuing a discussion from the June 2011 Advisory Council meeting on principles for managing science in fiscally challenging times, Dr. Katz stated that one of the greatest challenges facing the NIH is how to maintain a vibrant, exciting research portfolio during times of flat or decreasing budgets. He thanked attendees of the last meeting for their feedback, and summarized that discussion, much of which concerned select pay. Dr. Katz noted that the NIAMS uses select pay less than most other NIH Institutes or Centers (ICs). He added that there seemed to be some comfort level among Council members for increasing the amount of the NIAMS budget used to fund select pay if metrics were used to aid in portfolio analysis.
Dr. Katz raised a question about the implications of program priority balance, noting that some Council members felt that critical areas may be left unfunded. He described the considerable discussion about the inherent difficulties of reconciling differences among the various review groups across the NIH, particularly those that review NIAMS applications and acknowledged Council members’ concerns over applications that did not fit neatly into a payline-driven approach. Dr. Katz concluded that while transparency is essential, communicating judgment remains a very challenging issue.
Regarding 2013 initiatives, Dr. Katz stated that the likely financial picture will entail difficult decisions. He said that the NIAMS must continue to look forward and identify areas which can be stimulated through appeals to the research community.
Dr. Katz also pointed out some particular highlights of NIAMS information dissemination efforts. Ms. Diane Rehm of National Public Radio was a special guest at the NIAMS 25th Anniversary Symposium. Later that week, when the U.S. Food and Drug Administration (FDA) released a new guideline on sunscreen labels, Dr. Katz appeared on a segment of the Diane Rehm Show on National Public Radio, about sunscreen labels and skin cancer with Dr. Janet Woodcock of the FDA and Dr. Lynn Schucter of the University of Pennsylvania. Dr. Katz was very pleased to have the opportunity to reach the show’s 2.2 million listeners with information about how people can protect themselves from excessive sun exposure.
The NIAMS has also been exploring various forms of social media. The NIAMS Office of Communications and Public Liaison (OCPL) launched a Twitter feed in January, which has attracted more than 700 followers and over 15,000 hits to the NIAMS website since January. Dr. Katz congratulated Rich Clark and the OCPL team for their efforts to disseminate information on arthritis and musculoskeletal and skin diseases.
As part of a continuing commitment to engage members of the NIAMS Coalition, the NIAMS will be hosting the third Coalition Outreach and Education Day at the Pooks Hill Marriott on October 11, 2011. The theme of the meeting for this year is "Creating Connections for Science," and the day will be organized to bring Coalition members up to date and to share best practices in collaborating with the Institute. This event has been popular in the past, and Dr. Katz expects it to be well attended this year as well.
Dr. Katz remarked that Dr. Henry Kronenberg, Chief of the Endocrine Unit at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School, had been honored with the Gideon A. Rodan Award from the American Society for Bone and Mineral Research.
Council discussion focused on potential changes to the Common Rule and the ability to actually de-identify samples in this age of DNA sequence analysis. It was suggested that the proposed changes to the Common Rule could present potential challenges to many of the biorepositories supported by the NIH. At present, the requirements for samples to be completely de-identified would realistically eliminate any potential for creating and maintaining repositories of preexisting or clinically-obtained material. Program staff agreed; those with experience working with shared genetic data from genome-wide association studies thought that de-identified genetic data were still identifiable. It was also suggested that the placement of fairly elaborately controlled access systems might be helpful in creating more secure repositories and collections, and that anyone who makes use of these resources is taking on a fairly substantial obligation in protecting participants’ privacy. It may also be possible to gain consent from some patients to be identified, such as those in some of the current osteoarthritis studies.
REPORT ON THE COUNCIL OF COUNCILS
Dr. Regis O’Keefe, Chair of the Department of Orthopaedics and Rehabilitation at the University of Rochester Medical Center, is the NIAMS representative to the Council of Councils. He began his presentation with a brief history of the advisory group and noted that since his last report in the winter of last year, three initiatives have been presented to the Council of Councils for concept clearance. He described the three phases of how concepts are developed: the NIH Director develops concepts in conjunction with IC Directors initiatives are refined through a strategic planning process, and finally concepts are cleared with the Council of Councils’s approval, leading to program implementation. This cycle is meant to last five years, with the goal that many ICs will assume responsibility for the programs at the end of the cycle.
When potential initiatives come before the Council of Councils for clearance, the Council addresses two main questions: Is this initiative transformative? Does it advance the individual Institutes’ missions? The first of the three initiatives presented was Single Cell Analysis, Dr. O’Keefe noted the initiative was found to be applicable across all cell types and organ systems, and that 22 Institutes already had active programs in this area. There was also, importantly, a recent convergence in the field due to advances in technology. The Single Cell Analysis Initiative was approved.
The second initiative presented to the Council of Councils for concept clearance was in the area of metabolomics. A portfolio analysis revealed that, relative to proteomics and genomics, metabolomics was underfunded, and, as expected, associated with fewer publications. The initiative was passed, with the goal of setting up an infrastructure that will include comprehensive metabolomic resource cores, training, technology development, reference standards development, and sharing of data and reagents. The infrastructure created by this initiative will be available to researchers across the NIH, throughout the United States, and around the world to advance understanding of these disease processes.
The third potential initiative that Dr. O’Keefe discussed was the Human Heredity and Health in Africa (H3Africa) Initiative. Because the initiative was so transformative, because Wellcome Trust was a partner — giving it an international aspect — and because the creation of the infrastructure could initiate a process across Africa that would lead to continued engagement and continued investment throughout the continent, the initiative was approved on August 15, 2011.
The creation of the NIH NIH-CRM also came up for clearance at the August 15, 2011 meeting. This initiative was very appealing to the Council based on its very detailed timeline and the impacts the program could have, including extending to clinical trials.
Council members had questions about the reorganization of NCRR programs as NCATS is established. There was interest in understanding the fate of large equipment and biological resources since these support trans-NIH areas of basic science, and concern about how the implementation would come about. Some major aspects of Common Fund activities are going into the NCATS. Those elements include the NIH Office of Rare Diseases Research (ORDR), the Therapeutics for Rare and Neglected Diseases program, and the Rapid Access to Interventional Development (RAID) program. The Research Centers in Minority Institutions will be moving to the National Institute on Minority Health and Health Disparities, and the Institutional Development Awards and many smaller programs will go into the Office of the Director for the time being.
All programs, including the large equipment and biological resources programs, will find a place, although the details are yet to be determined. At this time, NCRR programs without permanent homes would be managed temporarily by the NIGMS. A subcommittee of eight IC directors will develop recommendations for the remaining NCRR programs.
NIH CENTER FOR REGENERATIVE MEDICINE (CRM)
Dr. Katz introduced Dr. John O’Shea, Scientific Director of the Intramural Research Program at the NIAMS, as being instrumental in putting together the NIH-CRM by identifying not only the scope of the NIH-CRM but also leading the search for the Center’s director There was a very aggressive schedule for looking at candidates to lead the Center, and many candidates had great research and articles published in single name journals. Dr. Mahendra Rao, chosen as Director of the new NIH-CRM, stood out as someone who could translate an exciting technology to help people. Dr. O’Shea introduced Dr. Rao by giving his background:
Dr. Rao began his presentation by giving a broad outline of the Center and the plans to move it forward. First he noted that the field of regenerative medicine is not a simple field in terms of government regulations. There are two regulatory extremes: cell-based nutraceuticals, which have no regulations whatsoever, versus mixed therapies, including engineering, scaffolding, and cells, which have a very complicated regulatory landscape. He noted that despite that range — or maybe because of it — the field is already very active with companies and available products, which serves as an important backdrop to thinking about what the NIH-CRM may or may not be able to do. He also discussed how the regulations vary in different situations and how that is a factor is determining timing issues for translation.
Based on his own experience, Dr. Rao ranked metabolic stem cells as the largest part of the regenerative medicine field, followed by mesenchymal stem cells, and then neural stem cells. He stated that the goal of the Center — to move the field forward — requires that it prioritize its work based on the realities that allogenic stem cells will have a longer development time line and that the cells and cell types that are used the most should be supported the most. He noted that it takes a very long time to grow cells, and recommended that if adult cells are available in sufficient numbers, researchers should use them. If not, pluripotent cells are an important source, although they are less important than their derivatives, which are used for screening or therapy.
Dr. Rao also described the organizational structure of the Center, which has an external council, an oversight committee (comprising members of the Office of the Scientific Director of the Intramural Research Program of the NIAMS and other ICs), and a separate laboratory component with its own oversight by the Board of Scientific Counselors from the appropriate institutions. The Center’s activities will have several focus areas which are already part of an active program with funding and collaborators.
Dr. Rao next discussed roadblocks to therapy. He noted that the Center’s mandate is to look at roadblocks, identify the process by which they work, and then decide whether they should be addressed internally or in collaboration with other institutions. He described the Center’s strategies to get past roadblocks.
- Develop a widely used set of standards that are generated by the NIH and available as a database to the community at a reasonable cost by a non-profit distributor;
- Develop a translational roadmap for intra- and extramural investigators based on the experience of those at the NIH-CRM;
- Create a standard model for manufacturing clinical grade stem cells;
- Identify two or three high potential therapies to move forward to the NIH Clinical Center;
- Share key findings with extramural investigators through the NIH Task Force and program managers;
- Use Parkinson’s disease to showcase a model of how similar programs have moved forward; and
- Develop a parallel screening strategy in collaboration with the NIH Chemical Genomics Center (NCGC).
Finally, Dr. Rao cited the need for metrics to measure the Center’s successes or failures. The long-term goal for the Center is having a therapeutic approach that is widely used and available at the clinic level. Intermediate goals include ensuring that lines are deposited, distributed, and well characterized, and having appropriate consent forms, validated protocols and standard operating procedures, and an established screening interaction. Dr. Rao concluded his presentation by remarking that he believes that the Center can achieve many of these goals in the first year.
Council members began the discussion by asking Dr. Rao the difference between the NIH-CRM and other bioresources that provide stem cells for research but not clinical uses. It was also noted that other countries have very different litigation environments, much more trust between doctors and patients, and different cultural barriers to translation. Dr. Rao responded that there are extramural centers that conduct mesenchymal stem cell-based work, and a couple of other stem cell banks that do the same sort of distribution. Dr. Rao explained that the NIH-CRM is trying to coordinate with them, rather than doing the same thing as an independent effort. He noted that the Center doesn’t focus on mesenchymal stem cells or metabolic stem cells because they are already in adequate supply to the community. In terms of international protocols and standards, the NIH-CRM is part of two or three ongoing initiatives, including one by the FDA to harmonize regulations. To address ethics issues, the NIH-CRM is trying to develop model forms and participating with standard associations to address the specific issue of reimbursement for participants in clinical trials.
Council also asked for more information about the extramural part of the Center and the so-called suicide gene. Dr. Rao responded that the NIH has a very specific mandate in allocating resources between the intra- and extramural sections. He added that the NIH-CRM is developing mechanisms to interact with the extramural side. He also explained that there is concern over the safety of cells used for long-term therapy. Several groups have identified what have been termed “suicide genes,” which can be regulated externally to kill the cells. Even though these genes are not useful in clinical therapy, they may be useful in understanding the mechanisms of disease processes in animal models.
In response to a question about how embryonic stem cells fit into the induced pluripotent stem cell (iPSC) initiatives, Dr. Rao noted that embryonic stem cells are still the gold standard, while iPSCs involve engineering of some form, and therefore they are under much stricter regulation than embryonic stem cells. He concluded that it is important to continue the efforts that the NIH has embarked upon with embryonic stem cells.
Finally, Dr. Rao was asked if he would consider banking cells from extramural projects. Dr. Sweeney explained that his lab has been collecting patient-specific cells from muscular dystrophy patients that they have followed clinically for years. He added that they considered generating iPSCs but have not done so because of the cost. Dr. Rao noted that banking cells and converting them into allogenic stem cells is a practical issue for the NIH-CRM, and the high cost of generating an iPSC line forces them to prioritize. To do so, he has come up with a strategy to rank diseases based on which diseases-related research is being funded and which have been identified by other entities as of high importance. Based on that, Dr. Rao said that the NIH-CRM has been working with repositories to ensure that they leverage existing infrastructure rather than building up a whole new infrastructure. He added that NINDS already has repositories for Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis (ALS) He continued that NIH-CRM needs to focus on rare and neglected diseases based on their mandate from the Rare Diseases Clinical Research network, with whom they have been working to develop an optimal way to deposit and distribute tissue.
Dr. O’Shea added that although they can’t afford to turn all the cells into iPSC lines, they could bank a range of around 100 mutations that could serve as a source of specific mutations for investigators. He suggested a three-way collaboration between Dr. Sweeney’s lab, the NIH-CRM, and the NCGC to think about a chemical screen. Dr. Katz added that there could be a four-way collaboration that included the NINDS as well. Dr. Sweeney said that his lab has created cell lines for small molecule screening, which he could make available to the NIH-CRM to share with other investigators.
COMPARATIVE EFFECTIVENESS RESEARCH (CER) AND PATIENT-CENTERED OUTCOMES RESEARCH INITIATIVE (PCORI)
Dr. Katz introduced Dr. Michael Lauer, Director of the National Heart, Lung and Blood Institute’s (NHLBI) Division of Prevention and Population Sciences, who gave a presentation entitled, "Science to Improve the Nation’s Health Care: Comparative Effectiveness Research." Dr. Katz cited Dr. Lauer’s background as a physician with extensive postgraduate experience. Dr. Katz added that Dr. Lauer has led the effort at the NIH in Comparative Effectiveness Research (CER) and been very active in the Patient-Centered Outcomes Research Initiative (PCORI).
Dr. Lauer began his discussion by discussing the letters in CER:
- C stands for comparison or contest between the options available for clinicians;
- E stands for effectiveness or outcomes, with a focus on how outcomes relate to patients or to health care systems; and
- R — the most misunderstood part of the equation, which does not stand for rationing — it stands for research, which can include systematic syntheses and experiments, which are clinical trials and observational studies.
CER has attracted much attention, mainly due to two pieces of legislation. As part of the 2009 American Recovery and Reinvestment Act (ARRA), Congress specifically allocated $1.1 billion to be spent on CER, of which $400 million was allocated to the NIH. Last year, as part of the Affordable Care Act, Congress established the PCORI, which is a non-profit, non-governmental entity; of the 21 people on its Board of Governors, only two are from the government (Dr. Francis Collins and Dr. Carolyn Clancy, Director of the Agency for Healthcare Research and Quality). By statute, there is also a Methods Committee, which has 15 members. Dr. Lauer is the NIH representative on that committee.
Dr. Lauer noted that the PCORI is only about a year old and has not yet started giving out money for research. He added that it should start soon, and when it is at full strength, it will give out $200-500 million per year. For now, the money is coming from appropriations, but when that ends, money will start coming from public and private insurance.
Dr. Lauer stated that CER has already attracted headlines. Sharon Begley of Newsweek wrote an article entitled "Why Doctors Hate Science: Scaremongers warn that ‘effectiveness research threatens the lives of Americans’." The article, which goes on to assert that CER has transformed into cost-benefit analyses, asserts that it will lead to the rationing of health care and ultimately threaten lives as "government decides who gets lifesaving treatment and who doesn’t."
Shortly before this article came out, when Peter Orszag (then Director of the Congressional Budget Office) published a report calling for increased national attention to CER, saying the same thing as the article but in a more nuanced way. Mr. Orszag argued that with only limited evidence, current practice tends to adopt more expensive treatments, even in the absence of rigorous assessments of their impact.
Dr. Lauer presented an historical review of CER, and then illustrated a different approach to CER with the story of a smaller scale study that is currently being funded by the NHLBI . This study compares the effects of losartan to those of atenolol for improving the natural history of patients with Marfan syndrome. The National Marfan Foundation, a patient advocacy group, has joined with the investigators and the NHLBI to strongly promote this trial, while stating on their website that the group does not recommend switching to losartan, because they do not know that losartan is clearly better than atenolol for treating people with Marfan syndrome. Dr. Lauer remarked that this example is inspiring because it demonstrates the scientific method of using rigorous trials to answer scientific questions.
About a year ago, Dr. Lauer and Dr. Collins wrote a commentary for the Journal of the American Medical Association about the contemporary challenges for the NIH in CER. They identified five issues:
- What are the criteria for priorities?
- How can we do affordable and pragmatic trials?
- When can we trust observational data?
- Implementation research: does knowing the right answer necessarily improve medical care?
- What about the role of personalized medicine?
The issue of establishing criteria is complicated by the engagement of multiple stakeholders, whose conflicts of interest may complicate the decision-making process. Dr. Lauer remarked that this issue has not been adequately addressed, and offered an applicable definition of conflict of interest from Upton Sinclair: "It is difficult to get a man to understand something when his salary depends upon his not understanding it."
Dr. Lauer continued that the second issue, doing pragmatic trials that can be designed, implemented, and applied directly to the real world, is a big issue with CER. Pragmatic trials have been defined as those having broad eligibility, flexible interventions, testing done by typical practitioners, no research follow-up visits, objective clinical outcomes, no special methods to enhance compliance, and the intent-to-treat principle scrupulously applied. Like CER, pragmatic trials have been around for a long time.
Dr. Lauer cited an example of a pragmatic trial, and described another recent large-scale practical trial, the National Lung Screening Trial, which randomly screened heavy smokers by CT scans or x-rays once every three years. The trial had to be stopped prematurely due to a remarkably reduced death rate from lung cancer for those in the CT scan group.
He also stated that there is a phenomenon of robust evidence not getting translated into practice, as with bloodletting, and cited other examples, including an article by Ezekial Emanuel and Victor Fuchs that identified factors that cause doctors to engage in practices that are not evidence-based. These factors include a culture that favors a thorough approach, fee-for-service incentives, a fear of malpractice, patient preferences for high technology treatment, cost shielding by third parties, and marketing directly to consumers and doctors.
In summary, Dr. Lauer noted that CER is an exciting area but not a new one. He recommended looking at the lessons of history, including the cases of bloodletting and high-dose chemotherapy. He identified the priorities of CER as identifying "evidence-free" medicine; engaging stakeholders while recognizing that there will be conflicts of interest; making trials pragmatic, large, and inexpensive; preserving the controlled randomized trial as the gold standard; and not assuming that knowledge will necessarily translate into practice.
Council discussion was inclusive and extended. It began by asking Dr. Lauer to comment on the emerging tension between the tenets of evidence-based medicine and personalized medicine; there are arguments to be made for making trials small, focused, and homogeneous.
Dr. Lauer responded by offering two vignettes. The first, the NHLBI trial called ACCORD, examined different interventions for diabetes patients. One part of this study looked at the effects of a statin. Although the findings were negative overall, they were positive in a subset of the patients with high triglycerides and low HDL. While this finding created excitement, Dr. Lauer stated that a positive subset result in a large trial has a high probability of being a false positive. Therefore, a subsequent study focused on the subgroup is necessary to answer the question. His second vignette was a genomic study of the responses of asthma patients to glucocorticoids. The researchers did a genome-wide assessment on data from a 10-year-old study and found a specific gene that predicted a better response; these results were replicated in four subsequent studies. Dr. Lauer concluded from these vignettes that the pathway to personalized approaches is through large randomized trials, and that bringing in larger and larger groups of people is the way to get larger subgroups and more robust findings.
When asked whether there was a mandate to do subgroup analyses in order to generate hypotheses, Dr. Lauer responded that there is an intellectual mandate, and that every major randomized trial involves subset analyses. Dr. Katz added that subset analyses need to be done prospectively, and Dr. Lauer remarked that if you analyze 20 subsets, there is a 75 percent chance of identifying at least one false positive. He mentioned that Rory Collins at Oxford calls this "torturing the data until it confesses."
Dr. Lauer was also asked to talk more on the question of smaller versus larger studies since he seemed to be advocating bigger and bigger studies to tease out subset analysis, as opposed to using the biology of the disease to initially identify those subsets. For example, in cancer research, large investigations or interventional studies won’t generate hypotheses. Dr. Lauer agreed and suggested that there are two ways to look at the same question. With solid biology that predicts a large effect size, it makes perfect sense to do a small focused trial. But when the knowledge is not there yet, the only way to find out is by bringing in as many people as possible and trying to tease out important distinctions. He added that trials get smaller as hypotheses get better developed, and concluded that these are not mutually exclusive problems.
There were additional comments from Council about physician training and it was pointed out that 95 percent of randomized controlled trials don’t match Dr. Lauer’s ideal criteria and usually involve patient groups that differ from patients actually seen in treatment. Doctors usually extrapolate from large trials, either without thinking or based on personal experience, and while medical students are taught that while evidence-based medicine is a good place to start, it is not the only way to think about practice. The perception that evidence-based medicine is a straitjacket is one reason people respond negatively to CER.
Dr. Lauer cited two examples in which this issue has been handled very well: the GISSI trial, in which the researchers were themselves practitioners and therefore invested in the results, and a clinical registry study that is currently taking place in Sweden, Denmark, and Iceland. This study involves all of the doctors and a registry of all patients undergoing interventional procedures in those countries. The current study, a randomized trial comparing a particular device used to aspirate a thrombus out of arteries, is very inexpensive because all of the data being collected for the trial are already being collected for the registry. Dr. Lauer stated that because all the doctors are involved in the study, they are invested in the results and likely to embrace the findings. This type of study, a clinical registry trial, has been done a few times in the United States. Dr. Lauer pointed out that right now less than 10 percent of doctors participate in clinical research, and it would help to get them directly engaged in the process.
There were additional comments from Council about personalized medicine, and how to incorporate data related to patient behavior into comparative effectiveness research. An example given is the effect of diet and exercise on Type 2 diabetes patients. Dr. Lauer replied that the beauty of CER is that it can be applied to any therapeutic modality. Although it’s harder to administer a lifestyle intervention than a pill or a procedure, behavioral and lifestyle interventions can be and have been done.
The discussion turned to the topic of those who control health care in the United States and how they think in terms of value, or patient outcomes per dollar spent. Where does CER fit with systems-based processes of health care delivery, since CER doesn’t change care or add value? Investment in the PCORI " $700 million per year " is very small compared to the money spent on health care beneficiaries. How can CER fit into value and health care reform and is there a strategy for putting those things together? How is the FDA likely to be involved in the process??
Dr. Lauer responded that the law states that the PCORI must be used for clinical effectiveness research, rather than for cost effectiveness research. In addition, payers are not permitted to directly use the PCORI results to make decisions, although they can incorporate them into many other areas. He continued that CER can be used to study systems interventions to figure out better ways to deliver health care, which is one of the top priorities of the Institute of Medicine (IOM). He cited two examples of ways in which low intensity interventions have been used to improve practice: one from a study about improving physician care for women in labor, and another from a study by the Society for Thoracic Surgery to encourage physicians to use mammary artery grafts more often.
Interest at the FDA is very high. The Center for Medical Technology Policy is trying to bring together stakeholders, including the NIH, the FDA, and drug companies, with the argument that by the time they are doing phase III trials, they should already be thinking ahead to the comparative effectiveness issue. Although CER goes beyond the FDA’s mandate and drug companies’ common practices, they are feeling pressure from payers who want this information.
Dr. Katz asked whether the European Medical Association is ahead of the United States and how the IOM determines the rankings of the top 100 initiatives. Dr. Lauer replied that in Europe there have been some fits and starts. The best example is the National Institute for Health and Clinical Excellence in the United Kingdom, which has used explicit criteria to determine what they will approve and has been met with resistance. He stated that, in general, Europe is more proactive in using the results of CER to make payment decisions, but they are encountering some problems. In terms of the IOM’s priorities, Dr. Lauer explained that there was a very quick process (three months) of holding very intense meetings, but given their limited time and resources, they did a very good job. Of the top 100 priorities, the NIH now has 99 of them covered. Dr. Katz asked whether the PCORI will use the IOM’s priorities as an index for initiatives. Dr. Lauer responded that the PCORI has been charged with coming up with its own set of priorities, and it will not be able to fund much research until it does.
Dr. Katz presented a list of potential 2013 initiatives from discussions at retreats, roundtable discussions, and individual program directors (with agreement from their division directors). He noted that all of the initiatives depend on the 2013 budget, which does not look very good at this point. He added that despite the poor outlook, the NIAMS and the NIH in general will start certain initiatives because Congress wants to see new and innovative work. The NIAMS leadership is in the midst of putting together possible initiatives to offer to Dr. Collins for the NIH in general. The initiatives listed are not specific or definite; they are merely suggestions. Center renewals are not included in the following list of proposed initiatives:
- Advancing Systemic Sclerosis Research
- Reduce Racial and Ethnic Disparities in Rheumatic, Musculoskeletal, and Skin Diseases
- Correlative and Mechanistic Studies on the Role of the Microbiome on Health and on Skin and Rheumatic Diseases
- Bridging the Gap between Basic Discovery and Chemical Genetics and Molecular Therapeutics
- NIAMS Cooperative Agreement for Scientific Workshops
- Research Grants Using the Resources from the Osteoarthritis Initiative (OAI)
- Functions of Skeletal Muscle Beyond Contraction
- Studies in Preclinical Skin and Rheumatic Autoimmune Diseases
- Innovative Therapies for Rheumatic, Skin and Musculoskeletal Diseases
Council inquired about the process for making decisions on the initiatives, particularly those at the NIH level. Dr. Katz replied that each proposal is discussed internally within the Institute in terms of the budget and how compelling each one is. The three initiatives thought to be most useful in moving the field ahead will go to Dr. Collins, and Dr. Collins will choose five or six directors to give him feedback on the proposals. The group of advisors usually rotates to spread out the influence. Last year’s group was tasked with recommending what shouldn’t be done. Finally, the proposals are considered in an open session.
Dr. Katz introduced Drs. Amanda Boyce and Marie Mancini, from the NIAMS Division of Skin and Rheumatic Diseases, who addressed the commitments from academic institutions in Pathway to Independence Awards (K99/R00)
Dr. Boyce began by giving a brief history of the awards. Dr. Boyce stressed that one of the main goals of the award is to support researchers at an earlier age and stage of career; thus, basic eligibility is limited to investigators with no more than five years of postdoctoral experience and not a full-time tenure-track assistant professor position. Both intramural and extramural investigators are eligible, although there is no money associated with awards that go to intramural candidates (though funding may be available at a later time). She reiterated that this is the only K award for which U.S. and non-U.S. citizens are eligible, and added that candidates must have a clinical or research doctorate.
Dr. Katz emphasized that this is the only K award for which foreign nationals are eligible.
Dr. Boyce noted that the award consists of two phases over the course of five years. The initial phase — the K99 phase — includes one to two years of mentored support as a postdoctoral fellow. To reach the R00 phase, the applicant must submit a transition package, which will be the focus of today’s discussion.
The transition package is administratively reviewed at the Institute level by staff in the Office of Extramural Research. Those who receive an R00 are provided with up to three years of independent support, so long as they remain independent full-time. Dr. Boyce pointed out that this award is very competitive.
Of the awards given to date, 908 K99s have been awarded across the NIH with 553 awardees transitioning to an R00. Of the 23 K99s awarded by the NIAMS, 13 researchers have transitioned to R00s. Three — who are in the NIH Intramural Program — aren’t technically eligible to receive funding, and one accepted an intramural position, making her ineligible to transition but still considered a program success. These numbers translate into success rates of four out of five in 2007, three out of four in 2008, and five out of five in 2009.
Dr. Boyce emphasized that the transition to an R00 is not automatic. The application package must be submitted to extramural program staff no later than two months prior to the proposed activation date, and applicants are strongly urged to contact their NIH program official no later than six months prior to the end of the K99 phase. Two reasons for this are that the negotiated offer letter may not yet be finalized, giving the applicant an opportunity to discuss the start-up package, and to make sure that all of the administrative requirements have been fulfilled. She described the components that constitute a transition package, how it is administratively evaluated by the NIAMS staff, and she talked about the role of the program directors as they worked with applicants.
Dr. Boyce posed the question of whether NIAMS R00 applicants are receiving salaries and start-up packages that are in line with other new faculty. She presented three sources of data to answer that question: the Cornell Higher Education Research Institute Survey on Start-up Costs, the Association of Chairs of Departments of Physiology — Start-up Funds for New Faculty Hires Survey, and data about start-up packages for those who have transitioned out of the Burroughs Wellcome Fund Career Awards in the Biomedical Sciences (CABS), who are very similar to the K99 applicants. The CABS program awards $500,000 over five years on top of a start-up package that ranges from $500,000 to $1,400,000, with a median of $750,000. Dr. Boyce noted that the NIAMS program is right in line with the CABS program, with a majority of the packages ranging from $600,000 to $700,000.
Council members remarked that these data seem to reflect that applicants are getting jobs at institutions with better start-up packages as opposed to getting better packages because they have R00s and asked whether the data show any difference between citizens and non-citizens. Dr. Boyce responded that there is no difference.
It was also mentioned that these numbers are similar to those seen at Council members’ institutions, and that packages for internal candidates — whether or not they have R00 awards — tend to be smaller than offers to outsiders.
Dr. Boyce noted that of the 13 offers to those who have transitioned to R00s, only 8 had associated 9-month hard salary offers.
Dr. Katz asked Dr. Boyce to describe some of her more difficult negotiations. Dr. Boyce gave an example of a situation that involved someone who wished to stay at the same institution, a situation that she noted is almost always the most difficult. The issue, she stated, is that candidates are not getting formalized letter offers. One reason for this is that those who stay in-house move to a lab which is already filled with equipment, requiring the worth of the equipment to be quantified. Another is the issue of support staff, which is both the largest cost of running a lab and the biggest issue in transitioning to an R00.
Dr. Joan McGowan, agreed that there is an issue with transitions of in-house researchers at top institutions, and that program directors often feel that the offered start-up packages are insufficient. She added that for the first time, they have been able to negotiate better packages for applicants. Dr. Katz noted that the appointment must be a tenure-track or tenure-track-like appointment, not just a continued career appointment. He added that the internal controls within the Institute for packages are not just at the level of program directors, but at the level of division directors, and if the grantee is in one of the divisions, the other division director is the one who signs off on whether the package is adequate or not.
Some Council members expressed surprise that the NIAMS staff were negotiating on behalf of potential faculty. Although packages are very important, the fact that an institution wants to support a researcher and enable his or her success is even more important. It raises some concerns about the institution’s commitment to that support if an institution has to be pushed to support a young investigator.
Dr. Katz said that the NIAMS is unambiguous about wanting its part in this to be meaningful, and that it falls upon the NIAMS staff to assess whether or not the package is acceptable. The awards are meant for investigators who are ready to transition into independent researchers, not those who will remain postdoctoral fellows indefinitely. Council members expressed approval of taking on the ambiguities associated with in-house applicants and the NIAMS role in the process in general.
Dr. Susana Serrate-Sztein, Director, Division of Skin and Rheumatic Diseases, suggested that professional societies might have a role to play in mentoring new K99s with respect to what a package should contain and how to approach the transition from K99 to R00.
Other Council members noted that requirements vary from institution to institution on how long a researcher can remain a postdoctoral fellow. It was also noted that there is no uniform definition of hard salary. Dr. Boyce responded that hard salary is not an expectation of the award, and that start-up packages that include hard salaries for three years look very different from those that don’t.
There were questions about how the transition is determined. Dr. Katz replied that although the transition is determined by program staff, it is up to the university or academic center as to whether and when they wish to hire the applicant. Dr. Boyce compared the process to a progress report. Dr. Serrate-Sztein added that program staff considers the specific aims in the original application, the timeline, the progress made towards those aims, whether there were publications with meaningful findings, and the mentor’s statement. She concluded that for the most part, these have been very successful K99 applicants.
Dr. Katz brought up Dr. Boyce’s final question: At what point would a K99 be considered expired and no longer eligible for transition to a R00? Dr. Serrate-Sztein added that researchers may not find a suitable offer, and asked how long we can extend the K99 phase.
Dr. Boyce questioned whether the K99/R00 program has attained its goal of assisting investigators in securing a stable research position at an earlier age. She presented data that show that it takes investigators 6.2 years on average to find a tenure track position after receiving a Ph.D., and three years to get an R01 after taking a tenure track position. She concluded that while the program may not be speeding up the length of time it takes for applicants to get a tenure-track position, they are getting their R01s earlier.Dr. Boyce presented three discussion points:
- What is a minimally acceptable start-up package?
- Should there be a minimum amount of time spent in the K99 phase before an applicant can transition to the R00?
- At what point would a K99 be considered “expired” and no longer eligible for transition to an R00?
Council noted that how long postdoctoral fellows take before getting this award has to do with how they were chosen. On member indicated that his vote would be for maximum flexibility, because negotiating a position can be difficult, and that he wouldn’t oppose giving applicants an additional year or two to find one.
Others asked whether this program is really accelerating people’s progress to R01s or are these people just the stars. Dr. Boyce replied that a bubble analysis of the paylines of K awards in general found that the pool of people was equivalent, and she expects they will do a similar analysis of the K99s.
CONSIDERATION OF APPLICATIONS
The Council reviewed a total of 685 applications in closed session requesting $828,071,039 in total costs and recommended 685 for $828,071,039 in total costs. Of these, 96 applications were considered and approved by Early Concurrence.
UPDATE ON CLINICAL TRIALS
The 75th National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Meeting was adjourned at 3:00 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.