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

MINUTES OF THE 53rd MEETING
June 3, 2004
8:30 a.m. to 4:00 p.m.

1. CALL TO ORDER

   The 53rd meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council was held on June 3, 2004, at the National Institutes of Health (NIH) Campus, Building 31, Conference Room 10. The meeting began at 8:30 a.m.

   Attendance

   Council members present

   Dr. Graciela Alarcon Dr. Bess Dawson-Hughes Ms. Victoria Kalabokes Dr. Brian Kotzin Dr. Cato T. Laurencin Dr. Richard T. Moxley Dr. Jack E. Parr Dr. Francesco B. Ramirez

   Ms. Mary Elizabeth Replogle Dr. Randy N. Rosier Dr. Raymond Scalettar Dr. John R. Stanley Ms. Sharon F. Terry Dr. Jouni J. Uitto

   Council members not present

   Dr. Gunnar Bengt Johan Andersson
   Dr. Michael M. Frank
   Dr. Steven Teitelbaum
   Dr. Oretta Mae Todd
   Dr. Robert Oglesby (Ex Officio)
   Dr. Charles S. Via (Ex Officio)

   Staff and Guests

   The following National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) staff and guests attended:

   Staff

   Dr. Deborah Ader Dr. Aftab Ansari Dr. Janet Austin Mr. Steve Austin Ms. Susan Bettendorf Mr. Melvin Broadus Dr. Tommy Broadwater Ms. Shelley Carow Ms. Kelli Carrington Ms. Jennifer Curry Dr. Julia B. Freeman Dr. Elizabeth Gretz Dr. Steven Hausman Ms. Jane Hymiller Dr. Stephen I. Katz Dr. Cheryl A. Kitt Dr. Charisee Lamar Dr. Gayle Lester Ms. Anita Linde

   Dr. Peter Lipsky Dr. Richard Lymn Dr. Joan A. McGowan Ms. Leslie McIntire Mr. Robert Miranda-Acevedo Mr. Michael Morse Dr. Alan N. Moshell Ms. Melinda Nelson Mr. Aaron Nicholas Dr. Glen Nuckolls Dr. James Panagis Mr. Richard Proper Dr. Susanna A. Serrate-Sztein Dr. William Sharrock Ms. Helen Simon Ms. Robyn Strachan Dr. Bernadette Tyree Dr. Yan Wang

   Guests

   Dr. Duane Alexander
   Ms. Roberta Biegel
   Mr. William Branson
   Dr. Jennifer Burnell
   Mr. Dale P. Dirks
   Ms. Lorraine Fitzsimmons
   Ms. Mary Glynn
   Ms. Kathy Hancock
   Ms. Darlene Kerr
   Dr. Story Landis
   Dr. Audrey Penn
   Ms. Eileen Resnick
   Ms. Heather Rieff
   Dr. Anne P. Sassaman
   Ms. Alison Strock
   Ms. Susan Whittier

   Other NIAMS staff members and guests also were present. Dr. Stephen Katz, Director of NIAMS, chaired the meeting.

   Dr. Katz called the Council meeting to order and expressed his appreciation to the Council members for making this meeting a high priority. Dr. Oretta May Todd sent her regrets, as she was participating in commencement exercises at Skidmore College. Dr. Steven Teitelbaum could not attend, as he was receiving an honorary degree at a university in New York. Drs. Michael Frank and Gunnar Andersson also were unable to attend.

   Dr. Katz indicated that future Council meeting dates were available in the agenda book, and that he will try to avoid Thursdays as meeting dates due to conflicts with NIH Steering Committee meetings.

2. CONSIDERATION OF THE MINUTES

   A motion was made and seconded to accept the minutes of the 52nd Council meeting, held in January 2004, with a slight correction of the misattribution of statements to Dr. John Stanley. Dr. Stanley will indicate which statements were misattributed.

3. FUTURE COUNCIL DATES

   Future Council meetings are planned on the following dates:

   September 21, 2004
   February 8, 2005
   June 14, 2005
   September 13, 2005

4. DIRECTOR’S REPORT AND DISCUSSION

   New Council Members

   Dr. Katz introduced and welcomed four new members of the Council. Dr. Jack Parr is the Executive Vice President for Research and Development and Chief Science Officer at Wright Medical Technologies in Arlington, TN. Dr. Raymond Scalettar is a Clinical Professor of Medicine at George Washington University Medical Center. He also is a former Commissioner and Senior Consultant of the Joint Commission on Accreditation of Health Care Organizations and Co-Founder and Director of National Capitol Reciprocal Insurance, a physician professional liability company. He also is a health policy consultant and a practicing physician, and has been very active in leadership positions in the American Medical Association. Dr. Scalettar brings a public perspective to the Council. Dr. Brian Kotzin is a Professor in the Department of Medicine and Clinical Immunology at the University of Colorado Health Sciences Center, Head of the Division of Clinical Immunology, and Director of an Autoimmunity Center of Excellence. He also is a member of the committee that reviewed the Specialized Centers of Research (SCOR) Program. Dr. Kotzin will soon be joining AMGEN in California. He has specific expertise in inflammation, particularly in immunogenetics in mice, and will be starting to translate these studies to humans at AMGEN. The fourth new Council member is Dr. Jouni Uitto. He is a Professor and Chair of the Department of Dermatology and Cutaneous Biology at the Thomas Jefferson Medical College. He also is the Director of the Jefferson Institute of Molecular Medicine, which is on the leading edge of research on the molecular evolution of dermatology and general medicine. Dr. Uitto has an interest in many of the tissues that are in the purview of the NIAMS research mandate.

   Personnel Changes

   Dr. Katz welcomed back Dr. Tommy Broadwater, who was Chief of the NIAMS Review Branch, and has returned as Acting Chief after a 1.5 year leave of absence. Dr. Teresa Nesbitt, who was the Director of the Review Branch for approximately 1 year, will be leaving the NIAMS to accept a position in the Review Branch of the National Institute of Environmental Health Sciences. Dr. Glen Nuckolls, who also was in the Review Branch, is now the Program Director of the Muscle Disorders and Therapies Program.

   NIH News

   Work on the NIH Roadmap for Biomedical Research is proceeding. A number of initiatives have been defined and disseminated. Dr. Deborah Ader will report later in this meeting on an initiative for which the NIAMS has the lead, detailing the Institute’s responsibilities and leadership roles.

   Dr. Katz next discussed a report from the NIH Director’s Council on Public Representatives (COPR), designed to address the issues of enhancing public input and transparency in the NIH research priority-setting process. Ms. Barbara Butler (formerly active in the Psoriasis Foundation and Lupus Foundation of America) and Mr. James Armstrong presented this report at the COPR meeting. This important document underscored the need for public participation not only in processes such as this meeting, but also in the more public process of engaging the American public at large. Many useful recommendations were made, including:

   • Going beyond the NIH Campus to engage the American public where they live.
   • Partnering with local communities, grassroots organizations, and community leaders. The Health Partnership Program was used as a “best example.”
   • Using proactive outreach to provide access for non-Web users.
   • Developing more partnerships among Institutes and Centers, fostering cross-Institute communication.
   • Fostering 2-way dialog at the individual level in communities where research is performed.

   In general, the report was very positive and tried to identify “best practices,” which NIAMS also will address. Each NIAMS Council member has asked what else he or she can do with regard to the NIH as a whole. Dr. Katz asked Ms. Butler to come to the next Council meeting.

   Ms. Victoria Kalabokes mentioned that as a COPR alumnus, she has input on COPR documents and can have conversations and discussions with fellow alumni via a COPR alumni listserv. Dr. Katz replied that having COPR members at a future Council meeting would lead to interesting and interactive discussions.

   Update on Congressional Activity

   Recently, Congressional hearings were held on alleged conflicts of interest at the NIH, concerning whether and how the NIH should deal with outside consultancies for government employees. The discussions are ongoing, and a blue ribbon panel report is available on the NIH Web Site.

   Dr. Katz next discussed a hearing held June 2, 2004. The Honorable Joseph Barton, Chair of the Committee on Energy and Commerce, headed the hearing, which discussed priority setting at the NIH. In addition to NIH Director Dr. Elias Zerhouni, Drs. Anthony Fauci, Andrew von Eschenbach, and Norka Ruiz Bravo also attended. The question was posed to Dr. Zerhouni, if the NIH were to be designed today, would it be the same as it is currently? The answer was, that since the design was historically driven, the NIH if designed today would probably differ from the current structure. The Institute of Medicine has assessed the NIH and did not recommend many structural changes. The functionality of the NIH depends on current allocations and national “spirit,” on the interconnectedness between the Institutes, and on funding available for the type of work done. The state of affairs in the United States also is important. For example, the NIH currently needs the flexibility to address issues such as bioterrorism; 15 years ago, AIDS research was of primary importance. These issues illustrate the importance of flexibility to allow the NIH to adapt to impending needs.

   Another question concerned whether Congress should define NIH’s structure or whether the NIH Director should have primary authority in this area. Dr. Katz sensed that the consensus was that flexibility should be allowed, but not necessarily built into the structure. Congress also is proposing to re-authorize the NIH (which has not been done since the early 1990s); re-authorizing concerns rules and regulations upon which the NIH operates. Whether re-authorization will occur is not clear, but there have been meetings with the re-authorizers to discuss previous limitations.

   Scientific Advances

   The NIAMShorttakes Message from the Director focused on translational research for this issue. Dr. Katz reported on a number of scientific advances to the Council:

   • A randomized clinical trial to test the effects of alendronate and calcitriol on bone loss after heart transplant was conducted by Dr. Elizabeth Shane and colleagues at the Columbia University College of Physicians and Surgeons in New York and colleagues at the Newark-Beth Israel Medical Center in New Jersey. Alendronate was shown to help prevent bone loss and reduce fracture rate as effectively as calcitriol, and may be easier to monitor in these patients.
     
   • Three papers concerning genetic studies were discussed:
     
     1. In Science, work by Dr. Robert Klein and colleagues at the Oregon Health and Science University in Portland showed that the gene Alox15, which encodes 12/15 lipoxygenase, was more active in low-bone mass mouse strains than in high-bone mass strains and may be a negative regulator of peak bone mineral density. Further research showed that inhibitors of this enzyme may improve bone density and strength.
     2. Drs. Susan Thompson and David Glass reported continued large studies on juvenile arthritis and potential association of this disease with certain types of IL6 alleles and nucleotide variants. These variants may influence age of onset and perhaps severity of disease.
     3. A team led by Dr. Anne M. Bowcock at the Washington University School of Medicine in St. Louis, has identified two genes on chromosome 17, SLC9A3R1 and NAT9, which are associated with psoriasis. Uniform linkage was not observed, but in some families linkage appears to be related to the area between these two genes, which acts as a binding site for the protein RUNX1, which regulates genes involved in immune reactions.
   A NIAMS Intramural Research Program being conducted at the NIH also was discussed. Researchers in the intramural research program are studying hematopoietic stem cell transplants as a potential treatment for severe, conventional treatment-resistant systemic lupus erythematosus. This is a multi-institute endeavor, using expertise from the National Cancer Institute (NCI), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the NIAMS, involving both basic and clinical research.

   In addition, the Osteoarthritis Initiative was discussed. Since the last Council meeting, there has been good accrual of individuals to this program. In the next or subsequent meeting, Dr. Gayle Lester will update the Council on the progress of this Initiative.

   A summary of work done by the Osteoarthritis Biomarkers Network led by Dr. Bernadette Tyree will be available on the NIAMS Web Site shortly.

   The NIAMS Health Partnership Program celebrated its fourth anniversary. Dr. Katz commented that the Council should try to visit the Program in the future. This Program involves multiple Institutes (National Institute on Alcohol Abuse and Alcoholism; the NCI, which is conducting a screening program; and the National Institute of Nursing Research, which is conducting a bioethics study) as well as Howard University. The Program provides care and patient sources for many different studies—observational, participation and intervention. Kelly Carrington, in the NIAMS Office of Communications and Public Liaison, served as Master of Ceremonies for the event.

5. NIAMS FINANCIAL MANAGEMENT STRATEGIES

   Dr. Steven Hausman gave a funding overview comparing NIAMS funding strategies to those of the NIH in general. The funding plan for NIAMS is available on the Institute’s Web Site.

   The goal of the NIAMS budget strategies is to fund as much as possible of the best science. The budget covers funding for research grants, investigator training, clinical research, and contract work. Dr. Hausman emphasized that any funding changes on one part of the budget would have an effect on another part—funding cannot be changed in isolation. One goal is to try to maximize certain budget categories in keeping with the Institute’s research philosophy.

   Dr. Hausman discussed several different financial management issues, including: (1) accelerated funding, (2) percentile rank, (3) select pay process, and (4) success rate and payline. The NIAMS funding plan is prepared once the appropriation has been received. Ideally, it is received at the beginning of the fiscal year; if not, an interim operating plan is needed to ensure that grants can be funded as early as possible. Once the appropriation is received, a funding plan is developed that is subject to change over the entire year, due to changing conditions, opportunities in science, and a variety of other matters.

   Dr. Katz mentioned that the Budget Office usually has an estimate of what the appropriation will be. The Budget Office works out “what if” scenarios—if the current year begins without a budget, they will need to work on certain assumptions. The final decision on a financial operating plan is made after the appropriation is received, but plans still need to be made concerning how the money will be spent before it arrives.

   Dr. Hausman confirmed that the Institute is not allowed to have deficit spending, but can only spend what it has. The Budget Office also allocates funds more conservatively at the beginning of the fiscal year, but as the exact amount of funds becomes more defined, spending can increase.

   Dr. Hausman focused his discussion mainly on research project grants (RPGs). These include: (1) R01s (investigator-initiated grants); (2) R03s (small grants); (3) R21s (exploratory/developmental grants); and (4) R37s, R41s, P01s, and U01s (MERIT awards, small business technology transfer [STTR] grants, program projects, and cooperative agreements). These grants all are counted as RPGs, as opposed to projects such as Centers, which are funded under a different budget category. NIAMS sets aside a pool of funds, the amount of which varies from year to year based on financial conditions, to use for select payment of certain applications—the funding strategy used does not necessarily pay only for a given number of the best applications in rank order until funding is exhausted. There is some subjectivity in awarding grant money, as some applications beyond the payline must be funded for a variety of reasons. Another way to expand the number of projects that can be funded is to make reductions from direct costs, sometimes called negotiated reductions.

   Dr. Hausman presented budget data concerning how the NIAMS and the NIH allocate funding to extramural and intramural projects.

   NIAMS	NIH
   Extramural = 86 percent	Extramural = 79.8 percent
   Intramural/RMS = 14 percent	Intramural/RMS = 20 percent

   The main difference between the NIAMS and the NIH overall is in the funding of RPGs. The NIAMS devotes more resources to RPGs (65 percent) than do most other NIH Institutes (53 percent, on average). Also, 75 percent of the money allocated for RPGs is committed to existing grants that are due to receive further funding for 3-5 years (noncompetitive renewal). The remaining 25 percent provides flexibility in funding.

   Percentile Rank and Payline

   Dr. Hausman next discussed percentile rank. In addition to a priority score (ranging from 100-500), each application receives a percentile rank. This is a correction factor, to account for differences in scoring among study sections. The lower the percentile rank, the better the application and the higher the likelihood of being funded. Percentile rank is not computed for small business grants, technology transfer, or training fellowships; it is used mainly for awarding RPG applications.

   The payline is the percentile-based funding cutoff. All applications are rank ordered from best (0.1 percent) to worst (100 percent); at a certain point, a percentile is reached at which payment stops. Currently, the payline is set at the 17th percentile. Any grants below the payline (i.e., a percentile rank between 0.1 percent and 17 percent) are funded, while those above (percentile rank of 17.1 percent to 100 percent) are not. The number of grant applications received is balanced against the amount of funds available. The NIAMS tends to fund most, but not all, applications in percentile order.

   Approximately 65 percent of the NIAMS budget is used to fund RPGs. Dr. Hausman presented information showing the number of awards per Institute compared to the total number of dollars spent from 1994 to 2003. The NIAMS budget has been gradually increasing, and the number of awards made also has risen (except for a slight decrease in 2001). Over the years, the average cost of an RPG also has increased.

   Dr. Uitto asked how much of the average cost of an RPG goes to direct versus indirect costs. He also asked whether the indirect cost pool was increasing or decreasing. For many institutions, the percentage of grant funds that can be used to pay indirect costs has been reduced. More universities are spending the full amount allowed for indirect costs than ever before. Dr. Katz responded that it is unusual for indirect costs to decrease because they are capped at 26 percent; if there were not a cap, much more money would be used for indirect costs at most institutions. There is reluctance to address this issue—according to the Office of Management and Budget ruling Circular 110, indirect costs generally do not decrease. One way indirect costs could decrease would be if an institution had an enormous investment in NIH awards that carried a maximum of 8 percent indirect costs. An example of this is the K awards, which carry an 8 percent indirect cost rate. These are a very small part of the budget, and are not RPGs. Universities may retrieve less in terms of indirect costs, but generally what they receive in indirect costs from the NIH is constant.

   Dr. Lymn commented that indirect costs could decrease if academic institutions are not making major capital investments and have paid off old equipment. Dr. Katz asked if Dr. Lymn or any of the other Council members had heard of these types of situations. He is under the impression that this almost never happens. He also clarified that the 26 percent cap for indirect costs is for administrative costs only, and that indirect costs as a whole are much higher for many institutions. Dr. Lymn replied that he is not familiar with any of these types of situations, but that state universities typically have lower indirect cost rates because equipment and building costs generally are paid for by the states.

   Accelerated Funding

   Dr. Hausman next described accelerated funding, which was a method the Institute used to free up more money. It was known that the NIH budget would double, but also that the doubling would stop and there would be fall-off in funds. This strategy was implemented as a way to free up funds in the future when the budget decrease began. This accelerated funding strategy will not be continued in fiscal year 2004.

   As an example, Dr. Hausman discussed a typical grant for $200,000 per year, for 5 years, making $1,000,000 the total cost of the grant. If the grant is reduced by 9 percent, the total cost is reduced to $910,000. There are two ways to make this reduction: (1) allocate $182,000 per year, or (2) allocate $188,000 for the first three years, then $173,000 for the remaining two years.

   The benefit of the second approach is that the Institute will have more money to use for competing grants in year 4 and 5. Dr. Katz commented that this funding strategy was implemented in 2002 (year 1), making 2003 the second year of implementation; thus it is believed that the benefits of this approach will begin to be realized in 2005, with greater benefits in 2006.

   Dr. Hausman continued that the purpose of accelerated funding is to redistribute competing funds when it is known that budget growth is expected to slow. This decision was not made unilaterally; there were discussions with the Council concerning how to implement accelerated funding, and the results of these discussions are available on the NIAMS Web Site. Investigators receiving the grants were aware that funding would be allocated in this way. It was thought that it would be better to receive more money at the beginning of a grant, which would allow the investigator to purchase needed equipment. Dr. Katz commented that this was not “forward funding,” because no grantees received more in the first year than was recommended by the study section.

   Dr. Hausman confirmed that if an Initial Review Group (IRG) recommended an award of $200,000 the first year, the most ever paid was $188,000, which varied depending on the specific amount of each grant.

   Percentile Payline and Select Pay

   Dr. Hausman next discussed the percentile payline. The NIAMS payline in 1994 was approximately 16.5 percent; in 2000 it was approximately 24 percent, and gradually has been dropping in subsequent years. The current 2004 payline is estimated to be between 16 and 18 percent.

   Dr. Hausman then defined the success rate as the number of applications funded divided by the number peer reviewed, multiplied by 100 to get percent success rate. Applications resubmitted during the fiscal year are counted only once. The success rate includes Requests for Applications (RFAs) and all RPGs.

   Dr. Katz commented that R03 awards are $50,000 per year for 3 years. Dr. Hausman noted that the NIAMS R03s are limited to new investigators, and are funded for 3 years rather than 2 years, as is the case in most other Institutes. Dr. Hausman then showed data indicating that the NIAMS success rate, for years 1994 through 2003, is uniformly lower than the average rate across all NIH Institutes.

   Concerning the number of applications received versus the number awarded, the NIAMS has seen a large increase (approximately 50 percent) in the number of grant applications received and reviewed. The number awarded has remained more or less constant, which would explain a decrease in the success rate. Dr. Stanley asked why the NIAMS has seen such an increase in grant applications. Dr. Hausman responded that resubmission of some applications has contributed to the increase, and that another factor is the R03 Program. This year, NIAMS received 220 R03 applications. The Institute has also had more RFAs, and with the previous budget doubling, NIAMS has been able to launch new initiatives.

   Dr. Hausman next discussed select pay and the pool of funds set aside for this purpose, as well as how applications beyond the payline were chosen to be funded. A number of criteria influence these decisions:

   • High priority research area—the research may be particularly important to the progression of science.
   • Responses to program announcements in which the Institute informs the scientific community that it is interested in a certain area of research. No dollars are set aside, but an application can be funded beyond the payline in a targeted area.
   • Unique areas of research—these include animal resources available only at a single institution, funded by a single grant. If that grant is beyond the payline, the Institute might decide it is important enough to ensure the work continues by funding the grant.
   • New investigators and minority investigators—the NIAMS wants to facilitate the success of new and minority investigators.
   • Leveraging resources with other Institutes—if the NIAMS wants to collaborate with other Institutes and have collaborative projects, awards beyond the payline may be necessary.

   Program staff and Council members recommend all select pay proposals. Any applications that are not paid because of diversion of funds for select pays have to be justified.

   Dr. Hausman explained that there has been a decline in select pay awards over the years, due to more RFAs and a desire to maintain the payline despite the potential for decreasing budgets in the future, leaving less money available for select pays. Across the NIH, the total percentage of RPGs funded out of payline order (select pays) varies, although the NIAMS is in line with most of the Institutes.

   Dr. Katz commented that 5 years ago, each Institute’s Web page had a strategic budget plan, transparent to the community. The payline is not a secret, and the funds for select pay are reported to the Council every year. Funds set aside for select pay vary according to the needs of the Institute. The strategy NIAMS uses is similar to strategies of most NIH Institutes, but some Institutes set aside a large portion of their budget for select pay.

   Dr. Randy Rosier asked how the increase in applications that the NIAMS received compares to other Institutes and to the NIH as a whole. Dr. Hausman responded that the number of applications reviewed by the NIH as a whole has risen dramatically. Electronic scanning of applications started in 2002. In that year, 56,001 applications were scanned, about 65,000 were scanned in 2003, and this year approximately 75,000 applications will be scanned.

   Dr. Katz commented that a major issue is predictability; if funds are limited, will applications decrease? More limited funds with lower paylines may lead to an increase in A1 and A2 applications; the Center for Scientific Review has experienced a very large increase in amended applications.

   Dr. Kotzin commented that the success rate for NIAMS appears to be diverging away from the NIH average. It appears as though the NIAMS success rate is decreasing, which was attributed to a large increase in R03s. If so, it becomes important to examine this gap for more representative awards, such as R01s. Dr. Kotzin noted that a true divergence in the gap is worrisome. A negative message is sent to the scientific community when the success rate drops toward 15 percent or goes below. In the early 1990s, paylines were close to 10 percent, and this was a time of very low morale for researchers.

   Dr. Katz clarified the distinction between payline and success rate. The payline has varied, from a low of 14 percent in 1995 to a high of 24 percent in 2000 and 2001; the current payline is estimated to be around 17 percent. The success rate for the NIAMS has not been lower than 19 percent (in 2003, the success rate was 20.4 percent). This points to a need to look at differences between what the effects of RFAs and R03s are on the success rate. In 2001, the success rate for NIAMS investigator-initiated awards was 28 percent, while the total NIH success rate was 30.8 percent. In 2000, it was 28.1 percent for NIAMS, counting investigator-initiated grants only. The NIAMS success rate has dropped because of many other initiatives.

   Reduction From Full Costs

   Dr. Hausman next discussed ways to have more money available to use to increase the payline. One strategy is reduction from full costs. This was initiated to allow funding of more applications. Program Directors review grant applications on a case-by-case basis; the decision to decrease the total amount of dollars received is not made arbitrarily.

   Dr. Hausman presented information on this strategy. In Fiscal Year 2004:

   • Applications with percentile ranks of 9.9 percent or below are being reduced by 9 percent on average.
   • Applications with percentile ranks of 10.0 percent or above are being reduced by 12 percent on average.
   • Applications with direct costs of $500,000 or more are being reduced by 12 percent on average.
   • Applications with direct costs of less than $100,000 are not being reduced

   Dr. Hausman then presented historical data on the reductions. In 1994-1995, grants were reduced by 20 percent, with Centers reduced more. In 1996-1999, grants were reduced by 10 percent. In 1999, a two-phase reduction strategy was implemented. Grants with better scores were reduced less than grants with poorer scores. In 2001, better grants were not reduced, while poorer grants were reduced less than in 1999.

   Dr. Katz noted that “poorer” is a relative term; all of the grants that are funded are outstanding. Dr. Hausman agreed and continued to describe reductions for 2004, estimated to range from 9 percent to 12 percent.

   Dr. Hausman next presented data showing the effect of reductions on the percent of grants funded; this is based on a $50 million funding pool.

   Reduction Scheme	Approximate Payline That Can Be Reached
   None = no cuts	15 percent
   A = - 5 percent across board	16 percent
   B = - 6 percent for below 9.9 percent rank, - 9 percent for above	16.5 percent
   C = -10 percent to all	16.5 percent
   D = - 9 percent for below 9.9 percent rank, -12 percent for above	16.5 percent
   E = - 15 percent to all	17.5 percent
   F = -20 percent to all	18.5 percent

   Dr. Katz asked which strategies are realistic for extending the payline; reduced funding should not negatively impact the quality and outcome of research. In 1994-95, a 20 percent decrease in funding was considered to have a significant negative effect on research projects.

   Dr. Dawson-Hughes asked if knowing that the grant will be reduced 10-12 percent creates an inclination to pad the budgets. Is there any way to know what the net effect of the strategy is on this inclination? Padding of budgets will result in an internal correction for the decrease.

   Dr. Katz asked if there were an Institute that does not use downward negotiations, and thus has an “agreement” with grantees that there will be no padding of the budget. However, applicants do not always know to which Institute their application will be assigned. Dr. Katz also asked about the effects of modular grants, initiated approximately 4 years ago, and whether these are artificially increasing the cost of grants. Dr. William Sharrock responded that a quick-and-dirty, anecdotal analysis assessing trends over the past 5-7 years saw a modest upward trend in average budget requests, but it did not appear to be affected by modular grants.

   Dr. Katz commented that with increased costs, once the top module of $250,000 is reached, there is a tendency to keep the cost at that level. He then asked Ms. Melinda Nelson, Chief of the NIAMS Grants Management Branch to address this issue. Ms. Nelson responded that she has observed the same trends as Dr. Sharrock (i.e., that no artificial increase has been noticed). Researchers have been rounding down to $250,000 to retain their eligibility for a modular grant. Dr. Katz commented that approximately 80 percent of grants are modular.

   Dr. Francesco Ramirez asked how the average of what is paid for an R01 today compares to the average paid in the 1990s. He asked whether R01s increased proportionally with the increased cost of science. One problem in assessing this rises from investigators submitting multiple grants to compensate for increased costs, which may not be reflected in any analyses. Dr. Katz commented that data comparing the average cost of an R01 in 1994 to the average cost in 2004 should be available.

   Dr. Kotzin asked about true negotiated reductions and the possibility of looking at each application individually, instead of implementing across-the-board cuts. This would require a large increase in labor. Dr. Katz compared this to the situation in awarding contracts, for which negotiations are very detailed. Most contracts involve clinical trials. A monetary figure is decided upon and set, and cannot be reduced. To do this on every single grant would require a lot of work, but individual investigators can appeal cuts.

   Dr. Alan Moshell commented that at the study section level, a grant’s dollar request could be reviewed. Modular grants are required to provide less budget information than regular grants, resulting in less of a tendency to cut modular grants. More cuts are made from grants that submit detailed budgets. Because of this, the study section should notice very obvious budget padding. Dr. Kotzin interjected that it is not the primary purpose of the study section to assess the budget, they mostly concentrate on scientific merit; therefore, the budget probably is not scrutinized as closely.

   Dr. Parr discussed indirect costs, noting that a certain number of research programs are funded by industry, and their objective is to fund research, not to pay for university services or infrastructure. They consider their funding programs to be competitive and have been successful at holding gross overhead costs very low. Everyone is under pressure to reduce overhead and be more effective and efficient in running their organizations. However, the “exorbitant,” as he termed it, percentage of overhead that the NIH pays is a hurdle to improving efficiency, and also makes it difficult for industry to compete to fund research programs. Ms. Nelson commented that the maximum overhead that the NIH pays is 50 percent. Dr. Parr responded that his maximum was 20 percent.

   Dr. Katz commented on ways public-private partnerships reduce indirect costs. Industry, voluntary organizations, and foundations award many fellowships, and indirect costs associated with these are very small or nonexistent. The K awards, for example, have no provision for indirect costs. Universities feel these awards cost them money, and they often are reluctant to accept them. One reason universities may be able to accept industry funding is because the NIH has funded the major infrastructure, reducing the need to recoup indirect costs from this funding. The implementation of efficiencies to reduce indirect costs are beyond the scope of this Council, but is recognized as an important issue.

   Ms. Kalabokes described a National Health Council meeting of voluntary health agencies that examined the issue of indirect costs. Smaller agencies usually contributed nothing in indirect costs, but indirect costs increased as the agency’s budget increased; the highest were from the American Cancer Society, which gave approximately 25 percent in indirect costs. Dr. Katz commented that failure of the smaller agencies to provide funding for indirect costs is viewed negatively at some universities.

   Dr. Stanley commented that at the University of Pennsylvania, administrators have decided that if funding is received from foundations that do not pay indirect costs, either the department has to pay for them, which means the money comes out of clinicians’ salaries, or the University will not accept the money. The expense of doing research is increasing dramatically, mainly due to increased regulations. The NIH has a cap on indirect costs, which means that many indirect costs are not paid, from the point of view of department Chairs. Indirect cost funds go to the university, not the department, so the department has to pay administrative costs, such as paying for faxes, mail, etc., which should be paid by indirect costs. In essence, what indirect costs pay for is under tremendous pressure from the universities.

   Dr. Parr commented that the increased cost of doing research should be covered by “direct” costs. Indirect costs cover the overhead of the institution. The primary purpose of the university is to be an educational facility, and funding research covers a portion of their responsibility to conduct research. The funding given to the university should only cover direct costs, which Dr. Parr defined as including equipment; in some cases, he (Dr. Parr) will maintain title to the equipment until the research is completed, and then give the equipment to the university as a gift.

   Dr. Laurencin commented on percentile reductions. He felt it would be beneficial for investigators to see Dr. Hausman’s chart, to see how reductions affect the payline. He thought that the lower reductions (6-10 percent range) looked reasonable.

   Dr. Katz questioned the disparity between those in the 10 percent range and above, some Institutes distinguish between these applications, some do not. The NIAMS does make this distinction. He emphasized that this does not mean that research that escapes the cut is more worthwhile than research that does not.

   Dr. Laurencin asked whether an “ideal” success rate had been identified. Dr. Katz responded that he thought that a success rate between 32 and 35 percent would encompass research that the NIAMS feels should be supported and is enthusiastic to fund. Dr. Susana Serrate-Sztein agreed with the 35 percent success rate. Dr. Laurencin asked what would be the lowest the success rate could be without causing problems. Dr. Katz replied that he did not want to go below 20 percent. The percentile might be 17 percent, but the current success rate is still greater than 20 percent.

   Dr. Laurencin expressed concern about funding allocated to R03 grants. The current system appears to involve identifying a block of money, receiving the applications, and then paying some percentage of the applications. The success rate therefore is based on the number of applications that come in, given a constant amount of money. This grant represents an important entry level into the NIH funding system, so Dr. Laurencin feels that the Institute should set the success rate at a certain level, and then pay a dollar amount based on the number of applications that are received. Many believe that that this provides an easier entry into the NIH system, which may be the reason the number of R03 applications has increased. If investigators start seeing low R03 success rates, success rates that are lower than for the rest of the RPGs, this may frustrate researchers from entering the NIH funding system.

   Dr. Katz replied that he has seen the opposite situation; he has seen an increase in the number of R03 applications, and it appears that R03s provide a route to further funding (K awards, R01s). It is impressive that R03 grants have helped investigators acquire more funding. He anticipated that the R03 success rate might be 12-13 percent, but if the R03 payline is set the same as that for the R01 grants, this will decrease the R01 payline.

   Dr. Uitto commented that in reduction scheme D (see previous table), there appeared to be no difference in quality, from a practical point of view, between grants ranked 9.9 percent vs. 10.1 percent, and that the cutoff seems arbitrary. The impact of scheme C is the same, and a flat 10 percent negotiated decrease might be more appropriate. Dr. Katz asked for Council members’ input on this point. Dr. Stanley disagreed with Dr. Uitto, explaining that it is a good idea to make cuts gradually, based on the payline. If nothing is done, a grant at 16.8 percent gets full funding, while a grant at 16.9 percent gets nothing. Looking at the payline, as grant percentile rank goes up (indicating a poorer quality grant), the study section may suggest that some of the science described in the grant is not as good as the rest of the science within that grant. Therefore, funding should be cut as the payline goes up so that more money will go to better science. He expressed preference for the graduated cut outlined in reduction scheme D.

   Dr. Uitto asked if the Council wanted to go back to the old Veteran’s Administration system, where a grant could get 5 percent of what was asked for; clearly, this is not sufficient for doing research. Dr. Katz agreed with the philosophy that a critical amount of money is required to do substantive research. Dr. Graciela Alarcon commented that the end result is the same. The difference between a grant application at 9.9 percent and one at 10.1 percent is nil. She would favor a floating 10 percent reduction because the end result is the same in terms of how many grants get funded.

   Dr. Landis described the different mechanism in use at NINDS. Cuts are based on the type of grant—modular grants get a 7.5 percent cut, non-modular grants get a 12.5 percent cut. The philosophy is that modular grants have less flexibility (the maximum award is $250,000), so there is not as much room to make cuts. Non-modular grants are large, providing more options for making cuts.

   Dr. Katz referred to Dr. Dawson-Hughes’ question concerning whether it was known if budgets for modular grants were padded. Dr. Landis replied that she did not know, and that NINDS has had the same discussion with their Advisory Council. As budget increases failed to keep pace with the number of grant applications received, the NINDS began to institute cuts, and had a discussion of how to create funds to fund more grants. This is the system the NINDS developed, but there has been no systematic study of how this affected the science being conducted.

   Dr. Hausman commented that the number of RPG dollars used for set-asides has increased in the past few years in part because the number of RFAs has increased significantly. Dr. Hausman was asked about the RFA versus non-RFA success rate in recent years. He replied that the RFA success rate was just slightly less than that for investigator-initiated projects and noted that the NIAMS set-aside rate is close to that of the NIH average.

   Challenges and Achievements

   Dr. Hausman stated that many factors are involved in the financial management process. Achievements of, and challenges to, NIAMS over the past 5 years include:

   • Large increases in the amount of clinical research performed (mostly contracted, not part of RPG money).
   • Increases in the number of new investigators funded, through K awards.
   • Grant costs have increased in the past 5 years.
   • Commencement of major initiatives such as the Osteoarthritis Initiative.

   In the near future, the NIH budget will flatten; thus, it is important to maintain some degree of flexibility.

   Discussion

   Dr. Katz asked Council members to consider the “big picture,” specifically the percentage of dollars that go to RPGs, extramural versus intramural research, and administrative costs. Although this is higher than the NIH, generally, the NIAMS could look at other programs and put more money into the RPG line, although there is little flexibility there. Major flexibility could be found in the intramural research program, or in the contracts. The NIAMS could move money from contracts to mechanisms through which the Institute can most efficiently support some of these other programs.

   Other areas that were discussed included program project grants, and Dr. Katz asked about the percentage of the RPG line that comprises program project grants. NIAMS program project grants accounted for about 2.5 percent of RPGs and about 10 percent of total dollars, which is line with most Institutes.

   Call for Final Comments on the NIAMS Financial Management Strategies

   Dr. Uitto asked whether there was a significant increase in the number and amount of money set aside for RFAs over the past 3 years. He asked whether the Institute had a mechanism to evaluate the effectiveness of the RFAs. He gave as an example the 1999 fibromyalgia RFA, and asked about its effectiveness and outcome.

   Dr. Serrate-Sztein replied that the Institute does examine the outcome of RFAs. It takes more than 3-4 years to fully assess whether funded projects have made a difference in terms of major discoveries in the scientific area that was covered by the RFA. When she first joined the NIAMS 10 years ago, the Institute had embarked on two major efforts in lupus research—just now, they are seeing some of the major advances being realized and published. One project concerned the pathogenesis of lupus, the other was focused on genetics and ethnic factors affecting development of the disease. These projects were funded through two RFAs and have contributed major advances to the field. Concerning ethnic and other factors that affect susceptibility to lupus among populations, the NIAMS funded two nationwide projects that have produced a significant amount of valuable information. Also about 10 years ago, the NIAMS created a joint RFA with the National Institute of Allergy and Infectious Diseases on Lyme disease, and many major advances leading to the development of vaccines resulted. Overall, in terms of advances, publications, and discoveries that have advanced the field, many of the RFAs have been successful. Others have not been quite so successful, such as a 1995 RFA for R01s for juvenile rheumatic diseases. Many projects did not continue after the initial period of funding, mostly because of a failure to attract a critical mass of investigators, plus the clinical research was very difficult. This RFA was not repeated.

   In response to a question concerning the outcome of RFA investments, Dr. Katz commented that RFA investments could be compared to select pays. The Institute has looked in a critical way at select pays, and found that some spectacular successes, one of which resulted in a recent Science paper, were funded beyond the payline.

   Dr. Dawson-Hughes asked what proportion of the NIAMS budget goes to contracts, and what NIAMS’ main contracts are. Dr. Katz replied that contracts account for approximately 6 percent of the total budget of the NIAMS. Most clinical studies, as well as most or all of the repositories and registries are in the contract line of the budget. The NIH Osteoporosis and Related Bone Diseases – National Resource Center, carried out by the National Osteoporosis Foundation, also is in the contract line.

6. TRANS-NIH MUSCULAR DYSTROPHY ACTIVITIES

   Dr. Katz introduced Dr. Storey Landis, Director of the NINDS, Dr. Duane Alexander, Director of the National Institute of Child Health and Human Development (NICHD), Dr. Audrey Penn, Deputy Director of the NINDS, and Ms. Heather Rieff (NINDS), who participated with Ms. Lorraine Fitzsimmons of the NINDS on the Muscular Dystrophy Coordinating Committee (MDCC) and in generating reports from this Committee. Dr. Cheryl Kitt, Executive Secretary of the NIAMS Advisory Council, reported on the Centers and introduced further participants.

   Dr. Kitt reported that the Muscular Dystrophy Cooperative Research Centers represent a collaboration between NIAMS, NINDS, NICHD and the Office of Rare Diseases (ORD). She also acknowledged the participation of Dr. James Hanson from the NICHD. Ms. Lorraine Fitzsimmons was introduced as the Chief of the Office of Science Policy and Planning in the NINDS. From NIAMS, representation includes Drs. Kitt, Katz, Lymn, and Glen Nuckolls. Ms. Anita Linde is the chief legislative contact at NIAMS and Senior Policy Analyst.

   The activities of this team were described. These included establishment of a muscular dystrophy (MD) research task force, which will partner with outside science and advocacy groups. Reports of the task force are available on the NIAMS and NINDS Web Sites.

   The task force has collaborated to fund a national registry for facioscapulohumeral dystrophy (FSHD); this is the only national resource of patient information related to FSHD. They have issued a program announcement with set-asides related to pathogenic and therapeutic approaches to the various MDs. Any Institute may support applications, and applications also can be co-funded.

   Ms. Linde provided a legislative backdrop to programmatic activities and an overview of the MD Community Assistance, Research, and Education Amendments of 2001, or the MD-CARE Act. The MD-CARE Act was introduced by Representative Roger Wicker (R-Mississippi) in February 2001. Representative Wicker is a member of the NIH Appropriations Subcommittee in the House of Representatives. A counterpart measure in the Senate was introduced by the late Senator Paul Wellstone, a major champion of MD issues in the Senate and one of the chief architects of the bill. The House and Senate versions are similar, but not identical. Between the time the Senate introduced their version in Spring 2001 and President Bush signed the final version in December 2001, changes had been made that mainly affected the scope of the Act, which was expanded to capture all of the MDs, including both childhood and adult-onset forms.

   Advocacy groups have played a key role, initiating the bill largely through interactions that some of the major MD health voluntary organizations had with Congressional colleagues. Ms. Linde acknowledged the Parent Project Muscular Dystrophy as an organization that played a major role in this process; this organization focuses mainly on Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy. The FSH Society also was a major participant; this organization supports patients and families affected by FSHD. The Muscular Dystrophy Association (MDA), which is concerned with all forms of MD, also participated. These groups worked with both House and Senate sponsors and persuaded Senator Specter (Chairman of the Appropriations Subcommittee on Labor, Health, Human Services and Education, that oversees funding for the NIH) to hold a hearing on the bill in spring of 2001. Dr. Audrey Penn was Acting Director of NINDS and represented the NIH at that hearing. The groups have been active in maintaining momentum for implementation and keeping this issue on the priority list for members of Congress.

   Key Provisions of the MD-CARE Act

   NIH’s responsibilities pertaining to the MD-CARE Act include expanding, intensifying, and coordinating MD activities more systematically across the three Institutes that have lead responsibility for MD. The NIH also was mandated to establish Centers of Excellence to boost research across the spectrum of basic, translational, and clinical research. The NIH will facilitate research through developing and disseminating research resources such as tissue samples and genetic materials to be used by muscle biology and neuromuscular communities; this will be accomplished in part through the new Centers. The Act requires creation of an inter-agency coordinating committee that includes both federal officials and non-federal members who represent the MD patient and voluntary communities to better coordinate activities and put added emphasis on activities across the agencies. A primary responsibility is development of an MD Research and Education Plan; this plan will attempt to map out opportunities and priorities in this area. Ms. Linde acknowledged the participation of Ms. Rieff as instrumental in keeping Congress and interested constituencies apprised of the progress made as implementation of the Act has unfolded. Regular progress reports to Congress are required, and there also is a requirement to transmit research plans and periodic updates to the plan.

   The responsibilities of the Centers for Disease Control and Prevention (CDC) include development of an epidemiology program that was related initially to DMD and Becker’s; over time they hope to expand the program to all MDs. They will work with state-based programs to improve the infrastructure for surveillance programs for MD. They also will, as appropriate, work to coordinate with NIH Centers and tap resources being developed in the context of those centers to supplement work of investigators that the CDC is funding.

   The responsibility of the Department of Health and Human Services (DHHS) is to develop a program to provide MD information and education to health professionals and to the general public. A Web site has been developed for the MDCC to provide information on the work of the group and for posting reports.

   At the NIH, the education mandate primarily will involve training for basic and clinical scientists, but other agencies represented on the larger coordinating committee also will have a role in education and professional training.

   Congress has conveyed an ongoing interest in this issue. Two years ago, at NIH Director Dr. Elias Zerhouni’s Senate confirmation hearings, he was asked about NIH’s efforts to implement the mandates of this particular Act. He and Dr. Katz met with Senators Wellstone and Susan Collins (R-ME), along with some patient representatives, and have had ongoing meetings both with members of Congress and their staff who interact regularly with the advocacy community. Encouragement and directives through appropriators is received in the context of annual report language. During a priority-setting hearing at which Dr. Zerhouni testified, questions were posed concerning how the NIH is working in the area of MD and about the progress of the MDCC.

   Dr. Kitt commented that one of the provisions of the MD-CARE Act was to establish Centers of Excellence in MD research; the NIH team came together to formulate and issue an RFA to establish the Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers. Dr. Lymn, Muscle Biology Branch Chief, presented information on these Centers.

   Overview of Trans-NIH MD Activities

   Dr. Lymn noted that there was a great deal of activity concerning MD research and opportunities before the MD-CARE Act was passed. Previous meetings with researchers and advocacy groups identified a need for national resources that could help focus research efforts. When the Act was passed, the MDCC examined the legislation and ideas and met with researchers to develop additional ideas. This meeting resulted in two RFAs. One resulted in three grants funded last September—RFA AR-03-001. Another RFA active currently is AR-04-008 (receipt date is 8/26/04). These grants will be funded next spring.

   The purpose of RFA AR-04-008 is to promote side-by-side basic, translational, and clinical research focused on major questions about MD. This was a very important objective for the lay advocates—there is a great deal of information concerning DMD, but little change in patient treatment for any of the other MDs. The goal is to develop a mechanism to help move basic research findings in concert with clinical findings and challenges. This RFA also includes resources that can be shared and would be part of a national program. The MDCC decided that the best way to focus a national effort was to establish collaborative Centers funded as cooperative agreements with the NIH. All Centers are to meet on a regular basis, with meetings coordinated by the Steering Committee, and will meet with NIH scientific officers and look for opportunities to combine efforts to allow work to progress more rapidly.

   The following three Muscular Dystrophy Cooperative Research Centers have been funded:

   • University of Washington–Seattle: this Center is directed by Dr. Jeffrey S. Chamberlain, and its primary focus is working toward gene therapy and cellular approaches for DMD. They also have some projects on other MDs. Their national research resource core will be to work on providing research-grade recombinant viral vectors for other institutions and research centers. Investigators do not have to be at a Center to take advantage of these resources. Dr. Katz commented that although each Center is funded by a different Institute, they are working collaboratively and are viewed as part of the NIH as a whole. This Center is supported by the NICHD. Dr. Lymn commented that the MDA is partnering with the NIH on these Centers by providing supplements. There is a Memorandum of Understanding with this group.
   • University of Pittsburgh: this Center is directed by Dr. Joseph C. Glorioso, and funded by the NIAMS. The Center’s strengths are gene therapy and cell therapy using a different type of precursor cells. Their major clinical thrust is to work on DMD and limb girdle MD. Their scientific research resource core will provide adeno-associated virus and herpes simplex virus vectors. This work complements work performed at the University of Washington Center. The MDCC is trying to develop ways for Centers to complement each other and make the Centers a better resource for the research community.
   • University of Rochester, New York: this Center is directed by Dr. Richard T. Moxley, and funded by the NINDS. The focus of this Center is myotonic dystrophy and FSHD (adult onset). The Center’s scientific research resource core will be genetic models (transgenic mice); they currently have a myotonic dystrophy model. This Center also will share tissues from biopsies.

   The Steering Committee is working with researchers at all points in the process to determine how to make these resources more accessible to all researchers, clarify how they are accessible, and explain how to request samples. Resources for applicants are available on the Web at http://niams.nih.gov/rtac/funding/grants/ muscular_dystrophy_2004.htm, as are notices of NIH initiatives related to MD activities, older program announcements (these will be updated), workshop summaries since 2000, and instructions.

   Discussion

   Dr. Moxley congratulated Drs. Katz, Landis, Penn, Alexander, Hanson, and Lymn for spearheading this effort, noting that he was impressed by the dedication and determination of these individuals in working together in a committee format and in working with the heads of the Centers.

   Examples of these efforts were discussed. There have been a number of productive meetings bringing the heads of the Centers together to develop a platform for communication between the three Centers. One priority is determining how better to educate other investigators and the public on opportunities to use the Centers’ resources. The MDA was asked to try to determine the feasibility of setting up a national clinical trials network for DMD, and ultimately for all major MDs listed under the MD-CARE Act. Representatives from the MDCC, Centers, Dr. Lymn, and participants from other Institutes (~40 people) will attend a meeting to discuss this network. Their goal is to identify whether there are ways to take existing resources, some of which are at the CDC, some of which are at the NIH, including grants, and have investigators work together to develop a more effective way of utilizing what already is established, and pioneer new ideas for how to be more effective in meeting very broad goals. Questions to be addressed include those concerning the status of existing therapeutic trials and databases, whether the data that exist could help facilitate basic and translational research as well as new clinical trials. It also was asked whether this information could help to further develop the present understanding of the current gold standard for care and management of MD. The meeting is planned for June 10, 2004. The focus of this meeting will be on clinical care, the natural history and diagnosis of MD, and a possible role for private industry. A group that deals with organizational issues also will be present, to help determine how the NIH, CDC, private industry, and other groups could work together to develop an MD clinical trials network.

   Dr. Katz noted that other Institutes may have some of the expertise needed for this project. Dr. Moxley responded that representatives from NINDS and NICHD have been invited. He also commented that this is not a final meeting, but is a first step. They hope to establish whether a clinical trials network is feasible and supported; then planning will begin to identify and decide on the best people to guide this venture.

   Dr. Alarcon asked whether there will be a set number of Centers. Dr. Kitt answered that they hope to fund two to three Centers in addition to the three that have already been funded. Dr. Landis asked Dr. Lymn how many people came to the meeting for pre-application discussions, and how many groups or Centers were expected to apply. Dr. Lymn responded that they expected 7-10 applications, and had representatives from at least five different institutions at the meeting.

   Ms. Fitzsimmons, Chief of the Office of Science Policy and Planning for the NINDS, and the Executive Secretary of the MDCC gave a brief overview of the MDCC. The MDCC was mandated by the MD-CARE Act, and was required to be an interagency committee.

   Primary functions of the MDCC as established by law include the coordination of activities across the NIH and with other health programs and activities that relate to various forms of MD. The first charge of the MDCC was to develop a research and education plan in MD for the NIH, focused on activities that fall within the mission of the NIH Institutes.

   The composition of the Committee also is mandated by law; the MDCC has a maximum of 15 members appointed by the Secretary of DHHS. Two-thirds of these members must represent government agencies that have some responsibilities for MD. These include the NIAMS (current Chair), the NINDS, and the NICHD. The Chair is appointed by the Secretary of DHHS. The Chair serves as principal advisor on MD research to the Secretary and Assistant Secretary of DHHS and to the NIH Director. The Committee also has representatives from the CDC and the Food and Drug Administration, also mandated to be present by law. Other agencies with roles in MD include the Health Resources and Services Administration, Centers for Medicare and Medicaid Services, Agency for Children and Families, Department of Defense (DoD), and the Department of Education.

   The remaining one-third of the members are public members, and must represent a cross-section of persons affected by MD. These can include patients, caregivers, parents, and researchers. MD research is represented in all its forms on the Committee—members include the Director of Research for MDA, advocates for DMD, Becker, limb girdle dystrophy, and FSHD. There also are patients who are key founders or members of formal advocacy groups, and the Committee also includes at least one parent who is active as an advocate.

   MD Research and Education Plan for NIH

   General requirements for NIH’s Research and Education Plan include:

   • Support a broad range of research and educational activities related to biomedical, epidemiological, psychosocial, and rehabilitative issues.
   • For each form of MD, as appropriate, the plan must provide for the following areas:
     1. Research to determine reasons for incidence and prevalence of MD (the CDC has specific activities concerning surveillance and epidemiology), taking care not to duplicate efforts with the NIH; a registry for myotonic dystrophy or FSHD would be included in this.
     2. Research concerning etiology and genetics of MD.
     3. Research to develop improved screening for MD.
     4. Basic and clinical research to develop improved treatment for MD.
     5. Information and education programs for health professionals and the public.

   Process for Development

   This process must reflect input from scientists, patients, and advocacy groups. Patient and advocacy group input is obtained primarily through the MDCC, and there were discussions at the first meeting of the MDCC to determine how they might develop this research plan. The first meeting was held in July 2003, with a charge to establish a plan within 1 year.

   During these discussions, participants examined other plans that the NIH had developed for Parkinson’s disease, brain tumor, and epilepsy research. These programs will be used as models to help decide the best way to develop an MD research plan.

   A consensus was reached to establish a scientific working group to draft a proposed plan for consideration by the MDCC. A working group was organized using members already on a previously established task group described by Dr. Kitt. Advocacy groups also were asked to recommend researchers who could represent their particular form of MD, and input was solicited from the field.

   The working group has 17 extramural researchers, two NIH investigators, and four members from the MDCC (from the CDC, DoD, and NIH). Program staff from several other NIH components were also invited and participated in discussions, including investigators from the National Human Genome Research Institute, the NIH Office of Rare Diseases, and the National Heart, Lung, and Blood Institute.

   The working group was organized around themes of genetics, pathophysiology of MD, screening and diagnosis, treatment, and rehabilitation. Individuals gave overviews of particular areas and specifically identified needs and opportunities.

   These were discussed, and extensive minutes were taken. Ms. Fitzsimmons’ office took all the information and extracted goals to be addressed, vetted it through working group members over the following months, and refined the information to a consensus document distributed to members of the MDCC. A meeting was held in March 2004, for the purpose of vetting the plan through all the membership. Members of the working group wanted to fit goals into a time-risk matrix and felt that some of the goals needed to be broader, with fewer specifics.

   Ms. Fitzsimmons explained that the plan had been expanded to include background information on the MD-CARE Act and on the workings of the MDCC and how the plan was developed, as well as extensive disease-related information so that the plan is complete and has background information. A final expanded report will be sent to MDCC members next week, and will ultimately be submitted to appropriate members of Congress.

   The next step will involve the NIH using the research plan to develop a more detailed implementation plan and consider a time frame in which goals might be addressed. This will include analysis of current research and ongoing and planned initiatives. During development of the initial plan, when the goals were described, this was done irrespective of what research was currently ongoing or might be in the planning stages, because members wanted to ensure that the plan was comprehensive and would address all areas deemed necessary for MD research toward the development of effective treatment. This will involve a portfolio analysis and examining ongoing research that the MDA and other advocacy groups support as well as their future plans. This is a research plan for the NIH, and duplication of efforts should be avoided. Once the plan is finalized and submitted to Congress, it also will also be posted on the MDCC Web Site.

   Finally, although this plan is focused on the NIH, the charge is across the NIH and other agencies to define more broadly what needs to be addressed for MD research. In the future, activities that fall outside the purview of the NIH (such as screening and education) will be identified and appropriate lead agencies to develop plans to address these needs will be designated. Dr. Katz noted that ongoing consultation with the scientific community is critical, and that it is important to include researchers on the MDCC.

   Dr. Landis reiterated that this is an ongoing process. For the investigator community, it is one of the first major MD efforts from the NIH, and is of great importance because it helps to keep researchers informed of their colleagues’ activities, and promotes the concept of sharing resources and information.

   Ms. Sharon Terry asked if this effort had been successful. Dr. Katz replied that it may be too soon to judge the program’s success. Ms. Terry responded that the planning appears to have been successful. She then raised concerns about advocacy groups or legislators deciding on what science will be done. As president of The Genetic Alliance, she discourages earmarking and using Congress to mandate certain types of research. If this program is successful, it might be a good model for identifying other areas where creating this sort of partnership would be useful.

   Dr. Katz commented that something positive will come out of this effort; the question is, how good it will be. He also commented that defined parameters or tests would be necessary to answer whether or not the program is successful.

   Dr. Landis described the NINDS experience with this type of strategy for Parkinson’s disease. The NINDS was asked to develop a Parkinson’s disease research agenda. The Institute held a planning meeting that included scientists, physicians, ethicists, and volunteers, and developed an agenda that led to the creation of the Udall Centers. Dr. Landis noted that this system has worked well. The NINDS, as the lead Institute, has most of the funding, as well as a mechanism to collect information from all 13 NIH Institutes that fund Parkinson’s disease research. The NINDS collects information from other agencies and from advocacy groups, and works with the NIH and these other agencies, enabling cooperation for planning and work. The Udall Centers may serve as a model—they are expected to collaborate, share resources, and provide resources to investigators both within and outside of the Udall Center Network. This project is approximately 3-4 years ahead of the MD plan. There are positives and negatives to this arrangement; complications can arise when different groups with specific agendas collaborate.

   Dr. Katz described a spinal muscular atrophy (SMA) initiative. Dr. Landis noted that in this case, a disease was chosen that seemed close to having a potential therapeutic application. A contract for $20 million was established, as was an advisory committee. In a very focused, benchmark-driven fashion, the initiative is soliciting proposals for research that those sponsoring the initiative feel would advance the state-of-the-art for this disease—for example, animal models, tissue culture models, and assays for protein. This is a huge experiment, and the contract is under scrutiny from other advocacy groups that hope to use a similar approach. The MDA asked whether a similar program should be established for MD. The NINDS is optimistic that the SMA experiment will be successful, but the Institute is reluctant to expand to other diseases until there is evidence that this approach works.

   Dr. Landis explained that the Udall Centers were funded as a result of an RFA and are now coming in for competing renewal. Some have been successful, others not as successful. The advocacy community is interested in how the NIH addresses differing perceptions of success.

   Dr. Uitto asked about the number of Udall Centers. Dr. Landis answered that at most there are 13, 1 will not be renewed, and 7 are likely to be refunded. Dr. Uitto asked if this was a competitive renewal; Dr. Landis responded that it was. When the Centers were established, the Institute envisioned a significant investment in a broad base of different kinds of research in Parkinson’s disease. The idea was that, when the initial 5 years of funding expired, they would need to compete successfully with all other NINDS programs. The RFA with the set-aside money was intended to establish the Centers, but renewal would depend on success and excellent priority scores.

   Ms. Fitzsimmons asked if there were opportunities for new Centers. Dr. Landis explained that two new Centers were added to the original 11, and that during every funding round there are new Centers that wish to join. This is a mechanism by which there can be renewals, less effective Centers can be closed, and new Centers can be added.

   Dr. Uitto asked if there were a limit to how many times a Center could renew. Dr. Landis answered that there was no limit, although some Institutes have chosen to sunset certain Centers. Some Centers are in their 36th year, albeit with significant turnover in primary investigators and projects.

7. NIAMS EXTRAMURAL PROGRAM SCIENTIFIC RETREAT

   The NIAMS Extramural Program Scientific Retreat was held March 29-30, 2004. The retreat had a new format that was more dominated by discussion, with fewer formal presentations. Members of the NIAMS staff attended, including Drs. Katz, Lipsky, Kitt, and Hausman, and Program Directors as well as six outside consultants. The emphasis of the retreat was to determine the direction NIAMS will take in the next 2-3 years.

   There was a great deal of discussion about the NIH Roadmap. The Roadmap initiative is a wide-ranging work in progress, and it is important that many communities participate. Discussion focused on the three components of the Roadmap: (1) new pathways to discovery, (2) research teams of the future, and (3) re-engineering the clinical research enterprise.

   Topics included a discussion led by Dr. Ader on the dynamic assessment of patient-reported chronic disease outcomes. This involves a relatively complicated RFA that tries to standardize and fund ways to reliably identify clinical outcomes from the patient’s perspective, using a specific computerized instrument that asks the minimum number of questions necessary, without loss of measurement precision. This network is expected to involve primary researchers in cooperation with expected significant NIH input, and the NIH will fund three or four of these centers in the future.

   Dr. Alan Moshell led a discussion of the multidisciplinary clinical research career development programs (K12 program), developed to train people in medical specialties and related allied health professionals to work as a multidisciplinary team in a clinical research environment, with the goal of having this team in place by the time studies are ready to begin. It is intended that this will be part of the permanent infrastructure. The NICHD has such a program, which will be a $35 million program once fully implemented.

   Dr. Sharrock discussed work on the genetics of complex traits. The challenge is to identify interacting modifier genes that have a role in many complex traits. One issue is assembling clinical cohorts large enough to do these studies. Participants discussed whether cohorts could be combined for a meta-analysis type of approach, and whether the HapMap would be helpful.

   Dr. Joan McGowan reviewed ongoing work on bone mass in human populations, focusing specifically on possible genetic approaches. She noted that there are a number of ongoing, relatively large studies that examine bone mass in various populations, but these were not originally designed for genetic studies and instead are largely epidemiological studies. Questions were asked as to whether these studies could be re-utilized for genetic studies. There are some smaller studies on diverse populations, for example osteoporosis in the Amish and bone loss in African men in Tobago. A collection of human populations is available for these studies, but questions are still being addressed on how to combine these populations appropriately.

   Dr. Susana Serrate-Sztein reviewed results of a 2003 meeting on collaborative approaches to genetic studies on rheumatic and autoimmune skin diseases. She pointed out that in 1993 there was an initial study on lupus genetics performed in multiple independent laboratories, in contrast to a very large rheumatoid arthritis consortium. In one collaborative effort, there are almost 1,000 affected sib pairs that have been collected, in partnership with Celera Diagnostics, to use for single nucleotide polymorphism analysis. These efforts have specifically identified 10 genes with significant association, and the results have been replicated. In particular, a novel phosphatase has been identified in all or most immune cells, which has subtle modulating effects on immune cells and potentially is a significant candidate gene for association with rheumatoid arthritis. Data also were presented concerning progress in mapping osteoporosis genes in mice. Some quantitative trait loci have been identified, although questions were raised as to how readily the findings can be extrapolated from mice to humans.

   There was extensive discussion of the Specialized Centers of Research (SCOR) program review, with the rationale that this program is more than 15 years old; thus, it was reasonable to initiate a review to determine how well the SCOR mechanism served a purpose in translating research. An ad hoc committee was established to make recommendations on and discuss this issue. In general, the retreat participants thought favorably of the Center of Research Translation mechanism, and several issues were discussed—roles of scientific advisory groups versus translational advisory groups, whether both are needed, if there is overlap, and the extent to which translational advisory groups include patient advocacy organizations. Questions were raised as to whether there should be an emphasis on disease, or if the focus should be broader than an individual disease, for example, studying regenerative medicine with a view towards skin or tissue engineering of cartilage.

   Work on biomarkers was reviewed; these have potential use as valuable tools to treat and understand human diseases. It was pointed out that there are exciting technologies and technological opportunities available, providing better assessment, earlier diagnosis, and more effective ways of gauging interventional therapies, which would make current therapeutic trials shorter, more precise, and more informative.

   Research performed by investigators at institutions other than the NIAMS was discussed. Dr. David Eyre reviewed the use of a urinary excretion of type I procollagen telopeptide assay as a biomarker for bone catabolism and remodeling, pointing out some good examples where this is a very useful, early, quantitative marker for events taking place in skin. Dr. Jill Buyon discussed biomarkers for lupus, a challenging task because of the multiple phenotypic presentations of lupus. Dr. Peter Gregerson talked about immune biomarkers, and a collaborative network trying to specifically identify new biomarkers for lupus and rheumatoid arthritis using emerging technologies. Program Directors gave updates on activities in their specific areas.

8. NIH ROADMAP INITIATIVES IMPLEMENTATION PROCESS

   Dr. Katz asked Dr. Ader to discuss second-level reviews for NIH Roadmap initiatives. Dr. Ader noted that NIH Roadmap initiatives will be discussed at the September Council Meeting, and these initiatives are to be paid with FY 2004 money. Applications are scheduled to be reviewed July 8th and 9th, 2004, and need to be approved and ready to be funded before the end of September. The Council meets September 20th, 2004. To make the timeline, some of the Council members will be contacted by e-mail to provide early en bloc concurrence for those applications after they have been reviewed.

9. MEETING REPORT: ADVANCES IN SKELETAL ANABOLIC AGENTS FOR THE TREATMENT OF OSTEOPOROSIS

   Dr. Dawson-Hughes reported on a meeting on skeletal anabolic agents that was supported by five Institutes. An anabolic agent was defined as an agent that increased bone mass and strength by means other than closing the remodeling space. One of the most exciting developments involved identification of an array of cellular proteins that increase the action of osteoblasts. One example was the protein delta-fos-theta, a transcription factor in osteoblasts that increases differentiation. It also is present in fat tissue, and is leptin-like, although not leptin itself.

   Another osteoblast differentiation factor is Runx-1, which may be a master switch to activate proteins leading to osteoblastic increases while turning off switches that may be barriers to this. Dr. Jane B. Lian of the University of Massachusetts presented this work, and commented that most genes have more than one Runx site. Another protein discussed was phosphophorin, an extracellular matrix protein that stimulates the gene encoding osteocalcin (a protein material that forms the bulk of osteoid that is then mineralized). Two genes were identified as a result of finding unusual patients:

   1. LRP5, found by the study of a patient who had been in a serious accident but had no fractures. The patient’s bone density was 5-10 standard deviations above average bone density. Dr. Robert Recker’s laboratory identified this patient. It appears that individuals with this mutation have increased bone response to mechanical stimulation; this gene helps to identify a way in which loading or exercise can influence bone formation.

   2. Sclerostosis disease, an autosomal recessive condition, was discussed. About 100 cases have been reported. This disease arises due to a lack of a protein called sclerostin. Sclerostin is produced by osteocytes. The action of this protein also is mechanical strain-related. Researchers have known that osteocytes are involved in some way in transmitting the message from exercise to bone, and this may be one way of accomplishing this task.

   Insulin-like growth factor-1 (IGF-I) also was discussed. It is produced in the liver, and another form is produced in osteoblasts in response to parathyroid hormone. The production of IGF-1 increases with mechanical strain. If IGF-1 receptors are knocked out, development of osteoblasts and osteoid are observed, but there is a complete failure of mineralization. It is difficult to administer IGF-1 clinically, and it is poorly tolerated, so trials have found that IGF-1 is not a good therapeutic agent. However, there is hope that IGF-1 bound to binding protein-2 (one of six known binding proteins) may be better tolerated, so there is renewed interest in IGF-1 as a therapeutic agent.

   Lastly, parathyroid hormone was discussed. This hormone serves as a therapeutic agent, in the form of the 1-34 amino acid amino terminus of the molecule. Parathyroid hormone increases osteoblast number by decreasing the apoptosis rate, which extends the life of the osteoblast, and also works in several other ways. To use this hormone therapeutically, spiking levels are required, followed by off-periods. It is administered once a day subcutaneously. There is increased understanding of why it is necessary to administer the hormone this way; signal transmitted from parathyroid hormone is very short-lived, so it is necessary to reduce levels and exposure to be able to come back in and initiate another signal.

   Dr. Katz asked whether the larger peptide works in the same way. Dr. Dawson-Hughes responded that this was not known, because only the 1-34 amino acid peptide was available for therapeutic use.

   Dr. Dawson-Hughes commented that the future of the bone field will be exciting in terms of being able to increase bone mass and make inroads into treatment of osteoporosis during the next 10 years. Dr. Katz added that 100 people were anticipated to attend the meeting, but between 400 and 500 attended.

   Dr. McGowan commented that research on anabolic therapy for bone is in its infancy. Although there is one approved drug that is anabolic in action, there are many questions about how to use the drug—in conjunction with something that is anti-catabolic, timing of administration, best way to optimize bone mass, etc. All of these agents have many potential targets that may not be bone-specific, so one strategy discussed was how to make bone cells produce these targets locally, or at a site where bone growth is desired. At another meeting—the Bone Summit at the Cleveland Clinic in May—a much more orthopaedic, bioengineering approach was discussed. A better marriage of bone endocrinologists and orthopaedics/bioengineering is needed, which may lead to different approaches and perhaps better ways to achieve site-specific drug action in bone without affecting other tissues adversely. Dr. Katz commented that orthopaedic surgeons are on the Council, so some of these issues can be discussed with them.

10. ADJOURNMENT

    The 53rd National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Meeting was adjourned at 4:00 p.m. Proceedings of the public portion of this meeting are recorded in this summary.

CONSIDERATION OF APPLICATIONS

The Council reviewed a total of 595 applications in closed session requesting $121,523,644 and recommended for $121,298,644.

Cheryl A. Kitt, Ph.D. Executive Secretary, National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Director, Extramural Program National Institute of Arthritis and Musculoskeletal and Skin Diseases

Stephen I. Katz, M.D., Ph.D. Chairman, National Arthritis and Musculoskeletal and Skin Diseases Advisory Council Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases