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Advisory Council Minutes

May 2003 (historical)

Minutes of the 50th meeting
May 22, 2003
8:30 a.m. to 4:15 p.m.

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

1. CALL TO ORDER

   The 50th meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council was held on May 22, 2003, at the National Institutes of Health (NIH) Campus, Building 31, Conference Room 6. The meeting began at 8:30 a.m.

   Attendance

   Council members present

   Dr. Graciela Alarcon Mr. Chris Allen Dr. Gunnar Andersson Dr. John P. Atkinson Dr. Paul R. Bergstresser Dr. Bess Dawson-Hughes Dr. Michael Frank Ms. Victoria Kalabokes Dr. Cato T. Laurencin Dr. Matthew Liang Ms. Jean Mandeville

   Dr. Richard T. Moxley Dr. Robert J. Oglesby (Ex Officio) Dr. Francesco B. Ramirez Ms. Mary Elizabeth Replogle Dr. Randy N. Rosier Dr. Steven L. Teitelbaum Ms. Sharon F. Terry Dr. Oretta Mae Todd 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 Ms. Steve Austin Mr. Melvin Broadus Dr. Jenn Bruneue Ms. Karen Butler Ms. Anne Connors Dr. Julia B. Freeman Ms. Janette Gabriel Dr. Elizabeth Gretz Dr. Steven J. Hausman Dr. Stephen I. Katz Dr. Cheryl A. Kitt Ms. Cammie La Dr. Charisse Lamar Dr. Reva Lawrence Dr. Gayle Lester Ms. Anita Linde Dr. Peter Lipsky Dr. John Lymangrover Dr. Richard Lymn Dr. Joan A. McGowan

   Ms. Leslie McIntire Ms. Rachael Moore Dr. Michael Morse Dr. Alan Moshell Mr. Eddie Myrbeck Dr. Melinda Nelson Dr. James Panagis Mr. Monte Parham Ms. Wilma Peterman Ms. Geraldine Pollen Dr. Tondalayo Royster Ms. Nicole Schuett Dr. Susana A. Serrate-Sztein Dr. Tracey Shahan Dr. William J. Sharrock Dr. Lawrence Shulman Ms. Helen Simon Ms. Robyn Strachan Dr. Bernadette Tyree Dr. Fei Wang Ms. Eileen Webster-Cissel

   Guests

   Ms. Angela Bates
   Ms. Janet Craigie
   Ms. Joan Goldberg
   Mr. David Lovett
   Mr. Benjamin Lum
   Dr. Vivian Pinn
   Ms. Dana Richter
   Ms. Susan Whittier

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

2. CONSIDERATION OF THE MINUTES

   The minutes of the 49th Council meeting, held in January 2003, were accepted.

3. FUTURE COUNCIL DATES

   Future Council meetings are planned on the following dates:

   September 25, 2003
   January 29, 2004
   June 3, 2004
   September 20, 2004
   February 8, 2005
   June 14, 2005
   September 13, 2005

4. DIRECTOR'S REPORT AND DISCUSSION

   Dr. Katz introduced five new members of the NIAMS Advisory Council, including:

   • Dr. Graciela Alarcon, Professor of Medicine, University of Alabama. Dr. Alarcon specializes in rheumatology.
   
   
   
   • Dr. Randy Rosier, Professor of Orthopaedics, University of Rochester, Minnesota. Dr. Rosier has a special interest in molecular biology and translational research.
   
   
   
   • Dr. Steven Teitelbaum, Washington University School of Medicine, who also heads the Federation of the American Society of Experimental Biology (FASEB). Dr. Teitelbaum specializes in bone biology and pathology and also is interested in translation of molecular mechanisms research.
   
   
   
   • Ms. Sharon Terry, founder of Pseudoxanthoma Elasticum (PXE) International. Ms. Terry has published in Nature Medicine and PMAS about the gene mutation associated with PXE.
   
   
   
   • Dr. John R. Stanley, Professor and Chair of Dermatology, University of Pennsylvania School of Medicine. Dr. Stanley specializes in blistering skin diseases.
   
   
   

   Dr. Katz recommended that new Council members visit the NIAMS Shorttakes Web Page, with special attention to information about the Loan Repayment Program.

   Personnel Changes

   Dr. Katz announced several personnel changes. Dr. Teresa Nesbitt will serve as the new Chief of the NIAMS Review Branch. Dr. Nesbitt specializes in bone biology. Mr. Melvin Broadus will serve as the new Acting Associate Director for Management and Operations at NIAMS.

   Dr. Raynard Kington has been appointed the new NIH Deputy Director. Dr. Kington formerly led the NIH Office of Behavioral and Social Sciences Research. He also served as Acting Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Dr. Nora Volkow has been appointed the new Director of the National Institute on Drug Abuse (NIDA).

   Dr. Katz noted that the NIH Director has revitalized the review of all Institute Directors every 5 years. Criteria for assessing the Directors include leadership, scientific stewardship of funds, interaction with the community, and collaboration. Participants at this meeting may be contacted to evaluate Dr. Katz's performance as NIAMS Director.

   NIAMS Staff Awards

   Several NIAMS staff members have been recipients of recent awards. Dr. Kitt received an American Pain Society's John and Emma Bonica Public Service Award, which recognizes distinguished contributions to the field of pain through public education, information dissemination, public service, or other efforts that further knowledge about pain. Ms. Elizabeth Freedman and Ms. Rachel Moore of the NIAMS Office of Communications received an NIH Plain Language Award. The NIAMS Community Health Center received the Arthritis Foundation Breakthroughs in Arthritis Award.

   NIH-Wide Activities

   Dr. Katz provided updates on two NIH-wide activities. The first, Dr. Elias Zerhouni's 3 to 5-Year Roadmap Initiative, has the goal of developing a compelling mission to build infrastructure across Institutes that accelerates the research process. Focus areas for this Initiative are: (1) new pathways to discovery, (2) research teams of the future, and (3) re-engineering the clinical research enterprise. The second activity discussed was the extramural Loan Repayment Program. In 2002, the NIH-wide success rate for applicants to this Program was over 70 percent, and applicants were required to be receiving NIH support. Applicants in fiscal year (FY) 2003 no longer are required to have NIH support (they may have federal or non-profit organization support). A subgroup of the Council will be asked to assist with the planning of the FY 2004 Loan Repayment Program for NIAMS.

   NIAMS Budget

   The NIH FY 2003 budget is $27.2 billion. The President requested an NIH budget of $27.8 billion for FY 2004. A 9-percent increase in the NIAMS budget was approved for FY 2003, for a total of $489.3 million. This amount later was reduced to $486.1 million. For NIAMS, $502.8 million was requested for FY 2004. NIAMS testimony before the Senate Appropriations Subcommittee focused on scleroderma initiatives. The House Appropriations Subcommittee expressed strong interest in rheumatic disease research, and the benefits and drawbacks of advertising drugs for rheumatic diseases. More details about the NIAMS funding plan are available on the NIAMS Web Site.

   Recent Scientific Advances

   A Nature Insight supplement on bone and cartilage research was published on May 15, 2003. This publication was the result of collaboration between NIAMS and five other NIH components. A recent PNAS paper was published on the identification of genes linked to the severity of systemic lupus erythematosus (SLE) in a subset of patients. NIAMS provided significant support for this study. A recent report in the Annals of Internal Medicine discussed a study of quadriceps exercises and their effect on the progression of osteoarthritis. Preliminary findings suggest that quadriceps strength actually may accelerate the progression of osteoarthritis.

   Some highlights of ongoing NIAMS-supported research include:

   • A study identifying two variants of a gene that promotes the formation of nitric oxide as potential risk factors for the development of lupus in some African-American women.
   
   
   
   • A study of muscular dystrophy in mice identifying a molecule that, when mutated, produces a structural instability of the membrane that surrounds the muscle.
   
   
   

   Recent NIAMS Activities and Plans for the Future

   Muscular Dystrophy Research

   The Muscular Dystrophy (MD) Coordinating Committee is now established. This Committee, mandated by the MD-CARE Act, involves three NIH Institutes (NIAMS, the National Institute of Neurological Disorders and Stroke [NINDS], and the National Institute of Child Health and Human Development [NICHD]) and seven government agencies. The Committee is responsible for developing a plan to conduct and support research and education and for periodically reviewing and revising this plan. The first meeting of the Committee is scheduled for July 1, 2003.

   A Memorandum of Understanding (MOU) also is being developed between the above-mentioned three NIH Institutes and the Muscular Dystrophy Association to fund Cooperative Research Centers. Up to three Centers are expected to be funded in FY 2003, as well as developmental planning grants for the Centers.

   Consensus Development Conference On Primary Knee Replacement

   Approximately 300,000 total knee replacements are performed in the United States each year for end-stage arthritis of the knee joint. The Consensus Development Conference On Primary Knee Replacement on December 8-10, 2003, will involve both lay people and scientists and will focus on research opportunities and needs. Specific questions to be addressed at this Conference are: (1) What are the current indications and outcomes for primary total knee replacement? (2) How do specific characteristics of the patient, material and design of the prosthesis, and surgical factors affect the short- and long-term outcomes of primary knee replacement? (3) Are there important perioperative interventions that influence outcomes? (4) What are the indications, approaches, and outcomes for revision total knee replacement? (5) What factors explain disparities in utilization of total knee replacement in different populations? (6) What are future research directions?

   Immune Modulation of Skin Diseases

   NIAMS is supporting a Workshop on Immune Modulation of Skin Diseases scheduled for September 2003 to address new treatments for psoriasis, atopic dermatitis, autoimmune blistering diseases, and other skin conditions. The Workshop will focus on understanding how new immune modulatory treatments can enhance knowledge about pathomechanisms of disease. Dr. Moshell is organizing this Workshop.

   Specialized Centers of Research Program

   NIAMS currently supports nine Specialized Centers of Research (SCORs) devoted to the study of osteoarthritis, osteoporosis, SLE, scleroderma, and rheumatoid arthritis. NIAMS plans to evaluate whether the SCORs program, in its current form, is an effective tool for fostering translational research. The committee of external evaluators to be formed will be chaired by Dr. Sue Donaldson, a former Council member, and will include some other Council members.

   
   

5. INFORMATION DISSEMINATION PROGRAM

   Dr. Janet Austin, Director of the Office of Communications and Public Liaison at NIAMS, discussed health communication efforts at NIAMS. She noted that the three NIH mandates are research, training, and information dissemination. Dr. Austin asked Council members for input regarding the relative advantages of print versus electronic information and requested guidance in managing the increasing number of bulk orders received from intermediaries. She indicated that distribution of print materials is becoming costly.

   NIAMS has developed guidelines for information development and dissemination, including: (1) provide culturally-appropriate, audience-specific educational materials written in plain language; (2) routinely update and revise existing materials; (3) facilitate rigorous review of materials by scientists and lay people; (4) collaborate with other NIH components and Department of Health and Human Services (HHS) agencies, voluntary and professional groups, and universities and medical centers in developing materials; and (5) effectively use intermediaries for distribution, including faith- and community-based organizations, NIAMS partners, the Federal Consumer Information Center (FCIC), and health professionals.

   NIAMS currently produces over 80 publications. These are updated every 3 years, and new topics are added each year. Over the past 2 years, NIAMS received over 377 media requests for publications. Publications are disseminated through the following channels: (1) online, (2) through professional and voluntary organizations, (3) at meetings of these organizations, (4) at local health fairs and programs, and (5) through the FCIC. The FCIC selects NIAMS materials to include in its catalog, which is marketed to medically underserved populations (e.g., racial/ethnic minorities).

   NIAMS disseminates information through the following three mechanisms: (1) the NIAMS Office of Communications and Public Liaison; (2) NIAMS Information Clearinghouse (addressing rheumatic disease, musculoskeletal disorders, and skin disorders); and (3) the NIH Osteoporosis and Related Bone Diseases National Resource Center. Requests for information to both the Clearinghouse and the National Resource Center have been increasing, but the Clearinghouse (which handles more print than electronic materials) receives many more requests. The number of requests to the Clearinghouse is leveling off as more materials are distributed through intermediary organizations. Most requests to the National Resource Center are received by Internet, whereas the Clearinghouse receives about half of its requests by telephone and half by e-mail. The National Resource Center also receives more requests from health professionals.

   An outside firm recently evaluated the effectiveness and quality of services of the NIAMS Information Clearinghouse. The evaluating firm sent surveys to approximately 1,600 individuals, with a 20-percent response rate. Two focus groups also were conducted to obtain qualitative input. In addition, a Web survey was conducted but with very low response. Results of the print survey indicated that:

   • Most respondents (93%) thought that the Clearinghouse was helpful.
   
   
   
   • About half of respondents (52%) contacted the Clearinghouse by telephone, and 38 percent contacted it by mail.
   
   
   
   • Most respondents (89%) sought disease information. Nine percent sought information on clinical trials.
   
   
   
   • Most respondents (96%) were satisfied with services received, and 83 percent of this group was very satisfied.
   
   
   
   • Although 75 to 80 percent of respondents liked the content of NIAMS materials, some recommended more appealing cover designs with more photos and graphics.
   
   
   

   Challenges for the NIAMS Information Dissemination Program include:

   • Reaching every American
   
   
   
   • Deciding when and how to communicate
   
   
   
   • Packaging materials to reach different populations
   
   
   
   • Ensuring that information is accurate
   
   
   
   • Promoting healthy behaviors
   
   
   
   • Accomplishing these goals in a cost-effective manner.
   
   
   

   Discussion

   Mr. Allen asked about the approaches used to reach underserved populations, who may be less likely to have access to and use the Internet and other technologies. Dr. Austin indicated that an NIAMS Advisory Council Ad Hoc Group on Information Dissemination and Communications recently met and discussed this concern. This Council agreed that resources must continue to be used to develop and disseminate print media because of the low use of information technology among certain populations. The FCIC can take primary responsibility for disseminating printed materials to these populations. Dr. Katz noted that dissemination of the new Surgeon General Report on Osteoporosis and Bone Health will provide an opportunity for reaching the general public with more specific information on preventing and treating osteoporosis.

   Dr. Andersson inquired about the reading level at which NIAMS materials are written. The majority of materials are written at an 11th or 12th grade reading level. Voluntary organizations use NIAMS publications as source material for developing their own literature for the public. This literature usually is written at the 8th grade reading level. Increasingly, voluntary organizations are expressing a need for low-literacy and Spanish-language resources from NIAMS. The NIAMS Advisory Council Ad Hoc Group on Information Dissemination and Communications is developing a strategy to address this gap.

   Dr. Moxley wondered whether a mechanism exists for updating materials using technology, so that updating can be done more often. Dr. Austin responded that materials must be printed in bulk, making frequent updating less feasible. Online information, however, is updated more often. Special publications may be developed to provide information about important new findings, such as the hormone replacement therapy information released by the Women's Health Initiative. Inserts also can be added to print materials. Dr. Katz added that all information published by NIAMS must be evidence-based.

   Dr. Bergstresser recommended that the NIAMS information dissemination program plan to begin to charge for bulk orders. He asked if the program had examined the characteristics of the 80 percent who did not respond to the survey, because the respondents likely are the ones most pleased with the program. Dr. Austin indicated that the nonrespondents were not examined but that 20 percent is a good response rate for this type of survey.

   For the Eastern Missouri Chapter of the National Arthritis Foundation (NAF), Dr. Atkinson compared pamphlets distributed by NIAMS and NAF. He determined that NIAMS pamphlets provided higher quality information and were less expensive (or free). The Eastern Missouri Chapter determined that obtaining pamphlets from NIAMS rather than NAF saved $13,000. Free materials, therefore, are important to non-profit organizations that operate on very limited budgets at this time.

   Dr. Katz noted that the National Heart, Lung, and Blood Institute (NHLBI) charges for materials. NHLBI has stated that a critical mass of material requests must be reached before it recommends charging a fee. Dr. Katz recommended that NIAMS investigate the feasibility of charging for its print materials.

   Ms. Kalabokes noted that the National Alopecia Areata Foundation conducted a survey of its constituents and found that 65 percent of respondents preferred print materials to PDF files. CD-ROMs may provide an acceptable alternative to print or online materials, particularly for elderly populations.

   Dr. Katz asked participants to consider strategies for reaching populations that do not know that they need the information provided by NIAMS. Ms. Terry responded that distribution through intermediaries, particularly faith- and community-based organizations, is key to reaching underserved populations. The most recent PEW Internet survey found that only 17 percent of Americans do not have at least second-degree access to the Internet (i.e., a friend or family member who can obtain online information for them). Dr. Todd added that it might be challenging to collaborate with organizations that serve special populations. Many strategies have been developed to reach and collaborate with these organizations, but persistence is critical. Once these intermediaries view an entity such as NIAMS as a trustworthy source, they may initiate contact to obtain information and education.

   Dr. Serrate-Sztein added that many individuals have access to the Internet but do not know how to effectively search for reliable information online. She recommended that NIAMS use professional search companies to assist consumers in conducting online health information searches. Dr. Austin indicated that professional search assistance likely is a major component of the NIH Director's Communication Plan under development. NIAMS also produces a popular booklet entitled "How to Find Medical Information."

   
   

6. A SUCCESSFUL PARTNERSHIP: THE OFFICE OF RESEARCH ON WOMEN'S HEALTH AND NIAMS

   Dr. Vivian Pinn, Associate Director for the NIH Office of Research on Women's Health (ORWH), discussed the ORWH's mission and activities, as well as collaborative activities with NIAMS. She distributed a handout of her presentation detailing the collaborative projects of NIAMS and the ORWH. Dr. Katz noted that many diseases addressed by NIAMS predominately affect women.

   The ORWH, established in 1990, operates through the NIH Office of the Director and, therefore, does not have direct funding authority. All ORWH funding is provided through NIH Institutes, and the ORWH attempts to expand the research portfolios of these Institutes. The ORWH mission is to: (1) set a research agenda for future directions in women's health; (2) increase research on women's health and gender-related factors that impact health; (3) ensure that women and minorities are adequately represented in clinical studies; and (4) develop opportunities for recruitment, retention, re-entry, and advancement of women and girls in biomedical careers; as well as creating opportunities for men and women to participate in women's health research.

   Some examples of collaborative efforts between ORWH and NIAMS include:

   • Several workshops conducted around the United States to establish a Research Agenda on Women's Health for the 21st Century. An eight-volume summary of these workshops has been developed in English and Spanish.
   
   
   
   • Funding of several research projects on women's health and related gender factors. Dr. Pinn distributed a summary of ORWH projects funded by NIAMS. Total funding for these projects in FY 2002 was $3,691,796. With the exception of NICHD, NIAMS is the Institute that receives the most funding from ORWH for co-funded projects. NICHD leads the Building Interdisciplinary Research Careers in Women's Health (BIRWCH) program. BIRWCH supports development of junior faculty members engaged in women's health research in OB-GYN departments around the United States.
   
   
   
   • The Women's Health Research Enhancement Awards Program (REAP) of ORWH. REAP helps fund quality grant applications relevant to the ORWH mission that were reviewed by NIAMS and other Institutes but were below the pay line for funding. NIAMS staff were involved in the development of REAP, and currently perform administrative review of requests for supplemental funding from this Program. The efficacy of REAP currently is being evaluated.
   
   
   
   • NIAMS co-funding of the BIRWCH program. NIAMS is a major funder of BIRWCH I and II Centers.
   
   
   
   • NIAMS primary funding and administration of the Specialized Centers of Research on Sex and Gender Factors Affecting Women's Health.
   
   
   
   • NIAMS support of the Women's Health Initiative.
   
   
   
   • Dr. Julia Freeman's chairing of the Coordinating Committee for Research on Women's Health Career Development Subcommittee. This Subcommittee has developed several intramural and extramural programs across the NIH that provide opportunities for participation and advancement of women and girls in biomedical careers.
   
   
   
   • NIAMS leadership of the ORWH/Institute of Medicine review of breast implant safety.
   
   
   
   • NIAMS planning and development of a workshop on lupus, with co-funding from the ORWH, HHS Office of Women's Health, and offices of women's health in other HHS agencies.
   
   
   

   Discussion

   In response to Dr. Atkinson's inquiry about ORWH project funding, Dr. Pinn explained that her Office targets funds for projects that support its mission and that would not go forward without this funding. The ORWH may commit to providing supplemental funding for applications received in response to Requests for Applications (RFAs) or Program Announcements (PAs) that were developed in collaboration with and approved by the ORWH. With regard to investigator-initiated research, the ORWH regularly contacts certain Institutes to inquire about plans to fund studies that could address gaps in the understanding of women's health and sex- and gender-related factors that influence disease. An Institute may contact the ORWH to discuss collaboration on a project relevant to the ORWH mission. For example, NIAMS approached the ORWH about co-funding the Osteoarthritis Initiative. The ORWH has a Research Subcommittee comprised of representatives from various Institutes, as well as an Advisory Council of researchers outside the NIH. Overall, the ORWH provides from $50,000 to $250,000 per project. Dr. Pinn prefers to fund projects to which the ORWH can make a 5-year commitment to allow the ORWH to be involved in the oversight of these projects.

   Dr. Teitelbaum asked about the ORWH criteria for cofunding studies that focus on a disease that may be more common among, but not unique to, women. Dr. Pinn responded that the ORWH cofunds studies of diseases that affect both women and men, but that may be more common among women, such as osteoarthritis. This type of research permits the examination of sex- or gender-related differences in disease outcomes. Dr. Pinn added that, since the formation of the ORWH, women have ceased to be underrepresented in NIH-funded clinical trials. At present, representation of women in clinical trials across NIH ranges from 60 to 70 percent. This high participation of women in NIH studies has led to the men's health community's advocating for increased representation of men in these studies. Dr. Pinn emphasized that representation of women in NIH-funded studies that do not address health concerns unique to women is about 51 percent.

   
   

7. PLANNING FOR CLINICAL TRIALS

   Examples of large clinical studies supported by NIAMS over the past 5 years include: (1) a multi-center study of the benefits of surgery versus no surgery to treat low back pain; (2) a study of combination therapies for osteoporosis; (3) a large, observational study of men with osteoporosis; (4) clinical interventions for skin wound healing; and (5) a multi-center study of the use of statins to prevent cardiovascular disease in children with lupus erythematosus. NIAMS will be able fund more translational research because of its recent budget increases.

   NIAMS has conducted several roundtable meetings to help the Institute develop an approach for evaluating applications for large, clinical studies and setting priorities for funding these types of studies. Dr. Katz noted that the primary criterion for funding any study should be whether or not the study is expected to make a difference in disease outcomes.

   NIAMS currently funds clinical studies through RFAs, Requests for Proposals (RFPs), and investigator-initiated applications. The NIAMS Review Branch reviews applications for clinical trials that will be conducted at three or more sites. Applications for trials to be conducted at one or two sites are reviewed by the Center for Scientific Review (CSR).

   Dr. Hausman conducted a survey of the approaches used by six other NIH Institutes to solicit, evaluate, and prioritize the funding of applications for large clinical studies ($800,000 or more annual funding). These Institutes included the NHLBI; National Institute of Dental and Craniofacial Research (NIDCR); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); NINDS; NIAAA; and the National Institute on Aging (NIA). The main survey questions were: (1) How do you plan for large clinical studies? (Who has input into the process? Are outside experts and/or members of the public included in the planning process? What is the role of staff in this process?); (2) What are the criteria for acceptance of large clinical studies? (Are applications accepted from anyone? Are they accepted only via solicitation?); and (3) How are large clinical study applications reviewed? (by the Institute? CSR?)

   Responses to the first main question in the survey (How do you plan for large clinical studies?) revealed that program staff within the Institutes conducted most planning. Some Institutes reported that solicitations for clinical studies were developed with input and concept review from an advisory council as well as from program staff. Few Institutes reported having a standard, formal process for planning for large, clinical studies. Some Institutes, however, were attempting to formalize this process. For example, one Institute reported that an internal Clinical Trial Working Group may screen concepts for future trials.

   Responses to the second question in the survey (What are the criteria for acceptance of large clinical studies?) revealed that most Institutes were willing to fund both solicited and unsolicited studies. Funding requests for $1 million or more generally required approval by the Institute Directors. Two Institutes required that these funding requests also be approved another group (i.e., a committee of Division Directors, an advisory council subcommittee).

   Responses to the third question in the survey (How are large clinical study applications reviewed?) revealed that most Institutes sent applications to Clinical Trials Review Committees (CTRCs) in the Review Branch. Applications for trials at only one or two sites (particularly if the application was unsolicited) were reviewed by the CSR at certain Institutes. One Institute reported the use of study sections to review clinical trial applications (including a separate study section for epidemiological studies). Another Institute reported conducting external review of applications on an ad hoc basis.

   Dr. Katz noted that internal review might indicate review by an ad hoc or standing committee organized by an Institute. NIAMS and other Institutes continue to adhere to NIH guidelines recommending that applications for $500,000 or more be reviewed within the Institute. NIAMS conducts review of applications for $500,000 or more by: (1) distributing applications to program directors, (2) discussing the relevance of these applications to the NIAMS mission at a meeting of program directors, and (3) sending applications to the CTRC. Dr. Katz asked NIAMS Advisory Council members for guidance in developing a strategy for determining which large clinical trial applications to accept for review. For example: On what timeline should applications be accepted? What should be the criteria for prioritizing these applications? Who sets these priorities? Should NIAMS accept any unsolicited application, or work with stakeholders to determine what research areas applications should focus on?

   Dr. Frank asked whether constituents have expressed concerns about the type of research NIAMS is funding. Dr. Katz indicated that groups of constituents have not expressed such concerns. However, more careful prioritizing of large clinical research applications is necessary as budgets become more limited and the need for research dollars to produce maximum impact on disease outcomes increases.

   Dr. Serrate-Sztein indicated that NIAMS may miss some opportunities to conduct clinical trials of new treatments before health care providers use them. Many treatments (particularly for rheumatic diseases) are used without a strong body of scientific evidence to support their efficacy and safety. Dr. Alarcon added that the time period between the receipt of a planning grant and the funding of a clinical trial often is long. The time period between initiation of a trial and final results is longer. Many trials, therefore, produce some results that are no longer relevant. For this reason, an efficient process for reviewing clinical trial applications is critical.

   Dr. Ramirez noted that trials that examine new treatments cannot be compared with those that examine existing treatments. The issue of the missed window of opportunity is most important for studies of new treatments, which may be best funded by the NIH. NIH-funded studies of new treatments may be particularly important for rare diseases. Dr. Katz responded that studies of existing treatments are important and may impact larger numbers of people, which would increase their importance to the NIH. Both types of trials are important, but should be reviewed using different criteria.

   Dr. Andersson noted that many clinical trials are underpowered. The NIH may be the entity most able to support adequately powered clinical trials. The NIH also may be most able to garner support for trials from a wide range of communities, which can increase statistical power. Collaboration with the community is needed to identify research opportunities and determine the probability of their success.

   Dr. Lipsky highlighted the need to consider the financial impact of all trials on the United States population. NIAMS has access to the resources needed to ensure that clinical trials are cost effective.

   Mr. Allen recommended that NIAMS track and examine research conducted by other entities (both federal and nonfederal) that may overlap research supported by NIAMS. NIAMS will need to collaborate with these other entities supporting research relevant to its mission to avoid duplication of effort, make the best use of existing infrastructure, and capitalize on lessons learned by these entities.

   Dr. Atkinson recommended that a process similar to that used to review applications for smaller, investigator-initiated studies be used to review applications for large clinical trials. He also recommended that a review committee monitor and evaluate the progress of these trials several times annually. Dr. Katz responded that this approach would be very time- and labor-intensive for large trials, particularly because multiple review groups would need to be coordinated. Review and evaluation by program staff or a subgroup of the Advisory Council may be more feasible.

   Dr. Andersson noted that the main criteria for prioritizing applications should be the importance of the outcomes and the possibility of success. He questioned, however, how easily applications for clinical trials focusing on very different conditions could be compared. Dr. Andersson also questioned whether the program directors are most qualified to determine the importance of outcomes and the possibility of success, or an additional group is needed to make this decision. He also suggested that NIAMS carefully consider its process for determining what types of research to solicit.

   Dr. Kitt, who formerly was with NINDS, noted that the NINDS Advisory Council was asked to set priorities for funding proposed clinical trials. The NINDS Advisory Council decided to form a subcommittee that included individuals with expertise in conducting clinical trials. NINDS also decided to ask investigators in the initial stages of research to submit planning grant applications. If NINDS accepts planning grant applications, it makes a commitment to accept the application for the next phase of the clinical trial. Prior to submitting clinical trial grant applications, investigators contact and work with NINDS program staff to develop their research proposal. NINDS program staff assist investigators in refining their proposal by reviewing proposals and providing feedback. NINDS staff have expertise in biostatistics, clinical trial design, and medical economics to assist investigators in developing the best proposals possible. Final research proposals are presented to the Council subcommittee, which makes recommendations to the full Council and the NINDS Director. This process allows NINDS staff to screen out proposals for duplicative or low-priority research.

   About 3 years ago, NIAMS instituted a planning grant program to save review time, money, and startup time for the investigators. NIAMS also requests that all investigators submit pre-applications, which are used to select studies that address issues of interest to NIAMS. Dr. Dawson-Hughes suggested that these pre-applications be sorted based on established NIAMS research priorities. Pre-applications would be accepted for further development in collaboration with NIAMS staff, rejected because the proposed study topic currently is not a NIAMS priority (or is duplicative), or held for later consideration.

   Ms. Terry added that NIAMS needs a system to screen applications for translational research. She recommended that NIAMS take the lead in screening these applications because its staff have a broader perspective of specific research topics and gaps.

   Dr. Laurencin recommended that all clinical trials be funded through NIAMS solicitations to ensure that high-priority areas are addressed. He recommended that roundtable meetings (which NIAMS currently uses) and consensus conferences be conducted to determine clinical research priorities. Consensus conferences frequently produce RFAs, and may productively involve advocacy and academic organizations.

   Dr. Katz noted that most clinical trial applications to NIAMS are unsolicited. NIAMS may need to compare the relative benefits of funding solicited versus unsolicited applications. Many participants noted that NIAMS resources might be more effectively used by funding solicited applications. The planning grant process could be used to review, select, and refine unsolicited applications that show promise for addressing high-priority areas of research.

   Participants generally recommended that NIAMS establish research priorities that will facilitate more efficient selection of clinical trial applications for funding. Many participants agreed that NIAMS should conduct internal review of translational and other clinical trial applications, without precluding input from external experts (including this Advisory Council). Many participants emphasized the importance of seeking input from a diversity of experts outside of the NIAMS to determine research priorities and to evaluate and refine the process for soliciting and reviewing applications. Dr. Katz added that NIAMS will need to accept applications only at specified times each year, which will be publicly announced. He plans to work with some Council members to revise the NIAMS process for reviewing clinical trial applications.

   
   

8. NIAMS SCIENTIFIC PLANNING RETREAT REPORT

   Dr. Richard Moxley delivered a report of the NIAMS Scientific Planning Retreat. He noted that the Retreat focused on planning for new initiatives and involved some individuals from outside the NIH. New NIAMS initiatives may focus on approaches identified in Dr. Zerhouni's Roadmap Initiative, particularly multidisciplinary research teams and collaboration with other Institutes, agencies, and organizations to maximize resources and infrastructure.

   Program directors presented research needs and opportunities, rationale, and possible initiatives. The main theme of these discussions was to identify and develop approaches for encouraging and enhancing interdisciplinary research. Questions addressed during these discussions included:

   • How can research at the NIH Centers be enhanced?
   
   
   
   • How can collaborations with minority-serving institutions be increased?
   
   
   
   • How can communication between clinicians and basic scientists across the various areas of specialization be facilitated?
   
   
   
   • How can translational projects be integrated into large, therapeutic trials?
   
   
   
   • How can the burden of specific diseases and conditions be measured?
   
   
   
   • How can mouse models be better utilized? For example, could findings of a large Phase III clinical trial with human subjects be used to develop more useful mouse models?
   
   
   
   • What are the opportunities for advancing research using biopsychosocial expertise (e.g., pain control, the impact of developmental changes on treatment)?
   
   
   
   • What is the role of imaging techniques to determine disease status?
   
   
   
   • What are the opportunities for using genomics and proteomics in research?
   
   
   
   • How can research be translated into practice and involve patients, advocates, caregivers, health care providers, policymakers, and scientists in the process?
   
   
   
   
   

9. AUTOIMMUNITY REPORT

   Dr. Serrate-Sztein discussed the process leading to the development of an NIH Autoimmune Diseases Research Plan. The development of this Plan was a collaborative effort of the NIH, the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Veterans Administration (VA), and private organizations. The Plan was developed to respond to research findings indicating that autoimmune diseases share some characteristics, including: (1) immune dysregulation, (2) a tendency to be antigen driven, and (3) manifestation as organ-specific and systemic disease and damage resulting from immune and inflammatory processes.

   Dr. Serrate-Sztein presented the amount of funding dedicated to autoimmune disease research by Institute. In FY 2002, the National Institute of Allergy and Infectious Diseases (NIAID) provided the largest amount of funding for autoimmune disease research. NIAMS provided the second largest amount of funding in this area, followed by NIDDK. Within NIAMS, autoimmune disease research is supported through the Rheumatic Diseases Branch, the Centers program, the Skin Diseases Branch, the Muscle Biology Branch, and the Intramural Program. In FY 2000, most NIH funding of autoimmune diseases research was dedicated to studies of multiple autoimmune diseases, followed by studies of Type I diabetes, multiple sclerosis, SLE, and rheumatoid arthritis.

   NIH funding of autoimmune disease research is increasing. Collaborations across Institutes also are increasing to promote clinical and translational research into autoimmune diseases. Much of the NIH-funded research that addresses autoimmune diseases focuses on pathogenesis and immune dysfunction. A large amount of the NIH-funded research in this area also focuses on genetics, therapies, and immune mechanisms of organ damage. Promising areas for future autoimmune diseases research include health services and epidemiology.

   The NIH Autoimmune Diseases (AD) Coordinating Committee was established in 1998 to develop a strategic plan for research in this area. The Committee included representatives from several federal agencies and advocacy organizations. The AD Coordinating Committee presented a report of its strategic plan to Congress in April 2003. This report also was distributed to members of the NIAMS Advisory Council and is available on the NIH Web Site. NIAMS staff involved in the development of this report included Drs. Gretz, Serrate-Sztein, Barbara Mittleman, and Ader.

   The report of the AD Coordinating Committee will provide a framework for evaluating current NIH initiatives and planning future initiatives. This report recommended that the NIH focus on several specific research areas, including biomarkers, bioinformatics, clinical trials, epidemiology, repositories and other resources that support translational and clinical research, basic research focusing on etiology and pathogenesis, and outreach and education programs.

   Biomarker research is needed to determine surrogate endpoints for clinical trials. An Autoimmune Biomarkers Collaborative Network (ABCoN) has been established to identify and characterize biomarkers for lupus and rheumatoid arthritis. These biomarkers are needed to identify disease subsets, identify and predict the occurrence of symptoms and outcomes, and predict response to therapy. ABCoN is a collaborative effort of the University of Minnesota, North Shore Long Island Jewish Research Institute, and a private research technology company. This company will provide technology and conduct proteomic analyses.

   NIAID and NIDDK are leading the development of bioinformatics technology for autoimmune research at NIH. The Autoimmunity Center of Excellence (ACE) and the Immune Tolerance Network have been established to support clinical trials focusing on autoimmune diseases and to provide infrastructure for mechanistic studies. NIAMS contributed to the development of ACE. Infrastructure for conducting epidemiology and outcomes research is being developed at multiple Institutes. Epidemiological research is needed to examine the influence of the environment, specifically infections, in the etiology of autoimmune disease.

   Dr. Serrate-Sztein indicated that future reports of the AD Coordinating Committee would address other important research areas, including behavioral studies of biopsychosocial factors that affect disease progression and outcomes.

   Discussion

   Ms. Kalabokes noted that the first report of the AD Coordinating Committee was well received by Congress. A large number of Congressional members attended the presentation of this report.

   Dr. Atkinson praised the report for emphasizing the relationship between the various autoimmune disorders. He emphasized the need to identify the basic mechanism behind these disorders.

   Dr. Teitelbaum recommended that future reports of the AD Coordinating Committee address postmenopausal osteoporosis. This disease has been found to have a major autoimmune component.

   Dr. McGowan asked why autoimmune thyroid disease was not mentioned in the report. Dr. Serrate-Sztein agreed that little research has focused on autoimmune thyroid disease, perhaps because it is treatable. The key to expanding research on autoimmune thyroid disease may be to promote interest among researchers in this disease and autoimmune disorders in general. Dr. Katz noted that gout also was understudied, again, because it has been treatable for many years.

   
   

10. DISCUSSION OF THE RO3 PROGRAM

    Dr. Hausman presented an overview of the implementation of the R03 program at NIAMS and an assessment of its success. He noted that the purpose of the R03 program was to provide startup funds for new investigators. The NIAMS R03 program was phased in over multiple years, beginning with annual RFAs, then tri-annual PAs. Former and current recipients of R15, R03, K08, K01, R55, F32, T32, and National Research Service awards are eligible for R03 grants. Current and former recipients of R01, R29, and P01 subproject and Center principal investigators are not eligible. Principal investigators for National Science Foundation and VA grants also are ineligible. NIAMS R03 grants provide recipients with up to $50,000 per year for 3 years.

    NIAMS recently attempted to address the following questions regarding its R03 program: When is the appropriate time to conduct an evaluation of this program? How is R03 program success defined (e.g., grantees receiving a subsequent R01 or accepting a position with private industry)? What is the most appropriate control group in evaluating this program? Are there differences in program/branch distribution of R03 awards? The key questions to be addressed in the assessment of the NIAMS R03 program were: Has the R03 program been successful? Should this program be altered in any way?

    NIAMS staff decided to evaluate only the indicators of the success of the R03 program that are measurable using the NIH information system. This information system includes information about every grant that an applicant subsequently applied for and was awarded from the NIH. An analysis of applications to the NIAMS R03 program indicated that:

    • A total of 323 applications were received in response to RFAs, from 297 applicants.
    
    
    
    • In 1997, 153 applications were received with a 17 percent success rate. Forty-two percent of these grantees has since been awarded an R01. Only 17 percent of the applicants who were unsuccessful in obtaining a NIAMS R03 in 1997 later were awarded an R01. Twenty-five percent of all 153 applicants subsequently was awarded an R01.
    
    
    
    • In 1998, 94 applications were received with a success rate of 25.5 percent. Thirty-one percent of these grantees has since been awarded an R01. Only 12 percent of the applicants who were unsuccessful in obtaining a NIAMS R03 in 1998 later were awarded an R01. Twenty-six percent of all 94 applicants later were awarded an R01.
    
    
    
    • In 1999, 76 applications were received with a 34.2 percent success rate. Twenty-four percent of these grantees has since been awarded an R01. Only 7 percent of the applicants who were unsuccessful in obtaining a NIAMS R03 in 1999 later were awarded an R01. Eighteen percent of all 76 applicants has since been awarded an R01.
    
    
    
    • A total of 360 applications were received in response to PAs with an overall success rate of 22.5 percent.
    
    
    

    Possible explanations for these results are: (1) Successful R03 applicants are more likely to be successful R01 applicants. (2) With increasing time since award of an R03, the likelihood of being awarded an R01 increases.

    Combined data for RFA applicants from 1997-1999 reveal the following success rates by Branch:

    Branch	Success Rate for 3 RFAs (1997-1999)
    Rheumatic Diseases	22.5%
    Muscle Biology	19.2%
    Skin Disease	30.4%
    Musculoskeletal Disease	22.1%

    Dr. Hausman indicated that the total number of applications per branch was too low to determine whether or not success rates differed significantly by branch.

    Discussion

    Dr. Teitelbaum noted that R03 and R21 grants account for most of the recent growth in grant applications across the NIH. The number of R01 applications has not increased over the last 5 to 6 years. Dr. Teitelbaum also noted that the data presented by Dr. Hausman suggest that the NIAMS R03 program is not a failure, but do not provide enough information to confirm that the program is a success. Dr. Moshell added that the R01 award rates for unsuccessful R03 applicants are about the same as the success rates of new investigators applying for R01 grants across the NIH.

    Dr. Teitelbaum suggested that NIAMS compare success rates for R01 and R03 grant applications. Dr. Katz indicated that NIAMS collects data on success rates for both mechanisms. He indicated that success rates were lower for R03 applications when the program was first implemented and in FY 2002. Success rates for R03 and R01 grants were similar in other years.

    Dr. Alarcon recommended comparing publications of successful and unsuccessful applicants. Dr. Hausman agreed that publications were another good measure of success and indicated that information on applicant publications may be available through NIH. Dr. Katz responded that a review of applicant publications might not be worth the effort because funding success is a good proxy measure of publications. Dr. Alarcon also recommended collecting outcome data on R03 applicants over a longer time period to determine whether or not this program makes a difference in science.

    Dr. Laurencin recommended polling R03 grantees and asking them whether or not the R03 award had an impact on their career, in what way, and how much of an impact it had. Dr. Laurencin also inquired about the number of R03 applications received from orthopedic surgeons. He noted that many in the orthopedic surgery community believe that the success rate for applications in this area is very low. The R03 may not provide the best mechanism for involving clinicians in biomedical research. Few applications are received to study orthopedic issues. Dr. Katz added that the American Society for Bone and Mineral Research (ASBMR) has cofunded quality bone research applications that NIAMS was not able to fully fund.

    Ms. Goldberg, Executive Director of the ASBMR, indicated that this organization conducted an informal evaluation of the R03 grants cofunded with NIAMS in 2000. Publications, presentations, and other indicators of success were examined. The program was terminated in 2003, in part because other grant mechanisms were determined to more effectively support new investigators in initiating their research careers. The ASBMR is interested in collaborating with NIAMS to plan new mechanisms for supporting new investigators.

    Drs. Atkinson and Laurencin were concerned that new investigators may become discouraged when quality applications are not funded. Dr. Katz noted that R01 and R03 grants are funded from a single budget, so that increasing success rates for R03 applications would reduce funds available for R01 grants. The K23 mechanism is another option for funding quality applications that cannot be funded through the R03 program.

    Dr. Frank inquired about the criteria for determining which R03 applications to fund. Dr. Katz responded that funding decisions are based on financial planning conducted prior to the review of applications. Dr. Frank also questioned how many applicants have Ph.D. versus M.D. degrees. Dr. Katz indicated that these data are not compiled.

    Dr. Andersson asked if data are collected on the time period between the termination of R03 funding and the award of an R01 grant. Dr. Katz responded that the R03 program is too new to collect these data.

    The Council agreed to continue monitoring the NIAMS R03 program (especially in terms of prospective funding). The K23 and R21 programs also should be evaluated.

11. ADJOURMENT

    The 50th National Arthritis and Musculoskeletal and Skin Diseases Advisory Council meeting was adjourned at 4:15 p.m. Proceedings of the public portion of this meeting, which lasted until 2:00 p.m., are recorded in this summary.

    
    

12. CONSIDERATION OF APPLICATIONS

    The Council reviewed a total of 711 applications in closed session requesting $155,924,371 and recommended for $143,533,981.

    I hereby certify that, to the best of my knowledge, the foregoing summary and attachments are accurate and complete.

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