The National Institute of Diabetes & Digestive & Kidney Diseases

September 1997 Meeting Minutes

Department of Health and Human Services
Public Health Service
National Diabetes and Digestive and Kidney Diseases
Advisory Council
September 17-18, 1997

I. Call to Order

Dr. Gorden called to order the 145th National Diabetes and Digestive and Kidney Diseases Advisory Council meeting on September 17, 1997, at 8:40 a.m.

A. Attendance

Council Members Present (See Attachment A)

Dr. Irwin M. Arias
Dr. Judith Bond
Dr. Richard J. Boxer
Dr. Jack E. Dixon
Dr. David M. Harlan (Ex Officio)
Ms. Ruby R. Haughton
Dr. Barbara E. Hayes
Dr. Saulo Klahr
Dr. S. Robert Levine
Dr. Eric G. Neilson
Dr. Don W. Powell
Dr. Jerrold M. Olefsky
Dr. Barbara J. Rolls
Ms. Suzanne Rosenthal
Dr. Joseph T. Spence (Ex Officio)
Dr. George Stamatoyannopoulos
Dr. Richard D. Williams

Council Members Absent

Dr. James R. Gavin III
Dr. James E. Rothman
Dr. Joseph H. Szurszewski

Staff and Guests

In addition to Council members, others in attendance at the meeting included staff members from NIDDK, NIH Office of the Director (OD), Center for Scientific Review (CSR), and other organizational units within NIH. Guests were present during the open parts of the meeting. Attendees included the following:

C. Conflict of Interest Statement (See Attachment B)

Dr. Gorden called to the attention of the Council the Confidentiality and Conflict of Interest Statements. After discussing the scope of confidentiality and conflict of interest, he requested that Council members comply with the requirements. He reminded Council members to avoid a conflict of interest by leaving the room when the Council discussed individual applications in which an actual or perceived conflict of interest might occur. Members were asked to sign a statement to this effect. This did not apply to "en bloc" actions. Dr. Gorden announced that the Council meeting would be open to the public in accordance with the provisions of Public Law 92-463 on Wednesday, September 17, 1997, from 8:40 a.m. to 1:00 p.m., closed from 2:00 p.m. until 5:00 p.m., closed on Thursday, September 18, 1997, from 8:30 a.m. to 11:00 a.m. for review, Discussion, and evaluation of grant applications, and open from 11:00 a.m. to 12 Noon.

II. Consideration of the Summary Minutes of the Previous Meeting

The NDDK Advisory Council Summary Minutes of the last Council meeting were accepted unanimously by the Council members present.

III. Future Meeting Dates

Dr. Gorden asked for consideration of meeting dates for future NDDK Advisory Council meetings, and the following meeting dates were proposed and accepted:

• February 4-5, 1998
  
• May 27-28, 1998
  
• September 14-15, 1998
  
• February 17-18, 1999
  
• June 16-17, 1999
  
• September 8-9, 1999

Dr. Gorden began his report by paying tribute to the late Dr. Julio Santiago and mentioning some of his numerous contributions to the NIDDK, the NIH, and diabetes research.

He continued his report by describing the conference on "Diabetes Mellitus: Challenges and Opportunities" held September 4-5, 1997, and sponsored by NIDDK and eight other institutes as well as the Office of the Director, NIH.

Dr. Gorden then mentioned the appropriation bills pending in the Senate and the House that would give the NIDDK an increase in its Budget of about 7.0 to 7.5 percent above its FY 1997 Budget. He also described provisions in the Balanced Budget Act of 1997 that included several initiatives related to diabetes research and care. One provision will provide $30 million annually for 5 years for research on type 1 diabetes.

IV. Reports and Discussions

A. Budget Summary: FY 1997 and FY 1998 (See Attachment C)

Mr. Earl Laurence reported in more detail on the Budget for the coming year. He pointed out that during certain periods in the past, the NIH Budget did not keep up with inflation; but in FY 1998, the Congress was giving a real increase to the NIH, even when expressed in constant dollars. He discussed the impact of the Budget increase for each funding mechanism. He said that diabetes research programs stemming from the Balanced Budget Act of 1997 would carry dollars in addition to those in the regular appropriation.

Discussion

A Council member commented that the research training Budget did not increase and that Council members were concerned about attracting people to research.

A Council member pointed out that a part of the increase in funding for diabetes research grew out of the Diabetes Control and Complications Trial as well as the support of the diabetes advocacy groups.

B. Recent Activities Relating to Diabetes (See Attachment D)

Council member Dr. S. Robert Levine reported on the trans-NIH conference "Diabetes Mellitus: Challenges and Opportunities," held September 4-5, 1997, at the NIH. He described the background and purpose of the conference and compared the dollars spent for diabetes with those spent for AIDS research and related those figures to the lives lost to both diseases. He pointed out that both the conference and the additional funds for diabetes research came out of 2 years of efforts by the diabetes advocacy groups to adopt a national effort to increase the pace of diabetes research. He said that the focus of the conference was to foster an integrated approach to diabetes research, including identifying priorities, opportunities, and needed resources and establishing a method of greater accountability.

Discussion

Several Council members who attended the conference gave their impressions of the various presentations and Discussions and agreed that the meeting had been very successful.

A Council member pointed out that diabetic nephropathy was the leading cause of end-stage renal disease and that diabetic patients with end-stage renal disease accounted for the highest numbers of people on dialysis and recipients of transplanted kidneys. He pointed out that the translation of new treatment modalities from research to the general practitioner and the patient was not complete. Dr. Gorden pointed out that the National Diabetes Education Program, currently being developed by the NIDDK, would address this issue.

C. Update on the NIDDK Planning Process

Ms. Carol Feld reported on the NIDDK planning process. She described how the current planning process differed from that used in the past. She referred to the new funds coming to the Institute for diabetes and described how previous planning documents had been important in answering inquiries from the congressional staff members and in preparing Dr. Gorden's testimony before Congress. She described the current planning document and the importance of Council member's review of the document as a way of involving the Institute's constituencies in the planning process. She pointed out that planning was ongoing and that the focus should be on scientific goals and not on michanisms.

Discussion

A Council member asked about how the Division portfolios addressed the NIH emphasis areas of research. Dr. Gorden pointed out that the current planning document discussed the NIH emphasis areas as they related to the Institute's portfolio.

A Council member pointed out that investigator initiated research was the best way to develop innovative ideas and that creativity could not be legislated. He said that science was driven by creativity not by advocacy for a particular disease.

A Council member pointed out that legislation does affect creativity by establishing an environment in which creativity could thrive. He said that none of the advocacy group's efforts are detrimental to this effort.

D. NIDDK Career Development Award Program (See Attachment E)

Dr. Gorden introduced the topic of career development by pointing out that Discussions of the career program could not be separated from the broader concept of training, but he asked the Council members to focus on the Career Development Award Program for purposes of the present Discussion.

Dr. Stolz described the career development program as it has been implemented in the Institute. He pointed out that the program had two very separate objectives: (1) to provide support for mentored research experiences for physicians in the early stages of their research careers, and (2) to provide salary support to investigators who have achieved independence but who are not yet established in their fields. He said that the NIDDK focus has been on the first objective which was to give the physician scientists mentored support and that over 90 percent of the career development resources were given in this area.

To illustrate the effectiveness of the Clinical Investigator Award (K08) in preparing physicians for careers in research, he reported data on 48 physicians supported on K08s by the Division of Digestive Diseases and Nutrition between the late 1980s and 1996. Forty of the 48 awardees subsequently applied for research project grants. Of those applicants, 28 received NIH support. He said of 21 applicants for the K08 who were unsuccessful in obtaining an award, 11 subsequently applied for NIH support and five received it. He then reported data from all of the NIH. He said that of 920 applicants for K08-type awards in 1987-1989, 547 received awards and of these 357 subsequently applied for research awards, with 178 receiving awards. He said these numbers were an impressive showing for the success of the "K" awards.

Dr. Stolz described the available awards and their differences. He pointed out that in FY 1997, NIDDK would support about 200 "K" awards while 206 were supported in FY 1996, and that there had been a slight decrease in numbers of applications received in recent years.

Dr. Stolz said the questions to be considered by Council members were: (1) was the program effective? (2) should the program be retained? (3) should the number of awards be increased, decreased, or held about the same? He reported that about 40 physician-scientists completed their "K" awards each year, and he asked Council members to consider whether this number was sufficient. He asked them if the terms and conditions of the awards should be revised, and if there were more efficient ways to ensure a flow of clinically-trained people into science. He asked them to consider if there was a need for a Ph.D. career development program.

Discussion

Dr. Gorden pointed out that, in the past, NIDDK had tried to reserve as much funds as possible for research project grants. He said it was time to review the appropriate balance of funds across all mechanisms.

A Council member pointed out that few newly trained physicians applied for the career development awards and that young physicians needed to be attracted to research earlier in their career path before they had accumulated a lot of debt. This meant that they should be introduced to research before they became physicians since it was too late once they had committed themselves to a path that did not include research. He also suggested that the award amount was too small and the supply Budget should be increased during the last 2 years to give the awardees more independence.

Another Council member said that the numbers presented were not as positive as they should be because the applicants were highly selected and should make a better showing when applying for subsequent grants. He recommended increasing the value of the awards so that the very best potential candidates would be attracted to apply for the awards.

Another Council member pointed out that, to attract the best people, his department had to do "creative funding." He recommended increasing the amount of the award. He also pointed out that one problem with the award was that the awardees could not build up a portfolio of other grant support while on the award so they were at a disadvantage when the award ended. He recommended the award be made highly desirable to attract the best candidates and that it create an opportunity for these individuals to feel successful after completing one of these awards. He said that these were good awards, but that they were outdated.

A Council member pointed out that his institution would not hire physician-scientists unless they planned to spend 80 percent of their time on research. He said that as the award was now structured, when the award ended, his institution would hesitate to commit to hiring physician-scientists without assurance that they would be able to obtain research grants of their own in a year or two. This put pressure on the awardees, who then decided to do more clinical work, which was counter to the intent of the award. He pointed out that there are no funds left in the institutions to carry these people for long.

A Council member pointed out that the issues were different for the physician scientist and the Ph.D. He pointed out that Ph.D.s were stepping in because there was a scarcity of physician scientist researchers at the junior level, and he recommended reviewing NIDDK award data for divisions to see if there were any patterns that emerged.

Dr. Gorden described steps taken in the past to stabilize funding across the divisions, and he said that with more funds than applicants, the lid had been taken off funding constraints within the divisions.

A Council member pointed out changes that had occurred in academic institutions because of managed health care. He recommended that a program that could retire their debt might be a more sensible financial approach for attracting physicians to research than increasing the amount of the award.

A Council member pointed out that the nurturing of physician scientists might be an issue to be discussed with representatives of the managed care industry in the changing environment of health care.

A Council member said that the K08 was probably better than the R29 award. He said that at his institution, they tried to assess the potential of the individuals in their first year and not to wait until the third or fourth year. He said they recommended that their fellows apply for the K08 award after the first or second years. He said they used it to bring in people from other institutions, and it gave them a higher salary than the NRSA awards. He recommended increasing the award or restructuring it so the salary during the fourth and fifth years would be competitive for placement of the individual at the end of the award. He also recommended that an award similar to the K08 be developed for the Ph.D. He pointed out that many excellent people were taking positions in the biotechnology industry for lack of bridging positions.

A Council member recommended a similar award for Ph.D.s as many new faculty members were being lost from research because of the difficulty in obtaining tenure. He asked if the physicians receiving K08s were also enrolled in Ph.D. programs. Dr. Stolz said that of those in the K11 program, about one-fourth also received Ph.D. degrees; but now that the K11 was not a separate mechanism, he did not have statistics on how many K08s also received Ph.D.s.

A Council member commented that the numbers of surgeon physician scientists are very few today. He said that with emphasis on clinical productivity there had been immense changes in the past few years. He pointed out that funds previously available within departments to help support research were no longer available. He recommended flexibility in allowing the awardees to do research in a way that would be compatible with the demands of their departments.

A Council member recommended more creative ways for training physician scientists. He said that they needed both training and experience in fundamental research design, execution, and reporting, no matter what the content area. He recommended dual mentors, one in basic science and one in clinical science, to maximize the awardees' training experience. He also recommended an award similar to the K08 for the Ph.D.

A Council member pointed out that at his institution, those graduating with M.D./Ph.D. degrees had little debt because their education was paid for out of grant support. He said that in spite of being well trained in the basic sciences, recent M.D./Ph.D. graduates had elected to go into private practice and not to stay in research. He said that an issue that needed to be considered was the future replacement needs in the medical research community. He pointed out that in the 1960s, when he joined the faculty as an instructor, there were 16 people full-time in the Department of Medicine, and now there are 300. He said that these large numbers could not continue and that there would probably be some retrenchment since funds had dried up. He also recommended that two sponsors be assigned to each K08, one a clinical scientist and the other a basic scientist.

A Council member said that there were many bright young scientists being lost to the biomedical area. He said that when young Ph.D. students who came to the basic science departments in the medical school were asked why they came there, 99 percent responded that they wanted to do something that impacted on human health. At the end of their program, when asked where they wanted to go, all wanted to go someplace other than a medical center because they did not want to be second class citizens. He said that over the past 5 to 6 years this situation had changed somewhat. He said that he found it easier to demystify medicine for Ph.D. students than to train ex-medical residents in cutting edge aspects of science. He said that in his program Ph.D. students see patients, handle pathology, and are exposed to every major diagnostic and therapeutic facility in a modern hospital; and he said their ability to assimilate clinical information was extraordinary. He said that the outcome of this program resulted in about one-third of the Ph.D. students becoming tenure-track assistant professors in clinical departments in some of the best medical schools in the country. He recommended that there be a program such as the K08 so that Ph.D.s could become familiar with the diseases of interest to the NIDDK. He also recommended that Ph.D.s be pulled in while they were receiving their Ph.D. training so they would have a degree that could cross over into biomedicine.

V. Scientific Presentation: Advances to Prevent the Rejection of a Transplanted Organ

Council member Dr. David Harlan gave the scientific presentation on the status and results of research efforts to prevent the rejection of a transplanted organ without suppression of the entire immune system. His approach involved selective inhibition of T cell co-stimulation using the B7-specific fusion protein CTLA4-Ig. He pointed out that antibodies preventing the interaction between CD40 and its T cell-based ligand CD154 (CD40L) had been shown in rodents to act synergistically with CTLA4-Ig. He described some studies using this approach with kidney transplantation in tissue mismatched rhesus monkeys. He also presented some data from studies of transplanted pancreatic islets.

Discussion

Dr. Harlan was asked to elaborate on the application of this approach to diabetes. He said that the first clinical trials would be in patients with type 1 diabetes. They would receive transplanted islet cells and the therapy.

A Council member pointed out that if this treatment interrupted the primary autoimmune response against a person's own islet cells, then it would be potentially a primary prevention treatment as well.

Dr. Gorden pointed out that one of the collaborations Dr. Harlan had mentioned grew out of a NIDDK-JDF partnership and had been part of the original program developed with the JDF.

VI. Division Director's Reports

A. Division of Diabetes, Endocrinology, and Metabolic Diseases

Dr. Philip Smith gave the Division report by describing a conference on the "The Brain and the Adipocyte: Integrating of Diverse Signaling Pathways" that had been held September 14-16, 1997. He said that this conference had been organized in response to Dr. Varmus' request for topics that cut across the NIH emphasis areas. The conference was co-chaired by Drs. Mary Dallman, Barry Levin, and Bruce Spiegelman. Dr. Smith reported that there had been an explosion of new data related to the regulation of energy and body composition, but that these data came from many diverse research communities, some of which did not often talk to one another. As examples of the diversity of topics covered, he said cell biologists reported on differentiation of fat cells and delineation of their function; neuroscientists reported on neuro-lipid controls of energy balance and feeding behavior; and zoologists reported on hibernation. Also, he said clinicians presented their data on human subjects.

B. Division of Digestive Diseases and Nutrition

Dr. Hoofnagle began his report for the Division by describing a Request for Applications for research on helicobactor pylori and he said that 10-11 grants would be awarded from this announcement. In addition to those grants funded by the NIDDK, he said that NCI planned to fund two grants, NIAID planned to fund one or two grants, and the Office of Women’s Health planned to fund two grants. He said that the American Digestive Health Foundation would be contributing funds to the awards also.

He announced that the proceedings of the NIH Consensus Conference on the management of hepatitis C were published in the September issue of Hepatology. He announced that a conference had been held on AIDS and mucosal immunity, co-sponsored by the Division, and that the proceedings would be published in the Journal of Infectious Diseases. He expressed sadness that the Division was losing three of its Council members this year and described their many contributions to the Council and the Institute.

He then introduced Dr. Susan Yanovski to report on the newly identified relationship between the weight loss drug combination of fenfluramine and phentermine (fen-phen) and heart disease. Dr. Yanovski reported that on July 8, 1997, the New England Journal of Medicine lifted its embargo on an article describing 24 women who developed an unusual form of valvular heart disease while taking fen-phen. She said that the Mayo Clinic posted the article on its Internet home page, and on the same day, the FDA issued an advisory to physicians alerting them to these findings and advising caution in the use of these medications. The FDA also requested that physicians report additional cases to the FDA's MedWatch program. She said that over the next 2 months, individual case reports were submitted by physicians via MedWatch, and physicians at five sites provided data to the FDA regarding patients (primarily asymtomatic) who underwent echocardiography. Among the studied patients at these sites, a high prevalence (30 percent) of valvular heart disease was found, and included in these sites was a NIDDK/CDC sponsored pilot and feasibility study at Minnesota. She said that while these preliminary reports lacked a control group, the consistency of the data and the high prevalence of a potentially serious complication were sufficiently compelling that the FDA met with the makers of fenfluramine and dexfenfluramine and asked them to voluntarily recall these drugs, which they did on September 15, 1997. Dr. Yanovski said that ongoing studies were attempting to determine the prevalence of the valvular disease using unexposed weight and age-matched controls, as well as controls who had undergone weight loss without drugs. She said that studies would also attempt to determine the natural history of this particular type of valvular disease so public health recommendations for treatment and follow-up could be developed. She pointed out that the magnitude of the problem with these drugs was extensive because 10 million prescriptions were written last year for them. She described ongoing studies that were being done to assess the problem.

Discussion

A Council member asked why, if these drugs had been used for a number of years, was this problem showing up now.

Dr. Yanovski responded that the drugs originally were used as short-term treatment and that it only had been in the past 2 years that the drugs were used as long-term therapy. Also, she said most patients were asymtomatic, and that it was hoped that once the drugs were discontinued the damage would be reversed.

A Council member asked if there were common features among the patients affected. Dr. Yanovski said the studies would be looking at dosage, length of exposure to the drugs, concomitant drugs, and blood pressure.

A Council member pointed out that this was a public health emergency before it was recognized as such because of the way these drugs were used. He said that inappropriate use of medication was a cause of public health crises, and that the use of antibiotics was another example.

Council members were in agreement in saying they owed a vote of gratitude to Drs. Hubbard and Yanovski for moving on this problem so quickly.

Council members were interested in any studies on both weight loss drugs and prozac. Dr. Yanovski responded that there were none so far.

C. Division of Kidney, Urologic, and Hematologic Diseases

Dr. Briggs gave the report for the Division. She described a new initiative of the Division to elucidate the genome of the zebra fish, and she discussed why the zebra fish was a useful tool for learning about developmental and cellular biology.

Discussion

A Council member asked why the zebrafish were considered a good model. Dr. Briggs responded that they had transparent embryos, had a short development time, were easy to breed, and were easy to maintain.

Dr. Gorden said that the zebrafish project was part of a broader NIH interest, and the Institute would be taking a leadership role because there was relevance to many other programs in the Institute.

A Council member asked how the zebrafish project related to the mouse genome project and if the Institute was involved in the mouse project. Dr. Briggs responded that the two systems would be complementary because there were many experiments that could be done in the zebrafish that were too expensive or could not be done in the mouse model. She said that there were different levels of approach in which the less complex models would be used first and, if successful, then investigators would move on to more complex models.

D. Division of Extramural Activities

After a few announcements, Dr. Stolz invited the Council members to continue the Discussion on the Career Development Award that had begun the previous day.

Discussion

A Council member reported that the Kidney, Urologic, and Hematologic Diseases Division wished to make five recommendations:

1. The maximum salary of Career Development Awards should be raised from the current level of $50,000 per year to $75,000 per year. Also the academic institution should give 25 percent toward support of the awardee

2. Additional salary support could come from a variety of sources including Federal funds.

3. The supplies Budget during the last 3 years of the grant could be increased up to $30,000.

4. The "K" program should be expanded to include Ph.D.s.

5. The role of NIDDK in pre-doctoral training should be re-evaluated for expansion.

Dr. Briggs pointed out that it was important to develop mechanisms to provide continuity for a research career after the Career Development Award. She said requiring 25 percent support from the academic institution would identify other areas of support for the awardee and would gain commitment from the academic institution for the awardee.

A Council member pointed out that by enriching the award, a different pool of applicants might be attracted to apply for the award.

A Council member pointed out that there had been a consistent theme in the Council over the past year or two of encouraging new researchers to come into the fields supported by the NIDDK. He pointed out that it had started with modifying the R29 award and now the K08 award. He said that it should be a top priority of the NIDDK and the NIH to review novel ways of recruitment and training of new researchers in the medical sciences. He pointed out that recommendations had been made and discussed of utilizing the new clinical center at the NIH and the NIH intramural programs to develop new mentoring programs. He recommended designating a portion of the increased funds in the Institute's Budget for a special initiative related to the development of new researchers.

A Council member recommended that the whole subject of manpower should be reviewed. He pointed out that there were not enough good physician-scientists to apply for the K08 awards.

Dr. Hoofnagle said that the Digestive Diseases and Nutrition Division had always favored the K08 and considered it as essential to producing many of the stars in these fields. He pointed out that at this Council meeting, his division had 26 applications for the K08 award with 12 applications receiving good scores. He said that the great majority of the K08s in his division were in digestive diseases rather than nutrition, even though nutrition research accounted for about a third of the overall portfolio of research grants. He said that Council members in his division strongly endorsed strengthening the K08 award and recommended an award for the Ph.D. similar to the K08 award to bring basic researchers into the field and to help the nutrition program. He pointed out that the issues that had been raised should also include efforts aimed at high school and college students.

He said that Budgetary constraints would have to be taken into consideration as the Council members redesigned the K08, and that decisions would have to be made about the number of awards. He pointed out that if Council members decided upon 200 awards a year as sufficient, then a decision of limiting the awards to physicians or including Ph.D.s also, would need to be made. He said that these were options that would have to be considered including whether Council members wanted to divert additional funds to the K08 awards. Dr. Gorden said these issues would be discussed at the next meeting when the Budget implications for various scenarios would be available.

VII. Consideration of Review of Grant Applications

Summary Table 1

* Includes both DK primary and secondary
^ Minority Biomedical Support Program
This program is administered by the NIGMS but jointly funded by other ICDs.
Of these applications, 3 were received from institutions outside the U.S.A.
Council members made changes from the IRG recommendations in dollar amounts on 20 R29 applications and in years and/or dollar amounts on 9 applications.

Summary Table 2

Council members made changes from the IRG recommendations in dollar amounts on 20 R29 applications and in years and/or dollar amounts on 9 applications.

VIII. Adjournment

Dr. Gorden thanked the Council members for their attendance and advice. There being no other business, Dr. Gorden adjourned the 145th meeting of the NDDK Advisory Council on September 18, 1997, at 12:10 p.m.

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

Phillip Gorden, M.D.

Director, National Institute of Diabetes and Digestive and Kidney Diseases
and
Chairman, National Diabetes and Digestive and Kidney Diseases Advisory Council