- Emphasize basic research.
- Employ all available mechanisms of research support.
- Encourage inter-Institute and interagency collaborations.
- Increase the pool of investigators.
- Enhance communications and collaborations.
- Develop approaches to treatment and prevention.
- Attempt an organic growth of the plan.
The Plan encompasses 16 areas or clinical conditions of liver disease, with the rationale that the people to whom the Plan is directed, Congress and lay organizations, would understand clinical conditions more readily than scientific research terminology. The areas covered by the Plan are:
- Acute viral hepatitis
- Chronic hepatitis C
- Chronic hepatitis B and D
- Alcoholic liver disease
- Autoimmune liver disease
- Genetic liver disease
- Pediatric liver disease
- Drug- and toxicant-induced liver disease
- Parasitic liver disease
- Liver cancer
- Acute liver failure
- End stage liver disease and complications
- Liver transplantation
- Women's health and liver disease
- Minority health and liver disease
The NIDDK has developed various initiatives in liver disease that support the Strategic Plan and seeks to encourage research in areas underrepresented in liver disease. The areas supported by NIDDK include hepatitis C, nonalcoholic steatohepatitis, iron and hemochromatosis, hepatotoxicity, alternative medicine, gene therapy, pediatric liver disease, developmental biology, liver disease in minorities, and clinical trials and epidemiology.
Following Dr. Hoofnagle=s summary of the Plan, presentations were made, handouts were provided on initiatives and activities in liver disease research being conducted by various programs and other Institutes.
NIDDK Liver Program: Dr. Kresina, Director
The Liver Program is in the NIDDK Grants Program and is one of the five or six programs that support liver research. The other programs are the Centers Program, the Clinical Trials Program, Research and Training, and the SBIR Program. Dr. Kresina indicated that the grants that come in to the specific program are defined both by the depth of the basic and clinical research supported and by the research award mechanisms used. The Liver Program supports a broad area of both basic and clinical liver disease research and uses RO1, R29, RO3, R21, and program project award mechanisms. Overall, there has been a slight rise from FY89 to FY98 in dollars spent ($22.8 to $32 million) and grants awarded (126 to132). The Liver Program does not fund aspects of liver research that are part of other Institute programs, but does seek to interact with them at some level to complement research. Dr. Kresina summarized the kinds and numbers of grants used to fund research in the seven areas of liver disease supported by the Liver Program:
- Autoimmune liver disease: 7 RO1s/ 1 R29
- Genetic liver disease: 1 PO1/ 25 RO1s/ 3 R29s
- Pediatric liver disease: 7 RO1s/ 1 RO3
- Gallstones and bile acid: 1 PO1/ 21 RO1s/ 3 R29s
- Acute liver failure: 6 RO1s/ 1 R 29/ 2 RO3s
- End stage liver disease and complications: 11 RO1s
- Liver transplantation: 25 RO1s/ 3 R29s/ 2 RO3s
Dr. Kresina also said that research in the basic science liver disease is also supported by U series grants. The NIDDK has a U19 grant for a multicenter study using a SCID/Hu model of hepatitis C, and a UO1 grant for a liver transplant database to monitor post-transplantation outcome. With regard to program initiatives, three Program Announcements (PA's) recently expired. Six RO3 grants were funded from the PA-96-045 involving pediatric liver disease. Three RO1 grants and 3 RO3 grants were funded from the PA-96-079 involving ontogeny of the liver and biliary tree; funding for one other RO1 is pending. The third PA expiring in this fiscal year related to small grants in international research. Three Program Announcements are currently active. PA-97-053, cosponsored by NIAID entitled "Enteric and Hepatic Infectious Diseases", has generated many AI applications, including 12 DK applications, of which 7 are RO1s, 2 R29s and 3 RO3s. Two of the 7 RO1s have been funded. Two applications have been received for PA-98-086 requesting applications for research in liver disease related to women and /or minority populations and are currently under review. The PA-98-091 for AIDS pathogenesis has not yet received any applications. Dr. Kresina informed members that the RFA for hepatitis C that just concluded generated over 80 applications. This RFA is a multi-institute set aside for $5.2 million. It is anticipated that these applications will compete well and provide a large profile in the applications that they fund. A NASH meeting is planned for December 1998.
Dr. Kresina stated that NIDDK would like to find ways to encourage research in pediatric liver disease and the basic biology of the liver. Suggestions as to how to achieve these goals included bringing more new people into the field, finding ways to heighten interest in liver research, and increasing access to grant funds through a better understanding of the mechanism of grant review. It was noted that if the Principal Investigator (PI) does not request placement of a grant submission in a particular study section, CSR directs its placement. Assignment of Institute and study section is totally independent. It was also suggested that forums could be conducted that explain both how to write grant proposals and how to target and submit them to the desired study section. Another suggestion was to have meetings that would identify areas of need in liver research and stimulate interest in the field. The suggestion was also made that generating interest in liver research at the postdoctoral level rather than the PI level might arouse renewed interest in the field and attract a new group of young investigators.
NIDDK Liver Clinical Trials Program: Ms. Tralka, Director
Ms. Tralka presented a summary of liver initiatives in the Clinical Trials Program. Currently, there are 4 RO1s funding large, multi-center trials involving primary biliary hepatitis, autoimmune liver disease, end stage liver failure, prevention of esophageal varices, and pleural hypertension. Six RO3s fund small pilot studies for prevention of occurrence of hepatitis C after transplantation, prevention of occurrence of hepatitis B after transplantation, acute liver failure, autoimmune liver disease, and a hemochromatosis liver registry. Also supported is a new epidemiology program with trials involving modeling of survival after liver transplantation. Ms. Tralka said that the Clinical Trials Program is initiating a trial for a multicenter study of therapy of hepatitis C using interferon and that three Program Announcements have recently been published to initiate small planning grants. Currently there are no clinical trials or planning grants for autoimmune hepatitis, chronic hepatitis B and C, biliary atresia and neonatal hepatitis, gallstones, nonalcoholic steatohepatitis, Wilson=s disease, porphyria, alpha 1-antitrypsin, and progressive familiary intrahepatic cholestasis.
NIDDK Centers Program and Training in Liver Research: Dr. Podskalny, Director
Dr. Podskalny summarized the status of liver research funded by the Centers Program and Training Program. The number of career awards in liver research has increased, with 30 people either on career awards or individual fellowships. Of the 50 institutional training grants, 7 are in the area of liver research and include 20 liver-related K awards and 10 liver-related F32 awards for FY98. This makes a total of 60 people a year being trained in liver disease. Dr. Podskalny indicated that the existing training grants do not cover all of the 16 areas specified in the Plan. Four of the 12 Disease Centers currently fund liver disease research and these centers touch upon many of the 16 areas. Dr. Podskalny noted that it is still too early to know whether the new types of K awards (KO1s, K23s and K24s) will involve liver research.
NCI: Dr. Gomez, Program Director
Dr. Gomez provided a handout and reviewed the NCI research program areas that support liver research. NCI funds over $29 million in liver disease research, with most of the grants being funded by the RO1 mechanism. NCI has also begun an analysis of translational research, research that bridges the area between basic and clinical research. A SPOR program has been started with a focus on organ-specific cancers. Currently there are no SPORs for liver cancer, but this program has potential for expansion to liver disease research. Dr. Gomez also noted that the NCI has begun a shift to PO1s and other mechanisms of support.
NIAID: presented by Dr. Kresina
A NIAID handout was provided and reviewed by Dr. Kresina. Overall, NIAID has shown a 4.2% decrease, compared with FY97, for funding of liver related research. Currently there are two Program Announcements that relate to liver disease. PA-97-053 noted above, has funded four hepatitis C grants. PA-98-045 involves antiviral therapy; grants have come inin response to this PA and applications are coming up for review at the May Council. NIAID has an ICIDR Program that involves grants with an international aspect. The Tropical Disease Program RFA recompetition has expanded the scope of this program to include viral hepatitis. Five of the 57 applications are hepatitis related and will be reviewed in March 1999. FY1999 initiatives include an SBIR RFA99-001 for animal models of hepatitis C virus (HCV) infection. FY2000 planned initiatives include an RFA recompetition of hepatitis C research centers. It is anticipated that the number of research centers will increase. Dr. Kresina said that because NIAID plans initiatives two years in advance they are locked in to certain activities, making it difficult to interact with initiatives from other Institutes. Current NIAID contracts relating to liver disease are an RFP for a hepatitis animal model network and other small contracts related to specific antiviral clinical protocols. NIAID has various meetings planned that involve liver disease and is cofunding the alternative medicine meeting in September 1999.
OAR: Dr. Cargill, Director
Dr. Cargill presented data to show how HCV affects minorities. Data show that IV drug users have a dramatic increase in HCV infection and that coinfection with HIV is growing. She indicated that the conclusion could be drawn that hepatitis C and HIV are intersecting and the HCV epidemic is poorly controlled among users. Dr. Cargill also noted that the ramifications of liver dysfunction in the setting of HIV have enormous clinical significance. The role of HAART in dual disease is just becoming appreciated. Dr. Cargill said that while HIV response to HAART is efficacious, the complications of liver dysfunction create intolerance to this therapy and treatment of the liver disease itself remains unmanageable. In closing, Dr. Cargill suggested that the NIDDK and OAR would be logical partners, bringing unique expertise to the area of liver research, in determining the role hepatitis C plays in HIV infection and HIV transmission from mother to child.
NIDA: Dr. Khalsa
The Center for AIDS at NIDA is a merger of the NIDA Office of AIDS and NIDA's Drug Abuse Programs to form the Center on AIDS and Other Medical Consequences of Drug Abuse at NIDA. This office now has a larger budget and hopes to put more emphasis on hepatitis C research. The Center cosponsored an RFA on hepatitis C and nine of the applications are specifically related to drug abuse and hepatitis C. Dr. Khalsa said that various meetings recently sponsored by a new research program for metabolic, endocrine, and gastrointestinal disorders in drug abuser/HIV-infected subjects generated interest in liver disease and elicited new applications for liver research. It is hoped that there will be future collaboration with other Institutes that will result in more funding in the area of liver research. The concern was raised that there does not seem to be much interest in GI research and that mechanisms should be found that attract people to the field and encourage opportunities that enable researchers to apply results of their basic work to the clinical setting. Dr. Khalsa suggested that one means to encourage this kind of effort would be to provide supplemental money to NIDDK grantees, funding pilot studies to determine the feasibility of this kind of transition.
Following the individual presentations, advisory panel members were invited to focus attention on areas within liver research that need additional direction or support, and to identify what efforts are needed to generate specific initiatives to encourage research.
Dr. Arias, advisory panel member
Dr. Arias directed attention to four areas in which he saw a need for greater support:
1. Lack of manpower. The number of new young physicians is dwindling at a rapid rate, and within this declining number there is an even greater shortage of physicians interested in liver related research. He suggested that due to an assortment of reasons, including lack of funds, opportunities within the field are not being seen. Referring to Dr. Rosenberg=s presentation at the Shannon lecture, Dr. Arias said that if the application trend remains the same, there would be no first-time physician applications for NIH liver research by the year 2000. He felt that high priority should be given to stimulating areas of research that would attract those already in the field and to identifying topics of interest that would encourage those not in liver research to enter the field. Additionally, he emphasized the need for two other activities: gathering information that speaks to the losses in manpower and developing mechanisms that make this information available to outside groups so that the process to reverse this trend can begin.
2. Translational Research. Dr. Arias suggested that neither lack of knowledge nor lack of knowing what needs to be done are the real problems in the area of liver research, but the lack of coordination of this knowledge is a major deterrent. New initiatives should be developed that bridge the gap between basic research and treatment and bring the work being done by people in basic science to effective practice in the clinical setting.
3. Epidemiology of HCV infection. Dr. Arias speculated that because funding and oversight of liver research is spread among Institutes, it is not a number one priority for any one Institute. This lack of focus potentially contributes to the lack of understanding of the epidemiology of HCV infection. The question was raised whether NIDDK should play a larger role in directing these issues.
4. Pediatric liver disease and developmental biology of the liver. Dr. Arias stated that he was concerned that research in these areas of pediatric liver disease and developmental biology does not appear to be reflected in any RO1s. Dr. Perlmutter indicated that cholestasis research may be found in the genetic study section and that there are training grants in NICHD for pediatric liver research.
Dr. Gomez said that NCI is expanding the K awards and expects funding to increase in the area of general clinical oncology, but he did not think that this would cover training for any specific type of cancer. The NCI will also have a proposal next year for a new mechanism for translational training. Dr. Hoofnagle indicated that the shortage of physicians in liver research was thought to be due to a shortage of funds rather than lack of interest in the field. Initial attention was therefore given to increasing grant funding rather than to increasing training, but expansion of the K programs should begin to address the problem of lack of manpower.
Dr. Diehl, advisory panel member
Dr. Diehl suggested that a major problem in attracting new physicians/investigators to the field is the perceived burdensome lifestyle and lack of personal time. She speculated that a centers-type mechanism might offer the kind of environment that would be seen as conducive to research and supportive to the physician/scientist. To facilitate this kind of program, Dr. Diehl suggested that funding would be needed that would provide a strong infrastructure for the Center and ensure job security to the senior scientist. These goals might be achieved either by applications set up as multi-Institute collaborations focusing on disease-oriented scientific research or by grant proposals that cross Institutes to bring together people interested in a single topic. Dr. Hoofnagle suggested that liver cancer is one area that would benefit greatly from the kind of collaboration that would span applied and basic research and involve a wide variety of disciplines. A SPOR mechanism that might use colon technology to investigate liver or bile duct disease would also be useful.
Dr. Perlmutter, advisory panel member
Dr. Perlmutter identified the following areas in which he thought additional funding and focus are needed in liver research:
1. Increase research in the pathogenesis of biliary atresia and neonatal liver disease via clinical trials or some type of contract mechanism.
2. Increase research for developmental biology of liver and biliary tree via RFAs, or Program Announcements for RO1s pertaining to the study of stem cells, signal transduction pathways, or other pertinent molecular research. Dr. Diehl noted that two groups have recently published their studies of the pleuripotent hematopoietic stem cells and wondered whether efforts were being considered to engage these investigators in liver disease research.
3. Encourage research in the areas of cell transplantation and cell biology by developing animal models that mimic pediatric liver disease via RFA or RO1 mechanisms.
4. Stimulate the study of pathogenesis of metabolic liver disease by tapping into new technologies such as molecular and cellular biology, computer technology, and gene technology. Use this knowledge to study genetic and environmental modifiers of liver metabolism and provide models to use this information in a clinical setting. These efforts could be supported through program projects, multi-institutional research, and collaborations with biotechnology firms.
Open discussion revisited the issues of translational work and a centers-type research environment. Dr. Diehl suggested that a centers-type environment would foster interaction of diverse areas of expertise in the field as well as ensure continued participation by the senior people with the most clinical experience. It was noted that this kind of setting also provides an environment where bright people in the clinic could be enticed into research. Other comments focused on ways to take advantage of information and ideas generated at small meetings and conferences. Small meetings that bring together researchers interested in a specific field of study are very useful in generating ideas, but many researchers find that implementing the ideas proves rather difficult when they return to their separate areas. It was suggested that a mechanism should be developed that encourages clinical focus groups to interact with and disseminate information to the research lab. It is beyond the scope of the RO1 mechanisms to expand the scope of focus groups, but the U type mechanism could be used to develop such a program. Members were also informed that there are programs available for generating pilot data and role models for regional collaborations. The comment was also offered that to get new therapies and treatments for liver disease, money is needed that moves discoveries in applied research to effective treatments at the bedside.
Dr. Hoofnagle indicated that there are two exciting grants that may offer interest to the research lab. One is a grant that involves 13 groups collecting data on acute liver failure, and one is an RO3 grant for a hemochromatosis of transplantation registry program that monitors outcome of transplantation to view the issue of iron and iron loading.
In closing Dr. Hoofnagle thanked everyone for their input.