Full Text PA-97-107 PREVENTION OF RECURRENT DISEASE AFTER LIVER TRANSPLANTATION NIH GUIDE, Volume 26, Number 31, September 19, 1997 PA NUMBER: PA-97-107 P.T. Keywords: National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Alcohol Abuse and Alcoholism National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: December 9, 1997 Application Receipt Date: January 9, 1998 PURPOSE To encourage experienced and new investigators to submit small grants (R03s) to plan or research project grants (R01s) to conduct full- scale multicenter clinical trials on methods for preventing the recurrence of disease after liver transplantation. Of major relevance are studies on preventing the recurrence of alcoholic liver disease, and preventing the recurrence of hepatitis B and C virus infection after liver transplantation. Specific interventions should be compared. It is of interest to learn about the natural history of these diseases in patients undergoing standard therapy. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This program announcement (PA), Prevention of Recurrent Disease after Liver Transplantation, is related to the priority area of chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000 (Full Report: Stock No. 017-001-00474-0) or Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, D.C. 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. A component of the R01 can be foreign. Applications may be from a single institution or several institutions (collaborating institutions or consortia), if appropriate. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The support for this program announcement will be through the NIH research project grant (R01) and the small grant (R03) award. The R01 is a five year grant that may be renewable. The support for it is limited to $500,000 direct costs per year. The small grant research program (R03) provides limited funds (maximum of $50,000 direct costs per year) for a planning grant with a term up to two years. These grants are non-renewable, but continuation of projects developed under this program can be supported by the investigator- initiated research project grant (R01 funding mechanism). Applicants will be responsible for the planning, direction, and execution of the proposed project. A Data Coordinating Center should exist as a component of one of the clinical centers or as a separate subcontract. Applications submitted in response to this PA will compete for funds with all other R03 and regular research (R01 and R29) grant applications assigned to NIDDK, NIAAA and NIAID. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources, may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE The direct costs for the R03 grant should not exceed $50,000 in years 01 and 02, and the grant must be short term (not to exceed two years). The total award must not exceed $100,000 in direct costs. Indirect costs will be awarded based on the negotiated rate at the time of each award. The direct costs for an R01 should not exceed $500,000 for any year. Where subcontracts are used, the indirect costs related to the subcontracts will be excluded from the requested direct cost levels prior to the application of the cap. The initial award must not exceed five years, but a competing continuation application may be submitted in a future year. The award of grants in response to this PA is contingent upon the availability of funds. Awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement (rev. 4/94). RESEARCH OBJECTIVES Summary: This is a Program Announcement (PA) for investigator initiated research project grants (R01s) and small planning grants (R03s). These grants should focus on practical means of prevention of recurrence of primary disease after liver transplantation, a problem of growing proportions among recipients of liver grafts. At present, approximately 4000 liver transplants are done yearly in the United States, and 25 percent are done for end-stage alcoholic liver disease (ALD). ALD is believed to be the major cause of cirrhosis in the United States and the main indication for liver transplantation which is the only successful means of restoring health for the patient with end-stage ALD. At present, the relapse rate to drinking after transplantation for ALD is estimated to be 30 percent within three years. Alcohol consumption can lead to recurrence of alcoholic liver disease and can also cause major difficulties in clinical management. Information based on systematic follow-up is needed on the rate of relapse to consumption of alcohol and alcohol abuse after transplant. Also, more information is needed about factors that predict alcohol abuse after transplant. Methods for establishing long-term abstinence are critical for the optimal management of patients undergoing this life-saving procedure. Clinical trials are needed to determine whether state-of-the-art alcoholism treatment modalities are more effective in achieving this goal than standard procedures for encouraging abstinence usually employed in transplant programs. Chronic hepatitis C ranks only slightly below ALD as a cause of cirrhosis in the United States and as an indication for liver transplantation. While overall survival of patients with hepatitis C after transplantation is excellent, recurrence of infection occurs in virtually all patients who are viremic before transplant. At present there are no established means of preventing hepatitis C and no studies of potential preventive measures or therapies. The course of recurrent hepatitis C may be insidious and progresses slowly, so that ultimately a large number of patients with recurrent hepatitis C need re-transplantation. Chronic hepatitis B accounts for five to 10 percent of end-stage liver disease and a similar percentage of liver transplants done in the United States each year. Hepatitis B recurs in most patients who undergo liver transplantation unless active measures are taken to prevent recurrence. At present, two approaches include either high doses of hepatitis B immune globulin (HBIG) with and without preventive therapy with antiviral nucleoside analogues, such as lamivudine (3TC: Epivir) or famciclovir (Famvir). Both methods appear to be successful in preventing recurrence of hepatitis B in 70 percent to 90 percent of patients, but follow-up studies so far have been brief, and there have been no studies comparing these approaches or assessing various combinations of approaches to help achieve prevention in all cases. There also are questions related to the need for extended therapy and the development of resistance. Prevention of recurrence of hepatitis B is particularly important, as the recurrent disease is often severe and leads rapidly to destruction of the graft. Clinical trials form a solid base from which to explore and address important research questions related to HBV and HCV reinfection of the liver. Investigators are encouraged to begin to address these as ancillary components of proposed clinical trials. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and concerning the Inclusion of Minorities in Study Populations), that have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. "Suggestions for Preparing Research Project (R01), Investigator-initiated Clinical Trial Grant Applications" is available from the listed NIH contacts. LETTER OF INTENT Prospective applicants are asked to submit, by December 9, 1997, a letter of intent that includes a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; the identities of other key personnel and participating institutions; and the number and title of the PA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK Room 6AS-37F 45 CENTER DR MSC 6600 BETHESDA MD 20892-6600 Telephone: (301) 594-8886 FAX: (301) 480-3505 (optional) APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, or may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: asknih@odrockm1.nih.gov. The program announcement title and number must be typed on line two of the face page of the application form and the YES box must be marked. Mail the signed, original, single-sided application, along with five exact, single-sided copies and five collated sets of appendix materials to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At time of submission, two additional copies of the application must be sent to: Chief, Review Branch NIDDK, Division of Extramural Activities Room 6AS-37F 45 CENTER DR MSC 6600 BETHESDA MD 20892-6600 Applications must be received by 01/09/98. If an application is received after that date, it will be returned to the applicant without review. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. An appropriate peer review group convened in accordance with NIH peer review procedures will evaluate applications that are complete for scientific and technical merit. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria for regular research grant (R01) and small grant (R03) applications: (1) Significance Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? (6) Human Subjects Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human subjects, and the safety of the research environment. For the initial review of the overall clinical trial application, the review criteria will include: o The importance of the question(s) being asked and the need for and significance of the clinical trial, i.e., its potential impact. o The scientific and technical merit of the clinical aspects of the study. o The overall feasibility and the likelihood of achieving the clinical trial goals and the potential for a successful trial. o The pilot phase experience including evidence of patient accession and retention and the functioning of any laboratory coordinating center(s). o The adequacy of the statistical features of the study, including sample size projections and power estimates, methods of analysis, and the use of sequential analyses of data. o The logistical aspects of the project, including the accumulation, flow, and quality control of data; proper randomization and masking procedures, the operation of any central laboratories, and plans for defining access and restriction to data. o The availability of subjects suitable for the clinical trial and the likelihood of them participating and remaining in the study until the completion of follow-up. o The qualifications, experience, and availability of key investigators in the content area of the trial and in the conduct of clinical trials in general. o The adequacy of ethical and human safety issues, including current Institutional Review Board (IRB) human subjects approval(s). o An adequately documented working plan for the trial. o The likelihood of successfully administering a cohesive collaborative effort. o The appropriateness of the proposed budget. For the initial review of the individual institutions participating in a multicenter clinical trial, the review criteria will include: o The commitment of the institution and staff to a collaborative protocol and to the success of the study. The inclusion of letters of agreement from collaborating investigators, countersigned by the appropriate institutional official is necessary. o The qualifications and the experience of the investigators, and availability of subjects suitable for the trial and the likelihood of their participation. o The adequacy of the facilities, including technical resources and space. o The appropriateness of the local organization and administration. o The appropriateness of the budget. For the initial review of a data-coordinating center (DCC), the criteria also will include: O The DCC should be associated with one of the participating centers or a subcontract. o Applicable criteria for participating centers (budget, experience, facilities, etc.) o The adequacy of plans for monitoring the collection, management, and statistical analysis of the data. o Plans for periodic reports to a Data and Safety Monitoring Board and the Institute staff. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Alcohol Abuse and Alcoholism, and National Institute of Allergy and Infectious Diseases. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review. o Availability of funds. o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues related to the National Institute of Diabetes and Digestive and Kidney Diseases to: Tommie Sue Tralka Division of Digestive Diseases & Nutrition NIDDK 45 CENTER DR MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8879 FAX: (301) 480-8300 E-mail: tralkat@ep.niddk.nih.gov Direct inquiries regarding programmatic issues related to the National Institute on Alcohol Abuse and Alcoholism to: Richard Fuller, M.D. NIAAA Willco Bldg, Suite 505 6000 Executive Blvd Bethesda, MD 20892-7003 Telephone: (301) 443-1206 FAX: (301) 443-8744 E-mail: rfuller@niaaa.nih.gov Direct inquiries regarding programmatic issues related to the National Institute of Allergy and Infectious Diseases to: Leslye D. Johnson, Ph.D. NIAID Division of Microbiology and Infectious Diseases Enteric and Hepatic Diseases Branch Solar Bldg., Room 3A22 6003 Executive Blvd. Bethesda, MD 20892-7630 Telephone: (301) 496-7051 FAX: (301) 402-1456 E-mail: lj7m@nih.gov Direct inquiries regarding fiscal and administrative matters to: Sharon Bourque Division of Extramural Activities NIDDK 45 CENTER DR MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8846 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. Awards are under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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