Full Text PA-97-107
NIH GUIDE, Volume 26, Number 31, September 19, 1997
PA NUMBER:  PA-97-107


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
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.
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).
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.
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.
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).
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
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.
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.
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
The letter of intent is to be sent to:
Chief, Review Branch
Division of Extramural Activities, NIDDK
Room 6AS-37F
BETHESDA MD 20892-6600
Telephone:  (301) 594-8886
FAX:  (301) 480-3505 (optional)
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
Mail the signed, original, single-sided application, along with five
exact, single-sided copies and five collated sets of appendix
materials to:
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
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.
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
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
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.
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
o Quality of the proposed project as determined by peer review.
o Availability of funds.
o Program priority.
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
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.
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.
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
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8846
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
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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