ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION COHORT STUDY

Release Date:  July 9, 2001

RFA:  RFA-DK-02-010

Update: The following update relating to this announcement has been issued:

  December 12, 2008 - This RFA has been reissued as (RFA-DK-09-003).

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov/)

Letter of Intent Receipt Date:  October 16, 2001
Application Receipt Date:       November 28, 2001

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) invites cooperative agreement applications for clinical and 
coordinating centers to conduct a Living Donor Liver Transplantation 
(LDLT) Cohort Study among adults awaiting transplantation. The primary 
goal of this study will be to provide valuable information on the 
outcomes of LDLT. This information is needed to aid decisions made by 
physicians, patients, and potential donors.

Adult to adult LDLT is a relatively new procedure increasingly used at 
major transplantation centers. Too few cases are performed at any one 
center and approaches to the patient and donor are too diverse across 
centers to provide reliable and generalizable information on donor and 
recipient outcomes from individual centers.  The objective of this 
Request for Applications (RFA) is to establish and maintain the 
infrastructure required to accrue and follow sufficient numbers of 
patients being considered for and undergoing LDLT to provide 
generalizable data from adequately powered studies.  Up to 8 
Transplantation Centers (TCs) and a Data Coordinating Center (DCC) will 
be necessary to meet this objective.  

This is a one-time solicitation to support a Clinical Research 
Consortium for 7 years.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a 
PHS-led national activity for setting priority areas.  Potential 
applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and nonprofit 
organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and 
eligible agencies of the Federal government.  Foreign applications will 
not be accepted.  Racial/ethnic minority individuals, women, and 
persons with disabilities are encouraged to apply as principal 
investigators.

All current policies and requirements that govern the research grant 
programs of the National Institutes of Health (NIH) will apply to 
cooperative agreements awarded under this RFA.  Among the disciplines 
and expertise that may be appropriate for this program are hepatology, 
transplantation, ethics, epidemiology, radiology, pharmacology, 
clinical psychology, psychiatry, and clinical database management. 

A DCC will be a part of the LDLT Cohort Study.  In order to ensure that 
data analysis is done independently of data acquisition, the DCC cannot 
have the same Principal Investigator as a TC. Within the study 
consortium an institution may apply for both a TC and the DCC, but each 
must have separate principal investigators and submit a separate 
application with a specific plan of how the independent operation of 
each unit of the TC and DCC will be maintained.

Only TCs that are currently conducting adult to adult LDLT may apply.  
To be eligible, a TC must have performed a minimum of 10 adult to adult 
LDLT during the 18 months prior to October 16, 2002. 

MECHANISM OF SUPPORT

This RFA will use the NIH cooperative clinical research (U01) award 
mechanism of support, an  assistance  mechanism (rather than as 
 acquisition  mechanism) in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and stimulate the recipients  activity by 
involvement in the activity and otherwise working jointly with the 
award recipients in a partner role, but it is not to assume direction, 
prime responsibility, or a dominant role in the activity.  Details of 
the responsibilities, relationships and governance of the study to be 
funded under cooperative agreements are discussed below under Terms and 
Conditions of Award.

The total project period for an application submitted in response to 
this RFA may not exceed 7 years.

Applicants from institutions which 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.   In such a case, a letter of agreement from either the GCRC 
program director or principal investigator should be included with the 
application.  

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is 7/01/02.

FUNDS AVAILABLE

The NIDDK intends to commit approximately $2 million in FY 2002 in 
total costs (Direct plus Facilities and Administrative (F & A) costs) 
to fund as many as 8 TCs and 1 DCC in response to this RFA. A TC 
applicant may request a project period of up to 7 years and a budget 
for total costs (direct plus F & A) of up to $160,000 per year.  A DCC 
applicant may request a project period of up to 7 years and a budget 
for total costs (direct plus F & A) of up to $750,000 per year.  
Because the nature and scope of the research proposed may vary, it is 
anticipated that the size of each award will also vary. Although the 
financial plans of the NIDDK provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of applications of outstanding 
scientific and technical merit.  At this time, it is not known if this 
RFA will be reissued.

RESEARCH OBJECTIVES

A. Background

Over the last 20 years liver transplantation has become the standard of 
care and the only cure for end stage liver disease.  Its success has 
led to over 4,000 transplants performed yearly.  But there are at least 
17,000 patients on the transplantation list awaiting cadaveric liver 
donation.  As the waiting list has expanded, waiting time has also 
grown.  As a result, patient mortality has increased while awaiting 
transplantation and patients are often critically ill by the time of 
transplantation.  Among possible remedies, living donor transplantation 
has become widely accepted for pediatric transplantation.  Adult-to-
adult LDLT is a more challenging procedure and of potentially greater 
risk to the donor because of the larger portion of liver that is 
required.  Right lobe adult-to-adult LDLT is a recently developed 
procedure, but several hundred have already been performed in the 
United States.  Although still a small number relative to the several 
thousand adult cadaveric liver transplants performed annually, LDLT has 
the potential for changing the face of liver transplantation.  Not only 
does LDLT avoid the lengthening waiting period for a cadaveric 
transplant, it greatly reduces the ischemic period of the transplanted 
organ, allows more time for evaluation of the donor, and changes the 
operation from an emergency into a scheduled procedure.  In the special 
situation of hepatocellular carcinoma (HCC), early LDLT might improve 
survival among patients whose better liver function gives them a lower 
priority for cadaveric liver under current criteria.  The major 
disadvantage of LDLT is that it is a difficult and potentially fatal 
operation for the donor.  It also provides the recipient with a smaller 
portion of liver than would have been received with cadaveric 
transplantation.  

Although many questions remain about LDLT, the pressure of the waiting 
list has drawn many centers to consider implementing it.  As was noted 
at a November 2000 NIH workshop on adult LDLT, more than 20 centers in 
the United States are currently performing the procedure and at least 
as many are considering beginning it in the next year.  As LDLT becomes 
more frequently used, a number of research issues need to be addressed 
through a prospective, multi-center, cooperative effort among centers 
performing the procedure.  

B. Research Scope

The goal of this RFA is to select a Data Coordinating Center (DCC) and 
as many as eight Transplantation Centers (TC) to participate in 
planning and implementing a multi-center cohort study on adult living 
donor liver transplantation.

The research objectives of the LDLT Cohort Study concern factors that 
influence the outcomes of adult to adult LDLT.  Recruited into this 
longitudinal cohort study would be adult patients and potential donors 
being considered for LDLT.  Recipients and their donors would be 
followed for sufficient time to determine outcomes related to LDLT.  
These outcomes will be compared with those of appropriate comparison 
groups.  One such comparison group might be transplant candidates who 
are evaluated for but do not receive LDLT.  Another group might be 
patients not evaluated for LDLT, but who have the same diagnosis, 
severity of illness and other clinically significant features as 
patients who undergo LDLT.  Regardless of the specific criteria for 
selecting a comparison group, the primary objective concerns comparison 
of morbidity and mortality of patients who receive LDLT with a group or 
groups of patients with similar illnesses and prognosis.  A critical 
question to answer with this information is how do the outcomes of LDLT 
compare with those of cadaveric transplantation. Transplant physicians 
need this information on outcomes to advise patients and prospective 
donors.  Therefore, sufficient patient and donor pairs will be 
recruited to determine whether recipients of LDLT have substantially 
different survival than non-LDLT recipients.  A large number of donors 
and recipients from several geographically distributed institutions 
will be necessary to reliably determine if outcomes are different with 
the two approaches.  

Among other questions that could be addressed in the LDLT Cohort Study 
would be the following: What are the immediate as well as long-term 
risks for the donor?  Is long-term liver function preserved for the 
donor? What is the effect of donation on the donor’s quality of life? 
What are the financial and psycho-social effects on the donor? What is 
the minimal size of the donor organ?  How does the amount of fat in a 
donor liver affect outcomes?  What are the optimal operative 
procedures?  Can biliary tract and other surgical complications be 
minimized among donors and recipients?  Do costs differ substantially 
for LDLT and cadaveric transplantation?  Do donor factors such as age, 
sex, and whether the donor is a first degree relative affect recipient 
outcomes and the need for immunosuppression? Can accurate markers of 
hepatic regeneration be identified? Is disease recurrence affected by 
LDLT?  What is the impact of LDLT on a center’s waiting time? What is 
the optimal pre-operative preparation to prevent disease recurrence, 
rejection, and other morbidity?

These study questions are examples only.  Applicants should not feel 
limited to the subjects mentioned above and are encouraged to submit 
other topics pertinent to the objectives of the RFA.  Applicants may 
also suggest and justify other study designs.  

At least 250 adult to adult LDLT recipients and at least as many 
candidates who do not receive LDLT will need to be recruited 
prospectively and followed to determine if there are appreciable 
differences in mortality and graft loss between the two groups.  The 
ability to recruit all or nearly all of a TC’s LDLTs is important in 
order to meet the required study size and to ensure unbiased results.  
Participating centers would also be expected to pool outcome data on 
patients that have already undergone LDLT to provide preliminary 
information on the study’s major questions.

All projects must be completed within 7 years (84 months).

STUDY ORGANIZATION 

The LDLT Cohort Study will be a cooperative consortium of up to eight 
TCs and one DCC.  TCs will be responsible for proposing data to be 
collected for the database and protocols, participating in their 
overall development, patient recruitment, evaluation, and treatment, 
conducting the research, and disseminating research findings. All 
individual TCs will be required to participate in a cooperative and 
interactive manner with one another and with the DCC in all aspects of 
the LDLT Cohort Study.  The DCC will support development of a database 
of clinical information, serum and tissue samples, and protocols, 
provide sample size calculations, statistical advice, questionnaires, 
and data analysis, support manuscript preparation, and provide overall 
study coordination and quality assurance, including coordination of the 
activities of the Data and Safety Monitoring Board (if needed), the 
Steering Committee and other standing committees.  Applicants for the 
DCC should also propose a Specimen Core (serum and tissue) facility for 
central storage of specimens.  This specimen core will not be awarded 
until the Steering Committee has met and approved its structure and 
duties.

A.  Study Governance

A Steering Committee will be the main governing body of the LDLT Cohort 
Study. At a minimum, the Steering Committee will be composed of the 
principal investigators of each TC in the Consortium, the principal 
investigator of the DCC and the NIDDK Project Scientist.  The first 
meeting of the Steering Committee will be convened by the NIDDK Project 
Scientist with assistance from the DCC.  The logistics and agenda of 
subsequent meetings will be determined by the Steering Committee and 
arranged by the DCC.  By the end of the second meeting of the 
Committee, the NIDDK will name a study Chairperson from one of the TCs 
to oversee and guide Steering Committee activities.  The Steering 
Committee will meet three to six times during the first 12 months of 
the study, and two to four times per year thereafter.  All major 
scientific decisions will be determined by a majority vote of the 
Steering Committee.  Each TC, the DCC, and the NIDDK Project Scientist 
will have one vote.  The Steering Committee will have primary 
responsibility for the general organization of the study, finalizing 
common clinical protocols, facilitating the development of a 
standardized nomenclature, diagnostic criteria, histological 
definitions, and necessary components to the common database on 
patients.  The Steering Committee will be responsible for the conduct 
and monitoring of studies and reporting study results.  Protocol topics 
will be proposed and prioritized by the Steering Committee.

For each protocol, one TC will take the lead responsibility for 
drafting the protocol, although the Steering Committee will provide 
input and will be responsible for assuring development of a common 
protocol to be implemented by the TCs.  

Subcommittees of the Steering Committee will be established as 
necessary.  For example, a Publications Committee would be helpful to 
facilitate the process for authorship selection and to supervise 
preparation of manuscripts.
 
If experimental protocols are implemented, an independent Data and 
Safety Monitoring Board will be established by the NIDDK to review 
protocols and monitor patient safety and performance of the resulting 
studies.  As a part of its responsibilities, the Data and Safety 
Monitoring Board will submit recommendations to the NIDDK regarding the 
continuation of each study. 

Each investigational or therapeutic protocol will be implemented in a 
minimum of two and optimally in all of the TCs, depending on the number 
of patients and investigational expertise needed for the study.  As 
specific protocols are developed, support will depend on the 
availability of funds and will be provided on a per patient basis.  All 
the TCs must be willing to pursue this funding arrangement for each new 
protocol conducted.
 
Clinical protocols must be approved by local institutional review 
boards and, as appropriate, the LDLT Cohort Study Data and Safety 
Monitoring Board before initiation.  The exact number of protocols 
supported in the seven-year program will depend on the nature and 
extent of the investigations proposed by the Steering Committee.  A 
database will be developed to support epidemiological studies and other 
clinical studies.  Planning may be done for large clinical trials that 
would be submitted as separate R01s if further funding is necessary.  
The LDLT Cohort Study investigators are also encouraged to seek out 
separate funding for special projects and to develop collaboration with 
laboratory and basic research investigators to draw upon the resources 
(clinical data, serum, tissue, DNA) made available by the LDLT Cohort 
Study.  Any specific collaboration involving the resources of the LDLT 
Cohort Study will require approval by the Steering Committee.

B. Study Phases

During the first 9 months, investigators will develop the protocol with 
IRB and other approvals obtained by the end of the first year (Phase 
1). Recruitment of donor-recipient pairs and controls will take place 
between approximately 1 year to 4 years (Phase 2) with patient follow-
up for an additional 2 years (Phase 3).  Lengthy follow-up is needed to 
compare outcomes with recipients who receive cadaveric liver 
transplantation, which may occur long after initial evaluation.  Study 
analysis and close out would occur during the final year (Phase 4).  
All projects must be completed within the seven-year duration of this 
research program.

Parallel to the development of the protocol will be development of a 
study of outcomes of patients who had previously undergone LDLT at the 
TCs.  Initial data compilation on these patients would be expected 
within 18 months of the beginning of the study with analysis to follow 
over the following 2 years.

SPECIAL REQUIREMENTS

A. Participation in a Collaborative Program

To promote the development of a collaborative program among the 
awardees, the applicant should present evidence of experience in 
working cooperatively with other Clinical and Data Coordinating Centers 
and of ability to follow common protocols that are collaboratively 
developed.  

1.  TCs will be expected to communicate with the DCC and the NIDDK 
Project Scientist on a regular basis.

All TCs in the LDLT cohort study must agree to implement the protocols 
and manual of operations that will be developed cooperatively during 
planning stage and agree to electronically transmit all study data in a 
timely fashion to the DCC for combination and analysis.  An explicit 
statement of willingness to participate in a collaborative program 
should be included in the application.

2.  The DCC will be involved in collaborations with NIDDK and the TCs 
during all phases of the trial.  Thus, the applicant is expected to 
demonstrate experience in working cooperatively with Clinical Centers 
and sponsoring organizations in multicenter clinical studies and in 
overseeing the implementation of and adherence to a common protocol, as 
well as assuring quality control of the data collected.  In addition to 
organizing and attending regular meetings, the DCC will be expected to 
maintain close communications with the NIDDK Project Scientist and the 
Principal Investigators of the TCs.

B.Terms and Conditions of Award

The administrative and funding instrument used for this program is a 
cooperative agreement (U01), an "assistance" mechanism (rather than an 
"acquisition" mechanism) in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient"s activity by 
involvement in and otherwise working jointly with the award recipient 
in a partner role, but it is not to assume direction, prime 
responsibility, or a dominant role in the activity.  Consistent with 
this concept, the dominant role and prime responsibility for the 
activity resides with the awardee(s) for the project as a whole, 
although specific tasks and activities in carrying out the studies will 
be shared among the awardees and the NIDDK Project Scientists.

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator(s) as well as the 
institutional official at the time of award. These special Terms of 
Award are in addition to and not in lieu of otherwise applicable OMB 
administrative guidelines, HHS Grant Administration Regulations at 45 
CFR Parts 74 and 92, the NIH Grant Policy statement.

1. Awardee Rights and Responsibilities

o The awardees will have lead responsibilities in all aspects of their 
protocols, including any modification of study design, conduct of the 
study, quality control, data analysis and interpretation, preparation 
of publications, and collaboration with other investigators, unless 
otherwise provided for in these terms or by action of the Steering 
Committee.  Modifications and ancillary protocols will be approved by 
the Steering Committee and, if necessary, by the Data and Safety 
Monitoring Board.

o Awardees will retain custody of and have primary rights to their data 
developed under these awards, subject to Government rights of access 
consistent with current HHS, PHS, and NIH policies.  The collaborative 
protocol and governance policies will call for the continued submission 
of data centrally to the DCC for a collaborative database, the 
submission of copies of the collaborative data sets to each principal 
investigator upon completion of the study, procedures for data 
analysis, reporting and publication, and procedures to protect and 
ensure the privacy of medical and genetic data (if any) and records of 
individuals.  The NIDDK Project Scientist, on behalf of the NIDDK, will 
have the same access, privileges and responsibilities regarding the 
collaborative data as the other members of the Steering Committee.

o The DCC will be involved in collaborations with the NIDDK and the TCs 
during all phases of the trial and will maintain the Specimen Core 
facility.  Thus, the awardee is expected to work cooperatively with 
Clinical Centers and sponsoring organizations in a multicenter trial 
and oversee the implementation of and adherence to a common protocol, 
as well as assure quality control of the data collected and storage of 
collected tissue specimens.  In addition to organizing and attending 
regular meetings, the DCC will be expected to maintain close 
communications with the NIDDK Project Scientist and the Principal 
Investigators of the TCs.
 
o Awardees are encouraged to publish and to publicly release and 
disseminate results, data and other products of the study, concordant 
with the study protocol and governance and the approved plan for making 
data and materials available to the scientific community and the NIDDK.  
However, during or within three years beyond the end date of the 
project period of NIDDK support, unpublished data, unpublished results, 
data sets not previously released, or other study materials or products 
are to be made available to any third party only with the approval of 
the Steering Committee.

o Support or other involvement of industry or any other third party in 
any study performed by the Consortium-- e.g., participation by the 
third party, involvement of project resources or citing the name of the 
project or the NIDDK support, or special access to project results, 
data, findings or resources -- may be advantageous and appropriate.  
However, except for licensing of patents or copyrights, support or 
involvement of any third party will occur only following notification 
to, and concurrence by, NIDDK.

o Upon completion of the project, the DCC is expected to put all study 
intervention materials and procedure manuals into the public domain 
and/or make them available to other investigators, according to the 
approved plan for making data and materials available to the scientific 
community and the NIDDK, for the conduct of research at no charge other 
than the costs of reproduction and distribution.

2. NIDDK Staff Responsibilities

The NIDDK will name a Project Scientist from within the Division of 
Digestive Diseases and Nutrition whose function will be to assist the 
Steering Committee in carrying out the study.  The Project Scientist 
will have one vote for all key study group subcommittees.  The Project 
Scientist will have substantial scientific-programmatic involvement in 
quality control, interim data analysis, safety monitoring, and final 
data analysis and interpretation, preparation of publications, and 
coordination and performance monitoring.  The dominant role and prime 
responsibility for these activities resides with the awardees for the 
project as a whole, although specific tasks and activities in carrying 
out the studies will be shared among the awardees and the NIDDK Project 
Scientist.

The NIDDK reserves the right to terminate or curtail the study (or an 
individual award) in the event of (a) failure to develop or implement a 
mutually agreeable collaborative protocol, (b) substantial shortfall in 
participant recruitment, follow-up, data reporting, quality control, or 
other major breach of the protocol, (c) substantive changes in the 
agreed-upon protocol with which NIDDK cannot concur, (d) reaching a 
major study endpoint substantially before schedule with persuasive 
statistical significance, or (e) human subject ethical issues that may 
dictate a premature termination.

3.  Collaborative Responsibilities

The Steering Committee, composed of each of the Principal Investigators 
of the DCC and the TCs, and the NIDDK Project Scientist, will be the 
main governing board of the studies.  This committee will have the 
primary responsibility for approval of the common protocols, 
facilitating the conduct of participant follow-up, monitoring 
completeness of data collection and timely transmission of data to the 
DCC, and reporting the study results.  It will also be responsible for 
establishing study policies in such areas as access to patient data, 
study protocols, publications and presentations, and performance 
standards.  Each member of the Steering Committee will have one vote 
and all major scientific decisions will be determined by a majority 
vote of the Steering Committee.  A Chairperson will be chosen from 
among the Steering Committee members (but not the NIDDK Project 
Scientist or Data Coordinating Center Principal Investigator).  
Subcommittees will be established on topics such as ancillary studies, 
publications and presentations, quality control, recruitment, protocol 
adherence, among others.  

Each TC Awardee and the DCC Awardee agree to the governance of the 
study through the Steering Committee.  The Steering Committee voting 
membership shall consist of the Principal Investigators of the TCs and 
the DCC, and the NIDDK Project Scientist.  Meetings of the Steering 
Committee will ordinarily be held by telephone conference calls or in 
the Washington DC Metropolitan Area. 

The NIDDK Project Scientist (and other cited NIDDK scientists) may work 
with awardees on issues coming before the Steering Committee and, as 
appropriate, other committees, e.g., issues of recruitment, 
intervention, follow-up, quality control, standards and methods, 
adherence to protocol, assessment of problems affecting the study and 
potential changes in the protocol, interim data and safety monitoring, 
final data analysis and interpretation, preparation of publications, 
and development of solutions to major problems such as insufficient 
participant enrollment.  Regardless of the number of NIH staff 
participating in technical advisory roles, the NIDDK will be limited to 
one vote on the Steering Committee.

4. Arbitration

Any disagreement that may arise in scientific/programmatic matters 
(within the scope of the award), between award recipients and the NIDDK 
may be brought to arbitration.  An arbitration panel will be composed 
of three members one selected by the Steering Committee (with the NIDDK 
member not voting) or by the individual awardee in the event of an 
individual disagreement, a second member selected by NIDDK, and the 
third member selected by the two prior members.  This special 
arbitration procedure in no way affects the awardee"s right to appeal 
an adverse action that is otherwise appealable in accordance with the 
PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 
CFR part 16, or the rights of NIDDK under applicable statutes, 
regulations and terms of the award.

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 sub-populations must be included in all NIH-supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research.  This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 
103-43). 

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable, and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS.

It is the policy of NIH that children (i.e., individuals under the age 
of 21) must be included in all human subjects research, conducted or 
supported by the NIH, unless there are scientific and ethical reasons 
not to include them.  This policy applies to all initial (Type 1) 
applications submitted for receipt dates after October 1, 1998.  

All investigators proposing research involving human subjects should 
read the  NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects  that was published 
in the NIH Guide for Grants and Contracts, March 6, 1998, and is 
available at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

The LDLT cohort study is limited to adult donors and patients.  The 
NIDDK has determined that the adult to adult LDLT Cohort Study does not 
require inclusion of children for the following reasons: Adult to child 
LDLT is a well established procedure, the risks are substantially less 
for the donor and the recipient, and the surgical procedures are quite 
different.  For example, the right lobe of the liver is typically 
transplanted to adults and the left lobe to children. A number of the 
research questions of importance to the proposed study have either been 
addressed in children or are not as pressing in children as in adults.  

Investigators may also obtain copies of these policies from the program 
staff listed under INQUIRIES.  Program staff may also provide 
additional relevant information concerning the policy.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained 
within specified page limitations. Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no 
obligation to view the Internet sites. Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

DATA AND SAFETY MONITORING IN CLINICAL TRIALS

Applicants are directed to the full text of the NIH Policies regarding 
Data and Safety Monitoring and Reporting of Adverse Events that are 
found in the NIH Guide for Grants and Contracts Announcements at the 
following web sites:  
http://grants.nih.gov/grants/guide/notice-files/not98-084.html, 
http://grants.nih.gov/grants/guide/notice-files/not99-107.html, 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html

All applicants receiving an award under this RFA must comply with the 
NIH policy cited in these NIH Announcements and any other data safety 
and monitoring requirements found elsewhere in this RFA.

The following is a brief summary of the Data and Safety Monitoring and 
Adverse Event Reporting Requirements:

Data and Safety Monitoring is required for every clinical trial.  
Monitoring must be performed on a regular basis and the conclusions of 
the monitoring reported to the extramural Program Director.

If the LDLT cohort study includes experimental protocols or clinical 
trials, the DSM plan will be established at the time the protocol is 
developed and must be approved by both the Institutional Review Board 
(IRB) and the NIH and be in place before the protocol/trial begins.  If 
the protocol will be developed during the research funded under this 
RFA, a general description of the data and safety monitoring plan must 
be submitted as part of the proposal and will be reviewed by the 
initial review group.  If the protocol has been developed and is 
included as part of the submitted proposal, the complete and specific 
data and safety monitoring plan must be submitted as part of the 
proposal.

Monitoring plans, at a minimum, must include the prompt reporting of 
adverse events to the IRB, Food and Drug Administration and the NIH.  
The frequency of reporting of the conclusions of the monitoring 
activities should also be described in the plan.  The overall elements 
of each plan may vary depending on the size and complexity of the 
trial.  Examples of monitoring activities to be considered are 
described in the NIH Policy for Data and Safety Monitoring at 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  This policy announcement is found 
in the NIH Guide for Grants and Contracts Announcement dated June 5, 
2000, at the following website:  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at:  
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

LETTER OF INTENT 

Prospective applicants are asked to submit, by 10/16/2001, 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 RFA 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 plan the review.

The letter of intent is to be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch 
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

A.  Submission Instructions

The research grant application form PHS 398 is to be used in applying 
for these grants.  These forms are available at most institutional 
offices of sponsored research and may be obtained from the Division of 
Extramural Outreach and Information Resources, National Institutes of 
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, 
telephone 301-710-0267, email: GrantsInfo@nih.gov.

The RFA label available in the PHS 398 application form must be affixed 
to the bottom of the face page of the application and must display the 
RFA number.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review 
committee in time for review.  In addition, the RFA title and number 
must be typed on line 2 of the face page of the application form and 
the YES box must be marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change. Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed photocopies, in one package to:

Center for Scientific Review
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:

Francisco Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)

Applications must be received by the application receipt date listed in 
the heading of the RFA.  If an application is received after that date, 
it will be returned to the applicant without review. Supplemental 
documents containing significant revision or additions will not be 
accepted, unless applicants are notified by the Scientific Review 
Administrator.  

The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude 
the submission of substantial revisions of applications previously 
reviewed, but such applications must include an introduction addressing 
the previous critique.

B.  Application Requirements

1.  Transplantation Center and Data Coordinating Center Applications

Applicants must describe plans to accommodate the stated program 
requirements, criteria, and staff involvement.  Applicants must 
describe plans to achieve the RESEARCH OBJECTIVES and SPECIAL 
REQUIREMENTS stated in this RFA.  In addition, applicants should 
address the following issues that are important to the successful 
development of a collaborative program:  willingness to participate on 
the Steering Committee and appropriate subcommittees, to work 
cooperatively with other members of the Steering Committee, and to 
follow the common protocols established cooperatively by the Steering 
Committee.  

The research plan should follow the instructions in the PHS 398 
application form (http://grants.nih.gov/grants/funding/phs398/phs398.html).  
Applications may not exceed 25 pages for sections a - d, excluding 
appendices, which may contain copies of pertinent forms or examples of 
correspondence useful for required tasks.

2.  Transplantation Center Applications 

(a) Core Study

To meet the objectives of the study, each TC applicant should propose a 
research plan that includes the structure of a database and an 
information core that they believe should be collected on all 
participants that are prospectively enrolled: potential and actual 
donors, LDLT patients and non-LDLT control patients.  Justification for 
core data elements should be provided.  Core elements for the separate 
retrospective data collection should also be provided and discussed.  
Comparison of the proposed amount and quality of information gathered 
retrospectively and prospectively would be appropriate.  Discussion of 
the pros and cons of various non-LDLT comparison groups should be 
provided.  

Applicants must document that they have performed at least 10 adult to 
adult LDLTs within 18 months prior to October 16, 2001.  Applicants 
should provide a projection of the number of adult patients expected to 
receive either cadaveric or living donor transplants in the first year 
of the study.  Assurance of institutional support will be critical.  TC 
applicants should provide evidence of their success in recruitment and 
retention of liver transplant patients into research protocols.

(b) Clinical Research Protocols 

Each TC applicant should also propose two clinical research protocols 
as models that could be used within the suggested recruitment 
guidelines.  Within the 25 page application limit, a guideline for the 
clinical research protocols is two pages for each.  The protocols 
should demonstrate knowledge of the diseases and experience in treating 
and following patients undergoing living donor and cadaveric liver 
transplantation.  Each protocol should require sufficient subjects to 
necessitate the use of a consortium with multi-center participation.  
Applicants should indicate knowledge of the number of patients required 
for each study based on sample size calculations.  At least one 
protocol must focus on improvement of recipient outcomes.

For each of the two clinical research protocols include a description 
in approximately two pages of the rationale, research aims, outcome 
measures, and study design.  In addition, provide a description of the 
proposed patient populations with an estimate of the expected 
distribution across relevant sex, ethnic, and age groups and assurances 
of the applicant"s access to the patient populations. 

In both the core and clinical research proposals it is important to 
indicate appropriate objective measures of primary and secondary 
outcome.  The TC principal investigators are encouraged to explore, 
within the context of their proposed protocols, new technologies to 
monitor issues of clinical significance to donors and recipients.  
Funding for the relevant technology should be presently available for 
each clinical research protocol proposed.

The TC principal investigator should indicate for each clinical 
research protocol how many patients meeting proposed criteria are 
available in his/her TC and how many will be required from the entire 
Consortium (all of the TCs).  In the discussion of outcome measures, it 
will be important to indicate appropriate objective measures of primary 
and secondary outcome.  The TC principal investigators are encouraged 
to explore, within the context of their proposed protocols, new 
technologies to monitor disease progression and response to therapy.  

To promote development of a collaborative program, the issues discussed 
below need to be addressed in each application for a TC within the LDLT 
Cohort Study Consortium.  This material is in addition to the 
submission of a research plan, as described in the section entitled 
Research Scope.

(c) The following specific criteria should be addressed:

o Qualifications and experience.  Applicants for TCs must demonstrate 
experience and expertise to conduct clinical studies in LDLT. 

o Study population.  TCs must discuss the number of adult patients that 
have thus far been evaluated as well as transplanted using living 
donors. The number of patients at the center that might be eligible to 
enroll in protocols must be discussed.  The applicant for a TC in the 
Consortium must include a description of the pool of previous as well 
as future potential study participants by sex, age categories, and 
ethnic/racial distribution, as well as recruitment source.  It is 
important for TCs to demonstrate a willingness and ability to recruit 
all recipients and their living donors into the core study.

Applicants for a TC from institutions that have a General Clinical 
Research Center (GCRC) funded by the NIH National Center for Research 
Resources are encouraged to identify the GCRC as a resource for 
conducting the proposed research.  If so, a letter of agreement from 
either the GCRC Project Coordinator or Principal Investigator should be 
included with the application.

o Willingness to participate in a LDLT Cohort Study.  The principal 
investigator should state his/her general support of collaborative 
research and interaction with the NIDDK, the other TCs, and the DCC 
through the Consortium concept.  Applicants should discuss their 
willingness, and that of the institutions involved, to pursue a per 
patient basis (capitation) of operational costs for each protocol. TCs 
must be able to interact with the DCC to transmit and edit data and 
should discuss their capability to participate in a distributed data 
entry system.

o Institutional resources for patient care and follow-up including 
personnel, space, and special laboratory facilities should be 
described.

2. Data Coordinating Center Applications

A separate complete application is required from institutions applying 
to be the DCC for the LDLT Cohort Study.  Applicants for the DCC 
component are not required to be a transplantation site within the 
study, though applicants for transplantation sites may also submit an 
application to be the DCC. 

Applicants must address the following responsibilities of the DCC:  1) 
participation in the design of the final protocol and development of 
the manual of operation, data collection forms, and questionnaires, 2) 
development and implementation of systems for communication among 
Steering Committee members, and among study sites, 3) data collection, 
editing, processing, analysis, and reporting, 4) monitoring of 
adherence to the protocol and of data quality, and 5) establishment of 
procedures that insure the safety and confidentiality of all records.

Data management and quality control procedures must be detailed.  
Methods for assuring privacy and maintaining confidentiality should be 
included. There must be a data and safety management plan. Applicants 
must state their plans for the reporting of results that examine 
differences in treatment effects across these subgroups (see section, 
 Inclusion of Women and Minorities in  Research Involving Human 
Subjects ).

The following specific criteria should be addressed:

o Qualifications and experience.  The applicant for a DCC must 
demonstrate experience in the area of in coordinating multi-center 
clinical and epidemiological studies in all phases: protocol and manual 
of operations development, staff training in study procedures, research 
instrument development, data collection and management, quality 
assurance, data analysis, distributed data entry, electronic 
communications, administrative management and coordination. Specific 
experience in coordinating or monitoring studies of liver disease is 
not required, but the applicant may wish to include a transplantation 
surgeon or hepatologist in the application as a key collaborator and 
advisor.

o Study design and management. DCC proposals should discuss the 
applicant"s familiarity and experience with various aspects of study 
design that would be important in developing clinical protocols, for 
example: eligibility criteria, baseline and outcome measures, methods 
of randomization, important considerations for making sample size and 
power calculations, methods and frequency of data collection and entry, 
monitoring accuracy of data collection, quality control procedures 
including training and certification for multiple protocols, some of 
which may occur simultaneously, managing labeling and handling of serum 
and tissue samples (see below), and plans for statistical analysis. The 
DCC proposal should also describe their familiarity with model plans 
for managing Data and Safety Monitoring Boards.  

o Sample size calculations should be provided for the prospective core 
component between LDLT patients and possible control groups based on 
reasonable assumptions of mortality and graft loss of transplant 
candidates at large U.S. transplantation centers.  

o The applicant for the DCC should delineate how laboratory specimens 
will be handled.  NIDDK anticipates that some clinical outcome measures 
may be centrally assessed.  Laboratories responsible to the DCC will 
manage specimens and laboratory studies as required by the Steering 
Committee.  The costs of performing specific laboratory tests beyond 
those required for clinical care will be budgeted as a part of the per 
patient costs of each TC. The costs of specimen shipment as well as 
laboratory data acquisition and management will be a part of the budget 
of the DCC. The DCC does not need to prepare two protocols.  

o The applicant should describe the functions of a blood and tissue 
repository in the context of the design presented in this RFA.  
Included should be a discussion of shipping of biological specimens in 
a clinical setting, as well as the handling and tracking of specimens.  
This repository will be established during the planning phase.

BUDGET INSTRUCTIONS

Applicants should complete the budget information as directed in the 
PHS 398 application form. The applicants shall not submit budget 
information in modular format and cost projections should adequately 
correspond to the scope of research proposed. 

1.  Transplanation Center Applications 

TCs should consider the following additional issues regarding budgets.  
The underlying concept of the LDLT Cohort Study is that a core effort 
is essential to maintain the infrastructure and essential data 
collection.  Therefore, individual TCs should submit requests a budget 
to maintain these core features.  It is anticipated that this Core 
Budget will cover a minimum ten percent effort for the investigators 
(principal and any co-investigators), and a small percent effort for 
other key personnel to collect core study data.  Tasks conducted by 
these personnel include study recruitment, data entry, specimen 
shipment and quality control. Equipment costs, such as computers for 
data-entry and printers, should be included.  Include travel costs for 
three people to attend three one and one-half day LDLT Cohort Study 
meetings a year in Bethesda, MD (six in the first year).  These costs 
should be justified appropriately in budgets and may be distributed 
into subcontracts.  Escalation is allowed at three percent for future 
years.

In addition to the core budget, each TC will be provided funds for 
implementation of protocols.  The precise number of protocols conducted 
will be determined by the LDLT Cohort Study Steering Committee and will 
depend on availability of funds.  It is anticipated that during the 
first year, two to four protocols will be developed for implementation 
at the start of recruitment.  Allowable total costs for each TC (core 
costs, costs per patient to conduct the protocols, and indirect costs) 
will vary.  However, the maximum total costs for each Consortium to 
implement the protocols (including TCs and DCC and Specimen Core) are 
$200,000 per year.  

The TCs are requested to present the following information:

o For each year, each TC should include the core budget costs and costs 
to conduct protocols.  Estimated protocol implementation costs for Year 
2 should be based on the two proposals presented in the applicants  
research plan.  A table should be included showing estimated costs per 
patient for conducting each protocol.  A guideline is to devote between 
one-third and one-half of resources in Phase 2 to clinical research 
protocols and between one half and two-thirds of resources to the core 
prospective and retrospective data collection.

The budget for each clinical protocol should be developed on a cost per 
patient basis and include all direct and any applicable facilities and 
administrative costs. Costs of drugs or laboratory tests should be part 
of the per patient cost of conducting a protocol.  The clinical 
protocol should identify the potential source(s) for any drugs or 
substances that are being considered for clinical protocols that are 
currently unavailable commercially.  Investigators should only prepare 
budgets for their own TC to conduct the proposed study or trial, and 
not for the entire LDLT Cohort Study.  The yearly budget for each TC 
should include the number of patients available for the proposed 
protocol at that TC.  A budget based on the costs per patient for 
recruiting and maintaining the specified number of subjects at the 
applicant"s center should be included for each protocol. 

Note that ongoing annual budgets for protocols will be based on the 
protocols approved by the LDLT Cohort Study Steering Committee and will 
be funded through a per patient basis (capitation) funding mechanism.  
The individual TCs will be expected to project patient enrollment for a 
specific protocol during a specified time frame, continuation and level 
of funding for each TC will be based on actual recruitment and overall 
performance. 

The LDLT Cohort Study awards will be subject to administrative review 
annually.

2.  Data Coordinating Center Applications

Applicants for the DCC should prepare budgets for seven 12-month 
periods (not to exceed $750,000 total cost per year) that roughly 
correspond with the standard coordinating center responsibilities 
outlined in other sections of this RFA.  In the first year, DCC 
applicants should include all costs associated with the organization of 
all administrative aspects of the LDLT Cohort Study to be developed and 
with the initiation of one protocol to be developed and started.  For 
subsequent years, applicants may assume that two to four protocols a 
year will be active, i.e. either in the protocol development, 
implementation, or analysis and writing phase. DCC should include costs 
for managing the Data and Safety Monitoring Board as well as the cost 
of meeting three times/year in Bethesda (six times the first year).  
Approximately $30,000 for the whole 7 years should be budgeted for 
managing the Data and Safety Monitoring Board.

The DCC will be subject to administrative review annually. It is 
expected that all protocols will be performed in a manner consistent 
with United States Food and Drug Administration guidelines.

The DCC is expected to maintain a blood and tissue repository to be 
established during the planning stage of the LDLT Cohort Study.  Cost 
for shipping specimens from the TCs will be covered by the DCC.

REVIEW CONSIDERATIONS

Applications must be received by November 28, 2001.  If an application 
is received after that date, it will be returned to the applicant 
without review.  

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDDK.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further 
consideration. 
 
Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NIDDK in accordance with the review 
criteria stated below.  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 the applications under review, will be 
discussed, assigned a priority score, and receive a second level review 
by the National Diabetes and Digestive and Kidney Diseases Advisory 
Council.

REVIEW CRITERIA

A. Criteria for TCs and for DCC

All applications will be reviewed according to the criteria listed 
below.  The reviewers will be asked to evaluate the following aspects 
of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  
Each of these criteria will be addressed and considered in assigning 
the overall score, weighting them as appropriate for each application.  
Note that the application does not need to be strong in all categories 
to be judged likely to have major scientific impact and thus deserve a 
high priority score.

o Significance:  The application should address the problem outlined in 
the RFA.  The application should demonstrate how the study will advance 
scientific and/or medical knowledge.

o Approach:  The adequacy of the proposed conceptual framework, design, 
methods, and analyses.  Potential problem areas and consideration of 
alternative tactics should be acknowledged

Because the final protocol study design(s) will be developed 
collaboratively by the Steering Committee, the peer review group will 
focus on evidence that the applicant has carefully thought about the 
issues involved and possesses the knowledge necessary to contribute 
meaningfully to the final design, including understanding of the 
scientific, ethical, and practical issues underlying the proposed 
study.

o Innovation:  The applicant should demonstrate how the project 
challenges existing paradigms or develops new methodologies or 
technologies.

o Investigator:  The investigator should be appropriately trained and 
well suited to carry out this work.  The proposed study should be 
appropriate to the experience level of the principal investigator and 
other researchers (if any).  There should be evidence of prior 
experience in working collaboratively to carry out a clinical study or 
standard protocol as well as evidence of willingness to work 
cooperatively on the Steering Committee to develop and follow a unified 
protocol.

o Environment:  The environment in which the work will be done should 
contribute to the probability of success. The proposed protocol should 
take advantage of unique features of the scientific environment and 
employ useful collaborative arrangements. There should be evidence of 
institutional support.

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, 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.

o The reasonableness of the proposed budget and duration in relation to 
the proposed research

o The adequacy of the proposed protection for humans or the 
environment, to the extent they may be adversely affected by the 
project proposed in the application.  The initial review group will 
also examine the safety of the research environment.

B.  Review of TC applicants also will be based on the following 
specific criteria:

o Evidence of successful experience in recruitment and retention of 
research subjects in multicenter clinical studies, and particularly 
experience in the recruitment and retention of patients evaluated for 
liver transplantation.  Commitment to recruiting all eligible 
recipient-donor pairs and documentation of access to an adequate 
patient population from which to recruit at least 10 eligible 
recipient-donor pairs per year and. 

o The extent that the two clinical research studies proposed by the 
applicant will result in information that will further our 
understanding and management of LDLT patients or of transplantation or 
liver disease in general.

o Cogency of the discussion of appropriate controls for LDLT 
recipients.

o Adequacy of plans to ensure accurate collection and timely 
transmission of study data to the DCC and patient samples to the 
Specimen Core.  Documented experience in meticulous and expeditious 
handling of laboratory specimens and study data.

o Evidence of prior experience in working collaboratively in carrying 
out a developed study protocol.  Evidence of willingness to work 
cooperatively in this study.

o Demonstrated knowledge of clinical and epidemiological aspects of 
liver transplantation and specifically LDLT, including management of 
donors and recipients both pre- and post-operatively. 

o Collaborations between TCs within the LDLT Cohort Study: For those 
applicants that propose collaborative efforts between two groups to 
form a single TC, additional factors to be considered would include the 
advantages of the collaboration in terms of cost, recruitment, or 
facilities, the commitment of the participants to the collaboration, 
and the adequacy of plans to coordinate efforts.

C. Review of DCC applicants also will be based on the following 
specific criteria:

o Demonstration of the plans for exercising appropriate leadership in 
matters of study design, fostering cooperative relationships, data 
acquisition, data management, and data analysis.
 
o Demonstrated ability to identify, enlist, recruit and coordinate the 
efforts of a central Blood/Tissue repository. 

o Experience in and understanding of the scientific, statistical, 
logistical, and technical issues underlying multi-center studies.

o Understanding of issues related to management of liver disease and to 
organ transplantation.

o The administrative, supervisory, and collaborative arrangements for 
achieving the goals of the program, including willingness to cooperate 
with the principal investigators of the TCs and the NIDDK.

o Plans for determining the sample sizes necessary for the prospective 
core study and proposed statistical analyses of outcomes.

o Adequate assurances that personnel have experience in utilizing 
procedures that insure the safety and confidentiality of medical 
records.

SCHEDULE

Letter of Intent Receipt Date:    October 16, 2001
Application Receipt Date:         November 28, 2001
Peer Review Date:                 March 2002
Council Review:                   May 2002
Earliest Anticipated Start Date:  June 2002

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o The quality of response to the special requirements stated in this 
RFA.

o Scientific merit as determined by peer review,

o Availability of funds,

o Programmatic priorities.

o Geographic diversity

o A demonstrated ability to conduct a successful program in adult LDLT

o A demonstrated willingness on the part of the investigators to work 
as part of the LDLT Cohort Study and with the NIDDK Project Scientist.

o Program balance, including, in this instance, sufficient 
compatibility of features to make a successful collaborative program a 
reasonable likelihood.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to 
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

James Everhart, M.D., M.P.H. 
Division of Digestive Diseases and Nutrition, NIDDK 
Two Democracy Plaza Rm. 655
6707 DEMOCRACY BOULEVARD MSC 5450
BETHESDA MD 20892-5450
Telephone:  (301) 594-8878
FAX:  (301) 480-8300
E-mail:  je17g@nih.gov

Direct inquiries regarding review matters to:

Francisco Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
Room 752
6707 Democracy Blvd. MSC 5452
Bethesda, MD  20892-5452
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email:  fc15y@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Sharon Bourque
Senior Grants Management Specialist
Division of Extramural Affairs, NIDDK
6707 Democracy Blvd.
Room 719, MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8846
FAX:  (301) 480-3504
Email:  sb114m@nih.gov

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 NIH grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  
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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