CLINICAL RESEARCH NETWORK IN NON-ALCOHOLIC STEATOHEPATITIS (NASH)

Release Date:  February 12, 2001

RFA:  RFA-DK-01-025 - (Reissued as RFA-DK-08-505)

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  June 15, 2001
Application Receipt Date:       July 20, 2001

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
invites applications for establishment of a Clinical Research Network that 
focuses upon the etiology, contributing factors, natural history, 
complications, and therapy of non-alcoholic steatohepatitis (NASH).  NASH is 
a common but poorly understood liver disease that is characterized by 
accumulation of fat in the liver (steatosis), accompanied by inflammation, 
cell injury and fibrosis (hepatitis) that closely resembles alcoholic liver 
disease but occurs in patients who drink little or no alcohol.  NASH is most 
common in adults above the age of 40 who are overweight or have diabetes, 
insulin resistance or hyperlipidemia.  However, the disease also occurs in 
children and in persons who are not obese or diabetic. Currently, there are 
no effective therapies for NASH and its natural history and prognosis are not 
well understood.  The objective of this Request for Applications (RFA) is to 
establish and maintain the infrastructure required for a NASH Clinical 
Research Network consisting of a group of interactive Clinical Centers CCs) 
and a Data Coordinating Center (DCC).  The goal of this NASH Clinical 
Research Network is to facilitate and perform clinical, epidemiological and 
therapeutic research in NASH.  This is a one-time solicitation to support a 
Clinical Research Network for five 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.  This RFA, Clinical 
Research Network in Non-Alcoholic Steatohepatitis (NASH), is related to the 
priority areas of chronic disabling conditions and diabetes.  Potential 
applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.  

ELIGIBILITY REQUIREMENTS

Applications may be submitted only from domestic institutions.  This 
geographic constraint will be necessary because of the need for close 
communication among members of the program, the requirement for frequent 
steering committee meetings, and site visits for data verification.  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 may apply.

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 grants awarded under 
this RFA.  Among the disciplines and expertise that may be appropriate for 
this program are hepatology, pediatrics, internal medicine, epidemiology, 
physiology, pharmacology, therapeutic development, and clinical trials 
management. 

A DCC will be a part of this NASH Clinical Research Network.  In order to 
ensure that data analysis is done independently of data acquisition, the DCC 
cannot have the same Principal Investigator as a CC. Within the Network an 
institution may apply for both a CC and the DCC, but each must have separate 
principal investigators and submit a separate application with a specific 
plan of how the independent operation (i.e., confidentiality of the study-
wide data) of each unit of the CC and DCC will be maintained. 

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) administrative and funding 
mechanism of support.  Under the cooperative agreement, the NIH assists, 
supports, and/or stimulates, and is substantially involved with recipients in 
conducting a study by facilitating performance of the effort in a "partner" 
role.  Details of the responsibilities, relationships, and governance of a 
study funded under a cooperative agreement are discussed later in this 
document under the section entitled “Organization of NASH Clinical Research 
Network.”

The total project period for applications submitted in response to this RFA 
will be five years.  This RFA is a one-time solicitation.   Although not co-
sponsoring this RFA, other Institutes have interest in the research area 
discussed in this RFA.  

The anticipated award date is April 1, 2002. 

FUNDS AVAILABLE
 
A maximum of six awards for CCs and one award for a DCC will be made under 
this RFA. It is anticipated that the award for the DCC will be approximately 
$600,000 direct costs (no more than $900,000 total costs) per year.  The 
amount awarded to each CC per year will vary between $150,000 to $250,000 
direct costs (no more than $350,000 total costs) per year.  The total costs 
for the Network will be limited to $3 million total costs per year.  Because 
the nature and scope of the research proposed in response to this RFA may 
vary, it is anticipated that the size of an award will also vary in all 
years.  Future year costs will be distributed based on the recommended 
protocols, database development, epidemiological studies, pilot studies or 
planning studies for future clinical trials.

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.  Designated funding levels are subject to change at any 
time prior to final award, due to unforeseen budgetary, administrative, or 
scientific developments. 

RESEARCH OBJECTIVES

Background 

Non-alcoholic steatohepatitis (NASH), also known as fatty liver hepatitis, is 
a clinical-pathological condition that only recently has been recognized to 
be a common and potentially severe form of liver disease.  NASH is usually 
defined on the basis of liver biopsy histology, characterized by accumulation 
of fat in hepatocytes, spotty necrosis, inflammation, Mallory bodies and 
fibrosis.  These features resemble alcoholic liver disease, but this 
condition occurs in persons who drink little alcohol or none at all.  NASH 
appears to be common, although its prevalence in the population is not well 
defined.  Selected autopsy series have found fatty hepatitis in 3 percent of 
lean and up to 19 percent of obese subjects.  NASH is most common in middle-
aged persons but is found in all age groups including children.  NASH 
typically occurs in persons who are overweight or diabetic, but it has 
recently been shown to occur in subjects with normal body weight and normal 
glucose tolerance.  In some series, NASH has been found to be the single most 
common cause of serum aminotransferase abnormalities identified during 
routine blood testing. 

The prognosis and natural history of NASH have not been well defined.  In 
many patients, fatty liver is a benign condition and does not result in 
permanent injury or structural abnormalities in the liver. In other patients, 
however, progressive fibrosis occurs that leads to cirrhosis and end-stage 
liver disease.  In the advanced stages of disease, the classical histological 
findings of NASH (marked fatty change and Mallory bodies) may no longer be 
present and the cause of the liver disease considered to be cryptogenic. 

The cause of NASH is not yet defined.  The association of NASH with obesity 
and diabetes suggests that there is an underlying metabolic dysfunction, 
perhaps insulin resistance or inability to metabolize excess free fatty 
acids.  However, accumulating evidence indicates that there is a second 
factor that ultimately leads to cell injury and inflammation in fatty liver.  
The suspected second ”hit” may be intracellular oxidative stress that can be 
induced by multiple mechanisms, such as excess iron accumulation, endotoxin 
exposure, pro-inflammatory cytokines or other unknown factors.  Understanding 
the pathogenesis of NASH is of great importance in ultimately finding a 
treatment, cure or means of prevention of this disease. 

At present there is no clear means of treatment or prevention of NASH.  
Weight loss is usually recommended, but rarely achieved, and its ultimate 
effect on the course of this disease has not been shown.  Several approaches 
to therapy have been evaluated in small clinical trials, including vitamin E, 
ursodiol, metformin and the thiazolidinediones.  These studies have been 
promising but ultimately inconclusive, because of small sample size, lack of 
adequate follow up and lack of use of liver histology (as opposed to serum 
aminotransferase levels) as an endpoint for evaluating the benefit of 
therapy.

A NASH Clinical Research Network will accelerate clinical research and 
progress in understanding the pathogenesis of NASH defining its natural 
history, and developing safe and effective means of treatment.  The variable 
manifestations of NASH and its insidious and slowly progressive natural 
history makes it difficult to accumulate an adequate number of patients 
followed for an adequate period of time in one center.  Furthermore, a common 
and coordinated approach to evaluation and therapy will reduce the number of 
patients needed at each CC.  Also, the NASH Clinical Research Network 
mechanism will help pool the
necessary clinical expertise and administrative resources to facilitate the 
conduct of multiple and novel therapeutic trials in a timely, efficient 
manner.  This, in turn, will promote rapid dissemination of research findings 
to health care professionals. 

Organization of the NASH Clinical Research Network

The NASH Clinical Research Network will be a cooperative network of four to 
six CCs and one DCC.  CCs will be responsible for proposing protocols, 
participating in their overall development, conducting the research, and 
disseminating research findings. All individual CCs will be required to 
participate in a cooperative and interactive manner with one another and with 
the DCC in all aspects of the NASH Clinical Research Network.  The DCC will 
support protocol development, 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, 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.

Governance

A Steering Committee will be the main governing body of the NASH Clinical 
Research Network. At a minimum, the Steering Committee will be composed of 
the principal investigators of each CC in the Network, 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.  
By the end of the second meeting of the Committee, the NIDDK will name a 
study Chairperson from one of the CC to oversee and guide Steering Committee 
activities.  The Steering Committee will meet as often as three to six times 
during the first 12 months of the study, and two to four times thereafter.  
All major scientific decisions will be determined by a majority vote of the 
Steering Committee.  Each CC, the DCC, and the NIDDK Project Scientist will 
have one vote.  The Steering Committee will have primary responsibility for 
the general organization of the NASH Clinical Research Network, 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.  Topics for investigational and treatment protocols will be proposed 
and prioritized by the Steering Committee.

For each investigational or therapeutic protocol, one CC 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 CCs.  

A Pathology Committee will supplement the activities of the Steering 
Committee and will ensure a consistency of processing and interpretation of 
liver biopsies.  This committee will be composed of the hepatic pathologist 
from each CC as well as a lead hepatic pathologist who will be appointed by 
the NIDDK.  The lead hepatic pathologist will be either one of the hepatic 
pathologists from the CCs or the DCC, or an outside pathologist chosen 
specifically for this task.  

Other 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.
 
An independent Data and Safety Monitoring Board will be established by the 
NIDDK to review protocols and monitor patient safety and performance of each 
study.  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 CCs, 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 CCs must be willing to pursue this 
funding arrangement for each new protocol conducted.
 
Clinical protocols must be approved by local institutional review boards and 
the NASH Clinical Network Data and Safety Monitoring Board before initiation.  
The exact number of protocols supported in the five-year program will depend 
on the nature and extent of the investigations proposed by the Steering 
Committee.  Databases may be developed, epidemiological studies and other 
clinical studies may be performed.  Planning may be done for large clinical 
trials that would be submitted as separate R01s if further funding is 
necessary.  The NASH Clinical Research Network 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 NASH 
Clinical Research Network Database.  Any specific collaboration involving the 
resources of the NASH Clinical Research Network will require approval by the 
Steering Committee.

Research Scope  

The objective of this RFA is to establish a NASH Clinical Research Network 
that will accelerate advances in the understanding and clinical management of 
this common liver disease.  
 
The Network should initially focus upon development of a clinical database of 
patients with NASH.  An essential first step will be to develop common 
definitions, nomenclature and terms for the clinical diagnosis and staging of 
NASH.  In particular, histological criteria for the diagnosis as well as an 
accepted method of staging and grading the disease is needed.  Also important 
are clinical definitions, means of assessing symptoms and quality of life, 
standardized forms and questionnaires, and agreed upon essential information 
for the diagnosis and characterization of a patient cohort.  The database can 
also include control subjects and family members for genetic studies.  The 
database should be designed to address specific questions and to provide 
appropriate reagents or patient populations for clinical or laboratory 
investigation. The NASH Clinical Network should also provide the preliminary 
data and background for further investigator-initiated research.  For 
instance, the Network might generate a pilot study of therapy and clinical 
information to allow the investigators to submit a separate application for a 
full-scale clinical trial (R01).  The Network also is expected to interact 
with basic and laboratory research investigators with interest in these 
diseases by providing reagents, specimens or opportunities to assess 
hypotheses on the pathogenesis, prevention or treatment of the disease.  The 
Network can also provide a focus for training in clinical investigation.

All projects must be completed within the five-year duration of this research 
program.

THESE 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.  It is not the intent of the Network to provide 
support for only one or two protocols that run for the entire seven years. 
Multiple trials or clinical and epidemiological investigations will be 
conducted, possibly two to four a year, some large and some small.  It is 
anticipated that in the initial one or two years, trials and investigations 
will be selected from the studies proposed by the successful CCs in their 
applications. 

Each CC within the Network should propose a research plan that includes the 
structure of a large database as well as two clinical research protocols as 
models that could be used in the Network environment.  The protocols should 
demonstrate knowledge of the disease and its pathogenesis.  Each protocol 
should require sufficient subjects to necessitate the use of a Network with 
multicenter participation.  Applicants should indicate knowledge of the 
number of patients required for each study based on sample size calculations.  
One protocol must be a short-term study (one year or less) and one a long-
term study (one to three years).  The research plan should follow the 
instructions in the PHS 398 application form (revised 4/98, 
http://grants.nih.gov/grants/funding/phs398/phs398.html).  For the overall 
structure and factors that are included in the common database of patients 
include a justification for necessary information on patients to be included.  
For each of the two 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 of male and female patients, ages, 
and assurances of the applicant"s access to the patient populations. 

The CC principal investigator should indicate for each protocol how many 
patients meeting proposed criteria are available in his/her CC and how many 
will be required from the entire Network (all of the CCs).  In the discussion 
of outcome measures, it will be important to indicate appropriate objective 
measures of primary and secondary outcome.  The CC principal investigators 
are encouraged to explore, within the context of their proposed protocols, 
new technologies to monitor disease progression and response to therapy.  
Funding for the relevant technology should be presently available for each 
protocol proposed.  It will also be important to include strategies to assure 
adherence to therapy as part of the protocol.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

The cooperative agreement is an award instrument establishing an "assistance" 
relationship (in contrast to an "acquisition" relationship) between NIDDK and 
a recipient, in which substantial NIDDK scientific and/or programmatic 
involvement with the recipient is anticipated during performance of the
activity.  The NIDDK purpose is to support and/or stimulate the recipient"s 
activity by involvement in and facilitation of the activity in a "partner" 
role. The dominant role and prime responsibility for the planned activity 
reside with the awardees for the project as a whole, although specific tasks 
and activities in carrying out the activity will be shared among the awardees 
and NIDDK Project Scientist.  The terms and conditions below elaborate on 
these interactions and responsibilities, and the awardee agrees to these 
collaborative actions toward achieving the project objectives.  It is 
anticipated that these terms and conditions will enhance the relationships 
among the awardees and with the NIDDK Project Scientist, and will facilitate 
the successful conduct and completion of the study.  These agreements will be 
in addition to, and not in lieu of, the relevant NIH procedures for grants 
administration.  The terms will be as follows:

1) Awardees Rights and Responsibilities

The awardee(s) 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 the Data and Safety Monitoring Board.

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.

The Data Coordinating Center will be involved in collaborations with the 
NIDDK and the Clinical Centers 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 Data Coordinating Center will be expected to maintain 
close communications with the NIDDK Project Scientist and the Principal 
Investigators of the Clinical Centers.
 
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.

Support or other involvement of industry or any other third party in any 
study performed by the Network -- 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.

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

a) The Steering Committee, composed of each of the Principal Investigators of 
the DCC and the CCs, the NIDDK Project Scientist, and the Chairman of the 
Steering Committee, 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, 
ancillary studies, 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), or alternatively, from among experts in the field of 
liver diseases who are not participating directly in the study.  
Subcommittees will be established on topics such as ancillary studies, 
publications and presentations, quality control, recruitment, protocol 
adherence, among others.  

Each Network CC 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 CCs 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 the 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.

Under the statute, when an NIH defined Phase III clinical trial is proposed, 
evidence must be reviewed to show whether or not clinically important 
sex/gender and/or race/ethnicity differences in the intervention effect are 
to be expected.  This evidence may include, but is not limited to, data 
derived from prior animal studies, clinical observations, metabolic studies, 
genetic studies, pharmacology studies, and observational, natural history, 
epidemiology and other relevant studies.

Cost is not an acceptable reason for exclusion of women and minorities from 
clinical trials.

When planning, conducting, and reporting an NIH defined Phase III clinical 
trial, it must be considered whether, based on prior studies, one of the 
following three situations apply:  that prior studies support the existence 
of significant differences, that prior studies support no significant 
differences, and that prior studies neither support nor negate significant 
differences.

The NIDDK believes that prior studies neither strongly support nor negate 
significant differences in expected intervention effects by sex/gender and/or 
race/ethnicity.  

In this case, the NIH Phase III clinical trial will be required to include 
sufficient and appropriate entry of sex/gender and/or racial/ethnic 
subgroups, so that valid analysis of the intervention effect in subgroups can 
be performed.  However, the trial will not be required to provide high 
statistical power for each subgroup.

The Research Plan in the application or proposal must include a description 
of plans to conduct the valid analyses of the intervention effect in 
subgroups.  The final protocol(s) approved by the IRB(s) must include these 
plans for analysis.  The award will require that the results of subset 
analyses must be reported to NIH in Progress Reports, Competitive Renewal 
Applications, and in the required Final Progress Report.

Inclusion of the results of subset analyses is strongly encouraged in all 
publication submissions.  If the analysis reveals no subset differences, a 
brief statement to that effect, indicating the subsets analyzed, will 
suffice.

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.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 15, 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, whether the 
application is for a CC or the DCC, 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 Calvo, Ph.D.
Chief, Review Branch 
Division of Extramural Activities, NIDDK
6707 Democracy Blvd.
Room 655, MSC 5452
Bethesda, MD 20892-5452 
Telephone:  (301) 594-8897
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach 
and Information Resources, National Institutes of Health, 6701 Rockledge 
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
GrantsInfo@nih.gov.  The PHS 398 application kit is also available on the 
Internet at http://grants.nih.gov/grants/forms.htm

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  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.

Special Instructions for Use in Preparing an Application

Applicants must describe plans to accommodate the stated program 
requirements, criteria, and staff involvement.  Applicants must address 
points discussed in the SPECIAL REQUIREMENTS section of this RFA.

Applications for CCs:

Each CC within the Network should propose a research plan that includes the 
structure of a large database as well as two clinical research protocols as 
models that could be used in the Network environment.  The protocols should 
demonstrate knowledge of the disease and its pathogenesis.  Each protocol 
should require sufficient subjects to necessitate the use of a Network with 
multicenter participation.  Applicants should indicate knowledge of the 
number of patients required for each study based on sample size calculations.  
One protocol must be a short-term study (one year or less) and one a long-
term study (one to three years).  The research plan should follow the 
instructions in the PHS 398 application form (revised 4/98, 
http://grants.nih.gov/grants/forms.htm.   For the overall structure and factors 
that are included in the common database of patients include a justification 
for necessary information on patients to be included.  For each of the two 
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 of male and female patients, ages, and assurances of 
the applicant"s access to the patient populations. 

The CC principal investigator should indicate for each protocol how many 
patients meeting proposed criteria are available in his/her CC and how many 
will be required from the entire Network (all of the CCs).  In the discussion 
of outcome measures, it will be important to indicate appropriate objective 
measures of primary and secondary outcome.  The CC principal investigators 
are encouraged to explore, within the context of their proposed protocols, 
new technologies to monitor disease progression and response to therapy.  
Funding for the relevant technology should be presently available for each 
protocol proposed.  It will also be important to include strategies to assure 
adherence to therapy as part of the protocol.

To promote development of a collaborative program, the issues discussed below 
need to be addressed in each application for a CC within the NASH Clinical 
Research Network.  This material is in addition to the submission of a 
research plan, as described in the section entitled Research Scope.

o Qualifications and experience.  Applicants for CCs must demonstrate 
experience and expertise to conduct clinical studies in NASH. This must 
include documentation of experience in the diagnosis and management of 
patients with NASH. Of particular importance, is the availability of an 
expert hepatic pathologist as a collaborator in the CC application. 

o Study population.  CCs must discuss the number of patients with NASH seen 
and followed at the center who might be eligible to enroll in protocols.  
Approximately half of the patients enrolled in the NASH Clinical Research 
Network should be females.  Furthermore, inclusion of children is required, 
although not all Centers can be expected to include a pediatric cohort of 
patients.  The applicant for a CC in the Network must include a description 
of the pool of potential study participants by sex, age categories, and 
ethnic/racial distribution, as well as recruitment source. Patient access may 
be developed by establishing links with other groups outside the CC"s 
institution. If outside links are proposed, there must be a well described 
plan to link the individual CCs with community health care providers such as 
HMOs, clinics, or private practice physicians to ensure adequate numbers 
patients for clinical studies of therapeutic agents and management 
strategies. 

Applicants for a CC 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 NASH Clinical Research Network.  The 
principal investigator should state his/her general support of collaborative 
research and interaction with the NIDDK, the other CCs, and the DCC through 
the Network 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. CCs 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.

Applications for a DCC:

o Qualifications and experience.  The applicant for a DCC must demonstrate 
experience in the area of in coordinating multi-center clinical trials 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 hepatologist or hepatic pathologist 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 the Data and Safety Monitoring Board. 
Approximately $20,000 for the whole 5 years should be budgeted for managing 
the Data and Safety Monitoring Board.

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 will be budgeted as a part of 
the per patient costs of each CC. 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.  Estimated shipping 
and handling costs of $25,000 for specimens should be included in the budget 
of DCC. 

BUDGET AND RELATED ISSUES

Applicants should complete the budget information as directed in the PHS 398 
application form. 

Applications for CCs:
 
CCs should consider the following additional issues regarding budgets.  The 
underlying concept of the NASH Clinical Research Network is that a core 
effort is essential to maintain the infrastructure required to perform 
multiple clinical trials or clinical studies.  Based on this approach, it is 
estimated that the individual CCs will require a minimum level of effort to 
sustain the organizational aspects of the Clinical Research Network.  
Therefore, individual CCs should submit requests for a CORE BUDGET not to 
exceed $150,000 total costs per year.  It is anticipated that this core 
budget will cover a minimum ten percent effort for the principal 
investigator, and a small percent effort for other key personnel (nurse, 
technician, clinic coordinator, secretary), and travel costs for two people 
to attend three NASH Clinical Research Network meetings a year in Bethesda, 
MD.  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 CC will be provided funds for 
implementation of protocols.  The precise number of protocols conducted will 
be determined by the NASH Clinical Research Network Steering Committee and 
will depend on availability of funds.  It is anticipated that after the first 
year, two to four protocols may be active each year.  CCs may request PATIENT 
CARE costs.  This amount should be placed in the patient care category.  
Patient care costs may be escalated at three percent for future years.  
Allowable total costs for each CC  (core costs, costs per patient to conduct 
the protocols, and indirect costs) will vary.  However, the maximum total 
costs for each Network to implement the protocols (including CCs and DCC and 
Specimen Core) are $200,000 per year.  

The CCs are requested to present the following information:

o For each year, each CC should include the core budget costs (not to exceed 
$150,000 total costs) and patient care costs.  Estimated protocol 
implementation costs for Year 1 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. Total cost 
for implementation of both protocols should not exceed $200,000.

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 CC to 
conduct the proposed study or trial, and not for the entire NASH Clinical 
Research Network.  The CC should state the total number of patients required 
by the entire Network to complete each proposed study or trial.  The yearly 
budget for each CC should include the number of patients available for the 
proposed protocol at that CC. 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 NASH Clinical Research Network Steering Committee and will be 
funded through a per patient basis (capitation) funding mechanism.  The 
individual CCs will be expected to project patient enrollment for a specific 
protocol during a specified time frame, continuation and level of funding for 
each CC will be based on actual recruitment and overall performance. 

The NASH Clinical Research Network awards will be subject to administrative 
review annually.

DCC Budget:

Applicants for the DCC should prepare budgets for five 12-month periods (not 
to exceed $900,000 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 NASH 
Clinical Research Network 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 
including the cost of meeting three times/year in Bethesda.   

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.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED 
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

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 Blvd.
Room 655, MSC 5452
Bethesda, MD  20892-5452
Telephone:  (301) 594-8897
FAX:  (301) 480-3505

Applications must be received by July 20, 2001.  If an application is 
received after that date, it will be returned to the applicant without 
review.  

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.

REVIEW CONSIDERATIONS

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, a process will be used by the initial 
review group in which applications 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

In the written comments 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:  Does this study address an important problem?  Is there a 
need for research in this area? If the aims of the applications 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?

o Approach: Are the conceptual framework, design, and methods adequately 
developed, well integrated, and appropriate to the aims of the project?  Does 
the applicant acknowledge potential problem areas and consider alternative 
tactics?

Since the final study design(s) will be developed collaboratively by the 
Steering Committee for the protocols, 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: Does the project employ novel concepts, approaches or methods?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

o 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)?  

o Environment: Does the scientific environment in which the work will be done 
contribute to the probability of success?  Is there evidence of institutional 
support and commitment for the proposed program?

Review of CC applicants also will be based on the following specific 
criteria:

o Scientific and technical merit of the proposed approach to managing the 
requirements of the study as outlined in the RFA.

o Staff Qualifications:  Specific competence and previous experience of 
professional, technical, and administrative staff relevant to the operation 
of a CC in the proposed study. 

o Recruitment Capability:  Evidence of successful experience in recruitment 
and retention of research subjects in multicenter clinical trials. Evidence 
of ability to recruit, enroll, and maintain minority subjects in a randomized 
trial or other clinical studies at the proposed center.  This includes 
documentation of access to an adequate patient population for the proposed 
protocols. 

o Resources:  Documented adequacy of the proposed facility, space, and 
resources for the work proposed.  This includes evidence of an appropriate 
organizational structure and institutional support.

o Data and Sample Management:  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 Knowledge of Problems:  Demonstrable knowledge of the potential problems 
associated with the conduct of this study and possible solutions.

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

o Collaborations between CCs within the NASH Clinical Research Network: For 
those applicants that propose collaborative efforts between two groups to 
form a single CC, 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.

DCC:

Considerations for the review of applications for the DCC for the NASH 
Clinical Research Network include the following issues:

o Understanding of the scientific, statistical, logistical, and technical 
issues underlying multi-center studies, including issues relating to 
treatment and management of liver disease, and knowledge necessary to resume 
a leadership role in the area of study design, statistics, logistics, data 
acquisition and management, handling of laboratory specimens, quality 
control, data analysis, and network coordination.

o Adequacy of the proposed plans for acquisition, transfer, management, and 
analysis of data, quality control of data collection and monitoring, and 
overall coordination of the NASH Clinical Research Network activities.

o The expertise, training, and experience of the investigators and staff, 
including the administrative abilities of the Principal Investigator and co-
investigators, and the time they plan to devote to the effective coordination 
of the NASH Clinical Research Network.

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

o Facilities, equipment, and organizational structure to effectively 
coordinate the NASH Clinical Research Network activities in implementing the 
protocols, providing for specialized laboratory testing, and collecting data.

o Appropriateness of the budget for the work proposed.

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.  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, and children for the scientific goals of the research.  Plans for 
the recruitment and retention of subjects will also be evaluated.

Applicants are encouraged to submit and describe their own ideas on how best 
to meet the goals of the NASH Clinical Research Network, but they are 
expected to address issues identified under APPLICATION PROCEDURES of the 
RFA.  Applications will be judged primarily on the scientific quality of the 
application, however, the scientific merit of the proposed research plan will 
not be the sole criterion for selection of a CC. Further considerations for 
the review include: access to patients including children and minority 
individuals, multi disciplinary nature of the proposed studies, the 
discussion of considerations relevant to this RFA, and a demonstrated 
willingness on the part of the investigators to work as part of the NASH 
Clinical Research Network and with the NIDDK Project Scientist.

Schedule

Letter of Intent Receipt Date:    June 15, 2001
Application Receipt Date:         July 20, 2001
Peer Review Date:                 November 2001
Council Review:                   February 2002
Earliest Anticipated Start Date:  April 2002

AWARD CRITERIA

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

o Scientific and technical merit of the application for a Clinical Center or 
a Data Coordinating Center.

o The multi-disciplinary nature of the proposed studies (CC).

o Demonstration of expertise to manage, design and coordinate multicenter 
clinical trials that include handling and storage of laboratory specimens 
(DCC).

o The multi-disciplinary nature of the proposed studies.

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

o Relevance to the overall programmatic balance and priorities of the NIDDK 
and sufficient compatibility of features proposed in the research plan and 
qualifications of the investigators to make a collaborative program within 
the NASH Clinical Research Network a reasonable likelihood. 

o Availability of funds

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:

Patricia Robuck, Ph.D., M.P.H.
Director, Clinical Trials Program
Division of Digestive Diseases and Nutrition, NIDDK
6707 Democracy Blvd.
Room 675, MSC 5450
Bethesda, MD  20892-5450
Telephone:  (301) 594-8879
FAX:  (301) 480-8300
Email: robuckp@extra.niddk.nih.gov
 
Direct inquiries regarding review matters to:

Francisco Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Blvd.
Room 655, MSC 5452
Bethesda, MD  20892-5452
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email:  calvof@extra.niddk.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Sharon Bourque
Grants Management Specialist
Division of Extramural Affairs, NIDDK
6707 Democracy Blvd.
Room 612, MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8846
FAX:  (301) 480-3504
Email:  bourques@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.848.  Awards are made 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Department of Health and Human Services

National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892