INFLAMMATORY BOWEL DISEASE GENETICS RESEARCH CONSORTIUM

Release Date:  July 24, 2001

RFA:  RFA-DK-02-011 (Reissued as RFA-DK-06-504)

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

Letter of Intent Receipt Date:  October 17, 2001
Application Receipt Date:       November 20, 2001

PURPOSE

The Division of Digestive Diseases and Nutrition (DDN) of the National 
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites 
Cooperative Agreement Applications for a single Genetic Analysis, DNA 
and cell line repository and Data Coordinating Center (DCC) and for 
multiple inflammatory bowel disease (IBD) Genetic Research Centers 
(GRC) to participate in the development and implementation of studies 
to identify genes which are associated with Crohn’s disease and 
ulcerative colitis.  The DCC and GRCs will work together cooperatively 
as a Consortium.

The primary objective(s) of this investigation will be identification 
of genes or genomic regions that are associated with increased risk of 
IBD and with specific phenotypic manifestations, such as early age of 
onset, location, complications, rate of progression, response to 
therapy or susceptibility to environmental risk factors.  To achieve 
this objective, two different types of centers will form a consortium 
consisting of centers which will work together with staff from NIDDK to 
achieve the study objectives.

There will be a single Genetic Analysis, DNA and cell line repository 
and Data Coordinating Center (DCC).  This center will be responsible 
for the collection, management and support of analysis of both the 
genetic and clinical data.  The DCC will coordinate communication and 
research with the GRCs. The DCC may apply both existing and novel 
methods for data collection and genetic analysis.  The DCC will play a 
key role in the logistics of the planning and development stage. In 
addition to assisting the GRCs in finalizing the study protocols, the 
DCC will establish the data acquisition, transfer, and management 
system, develop procedures for ensuring subject and control 
confidentiality and safety, develop procedures for quality control, 
training, and certification, develop and produce a manual of 
operations, and supervise the orderly collection and transmission of 
data.

To achieve the aims of the study, the DCC will also be responsible for 
the creation and maintenance of a DNA and cell line repository 
containing appropriate patient and control samples that are required to 
achieve aims of specific research studies.  It is anticipated that the 
repository may be maintained through a contract mechanism from the DCC.  
In addition, the DCC may propose cost-efficient methods to provide 
services, such as genotyping, to GRCs.  Although a DCC and GRC may 
exist at the same institution, the two types of centers will require 
separate applications and these will be evaluated independently, by 
criteria outlined below.

The GRCs will be composed of one or more sites having investigators 
with expertise in genetics and inflammatory bowel disease which will 
participate in the collection of data and genetic materials from 
appropriate groups of patients and propose and execute individual 
research projects.  It is envisioned that the GRC will need to 
concentrate on details of study design, including the development of 
phenotypic criteria and realistic estimates of the appropriate number 
of well-characterized selected patient, family and control subjects to 
achieve the goals of the study. The GRCs will have full responsibility 
for identifying, recruiting and enrolling the necessary number of study 
participants to meet the study goals and bring the study to completion.  
The GRCs will collect and transmit genetic, familial and clinical data 
as delineated in the Manual of Operation. As a part of this 
solicitation, each GRC will propose one or more genetic studies which 
are aimed at the overall objective, stated above, and which will 
effectively use the resources of the consortium.  

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 Request for 
Application (RFA), Inflammatory Bowel Disease Genetics Research 
Consortium, is related to the priority areas of chronic disease and 
childhood illnesses. Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/.  

ELIGIBILITY REQUIREMENTS

Applications may be submitted from either domestic or foreign 
institutions, 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. 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 gastroenterology, 
pediatrics, genetics, and epidemiology. 

Within the Consortium an institution may apply for both a GRC and the 
DCC,  however, each component must have separate application with a 
specific plan of how the independent operation of each unit of the GRC 
and DCC will be maintained. 

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 5 years. This is a one time solicitation. At 
this time, the NIDDK has not determined whether or how this 
solicitation will be continued beyond the present RFA. 
The anticipated award date is July 2002. 

FUNDS AVAILABLE
 
The NIDDK intends to commit approximately $2 million in total costs 
(direct plus Facilities and Administrative (F & A) costs) in FY 2002 to 
fund approximately six IBD Genetics Research Center (GRC) applications 
and one Genetic Analysis, DNA and cell line repository and Data 
Coordinating Center (DCC) application in response to this RFA.  
Applicants for the GRCs may request a project period up to five years 
and a budget for total costs (direct plus F & A) of up to 
$225,000/year.  Applicants for the DCC may request a project period up 
to five years and a budget for total costs (direct plus F & A) of up to 
$650,000/year.  However, exceptions to these guidelines will be 
accepted if, for example, a single GRC consists of a cooperative group 
located at multiple clinical sites.  Because the nature and scope of 
the research proposed in response to this RFA may vary, it is 
anticipated that the size of each award may vary in all years.  Future 
year costs will be distributed based on the recommended protocols, 
database development, patient sample acquisition costs, and research 
protocols proposed and approved by the Steering and Planning Committee.

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 

The human inflammatory bowel diseases, ulcerative colitis (UC) and 
Crohn’s disease (CD) are relatively common chronic diseases of the 
gastrointestinal tract that cause significant morbidity and high 
utilization of health care resources.    The etiology and pathogenesis 
of these diseases remains elusive and therapy is imperfect.  A wealth 
of clinical and basic research information concerning IBD and related 
animal models has appeared in the literature in recent years.  Multiple 
hypotheses regarding pathogenesis are currently under investigation, 
including, among others, possible host immune defects, differences in 
mucosal barrier function and mucosal repair, and interactions between 
the host with the GI mucosal flora.  IBD may be associated with 
distinctly different phenotypic characteristics which may be due to 
differences in underlying host susceptibility and differences in 
environmental factors.  

There is substantial evidence that genetic factors are important in 
IBD.  Multiple lines of evidence based on twin studies, familial risk 
and segregation analysis have suggested that IBD is a complex, non-
Mendelian genetic disorder.  Between 8% and 30% of patients have a 
positive family history.  Based on concordance in twin studies, a much 
greater role for genetic factors has been suggested for Crohn’s disease 
than ulcerative colitis.  However, the pattern of inheritance in IBD 
does not appear to be Mendelian.  Further, the majority of patients 
with both diseases do not have a family history of IBD.

Multiple genes have been examined using a candidate gene approach.  
While HLA loci are associated with IBD in specific populations, the 
role of HLA genes does not appear to be dominant.  Multiple groups of 
investigators have carried out genome wide scans using microsatellite 
markers in families with IBD, and a number of loci have been identified 
with significant, reproducible Lod scores on chromosomes 16, 12 and 1.   
The most widely studied locus on chromosome 16, IBD1, has been recently 
shown to represent mutations in the gene Nod2, about which relatively 
little is known at the present time.  

There are numerous animal models of gastrointestinal inflammation, some 
spontaneous and some experimentally induced or related to selective 
gene inactivation, which have also suggested that gastrointestinal 
inflammatory disease is under complex genetic control and possibly 
intimately related to interactions of the host with the resident 
microbial flora.  It is expected that the identification of genetic 
loci that are critical in gastrointestinal inflammation in the mouse 
will accelerate the identification of syntenic regions in humans that 
may contribute to IBD, although studies of murine genetics do not fall 
within the scope of this solicitation.

The long term goal of this solicitation is a detailed characterization 
of the genetic susceptibility and resistance loci for IBD, which 
hopefully will lead to a better understanding of disease pathogenesis, 
environmental modifying factors, rational design of specific 
pharmaceutical or biological therapies, accurate diagnostic testing for 
risk of IBD, and better rationale for selection of available therapies 
and prognosis.

Research Goals and Scope

It is the intent of this solicitation to invite applications from 
investigators with diverse scientific interests, who wish to apply 
their expertise to the discovery of gene sequences associated with the 
development of IBD.  The specific goals of this solicitation are:  (1) 
to encourage novel approaches to identification of genes and 
interacting environmental factors that contribute to IBD pathogenesis 
through a coordinated genetic analysis and data collection center (2) 
to facilitate collaborative interactions among scientists by formation 
of a cooperative consortium for genetic research (3) to facilitate the 
recruitment of representative patients and families with well-
characterized IBD for prospective studies to delineate genomic regions 
associated with the development and progression of disease(s),  (4) to 
establish a resource for genetic studies of IBD by creating a DNA and 
cell line repository, and (5) to improve outcomes in people having or 
at risk for IBD through genetic research.  

It is anticipated that the study will take place in up to six GRCs  and 
one DCC over a period of five years.  

Study Design

It is anticipated that over the five-year period, several cohorts of 
patients, families and control subjects will be studied by the 
Principal Investigators.  The individual GRCs and the DCC participating 
in the cooperative study should conduct mutually agreed upon protocols 
for characterization of study subjects and for genetic analytic 
strategies.  The GRCs will also conduct independent analyses, and will 
have exclusive access to data from their study populations for a period 
of time, to be determined by the Steering and Planning Committee (see 
below).  The Steering and Planning Committee, will also develop 
policies and procedures that permit utilization of the DNA and cell 
line repository by other investigators who are not members of the 
consortium.

The design of the final research protocol for implementation, including 
the eligibility criteria for the final study population and the studies 
to be undertaken, will be effected by the Steering and Planning 
Committee (see below), which will take into consideration protocols 
submitted and evaluated by the Scientific Review Group during the 
review process.

Study Components

1.  IBD Genetic Research Centers (GRCs)

A GRC is an institution that is actively involved in the recruitment 
and evaluation of patients, family members and control subjects and the 
initiation of individual, center-specific genetic studies taking 
advantage of special patient populations.  The GRC should consist of an 
interdisciplinary team of investigators and appropriate personnel, such 
as a research coordinator and clerical staff.

GRCs will be required to submit familial, phenotypic, diagnostic, 
medical therapeutic and genetic data as well as blood samples for the 
DNA and cell line repository to the DCC.  The GRC must work in concert 
with the DCC to implement procedures for uniform data collection, 
handling and transmittal of data, as well as data audits and other data 
quality control procedures, as established by the study protocol.  The 
GRC will be required to share data and patient specimens derived from 
collaborative studies.  The Principal Investigator and Co-Investigators 
in each GRC should be skilled in collaborative clinical investigation. 
It is anticipated that the GRCs will conduct independent analyses and 
will have exclusive access to data from their study populations for a 
period of time to be determined by the Steering and Planning Committee.  
Individual, center-specific projects may be conducted through the 
auspices of the DCC.  The GRCs and DCC will develop uniform procedures 
and data sharing policies, and independently and collectively allocate 
resources and personnel for the performance of independent, center-
specific analyses and studies.

2. Genetic Analysis, DNA and cell line repository and Data Coordinating 
Center (DCC)

There will be a single DCC.  This center will be responsible for the 
collection, management and analysis of both the genetic and clinical 
data and coordinating communication and research with the Participating 
Investigating Centers. The DCC is encouraged to propose to use both 
existing and novel methods for data collection and genetic analysis.  
The DCC will play a key role in the logistics of the planning and 
development stage. It is anticipated that in the proposal, criteria for 
standardization of patient, family member and control population 
selection criteria and genetic studies, and data collection for the 
investigations to be performed will be outlined.  In addition to 
assisting the GRCs in finalizing the study protocols, the DCC will 
establish the data acquisition, transfer, and management system, 
develop procedures for ensuring subject and control confidentiality and 
safety, develop procedures for quality control, training, and 
certification, develop and produce a manual of operations, and 
supervise the orderly collection and transmission of data. The DCC 
should be prepared to assume a key role in overseeing implementation 
and adherence to the study protocols, and assuring quality control of 
the data collected.  

To achieve the aims of the study, the DCC will also be responsible for 
the creation and maintenance of a DNA and cell line repository 
containing appropriate patient and control samples that are required to 
achieve aims of specific research studies.  It is anticipated that the 
repository may be maintained through a contract mechanism from the DCC.  
In addition, the DCC will have overall responsibility for genotyping 
and may propose cost-efficient methods to provide services to GRCS.  
Although a DCC and GRC may exist at the same institution, the two types 
of centers will require separate applications and these will be 
evaluated independently, by criteria outlined below.

The DCC will be expected to provide appropriate molecular biologic, 
biostatistical, data management, and coordination and genetic analysis 
expertise, as well as supporting the special independent studies 
proposed by the individual GRCs and approved by the Steering and 
Planning Committee (see below).  Sub-contracting of various aspects of 
the DCC to other institutions with special expertise may be included in 
the application. The DCC also will be expected to generate 
appropriately detailed reports to the Steering and Planning Committee 
and to the NIDDK staff (see below) at regular intervals, and will be 
responsible for the logistics and planning of the meeting of these 
committees and their subcommittees.

3.  Steering and Planning Committee

The primary governing body of the study will be the Steering and 
Planning Committee comprised of each of the Principal Investigators of 
the GRCs and the DCC, the Chairperson of the Steering and Planning 
Committee, and the NIDDK Project Coordinator (described in detail under 
Terms and Conditions).  The NIDDK staff will initially appoint an 
interim chairperson prior to the first meeting of the Steering 
Committee.

4.  Project Coordinator

The NIDDK will appoint a Project Coordinator, within the Division of 
Digestive Diseases and Nutrition, to assist the Steering and Planning 
Committee in carrying out the proposed studies (described in detail 
under Terms and Conditions).  The Project Coordinator will provide 
scientific support to awardees activities, including protocol 
development, quality control, interim data monitoring, final data 
analysis and interpretation, preparation of publications, and overall 
performance monitoring.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

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.

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.

1) Awardees Rights and Responsibilities

o 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 of protocols will be 
approved by the Steering Committee.

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 
GRCs during all phases of the research studies and will maintain the 
specimen repository.  Thus, the awardee is expected to work 
cooperatively with GRCs and sponsoring organizations in a multi-center 
study 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 GRCs.
 
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 
design 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 GRCs, 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 
alternatively, from among experts in the field of IBD who are not 
participating directly in the study.  Subcommittees will be established 
for specific purposes as needed, such as for ancillary studies, 
publications and presentations, quality control, recruitment, protocol 
adherence, among others.  

Each Consortium GRC 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 
GRCs 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.

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

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

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.

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.

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 October 17, 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 GRC 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 avoid conflict of interest 
in the review.

The letter of intent is to be sent to the Chief, Review Branch at the 
address listed under INQUIRIES, below.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/01) 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

Application Requirements

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.

1.  GRC Applications

Applicants for the GRCs should respond with research protocols 
involving multicenter participation to address the objectives of the 
study and to reach the study goals.  It is anticipated that applicants 
will develop criteria for studying specific subgroups of patients with 
IBD.  Applicants should outline the rationale and background of the 
proposed studies, study design and protocols, eligibility criteria, 
type of patients, family members and control subjects to be included in 
the studies, and initial power analyses in their applications.  For 
each of the clinical protocols, the GRC applicants should discuss the 
characteristics and number of potential participants that would be 
available from their own geographic region.  It is anticipated that GRC 
applicants will propose a varying number of studies, but the submitted 
research plan should remain within the 25 page limit.  

Genetic studies involving individual subjects and groups of people 
necessarily involve information that should be kept highly 
confidential.  It will be critical that at all phases of the study, the 
investigators understand and minimize the risks involved in such 
genetic research,  protecting both individual subjects and research 
participants in groups, and optimize procedures for obtaining informed
consent.

An application for a GRC should provide evidence that the investigators 
are capable of recruiting a sufficient number of participants for the 
proposed studies, and initiating and completing independent studies 
consistent with the overall goals of this RFA.  Applicants for GRCs 
should describe the target population from which they expect to recruit 
the required number of patients, family members and control subjects as 
study participants, and plans for recruitment of women, minorities, and 
children, as required. In addition, applicants for a GRC will submit 
proposals and power analyses for cost-effective strategies to address 
their individual study questions, taking advantage of their particular 
geographic locations and patient populations.  Proposed provisions to
ensure confidentiality and to optimize informed consent procedures must 
be presented in the application.

There should be evidence of strong institutional support for the GRC, 
including adequate space in which to conduct clinical and research 
activities and office space for staff. An organizational structure for 
the GRC should be set forth in the application, delineating lines of 
authority and responsibility for dealing with problems in all general 
areas as well as stated willingness to follow commonly agreed upon
protocols.  The principal investigator should indicate their 
willingness to participate in a per patient basis for operational costs 
of patient specimen acquisition and processing.  There must be ability 
to interact with the DCC and transmit and edit data.

The applicant should include a succinct discussion of previous relevant 
research efforts.  Applicants for GRCs should consider the economies of 
scale to be gained and cost effectiveness of strategies of research 
plans involving large numbers of patients.  The applicant should also 
discuss in detail the recruitment strategies to procure the expected 
number of study participants.  Specific plans for recruitment of 
minority participants and children must also be discussed.  

The applicant should indicate willingness to participate in the 
Consortium concept outlined in this solicitation, participate in the 
Steering Committee meetings and abide by its decisions, and indicate 
prior experience in collaborative, multi-center research.  

2. DCC Applications

A separate complete application is required from institutions applying 
to be the DCC.  Applicants for the DCC component are not required to be 
a GRC site within the Consortium,  however applicants for the DCC are 
also encouraged to submit an application for a GRC.   It is anticipated 
that there may be considerable areas of overlap if both applications 
are submitted from the same group of investigators.

Applicants must describe plans to achieve the stated “Objectives and 
Scope,” ”Special Requirements,” and “Terms and Conditions of Award” 
stated in this RFA.  In addition, applicants should document their 
willingness to participate on the Steering Committee and appropriate 
subcommittees, work cooperatively with other members of the Steering 
Committee, and follow the common protocol established cooperatively by 
the Steering Committee.  It is expected that the PI of the DCC would 
carry out a significant leadership role in the consortium.  

Applicants must also address the following regarding responsibilities 
and requirements for the DCC:  

Participation in the design of the genetic analyses to be undertaken, 
development of research studies and development of the manual of 
operation, data collection forms, and questionnaires, 

Development and implementation of systems for communication among 
Steering Committee members, and among study sites, 

Data collection, editing, processing, analysis, and reporting,

Monitoring of adherence to the research plan and of data quality,

Establishment of procedures that insure the safety and confidentiality 
of all records.

Specific experience in coordinating or monitoring studies of IBD is 
highly desirable, but if this does not exist collaboration with experts 
in IBD is strongly encouraged.

The applicant for the DCC must delineate a plan for development and 
operation of a DNA and cell line repository.  

The applicant for the DCC should also address any issues regarding 
common services, such as genotyping, that could be provided to the 
various participating GRCs.

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 coordinating tasks.

BUDGET AND RELATED ISSUES

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

1.  GRC Applications 
 
GRCs should consider the following issues regarding budgets.  A central 
concept is that a core clinical effort will be required to maintain the 
infrastructure required to accurately phenotype patients and acquire 
clinical specimens.  Based on this approach, it is estimated that the 
individual GRCs will require a minimum level of effort to sustain the 
organizational aspects of this aspect of the study.  Therefore, 
individual GRCs should submit requests for a CORE BUDGET.  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 one or two individuals to attend consortium 
meetings up to four times a year in Bethesda, MD.  Depending on the 
sample size requirements, it may be necessary for GRCs to subcontract 
to other clinical sites to obtain a sufficient number of patients and 
specimens for analysis.  The core budget will include per patient costs 
for obtaining specimens from patients to forward to the DNA and cell 
line repository.  These costs should be justified appropriately in 
budgets and may be distributed into subcontracts.  Escalation is 
allowed at three percent for future years.  Costs for clinical care are 
not permitted.

In addition to the core budget, each GRC will be provided funds for 
implementation of research studies.  The precise number of protocols 
conducted will be determined by the Consortium Steering Committee and 
will depend on availability of funds.  It is anticipated that one or 
more studies may originate at each center.  Allowable total costs for 
each GRC  (core costs, costs per patient to conduct the protocols, and 
indirect costs) will vary.  However, it is anticipated that the average 
total costs for each GRC will be $225,000 per year.  

The Consortium awards will be subject to administrative review 
annually.

2.  DCC applications

Applicants for the DCC should prepare budgets for five 12-month periods 
(not to exceed $650,000 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 Consortium to be developed and with the 
initiation of at least one research protocol.  For subsequent years, 
applicants may assume that multiple research studies will be active, 
i.e. either in the protocol development, implementation, or analysis 
and writing phase.  

The DCC will be subject to administrative review annually. 

SUBMISSION INSTRUCTIONS

The RFA label available in the PHS 398 (rev. 7/01) application form 
must be stapled to the bottom of the face page of the application and 
must display the RFA number DK-02-011.  A sample RFA label is available 
at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  Please 
note this is in the pdf format.  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.
 
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 O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Blvd.
Room 752, MSC 5452
Bethesda, MD  20892-5452 (Courier use ZIP 20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

Applications must be received by November 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

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.  The  acknowledgement of  potential problem 
areas and the consideration of 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:  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.

Applicants are encouraged to submit and describe their own ideas about 
how best to meet the goals of the cooperative study and their specific 
protocols. The evaluation of applications for GRCs and the DCC will be 
based primarily on the scientific merit of the proposed studies, as 
defined above.  Specific criteria for review of applications will also 
include:

For both Participating Investigating Centers and the Genetic Analysis 
and Data Coordinating Center:

1.  The scientific merit of the proposed study design(s) to address the
objectives of the RFA, including strategies for patient identification 
and recruitment, and data collection and management, as outlined in the 
RFA.

2.  Adequacy of the facilities and space.

3.  Understanding and awareness of the scientific, ethical, and 
practical issues underlying the proposed studies and appropriateness of 
plans to deal with them.

4.  Evidence of the degree of institutional commitment and support for 
the proposed program, including the relative position of the proposed 
project staff within the applicant"s organizational structure.

5.  Willingness to carry out a commonly agreed upon study protocol, and 
to share patient data and specimens derived from collaborative studies.

6.  Adequacy of plans to ensure accurate collection, confidentiality 
and timely transmission of study data.

7.  The organizational and administrative structure of the proposed 
program.

For GRCs:

1.  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the 
operation of a GRC in previous collaborative clinical investigations. 
Evaluation will include the following: familiarity with and experience 
in recruiting participants in a study, handling laboratory specimens, 
working in collaboration with other investigators under a common 
protocol, ability to implement study procedures, and meticulous and 
expeditious handling of study data.

2.  Documentation of access to patient population(s) from which a 
substantial number of participants can be recruited in sufficient 
numbers to meet the goals specified in the RFA.

3.  Ability to recruit representative minority populations and 
children, as required.

4.  Adequacy of proposed sample sizes and strategies for cost effective 
patient recruitment and data collection.

For the DCC:

1.  Documentation of the specific competence and experience of 
professional, technical, and administrative staff pertinent to both the 
molecular biologic, biostatistical and data coordination aspects of the 
proposed study.  Prior experience in similar studies, in the collection 
of data and patient specimens from multiple locations, as well as 
experience in monitoring the quality and timeliness of such data, 
should be demonstrated.

2.  Demonstrable knowledge of the potential problems associated with 
the conduct of this study and possible solutions must be demonstrated.

3.  Suitability of proposed data management and data analytic plans.

4.  Ability to design, implement and maintain a distributed data entry 
system for the GRCs.

5.  The approach to and likelihood of soliciting cooperation from the
participating GRCs and exercising appropriate leadership in matters of 
study design and protocol revisions, and data acquisition, management, 
and analysis.  Specific plans for ensuring standardization and quality 
control of data collection across all study sites are required.

6.  The adequacy of the proposed technical hardware.

7.  Provision of cost-effective strategies for genotyping large 
populations and reliable estimates of genotyping costs for the 
contemplated joint and independent large-scale, high-throughput 
studies.

8.  Ability to organize and provide oversight for a DNA and cell line 
repository suitable for the proposed studies for the consortium.

SCHEDULE

Letter of Intent Receipt Date:    October 17, 2001
Application Receipt Date:         November 20, 2001
Peer Review Date:                 March/April 2002
Council Review:                   May 2002
Earliest Anticipated Start Date:  July 2002

AWARD CRITERIA

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

o Scientific and technical merit of the application for a GRC or a DCC.

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

o Demonstration of expertise to manage, design and coordinate 
multicenter clinical research studies, including handling and storage 
of laboratory specimens (DCC).

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 Consortium a reasonable likelihood. 

o Availability of funds.

o Access to patients including children and minority individuals.

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

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:

Stephen P. James, M.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd.
Room 675, MSC 5450
Bethesda, MD  20892-5450
Telephone:  (301) 594-7680
FAX:  (301) 480-8300
Email: sj158p@nih.gov
 
Direct inquiries regarding review matters to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd.
Room 752, MSC 5452
Bethesda, MD  20892-5452
Telephone:  (301) 594-8885
FAX:  (301) 480-3505
Email:  fc15y@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Carolyn Kofa
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd.
Room 727, MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-7687
FAX:  (301) 480-3504
Email:  ck104i@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.



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