BARRETT’S ESOPHAGUS, GASTROESOPHAGEAL REFLUX DISEASE AND ADENOCARCINOMA OF 
THE ESOPHAGUS

Release Date:  September 17, 2001

RFA:  RFA-DK-02-015

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

Letter of Intent Receipt Date:  February 20, 2002
Application Receipt Date:       March 20, 2002

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS 
THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED 
IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

This initiative is designed to stimulate and solicit studies to broadly 
address the problem of Barrett’s esophagus and its etiology and relationship 
to gastroesophageal reflux disease (GERD) and its link to the rising 
incidence of adenocarcinoma of the esophagus.  The specific areas of emphasis 
of this initiative will include novel approaches for molecular 
characterization of Barrett’s metaplasia and dysplasia in comparison to 
normal squamous and intestinal epithelium, identification of esophageal stem 
cells and the factors responsible for specific differentiation pathways into 
either squamous or intestinal epithelium, regeneration of squamous mucosa, 
the molecular precursors or predictors of dysplasia, identification of serum 
biomarkers of metaplasia or dysplasia, development of suitable animal models 
to study pathogenesis, chemoprevention or treatment strategies, and clinical 
studies aimed at revealing environmental or genetic risk factors or the role 
of gastroesophageal reflux in Barrett’s esophagus.  In addition to 
hypothesis-driven R01 projects, this initiative will encourage development of 
new research tools through Exploratory/Developmental Grants (R21).

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 
Applications (RFA), “Barrett’s Esophagus, Gastroesophageal Reflux Disease, 
and Adenocarcinoma of the Esophagus,” is related to one or more of the 
priority areas.  Potential applicants may obtain a copy of "Healthy People 
2010" at http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and 
nonprofit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal Government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 
investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) and exploratory research grant (R21) mechanisms.  Except as 
otherwise noted in this announcement, awards will be administered under 
policies as stated in the NIH Grants Policy Statement. R01 applications 
submitted in response to this RFA may not request a total project period of 
more than five years.  The maximum budget request for R01 applications should 
be limited to $250,000 in direct costs for each budget year.  Exploratory 
research grant (R21) applications may not exceed two years for the total 
project period.  The maximum budget request for R21 applications may not 
exceed $100,000 in direct costs for each budget year.  The R21 grant 
mechanism may be used by new investigators or experienced investigators to 
develop pilot and feasibility studies for new and innovative approaches.  R21 
applications generally are expected to have little preliminary data and are 
reviewed based on the development of hypotheses and supporting literature.

Applicants from institutions that have a General Clinical Research Center 
(GCRC) funded by the NIH's National Center for Research Resources may wish to 
identify the GCRC as a resource for conducting the proposed research. In such 
a case, a letter of agreement from either the GCRC Program Director or 
principal investigator should be included with the application.  

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
applications and be reviewed according to customary peer review procedures.  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The anticipated award date is 
September 30, 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

FUNDS AVAILABLE

The NIDDK and NCI intend to commit approximately $2.5 million in FY 2002 to 
fund approximately six new research project grants (R01) and six new 
exploratory research grants (R21) in response to this RFA.  Although the 
financial plans of the NIDDK and NCI 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. 

RESEARCH OBJECTIVES

Background

Barrett’s esophagus (BE) is a pre-malignant condition of the esophagus 
characterized by the presence of specialized intestinal metaplasia in the 
esophagus that is normally lined by squamous epithelium.  The prevalence of 
BE is significantly increased in patients with long-standing gastroesophageal 
reflux disease (GERD), one of the most common gastrointestinal disorders.  
Furthermore, in some patients BE undergoes neoplastic transformation into 
dysplasia and esophageal adenocarcinoma, a disease of high morbidity and 
mortality that has a rapidly rising incidence in the United States.  At the 
present time there are many unanswered questions about BE suitable for 
further research that are the subject of this solicitation.

A number of studies have attempted to define the epidemiology of BE.  It is 
found in about 1% of the older population and in 3% to 5% of patients with 
gastroesophageal reflux, which is the primary risk factor associated with BE.  
However, the great majority of patients with BE remain undiagnosed, as 
patients with BE are more likely to have clinically silent gastroesophageal 
reflux.  Accurate population based data on the prevalence, incidence, and 
long-term natural history of BE are currently unavailable.  

At the present time the only clinically accepted method to diagnose BE is by 
endoscopy and biopsy, which entails high cost, patient and provider time, and 
potential risks.  The diagnosis is complicated by concerns about non uniform 
endoscopic and histologic criteria for diagnosis.  

The etiologic factor(s) and pathophysiological steps responsible for 
transformation of the normal squamous lined esophagus into BE are unknown. 
There are no accepted animal models that faithfully reproduce the human 
condition that are suitable for pathophysiological studies.  The major 
factors controlling the extent, progression or potentially, regression of BE 
are similarly unknown.

The major health care concern regarding BE is the predisposition for 
transformation into dysplasia and adenocarcinoma.  The factors and 
pathophysiological steps responsible for transformation of metaplasia into 
dysplasia or into invasive carcinoma are unknown.  Molecular techniques have 
identified candidate molecular markers that may characterize dysplasia and 
carcinoma.  However, there are no accurate predictive factors that 
distinguish patients who are likely to progress to adenocarcinoma vs. 
patients with a benign course, which is the most common outcome.  As for 
diagnosis of BE, the only currently accepted procedure for identification of 
dysplasia and/or adenocarcinoma is endoscopy and biopsy.  The risk/benefit 
estimates for surveillance in patients with known BE have led to guidelines 
for repeated endoscopic surveillance.  However, many patients with BE remain 
undiagnosed and for those with the diagnosis, surveillance for dysplasia and 
cancer remain imperfect.  Most patients presenting with adenocarcinoma have 
not had a prior diagnosis of BE or surveillance.

At the present time, no medical therapy has proved effective in preventing 
the development of BE or the progression of BE to dysplasia or carcinoma, 
short of esophagectomy, a radical surgical procedure with high potential 
morbidity and mortality.  A variety of experimental procedures exist with the 
potential for elimination of BE or  dysplasia, but the long term outcomes of 
these approaches are currently unknown. 

Research Scope

This initiative encourages further basic and clinical investigation aimed at 
a broad range of problems, including epidemiology, mechanisms responsible for 
BE, it progression, diagnosis, mechanisms of transformation to dysplasia and 
adenocarcinoma, diagnosis, treatment and prevention.  Research aimed at 
fundamental biological and physiological processes in the esophagus that 
might be relevant to BE are also appropriate subjects for this solicitation.  
This solicitation specifically excludes applications for clinical trials of 
esophageal cancer therapy, which should be submitted through other 
mechanisms.  

Areas of particular focus for R01 grant applications include, but are not 
limited to:

o Identification of the cell of origin of BE metaplasia, the nature of 
esophageal stem cells, and factors that determine differentiation into 
mature squamous epithelium.

o Molecular characterization of BE and dysplasia.

o Validation of animal models suitable for research on BE involving 
pathogenesis, prevention or treatment.

o Identification of genetic risk factors for BE, dysplasia or 
adenocarcinoma.

o Identification and validation of biomarkers for BE, dysplasia or early 
adenocarcinoma.  

o Identification of the pathophysiological steps leading from GERD to BE 
metaplasia;  factors controlling injury and repair relevant to BE.

o Identification of alternative strategies for diagnosis of BE or 
surveillance strategies for dysplasia in patients with known BE.

o Epidemiological studies of incidence, prevalence, natural history and 
risk factors of BE and factors determining progression to dysplasia or 
adenocarcinoma that provide important new insights that can be achieved 
within the budget and time constraints of this solicitation.

o Identification of novel environmental risk factors for BE, dysplasia, 
or adenocarcinoma.

In addition to hypothesis-driven R01 applications, this initiative will 
support exploratory/ developmental efforts using the R21 mechanism that seek 
to explore highly innovative and potentially high risk approaches for the 
study of BE for which there may be limited preliminary data.  This mechanism 
would be acceptable for new investigators entering the field or established 
investigators not currently working in the field of BE who wish to apply 
novel technologies or approaches to this problem.

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 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 February 20, 2002, a letter of 
intent that includes a descriptive title of the proposed research; the name, 
address, and telephone number of the Principal Investigator; the identities 
of other key personnel and participating institutions; and the number and 
title of the RFA in response to which the application may be submitted.

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NIDDK and NCI staff to estimate the potential review workload 
and plan the review.

The letter of intent is to be sent to:

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

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format. For further assistance contact 
GrantsInfo, Telephone 301/435-0714, Email: GrantsInfo@nih.gov.

All application instructions outlined in the PHS 398 application kit are to 
be followed.  All applications will use the “MODULAR GRANT” and “JUST-IN-
TIME” concepts, with direct costs requested in $25,000 modules.  The 
following requirements apply specifically to R21 applications:  

1.  R21 applications may request up to $100,000 per year in total direct 
costs. 

2. Although preliminary data are not required for an R21 application, they 
may be included.

3.  Sections a-d of the Research Plan of the R21 application may not exceed 
15 pages, including tables and figures.  

4.  R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to circumvent 
the page limit for the research plan.   Copies of appendix material will only 
be provided to the primary reviewers of the application and will not be 
reproduced for wider distribution.  The following materials may be included 
in the appendix:

o Up to five publications, including manuscripts (submitted or accepted 
for publication), abstracts, patents, or other printed materials 
directly relevant to the project.  These may be stapled as sets.
o Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.
o Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included 
within the 15 page limit of items a-d of the research plan

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award. It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers 
and NIH staff.  The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  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 RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

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 Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service:  Bethesda, MD  20817)

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

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

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK and NCI.  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 review criteria stated below.  As 
part of the initial merit review, all applications will receive a written 
critique and undergo a process in which only those applications deemed to 
have the highest scientific merit, generally the top half of the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by appropriate National Advisory Council/Board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss 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.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

o Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

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

o Innovation:  Does the applicant employ novel tools, 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?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there 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 Adequacy of plans to include both genders, minorities and their subgroups, 
and children as appropriate for the scientific goals of the research.  Plans 
for the recruitment and retention of subjects will also be evaluated.  The 
reasonableness of the proposed budget and duration to the proposed research 
will also be reviewed.

o The adequacy of the proposed protection of humans, animals, or the 
environment, to the extent that they may be adversely affected by the project 
proposed in the application.

o Availability of special opportunities for furthering research programs 
through the use of unusual talent resources, populations, or environmental 
conditions in other countries which are not readily available in the United 
States or which provide augmentation of existing U.S. resources.

SCHEDULE

Letter of Intent Receipt Date:    February 20, 2002
Application Receipt Date:         March 20, 2002
Peer Review Date:                 July, 2002
Council Review:                   September, 2002
Earliest Anticipated Start Date:  September 30, 2002

AWARD CRITERIA 

The following will be considered in making funding decisions:

o Quality of the proposed project as determined by peer review;
o Availability of funds;
o Program priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Frank Hamilton, M.D., M.P.H.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 663
Bethesda, MD  20892-5458
Telephone:  (301) 594-8877
FAX:  (301) 480-8300 
E-mail:  fh14e@nih.gov
 
Ellen Richmond, M.S., R.N., C.S.
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North
6130 Executive Boulevard, Room 2148
Bethesda, MD  20892
Telephone:  (301) 435-2466
FAX:  (301) 435-6344
E-mail:  richmone@mail.nih.gov

Direct inquiries regarding NIDDK fiscal and administrative matters to:

Ms. Carolyn Kofa
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 727
Bethesda, MD  20892
Telephone:  (301) 594-7687
FAX:  (301) 480-3504
E-Mail:  ck104i@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.848 and No 93.393.  Awards are under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 
99-158, 42 USC 241 and 285) and administered under NIH grants policies and 
Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This program is 
not subject to the intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-use of all tobacco products.  In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking 
in certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care or early 
childhood development services are provided to children.   This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.


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