Full Text DK-92-15


NIH GUIDE, Volume 21, Number 8, February 28, 1992

RFA:  DK-92-15

P.T. 34

  Clinical Trial 
  Digestive Diseases & Disorders 

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  May 15, 1992
Application Receipt Date:  July 15, 1992


The Division of Digestive Diseases and Nutrition of the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites
applications for single and multicenter clinical trials in digestive
and nutritional diseases.  Diseases and research areas of particular
importance include, but are not limited to, definitive treatments of
helicobacter pylori infection, inflammatory bowel disease, primary
biliary cirrhosis and primary sclerosing cholangitis.  Other areas of
importance are innovative approaches to prevention, management and
treatment of portal hypertension, recurrent liver disease after hepatic
transplantation and adolescent and adult obesity.  This Request for
Applications (RFA) is a follow-up to an RFA (DK-91-02) entitled
"Planning Grants for Clinical Trials in Digestive and Nutritional
Diseases, NIH Guide for Grants and Contracts, Vol. 19, No. 39, November
2, 1990.  Responses, however, are not limited to recipients of that


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Clinical Trials for Digestive and Nutritional Diseases, is related to
the priority area of diabetes and chronic disabling conditions.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325,
(telephone 202-783-3238).


Applications may be submitted by domestic and foreign public and
private, non-profit and for-profit organizations such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal Government.  Women
and minority investigators are encouraged to apply.


Support of this program will be through the NIH research project grant
(R01).  Responsibility for the planning, direction, and execution of
the proposed project will be solely that of the applicant.  Except as
otherwise stated in this announcement, awards will be administered
under the PHS grants policy as stated in the PHS Grants Policy

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications.  The total requested project period for applications
submitted in response to this RFA may not exceed five years.  The
earliest possible award date will be April 1, 1993.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research Resources
may wish to identify the GCRC as a resource for conducting the proposed
research.  In such a case, a letter of agreement from either the GCRC
program director or a Principal Investigator must be included with the


For FY 93, up to $1.2 million in total costs (direct plus indirect)
will be committed to fund applications submitted in response to this
RFA.  It is anticipated that two awards will be made.  However, this
funding level is dependent upon the receipt of a sufficient number of
applications of high scientific merit.  In order to help meet NIDDK
goals for managing the costs of biomedical research, applicants must
limit the requests to not more than $400,000 direct costs for the
initial budget period.  Although this program is provided for in the
financial plans of the NIDDK, the award of grants pursuant to this RFA
is also contingent upon the availability of funds for this purpose.


Recent advances in basic biomedical research have provided new insights
into the pathogenesis of many nutritional and digestive diseases.
These advances have led to new possibilities for therapeutic
intervention in these diseases.  New therapies or interventions are
best evaluated in prospective, randomized controlled clinical trials.

In the area of digestive diseases and nutrition there are several
diseases and conditions that warrant studies of new therapeutic
interventions.  Digestive and nutritional diseases and conditions for
which no satisfactory long-term therapies exist include helicobacter
pylori, portal hypertension, severe obesity, inflammatory bowel
disease, recurrent liver disease after hepatic transplantation, and
primary biliary cirrhosis.  These are important conditions that affect
many Americans and cause considerable morbidity and mortality.  Primary
biliary cirrhosis, for example, is an autoimmune disease of the liver
that largely affects women and leads slowly but inexorably to cirrhosis
and death from liver failure. Primary biliary cirrhosis is currently
one of the leading indications for liver transplantation in adults.
Despite these features, there is currently no therapy of proven benefit
for primary biliary cirrhosis.  In recent years, several small clinical
trials in primary biliary cirrhosis have reported some benefit of
several agents including ursodeoxycholic acid, chlorambucil,
cyclosporine A, methotrexate, Prednisone, and Colchicine.  Although
results from several of these studies have been promising, they have
not been convincing enough to provide firm guidance for therapy of
patients with this disease.  It is obvious, however, that one or
several of these agents could be adequately evaluated in an
appropriately designed, large, multicenter, randomized controlled

Treatments of several major digestive and nutritional diseases are
unsatisfactory and the consequences of these conditions often involve
major physical, personal, emotional, and financial burdens.  For
example, duodenal ulcer disease affects 5 to 10 percent of the United
States population and is a major cause of absenteeism from work,
physician visits, hospitalization, and health care costs. In recent
years, asymptomatic gastrointestinal infection with helicobacter pylori
has been linked to the development of duodenal ulcer disease.  It may
be that eradication of an underlying helicobacter pylori infection by
antibiotic therapy may not only speed healing of an active duodenal
ulcer but also prevent recurrences.  Randomized, controlled clinical
trials with long-term follow up are needed to establish whether or not
eradication of helicobacter pylori should be the routine approach to
the patient with duodenal ulcer disease and whether or not it will
reduce the morbidity, recurrence rate, and medical care costs of this
disease.  The recent link of helicobacter pylori infection with gastric
cancer makes the need for better knowledge regarding the natural
history of helicobacter pylori infection and its modification by
treatment all the more important.

Among nutritional disorders, perhaps the most common and most
clinically challenging condition is obesity.  At least 26 percent of
all adult Americans are overweight or obese, and twice this proportion
of Black and Mexican-American women are overweight or obese.  Obesity
is linked to many significant medical problems including coronary
artery disease, stroke, hypertension, diabetes, gallbladder disease,
and some forms of cancer.  Innovative approaches are needed for both
the treatment and prevention of obesity.  These approaches might
include surgery for severe obesity; combinations of exercise, diet, and
behavior modification for mild to moderate obesity; and early
identification of persons at risk and suitable interventions for the
prevention of obesity.  Successful interventions may vary with the
population studied.


Awardees will be required to submit quarterly progress reports to the
NIDDK the include recruitment data, indices of quality control,
mortality, morbidity, and changes in the protocol.  Applicants must
include such plans in the budget requests and a statement about
willingness to participate in coordination among investigators.


It is NIH policy that women and minorities must be included in clinical
study populations unless there is a good reason to exclude them.  The
study design must seek to identify any pertinent gender or minority
population differences.


NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements are required to include
minorities and women in study populations so that research findings can
be of benefit to all persons at risk of the disease, disorder or
condition under study; special emphasis must be placed on the need for
inclusion of women and minorities in studies of diseases, disorders and
conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in a clinical
research project, particularly in proposed population-based studies, a
clear compelling rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 in Sections 2,
A-D of the Research Plan AND summarized in Section 2, E, Human
Subjects.  Applicants/offerors are urged to assess carefully the
feasibility of including the broadest possible representation of
minority groups. However, the NIH recognizes that it may not be
feasible or appropriate in all research projects to include
representation of the full array of United States racial/ethnic
minority populations (i.e., Native Americans [including American
Indians or Alaskan Natives], Asian/Pacific Islanders, African Americans
[blacks] Hispanics.  The rationale for studies on single minority
population groups should be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly,and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.


Prospective applicants are asked to submit, by May 15, 1992, 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 is being submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of applications.
It allows NIDDK staff to estimate the potential review workload and to
avoid possible conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-7083


The research grant application form PHS-398 (revised 9/91) is to be
used in applying for these grants.  The form is available from most
institutional business offices and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/496-7441.

Applicants are strongly encouraged to obtain the Administrative
Guidelines for Clinical Trials which are available from the NIH
Clinical Trials Program Director listed under INQUIRIES, prior to
preparing an application

The RFA label available in the PHS 398 application kit must be affixed
to the bottom of the face page.  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 check the YES box.

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

National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional copies of the application must
also be sent under separate cover to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
5333 Westbard Avenue
Bethesda, MD  20892

Applications must be received by July 15, 1992.  If an application is
received after that date, it will be returned to the applicant.  The
Division of Research Grants (DRG) will not accept any application in
response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  However, it is allowable to submit the same
project as both an R01 and as a component project of a P01.  The DRG
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.  Such applications must
not only include an introduction addressing the previous critique but
also be responsive to this RFA.


Upon receipt, applications will be reviewed by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for responsiveness
to the program requirements and criteria stated in the RFA is an NIDDK
staff function.  If the application is not responsive to the RFA, NIDDK
staff will contact the applicant to determine whether it will be
returned to the applicant, or held until the next receipt date for
unsolicited applications and reviewed by a study section in the DRG.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NIDDK Review

If the number of applications is large compared to the number of awards
to be made, the NIDDK may conduct a preliminary scientific peer review
(triage) and withdraw applications from further competition if they are
not competitive for award.  The NIDDK will notify the applicant and
institutional official of this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an NIDDK initial review group specifically
convened for this RFA.  Following study section review, the
applications will be given a secondary review by the NIDDK Advisory
Council unless not recommended for further consideration by the initial
review group.

In addition to the review criteria for clinical trials as stated below,
the following review criteria that are used for unsolicited research
grant applications will apply:

o  scientific/technical merit;

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly but not exclusively in the area of the proposed

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

For the initial review of the clinical trial application, the specific
review criteria are:

o  The importance of question(s) and the need for and significance of
the clinical trial, i.e., its potential impact.

o  The scientific and technical merit of the clinical aspects of the

o  The overall feasibility and the likelihood of achieving the clinical
trial goals and the potential for a successful trial.

o  The pilot phase experience including evidence of patient accession
and retention and the functioning of any laboratory coordinating

o  The adequacy of the statistical features of the study including
sample size projections and power estimates, methods of analysis, and
the use of sequential analyses of data.

o  The logistical aspects of the project including the accumulation
flow, quality control of data, proper randomization and masking
procedures, the operation of any central laboratories, and plans for
defining access and restriction to data.

o  The availability of suitable subjects for the clinical trial and the
likelihood of participation through to completion of the follow-up.

o  The qualifications, experience, and availability of key
investigators in the content area of the trial and in the conduct of
clinical trials in general.

o  The adequacy of ethical and human safety issues, including current
Institutional Review Board (IRB) human subjects approval(s).

o  An adequately documented working plan for the trial.

o  The likelihood of successfully administering a cohesive
collaborative effort.

o  The appropriateness of the proposed budget.

The initial review group will evaluate the proposed gender and minority
composition of the study population in relation to the scientific
issues being addressed during scientific and technical merit reviews.

An award will not be made until sufficient information on the study
population is provided.  This will assure compliance with the
NIH/ADAMHA policy on the inclusion of women and minorities in study
populations.  Since the need to modify sample design could delay the
award, cause re-review of the application, and affect the costs of the
study, applicants are strongly advised to address this issue in the
initial submission.  If costs or study designs are significantly
affected by such modifications, deferral with submission of a revised
grant application for initial review and/or reconsideration by an
appropriate National Advisory Council or Board may be necessary.  Note
that since this RFA is a one-time solicitation, any submission of an
amended application would very likely be in the general NIH
investigator-initiated competition.

For the initial review of the individual institutions participating in
a multicenter clinical trial as a participating center, the review
criteria will include:

o  The commitment of the institution and staff to a collaborative
protocol and to the success of the study. The inclusion of letters of
agreement from collaborating investigators, countersigned by the
appropriate institutional official is necessary.

o  The qualifications and the experience of the investigators and the
availability of suitable subjects for the trial and the likelihood of
full participation.

o  The adequacy of the facilities including technical resources and

o  The appropriateness of the local organization and administration.

o  The appropriateness of the budget.

For the initial review of a data coordinating center, the criteria also
will include:

o  Most of the criteria for participating center (e.g., budget,
experience, facilities).

o  The adequacy of plans for monitoring the collection, management, and
statistical analysis of the data.

o  Plans for periodic reports to a data and safety monitoring board and
the NIDDK staff.


The anticipated date of award is April 1, 1993.

Applications recommended for approval by the appropriate National
Advisory Council will be considered for funding on the basis of overall
scientific and technical merit of the research as determined by peer
review, program needs and balance, and availability of funds.


Written and telephone inquiries concerning this RFA are encouraged.

Direct inquiries regarding programmatic issues and requests for the
administrative Clinical Trial guidelines, to:

Tommie Sue Tralka
Director, Clinical Trials Program
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A15
Bethesda, MD  20892
Telephone:  (301) 496-9717

Direct inquiries regarding fiscal matters to:

Ms. Thelma Jones
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 630
Bethesda, MD  20892
Telephone:  (301) 496-7467


Letter of Intent:     May 15, 1992
Application Receipt:  July 15, 1992
Initial Review:       December 1992
Second Level Review:  February 1993
Anticipated Award:    April 1993


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 the 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.


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