NIH GUIDE, Volume 21, Number 12, March 27, 1992

PA NUMBER:  PA-92-60

P.T. 34



  Disease Prevention+ 


National Institute of Diabetes and Digestive and Kidney Diseases

National Institute of Allergy and Infectious Diseases

National Institute of Child Health and Human Development


The National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK), the National Institute of Allergy and Infectious Diseases

(NIAID), and the National Institute of Child Health and Human

Development (NICHD) are seeking applications for clinical studies

designed to test the hypothesis that immunomodulation will prevent

insulin-dependent diabetes mellitus (IDDM) in high-risk populations.


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 program

announcement, Clinical Trials to Prevent Insulin Dependent Diabetes

Mellitus by Immunomodulation, 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 public and private, foreign and

domestic, for-profit and non- profit organizations, such as

universities, colleges, hospitals and laboratories, units of State and

local governments, and authorized units of the Federal Government.

Women and minority investigators are encouraged to apply.


The mechanism for support for this program will be the individual

research grant (R01).  The application may include subcontracts or

consortia with several institutions.  Due to fiscal constraints, the

NIDDK does not anticipate being able to provide more than $500,000 in

total costs to any one application.



Over the past 10 years, significant progress has been made in defining

the autoimmune etiology and pathophysiology of IDDM.  Several clinical

trials of general immunosuppressive agents in patients with newly

diagnosed IDDM have induced a temporary clinical remission of this

disease.  These observations have led to the hypothesis that

immunomodulatory interventions may be effective in the prevention of

this disease in individuals who are asymptomatic but who are in an

earlier period of the autoimmune process.

A workshop on Clinical Trials of Immunosuppression for Prevention of

IDDM was held on April 19-20, 1990, in Bethesda, Maryland.  This

workshop was sponsored by the NIDDK, NIAID, and NICHD.  It was the

charge of this group to assess the status of scientific and medical

knowledge necessary to initiate a clinical trial of immunomodulatory

intervention for the prevention of IDDM.  Participants for the meeting

were drawn from the diabetes and immunology research communities and

were chosen to provide a broad range of insight and judgment in these

areas.  Several major issues were extensively discussed, and consensus

was reached in some areas while others remained open for continued

examination, evaluation, and debate.  There was general consensus based

on the published literature and discussion on the following important


o  IDDM in humans is an autoimmune disease and, as such, should be

amenable to immunotherapeutic intervention;

o  There are measurable parameters that can identify a group of

individuals at high risk for the development of IDDM; and

o  Further clinical studies in high-risk individuals to explore the

ability of immunomodulation to alter the natural history of IDDM are

timely and warranted.

Concerns were expressed by several of the participants that applicants

utilizing pediatric populations must strongly justify the risks and

benefits to the trial participants.  A summary of this workshop is

available from the NIDDK staff listed under INQUIRIES.

Goal and Scope

The goal of this program announcement is to stimulate clinical research

that will evaluate the effectiveness of immunomodulatory therapies for

the prevention of IDDM in high-risk populations.  The research scope of

this program will encompass a range of basic and clinical research

disciplines, such as immunology, endocrinology, genetics, biochemistry,

pharmacology, physiology, and pediatrics.  Some examples of relevant

research areas to be addressed by these clinical studies include:

o  Identification and characterization of markers that have value in

predicting remission or progression in pre- IDDM individuals on

long-term immunotherapy;

o  Using presently available markers, determine the natural history of

high-risk individuals; and

o  Evaluation of the effect of immunomodulatory interventions in

high-risk individuals including efficacy in prevention of progression

of the autoimmune process and parameters such as dosage, duration, and

deleterious side effects.

These recommendations are not necessarily all inclusive and any new

ideas with credible hypotheses that would appropriately fall within the

scope of this announcement may be the basis for an application.





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 should be placed on the need

for inclusion of minorities and women 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 clinical

research, particularly in proposed population-based studies, a clear

compelling rationale should 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 Section 2, 1-4

of the Research Plan and summarized in Section 2, E, Human Subjects.

Applicants are urged to assess carefully the feasibility of including

the broadest possible representation of minority groups. However, 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, Blacks,


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 preventative strategies), diagnosis, or treatment or 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.

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 will be 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.


Applicants are to use the research grant application form PHS 398 (rev.

9/91).  If application kits are not available at the institution's

business office or central application control office, a copy may be

obtain from the Office of Research Grants, National Institutes of

Health, Division of Research Grants, 5333 Westbard Avenue, Room 449,

Bethesda, MD, 20892, telephone 301-496-7441.

In order to identify the application as a response to this program

announcement, check "yes" on Item 2a of the application face page with

the title, "Prevention of IDDM by Immunomodulation, PA-92-60."

Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center of Research Resources

may wish to identify the Center as a resource for conducting the

proposed research.  In such a case, a letter of agreement from the GCRC

Program Director must be included in the application material.


Applications will be assigned on the basis of established Public Health

Service referral guidelines.  Applications in response to this

solicitation will be reviewed in accordance with the usual NIH peer

review procedures.  Applications will first be reviewed for scientific

and technical merit by a review group composed mostly of non-Federal

scientific consultants (study section).  Secondary reviews will be by

an appropriate national advisory council.


Applications recommended for further consideration will compete for

available funds with all other applications assigned to the Institutes.

However, because the NIDDK, NICHD, and NIAID and their Advisory

Councils have identified this research area to be of particular program

interest, applications responsive to this announcement will be brought

to the special attention of these Advisory Councils.  The following

will be considered in making funding decisions:  quality of the

proposed project as determined by peer review; availability of funds;

and program balance among research areas of the announcement.


Potential applicants are encouraged to discuss their plans with any of

the following NIH program staff:

Dr. Joan T. Harmon

Executive Director, Diabetes Research Program

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 622

Bethesda, MD  20892

Telephone:  (301) 496-7731

Dr. Howard B. Dickler

Chief, Clinical Immunology Branch

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4A-19

Bethesda, MD  20892

Telephone:  (301) 496-7104

Dr. Gilman D. Grave

Chief, Endocrinology, Nutrition and Growth Branch

National Institute of Child Health and Human Development

Executive Plaza North, Room 637

Bethesda, MD  20892

Telephone:  (301) 496-5593


This program is described in the Catalog of Federal Domestic Assistance

No. 93.847, Diabetes, Endocrinology and Metabolism Research; 93.855,

Immunology, Allergic and Immunologic Disease Research; 93.865, Research

for Mothers and Children.  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.


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