kristoff@GENBANK.BIO.NET (Dave Kristofferson) (01/17/91)
REQUEST FOR APPLICATIONS FOR RESEARCH PROJECT (RO1) GRANTS
RFA NUMBER: CA-91-06
ANALYSES AND PHYSIOLOGY OF ANTICARCINOGENS IN
SOYBEANS
P.T. 34; K.W. 0715035, 1007009, 0745027, 0710095
National Cancer Institute
Letter of Intent Receipt Date: March 1, 1991
Application Receipt Date: April 29, 1991
1. INTRODUCTION
The Division of Cancer Prevention and Control, National Cancer Institute
(NCI), invites applications for grants to quantify levels of total and
individual anticarcinogens in soybeans and soy products and to study
their absorption and metabolism in humans. Epidemiologic and animal
studies suggest soybean-rich diets may reduce cancer risk. Experimental
work indicates soybeans contain several classes of compounds in
particularly high concentrations with demonstrated anticancer activity.
Basic research on the absorption and metabolism of these compounds in
humans and accurate analytical data on the levels of these compounds in
commonly consumed soy products is needed. These data will help to
determine the potential impact of soybeans on cancer prevention.
The National Institute of Environmental Health Sciences (NIEHS) is also
interested in supporting research on the anticarcinogenic effects of
human dietary constituents, but from the standpoint of their abilities
to modify the carcinogenic effects of environmental agents.
Applications that focus in this area will be assigned according to
extant Referral Guidelines.
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,
"Analyses and Physiology of Anticarcinogens in Soybeans," is related to
the priority area of cancer prevention.
II. BACKGROUND INFORMATION
Populations consuming predominantly plant-based diets, for whom legumes
frequently represent an important protein source, tend to have lower
rates of several cancers than populations that rely heavily on animal
products. One legume, soybeans, via a variety of soy products (tofu,
miso, tempeh, soymilk, natto), is commonly consumed throughout much of
East Asia where breast and colon cancer rates are low in comparison to
Western countries. There are epidemiologic and experimental data that
suggest soybean-rich diets reduce cancer risk although the anticancer
potential of the various soy products may differ. Soybeans contain
several classes of compounds in particularly high concentrations with
demonstrated anticancer activity, such as isoflavones, protease
inhibitors, phytosterols, saponins, and inositol hexaphosphate. Other
compounds with anticancer activity may also exist in soybeans.
Isoflavones are weak estrogens that possess antioxidant activity,
inhibit the growth of neoplastic cells in vitro and the activity of
several enzymes thought to be involved in cell regulation. Dietary
supplementation with soybean extract containing approximately 50%
protease inhibitor suppresses experimental colon cancer, topical
application inhibits oral cancer in hamsters, and dietary
supplementation with pure protease inhibitor reduces liver cancer in
rodents. Inositol hexaphosphate enhances natural killer cell activity,
inhibits iron-generated free radicals and lipid peroxidation, slows the
growth of fibrosarcomas in experimental animals, and suppresses
chemically-induced colon cancer in rodents. Dietary supplementation
with B-sitosterol decreases colon cell proliferation, mitotic activity,
and the incidence and number of chemically induced colon tumors.
Saponins (from soybeans and other sources) increase natural killer cell
activity, are cytotoxic against sarcoma 37 cells in vitro and in vivo,
decrease the growth of human cervical carcinoma cells in vitro and
increase the life span of mice transplanted with leukemia cells.
To assess the potential impact of soybeans on cancer prevention,
research that will quantify the levels of anticarcinogens in soybeans
and soy products and study their absorption and metabolism in humans is
needed. These data will help determine the potential impact of soybeans
on cancer prevention.
III. RESEARCH GOALS AND SCOPE
The purpose of this Request for Applications (RFA) is to solicit
applications from qualified investigators to quantify levels of total
and individual anticarcinogens in soybeans and soy products and to study
their absorption and metabolism in humans. For the analytical work,
only those compounds in soybeans and soy products with demonstrated
anticancer activity and that are unique to soybeans and soy products or
present at substantially high levels (relative to other foods) should be
considered for analysis. Such components include but are not limited to
isoflavones, protease inhibitors, plant sterols, saponins, and inositol
hexaphosphate. It is essential that the validity and reliability of all
analytical procedures used in anticarcinogen assays be established and
that all methodology include quality control procedures. In cases where
methodology is inadequate or lacking, new methods can be developed.
Total as well as individual anticarcinogens (e.g., total isoflavones and
individual isoflavones, daidzein, genistein), should be quantified. All
factors potentially effecting anticarcinogen levels/activity should be
considered for investigation and include, but are not limited to,
anticarcinogen: (1) form - different forms of the same anticarcinogen,
e.g., conjugated versus unconjugated; (2) stability - effects of
storage, cooking, and other food processing techniques; (3) variation -
comparisons among different brands of similar soy products and/or among
varieties of soybeans and among different batches or lot numbers of the
same soy product.
For the human work, studies on the absorption and metabolism of
compounds in soybeans and soy products with demonstrated anticancer
activity are to be conducted. When feasible, dose-response
relationships between soy product/anticarcinogen intake and
anticarcinogen levels in blood and urine, and/or feces and bile should
be conducted. These data may help to establish an approximate level of
soy product intake necessary to elicit a biologic response. In all
cases, the soy product or extract under study should be carefully
analyzed for levels of the compound(s) to be monitored in blood, urinei,
and other biological materials. When available, both commonly consumed
soy products and soybean extracts or pure soybean anticarcinogens should
be studied. Both long-term feeding studies, in which anticarcinogen
levels in subjects consuming soy products/extracts over an extended
period of time and short-term studies, in which anticarcinogen levels
for a minimal period after the consumption of a single administration of
soy products, extracts, or pure compounds are studied are appropriate
under this RFA. Factors affecting absorption and metabolism should also
be considered for evaluation, such as diet composition and
anticarcinogen form (e.g., conjugated versus unconjugated isoflavones).
All applicants are required to justify the selection of
anticarcinogen(s) chosen for study. Selection should be based on the
evidence indicating the potential for a given compound to decrease
cancer risk. Preference will be given to those components that have the
strongest anticancer potential, are most unique to soybeans and soy
products, and/or are present in high concentrations relative to other
foods. Applicants are required to justify the specific area of research
proposed. Work can be conducted in one or both major categories, i.e.,
analyses and/or absorption/metabolism. Justification should be based on
the existing gaps in our knowledge and the importance of filling those
gaps to establishing the role of soybeans/soy products and/or compounds
in soybeans/soy products in the dietary prevention of cancer.
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF
NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDY POPULATIONS
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be 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 should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study. This information should be
included in the form PHS 398 in Section 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, 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, Hispanics).
The rationale for studies on single minority population groups
should be provided.
For the purpose of this policy, clinical research includes 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 minorities.
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.
IV. MECHANISM OF SUPPORT
Support of this program will be through the National Institutes of
Health (NIH) grant-in-aid (RO1). Applicants will be responsible for the
planning, direction, and execution of the proposed project. Except as
otherwise stated in this RFA, awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy
Statement, DHHS Publication No. (OASH) 82-50,000, revised October 1,
1990.
This RFA is a one-time solicitation. Future unsolicited competing
renewal applications will compete with all investigator-initiated
applications and be reviewed by the Division of Research Grants (DRG).
However, should the NCI determine that there is a sufficient continuing
program need, a request for renewal applications will be announced.
Only recipients of awards under this RFA will be eligible to apply.
Approximately $900,000 in total costs per year for 3 years will be
committed to specifically fund applications that are submitted in
response to this RFA. It is anticipated that 3 to 4 awards will be
made. This funding level is dependent on the receipt of a sufficient
number of applications of high scientific merit. The total project
period for applications submitted in response to the present RFA should
not exceed 3 years. The earliest feasible start date for the initial
awards will be December 1, 1991. Although this program is provided for
in the financial plans of the NCI, the award of grants pursuant to this
RFA is contingent upon the availability of funds for this purpose.
V. SPECIAL REQUIREMENTS
Progress reports should be included in the applications for continuation
grants each year by the Principal Investigator.
VI. ELIGIBILITY REQUIREMENTS
Both non-profit and for-profit organizations and institutions,
governments and their agencies, and foreign institutions are eligible to
apply.
VII. REVIEW PROCEDURES AND REVIEW CRITERIA
Upon receipt, applications will be reviewed (initially) by the Division
of Research Grants (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 NCI program staff function. Applications that are judged
non-responsive will be returned, but may be submitted as
investigator-initiated research grants. Questions concerning the
responsiveness of proposed research to the RFA should be directed to
program staff.
In cases where the number of applications is large compared to the
number of awards to be made, the NCI may conduct a preliminary
scientific peer review to eliminate those applications that are clearly
not competitive. The NCI will remove from competition those
applications judged to be noncompetitive for award and notify the
applicant and institutional business official.
Those applications judged to be both competitive and responsive will be
further evaluated according to the review criteria stated below for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI. The second
level of review by the National Cancer Advisory Board considers the
special needs of the Institute and the priorities of the National Cancer
Program.
REVIEW CRITERIA
The factors to be considered in evaluating the scientific
merit of each response to this RFA will be:
1. Extent of relevance to which the proposed research
addresses the overall goals and objectives of the
RFA.
2. Scientific merit of the study objective(s), design,
and methodology including considerations of
toxicity, safety, collection and analysis of fluids
and/or tissues, quality assurance, and statistical
parameters.
3. Basic and clinical scientific significance
and originality of the proposed research.
4. Research experience and/or competence of the
Principal Investigator and other key personnel to
conduct the proposed studies.
5. Adequacy of time (effort) which the Principal
Investigator and staff would devote to conduct the
proposed studies.
6. Degree to which assurances are provided that the
proposed project protects against adverse effects
upon humans and the environment.
7. Relevance and appropriateness of the specific
compounds chosen for study. Only those compounds in
soybeans and soy products with demonstrated
anticancer potential should be considered for study.
Preference will be given to those compounds for
which the evidence is strongest and that are unique
to soybeans and soy products and/or present in high
concentrations relative to other foods.
The review group will critically examine the submitted budget and will
recommend an appropriate budget and period of support of each approved
application.
VIII. METHOD OF APPLYING
The research grant application form PHS-398 (revised 10/88) must be used
in applying for these grants. These forms are available at most
institutional business offices and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, Room 449,
Westwood Building, 5333 Westwood Avenue, Bethesda, MD 20892, and from
the NCI Program Director named below.
The RFA label available in the 10/88 revision of Application Form 398
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
title and number of the RFA should be typed on line 2 of face page of
the application form.
Submit a signed, typewritten original of the application, including the
checklist, and four (4) signed, exact photocopies, in one package to the
DRG at the address listed below. The photocopies must be legible and
single sided.
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
At time of submission, send two (2) additional copies of the application
to
Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
5333 Westbard Avenue
Bethesda, MD 20892
Applications must be received by April 29, 1991. If an application is
received after that date, it will be returned. If the application
submitted in response to this RFA is substantially similar to a research
grant application already submitted to the NIH for review, but has not
yet been reviewed, the applicant will be asked to withdraw either the
pending application or the new one. Simultaneous submission of
identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
which is essentially identical to one that has already been reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
Introduction addressing the previous critique.
IX. LETTER OF INTENT
Prospective applicants are asked to submit by March 1, 1991, a letter of
intent that includes a descriptive title of the proposed research, the
name and address of the principal investigator, the names of other key
personnel, the 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 the review of subsequent applications, it is requested to
provide an indication of the number and scope of applications to be
reviewed.
The letter of intent should be sent to:
Mark J. Messina, Ph.D.
Program Director
National Cancer Institute
DCPC
Executive Plaza North, Room 212C
Bethesda, MD 20892
Telephone: (301) 496-8573
X. INQUIRIES
Written or telephone inquiries concerning the objectives and scope of
this RFA are encouraged and should be directed to Mark J. Messina,
Ph.D., at the above address. The program director welcomes the
opportunity to clarify any issues or questions from potential
applicants.
This program is described in the Catalog of Federal Domestic Assistance
No. 93.399, Cancer Control. Awards will be made under the authority of
the Public Health Service Act., Title IV, Section 403 (Public Law
78-410, as amended; 42 USC 284) and administered under PHS grant
policies and Federal regulations 42 CFR Part 52 and 45 CFR Part 74.
This program is not subject to the Intergovernmental review requirements
of Executive Order 12732 or Health Systems Agency review.
REQUEST FOR APPLICATIONS
ALZHEIMER'S DISEASE AND RELATED CEREBRAL DEGENERATIVE
DISORDERS
RFA: NS/AG-91-03
P.T. 34; K.W. 0715180, 0705010, 0710010, 1002030, 0755030, 0765033
National Institute of Neurological Disorders and Stroke
National Institute on Aging
Letter of Intent Receipt Date: April 1, 1991
Application Receipt Date: May 6, 1991
PURPOSE
The National Institute of Neurological Disorders and Stroke
(NINDS) and the National Institute of Aging (NIA) are
inviting research grant applications on the etiology,
pathogenesis, and diagnosis of Alzheimer's disease and
related cerebral degenerative disorders.
The importance of expanding support for Alzheimer's disease
research has been widely recognized by the Federal
Government. The U.S. Senate Appropriations Committee
report for Fiscal Year 1991 placed particular emphasis on
Alzheimer's disease and provided considerable additional
funds for expansion of the activities of the NIA and NINDS
in this area. The Advisory Panel on Alzheimer's Disease of
the Department of Health and Human Services (DHHS) issued a
special report on Alzheimer's disease (DHHS Pub. NO [ADM
89-1664]) urging that the Federal research budget for
Alzheimer's disease be substantially increased. The
implementation plan for the Decade of the Brain developed
by the National Advisory Neurological Disorders and Stroke
Council also emphasized the need for enhanced funding of
research on dementias. It is widely appreciated that there
are many scientific opportunities that can be taken
advantage of and significant progress can be made in
understanding the neurodegenerative diseases of later life,
especially Alzheimer's disease. Many governmental and
private groups and individuals are urging that the research
momentum be increased by expansion of research efforts on
etiology, pathogenesis, diagnosis, and treatment of
Alzheimer's disease and related disorders.
BACKGROUND
Present estimates indicate that as many as 4 million
Americans suffer from Alzheimer's disease (AD) or related
cerebral degenerative disorders. The personal and societal
burden of these disorders is enormous as a result of the
relentless and devastating course of the deterioration.
The total cost of caring for individuals with AD and
related disorders has been estimated at $90 billion
per year. The personal and societal costs of these
disorders underline the urgent need for an increase in
research efforts.
RESEARCH GOALS AND SCOPE
The NINDS/NIA are soliciting innovative research projects
designed to elucidate the etiology and pathogenesis of
Alzheimer's disease and related degenerative disorders as
well as studies aimed at improving diagnosis and treatment.
Individuals new to these areas of research as well as
established investigators are encouraged to submit research
proposals (R01) to enhance ongoing research and to
investigate new ideas that are exploratory in nature. When
practical, applicants are encouraged to consider submitting
applications that utilize and collaborate with existing
resources of the NIA-funded Alzheimer's Disease Research
Centers (ADRCs) or the Alzheimer's Disease Center Core
Grants (ADCCs), thus contributing to cost savings by
utilization of already funded research resources such as
the clinical and autopsy cores of these centers.
The need for new knowledge concerning the dementias of old
age covers a broad spectrum of topics. The following topics
are suggested to highlight some examples of areas that
could benefit by increased attention. The research topics
indicated below are not intended to be an exhaustive or
exclusive listing of interests. The list is compiled
merely to indicate examples of topics. Applications on
other related topics and problem areas are welcome.
o Genetics: Both environmental and genetic factors have
been suggested or implicated in the etiology of AD and
other cerebral degenerative disorders. Autosomal dominant
inheritance of AD has been demonstrated in certain
pedigrees and tentative map locations for familial AD
(FAD) genes have been identified. The heterogeneity of AD
etiologies is indicated by the different genetic loci
implicated and also by differences in age of onset in FAD
families. While most cases of AD occur sporadically, many
investigators believe that were a gene discovered for
familial forms of AD (FAD), it would likely shed
light on other potential causes. Much research is needed
on the mechanisms of interaction between aging processes
and the expression of a gene for a disorder of late life
onset. Further studies are needed as well to clarify the
relationship between genetic and possible environmental
factors (e.g., aluminum, certain viruses). The similarity
of symptoms and pathology of Alzheimer's
disease and adult Down's syndrome remains to be explained.
o Mechanisms of Cell Death: A major unanswered question
in AD is the cause of neuronal dysfunction and eventual
death of neurons. Neurons in certain regions of the brain
appear to exhibit selective age-related vulnerability to
cell death. Studies are encouraged on the selective
vulnerability of neuronal systems and the processes of
neuronal degeneration in AD and related degenerative
diseases of late life.
o Nerve Growth Factors: The infusion of nerve growth
factor has reversed the loss of memory in old rats and rats
with certain cholinergic lesions. Other factors have been
identified recently that may be neurotrophic for other
types of neurons. Additional work in this area is
necessary to evaluate the effect of these trophic
substances on model systems for the multiple
neurotransmitter deficits present in AD. Studies related
to the potential therapeutic role of nerve growth factors
in AD are strongly encouraged. The NIA sponsored Working
Group on Nerve Growth Factors recommended a number of lines
of inquiry requiring pursuit for further development of the
therapeutic potential of such agents (Phelps et al., 1989,
Neurobiology of Aging, 10, 205-207).
o Animal and Other Model Systems: The development of new
animal models is critical to progress in the study of AD
and related neurodegenerative diseases. Research oriented
toward useful animal and cell culture model systems is
encouraged. Data from aging primates and dogs may reflect
processes closely related to AD.
o Neuroimaging: Further investigations are needed to
understand and resolve conflicting data derived from the
multiple approaches to imaging the aging brain, both normal
and pathological. Greater precision is essential in the
localization of physiologic and anatomic dysfunctions that
produce the clinical symptomatology seen in dementing
disorders. Research on methods for merging data from PET
and MRI in AD and related cerebral neurodegenerative
diseases would be useful in resolving these questions.
o Differential Diagnosis: Early and accurate diagnosis
of AD has a major impact on the progress of research on
dementia. Research is needed to refine existing diagnostic
procedures and/or to develop more sensitive and reliable
techniques. The relationship between AD and other
dementias, such as vascular dementia, Parkinsonian
dementia, Pick's disease, Creutzfeld-Jakob disease, and
diffuse Lewy body disease needs to be addressed. Sensitive
and specific biological and chemical markers to identify
those at high risk of AD and those in the very early stages
of AD are required. Some of the recommendations of a 1987
Consensus Development Conference on the Differential
Diagnosis of Dementing Diseases for future research in this
area included: exploration of potential biological
diagnostic markers with special emphasis on families with
autopsy-diagnosed dementias; evaluation of neuroimaging by
long-term follow-up of patients, correlation with clinical
and neuropsychological findings, and tissue histopathology;
evaluation of current neuropsychologic instruments in
populations that differ in age, education, ethnic
composition, and social or cultural background, using
long-term follow-up and correlation with clinical,
neuroimaging, and neuropathologic findings; and design of
multivariate studies to determine the optimal combination
of diagnostic strategies needed to differentiate the
dementias common in each age group.
MECHANISM OF SUPPORT
The mechanism of support for this RFA will be the individual
research grant (R01). Applicants may request up to 5 years
of funding support. Funds will not be provided to cover
the costs of patient health care. Funds may be requested
to cover costs related to participation of research
patients in clinical protocols.
It is expected that at least 20 awards will be made. The
specific number will depend on the merit and total costs of the
applications. These applications are not
expected to compete for funding within the general pool of
dollars available for investigator-initiated research
grants.
While no future funds are set-aside, awards made in
response to this RFA may be renewed through the submission
of a competitive renewal application.
METHOD OF APPLICATION
LETTER OF INTENT:
The NINDS and the NIA urge applicants to submit a letter of
intent to both Dr. Oliver and Dr. Banner, at the addresses
listed below, no later than April 1, 1991. While a letter of
intent is not required, is not binding, and does not enter
into the review of the application, it
allows NINDS/NIA staff to plan for the review of
applications and to avoid possible conflict of interest in
the selection of reviewers as well as to ensure that
potential applicants receive relevant program information
prior to expending considerable effort in application
preparation. The letter of intent should include the name
and affiliation of the principal investigator, the names
and affiliation of co-investigators, a descriptive title of
the project, and identification of all
collaborating institutions.
FORMAT OF APPLICATIONS:
The application must be submitted on the 10/88 revision of
the form PHS 398. Application kits may be secured from
institutional offices of grants and contracts or from:
Office of Grants Inquiries/ DRG, NIH/ Westwood Building,
Room 449/ 5333 Westbard Avenue/ Bethesda, Maryland 20892.
To identify these applications as being in response to the
RFA, check "yes" on item 2 of page 1 of the application and
enter the title: "NINDS/NIA ALZHEIMER'S DISEASE" and the
RFA number NS/AG-91-03. The RFA label available in the
10/88 revision of the Application Form 398 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 the
review. All policies and requirements that normally
govern the grant programs of the Public Health Service
apply.
APPLICATION PROCEDURE:
The deadline for receipt of applications by the NIH
Division of Research Grants (DRG) is May 6, 1991. Send or
deliver the completed application and four (4) signed,
exact photocopies of the application to:
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, MD 20892**
In addition, send one (1) exact photocopy to Dr. Oliver and
one (1) exact photocopy to Dr. Banner at the addresses
listed below.
Applications must be received by May 6, 1991. An
application not received by this date will be considered
ineligible for consideration under this solicitation. The
review for scientific and technical merit of applications
judged responsive to the RFA will take place in June/July
1991, and NINDS and NIA Council review will be in September
1991. Awards will be made by September 30, 1991.
REVIEW PROCEDURES AND CRITERIA
REVIEW METHODS:
Upon receipt, applications will be reviewed by NINDS and
NIA staff to determine administrative and programmatic
responsiveness to this RFA. Applications judged
unresponsive will be returned to the applicant. NOTE:
APPLICATIONS THAT DO NOT CONFORM TO THE INSTRUCTIONS
CONTAINED IN THE PHS 398 (REV. 10/88) APPLICATION KITS WILL
BE JUDGED NONRESPONSIVE AND WILL BE RETURNED TO THE
APPLICANT.
All applications that are complete and responsive to this
RFA may be subjected to a triage by a peer review group to
determine relative scientific merit among the applications.
Applications judged to be noncompetitive for award will be
administratively withdrawn. Applicant Principal
Investigator and institutional business official will be
notified.
If the application submitted in response to this RFA is
substantially similar to a research grant application
already submitted to the NIH for review, but that has not
yet been reviewed, the applicant will be asked to withdraw
one of the applications. Simultaneous submission of
identical applications will not be allowed, nor will
essentially identical applications be reviewed by different
review committees. Therefore, an application cannot be
submitted in response to this RFA that is essentially
identical to one that has already been reviewed. This does
not preclude the submission of substantial revisions of
applications already reviewed but such applications must
include an introduction addressing the previous critique.
Those applications judged to be competitive for award will
be further reviewed for scientific and technical merit by
an initial review group convened by the Division of
Extramural Activities, NINDS, during June/July 1991. A
final level of review will be by the National Advisory
Neurological Disorders and Stroke Council and National
Advisory Council on Aging.
REVIEW CRITERIA:
The factors to be considered in the evaluation of each
application will be similar to those used in the review of
traditional research grant applications. The major factors
to be considered in the evaluation of applications will
include: the scientific merit of the proposed project,
including the originality and feasibility to the approach,
and the adequacy of the experimental design; the competence
of the investigator(s) to accomplish the proposed research
goals, their commitment, and the time they will devote to
the research; the adequacy of facilities for performance of
the proposed research, including the laboratory facilities,
the proposed instrumentation, and, when needed, the data
management systems; the integration of any
interdisciplinary components into a coherent enterprise
with adequate plans for interaction and communication of
new information and concepts among the collaborating
investigators; and the appropriateness of the budget for
the proposed research.
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF
NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDY POPULATIONS
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be 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 should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study. This information should be
included in the form PHS 398 in Section 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, 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, Hispanics).
The rationale for studies on single minority population groups
should be provided.
For the purpose of this policy, clinical research includes 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 minorities.
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.
INQUIRIES:
For further information, potential applicants should write
or call:
Eugene J. Oliver, Ph.D.
Demyelinating, Atrophic, and Dementing Disorders
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Federal Building, Room 806
Bethesda, MD 20892
Telephone: (301) 496-1431
Carl D. B. Banner, Ph.D.
Program Director, Etiology of Alzheimer's Disease
Dementias of Aging Branch, NNA
National Institute on Aging
National Institutes of Health
Building 31, Room 5C35
Bethesda, MD 20892
Telephone: (301) 496-9350
The programs to which the intended grants relate are
described in the Catalog of Federal Domestic Assistance,
entries number 93.853 ("Clinical Research Related
Neurological Disorders"), 93.854 ("Biological Basis
Research in the Neurosciences"), and 93.866 ("Neuroscience
and Neuropsychology of Aging"). Grants will be awarded
under the authority of the Public Health Service Act, Title
IV, Section 301 (Public Law 78-410, as amended; 42 USC 241)
and administered under PHS grant policies and Federal
Regulations 42 CFR Part 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.
MANAGEMENT OF ALZHEIMER'S DISEASE SYMPTOMS
RFA AVAILABLE: NR/AG-91-01
P.T. 34; K.W. 0715180, 0785035, 0404000
National Center for Nursing Research
National Institute on Aging
Letter of Intent Receipt Date: April 8, 1991
Application Receipt Date: May 20, 1991
PURPOSE
The National Center for Nursing Research (NCNR) and the
National Institute on Aging (NIA)
invite applications for R01 research applications
for preliminary investigations that will lead to large-
scale clinical studies on the assessment and
nonpharmacological management of secondary symptoms
exhibited by patients with Alzheimer's disease and related
disorders (AD).
The Alzheimer's Association is cooperating with NCNR and NIA in
this Request for Applications (RFA).
BACKGROUND INFORMATION
The NCNR is interested in
studies relevant to the diagnosis and treatment of human
responses to actual and potential health problems. As
such, nursing investigations focus on fundamental
biological and behavioral processes relevant to assessment
and management of patient care. An inter-disciplinary
approach holds great promise to the understanding of this
complex disease. Within this context, nursing research
can make a significant contribution to the scientific
knowledge base necessary to the care and management of
patients with health problems related to Alzheimer's
disease and related disorders.
The overall focus of the NIA's
efforts in Alzheimer's disease is to develop the knowledge
base to prevent and treat the biological course and to
manage and interrupt the behavioral manifestations of the
age-associated dementias. The treatment and management
work is addressed to the patient and his/her behavior, and
the goal is no less than the alteration of the clinical
course.
Estimates indicate that 4 million Americans presently
suffer from AD. The
impact of AD on patients, families, and society is severe
and is anticipated to grow as older persons, the group
most at risk for AD, continue to increase in number.
Although it may not yet be possible to prevent, treat, or
permanently alter the course of the underlying disease,
interventions can be developed and systematically tested
that reduce the patient's secondary symptoms and preserve
function. In addition to cognitive symptoms, non-
cognitive secondary symptoms are frequently seen across
the course of Alzheimer's disease and present significant
management problems. These symptoms of special concern
may include, but are not limited to, wandering, disturbed
sleep, pacing, agitation, feeding and dressing
difficulties, incontinence and toileting difficulties,
screaming and other vocalizations, aggression and
violence, and inappropriate sexual behavior. These
symptoms not only contribute to decisions to
institutionalize affected individuals, but also lead to
the use of chemical and physical restraints.
While there exists a great deal of clinical and anecdotal
information about methods that can effectively deal with
individual symptoms, little data exist that have been
obtained with the rigor of design and procedures of the
controlled clinical trial. Therefore, applications are
solicited for preliminary investigations and feasibility
studies that will lay the groundwork for the development
of rigorously controlled clinical trials to test
interventions for the management of the secondary
symptoms.
These preliminary studies may address any of the
scientific assessment, design, methodological, and
intervention problems to facilitate the launch of large-
scale clinical trials. For example, satisfactory
assessment techniques and instruments for addressing the
previously noted problematic symptoms are needed. Studies
are needed of strategies for enhancing AD patients' self-
care abilities. Delineation of appropriate interventions
for an individual symptom or cluster of symptoms and
methods for implementing the interventions must be
identified. In particular, attention is needed to the
affected person's past daily practices and preferences in
order to adjust care to such characteristics. Although
the primary focus is on nonpharmacologic interventions,
research is also needed that addresses the multimodal
treatment approaches including, but not limited to,
pharmacological interventions for managing symptoms.
Studies addressing only pharmacological interventions are
not acceptable.
Information on the acceptability, safety, and rationale
for the effectiveness of interventions must be obtained
prior to undertaking any large-scale trial. Carefully
developed interventions for testing in controlled clinical
trials in long-term care institutions are needed.
Procedures for maintaining interventions across the
duration of the trial, using existing nursing home staff,
are not clear. Therefore, behavioral, environmental,
social, or organizational interventions, individually or
in combinations, may be proposed and examined. Applicants
are encouraged to consider collaborative efforts with
sites that have established AD research programs, such as
the Alzheimer's Disease Centers currently funded by the
National Institute on Aging in locations throughout the
United States.
In addition to these research goals, naturalistic/field/
qualitative research is needed to examine the onset,
pattern and progress of the behavioral changes that occur
during the clinical course of Alzheimer's disease.
Careful scientific observations of the longitudinal,
natural history are critical to understanding the
disease progression and for relating the behavioral
changes to brain degeneration. The research in an
observational setting, either institutional or
noninstitutional, should accrue a representative sample
to develop clear, rigorous descriptions,
characterizations, and understandings of the behavioral
clinical course that can be ultimately related to
biological changes.
Applications are invited for support of projects to
address issues including, but not limited to:
o the identification of underlying factors in research
subjects that result in behavioral symptoms and methods
to address these factors.
o the development of preliminary work and early
investigations that will lead to the nonpharmacologic
management and treatment of the secondary symptoms
exhibited by patients with AD.
o provision of a rigorous scientific base that will lead
to controlled clinical trials in institutional or
noninstitutional settings by delineating approaches for
the management of symptoms, the duration of change, and
the procedures required to maintain the change, if
possible.
o development of instruments to assess behavioral
problems and monitor changes.
o careful scientific observations of the natural history/
clinical course of the behavioral changes that
occur during the progression of Alzheimer's disease.
MECHANISM OF SUPPORT
It is anticipated that ten to fifteen R01 applications
will be funded. This support level is dependent on the
receipt of a sufficient number of applications of high
scientific merit. Up to $75,000 in direct costs will be
allocated for each award for each funding year, not to
exceed three years. The anticipated award date will be
September 30, 1991. Although this program is accommodated
in the financial plans of the NCNR and NIA, the award of
grants pursuant to this Request for Applications (RFA) is also
contingent upon the
availability of funds for this purpose.
Applications may be submitted by for-profit or nonprofit
organizations, public or private, such as
universities, colleges, hospitals, laboratories, units of
State or local governments, and eligible agencies of the
Federal Government. Applications from minority
individuals and women are encouraged.
SPECIAL REQUIREMENTS
Applications submitted to the NIH will be reviewed
according to normal NIH peer review procedures. Principal
Investigators may submit their applications and summary
statements to the Alzheimer's Association for funding
consideration. The Alzheimer's Association may fund
selected applications at a maximum level of $45,000 total
costs each year with a 10 percent ceiling on indirect
costs, for a maximum of three years. The Alzheimer's
Association project start dates for funding may not
coincide with the NCNR or NIA award dates. Applicants may
not receive funding from both NIH and the Alzheimer's
Association for the same application.
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING
IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF
WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY
POPULATIONS
NIH and ADAMHA policy is that applicants for NIH/ADAMHA
clinical research grants and cooperative agreements will
be 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,
together with a rationale for its choice. In addition,
gender and racial/ethnic issues should be addressed in
developing a research design and sample size appropriate
for the scientific objectives of the study. This
information should be included in the form PHS 398 in
Section 2, A-D 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 recognize 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, Hispanics). The
rationale for studies on single minority population groups
should be provided.
For the purpose of this policy, clinical research includes
human biomedical and behavioral studies of etiology,
epidemiology, prevention (and preventive strategies),
diagnosis, or treatment of disease, 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 minorities.
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.
REVIEW PROCEDURES AND CRITERIA
Review Procedure
Upon receipt, applications will be reviewed by NIH staff
for completeness and responsiveness. Incomplete
applications will be returned to the applicant without
further consideration. If the application is not
responsive to the scientific intent identified in the RFA
or to the timeframe and budget guidelines, NIH staff will
return it to Division of Research Grants (DRG) for review with
other unsolicited grant
applications received during the next available NIH review
cycle.
Applications may be subjected to triage by a peer review
group to determine their scientific merit relative to
other applications received in response to this RFA.
Criteria for triage will be the same as the review
criteria listed below. The NIH will administratively
withdraw from competition those applications judged to be
noncompetitive and notify the applicant and institutional
official.
Those applications judged to be complete, responsive, and
competitive will be evaluated in accordance with the
criteria stated below for scientific/technical merit by an
appropriate peer review group convened by the NCNR and
NIA. The second level of review will be provided by the
NCNR and NIA National Advisory Councils.
Review Criteria
Applications will be reviewed in accord with the usual NIH
peer review criteria:
o scientific and technical 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 research;
o availability of resources necessary to perform the
research;
o appropriateness of the proposed budget and duration in
relation to the proposed research; and
o where an application involves activities that could
have an adverse effect upon humans, animals, or the
environment, the adequacy of the proposed means for
protecting against or minimizing such effects.
o appropriate inclusion of women and minorities in study
population.
METHOD OF APPLYING
The regular research grant application form PHS-398
(revised 10/88 or 9/89) must be used to apply for
these grants. These forms are available at most
institutional business offices or from the Office of
Grants Inquiries, Division of Research Grants, National
Institutes of Health, 5333 Westbard Avenue, Bethesda, MD
20892 (telephone 301-496-7441).
The RFA label available in the 10/88-9/89 revision of
application form PHS 398 must be affixed to the bottom of
the face page. Failure to use this label could delay
processing of your application. On Item 2 on the face
page of the application, enter "Management of Alzheimer's
Disease Symptoms, NR/AG-91-01" in the provided space.
Submit a signed original of the application, including the
Checklist, and four (4) signed, exact photocopies, in one
package to:
DIVISION OF RESEARCH GRANTS
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD 20892**
At the time of submission, send two (2) additional copies
of the application to:
John C. Chah, PhD
National Center for Nursing Research
Building 31, Room 5B19
9000 Rockville Pike
Bethesda, MD 20892
Applications must be received by May 20, 1991. If an
application is received after that date, it will be
submitted to the DRG for the
next regular grant cycle without benefit of this RFA.
If the application submitted in response to this RFA is
substantially similar to a research grant application already
submitted to the NIH for review, but has not yet been reviewed,
the applicant will be asked to withdraw either the pending
application or the new one. Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this
RFA that is essentially identical to one that has already been
reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.
LETTER OF INTENT
Prospective applicants are asked to submit by April 8,
1991, a letter of intent that includes a descriptive title
of the proposed research, the name, address, and telephone
number of the Principal Investigator, the names of other
key personnel, the participating institution(s), 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 which it contains is
extremely helpful in planning for the review of
applications. It allows ICD staff to estimate the
potential review workload and to avoid possible conflict
of interest in the review. The letter of intent should be
sent to:
John C. Chah, PhD
National Center for Nursing Research
Building 31, Room 5B19
9000 Rockville Pike
Bethesda, MD 20892
INQUIRIES
Written or telephone inquiries concerning this RFA are
encouraged and should be directed to either of the
following individuals. The program staff welcome the
opportunity to clarify any issues or questions from
potential applicants.
Mary D. Lucas, PhD, RN Teresa S. Radebaugh, Sc.D.
Chief, Acute & Chronic Chief, Dementias of Aging
Illness Branch Neuroscience and
National Center for Nursing Neuropsychology of Aging
Research National Institute on Aging
Building 31, Room 5B03 Building 31, Room 5C21
Bethesda, MD 20892 Bethesda, MD 20892
Telephone: (301) 496-0523 Telephone: (301) 496-9350
SCHEDULE
Letter of Intent: April 8, 1991
Application Receipt Date: May 20, 1991
Initial Review: June/July 1991
Secondary Review: September 1991
Anticipated Award Date: September 30, 1991
Other institutes and agencies are also interested in
research dealing with Alzheimer's disease and related
disorders, including:
The National Institute on Aging is developing a request
for cooperative agreement applications for "Special Care
Units for Alzheimer's Disease".
The program contacts are Marcia G. Ory,
PhD, Behavioral and Social Research Program, NIA, Building
31, Room 5C32, NIH, Bethesda, MD 20892, phone (301) 496-
3136 and Neil Buckholtz, PhD, Neuroscience and
Neuropsychology of Aging, NIA, Building 31, Room 5C35,
NIH, Bethesda, MD 20892, phone (301) 496-9350.
This RFA is in addition to the
ongoing program announcement on "Alzheimer's Disease and
Related Disorders: Issues in Caregiving," published in
the NIH Guide for Grants and Contracts, Vol. 18, No. 6,
February 24, 1989, sponsored by the National Institute on
Aging, National Center for Nursing Research, National
Institute of Mental Health, and the National Center for
Health Services Research (now the Agency for Health Care
Policy Research).
The National Institute of Mental Health (NIMH) is interested in
research dealing with the behavioral and emotional
consequences of Alzheimer's disease and related disorders.
The scope of NIMH interest is delineated in the
announcement "Alzheimer's Disease Treatment and Family
Stress." For more information concerning research
interests of the NIMH, contact Enid Light, PhD, NIMH, Room
11C-03, 5600 Fishers Lane, Rockville, MD 20857, phone
(301) 443-1185.
The National Institute of Neurological Disease and Stroke
program contact for Alzheimer's disease related research
is Dr. Eugene J. Oliver, NINDS, Federal Building, Room
806, Bethesda, MD 20892, phone (301) 496-1431.
This program is described in the Catalog of Federal
Domestic Assistance No. 93.336, Nursing Research, and No.
93.866. 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 PHS grant 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,
April 6, 1988.