EXPLORATORY STUDIES OF SUSTAINED CALORIC RESTRICTION IN NON-OBESE 
PERSONS:  PHYSIOLOGIC EFFECTS AND COMPARISONS/INTERACTIONS WITH PHYSICAL ACTIVITY 

Release Date:  October 12, 2000
 
RFA:  AG-01-001
 
National Institute on Aging
 (http://www.nih.gov/nia/)

Letter of Intent Receipt Date:  January 12, 2001
Application Receipt Date:       April 25, 2001

PURPOSE

The National Institute on Aging (NIA) invites applications for 
cooperative agreements (U01s) for exploratory controlled human 
intervention studies on the effects of caloric restriction (CR) 
interventions on physiology, body composition, and risk factors for 
age-related pathologies in non-obese persons. Applications are also 
invited for studies of similarities, differences and/or potential 
interactions between the effects of CR and of physical activity (PA) on 
these outcomes. Studies in young adults and/or middle-aged persons up 
to age 60 may be proposed. Subject populations of interest are 
overweight persons (Body Mass Index of 25.0-29.9), other individuals at 
high risk for becoming overweight or obese, and formerly obese persons 
at risk for recurrence of obesity.  Proposals for studies of 
interventions in persons currently obese will be considered non-
responsive to this Request for Applications (RFA). The use of reliable 
techniques for tracking caloric intake and expenditure (especially 
doubly-labeled water techniques), and level of physical activity are 
considered essential features of these exploratory studies. The results 
from these studies will be valuable in guiding the design of possible 
subsequent studies or clinical trials to determine the long-term 
effects of CR and PA on the development of age-related pathologies. 

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a 
PHS-led national activity for setting priority areas. This Request for 
Applications (RFA), “Sustained Caloric Restriction in Non-Obese 
Persons:  Physiologic Effects and Comparisons/Interactions with 
Physical Activity”, is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

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


MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) mechanism. The 
cooperative agreement is an assistance mechanism in which substantial 
involvement of the NIA with the recipient is anticipated during the 
performance of the planned activity. The nature of the NIA's 
involvement is described under Terms and Conditions of Award. 
Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant/awardee. 

The total project period for an application submitted in response to 
the present RFA may not exceed seven years. The anticipated award date 
is September, 2001.  This RFA is a one-time solicitation.  Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the 
customary peer review procedures.  

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.  If so, a letter of agreement from either the GCRC program 
director or principal investigator should be included with the 
application.

FUNDS AVAILABLE

For the initial year of funding, the amount of funds available to 
support projects submitted in response to this RFA is approximately 
$2,500,000, plus funds for the purchase of doubly labeled water (see 
“Research Goals and Scope” section). Total funding for the second year 
of awards will be at approximately the same level. Depending on the 
requirements for Phase 2 of funded projects  (see “Special 
Requirements” section), a larger amount may be available for years 3-7 
of the project period. 

It is anticipated that 2-4 awards will be made. However, awards will be 
contingent upon availability of funds and the receipt of a sufficient 
number of applications of outstanding scientific and technical merit.  
The number and size of awards made, may vary given the potential 
variation in the nature and scope of the research projects submitted in 
response to this RFA.

RESEARCH OBJECTIVES
 
Background
 
Numerous studies in laboratory animals have shown that chronic caloric 
restriction (CR), i.e., limiting caloric intake below ad libitum 
levels, extends maximum and average life span by as much as 40% and 
delays age-related pathologies correspondingly.  CR increases life span 
whether initiated in early adult life or middle age, but its effects 
diminish with increasing age of onset of CR.  The amount of life span 
extension increases with the degree of caloric restriction (up to 
approximately 40% restriction; substantial effects have occurred with 
20% restriction.  Among the aging changes slowed by these regimens are 
declines in glucose tolerance and insulin sensitivity, and increases in 
body weight.  (These regimens do not produce sustained weight loss: 
After transient weight loss, weight either remains stable or increases 
more slowly than in controls.)  Chronic CR in nonhuman primates has 
been found to produce parallel physiologic changes to those seen in 
rodents.  Studies of its effects on nonhuman primate life span have not 
been completed. 

An important question is whether these effects on life span and 
development of age-related pathologies can be explained by CR’s effects 
on weight, body composition, or physical activity.  CR prevents most or 
all of the weight gain and increase in fat mass over adult life in 
laboratory rodents, and increases spontaneous physical activity. Though 
the issue is not fully resolved, experimental animal data indicate that 
these factors may not fully explain CR’s effect on longevity and age-
related pathologies. Much of the evidence supporting this inference 
comes from studies of effects of chronic exercise in experimental 
animals.  In studies in which chronic exercise affected body weight and 
body fat comparably to CR, it had significantly less effect on mean 
life span.  In particular, though both interventions increased mean 
life span in the animals studied, only CR consistently increased 
maximum life span.  These findings have raised the possibility that 
either CR may have some beneficial effect on aging processes, not 
mediated by body weight, that exercise may lack, or that exercise may 
have some adverse effect that counteracts some of the benefits it may 
share with CR. 

The implications of these findings regarding effects of voluntary CR on 
life span and development of age-related diseases in humans are 
unknown.  There are essentially no data from epidemiologic studies on 
the relationship of caloric intake or voluntary caloric restraint over 
the life span to these outcomes. Human weight-loss intervention studies 
(primarily in obese or overweight persons) have included regimens for 
sustained reduction of caloric intake, but the duration of 
interventions has been at most only a few years. In most of these 
studies, the interventions have combined CR with other interventions 
such as physical activity.  In addition, caloric intake of individuals 
in these studies (as well as in epidemiologic studies) cannot be 
estimated well because of limitations in the accuracy of self-reported 
data on food intake.  As a result of these factors, a clear 
determination of the effects of sustained caloric restriction per se on 
life span, development of age-related pathologies, or on risk factors 
for these pathologies, is not possible from existing data.  Hence, it 
is also not possible to draw firm conclusions from existing data about 
similarities, differences, or interactions between sustained CR and PA 
in their effects on these outcomes in humans. 
 
In March 1999, the NIA and NIDDK (National Institute on Diabetes 
Digestive Diseases and Kidney) co-sponsored the Caloric Restriction 
Clinical Implications Advisory Group. The Advisory Group reviewed data 
and made recommendations for epidemiologic, experimental therapeutic, 
mechanistic, and human intervention studies relating to the 
relationships of caloric intake, energy balance, and weight gain over 
the lifespan with longevity and morbidity. The proceedings from this 
Advisory Group meeting will be published in the Journals of 
Gerontology: Series A Biological and Medical Sciences, with an 
anticipated publication date in late 2000.  Notice of publication will 
be posted on the NIA Website at http://www.nih.gov/nia/news/.

The Advisory Group recommended studies of human CR interventions in 
non-obese persons lasting for at least two years, to determine effects 
on a variety of physiologic and psychological factors and disease risk 
factors.  The Advisory Group noted that an effective initial target 
range for weight reduction in CR interventions in non-obese persons 
could be tentatively set at 15-20% of initial body weight, and also 
noted that several caloric restriction studies at different levels of 
dietary restriction will be needed to assess the potential benefits and 
disadvantages of CR in human populations. The Advisory Group also 
recommended studies comparing effects of chronic exercise with those of 
CR, and interactions between the effects of exercise and CR. This 
Request for Applications solicits projects that will address these 
topics. 

Research Goals and Scope

The primary goals of this RFA are:

1) to gain knowledge about the effects in humans of sustained CR on 
physiology, metabolism, body composition, risk factors for age-related 
pathologies, progression of age-related changes (where feasible), and 
its potential adverse effects
 
2) to gain knowledge of similarities, differences and interactions 
between the effects of CR and PA on the above outcomes when employed in 
interventions to prevent weight gain. 

Projects submitted in response to this RFA should consist of controlled 
human intervention studies of: 1) the effects of reduced calorie intake 
alone, or 2) comparison of the effects of CR to those of physical 
activity interventions that have the same effects on weight as the CR 
intervention, and/or 3) determining interactions between the effects of 
reduced calorie intake and increased physical activity, e.g., through 
factorial-design studies. Proposed projects that include only physical 
activity interventions will be considered non-responsive to this RFA.  

Studies in young adults, and/or middle-aged persons up to age 60 years 
at the time of the start of interventions, may be proposed.  
Participants should be free of major chronic diseases  (e.g., diabetes, 
cardiovascular disease, osteoporosis).  Participants in the study 
should be non-obese (Body Mass Index below 30.0).  Subject populations 
of interest are overweight persons (Body Mass Index 25.0-29.9), or 
other individuals at high risk for becoming overweight or obese, and 
previously obese persons at risk for recurrence of obesity.  Proposals 
for studies of interventions in obese persons will be considered non-
responsive to this RFA.

The intervention(s) should be at least 2 years in duration.  Studies 
that propose to carry out the intervention(s) for greater than two 
years must include plans for an interim analysis at two years. As 
described below, projects should include a pilot phase in which to 
acquire data on which to refine the selection of the CR regimen (and PA 
regimens, if these are proposed) to be tested. 

Proposed CR interventions to be tested should consist of a specified 
percentage reduction in individuals’ caloric intake below their pre-
study levels.  CR interventions should be designed to be maintained 
over the duration of the study, subject to periodic review of 
participant safety, protocol adherence, and other issues. The degree of 
CR should produce no more than a 20% reduction in body weight over the 
course of the study. (Applicants are reminded that focus of this RFA is 
on CR rather than weight loss per se. CR interventions which may result 
in weight stability over the study interval may be proposed.) CR 
protocols should be designed to assure that intake of micronutrients in 
subjects in the intervention groups and control groups is maintained at 
adequate levels, and is not diminished from baseline levels in subjects 
in the control groups.  

If comparisons between the effects of CR and PA (or studies of their 
interactions) are proposed, the type and/or intensity of the proposed 
PA intervention (or combined CR/PA intervention) should be designed to 
result in the same pattern and extent of weight change expected from 
the CR regimen selected. 

Proposals for studies should include study protocols, with clearly 
defined eligibility and exclusion criteria, and information on proposed 
subject recruitment, outcome measures/endpoints, sample size/power 
calculations, as well as baseline measures and follow-up examinations.  
Study design should include appropriate control group(s) and 
appropriate measures to blind study personnel to the intervention 
assignment of the study participants (e.g., studies may be single-
blinded).  It is also important that potential applicants consider the 
methods they may use to assess/monitor the behavioral and quality of 
life aspects of their proposed interventions.  Potential influences of 
behavioral and social factors on recruitment and retention into the 
studies should be considered in the study design.

Study endpoints must include: 

o  Energy intake and expenditure (see below for requirement of doubly-
labeled water technique)
o  Physical activity 
o  Body composition (as measured by DEXA or MRI; other techniques 
available and proposed for body composition will be in addition to DEXA 
or MRI)

Other outcome measures may include but are not limited to the 
following:

o  Endocrine responses, including reproductive hormones
o  Insulin sensitivity and glucose metabolism
o  Cardiovascular/respiratory measures
o  Bone density/metabolism
o  Immune function
o  Quality of life
o  Potential adverse effects 

The use of the most valid and reliable techniques for tracking caloric 
intake and expenditure (e.g., doubly-labeled water) and level of 
physical activity (e.g., accelerometers) are considered essential 
features of these exploratory studies. Proposals must include plans for 
tracking energy intake and expenditure using the doubly-labeled water 
technique unless they include a rationale for use of another method 
that provides equal or greater accuracy.  Applications should request 
funding for enough doubly-labeled water to assess energy expenditure at 
time intervals deemed optimal and appropriate within their study 
designs. The NIA recognizes the current limitations in availability, 
price uncertainty, and cost constraints of using doubly-labeled water, 
and is presently exploring possibilities to lessen or offset costs of 
doubly-labeled water for projects submitted in response to this RFA.  
Nevertheless, applicants should budget fully for the doubly-labeled 
water needed in their proposed projects, using their best estimates for 
prices at the time of the study. 

Applicants are also encouraged to consider including related data 
collection and analyses in their proposed studies, on topics such as 
the following: 

o  Factors affecting ability to identify and recruit appropriate 
subjects for CR interventions, and improved measures to identify non-
obese subjects at high risk for significant weight gain (to guide 
recruitment for future studies) 

o  Factors affecting adherence to CR and combined CR-PA interventions

o  Feasibility and differences in effects of alternative CR and PA 
intervention strategies.  

o  Dose-response and time-course of effects of CR, and combinations of 
CR and PA (including effects during the weight-stable phase of the 
interventions) on weight, physiologic function, disease risk factors, 
and potential short-term adverse effects 

o  Potential gender differences in the response to CR and PA

o  Effects of physical activity interventions on caloric intake, and/or 
effects of calorie restriction interventions on levels of physical 
activity

o  Correlation of questionnaires with more laboratory-based measures 
for caloric consumption/expenditure (e.g., doubly-labeled water) and 
physical activity (e.g., three-dimensional accelerometers)

o  Genetic factors predicting/influencing responses to CR, or 
combination of CR and PA interventions       

Potential applicants are encouraged to use interdisciplinary approaches 
in developing their study designs, including expertise (where 
appropriate) in such areas as nutrition, physiology, endocrinology, 
metabolism, body composition, clinical trials, behavioral sciences, 
biostatistics, and gerontology. 

Potential applicants interested in conducting research on molecular and 
neural aspects of caloric restriction in experimental animals are 
encouraged to review the concurrent NIA RFA, Molecular And Neural 
Mechanisms Underlying The Effects of Caloric Restriction on Health and 
Longevity, 
http://grants.nih.gov/grants/guide/rfa-files/RFA-AG-01-002.html.

SPECIAL REQUIREMENTS

Under the terms of the cooperative agreement, the awardee defines the 
details of the project within the guidelines of the RFA, retains 
primary responsibility for the performance of the activity and for the 
analysis and publication of the results.  The awardee agrees to accept 
assistance, close coordination and participation of the designated NIA 
program administrator in all aspects of the scientific and technical 
management of the project in accordance with the terms of this RFA. The 
NIH will have the option of halting the study or individual study sites 
if the program objectives are not being met, or have been met prior to 
the full 7-year period.  

After the scientific merit, personnel and resources of proposals have 
been assessed by peer review, modification of the individual study site 
protocols may be necessary. This may include use of common lab 
measures, instrumentation, and methods of specimen collection and 
storage (including arrangements to make the specimens available to 
outside investigators), in order to maximize achievement of the 
objectives of this RFA.  Needs for such modifications may arise both 
before and during implementation of protocols, and cannot always be 
foreseen before the intervention begins. 

The maximum duration of proposed studies may not exceed 7 years. The 
variations in project length will be due to differences in time needed 
for subject recruitment, duration of intervention (must be at least 2 
years) and period of follow-up. 

Studies supported through this RFA will consist of three phases:

Phase 1: Protocol Refinement (up to 2 years) Applicants should describe 
Phase 1 activities in detail in their proposals. Activities during this 
phase may include but are not limited to: 

o  recruitment and screening of subjects
o  identification of improved predictors of risk for weight gain, to 
guide recruitment
o  racial/ethnic and cultural appropriateness of protocols
o  determination of optimal recruitment strategies
o  verification of interventions’ feasibility
o  verification of techniques to determine protocol adherence
o  measurement of short-term effects of the intervention
o  potential adverse effects and tolerability
o  dose-response and time-course studies testing differing levels of CR 
and PA (the type and/or intensity of the PA intervention selected 
should match the magnitude of an effect(s) achieved through CR)
o  protocol refinement based on results during this phase  

Studies in this phase may be conducted in a clinical research center 
environment and/or with community-dwelling subjects.  In order to 
proceed to Phase 2, the study sites must demonstrate:

o  valid and reliable measurement of physical activity levels and 
energy intake
o  participants’ adherence to intervention protocol(s)
o  safety and tolerability of CR and PA interventions 
o  successful recruitment strategies

Phase 2. Protocol Implementation (at least two years).  Activities 
under this phase include the conduct of intervention activities, 
continued screening and recruitment of subjects (if necessary), and 
preliminary data analysis.

It is recognized that protocols for Phase 2 may be substantially 
modified from those described in the application, based on results of 
Phase 1. Applicants should nonetheless describe their proposed Phase 2 
intervention in detail, indicating what aspects are still to be 
finalized based on results of Phase 1 studies, and describing the 
resources available to implement protocol modifications based on Phase 
1 results.  (Examples include potential other population sources and/or 
clinical sites if additional participants are needed, or other 
facilities and equipment for determining body composition, if proposed 
methods prove infeasible.)  By the end of Phase 2, all study subjects 
should have completed the intervention protocol(s), and data analysis 
plans should be clearly established by the study sites.

Phase 3.  Data analysis and reporting (approximately one year). 

Applicants should also state their willingness to participate in 
meetings to track the progress of their studies and to promote exchange 
of experiences and ideas. A workshop may be convened at the end of the 
project period, to discuss future directions. It is anticipated that 
the awardees may meet more frequently than once a year during the first 
and last year of their project periods.  In addition, awardees from 
this RFA may meet periodically with the awardees of the NIA RFA, 
Molecular And Neural Mechanisms Underlying The Effects of Caloric 
Restriction on Health and Longevity, 
http://grants.nih.gov/grants/guide/rfa-files/RFA-AG-01-002.html.  An 
exchange of data and ideas between researchers conducting 
basic/molecular studies and clinical research on the effects of caloric 
restriction will be invaluable in guiding future studies in this area.  
Funds for travel to the Washington D.C. area for the principal 
investigator (and up to two co-investigators, if appropriate) for two 
one-day meetings should be included in the budgets for each year.

Applicants should also review the NIA document, “Policies For Human 
Intervention Studies” at 
http://www.nih.gov/nia/funding/policy/humint.htm for specific 
requirements for the safety of participants in intervention studies. 
This NIA policy does not replace existing NIH regulations on protection 
of human subjects, policies and guidelines for conduct of clinical 
research, inclusion of women and minorities, research project 
administration, reporting, and financial management, or requirements of 
local Institutional Review Boards (IRBs). DHHS regulations for the 
protection of human subjects are described in 45 CFR46. The 
implementation of these regulations for PHS research grants involving 
human subjects is found in the PHS 398 form (rev. 4/98) available on 
the NIH home page http://grants.nih.gov/grants/forms.htm.

Organizational Components

1. Study Sites

A study site is the Institution that receives an award for conducting 
the investigations under this RFA.  There should be evidence of strong 
Institutional support for the site and a stated willingness to follow 
common aspects of study design, lab measures and analyses as approved 
by the Steering Committee.  

2. Steering Committee

A Steering Committee will serve as the main decision-making body for 
the shared aspects of the exploratory studies.  The Steering Committee 
will have the overall responsibility for the development and 
finalization of standard definitions/lab measures common to the 
protocols of the study sites. The principal investigators of the study 
sites and the designated NIA Program Administrator will comprise the 
voting members of the Steering Committee. The studies will proceed into 
the next phase only after approval by the Steering Committee of the 
site protocols, review and approval by the Monitoring Board, and 
acceptance by the NIA. The Steering Committee will meet every three to 
six months, or as needed.

3. Monitoring Board

A Monitoring Board will be formed to advise the study sites by 
periodically reviewing their research progress and the safety of the 
study subjects, as well as resolve any serious conflicts over how the 
overall study should proceed. The Monitoring Board will be comprised of 
experts in relevant medical, statistical and bioethical fields. The 
Board’s approval will be required before initiation of Phase 1 study 
protocols, and before transition to Phase 2.  The Chairperson of the 
Steering Committee and the NIA Program Administrator will participate 
as non-voting members of this Board. 

Terms and Conditions of Award

The following special terms of award are in addition to, and not in 
lieu of, otherwise applicable OMB administrative guidelines, HHS Grant 
Administration Regulations at 45 CFR Parts 74 and 92 and other HHS, 
PHS, and NIH Grant Administration policy statements.

The administrative and funding instrument used for this program is a 
cooperative agreement (UO1), an assistance mechanism (rather than an 
acquisition mechanism) in which substantial NIH scientific and/or 
programmatic involvement with the awardees is anticipated during 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient’s activity by 
working jointly with the award recipient in a partner role, but it is 
not to assume direction, prime responsibility or a dominant role in the 
activity.  Consistent with this concept, the dominant role and prime 
responsibility for the activity resides with the awardees for the 
project as a whole, although specific tasks and activities in carrying 
out the collaborative aspects will be shared among the awardees and the 
designated NIA Program Administrator.

1. Awardee Responsibilities

Awardees will have primary authorities and responsibilities to define 
objectives and approaches, and for participant recruitment and follow-
up, quality control, data analysis and interpretation, and for 
preparation of publications from their projects. Awardees at the study 
sites shall retain custody of, and primary rights to, the site-specific 
data developed under their award, subject to Government rights of 
access consistent with current HHS, PHS, and NIH policies.  In 
addition, awardees will engage in collaborative activities through 
participation in Steering Committee meetings and potential conference 
calls in the development and implementation of common measures across 
study sites. The Steering Committee will define the rules regarding 
access to and publication of findings from analysis of common data.

2. Staff Responsibilities

The designated NIA Program Administrator will have substantial 
scientific/programmatic involvement during conduct of this activity, 
through technical assistance, advice and coordination above and beyond 
normal program stewardship of grants.  The awardee agrees to accept 
assistance from the designated NIA Program Administrator, as described 
below: 

o  Participate in the monitoring of issues relating to recruitment, 
treatment, follow-up, quality control, and adherence to protocols.

o  Assist in the development and/or adjustment of study protocols.

o  In conjunction with the Steering Committee, approve the transition 
of study sites from Phase 2 to Phase 3. After approval from the 
Monitoring Board, the NIA must accept (approval by the Director, NIA) 
the protocol before it can be implemented.  The NIA reserves the right 
to terminate or curtail the study (or an individual award) in the event 
of substantial shortfall in participant recruitment, follow-up, data 
reporting, quality control, or other major breech of the protocol; if 
human subject safety or ethical issues dictate a premature termination; 
or if there is failure to develop or implement mutually agreeable 
collaborative protocols. 

o  Assistance in data analyses

3. Collaborative Responsibilities

A Steering Committee will serve as the main decision-making body for 
the shared aspects of the exploratory studies.  The Steering Committee 
will have the overall responsibility for developing and finalizing 
standard definitions/lab measures common to the protocols of the study 
sites. The principal investigators of the study sites and the 
designated NIA Program Administrator will comprise the voting members 
of the Steering Committee. The studies will proceed into the next phase 
only after approval by the Steering Committee of the site protocols, 
review and approval by the Monitoring Board, and acceptance by the NIA. 
The Steering Committee will meet every three to six months, or as 
needed.

A Monitoring Board will be formed to advise the study sites by 
periodically reviewing their research progress and the safety of the 
study subjects, as well as resolve any serious conflicts over how the 
overall study should proceed. The Monitoring Board will be comprised of 
experts in relevant medical, statistical and bioethical fields. The 
Board’s approval will be required before initiation of Phase 1 study 
protocols, and before transition to Phase 2.  The Chairperson of the 
Steering Committee and the NIA Program Administrator will participate 
as non-voting members of this Board. 

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the U01 award), between U01 awardees and the NIA 
may be brought to arbitration.  An arbitration panel will be composed 
of three members:  one selected by the Steering Committee (without NIH 
representatives voting) or by the individual U01 awardee in the event 
of an individual disagreement; a second member selected by the NIA; 
and, the third member selected by the two prior selected members.  For 
U01 awardees, this special arbitration procedure will in no way affect 
the awardee’s right to appeal an adverse action in accordance with PHS 
regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR 
Part 16.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups 
and their sub-populations must be included in all NIH-supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research.  This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 
103-43). 

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

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

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained 
within specified page limitations.  Unless otherwise specified in an 
NIH solicitation, internet addresses (URLs) should not be used to 
provide information necessary to the review because reviewers are under 
no obligation to view the Internet sites.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the 
identities of other key personnel and participating institutions, and 
the number and title of the RFA in response to which the application 
may be submitted. Although a letter of intent is not required, is not 
binding, and does not enter into the review of a subsequent 
application, the information that it contains allows IC staff to 
estimate the potential review workload and avoid conflict of interest 
in the review.

The letter of intent is to be sent to the program staff listed under 
INQUIRIES by the letter of intent receipt date listed in the heading of 
this RFA.

APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants.  Applications kits are available at most 
institutional offices of sponsored research and from the Division of 
Extramural Outreach and Information Resources, National Institutes of 
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, 
telephone (301) 435-0714, email: GrantsInfo@nih.gov. Applications are 
also available on the Internet at:  
http://grants.nih.gov/grants/funding/phs398/phs398.html. 

The RFA label available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of the application.  
Type the RFA number on the label.  Failure to use this label could 
result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA 
title, and number, must be typed on line 2 of the face page of the 
application form and the YES box must be marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note that this sample label 
is in pdf format.

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

CENTER FOR SCIENTIFIC REVIEW 
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, send two additional copies of the 
application to:

Chhanda Dutta, Ph.D.
Director, Musculoskeletal Research and 
Nutrition, Metabolism and Gastroenterology Research 
Geriatrics Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3E-327 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 435-3048
FAX:  (301) 402-1784
Email:  cd23z@nih.gov

These copies are used to identify conflicts and to help ensure the 
appropriate and timely review of the application.

Applications must be received by the application receipt date listed in 
the heading of this RFA.  If an application is received after that 
date, it will be returned to the applicant without review.

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

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by the NIA.  Incomplete and/or nonresponsive 
applications will be returned to the applicant without further 
consideration.

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by NIH in accordance with the review criteria 
stated below. As part of the initial merit review, a process may be 
used by the initial review group in which applications receive a 
written critique and undergo a process in which only those applications 
deemed to have the highest scientific merit, generally the top half of 
the applications under review, will be discussed, assigned a priority 
score, and receive a second level review by the National Advisory 
Council on Aging.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
In the written comments reviewers will be asked to discuss the 
following aspects of the application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals.  Each of these criteria will be addressed and 
considered in assigning the overall score, weighting them as 
appropriate for each application.  Note that the application does not 
need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, 
an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

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

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

3.  Innovation:  Does the project employ novel concepts, approaches or 
method? Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 
technologies?

4.  Investigator:  Is the investigator appropriately trained and well 
suited to carry out this work?  Is the work proposed appropriate to the 
experience level of the principal investigator and other researchers 
(if any)?

5.  Environment:  Does the scientific environment in which the work 
will be done contribute to the probability of success?  Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements? Is there 
evidence of institutional support?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups, as appropriate for the scientific goals of the research. 
Plans for the recruitment and retention of subjects will also be 
evaluated.

o The reasonableness of the proposed budget and duration in relation to 
the proposed research.

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

Schedule:

Letter of Intent Receipt Date:  January 12, 2001
Application Receipt Date:       April 25, 2001
Date of Initial Review:         July 2001
Review by Advisory Council:     September 2001
Anticipated Award Date:         September 2001

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications. The following will be considered in making funding 
decisions:

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

INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to 
clarify any issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Chhanda Dutta, Ph.D.
Director, Musculoskeletal Research and 
Nutrition, Metabolism and Gastroenterology Research 
Geriatrics Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3E-327 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 435-3048
FAX:  (301) 402-1784
Email:  cd23z@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Cynthia Riddick
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone: (301) 496-1472
FAX:  (301) 402-3672
Email:  riddickc@exmur.nia.nih.gov


AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic Assistance 
No. 93.866.  Awards are made under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410), as amended by Public 
Law 99-158, 42 USC 241 and 285) and administered under PHS grants 
policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency 
review.
 
The PHS strongly encourages all grant and contract recipients to 
provide a smoke-free workplace and promote the non-use of all tobacco 
products.  In addition, Public Law 103-227, the Pro-Children Act of 
1994, prohibits smoking in certain facilities (or in some cases, any 
portion of a facility) in which regular or routine education, library, 
day care, health care or early childhood development services are 
provided to children.  This is consistent with the PHS mission to 
protect and advance the physical and mental health of the American 
people.


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