ANCILLARY STUDIES TO OBESITY-RELATED CLINICAL TRIALS

RELEASE DATE:  October 22, 2003
 
RFA Number: RFA DK-03-022 (see addenda NOT-DK-04-007 and NOT-DK-04-002)
February 4, 2011 - This RFA has been reissued as RFA-DK-10-503.

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATIONS:

National Institutes of Health (NIH) 
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATIONS:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 (http://www.niddk.nih.gov/)
National Institute on Aging (NIA)
 (http://www.nia.nih.gov/)
National Center for Complementary and Alternative Medicine (NCCAM)
 (http://nccam.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.847 and 93.848; NIA 
93.866; NCCAM 93.213
 
LETTER OF INTENT RECEIPT DATE: February 19, 2004; October 19, 2004; June 17, 
2005.

APPLICATION RECEIPT DATE: March 19, 2004; November 19, 2004; July 19, 2005.
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The goal of this initiative is to solicit research grant applications for 
ancillary studies investigating obesity-related research questions in 
conjunction with six NIDDK-sponsored cooperative agreement clinical trials 
and consortia and one NIA-sponsored cooperative agreement.  

These ancillary study proposals may utilize patients and/or patient materials 
from the seven clinical cooperative agreements cited below, subject to study-
specific restrictions.  Acceptable studies will vary depending upon the 
parent cooperative agreement and may include investigation of the genetic and 
environmental factors underlying obesity, of the pathogenesis of obesity and 
associated co-morbidities, of surrogate markers or biomarkers for obesity-
related disease and therapeutic effects of interventions, and of new 
technologies for measurement of diet, physical activity and energy balance. 

The NIA is particularly interested in ancillary projects elucidating the 
relationships of aging changes to the above topics. Potential applicants are 
encouraged to consider any of the cooperative agreements included in this RFA 
as a resource for addressing aging-relevant research questions.  

The NCCAM is interested in supporting investigations of complementary or 
alternative approaches to weight maintenance and the prevention and treatment 
of overweight or obesity.
  
The following seven major cooperative agreement clinical trials or networks 
qualify for submission of ancillary studies under this announcement: 

o  Look AHEAD: Action for Health in Diabetes
o  Diabetes Prevention Program Outcomes Study (DPPOS)
o  Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)
o  Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)
o  Bariatric Surgery Clinical Research Consortium (BSCRC). 
o  Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy 
(CALERIE) Studies
o  Weight Reduction for Incontinence Network (WIN)

These cooperative agreements are the only trials or networks for which 
ancillary study applications will be accepted under this announcement.  The 
first two of these cooperative agreements are currently in progress and can 
accommodate applications for all receipt dates.  The NASH CRN, the TODAY 
study, the Bariatric Surgery Clinical Research Consortium, and the WIN study 
are still in the design phase and CALERIE is in the pilot testing phase. 
These five studies will not be ready to accept ancillary study proposals 
until the later receipt dates.

RESEARCH OBJECTIVES

Background

The obesity epidemic has been well documented in the scientific literature 
and in the lay press.  Recent data from the National Health and Nutrition 
Examination Survey demonstrate that almost two thirds of Americans now are 
overweight, and over 30% now are obese (BMI ? 30).  Obesity is associated 
with a host of comorbid conditions, including diabetes, cardiovascular 
disease, certain cancers, osteoarthritis, and gallbladder disease.  Despite 
the enormous health impact of obesity and recent progress in our 
understanding of the condition at the molecular level, many aspects of the 
basic pathophysiology and genetics of obesity remain to be investigated.  In 
addition, interrelationships of factors that contribute to energy balance and 
to difficulties associated with weight loss over the long term are not well-
understood.  

The NIDDK has made a substantial investment in six cooperative agreements to 
investigate obesity-related diseases and conditions in large numbers of well-
characterized participants.  In addition, the NIA is supporting a set of 
obesity-related intervention studies supported via a cooperative agreement. 
These trials and networks can provide access to participants who have been 
screened for a range of obesity-associated phenotypes and for whom various 
associated biological samples have been collected.  Thus, ancillary studies 
to the seven unique parent agreements represent a cost-effective way to 
capitalize on these major clinical research investments.  In addition, 
ancillary studies to the trials and networks will encourage basic scientists 
and clinical investigators to work together, enabling more in-depth studies 
of pathogenesis mechanisms during ongoing clinical protocols.  Finally, this 
announcement offers the potential for access to existing NIDDK and NIA-
supported cooperative agreements by a wider community of investigators from 
outside the parent study sites.

The seven cooperative agreements eligible for ancillary studies funded under 
this announcement are briefly described below, along with links to more 
detailed information on study websites:

1)  Look AHEAD: Action for Health in Diabetes. Look AHEAD is a sixteen center 
randomized clinical trial investigating the long-term health consequences of 
weight loss.  The Look AHEAD cohort will comprise 5000 overweight or obese 
participants with type 2 diabetes, aged 45-75.  Participants are randomized 
to one of two interventions: an intensive lifestyle intervention designed to 
produce and sustain weight loss over the long term, or a diabetes support and 
education condition.  The study will complete enrollment of subjects in 
April, 2004.  Currently the Look AHEAD population is comprised of 
approximately 35% minority individuals and 59% females, with an average age 
of 58 years.  Due to heavy existing ancillary study burden, Look AHEAD will 
be open primarily to ancillary studies that propose using existing stored 
serum, plasma or DNA samples or involve little additional burden to 
participants.  The study has a well-defined ancillary study policy and 
process for submission of ancillary studies to be approved by the ancillary 
studies committee.  The policy and online proposal submission site may be 
found at: http://lookahead.phs.wfubmc.edu/index.cfm?fuseaction=public_sitemap  
Please note that Look AHEAD requires applicants to prepare an online summary 
of the proposed research 60 days before the NIH receipt date and to obtain a 
letter indicating willingness to collaborate from at least one Look AHEAD 
principal investigator before an application can be approved by the ancillary 
studies committee for submission to this RFA.  Applications may be submitted 
for all three receipt dates.

2)  The Diabetes Prevention Program Outcomes Study (DPPOS).  The Diabetes 
Prevention Program Outcomes Study or DPPOS is the follow-up study to the DPP 
that initiated interventions in 1996 and was ended one year early (May 2001) 
as a result of highly significant and positive study outcomes as reported in 
the New England Journal of Medicine (The DPP Research Group, Reduction in the 
incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl 
J Med 2002 Feb 7;346 (6):393-403).  These results demonstrated that lifestyle 
and drug interventions could markedly reduce the risk for developing type 2 
diabetes in a group at high risk due to the presence of impaired glucose 
tolerance, by 58% for lifestyle and 31% for metformin, regardless of 
ethnicity. The DPP included 45 percent of the study cohort from African 
American, Hispanic American, Asian American, Pacific Islander, and American 
Indian populations.  In addition, 20 percent of our study population was 
greater than age 60 and 68% of participants were women.  

While the primary goal of the DPP was to prevent the development of diabetes, 
an important secondary goal was to decrease the rate of cardiovascular 
disease and its risk factors.  These clinically important outcomes were 
considered as secondary during the DPP due to a lack of sufficient power to 
detect potential differences between the treatment groups.  The DPPOS will 
provide insights regarding the clinical course of newly diagnosed type 2 
diabetes and the persistence of the delay of diabetes onset seen in the DPP. 
In addition, the DPP is the longest follow-up study of sustained weight loss 
ever conducted.  Of major interest is the outcome of continued lifestyle and 
long-term weight loss, and metformin intervention in the gender specific and 
minority sub-groups randomized to the DPP and enrolled in the  DPPOS. The 
DPPOS website may be found at: http://www.bsc.gwu.edu/dpp/index.htmlvdoc
Studies may be submitted for all three receipt dates.

3) The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN).  
The NASH CRN was constituted to focus on the etiology, contributing factors, 
natural history, complications, and therapy of nonalcoholic steatohepatitis.  
Eight clinical centers and a data coordinating center make up the network.  
Approximately 1500 pediatric and adult participants with nonalcoholic liver 
disease will be included in both retrospective and prospective databases 
beginning in late 2003.  A three-arm randomized, placebo-controlled clinical 
trial (RCT) of an insulin sensitizing agent or vitamin E will be conducted in 
250 non-diabetic adult participants with documented NASH.  A trial in 
pediatric NASH patients will randomize 180 children to receive treatment with 
vitamin E, metformin, or placebo.  All patients in both clinical trials will 
have liver biopsies taken pre- and post-treatment.  Treatment will be for two 
years.  Enrollment into both trials will begin in early 2004.  The NASH CRN 
will be open to ancillary studies that involve limited additional burden to 
study participants.  The NASH CRN ancillary study policy is posted on the 
NASH CRN website: http://www.nashcrn.com.  Ancillary study proposals utilizing 
the NASH CRN may be submitted for the second and third receipt dates under this 
announcement.  

4)  Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)  

The TODAY study is a 12-site clinical trial to assess the best treatment for 
type 2 diabetes in the pediatric population. The TODAY cohort will consist of 
750 youth between the ages of 10 and 17 years, who will be randomized to one 
of three arms: 1) metformin alone; 2) metformin plus rosiglitazone; and 3) 
metformin plus an intensive lifestyle intervention.  All participants will 
receive standardized diabetes education. The primary outcome will be time to 
rescue, defined as a hemoglobin A1c < 8.5% for 6 months.  Secondary outcomes 
include beta cell function, comorbidities (dyslipidemia, hypertension), 
microvascular complications, side effects/QOL, and cost analysis.  The 
protocol has been finalized and is awaiting IRB approval.  We expect that 
enrollment will begin in late fall 2003.  The TODAY ancillary studies policy 
is in the process of being finalized and will be placed on the study website 
at http://www.todaystudy.org when it becomes available.  A link to study 
information also will be posted on the FAQ site for this RFA at: 
http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm. 

We anticipate that investigators will need to submit a 3-5 page proposal to 
the TODAY ancillary studies committee as part of the review process. 
Ancillary studies will be considered if they do not significantly add to 
participant burden and require the unique characteristics of the TODAY 
cohort.  Investigators outside of the trial who wish to conduct an ancillary 
study will need to have a TODAY study member as a co-investigator.  Ancillary 
study proposals to the TODAY trial may be submitted for the second and third 
receipt dates under this announcement. 

5)  Bariatric Surgery Clinical Research Consortium (BSCRC).  The goal of the 
BSCRC is to facilitate coordinated clinical, epidemiological, and behavioral 
research in the field of bariatric surgery, through the cooperative 
development of common clinical protocols and a bariatric surgery database to 
collect information from participating CCs.  The BSCRC will help pool the 
necessary clinical expertise and administrative resources to facilitate the 
conduct of multiple clinical studies in a timely, efficient manner.  Also, 
the use of standardized definitions, clinical protocols, and data collection 
instruments will enhance our ability to provide meaningful evidence-based 
recommendations for patient evaluation, selection, and follow-up care.   The 
consortium was funded in September 2003.  During the first 10-12 months after 
funding, investigators will collaboratively develop protocols, with IRB and 
other approvals to be obtained by September 2004.   Additional information 
about the BSCRC will be posted on the FAQ site for this RFA at: 
http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm.  Ancillary study 
proposals to the BSCRC may be submitted for the second and third receipt 
dates under this announcement.  

6)  Weight Reduction for Incontinence Network (WIN).  The WIN includes two 
clinical centers (recruiting sites) and a data coordinating center.  The 
purpose of the Network is to examine the effects of an intensive behavioral 
weight control program compared to usual care to determine the short-term 
effect of weight loss on frequency of urinary incontinence and quality of 
life.  A total of 330 overweight and obese women with urinary incontinence 
will be recruited beginning in 2004.  After completing the intensive weight 
reduction program, a second randomization will be done to test whether an 
enhanced weight maintenance program results in better long-term weight loss 
through 18 months compared to a standard maintenance program. Urodynamic 
studies will also be performed in the study cohort.  Procedures for the 
conduct of ancillary studies are under development.  Additional information 
about the WIN will be posted when available on the FAQ site for this RFA at: 
http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm.  Ancillary study 
proposals to the WIN may be submitted for the second and third receipt dates 
under this announcement. 

7) Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy 
(CALERIE) Studies.  

The NIA-supported CALERIE studies consist of three clinical site cooperative 
agreements testing different interventions of sustained caloric restriction 
(CR) in non-obese (but mostly overweight) individuals. Locations of the 
CALERIE clinical sites include the Washington University in St. Louis, Tufts 
University in Boston, and the Pennington Biomedical Research Center in Baton 
Rouge. The Coordinating Center is located at Duke Clinical Research 
Institute. The primary goals of CALERIE are to gain knowledge: 1) about CR 
effects in humans on physiology, metabolism, body composition, and risk 
factors for age-related pathologies, and 2) of similarities, differences and 
interactions between the effects of CR and physical activity on the 
physiological outcomes of interest (e.g., changes in energy metabolism, 
surrogate markers of oxidative stress, endocrine function). Initiated in 
early 2002, the CALERIE clinical sites are presently conducting  pilot 
projects of different CR interventions involving 20-30% restriction of energy 
intake.  Some of the feasibility studies also include physical activity 
interventions designed to achieve similar levels of negative energy balance 
as with CR. The CALERIE study participants are between 25-60 years old and 
most have BMI values between 25-29.9. The results of these feasibility 
studies will be subsequently used to design full-scale clinical trial(s) of 
CR sustained for at least two years. The NIA invites potential applicants to 
propose ancillary projects to the full-scale CALERIE projects, which are 
expected to begin mid 2004.  Further details of the CALERIE studies and 
ancillary study policy can be found at: http://calerie.dcri.duke.edu.  

Since the CALERIE studies are still in the pilot testing phase, ancillary 
study proposals to CALERIE will not be accepted until the second receipt 
date. Those proposing ancillary studies must submit a 3-4 page proposal to 
the CALERIE ancillary studies committee, and secure CALERIE’s permission for 
the study, as a prerequisite for submitting an application in response to 
this RFA. Ancillary studies may be permitted by CALERIE if they do not 
significantly add to participant burden, do not compromise achievement of 
CALERIE goals, do not duplicate currently planned CALERIE studies, and 
require the unique characteristics of the CALERIE study population. 

The following are examples of research topics that might be pursued through 
ancillary projects to CALERIE studies.  This list is not intended to be all-
inclusive:

o  Metabolic, physiologic and body composition adaptations to sustained 
caloric restriction (CR) during early weight loss and during weight stability 
on CR. 

o  Effects of sustained caloric restriction on processes that may affect rates 
of aging in humans (e.g., cell death, oxidative damage, mitochondrial 
functions) and on risk factors for age-related diseases. 

o  Differences between effects of sustained caloric restriction and effects of 
increased physical activity on physiologic functions, body composition, and 
disease risk factors. 

Research Scope

The link between obesity, especially visceral obesity, and a number of 
associated conditions, such as diabetes, cardiovascular disease, cancer and 
osteoarthritis, continues to be a critical research question.  The 
application of powerful new genetics tools to samples from well-characterized 
obese individuals may identify genes that lead to the development of obesity 
and its comorbidities as well as those that influence responses to obesity 
treatment.  Studies to identify biomarkers of obesity-associated disease risk 
should yield new targets for therapeutics to disrupt the development of 
obesity and its comorbidities and to help to identify those in whom 
preventive strategies might be implemented.  Environmental, behavioral and 
societal factors that contribute to the development of obesity and the 
ability to lose weight and sustain weight loss also need to be explored, as 
do physiologic pathways of the neuroendocrine and endocrine systems, GI 
function, adipocytes, liver, muscle biology, appetite, and energy 
expenditure.  Studies of innovative methodologies for measuring dietary 
intake or energy expenditure would also be encouraged.  

Ancillary studies consist of measurements not being conducted as part of the 
parent clinical trial or network.  They may be done on the entire participant 
cohort or on subsets of participants, depending on the sample size required 
to answer the research questions.  They may involve physiologic or behavioral 
measures, imaging techniques or analyses of biological specimens from 
participants.

The following are examples of research activities that might be pursued 
through ancillary studies in collaboration with one or more of the seven 
cooperative agreements.  These are examples only and are not meant to be 
limiting.  However, each of the seven cooperative agreements has its own 
unique restrictions on what types of investigations are acceptable, based on 
burden to participants and study staff.

o  Identification of genetic variants associated with short-term and/or 
longer-term weight loss in response to lifestyle, CAM practices, or other 
therapeutic interventions

o  Identification of genes associated with increased or decreased risk for 
obesity in metabolically well-characterized populations from diverse racial 
and ethnic groups.

o  Use of weight loss models (e.g., diet, surgery, physical activity, CAM) to 
understand biological and psychological factors contributing to weight regain 
in humans.

o  Determination of the relationship between inflammatory markers and 
obesity.

o  Identification of serum, urine and/or various depot specific markers of 
obesity phenotypes across diverse racial and ethnic groups.  

o  Evaluation of the short-term impact of bariatric surgery, behavioral 
interventions, or CAM practices (including mind-body therapies)on an obesity-
related co-morbid condition, such as non-alcoholic steatohepatitis or insulin 
resistance.

o  Investigation of the impact of bariatric surgery on long-term energy 
balance, including factors such as appetite, nutrient absorption, nutrient 
metabolism, energy expenditure, fitness, or body composition.

o  Development of tools to improve assessment of diet, caloric intake and 
physical activity.

o  Study of the role of microsomal oxidative stress in the pathogenesis of 
obesity-associated liver disease.

o  Investigation of behavioral and environmental correlates of weight 
maintenance.

o  Identification age-related differences in clinical and physiologic 
outcomes of interventions affecting weight, and factors responsible for these 
differences.  

o  Relationships of comorbid conditions in older persons (e.g., osteoporosis, 
osteoarthritis) to risks and benefits of interventions affecting body weight

The NCCAM is interested in the efficacy and safety of, patterns and 
prevalence of, use of, cost benefit of, and professional and patient 
attitudes towards complementary and alternative medicines (CAM) for weight 
loss and maintenance of weight loss, as well as for amelioration of side 
effects of bariatric surgery or pharmaceutical interventions.  In addition, 
the NCCAM is interested in interactions of CAM with other interventions.  
NCCAM groups CAM practices within five major domains, acknowledging that 
other groupings are possible: (1) alternative medical systems; 2) mind-body 
interventions; (3) biologically-based interventions; (4) (manipulative and 
body-based methods; (5) energy therapies 
(http://nccam.nih.gov/about/plans/fiveyear/fiveyear.pdf).

Limitations:

Please note that each of the seven cooperative agreements for which ancillary 
study proposals may be submitted has limitations on the type of 
investigations permissible and each has specific requirements for partnership 
with study investigators.  In general, the following types of investigations 
are permitted under this announcement, subject to the limitations set by each 
study's leadership:

o  Assay of archived biological samples from completed and ongoing studies; 
and
o  Collection of new data and samples from ongoing studies.

You may NOT propose to fund the activities that are part of the core protocol 
for the parent trial through this announcement.  Likewise, you may NOT seek 
funds for analysis of existing data or for studies that substantially 
duplicate ongoing ancillary studies to the parent trials.  

In most cases, modification of intervention protocols will not be permitted; 
however, in certain limited circumstances, this might be considered 
acceptable by the parent study.

MECHANISM OF SUPPORT
 
This RFA will use the NIH research project grant (R01) award mechanism.  As 
an applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  This RFA will be active for portions of 
three fiscal years (FY 2004 - FY 2006) contingent on the availability of 
funds.  Future unsolicited, competing-continuation applications based on this 
project will compete with all investigator-initiated applications and will be 
reviewed according to the customary peer review procedures. The anticipated 
award dates are September 30, 2004, July 1, 2005, and April 1, 2006.

Applications that are not funded in the first two rounds of competition 
described in this RFA may be revised and resubmitted under this RFA.  
Applications submitted for the third receipt date will not have the 
opportunity to revise and resubmit under this RFA.

This RFA uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular budget format.  Otherwise follow the instructions 
for non-modular budget research grant applications.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE

The participating ICs intend to commit at least $3.5 million to fund 7 to 11 
new grants in response to this RFA.  Given the multiple receipt dates, 
funding could be significantly more if applications of sufficient quality and 
institute priority are received.  Because the nature and scope of the 
proposed research will vary from application to application, we anticipate 
that the size and duration of each award also will vary.  An applicant may 
request a project period of up to 5 years and a budget for direct costs of up 
to $1 million per year, including fiscal and administrative costs on 
subcontracts.  You are strongly encouraged to discuss proposed budgets with 
the IC program official for the parent trial or network prior to extensive 
preparation of your application.

Although the financial plans of the ICs provide support for this program, 
awards pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of meritorious applications.
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics: 
   
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic 
o Foreign institutions are not eligible to apply.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs. 

You may respond to this announcement even if you are not an investigator who 
currently is part of the seven trials or networks.  However, you will be 
required to obtain appropriate approvals from the trial or network proposed 
in your ancillary study.

SPECIAL REQUIREMENTS

To be responsive to the requirements of this announcement, you must propose 
studies using the seven ongoing NIDDK- or NIA-funded cooperative agreements 
cited above.  

Ancillary studies associated with major clinical trials provide a valuable 
opportunity to gain insights into the origins and pathogenesis of obesity.  
However, the potential value of such studies must be balanced against the 
need to ensure that the main trial outcomes are not compromised by the burden 
of additional studies.  Hence, you must provide documentation at the time of 
grant submission that you have received approval from the appropriate 
governing body of the parent trial or network to conduct your proposed 
ancillary study.  Each clinical trial or network covered by this announcement 
has provided guidelines for which types of ancillary studies are currently 
acceptable and for the process of obtaining approval.  These study-specific 
guidelines either are currently posted on each study's website (provided in 
Background) or links will be provided as they become available via the FAQ 
website for this RFA at: 
http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm.  Please note that 
study-specific restrictions may limit the types of ancillary proposals that 
are acceptable.  

Applications not containing documentation of preliminary approval from the 
appropriate governing body (such as the Steering Committee) will be 
considered non-responsive to this announcement and will be returned to the 
Investigator without having undergone peer review.

You must include a statement of your willingness to work collaboratively with 
the parent study and to abide by all parent study policies, publication 
restrictions, data access provisions, etc.

You may be required by specific trials or networks to include funds in your 
application to travel to national Steering Committee meetings and/or to cover 
the cost of access to samples and data at held by the parent study 
Coordinating Center or by central repositories.

This RFA applies only to NEW applications, not to competing renewals of 
ongoing ancillary studies.

Data Sharing Plan

Due to the collaborative nature of the parent trials, all applicants will be 
required to submit a data sharing plan, regardless of the dollar amount of 
their application.  Reviewers will assess the adequacy of the proposed plan.  
Ancillary studies also will be required to abide by the data sharing policies 
of the parent trial or network.  

NIH policy requires that investigators make unique research resources readily 
available for research purposes to qualified individuals within the 
scientific community after publication [Principles and Guidelines for 
Recipients of NIH Research Grants and Contracts on Obtaining and 
Disseminating Biomedical Research Resources: Final Notice 
(http://www.ott.nih.gov/policy/rt_guide_final.html)].  Therefore, it is 
expected that the specimens and data collected in projects funded by this RFA 
will be made available to the broader scientific community, after a 
proprietary period, at no charge other than the costs of reproduction and 
distribution.

This RFA has a special requirement that applicants include a "Sharing Plan" 
in the application that describes how they will share the specimens and data 
collected with the wider scientific community. For NIDDK-funded studies, the 
Plan must include the eventual transfer of these materials to the NIDDK 
Central Biosample and Data Repositories or another archival storage facility 
designated by NIDDK.  Approval of the data sharing plan will be a condition 
of the award. The effectiveness of the resource sharing will be evaluated as 
part of administrative review of each Non-competing Grant Progress Report 
(PHS 2590).

Data and Safety Monitoring Plan

All applicants must include a data and safety monitoring plan for the 
ancillary study activities even when the parent trial already has a central 
Data and Safety Monitoring Board and even if the study is of minimal risk.  
In addition, each applicant should include $10,000 in the budget to provide 
for Coordinating Center tracking of ancillary study participants and any 
additional data management functions required for the parent trial because of 
the ancillary study activities.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  A website on the NIDDK homepage 
containing information pertaining to this RFA is located at 
http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm.  Answers to frequently 
asked questions and other information updates concerning this RFA will be 
posted on the site as they are developed.  Applicants are strongly encouraged 
to visit this website on a regular basis in the course of preparing their 
applications.  Inquiries may fall into three areas:  scientific/research, peer 
review, and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Barbara Harrison, M.S.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Blvd, Room 661
Bethesda, MD  20892-5450 
(for express/courier service: Bethesda, MD 20817)
Telephone: (301)594-8858
FAX: (301)480-8300 
E-mail: bh72k@nih.gov

Chhanda Dutta, PhD
Geriatrics and Clinical Gerontology Program
National Institute on Aging
Gateway Building, Suite 3C-307
7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Telephone: (301)435-3048
FAX: (301)402-1784
E-mail:  cd23z@nih.gov

Marguerite Klein
National Center for Complementary and Alternative Medicine
6707 Democracy Blvd., Suite 401
Bethesda, MD  20892-5475 (for express mail, use 20817)
Telephone:  (301)402-5860
Fax:  (301)480-3621
E-mail: mk443s@nih.gov

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301)594-8897
FAX:  (301)480-3505
Email: fc15y@nih.gov

o Direct your questions about financial or grants management matters to:

Sharon Bourque 
Grants Management Specialist
National Institute f Diabetes and Digestive and Kidney 
6707 Democracy Boulevard, Room 719
Bethesda, MD  20892
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8846  
FAX:  (301)480-3504 
Email: sb114m@nih.gov 
 
Grace Poe
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2N212
Bethesda, MD  20892-9205
Phone:  (301)402-1472
Fax:  (301)402-3672
E-mail:  gp101g@nih.gov

Marc Milton Pitts, M.B.A. 
Grants Management Specialist 
National Center for Complementary and Alternative Medicine 
National Institutes of Health 
6707 Democracy Blvd., Suite 401 
Bethesda, MD  20892 
Phone:  (301)594-9095 
Fax:  (301)480-1552 
E-mail: mp384x@nih.gov

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 plan 
the review.
 
The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email: fc15y@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements.  The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at  http://www.dunandbradstreet.com/. The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form.  The PHS 
398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.
 
SUPPLEMENTARY INSTRUCTIONS:

You must submit a letter documenting the preliminary approval of your 
proposed ancillary study by the parent trial or network.  The required 
documentation varies somewhat between the parent studies, so be sure to 
follow the procedures provided by the parent trial or network of interest to 
you. 

In addition, you must explicitly state your willingness to abide by the 
policies of the parent trial or network.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs, including indirect costs 
on subcontracts, must be submitted in a modular grant format.  The modular 
grant format simplifies the preparation of the budget in these applications 
by limiting the level of budgetary detail.  Applicants request direct costs 
in $25,000 modules.  Section C of the research grant application instructions 
for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked.  The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and all 
copies of the appendix material must be sent to:

Francisco Calvo, Ph.D.
Chief, Review Branch 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email: fc15y@nih.gov

APPLICATION PROCESSING: Applications must be received on or before 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. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.
 
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.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes from the 
previous unfunded version of the application. 

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK.  Incomplete applications will not be reviewed. 

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the NIDDK in accordance with the review criteria stated below.  
As part of the initial merit review, all applications will:

o 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 and assigned a priority score
o Receive a written critique
o Receive a second level review by an appropriate national advisory council or 
board.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application's overall score, weighting them as appropriate for each 
application.

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
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.

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?

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?

INNOVATION: Does the project employ novel concepts, approaches or methods? 
Are the aims original and  innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

o  Importance of the proposed topic to advancement of obesity research.

o  Justification of the need for access to a large trial or network as 
opposed to a simpler research setting.

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed.  (See criteria included in the 
section on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH:  The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.  (See Inclusion Criteria in the sections on Federal Citations, 
below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH:  If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed. 

ADDITIONAL REVIEW CONSIDERATIONS 

SHARING RESEARCH DATA:  All applicants must include a data sharing plan in 
their application.  The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the reviewers. 
However, reviewers will not factor the proposed data sharing plan into the 
determination of scientific merit or priority score.

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Dates: February 19, 2004; October 19, 2004; June 17, 
2005.

Application Receipt Dates: March 19, 2004; November 19, 2004; July 19, 2005.

Peer Review Dates:  June/July 2004, February/March 2005, October/November 
2005.

Council Review:  September 2004, May 2005, January/February 2006

Earliest Anticipated Start Date:  September 30, 2004, July 1, 2005, 
April 1, 2006.

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities:  Only very meritorious applications within the 
scientific interests and scope of the NIDDK mission will be supported.
o Cumulative burden:  The cumulative burden to the parent trial or network of 
all ancillary studies ongoing and proposed for funding under this RFA may 
become a limiting factor.  For example, if small quantities of biological 
samples are available, not all studies rated as highly meritorious may be 
able to access them.  Likewise, the cumulative burden of studies already 
approved for funding may be such that those of lower priority cannot be 
funded, regardless of priority score.
 
REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 

DATA AND SAFETY MONITORING  PLAN:  Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II); efficacy, 
effectiveness and comparative trials (phase III).  The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants.   (NIH Policy for Data and Safety Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA:
Starting with the October 1, 2003 receipt date, investigators submitting an 
NIH application seeking more than $500,000 or more in direct costs in any 
single year are expected to include a plan for data sharing or state why this 
is not possible. http://grants.nih.gov/grants/policy/data_sharing.  
Investigators should seek guidance from their institutions, on issues related 
to institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule.  Reviewers will 
consider the data sharing plan but will not factor the plan into the 
determination of the scientific merit or the priority score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a 
clear and compelling justification is 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 clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.    
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFAPA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:   The 
Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information”, 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as “covered entities”) must do so by April 14, 2003 (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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 
RFA is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. 

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All awards 
are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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