August 18, 2015 - See Issuance of RFA-AG-16-019.


THE ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE

RELEASE DATE:  October 2, 2003
 
RFA Number:  RFA-AG-04-005

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATIONS:

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

COMPONENTS OF PARTICIPATING ORGANIZATIONS:

National Institute on Aging (NIA)
 (http://www.nia.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.866

LETTER OF INTENT RECEIPT DATE:  December 16, 2003  
APPLICATION RECEIPT DATE:  January 16, 2004 

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism 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 National Institute on Aging (NIA) invites applications from 
qualified institutions for a Cooperative Agreement (UO1) to establish a 
Coordinating Center (CC) together with a Neuroimaging Center (NC) and a 
consortium of clinical sites for the NIA Neuroimaging Initiative. The 
purpose of this Initiative, planned as a public-private partnership, is 
to develop a multi-site, longitudinal, prospective, naturalistic study 
of normal cognitive aging, mild cognitive impairment (MCI), and early 
Alzheimer's disease (AD) as a public domain research resource to 
facilitate the scientific evaluation of neuroimaging (magnetic 
resonance imaging [MRI], positron emission tomography [PET]), and other 
biomarkers for the onset and progression of MCI and AD. A primary goal 
is to identify the biomarkers of disease progression that are most 
promising for use as surrogate endpoints in phase 2 and 3 clinical 
trials for the prevention and treatment of AD. 

An essential feature of this initiative is that the clinical, 
neuropsychological, imaging, and biological data and samples will be 
made available to all qualified scientific investigators at time 
intervals to be determined by the Steering Committee and estimated to 
be every 3-6 months, with raw data available more frequently. The 
period of support for the Neuroimaging Initiative will be five years.  

RESEARCH OBJECTIVES

Advances in the understanding of the pathophysiology and genetics of AD 
are providing opportunities for developing disease-modifying therapies. 
A number of neuroimaging technologies and biological substances in the 
blood and cerebrospinal fluid (CSF) now appear to have considerable 
potential for measuring progression in this disease (Frank, R.A., et 
al., Neurobiology of Aging 24:521-36, 2003). A number of studies in AD 
and MCI have demonstrated that imaging parameters are more sensitive 
and consistent measures of disease progression than cognitive 
assessment. Some studies have shown that imaging measures correlate 
with cognitive test performance in MCI and AD   an initial step in the 
validation of markers that accurately predict the course of disease and 
that could be used as surrogate endpoints to establish claims for 
disease-modifying treatment. The technical feasibility of using 
structural MRI measures as a surrogate endpoint of disease progression 
in multi-center clinical trials has been demonstrated (Jack, C.R., et 
al., Neurology 60:253-260, 2003). 

A slowed rate of atrophy in a structure known to be affected by AD 
together with neuropsychological test data indicating that cognitive 
function was stabilizing or improving, would be strong evidence for a 
disease-modifying effect. In phase 2 trials, imaging and other markers 
can help to rapidly identify appropriate doses, assess safety, and 
compare drugs in early development. Biomarkers decrease the time and 
cost of phase 2 and 3 clinical trials, increasing the safety and 
efficiency of drug development.  
  
Collaborating with the Food and Drug Administration (FDA) on projects 
such as the Initiative helps the NIH bridge the gap between research 
and the regulatory process, speeding the fruits of research into 
treatments for disease, a priority for both agencies. The FDA is 
increasingly accepting of surrogate endpoints based on imaging, which 
are not yet fully validated, including as primary endpoints in pivotal 
trials (recent examples include Etanercept, Eloxatin), given the marker 
is reasonably likely to predict clinical benefit (CFR 314.510), a 
condition that the Initiative can help demonstrate.   

A group of cognitively normal older subjects will be studied in order 
to document changes in neuropsychological, imaging, and biochemical 
parameters that occur with normal aging. This will allow comparison 
with the changes occurring in the MCI and early AD groups. A fraction 
of the normal group would also be expected to develop MCI and possibly 
AD over the time period studied, so data may also be collected on very 
early measurable changes in the course of illness.

Primary objectives:  
1.Collect serial clinical, neuropsychological, biological, and imaging 
data (1.5T structural MRI on all subjects with a bridging study to 3T 
at a subset of sites, and 18fluoro-deoxyglucose (FDG) PET at a subset of 
sites) on subjects with MCI (followed for three years), normal controls 
(followed for three years), and subjects with early AD (followed for 2 
years), in order to define the rate and variance of change of 
neuroimaging and other markers of disease onset and progression for 
comparison with clinical and neuropsychological measures, using 
relatively frequent sampling points. The primary goal of these efforts 
is to identify useful surrogate markers of disease progression that 
will decrease the time and sample size needed to document disease-
modifying efficacy in clinical trials.   

2.Collect, process, and store serial blood, CSF, and urine samples in 
the three groups of subjects for analyses for potential biomarkers of 
disease progression, including genomic, proteomic, and metabolomic 
markers that can be correlated with clinical, neuropsychological, and 
imaging data. Immortalized cell lines will also be established.

3.Establish methodologies for the multi-site collection, quality 
assurance/quality control, and distribution/sharing of neuroimaging and 
other biological data, in conjunction with clinical and 
neuropsychological data. 

4.Place the longitudinal databases in the public domain and make the 
data available to all qualified investigators at time intervals to be 
determined by the Steering Committee (estimated to be every 3-6 months, 
with raw data available more frequently) for a variety of analyses that 
will provide insight into the natural history of MCI and AD, evaluate 
the ability of biomarkers to predict the onset and rates of progression 
of MCI and AD, including conversion from MCI to AD, and evaluate which 
methods provide the greatest statistical power for distinguishing 
pathological changes from normal aging.  

Initial MRI images will need to be evaluated as per inclusion/exclusion 
criteria, for example, ruling out potential participants with multiple 
lacunes in a critical memory structure. Calculation of measures such as 
hippocampal, entorhinal cortex, and temporal horn volumes for 
incorporation into the database is anticipated as being fundable 
through this Initiative. As such, applicants to the Initiative should 
use the anticipated rates of change in these or other potential 
biomarkers to generate primary hypotheses on how these measures relate 
to cognitive decline and conversion to AD. Using estimates of sources 
of variance and magnitude of treatment benefit, applicants are 
encouraged to generate hypothetical power calculations for clinical 
trial design. Minimal data analyses are included as part of this RFA, 
but funding for more extensive analyses will be encouraged through 
other mechanisms such as RO1, RO3, and R21 grants.

Applicants for the Neuroimaging Initiative will need to establish three 
components for the Initiative: (1) a CC for delineating protocols, 
organizing and monitoring data and sample collection, storage, and 
distribution, and other administrative functions such as organizing 
Steering Committee meetings; (2) a strong NC or Core for delineating 
imaging protocols, establishing and monitoring quality assurance (QA) 
and quality control(QC) procedures for the collection of imaging data 
among the sites, storage and distribution of imaging data, and image 
processing; and (3) clinical sites, each providing a core team of 
researchers skilled in the recruitment and clinical evaluation of 
subjects with normal cognition, MCI, and AD, and the implementation of 
assessment tools for MCI and AD. All sites must also have MRI (1.5T) 
capability and access to adequate time on an MRI scanner; a subset of 
sites must have capability and access to adequate time on a PET 
scanner; and a subset of sites, on a 3T MRI scanner. 
Individual potential clinical sites may be included in more than one 
application.

A Steering Committee, comprised of the principal investigator (PI) of 
the cooperative agreement, the leaders of the CC, NC, and each of the 
clinical sites, the NIA Program Administrator, representatives from 
partnering pharmaceutical and/or medical imaging companies, and the 
FDA, will have primary responsibility for finalizing standard 
definitions, procedures, and laboratory measures common to the 
protocols of the study sites.  The Steering Committee will also 
encourage and consider proposals for ancillary studies. These studies 
will most likely require funding from sources outside of this 
cooperative agreement.

The criteria for MCI should follow those discussed as amnestic and 
multiple-domain MCI in Petersen (2003), so may include subjects who 
have mild cognitive deficits outside of the domain of memory in 
addition to memory impairment (Petersen RC, Nature Reviews 2:646-653, 
2003). Inclusion of subjects with symptoms of depression or who are 
being treated with anti-depressant medications that do not have strong 
anti-cholinergic actions is encouraged, as many studies establish 
depression as a risk factor for AD. Applicants should include 
inclusion/exclusion criteria that will be uniform across all sites for 
each of the subject groups, although final details will be determined 
by the Steering Committee.   

NIA staff, in conjunction with four working groups of experts, 
discussed how to achieve the goals of the Initiative. Reports on the 
findings of these groups are posted on the NIA web site 
(http://www.nia.nih.gov). Suggested time points for assessment were as 
follows: 
o HEALTHY CONTROLS: Baseline, 12, 24, & 36 months; 
o MCI: Baseline, 3, 6, 12, 18, 24, 30, & 36 months; 
o MILD AD GROUP: Baseline, 3, 6, 12, 18, & 24 months.
  
All subjects would complete clinical, neuropsychological, 3D volumetric 
MRI (1.5T) evaluations, and blood sampling at each time point. At less 
frequent time points, in a sub-set of subjects, CSF samples would be 
collected and at those sites with the capability, PET scanning and 3T 
MRI.
 
Blood samples will be collected, processed and stored for the 
establishment of immortalized cell lines. The findings of a working 
group on promising biomarkers in blood, CSF, and urine, which are 
feasible to collect in a multi-center study are published in Frank, 
R.A., et al., Neurobiology of Aging 24:521-36, 2003. Applicants may 
propose other measures as well, and should also plan for the 
collection, shipment, and storage of aliquots of samples for analyses 
of substances to be determined by future research including proteomic 
and metabolomic studies. The results of all analyses will need to be 
submitted for inclusion in the centralized dataset, consistent with the 
data-sharing plans of the Initiative. 

Funding for the analysis of substances in the specimens collected is 
not anticipated to be available from the funds for this Initiative, 
with the exception of Apolipoprotein E alleles and standard clinical 
laboratory assessments. Funding for the establishment of cell lines is 
anticipated.  
 
To advise the Steering Committee, applicants should also plan to 
recruit an external advisory committee, consisting of scientists from 
outside the institutions awarded funding for the Initiative. External 
advisory committee members should not be recruited until the NIH review 
is complete. This committee will be used to evaluate the progress of 
the Initiative, ensure that data monitoring procedures are sufficient 
and that quality data are being collected to the highest standards 
possible, evaluate the effectiveness of communications among the CC, 
NC, and clinical sites, and any other activities for which outside 
expertise is required or desirable. The NIA project coordinator, who 
will also serve as the program administrator, will attend each meeting 
of this committee as an observer. 

The CC is expected to work in collaboration with its NC, the clinical 
sites, and the NIA project coordinator to assist in protocol 
development and planning, subject recruitment, project administration, 
and close-out. 

MECHANISM OF SUPPORT

This RFA will use the NIH cooperative agreement (U01) award mechanism. 
As an applicant you will be solely responsible for planning, directing, 
and executing the proposed project. This RFA is a one-time 
solicitation. 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 date is not later than 
September 30, 2004.  

The NIH U01 is a cooperative agreement award mechanism. In the 
cooperative agreement mechanism, the Principal Investigator retains the 
primary responsibility and dominant role for planning, directing, and 
executing the proposed project, with NIH staff being substantially 
involved as a partner with the Principal Investigator, as described 
under the section "Cooperative Agreement Terms and Conditions of 
Award." The total project period for an application submitted in 
response to the present RFA may not exceed 5 years. 

FUNDS AVAILABLE 

The NIA intends to commit up to $12 million in FY 2004 for the initial 
year of funding for the Neuroimaging Inititative. An applicant may 
request a project period of up to 5 years and a budget for total costs 
of up to $12 million per year. The size of the proposed budget for each 
year should be appropriate for the phase being conducted in that year. 
No more than one award will be made as a result of this RFA and funding 
of this award is contingent upon availability of funds.

ELIGIBLE INSTITUTIONS 

You may submit an application 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 institutions
o Foreign institutions are eligible to serve as clinical sites but not 
as the CC or NC.

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.   

SPECIAL REQUIREMENTS

The CC and the clinical sites should obtain IRB approvals consistent 
with the guidance on repositories from the NIH Office of Human Research 
Protections (OHRP): 
http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm. The NIH 
brochure on research on human specimens may also be useful and can be 
found at: http://www.cdp.ims.nci.nih.gov/policy.html
 
1. (A) Special requirements for the Neuroimaging Initiative CC are as 
follows:

o  The applicant should state the willingness and ability to cooperate 
with the Neuroimaging Initiative clinical sites and NC and NIA staff in 
all design, data collection, management and distribution functions. The 
applicant should provide a plan for developing a cooperative 
relationship among the clinical sites and between the various 
organizational components.

o  A formal data-sharing plan must be included in the application, 
including a plan for a system that allows databases to be queried, in 
conjunction with CC staff, by investigators not directly associated 
with the Initiative. 

(B) Special requirements for the NC or Core are as follows:

o  Images should be centrally archived for centralized analysis for 
those comparisons that address the primary aims of the study. 
Applicants should describe procedures that will allow investigators 
from different organizations to analyze data using other methods (e.g., 
different image reconstruction, image deformation, or normalization 
techniques) in order to optimize the study of imaging measures as 
putative surrogate markers of AD.  Data should be stored in the 
original and in any modified formats.

o  The NC applicant should state the willingness and ability to 
cooperate with the Neuroimaging Initiative CC and clinical sites and 
NIA staff in all design, data collection, management and distribution 
functions.

(C) Special requirements for clinical sites are as follows:

o  Site applicants should state the willingness and ability to 
cooperate with the Neuroimaging Initiative CC and Neuroimaging Center 
and NIA staff in all design, data collection, management and 
distribution functions.

2. Cooperative Agreement 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 project administrator.

A. Awardee Responsibilities

The Coordinating Center (CC) awardee agrees to work cooperatively with 
the Neuroimaging Initiative Neuroimaging Center (NC) and clinical sites 
and will have the primary responsibility for developing and 
implementing systems necessary for communications among the various 
Neuroimaging Initiative organizational components. The CC will 
facilitate the design and refinement of all protocols, manuals of 
operation, and forms. 

The awardee institution will retain custody of, and primary rights to, 
the data developed under this award, subject to Government rights of 
access consistent with current HHS, PHS, and NIH policies, with the 
added stipulation that all primary data shall be shared within time 
periods to be specified, as a fundamental purpose of this Initiative is 
the establishment of an unrestricted public database. 

The primary governing body of the study will be the Steering Committee, 
which will have responsibility for the final details of study design 
and policy decisions and will define the rules regarding access to 
common data.

B.  Staff Responsibilities

The designated NIA Project Administrator will serve as a member of the 
Steering Committee and have substantial scientific/programmatic 
involvement during conduct of this cooperative agreement, through 
technical assistance, advice and coordination above and beyond normal 
program stewardship of grants. The awardee agrees to accept assistance 
from the designated NIA Project Administrator, as described below:

o  Participation, through the Steering Committee, in the monitoring of 
issues relating to recruitment, follow-up, QA/QC, and adherence to 
protocols.

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

An NIA Program Director will be responsible for the normal program 
stewardship on this award. The Program Director may also be designated 
as the NIA Project Administrator described above. 

C. Collaborative Responsibilities

The Steering Committee, comprised of the PI of the cooperative 
agreement, the leaders of the CC, NC, and each of the clinical sites, 
the NIA project administrator, representatives from partnering 
pharmaceutical and/or medical imaging companies, and the FDA, will have 
primary responsibility for finalizing standard definitions, procedures, 
and laboratory measures common to the protocols of the study sites. The 
SC will meet every three to six months, or as dictated by the needs of 
the Neuroimaging Initiative. Each member of the Steering Committee will 
have one vote, and all major scientific decisions will be determined by 
majority vote of the Steering Committee. Subcommittees appointed by the 
Steering Committee, comprised of appropriate staff from the CC, NC, and 
clinical sites, will be involved in the design of protocols and manuals 
of operations, and in ongoing functions of the Neuroimaging Initiative, 
such as consideration of potential ancillary studies and preparation of 
publications. 

To oversee the allocation and distribution of biological specimens 
generated from the Neuroimaging Initiative, the Steering Committee will 
select a Resource Allocation Review Committee (RARC). This group will 
review applications for use of the biological specimens. The format of 
the application and criteria for the use of repository biological 
specimens will be developed by the RARC with advice and approval from 
the Steering Committee and made available to all potential users. The 
RARC will be made up of individuals not directly involved in the 
Neuroimaging Initiative and without conflicts of interest. Membership 
on this committee will rotate periodically according to a procedure 
developed by the RARC.  

D.  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, nor will it affect the government's rights with regards to 
grants enforcement.

WHERE TO SEND INQUIRIES 

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants. Inquiries may fall into 
three areas: scientific/research, peer review, and financial or grants 
management issues

o Direct inquiries regarding programmatic issues to:

Susan Molchan, M.D.
Program Director, Alzheimer's Disease Clinical Trials
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Bldg., Suite 350
7201 Wisconsin Ave.
Bethesda, MD 20892-9205
Telephone:(301)496-9350; FAX:(301)496-1494
E-mail:  [email protected]

o Direct inquiries regarding peer review issues to:

Mary Nekola, Ph.D.
Chief, Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C-212
Bethesda, Maryland 20892-9205
Express Mail Zip Code:  20814
Telephone:  301/496-9666; FAX:  301/402-0066
E-mail:  [email protected]

o Direct inquiries regarding financial or grants management matters to:

Linda Whipp
Grants Management Officer
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N-212
Bethesda, Maryland  20892-9205
Express Mail Zip Code:  20814
Telephone:  301/496-1472; FAX:  301/402-3672
E-mail: [email protected]

LETTER OF INTENT

Prospective applicants are asked to submit, by December 16, 2003, 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 for the CC, NC, and the clinical sites
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: 

Susan Molchan, M.D.
Program Director, Alzheimer's Disease Clinical Trials
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Bldg., Suite 350
7201 Wisconsin Ave.
Bethesda, MD 20892-9205
Telephone:(301)496-9350; FAX:(301)496-1494
E-mail:  [email protected]

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 is available 
at http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: [email protected].

SUPPLEMENTARY INSTRUCTIONS

Introduction and Background sections should be provided for the 
application as a whole. Following those sections three separate 
sections should be prepared, one for the CC (up to 25 pages), one for 
the NC or Core (up to 25 pages), and one for the clinical sites (3-4 
pages/site). In addition, please include a chart of the clinical sites 
summarizing patient (MCI and early AD) recruiting experience and 
potential, neuropsychological and clinical experience with MCI and AD 
patients, experience as part of multi-site studies, MRI (1.5T) 
experience, MRI scanner availability and access, and if applicable, PET 
experience and PET scanner availability and access, and/or 3T MRI 
experience, availability, and access. 

Individual potential clinical sites may be included in more than one 
application.
 
Provide a flow chart or time line of the evaluations and procedures 
planned for subjects. Plans for ensuring compliance with HIPAA, data 
integrity, quality control, and data sharing should be discussed.

Personnel: For each of the three components of the Initiative, the 
application must describe the expertise of key scientific, technical 
and administrative personnel and include a mechanism for replacing key 
professional or technical personnel should the need arise. 

Budget:  The budgets should be based on the applicant's best judgment 
of activities likely to be involved during the different phases of the 
Initiative as delineated under the section on Research Objectives. 
Budgets should include costs of organizing at least two Steering 
Committee meetings annually and for attendance of necessary CC, NC, and 
clinical site staff to these meetings. Budgets should include costs of 
at least two external scientific advisory committee meetings annually. 
Budgets should include projected data handling costs, reporting 
functions, meetings, and other communications costs. Funding for 
extensive analyses will be encouraged through other mechanisms such as 
research grants but budgets for evaluation of scans for exclusion 
criteria, for example, ruling out potential participants who have 
multiple lacunes in a critical memory structure, and determination of 
measures such as hippocampal, entorhinal cortex, and temporal horn 
volumes for incorporation into the database will be needed. Clinical 
sites will be reimbursed for costs on a per visit/per protocol basis. 

Attempts should be made by the applicant institution to utilize 
existing clinical facilities, such as General Clinical Research Centers 
and AD Centers. Costs relating to the clinical efforts for the 
Neuroimaging Initiative may be funded through the Initiative, provided 
there is no overlap of funding. Only those research patient costs 
directly related to Initiative activities may be charged to the 
Initiative.

Include an explanation of the programmatic, fiscal, and administrative 
arrangements made between the grantee administration and the 
collaborating institutions.

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/labels.pdf.

SENDING AN APPLICATION TO THE NIH: Submit a signed 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:

Mary Nekola, Ph.D.
Chief, Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C-212
Bethesda, Maryland 20892-9205
Express Mail Zip Code:  20814
Telephone:  301/496-9666; FAX:  301/402-0066
E-mail:  [email protected]

Material included in appendices must follow the instructions in PHS 
398. 

APPLICATION PROCESSING: 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.

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 Aging. Incomplete applications will not be 
reviewed. 
 
If the application is not responsive to the RFA, NIH staff may contact 
the applicant to determine whether to return the application to the 
applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

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 NIA 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 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 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 Approach
o Investigator
o Environment

APPROACH: Are the conceptual framework, hypotheses, design, and methods 
adequately developed, well-integrated, and appropriate to the aims of 
the project?  Are potential problem areas acknowledged and alternative 
tactics considered? Does the proposed approach in managing the 
logistical and data coordination have scientific and technical merit? 
Are the proposed plans and experience relating to subject recruitment 
and retention, staff training, data collection, monitoring, management, 
editing, processing, and reporting adequate? Has justification for 
specific acquisition parameters been provided? Are plans for the 
collection, shipment, and storage of biological samples adequate? Are 
the plans for coordination with the study site investigators adequate? 
Is the approach to developing a cooperative relationship among the 
study sites and between the various Neuroimaging Initiative 
organizational components adequate? Are the plans for exercising 
appropriate leadership in matters of study design, data acquisition, 
data management, and data distribution demonstrated? 

INVESTIGATOR: Are the applicant and his/her staff appropriately trained 
and well-suited to carry out this work? Is the work proposed 
appropriate to the applicant's experience level as the PI? Does the 
application provide evidence of specific competence and relevant 
experience of professional, technical, and administrative staff 
pertinent to the operation of a CC and NC for multi-site studies?  
Prior experience collecting data and patient specimens from multiple 
clinical sites and monitoring data quality should be demonstrated. Do 
NC applicants have experience with quality-controlled collecting, 
cleaning, processing, and analysis of MRI and FDG-PET scans of the 
brain, including studies of AD? Is there evidence of experience in and 
willingness to participate appropriately in a collaborative study as 
described in this RFA? Are there adequate assurances that the CC 
personnel have experience in utilizing procedures that insure the 
safety and confidentiality of medical records? These questions should 
also be addressed with reference to the lead investigator and staff of 
the NC. Investigators and staff at the clinical sites should document 
experience and capabilities as noted above under Special Requirements, 
and document experience recruiting and evaluating normal elderly, MCI, 
and early AD subjects, MRI (and if applicable PET) experience/access, 
and collecting blood and CSF for scientific protocols. 

ENVIRONMENT: For the CC, the NC, and the clinical sites, does the 
scientific environment in which the work will be done contribute to the 
probability of success? Is there evidence of institutional support? Has 
the application documented the adequacy of the proposed facility, 
technical hardware, and space for the CC/NC/clinical sites?  Is there 
an appropriate organizational and administrative structure to the 
proposed CC/NC?  Evidence of institutional support and commitment 
should be provided.

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the 
application will also be reviewed with respect to the following:
 
o The capability of recruiting an appropriate number of subjects during 
an approximately 18 month recruitment period. For clinical sites, a 
documented record of past success of recruiting efforts for MCI, normal 
control, and AD subjects. 
 
o All sites must also have 1.5T MRI capability and access to adequate 
time on an MRI scanner. Subsets of sites must have capability and 
access to adequate time on a PET scanner and 3T MRI. For clinical 
sites, a documented record of previous MRI (and PET if applicable) 
research experience.

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).

The Neuroimaging Initiative CC will be setting up a repository of 
samples from human subjects. Therefore, the CC must comply with current 
human subjects protection policies regarding potential patient 
identifier information that are associated with these stored samples. 

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH:  The adequacy of plans 
to include subjects from both genders and all racial and ethnic groups 
(and subgroups). Plans for recruitment and retention of subjects will 
also be evaluated. (See Inclusion Criteria in the sections on Federal 
Citations, below).

ADDITIONAL REVIEW CONSIDERATIONS

SHARING RESEARCH DATA:  Applicants requesting more than $500,000 in 
direct costs in any year of the proposed research 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 in relation to the 
proposed research.

RECEIPT AND REVIEW SCHEDULE 

Letter of Intent Receipt Date:     December 16, 2003
Application Receipt Date:        January 16, 2004
Peer Review Date:           April-May, 2004                       
Council Review:                         August, 2004
Earliest Anticipated Start Date:        September 1, 2004

AWARD CRITERIA

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

o Scientific/technical merit (as determined by peer review)
o Availability of funds
o Programmatic priorities

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 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

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.
 
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 will be placing data collected under this RFA in a public 
archive, which must provide protections for the data. 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.health.gov/healthypeople/.

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 authorization 
of Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and 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 to 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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