HIV/AIDS AND AGING:  BASIC AND CLINICAL RESEARCH

RELEASE DATE:  October 10, 2002

RFA:  MH-03-004

National Institute of Mental Health (NIMH)
 (http://www.nimh.nih.gov/)
National Institute on Aging (NIA)
 (http://www.nia.nih.gov/)
National Institute on Drug Abuse (NIDA)
 (http://www.nida.nih.gov/)

LETTER OF INTENT RECEIPT DATE:  December 13, 2002
APPLICATION RECEIPT DATE:  January 13, 2003

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  Where to Send Inquiries
o  Letter of Intent
o  Submitting an Application
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 of Mental Health (NIMH), the National Institute on Aging 
(NIA), and the National Institute on Drug Abuse (NIDA) invite research grant 
applications through this Request for Applications (RFA) to support research 
about older adults (greater than 50 years of age) infected with human 
immunodeficiency virus (HIV).  This is an age group that has been overlooked or 
ignored by many researchers throughout the pandemic.  A major goal of this RFA 
is to begin a process where basic and clinical scientists from various 
disciplines can overcome barriers to cross-disciplinary aging research in the 
context of HIV disease and its treatment.  The purpose of this initiative is to:  
(1) focus the attention of basic and clinical scientists on the 
neurodegenerative processes contributing to the central nervous system (CNS) 
complications in HIV infection in the elderly; (2) promote the interaction of 
basic and clinical scientists conducting research in HIV disease in the elderly; 
and (3) develop integrative research programs that advance our understanding of 
the substrates underlying CNS complications in HIV disease in the elderly.  The 
principal CNS complications addressed by this RFA include neurocognitive, 
neurobehavioral, and neuropsychiatric and drug abuse sequelae of HIV infection 
(these conditions as antecedents may also be of interest).  Because this is an 
emerging area of interest, but poorly understood and understudied, it is 
necessary to address a wide range of scientific opportunities to move the field 
forward.  We particularly encourage applications that demonstrate the 
establishment of collaborative research programs with researchers at existing 
centers of excellence with a focus on issues related to the elderly infected 
with HIV. 

RESEARCH OBJECTIVES

Background

People living with HIV disease are growing older.  Additionally, between 1991 
and 1996, the number of new AIDS cases rose twice as fast in persons 50-plus 
years of age than it did in persons younger than 50 (22% vs 9%, respectively; 
CDC, 1998).  According to the CDC, reported rates of persons living with AIDS 
suggest that older adults account for up to 15% of the AIDS caseload, 
representing an increase of about 5% from 1997-1999.  Further, as highly active 
antiretroviral therapy (HAART) prolongs periods of survival, the older 
population among those with HIV is likely to expand, as many persons who 
contracted HIV in their 30s and 40s are living well into their 50s, 60s, and 
70s.  In view of these trends, there is a need for basic epidemiological 
research on HIV and HIV-associated CNS complications in older adults.

Compelling evidence exists that natural history and symptom manifestations of
HIV infection in the elderly substantially differ from those seen in younger 
cohorts.  Relative to their younger counterparts, older adults living with 
HIV/AIDS have a more severe HIV disease course and a shorter survival rate; have 
less desirable health indices at diagnosis (e.g., lower CD4+ cell counts); have 
shorter AIDS-free intervals; have a higher number of opportunistic infections; 
and have earlier development of tumors and lesions.  These differences between 
older and younger HIV-infected adults could be due to immunosenescence; the 
presence of underlying conditions associated with aging; the existence of 
current and/or past history of drug abuse; HIV-related medical sequelae and CNS 
complications; and the adverse effects of certain medical treatments.  Research 
is needed to determine the mechanisms at work in an aging immune system and to 
determine whether there is a difference in immune reconstitution following HAART 
between younger and older HIV-infected populations and how this difference might 
impact the development of neurocognitive dysfunction.  In addition, older 
Americans have their own population-specific health challenges, such as 
Alzheimer's disease, osteoporosis, adult-onset diabetes, prostate cancer, 
menopause, and hypertension.  There is even evidence that an interaction between 
HIV-induced pathophysiologies and Alzheimer's disease-related pathophysiologies 
may be occurring, and this interaction would have important implications for 
aging.  HIV risk may also be intensified by a pre-existing compromised immune 
system caused by other health problems, drug abuse, or the aging process per se.

Among health risks that may be associated with HIV or its treatment via HAART 
are neurologic complications (such as myelopathy, neuropathy and neuropathic 
pain, changes in cognition, and dementia) and psychiatric complications (such as 
mania, depression, schizophrenia, and substance abuse and dependence).  It has 
been shown that increased neurocognitive complications occur as a function of 
chronological age, but we do not know whether this relationship can be accounted 
for by age-associated comorbidities.  Studies have also shown that HIV infection 
may exacerbate psychiatric conditions, including major depression, bipolar 
disorder, and schizophrenia, but this exacerbation has not been clearly 
documented in a population of older adults.  Moreover, since many individuals 
with HIV infection have either a history of and/or current drug 
abuse/dependence, the roles of these factors in the onset, pathophysiology, and 
course of HIV disease in the elderly need to be elucidated.  Thus, research is 
needed to distinguish the medical complications of aging from the psychiatric, 
substance abuse, and neurocognitive sequelae.  Presently, it is unclear whether 
the neuropsychiatric and neurocognitive complications in HIV disease are 
reflections of similar processes that cause functional aging or whether they are 
interactions of HIV disease with the aging process.  Fundamental to all of this 
work is the need for reassessment and refinement of HIV-associated dementia 
(HAD) in the elderly.  The pattern of cognitive impairment may be much different 
in older HIV-infected persons than in younger infected persons due to the 
presence of other dementing conditions in older adults (besides HAD) which 
confound the individual's cognitive dysfunction in the context of HIV.

HAART has been effective in improving neurocognitive performance and decreasing 
the incidence of HIV dementia.  However, prospective studies are needed among 
older persons to address appropriateness of current HAART dosage, susceptibility 
to HAART side effects, and the potential for increased vulnerability to adverse 
drug reactions due to changes associated with the aging process (e.g., body 
composition changes, decline in kidney function, and changes in the metabolism 
of older persons).  Purely on a pharmacokinetic basis, one might predict higher 
and steadier plasma concentrations because of reduced clearance and/or other 
metabolic processes/effects.  However, it is a significant concern that the 
metabolic complications of HAART therapy may compound or accelerate processes 
leading to vascular disease morbidity, which would become increasingly 
problematic with age and chronic use of the drugs.  In addition, research will 
need to address age-dependent changes in the blood-brain barrier (BBB) to design 
optimum therapies.

SCOPE

This RFA solicits applications to evaluate a large variety of outcomes in older 
HIV seropositive adults, including observational, biological, clinical, and 
treatment variables, and to address research questions in the following domains:  
(i) HIV-related medical and CNS complications; (ii) neuropsychiatric conditions 
and substance use disorders; (iii) neurobehavior, neurocognitive disorders, and 
neuroimaging; (iv) virology and immunology; (v) neuropathogenesis mechanisms; 
and (vi) drug treatment research.  Longitudinal designs may be needed for both 
observational cohort studies and hypothesis-driven experimental studies.  There 
may be benefit in drawing upon existing multicenter databases in HIV/AIDS 
research.  The areas of research below are illustrative; they are not intended 
to be exhaustive.  However, the proposed research should fall within the major 
category areas: (1) Epidemiology, Natural History, and Transmission, (2) Basic 
Science, (3) Human Clinical Investigations, and (4) Human Clinical Interventions.

Epidemiology, Natural History, and Transmission

o  Studies of the incidence, prevalence, and natural history of neurocognitive 
deficits and psychiatric and substance use disorders in older HIV-infected 
adults.  Are the nature, severity, course, or treatment of HIV-associated 
neurocognitive and psychiatric disorders in older HIV-infected adults different 
from the nature, severity, course, or treatment of those disorders in older 
uninfected controls and in younger HIV+ comparison groups?  Is there an 
additive/multiplicative effect of advancing age and brain disease?

o  Epidemiologic cohort studies in HIV-infected older adults to investigate the 
mechanisms of disease progression, key cofactors that modify HIV disease (i.e., 
infectious, nutritional, comorbidities), and the impact of therapy in changing 
the spectrum of HIV disease.

o  Investigations of HIV-associated neurocognitive deficits and psychiatric and 
substance use disorders in the elderly as predictors of later HIV-associated 
disease progression.  How does neurocognitive function, neuropsychiatric status, 
and substance use disorder vary as a function of disease stage in the elderly?  
What are the factors associated with fluctuations in neurocognitive and 
neuropsychiatric complications (e.g., adherence)?

o  Studies that characterize the epidemiology of sexual and drug-use risk 
behaviors among older adults infected with HIV.  What are the correlates and 
determinants of those behaviors and how does this inform the development of 
subsequent prevention efforts?

o  Research on the role of potential cofactors, correlates, and mediators of HIV 
disease progression in the elderly (e.g., gender, immunological decline, 
infectious agents, alcohol and drug use, neuropsychiatric status, neurocognitive 
dysfunction).

Basic Science

o  Develop relevant animal models for studying neurocognitive deficits in older 
adults infected with HIV.

o  Research to determine the cellular and molecular bases of and pathogenic 
mechanisms in HIV-associated neurocognitive, neurobehavioral, and 
neuropsychiatric dysfunction in the elderly.

o  Determine factors associated with clinical response and lack of response to 
HAART and other therapeutic interventions for neurocognitive, neurobehavioral, 
and neuropsychiatric complications of HIV disease in the elderly.

o  Studies that delineate the role of opportunistic infections, co-infections 
(e.g., hepatitis C, tuberculosis), and other age-related disease complications 
(e.g., hypertension, diabetes, metabolic disorders) on neurocognitive, 
neurobehavioral, and neuropsychiatric complications of AIDS in the elderly 
(including CNS dysfunction and peripheral neuropathies) and their impact on 
immune dysfunction and disease progression.

o  Investigate aspects of HIV infection that uniquely influence the aging 
nervous system and impact on the neurocognitive, neurobehavioral, and 
neuropsychiatric dysfunction in the elderly.

Human Clinical Investigations

o  Studies of the determinants of increased neurocognitive dysfunction in the 
elderly infected with HIV.  What roles do comorbidities, host factors, treatment 
toxicities, aberrant immune reconstitution, and HIV infection per se play in its 
development?

o  Studies that utilize novel imaging techniques for human neuroanatomy to 
examine the neural systems damaged in HIV infection of the elderly (e.g., MRI 
brain morphometry; MRI perfusion methods; MRI diffusion tensor analysis; MRI 
cytoarchitechtonic).  These studies should also investigate whether this 
information can be correlated with neurocognitive impairment and 
neuropsychiatric and substance use disorders seen in older HIV-infected patients.

o  Studies that examine the potential correlation between neurocognitive 
impairment and neuropsychiatric and substance use disorders with neuropathology 
in HIV-infected older adults.  What is the temporal relationship between 
pathology identified at end stage disease and the actual onset of the 
motor/cognitive impairment seen throughout the disease process in the elderly?

o  Research on neurocognitive and neuropsychiatric substrates of adherence to 
prevention and treatment programs in the elderly infected with HIV, focusing on 
such issues as executive functioning, aspects of memory related to adherence, 
neural systems involved in motivation, etc.

o  Studies that compare the effects of aging processes in the brain (e.g., 
atrophy, neurotransmitter changes, alterations in BBB integrity), age-related 
neurodegenerative disease (e.g., Alzheimer's disease, vascular dementia), and 
neuro-AIDS abnormalities in older adults.  

o  Studies of virological and immunological indicators in HIV infection in the 
elderly.  These studies should also investigate whether this information can be 
correlated with neurocognitive impairment and neuropsychiatric and substance use 
disorders seen in older HIV-infected patients.  What immune dysfunctions are 
common to aging and to HIV infection?  Is there increased immune activation in 
the elderly?  Can this be tied to the development of neurocognitive dysfunction
in the elderly?

Human Clinical Interventions

o  Clinical trials to determine the optimal therapeutic approaches to the 
management of HIV infection in the elderly, including when to start, change, or 
sequence therapy.  How can regimens be modified according to age, age-related 
comorbidities, and age-related deficiencies in the immune system and alterations 
in CD4 lymphocyte function?

o  Studies of the impact of antiretroviral therapies (with differing abilities 
to penetrate the CNS) on neurocognitive, neuropsychiatric, and substance use 
disorders in the elderly; drug interactions between antiretrovirals; and 
pharmacotherapeutics for neuropsychiatric and CNS complications and for other 
comorbid disorders.

o  Research to develop and evaluate new agents and strategies for preventing and 
treating opportunistic infections (shown to be increased in the elderly) or 
other co-infections (especially hepatitis C and tuberculosis) and for reducing 
the increased antiretroviral-related toxicity that might be anticipated because 
of immunocompromise in the elderly.

o  Studies to develop and evaluate therapeutic approaches that will improve and 
sustain immune function in the elderly.  What markers predict the efficacy of 
immune-based therapies in the elderly?  Investigations to develop 
neuroprotective agents for immune reconstitution to minimize impairment due to 
neurocognitive dysfunction and neuropsychiatric disorder in the elderly. 

o  Studies of antiretroviral-associated age-dependent differences in toxicities, 
metabolic complications, and immune reconstitution and their impact on improved 
neurocognitive function.

MECHANISM(S) OF SUPPORT

This RFA will use the NIH research project grant (R01), Collaborative R01, and 
exploratory/developmental (R21) award mechanisms.  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 earliest anticipated award date is July 1, 2003.

This RFA uses just-in-time concepts.  It also uses the modular 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 format.  Otherwise follow the instructions for non-modular 
research grant applications.

FUNDS AVAILABLE 

The NIMH intends to commit approximately $1,500,000 in FY 2003 to fund 6 to 8 
new and/or competitive continuation grants in response to this RFA.  The NIA 
intends to commit approximately $750,000 to fund 3 to 5 new and/or competitive 
continuation grants in response to this RFA.  The NIDA intends to commit 
approximately $750,000 to fund 3 to 5 new and/or competitive continuation grants 
in response to this RFA.

An applicant may request a project period of up to 3 years and a budget for 
direct costs of up to $125,000 per year for an Exploratory/Developmental Grant 
(R21).  For those applications that include a subcontractual/consortium 
arrangement, direct costs of up to $150,000 per year may be requested to allow 
for facilities and administrative (F&A) costs on those consortium arrangements.  

A research project grant (R01) may involve either a single Principal 
Investigator or a group of investigators using the Collaborative R01 mechanism; 
applicants may request a project period of up to 5 years, with a budget 
determined by the work proposed. 

Applicants for the Collaborative R01 Grant are strongly encouraged to 
familiarize themselves with the NIMH announcement 
(http://grants.nih.gov/grants/guide/pa-files/PA-01-123.html), most notably, the 
requirement to list all performance sites on page 2 of the 398 application kit 
and the requirement to provide an overview no longer than 2 pages to describe 
the overall rationale for applying as a collaborative study, the role of each 
site, any elements unique to a site, and the approach to project management.  
Questions regarding the use of the Collaborative R01 mechanism may be directed 
to program staff listed under INQUIRIES.

Because the nature and scope of the proposed research will vary from application 
to application, it is anticipated that the size and duration of each award will 
also vary.  Although the financial plans of the participating 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.  At this time, it is not known if this RFA will be reissued.

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 or foreign
o  Faith-based or community-based organizations

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

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

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 your questions about scientific/research issues to:

David M. Stoff, Ph.D.
Center for Mental Health Research on AIDS
Division of Mental Disorders, Behavioral Research and AIDS
National Institute of Mental Health
6001 Executive Boulevard, Room 6210, MSC 9619
Bethesda, MD  20892-9619
Telephone:  (301) 443-4625
FAX:  (301) 443-9719
Email:  dstoff@nih.gov

Andrew A. Monjan, Ph.D., M.P.H.
Chief, Neurobiology of Aging Branch
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Bethesda, MD  20892-9205
Bethesda, MD  20814(for express/courier service)
Telephone: (301) 496-9350
FAX:  (301) 496-1494
Email:  am39m@nih.gov

Sander Genser, M.D., M.P.H.
Head, Medical Consequences Unit
Center on AIDS and Other Medical Consequences of Drug Abuse (CAMCODA)
National Institute on Drug Abuse
6001 Executive Boulevard, Room 5198, MSC 9593
Bethesda, MD  20892-9593
Telephone:  (301) 443-1801
FAX:  (301) 594-6566
Email:  sg73f@nih.gov

o  Direct your questions about peer review issues to:

Michael Kozak, Ph.D. 
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9608
Bethesda, MD  20892-9608
Telephone:  (301-) 443-6471
FAX:  (301) 443-4720
Email:  mkozak@nih.gov

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

Brian Albertini
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6135, MSC 9605
Bethesda, MD  20892-9605
Telephone:  (301-) 443-0004
FAX:  (301) 443-6885
Email:  albertinib2@mail.nih.gov

Linda Whipp
Grants and Contracts Management Officer
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  whippl@nia.nih.gov

Gary Fleming, J.D.
Chief, Grants Management Branch
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD  20892-9541
Telephone:  (301-) 443-6710
FAX:  (301) 594-6847
Email:  gf6s@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:

David M. Stoff, Ph.D.
Center for Mental Health Research on AIDS
Division of Mental Disorders, Behavioral Research and AIDS
National Institute of Mental Health
6001 Executive Boulevard, Room 6210, MSC 9619
Bethesda, MD  20892-9619
Telephone:  (301) 443-4625
FAX:  (301) 443-9719
Email:  dstoff@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  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) 435-0714, 
Email: GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications requesting 
up to $250,000 per year in direct costs 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 
appendices) must be sent to:

Jean G. Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 44303367
FAX:  (301) 443-4720
Email:  jnoronha@mail.nih.gov

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.

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

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the participating ICs.  Incomplete applications will be 
returned to the applicant without further consideration.  And, if the 
application is not responsive to the RFA, CSR 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 participating ICs in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will:

o  Receive a written critique
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 second level review by the National Advisory Mental Health Council, 
the National Advisory Council on Aging, and the National Advisory Council on 
Drug Abuse (NIDA).

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In the 
written comments, reviewers will be asked to discuss the following aspects of 
your application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals:

o  Significance
o  Approach
o  Innovation
o  Investigator
o  Environment

The scientific review group will address and consider each of these criteria in 
assigning your application's overall score, weighting them as appropriate for 
each application.  Your 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, you may propose to carry out important work that 
by its nature is not innovative but is essential to move a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem?  If the aims of 
your application are achieved, how do they advance scientific knowledge?  What 
will be the effect of these studies on the concepts or methods that drive this 
field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 
tactics?

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

(4) INVESTIGATOR:  Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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, your application 
will also be reviewed with respect to the following:

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

o  INCLUSION:  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 included in the section 
on Federal Citations, below)

o  DATA SHARING:  The adequacy of the proposed plan to share data. 

o  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 Date:    December 13, 2002
Application Receipt Date:         January 13, 2003
Peer Review Date:                 March 2003
Council Review:                   May 2003
Earliest Anticipated Start Date:  July 1, 2003

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

REQUIRED FEDERAL CITATIONS

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD:  Research components 
involving Phase I and II clinical trials must include provisions for assessment 
of patient eligibility and status, rigorous data management, quality assurance, 
and auditing procedures.  In addition, it is NIH policy that all clinical trials 
require data and safety monitoring, with the method and degree of monitoring 
being commensurate with the risks (NIH Policy for Data Safety and Monitoring,
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

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 AMENDMENT "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.

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research on 
hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).  
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review.

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 PA 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.

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 No. 93.242, 93.866, and 93.279 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 administered 
under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92.

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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