HIV INFECTION OF THE CENTRAL NERVOUS SYSTEM

RELEASE DATE:  September 2, 2004

PA NUMBER:   PA-04-154

November 22, 2006 - The R01 portion of this funding opportunity has been replaced by PA-07-089, 
which now uses the electronic SF424 (R&R) application for February 5, 2007 submission dates and beyond.

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date for these 
mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms 
expires on the date indicated below. Other mechanisms relating to this announcement 
will continue to be accepted using paper PHS 398 applications until the stated 
expiration date below, or transition to electronic application submission. Parent 
R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been 
issued for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter. Applications relating to R33 and R34 activities 
must be in response to NIH Institute/Center (IC)-specific announcements.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 
EXPIRATION DATE for R01 Non-AIDS Applications: November 2, 2006 
EXPIRATION DATE for R01 AIDS and AIDS-Related Applications: January 3, 2007
Department of Health and Human Services (DHHS)

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

COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Mental Health (NIMH)
 (http://www.nimh.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
National Institute on Drug Abuse (NIDA)
 (http://www.nida.nih.gov)
National Institute of Alcohol Abuse and Alcoholism (NIAAA)
 (http://www.niaaa.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:  93.242 (NIMH), 93.853 (NINDS), 
93.279 (NIDA), 93.273 (NIAAA)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o  Purpose of the PA
o  Research Objectives
o  Mechanism(s) of Support 
o  Eligible Institutions
o  Individuals Eligible to Become Principal Investigators
o  Where to Send Inquiries
o  Submitting an Application
o  Peer Review Process
o  Review Criteria
o  Award Criteria
o  Required Federal Citations

PURPOSE OF THIS PA

This PA replaces PA-01-072.

The National Institute of Mental Health (NIMH), National Institute of Neurological 
Disorders and Stroke (NINDS), National Institute on Drug Abuse (NIDA), and National 
Institute of Alcohol Abuse and Alcoholism (NIAAA) invite research grant 
applications through this Program Announcement (PA) to support research focused on 
determining the pathogenic mechanisms involved in Human Immunodeficiency Virus 
(HIV)-1 associated neurobehavioral and neurological dysfunction in domestic and 
international settings.  The objective of this cooperative effort is to foster 
investigations that will provide the foundation for the rapid development of 
therapeutic interventions to prevent and treat the effects of HIV-1 on the central 
nervous system (CNS).  Applications ranging from basic research to clinical 
diagnosis and treatment are of interest.  Multidisciplinary research teams and 
collaborative alliances are encouraged but not required.

RESEARCH OBJECTIVES

The introduction of highly active anti-retroviral therapy (HAART) has resulted in 
significantly improved survival of AIDS patients and decreased incidence of HIV-
associated dementia (HAD).  HAD is estimated to constitute about 5% of new AIDS-
defining illnesses in the USA.  Despite the reduced incidence of HIV dementia, the 
improved survival has resulted in increased cumulative prevalence of nervous system 
complications of AIDS.  HAART does not provide full protection against neurological 
damage in HIV/AIDS in part, because the blood-brain barrier is only partially 
permeable to anti-retroviral agents.  The frequency of HIV-associated encephalitis 
observed in post-mortem tissue has remained constant, suggesting that HAART does 
not eliminate HIV-1 infection in the central nervous system.  Furthermore, while 
improvements in treatment for AIDS have occurred in the developed world, a 
significant number of new infections are being reported in the developing countries 
including China, India, Eastern Europe, and Sub-Saharan Africa.  The neurologic and 
neuropsychiatric complications resulting from new infections in the developing 
world are likely to cause significant morbidity and mortality.

Extensive research is underway to better understand the underlying mechanisms of 
neuropathogenesis of HIV-1.  Currently there is limited consensus on the pathways 
leading to neurologic and neuropsychiatric disease in the setting of HAART.  While 
HAART has resulted in increased prevalence of HIV dementia, the neurologic disease 
has been reported to be milder.  It has been suggested that in the era of HAART, 
distinct subtypes of HAD are observed.  The proposed subtypes include the 
following:  a) subacute progressive dementia; b) chronic active dementia; and c) 
chronic inactive dementia.

The research efforts over the last two decades have resulted in an improved 
understanding of the pathophysiology of HIV-induced nervous system disease.  
However, many fundamental gaps remain in our knowledge relating to mechanisms and 
pathways involved in the development of HIV-associated neurologic and 
neuropsychiatric disease.  An important emerging area of research interest is the 
exploding HIV epidemic in resource-poor settings and the impact on nervous system 
disease.  There is an urgent need for research on the epidemiology and natural 
history of neurologic and neuropsychiatric disease in the affected regions of the 
world.  Another critical research need relates to studies of mechanisms by which 
distinct viral clades impact on HIV-neuropathogenesis and associated co-infections 
and opportunistic infections in resource-poor settings.

In an effort to intensify the depth, focus, and coordination of key neuro-AIDS 
issues, NIMH, NINDS, NIDA, and NIAAA are jointly issuing this Program Announcement.  
The following are examples of research areas that are pertinent to this PA add 
examples only, not limited to these topics:

Primary and Secondary Mechanisms of HIV-1 Neuropathogenesis

o  Mechanisms of entry of cell-associated and cell-free virus into the CNS 
compartment through the blood-brain barrier.  Role of cytokines, chemokines, 
chemokine receptors, adhesion molecules and syndecans in facilitating HIV 
trafficking into the CNS.

o  Mechanisms of infection and productive replication of HIV in cells derived from 
the CNS compartment including microglia, macrophages and astrocytes.

o  Interactions of viral proteins (Tat, Vpr, Nef, gp 120) with CNS derived cells.  
These include studies of the impact of viral proteins on damage to blood-brain 
barrier, induction of release of mediators (chemokines, cytokines, excitotoxins) 
and activation of apoptotic pathways, particularly in neuronal cells.

o  Roles of excitotoxicity and the production of reactive oxygen species as 
mechanisms of neuropathogenesis in HIV-1 infection of the CNS.

o  Impact of host derived mediators and associated receptors (cytokines, 
chemokines, chemokine receptors, matrix metalloproteinases, thrombin, proteinase-
activated receptors)on HIV-neuropathogenesis.

o  Signaling pathways involved in neuronal damage and apoptosis or release of 
inflammatory mediators following interaction of virus or viral proteins with CNS-
derived cells.

o  Role of adaptive and innate immunity in regulating anti-viral responses in the 
CNS compartment.

o  Cellular and viral factors that maintain viral latency or promote viral 
activation and recrudescence in the brain.

o  Roles of pharmacomodulation of cytokine/chemokine receptor activity and related 
mechanisms of neuropathogenesis in HIV-1 infection of the CNS.

o  Neural-glial interactions focusing on interrelated cytokine/chemokine systems 
and the modulation by endogenous opiate/cannabinoid systems.

o  The ability of chronic alcohol intake to facilitate the entry of HIV-1 to the 
nervous system through the blood-brain barrier, and to augment the development and 
progression of HAD via potentiating HIV-induced neurotoxicity or excitotoxicity, 
activating apoptotic or other signal transduction pathways, or further compromising 
immune function.

o  Early morphologic or metabolic alterations that may precede or be associated 
with onset of cognitive impairment in HIV-positive individuals with confounding 
disease state/drug dependence.

Viral and Host Genetics

o  Viral Evolution in the CNS.

a.  The role of viral evolution and trafficking in establishing regional genetic 
heterogeneity of HIV-1 in CNS.
b.  Comparisons of sequences of HIV strains derived from CNS and other organs for 
assessment of compartmentalized virus evolution.

o  HIV-1 Molecular Diversity and Resulting Functional Consequences.

a.  Molecular diversity of various HIV-1 genes (e.g., Tat, Nef, Vpr) and resultant 
functional consequences in CNS.
b.  Correlation of molecular changes of HIV-1 strains derived from demented and 
non-demented individuals and associated impact on function.
c.  The role of HIV-1 envelope protein in inducing neurotoxicity and in stimulating 
release of toxic mediators.
d.  Comparisons of the ability of various CNS and non-CNS derived HIV-1 strains to 
release neurotoxins from glial cells and macrophages and assessment of the 
relationship, if any, to viral sequences and neurovirulence.
e.  Differences between HIV-1 envelopes in signaling of macrophages, microglial 
cells, astrocytes, endothelial cells, and neurons; identification of any 
relationships between signaling differences, HIV-1 envelope sequence diversity and 
functional effects.

o  Emergence of Drug Resistance in CNS parenchyma/CSF versus other body 
compartments.

a.  Independent emergence of drug resistance mutations in CNS parenchyma/CSF versus 
other body compartments.
b.  Sequence analysis of HIV-1 derived from patient populations with discordant 
control of HIV-1 in CSF and plasma to assess emergence of compartmentalized drug 
resistance as well as potential reseeding of peripheral compartments.

o  Host genetic factors and markers linked with susceptibility and progression of 
HIV-associated nervous system disease.

o  Pharmacogenomic studies to identify genetic markers and polymorphisms linked 
with host response to anti-retroviral therapy.  For example, polymorphisms in the 
mdr gene are associated with differences in protease inhibitor levels and magnitude 
of CD4+ count recovery under therapy.

Molecular Markers Associated with HIV-Induced Nervous System Disease

o  Microarray analysis of HIV-infected human CNS tissue or animal models of 
neuroAIDS at various stages of disease progression to identify modulation of unique 
genes.  Genes of interest can be further characterized to delineate their molecular 
identity as well as their functional role in neuropathogenesis.

o  Use of proteomics to uncover protein signatures associated with HIV infection in 
various peripheral and CNS cell populations and biological fluids of patients at 
various stages of disease progression.  Protein chip technologies may be utilized 
to identify unique protein profiles associated with neurological and 
neuropsychiatric manifestations of HIV infection.

Neuroimaging Studies 

o  Use of neuroimaging approaches such as magnetic resonance spectroscopy (MRS), 
positron emission tomography (PET), magnetic resonance imaging (MRI), functional 
MRI (fMRI), blood oxygenation level dependent functional magnetic resonance imaging 
(BOLD fMRI) and diffusion tensor imaging (DTI)to delineate key biological markers 
that correlate with disease symptoms and progression.  Neuroimaging studies are 
also useful in establishing relationships between spectroscopic markers and 
histopathologic markers of neuronal health and inflammation.  Studies of the role 
of unique inflammation-related markers identified by neuroimaging, in the 
pathophysiology of neuroAIDS, are relevant.

o  Unique issues associated with actions in IV drug abusers, especially focusing on 
regions or circuits relevant to drug abuse (e.g., mesocortical limbic system, 
hippocampus, frontal cortical areas, pyramidal and extrapyramidal motor areas).  
Studies on children and youth are encouraged.

o  Improved statistical and innovative neuroimaging methods for drug abuse.

HIV/Hepatitis C(HCV)Co-Infection and Opportunistic Infections of the CNS

o  The prevalence, qualitative and quantitative features of HCV induced 
neurocognitive impairment in the setting of co-infection with HIV.

o  Mechanisms of HCV-induced neurocognitive impairment including host and viral 
factors and their interactions.

o  Interactions between HIV-1 infection, immunodeficiency and the spread of other 
infectious agents in the CNS.

Therapeutics

o  Developing HIV-1 therapeutic agents capable of penetrating the blood-brain 
barrier (alternate approaches may include manipulation of efflux transporters, such 
as P-glycoproteins, to improve access of anti-HIV agents across the BBB).

o  Adjunctive therapies including neuroprotective strategies to treat HIV-induced 
nervous system disease.

NeuroAIDS Research in Resource-limited Settings

o  The incidence and prevalence of neurological and neuropsychiatric disease caused 
by HIV and associated opportunistic infections (toxoplasmosis, cryptococcal 
meningitis) and co-infections (hepatitis C, cerebral malaria) in the 
presence/absence of drug or alcohol abuse.

o  Molecular analysis of clades prevalent in resource-limited settings and studies 
of mechanisms of neuropathogenesis caused by non-subtype B viruses.

o  Impact of host-genetic factors in regulating susceptibility to nervous system 
disease caused by HIV and associated opportunistic infections and co-infections.

The use of animal models (non-human primates, transgenic mice/rats) is encouraged.  
Studies of HIV-1 infection of the brain have been slowed by the lack of well 
characterized human CNS tissues.  Such tissue samples (brain, spinal cord, cerebral 
spinal fluid, blood, lymphocytes) are currently available from the National 
NeuroAIDS Tissue Consortium (http://spitfire.emmes.com/study/hbb/), which can be 
used as a resource for these studies.  

MECHANISM(S) OF SUPPORT 

This PA will use the NIH research project grant (R01) and exploratory/developmental 
grant (R21) award mechanisms.  As an applicant you will be solely responsible for 
planning, directing, and executing the proposed project.  The R21 mechanism (see 
http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) is intended to 
encourage new exploratory/developmental research projects by providing support for 
the early stages of their development.  For example, such projects could assess the 
feasibility of a novel area of investigation or a new experimental system that has 
the potential to enhance health-related research.  These studies may involve 
considerable risk but may lead to a breakthrough in a particular area, or to the 
development of novel techniques, agents, methodologies, models or applications that 
could have a major impact on a field of biomedical, behavioral, or clinical 
research.

Applications for R21 awards should describe projects distinct from those supported 
through the traditional R01 mechanism.  For example, long-term projects, or 
projects designed to increase knowledge in a well-established area will not be 
considered for R21 awards.  Applications submitted under this mechanism should be 
exploratory and novel.  These studies should break new ground or extend previous 
discoveries toward new directions or applications.

R21 applications may request a project period of up to two years with a combined 
budget for direct costs of up to $275,000 for the two-year period.  For example, 
you may request $100,000 in the first year and $175,000 in the second year.  The 
request should be tailored to the needs of your project.  Normally, no more than 
$200,000 may be requested in any single year.

This PA 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/grants/policy/nihgps_2003/NIHGPS_Part2.htm.

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 institutions/organizations

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 

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two areas:  
scientific/research and financial or grants management issues:

o  Direct your questions about scientific/research issues to:

Jeymohan Joseph, Ph.D.
Chief, HIV Neurovirology, Genetics and Molecular Therapeutics Program 
Center for Mental Health Research on AIDS
National Institute of Mental Health
6001 Executive Boulevard, Room 6202
Bethesda, MD  20892
Telephone:  (301) 443-3012
FAX:  (301) 443-9719
Email:  jjeymoha@mail.nih.gov

Charles Sharp, Ph.D.
Division of Neuroscience and Behavioral Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4282, MSC 9555
Bethesda, MD  20892-9555 
Telephone:  (301) 443-1887
FAX:  (301) 594-6034
Email:  cs107m@nih.gov

Michael Nunn, Ph.D.
Neural Environment Cluster
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2118
Bethesda, MD  20892
Telephone:  (301) 496-1431
FAX:  (301) 480-2424
Email:  mn52e@nih.gov

Roger Sorensen, Ph.D., M.P.A.
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 2058, MSC 9304
Bethesda, MD  20892-9304
Telephone:  (301) 443-2678
FAX:  (301) 443-1650
Email:  rsorense@mail.nih.gov

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

Mr. Brian Albertini
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115
Bethesda, MD  20892
Telephone:  (301) 443-0004
FAX:  (301) 443-0219
Email:  albertib2@mail.nih.gov

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse/NIH/DHHS
6101 Executive Boulevard, Suite 270, MSC 8403
Bethesda, MD  20892-8403
Telephone:  (301) 443-6710
FAX:  (301) 594-6849
Email:  gf6s@nih.gov

James Washington, M.Ed.
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3254
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  washingj@ninds.nih.gov

Judy S. Fox
Chief Grants Management Officer
National Institute of Alcohol Abuse And Alcoholism
5635 Fishers Lane, Room 3021, MSC 9304
Bethesda, MD  20892-9304
Telephone:  (301) 443-9704
FAX:  (301) 443-4704
Email:  jfox@mail.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 D&B number can be 
obtained by calling (866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/.  The D&B 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) 435-0714, Email:  
GrantsInfo@nih.gov.

The title and number of this program announcement must be typed on line 2 of the 
face page of the application form and the YES box must be checked.

APPLICATION RECEIPT DATES:  Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which are 
available at http://grants.nih.gov/grants/dates.htm.  Application deadlines are 
also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a modular 
budget grant format.  The modular budget 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.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:  
Applications requesting $500,000 or more in direct costs for any year must include 
a cover letter identifying the NIH staff member within one of NIH institutes or 
centers who has agreed to accept assignment of the application.

Applicants requesting $500,000 or more must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, 
i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your application for 
consideration for award; and,

3) Identify, in a cover letter sent with the application, the staff member and IC 
who agreed to accept assignment of the application.

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised version of 
these grant application types.  Additional information on this policy is available 
in the NIH Guide for Grants and Contracts, October 19, 2001 at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of the 
application, including the checklist, and five 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)

APPLICATION PROCESSING:  Applications must be mailed on or before the receipt dates 
described at http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR 
will not accept any application in response to this PA 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 unfunded version of an application already reviewed, but such 
application must include an Introduction addressing the previous critique.

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.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of established PHS 
referral guidelines.  Appropriate scientific review groups convened in accordance 
with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) 
will evaluate applications for scientific and technical merit.

As part of the initial merit review, all applications will:

o  Undergo a selection process in which only those applications deemed to have the 
highest scientific merit, generally the top half of applications under review, will 
be discussed and assigned a priority score
o  Receive a written critique
o  Receive a second level review by the 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 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:

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) http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

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 will be 
assessed.  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:  Applicants requesting $500,000 or more in direct costs in 
any year of the proposed research are expected to 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.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds with 
all other recommended applications.  The following will be considered in making 
funding decisions:

o  Scientific merit of the proposed project as determined by peer review
o  Availability of funds
o  Relevance to program priorities

REQUIRED FEDERAL CITATIONS

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities involving 
live, vertebrate animals must comply with PHS Policy on Humane Care and Use of 
Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated 
by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal 
Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as 
applicable.

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:  Investigators submitting an NIH application seeking 
$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.  

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://stemcells.nih.gov/index.asp 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, in the project description and 
elsewhere in the application as appropriate, 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.

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).  

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 PA 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) 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 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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