CNS THERAPY DEVELOPMENT FOR LYSOSOMAL STORAGE DISORDERS

RELEASE DATE:  July 2, 2004

PA NUMBER:  PAS-04-120

The R01 portion of this funding opportunity has been replaced by PAS-07-195,
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. Accordingly, the R21 portion of this funding opportunity 
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. A replacement R21 (PAS-06-202) funding opportunity announcement 
has been issued for the submission date of June 1, 2006 and submission dates thereafter.

EXPIRATION DATE: for R21 Applications: March 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 ORGANIZATIONS: 
National Institutes of Health (NIH)
 (http://www.nih.gov/)
Lysosomal Storage Disease Research Consortium (LSDRC)
 (http://www.LSDResearch.org)

COMPONENTS OF PARTICIPATING ORGANIZATIONS:
National Institute of Neurological Disorders and Stroke (NINDS/NIH)
 (http://www.ninds.nih.gov/)
Office of Rare Diseases (ORD/NIH)
 (http://rarediseases.info.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.853 (NINDS)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanisms of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

The goal of this Program Announcement is to solicit applications on lysosomal 
storage disorders (LSDs) focused on improving CNS treatment outcomes, 
enhancing the effectiveness of delivery and targeting of cells, enzymes, drugs 
and genes into the brain, and developing novel therapeutic modalities, such as 
implantable biocapsules and micro-electro-mechanical systems (MEMS)-based 
devices. Lysosomal storage disorders constitute a group of recessive genetic 
diseases resulting from cellular enzymatic deficiencies of acid hydrolases 
that normally catalyze the metabolism of glycoproteins, glycolipids and other 
macromolecules, or from defects in transporter proteins leading to pathogenic 
accumulation of these substances in lysosomes. Treatment modalities for LSDs 
are currently limited to bone marrow transplantation (BMT) and enzyme 
replacement therapy (ERT). These approaches while providing significant 
promise for treatment of the visceral manifestations of LSDs, do little to 
address CNS pathologies for this group of disorders. Thus this announcement 
specifically encourages the transition from basic studies in LSDs to 
translational research for improved delivery of therapeutic cells, proteins, 
genes, and small molecules across the blood-brain barrier.

RESEARCH OBJECTIVES

Background

Lysosomal storage disorders encompass about 50 metabolic diseases, that 
include neuronal ceroid lipofucinoses, mucopolysaccharidoses (MPS), 
mucolipidoses IV, sphingolipidoses, sphingomylinoses (Niemann-Pick disease), 
gangliosidoses, glycoproteinoses, and other monogenic inborn errors of 
metabolism that collectively affect approximately 1 in 5000 live births. Each 
of these diseases has heterogeneous pathophysiology and clinical 
manifestation resulting from deficient activity of specific hydrolases that 
act to catabolize macromolecular substrates in the lumen of lysosmes. In some 
cases, the genetic defect can be in an activator protein for a lysosomal 
hydrolase or a transporter protein for the metabolites. All these 
deficiencies lead to a characteristic pathological accumulation and storage 
of the substrate for that enzyme in the lysosomes. The consequent 
accumulation of undigested metabolites in lysosomes leads to multi-systemic 
dysfunction, including progressive neurologic deterioration, mental 
retardation, organomegaly, blindness, and early death. 

In general, the residual amount of functional enzyme in the lysosomes of 
patients determines the severity and age at onset of the clinical symptoms, 
implying that even modest increases in enzyme activity might affect a cure. A 
critical issue for treatment of LSDs is the ability of soluble enzyme 
precursors to be secreted by one cell type and taken up by neighboring cells 
via receptor-mediated endocytosis. It has been estimated that as little as 
10% of normal or restored enzyme level is sufficient for non-autonomous cell 
correction and clearance of the storage materials. 

Significant advances have been made in the treatment of non-neuronopathic 
forms of LSDs via enzyme replacement therapy (ERT) and bone marrow 
transplantation (BMT) where a number of clinical trails are already underway. 
However addressing the CNS aspects of these diseases remains a formidable 
challenge. To date ERT has shown no major effect toward reversing preexisting 
CNS disease in neuronopathic forms of LSDs though it is possible that ERT may 
slow the progression of CNS deterioration if administered early on in the 
disease process. Bone marrow transplantation with hematopoietic stem cells 
has been successful in some forms of MPS with long term survival following 
successful engraftment. However optimal prevention of CNS deterioration in 
MPS is possible only when BMT occurs before onset of neurologic 
manifestations, generally at less than 2 years of age. This would suggest 
that the presence of irreversible damage must be considered prior to the 
initiation of therapy, thus early diagnosis and determination of optimal 
timing of intervention could also be a key to improved therapy. However, 
there are few detailed natural history studies on clinical outcomes or 
disease progression addressing CNS aspects of neuronopathic forms of LSDs. In 
addition there is a higher rate of associated morbidity and mortality with 
BMT. Clearly, additional treatment regimen alone or in conjunction with ERT 
or BMT is needed to significantly alter the course of CNS deterioration in 
LSDs. 

Research Scope

This initiative seeks to extend the recent advances in the treatment of the 
visceral aspects of LSDs to therapies geared towards the CNS abnormalities. 
The following are examples of topics that might be proposed for study in 
response to this announcement. These are only examples and are not meant to 
be limiting, however the focus should remain on therapy development for LSDs.

o Novel delivery methods for drugs, cells, enzymes and genes across/or around 
the BBB.

o New approaches for targeting the BBB, such as the use of endogenous 
transport systems, including carrier-mediated transporters like glucose and 
amino acid carriers; receptor-mediated transcytosis utilizing insulin or 
transferrin receptors; and active efflux transporters such as p-glycoprotein 
and the associated anti-porters.

o Use of peptide or pharmaceuticals as molecular  Trojan horses  that can bind 
to endogenous receptor-mediated transporters in the BBB.

o New types of therapy, including substrate reduction therapy.

o RNAi-mediated therapy of downstream targets.

o Use of microfluidic or MEMS devices for in-vivo spatial and temporal 
controlled delivery of exogenous biomolecules, such as drugs, gene transfer 
vectors, and cells.

o Assessment of the behavior of host cells in response to the short-term and 
long-term presence of transplanted human stem cells and/or their derivatives.

o Identification of therapeutic windows of opportunity by characterizing 
pathophysiological processes.

o Applications of neuroimaging and neurophysiological biomarkers to monitor 
disease progression, effects of therapeutic interventions, or complications.

o Use of non-invasive measures of organ function (e.g., functional MRI, 
magnetic resonance spectroscopy, ultrasound, PET) to identify, characterize, 
and validate diagnostic biomarkers, intermediate surrogate endpoints, and 
prognostic biomarkers.

o Identification and validation of natural history biomarkers that may 
predict clinical outcome.

o Estimation of the magnitude of treatment effects based on validated 
biomarkers that reflect underlying pathogenesis.

o Development and validation of clinical tools, such as a rating scale or 
predictor of clinical outcome.

This PA is not intended to support basic neuroscience research involving LSDs 
but instead emphasizes pre-clinical, translational and clinical research that 
targets the neurocognitive and neurodegenerative aspects of this group of 
diseases and is geared towards the development of therapeutic strategies. The 
NINDS supports in parallel other translational research projects, "NINDS 
Cooperative Program in Translational Research" 
(http://grants.nih.gov/grants/guide/pa-files/PAR-02-139.html) and "NINDS 
Exploratory/Developmental Projects in Translational Research" 
(http://grants.nih.gov/grants/guide/pa-files/PAR-02-138.html).

MECHANISMS 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 proposed project period during which the research will be 
conducted should adequately reflect the time required to accomplish the stated 
goals and should be no more than 5 years for R01 grants.  Applicants are 
encouraged to contact program staff for advice about choosing the appropriate 
grant mechanism.

R21 grants are one-time awards 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 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 $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. For further 
information on the R21 mechanism, including Institute-specific information, 
see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html and 
http://www.ninds.nih.gov/funding/r21guidelines.htm.  NINDS will not accept R21 
applications that include non-exempt human subjects research.

This PA 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.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.

Competing continuation applications submitted in response to this PA will 
compete with all investigator-initiated applications and be referred and 
reviewed according to the customary peer review procedures.

FUNDS AVAILABLE

Applications submitted in response to this PA will compete with all 
investigator-initiated applications for funding. The NINDS and ORD intend to 
commit a total of approximately $1,050,000 (total costs) in addition to funds 
available for applications sent in response to this program announcement that 
score within the NINDS payline (see NINDS Funding Strategy 
http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm), depending on 
the overall scientific merit of the applications and the availability of 
funds throughout the duration of this solicitation (3 years). 

Because the nature and scope of the research proposed may vary, it is 
anticipated that the size of each award will also vary.  Although the 
financial plans of the Institute provide support for this program, awards 
pursuant to this PA 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 PA will be reissued.

Additional funds may also be available through the Lysosomal Storage Disease 
Research Consortium (http://www.LSDresearch.org) for applications received and 
reviewed under this PA.

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 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

SPECIAL REQUIREMENTS 

Letter of Authorization

In order for applications to be considered for funding by the LSDRC 
(http://www.LSDresearch.org), all applicants should provide NIH with a letter 
of authority permitting NIH to share applications and the corresponding 
summary statements with LSDRC.  Letters of authorization should be prepared 
by the principal investigator and co-signed by the official signing for the 
applicant organization.  This letter may be submitted as a cover letter 
accompanying the application.

Plan for Dissemination of Data and Biomaterials

PHS policy requires that investigators make unique research resources 
available for research purposes to qualified individuals within the scientific 
community when they have been published (see the NIH Grants Policy Statement 
at http://grants.nih.gov/grants/guide/notice-files/not96-184.html).  In 
addition, NIH recently released a statement on the sharing of research data 
that applies to all investigator-initiated applications with direct costs 
greater than $500,000 in any single year 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html).  

The Initial Review Group will evaluate the proposed sharing plan and comment 
on its adequacy in an administrative note in the summary statement.  Reviewers 
will not factor the proposed data-sharing plan into the determination of 
scientific merit or priority score.  The adequacy of the plan will be 
considered by NIH staff in determining whether the grant shall be awarded. The 
sharing plan as approved, after negotiation with the applicant when necessary, 
will be a condition of the award.

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:

Danilo A. Tagle, Ph.D.
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2133
Bethesda, MD  20892
Telephone:  (301) 496-5745
FAX: (301) 402-1501
Email: [email protected]

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

Sheila S. Simmons
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3250
Bethesda, MD 20892
Telephone: 301-496-9231
Fax: 301-402-0219
Email: [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) 435-0714, Email: [email protected].

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.

SUPPLEMENTARY INSTRUCTIONS 

All instructions for the PHS 398 (rev. 5/2001) must be followed, with these 
exceptions:

o   Research Plan

For R21 applications only, items a   d of the Research Plan (Specific Aims, 
Background and Significance, Preliminary Studies, and Research Design and 
Methods) may not exceed a total of 15 pages.  No preliminary data is required 
for R21 proposals, but may be included if it is available.  Please note that 
a Progress Report is not needed for R21 awards; competing continuation 
applications for an exploratory/developmental grant will not be accepted.

Appendix.  Use the instructions for the appendix detailed in the PHS 398 
except that for R21 applications, no more than 5 manuscripts, previously 
accepted for publication, may be included.

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 more than $500,000 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 an appropriate national advisory council 
or board. 

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate 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?  

The NIH R21 exploratory/developmental grant is a mechanism for supporting 
novel scientific ideas or new model systems, tools or technologies that have 
the potential to significantly advance our knowledge or health-related 
research.  Because the research plan is limited to 15 pages, an R21 grant 
application need not have extensive background material or preliminary 
information as normally expected in an R01 application.  Reviewers will be 
instructed to focus their evaluation on the conceptual framework, the level 
of innovation, and the potential to significantly advance our knowledge or 
understanding.  Reviewers will thus place less emphasis on methodological 
details and certain indicators traditionally used in evaluating the 
scientific merit of R01 applications including supportive preliminary data.  
Appropriate justification for the proposed work can be provided through 
literature citations, data from other sources, or, when available, from 
investigator-generated data.  NINDS will not accept unsolicited R21 
applications that include non-exempt human subjects research.

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

Starting with the October 1, 2003 receipt date, 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.

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. If human 
subjects are involved, applicants should contact the Program Director to 
discuss their project prior to submission of the application.

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.

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