IMPROVED THERAPY FOR HEMOPHILIA AND HEREDITARY BLEEDING DISORDERS 

RELEASE DATE:  June 18, 2004
 
RFA Number:  RFA-HL-04-032  

EXPIRATION DATE:  January 16, 2005

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATIONS:  
National Institutes of Health (NIH)
 (http://www.nih.gov)
National Hemophilia Foundation (NHF)
 (http://www.hemophilia.org) 

COMPONENT OF PARTICIPATING ORGANIZATIONS:  
National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.839
 
LETTER OF INTENT RECEIPT DATE:  December 15, 2004
APPLICATION RECEIPT DATE:  January 14, 2005
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE OF THIS RFA 

The National Heart, Lung, and Blood Institute (NHLBI) and the National Hemophilia 
Foundation (NHF) invite applications for studies that will lead to improved 
treatment of hemophilia, von Willebrand disease, and other hereditary bleeding 
disorders with the ultimate goal of finding a cure for bleeding disorders.  The 
objectives of this program are to stimulate research to improve therapy, and 
enhance understanding of immune response and safety issues related to novel 
therapeutics, gene transfer or cell based therapies for bleeding disorders.  
  
RESEARCH OBJECTIVES
 
Background

Hemophilia is a hereditary bleeding disorder that results from a functional 
deficiency in either blood coagulation factor VIII (hemophilia A) or factor IX 
(hemophilia B). The severity of the disease is related to the levels of 
circulating functional clotting protein. Standard hemophilia treatment involves 
infusion of plasma derived or recombinant coagulation factor. About 25% of 
individuals with severe hemophilia develop neutralizing antibodies requiring 
higher doses or alternative therapy.  The current therapeutic options for these 
patients are recombinant factor VIIa (rfVIIa), plasma derived prothrombin complex 
concentrate (PCC) or porcine factor VIII.  Often more than one approach is tried 
before the bleeding is arrested. 

One of the most common hereditary bleeding disorders is von Willebrand Disease 
(VWD), which is associated with mucosal or trauma related bleeding.  It results 
from a quantitative or qualitative defect in von Willebrand factor (VWF).  
Approximately 80% of VWD patients have a mild to moderate form of the disease and 
are treated with desmopressin (DDAVP), which stimulates the release of stored VWF 
into the circulation.  However, tachyphylaxis occurs with repeated doses.  Plasma 
derived factor VIII products that contain a significant amount of VWF are an 
alternate therapy.  

Bleeding disorders may also be related to deficiencies in other coagulation 
factors: fibrinogen, prothrombin, factor V, factor VII, factor X, factor XI and 
factor XIII.  The incidence of a deficiency in any one of these factors is about 1 
in 1 million.  The available treatment options for a bleeding episode for someone 
with one of the clotting factor deficiencies is generally a plasma derived product 
such as; fresh frozen plasma, cryoprecipitate, or prothrombin complex 
concentrates.

Research Objectives

This initiative would support research on the discovery and development of 
improved therapeutics with a goal of finding a cure for hemophilia, VWD and other 
hereditary bleeding disorders.  The focus is on controlling the bleeding 
complications, the development of novel therapeutic agents, and reducing the 
immunogenicity or safety challenges of the products for the treatment of bleeding 
disorders.  

The introduction of recombinant factor VIII (fVIII) and factor IX (fIX) provided 
an alternative to plasma derived products and increased the supply of therapeutic 
agents.  Recombinant DNA technology also provides the ability to design fVIII and 
fIX molecules with specific properties, such as increased activity, longer half-
life, or reduced antigenicity. An inactivation resistant fVIII (IR8) had increased 
activity and corrected prolonged bleeding in the hemophilia A mouse model. The 
time fVIII remains in the circulation may be prolonged by simultaneous blocking 
the receptors, which are low-density lipoprotein receptor-related protein (LRP) 
and cell-surface heparan sulfate proteoglycans (HSPGs).  Specific fVIII residues 
that mediate binding to these receptors have been identified and are potential 
mutagenesis targets for an improved fVIII.  These or other protein modifications 
could lead to products that would require a reduced dose or less frequent 
administration. It may also be possible to design fVIII molecules with reduced 
antigenicity. 

Bioengineering of fVIII or fIX to improve expression may benefit the production of 
recombinant proteins and gene transfer applications. Recombinant fVIII with the B 
domain deleted (BDD) retains activity and has about a 20-fold higher expression 
level than wild type.  The safety and efficacy of this modified fVIII was 
demonstrated in clinical studies, which led to the introduction of the BDD-rfVIII 
product. FIX has complex post-translational modifications and poses different 
challenges for efficient expression.  The presence of intron 1 in fIX cDNA or the 
inclusion of three ATG triplets as a translation initiation signal results in 
increased production of fIX.  

The introduction of recombinant fVIIa provided a safe and effective therapy for 
many hemophilia patients with inhibitors.  However, some patients have shown low 
clinical responsiveness to rfVIIa, which may not be detected for several days.  
Sequential by-pass therapy with PCC, followed by rfVIIa, has been found to be 
effective for some patients.  The potential to develop novel by-pass agents needs 
to be further explored.  

Another possible area for exploration is the identification and development of 
agents that stimulate the release or increase expression of coagulation proteins. 
DDAVP, which can be administered as a nasal spray, works by stimulating the 
release of stored VWF and is an effective therapy for mild VWD.  Interleukin-11 
(IL 11) increases plasma levels of VWF and fVIII.  A report of heterozygous VWD 
and normal dogs treated with IL 11 or DDAVP showed that IL11 produced a gradual 
and sustained elevation of VWF and fVIII and DDAVP gave a rapid unsustained 
elevation of these factors.  In addition, the DDAVP releasable pool of VWF was 
maintained after IL 11 treatment.   

Treatment of bleeding disorders generally requires intravenous infusion.  The use 
of venous access devices has increased the ability to treat small children several 
times a week, but such devices induce significant risk of infection.  Studies have 
shown that fIX administered subcutaneously reaches the circulation but there may 
be an increased risk of an immune response.  FIX has been produced in porcine milk 
and has been shown to enter the circulation of hemophilia B mice when taken 
orally.  Studies in hemophilia B mice showed that oral tolerance to human fIX 
could protect against an immune response when mice were challenged with an 
injection of hfIX or underwent intramuscular gene transfer with AAV-hfIX.  Further 
research is needed on tolerance induction for replacement therapy and gene 
transfer approaches.  Additional research is also needed for development of 
improved delivery systems for therapeutic agents or cell/gene transfer 
technologies. 
 
The pursuit of novel pharmacologic agents should include consideration for the 
safety of the potential new therapy.  In particular new therapies must not 
increase risk of development of antibodies to the coagulation factor or other 
pathologic complications.  

Examples for research topics

The emphasis of this program is on the therapy of inherited bleeding disorders and 
related safety issues.  Areas of investigation that would be appropriate for this 
RFA include but are not limited to:

o  Development of modified factor VIII or factor IX proteins with improved 
biological activity and/or functional half life 

o  Identification of modifications that increase factor VIII or factor IX 
production of recombinant proteins or use in gene transfer applications    
 
o  Development of pharmacologic agents that would improve the release,           
activity or biological availability of coagulation factors, thereby improving the 
effectiveness of a hemostatic response

o  Development of novel hemostatic agents, design of small molecules that promote 
hemostasis, or factor VIII/IX analogues 

o  Identification of the processes that regulate potential for inhibitor 
formation, or the genetic and phenotypic signatures that affect immune response

o  Development of novel ways to avoid immune response, evaluation of 
risks/benefits of immunosuppressive agents
  
Basic studies on von Willebrand Factor not related to von Willebrand Disease or 
vector development research for gene transfer will not be considered appropriate 
for support by this program.  

MECHANISM OF SUPPORT
 
This RFA will use NIH R01 award mechanism.  National Hemophilia Foundation support 
of the RFA will be provided by monies collected under its “It’s Time for a Cure” 
campaign (http://www.hemophilia.org/programs/timeforacure/timeforacure.htm).  
Applications submitted in response to this RFA, whether supported by the NHLBI or 
the NHF, may have a project period of up to four years. As an applicant you will 
be solely responsible for planning, directing, and executing the proposed project.  
This RFA is a one-time solicitation.  Future unsolicited, competing-continuation 
applications based on this project will compete with all investigator-initiated 
applications and will be reviewed according to the customary peer review 
procedures. The anticipated award date is September 30, 2005. Applications that 
are not funded in the competition described in this RFA may be resubmitted as NEW 
investigator-initiated applications using the standard receipt dates for NEW 
applications described in the instructions to the PHS 398 application.  

This RFA uses just-in-time concepts.  It also uses the modular budgeting format. 
(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.  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.  

FUNDS AVAILABLE
 
The NHLBI intends to commit approximately $1.5 million in FY 2005 to fund 4 to 5 
new and/or competitive continuation grants in response to this RFA. The NHF 
intends to commit approximately $1.5 million in FY 2006 (NHF fiscal year runs from 
July 1 through June 30) to fund 4 to 5 new grants relevant to their mission.  The 
NHLBI intends to commit approximately $6 million for this program from FY 2005 to 
FY 2008.  The NHF intends to commit approximately $6 million for this program from 
FY 2006 to FY 2009.  The NHF funded grants will be awarded with the NHF indirect 
cost rate.  NHF will make the award of grants for meritorious applications of 
interest to them.  Applicants who wish to have their projects considered for 
funding by NHF should include with their application a letter stating that their 
application and summary statement may be shared with NHF.  An applicant may 
request a project period of up to 4 years and a budget for direct costs of up to 
$250,000 per year. Facilities and administrative costs (F&A) for consortia are not 
included in this direct cost ceiling.  Please see 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html for more 
information on the exclusion of the facilities and administrative (F&A) costs 
requested by consortium participants or contact the Grants Management Specialist 
listed under “where to send inquiries”, below.  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 NHLBI and the NHF provide support for this program, awards pursuant 
to this RFA are contingent upon the availability of funds and the receipt of a 
sufficient number of meritorious applications.  
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the following 
characteristics:   

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges,             
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based 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 

Grantee’s Meeting

The NHLBI and the NHF will sponsor annual meetings to encourage exchange of 
information among investigators who participate in this program.  In their 
budgets, applicants should include funds for annual one-day grantees’ meetings.  
Applicants should also include a statement in their applications indicating their 
willingness to participate in these meetings.

CONSIDERATION BY NHF

Applicants who wish to have their projects considered for funding by NHF should 
include with their application a letter stating that their application and summary 
statement may be shared with NHF. The Research Department at the National 
Hemophilia Foundation, with counsel from scientific and lay leaders, is 
responsible for the administration of it’s grant programs. Grantees are not 
employees of NHF but of their grantee institution and are subject to the policies 
and regulations of the grantee institution. Only noncommercial institutions and 
investigators associated with a noncommercial institution are eligible for NHF 
funding. NHF is a nonprofit organization and all grants are offered based on 
fundraising efforts; therefore, all grants and fellowships are contingent on funds 
available. Please see http://www.hemophilia.org/research/pol_proc_2003.pdf for 
further information and specific requirements.

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:

Rebecca P. Link, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung and Blood Institute 
6701 Rockledge Drive
Rockledge II, Room 10178, MSC 7950
Bethesda, MD  20892
Telephone:  (301) 435-0070
FAX: (301) 480-1046
Email: linkr@nhlbi.nih.gov

o Direct your questions about peer review issues to:

Valerie Prenger, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7214, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0270
FAX:  (301) 480-0730
Email: PrengerV@nhlbi.nih.gov
 
o Direct your questions about financial or grants management matters to:

Patricia Reyes
Division of Extramural Affairs
National Heart, Lung, and Blood Institute 
Rockledge II, Room 7140
Bethesda, MD  20892
Telephone:  (301) 435-0187
FAX:  (301) 480-3310
Email: reyesp@nhlbi.nih.gov 

Direct any questions regarding NHF to:
Steven Humes, MPH
Director of Research
National Hemophilia Foundation
Telephone:  (212) 328-3752
FAX:  (212) 328-3788
Email: shumes@hemophilia.org 
 
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 Dr. Valerie Prenger at the 
address listed under WHERE TO SEND INQUIRIES.

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet 
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier 
when applying for Federal grants or cooperative agreements. The DUNS number can be 
obtained by calling (866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of 
the face page of the PHS 398 form. The PHS 398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.  
For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: 
GrantsInfo@nih.gov.
 
SUPPLEMENTARY INSTRUCTIONS: 
 
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/labels.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the 
application, including the Checklist, and three signed, photocopies, in one 
package to:
 
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and all copies 
of the appendix material must be sent to Dr. Valerie Prenger at the address listed 
under WHERE TO SEND INQUIRIES. 
 
APPLICATION PROCESSING: Applications must be received on or before the application 
receipt date listed in the heading of this RFA.  If an application is received 
after that date, it will be returned to the applicant without review. 

Although there is no immediate acknowledgement of the receipt of an application, 
applicants are generally notified of the review and funding assignment within 8 
weeks.
 
The Center for Scientific Review (CSR) will not accept any application in response 
to this RFA that is essentially the same as one currently pending initial review, 
unless the applicant withdraws the pending application.  However, when a 
previously unfunded application, originally submitted as an investigator-initiated 
application, is to be submitted in response to an RFA, it is to be prepared as a 
NEW application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text must not 
be marked to indicate the changes from the previous unfunded version of the 
application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI. Incomplete and/or nonresponsive applications will not 
be reviewed.  
   
Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by the 
NHLBI in accordance with the review criteria stated below. This peer review group 
may include members recommended by the NHF.  As part of the initial merit review, 
all applications will:

o Undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, will be 
discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the NHLBI National Advisory Council 
o Receive a second level review by a NHF Review Board for applications considered 
for NHF funding

REVIEW CRITERIA

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

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

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

APPROACH: Are the conceptual framework, design, methods, and analyses adequately 
developed, well-integrated, and appropriate to the aims of the project? Does the 
applicant acknowledge potential problem areas and consider alternative tactics?

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

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

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success? Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements? Is there evidence of institutional support?  

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

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

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

ADDITIONAL REVIEW CONSIDERATIONS

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 15, 2004
Application Receipt Date:  January 14, 2005
Peer Review Date:  June/July 2005
Council Review:  September 2005
Earliest Anticipated Start Date:  September 30, 2005

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 

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: (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).  

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health Systems 
Agency review.  Awards are made under the authorization of Sections 301 and 405 of 
the Public Health Service Act as amended (42 USC 241 and 284)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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