MOLECULAR INTERACTIONS BETWEEN TUMOR CELLS AND BONE 

Release Date:  May 9, 2002 (also see NOT-AR-02-004)

RFA: CA-03-013   
 
National Cancer Institute (NCI)  
 (http://www.nci.nih.gov/)
National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) 
 (www.niddk.nih.gov)

LETTER OF INTENT RECEIPT DATE: October 17, 2002

APPLICATION RECEIPT DATE:  November 21, 2002
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE OF THIS RFA

The National Cancer Institute (NCI), the National Institute of Diabetes and 
Digestive and Kidney Diseases (NIDDK) solicit investigator-initiated 
applications to promote a better understanding of the pathophysiology of bone 
metastasis, especially as it relates to tumor cell-bone interactions. The 
overall goal is to delineate the role of bone microenvironment on tumor cell 
survival, and colonization. Collaborative interactions between bone 
biologists, clinical oncologists and cancer biologists are highly encouraged. 
These studies should contribute towards a better understanding of the 
molecular events that account for homing of tumor cells to the bone, and 
generating novel therapeutic reagents.  Both the exploratory (R21) and 
traditional (R01) grant applications will be accepted.

RESEARCH OBJECTIVES

Background 

Bone metastases are common in a number of cancers, and they contribute heavily 
to morbidity and mortality, most prominently in prostate, breast, and multiple 
myeloma.  Current understanding of the molecular underpinnings of bone 
metastasis is very limited.  Recognizing this, the Congress, in the FY2002 NCI 
Budget, encouraged the NCI "to conduct research to develop a better 
understanding of the unique role the bone microenvironment plays in metastasis 
of cancer to bone, in particular breast cancer, prostate cancer and myeloma, 
including the development of animal models of bone metastasis and 
identification of novel therapeutic targets and modalities to prevent and 
treat bone metastasis."  The different features of bone metastasis are 
illustrated by these three cancers but the importance and complexity of the 
problem is not limited to them. 

Advanced prostate cancer continues to kill more than 42,000 men per year in 
the United States, and currently there is there is no curative therapy for 
advanced prostate cancer.  The relationship between prostate cancer and the 
bone is unique among cancers.  Approximately 90% of advanced prostate cancer 
patients develop clinically significant bone metastasis, causing osteoblastic 
remodeling of the bone, and contributing to the morbidity and mortality of 
patients. One third of patients with a prostate specific antigen (PSA) >20 at 
the time of diagnosis have bone scan evidence of bone metastasis.  In 
addition, RT-PCR studies have identified PSA in bone marrow samples of 
patients thought to have localized disease and undergoing radical 
prostatectomy, suggesting that bone marrow metastasis may be an early event, 
even prior to clinical symptoms and nuclear radiographic positivity.  

In the case of breast cancer, in 2001 alone, an estimated 192,200 women were 
diagnosed with invasive breast cancer, with more than 40,200 deaths- 28,000 
deaths with breast cancer metastasis to the bone.  Both osteoblastic and 
osteoclastic lesions are seen in patients with bone metastasis.  

Multiple myeloma (MM) represents 13% of all lymphoid malignancies in the white 
population and 31% of lymphoid malignancies in the black population and is a 
severely debilitating, incurable neoplastic disease of B cell origin.  The 
major source of morbidity and mortality associated with MM are osteolytic 
lesions that form throughout the axial skeleton, resulting from increased 
osteoclastic bone resorption that occurs adjacent to the myeloma cells and not 
in areas of normal bone marrow.  New bone formation that normally occurs at 
the sites of bone destruction is also absent.  These data suggest that locally 
acting factors produced by myeloma cells induce extensive bone destruction and 
block new bone formation. 

Bisphosphonates, potent inhibitors of bone resorption, significantly reduce 
skeletal morbidity in patients with advanced breast cancer and can reduce 
metastasis to bone by human breast cancer cells in an experimental model.  
Pamidronate, a second generation bisphosphonate, has recently been approved by 
the FDA for treatment of breast cancer osteolysis.  Another inhibitor of bone 
resorption, the protein osteoprotegerin, is also effective in animal models of 
bone metastases in breast and prostate cancer, and in reducing bone pain in 
patients.  Although bisphosphonates significantly reduce skeletal morbidity 
associated with solid tumor metastases to bone, most studies indicate no 
improvement in survival.  Thus, in order to improve therapy and ultimately 
prevent bone metastases, a precise understanding of the pathophysiology of 
bone metastases is necessary. 

It is well recognized that once malignant cells have migrated to the bone, 
their ability to colonize is facilitated by various growth factors that are 
secreted by the bone.  Recent studies reveal that bone metastases result in 
increased circulating markers of bone resorption and formation, which may play 
more important future roles in early diagnosis of bone involvement and in 
monitoring response to treatment.   In addition, there is an active bi-
directional response between bone and associated tumor cells; the tumor cells 
acquire a more aggressive phenotype and accelerated bone turnover occurs in 
the localized skeletal lesions.  Although bone metastasis is of serious 
clinical relevance, relatively little is known of the important molecular 
mechanisms involved in the initial tumor cell-bone stroma interactions or in 
the subsequent colonization and growth of the cancer.

Several recent developments suggest that bone metastasis is a research area of 
great opportunities:  (A) The availability of a number of experimental models, 
obtained by intracardiac or orthotopic injections, to study bone metastasis in 
prostate, breast and multiple myeloma.  In addition, implantation of human 
bone in SCID mice allows successful homing of prostate cancer and multiple 
myeloma cells specifically to the human bone.  (B) The availability of high 
through-put technologies and laser capture micro-dissection technology permit 
evaluation of complex interactions, such as those involved in tumor-bone 
interactions.  (C) Significant advances in basic bone biology research, with 
development of a repertoire of critical reagents, have provided a large cohort 
of basic biologists who could enter the field of bone metastasis.    

Scope 

Strengthening research programs of relevance to understand tumor host 
interactions as it relates to bone metastasis is an important area of emphasis 
for the National Cancer Institute (NCI), the Institute of Diabetes and 
Digestive and Kidney Diseases (NIDDK).  The overall objective is to have a 
better understanding of the unique features of bone and its microenvironment 
that renders it an attractive site for tumor cells.  Areas in which such 
scientific opportunities exist include, but are not limited to:

Tumor Cell- Bone interactions: The identification of the molecular 
interactions between tumor and bone cells has previously used the candidate 
gene approach but is ready for the judicious application of gene array 
technology to identify new targets. Tumor growth does not appear to be a major 
point of regulation of bone metastases, although growth is the most common 
parameter assayed in vitro.  Microarray identification thus needs to use RNA 
from metastatic versus non-metastatic cells and be coupled to an efficient 
system for validating physiological significance of identified candidate genes 
in animal models.  Alternative approaches which address these issues should 
also be considered.  The role played by malignant tumor cells (e.g., breast 
and prostate cancer) on bone turnover needs to delineated. 

The relationship between tumor cell adhesion to bone marrow endothelial cells 
and the subsequent acquisition of motility, migration and invasive phenotype 
needs to be elucidated.  The mechanism by which the turnover of bone, bone 
matrix proteins and wound healing affect the process of cancer cell 
dissemination to bone is an area that needs examination. The key transcription 
factors that are turned on and are required to maintain cancer cell survival 
in visceral and bone sites need to be identified.

One of the interesting aspects of the bone microenvironment-tumor interaction 
is the difference between mouse and human. The issue of why human tumor cells 
prefer to colonize human bone but not mouse bone is yet to be addressed.

Factors that Promote Bone Metastases:  There are several mechanisms that 
contribute to bone metastases:  A) Synthesis, activation, and presentation of 
extracellular matrix-degrading proteases thought to be critical in enabling 
metastatic breast cancer cells cross multiple barriers and spread to distant 
tissue. Studies to identify and determine the functional signature of 
proteolytic mechanisms, however, are in their early stages; B) The molecules 
associated with preferential adhesion of invading tumor cells to the bone 
endothelium;  C) Bone-associated cytokines which act as chemoattractants;  D) 
Cytokines, survival factors and anti-apoptotic signals that support the growth 
and survival of cancer cells in the skeleton. These are areas that need to be 
actively pursued.

Critical Signaling Pathways:  The nature of the signaling pathways whereby 
hormones, growth factors, and adhesion molecules modulate metastasis to the 
bone is poorly understood.   For example, nm23, HER-2/neu, and p53 are several 
nonprotease genes associated with metastases, but despite intense study, the 
exact mechanism underlying their association with increased metastatic 
potential remains obscure. A comprehensive analysis of genetic changes 
occurring between primary tumor and bone metastases and the development of a 
tractable system to study bone metastases are needed.

Specific Roles of Osteoblasts, Osteocytes, and Osteoclasts:  Most research, 
until now, has focused on osteolytic metastases and suggests that osteolytic 
factors (such as PTHrP and IL 11) stimulate osteoclasts indirectly by 
activating the RANK ligand pathway on osteoblastic cells.  A role for the 
osteocyte in metastasis remains unaddressed and needs to be studied.

Tumor cell-endothelial cell interactions: The role of angiogenesis in bone 
metastasis remains largely unexplored.  It has been demonstrated that 
endothelial cells of various organs carry specific cell-surface addresses, 
which can be modulated by cytokines as well as the stromal and extracellular 
matrix environment with which they interact.  A comparison of gene expression 
profiles of endothelium derived from normal and tumor tissue revealed a number 
of genes specifically elevated in tumor-associated endothelium.  Many of these 
tumor endothelial cell markers were expressed in a wide range of tumor types 
as well as in normal vessels associated with wound healing, corpus luteum 
formation.  Although specific molecular adhesive interactions between 
circulating tumor cells and bone marrow endothelia have been shown in vitro, 
their physiological importance in vivo remains to be tested.  Considering the 
special fenestrated anatomy of the marrow microvasculature, the contributions 
of bone endothelial cells, stromal cells and mature osteoblasts, and the 
extracellular matrix in promoting tumor cell homing to the bone need to be 
identified.  Identification of critical factors involved in tumor cell 
survival and colonization in the bone environment need to be identified and 
their mechanisms delineated.  

Role of the Immune System:  The bone marrow is the primary site of 
hematopoiesis in the adult.  To fulfill this role, the stroma and the cytokine 
environment of the bone marrow are specialized to support the growth of 
lymphocytes and other hematopoietic cells.  These elements have a variety of 
direct and indirect effects on bone growth.  For example, many immune 
modulators (IFN, IL-1, -6, -18 and others) have potent effects on osteoclast 
formation, and RANK ligand is a T cell product. Osteoprotegerin not only 
neutralizes RANKL but also TRAIL, which stimulates immune cell destruction of 
breast cancer cells.  Very little is known about how such factors relate to 
other elements of the bone microenvironment, indicating that the role of 
immune cells in tumor bone interactions has been understudied.

Systemic Host Effects:  Standard treatment of cancer patients with 
chemotherapy creates a state of high bone turnover secondary to suppression of 
sex steroids.  High bone turnover may well enhance metastases to bone.  This 
important question can be studied with available animal models.  For a number 
of candidate factors involved in bone metastases, such as endothelin-1, VEGF, 
and PDGF, effective small molecule inhibitors are already available, such as 
receptor antagonists for endothelin and receptor kinase inhibitors for VEGF 
and PDGF.  The roles of these molecules in bone turnover are less well 
understood and the effects of the inhibitors need to be tested in preclinical 
animal models of normal bone homeostasis.
  
MECHANISM OF SUPPORT
 
This RFA will use NIH R01 and R21 award mechanisms.  As an applicant you will 
be solely responsible for planning, directing, and executing the proposed 
project.  This RFA is a one-time solicitation.  Future unsolicited, competing-
continuation applications based on this project will compete with all 
investigator-initiated applications and will be reviewed according to the 
customary peer review procedures. The anticipated award date is July 1, 2003.  

This RFA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.  

FUNDS AVAILABLE 

NCI and NIDDK intend to commit approximately $4 million in FY 2003 to fund 
approximately equal numbers of new R21 and R01 grants in response to this RFA.  
An applicant may request a project period of up to 2 years for an R21 or up to 
5 years for an R01 application. While the budgets for R01s are not capped, for 
the R21 a limit of $100,000 (four budget modules) per year is in place.  
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 ICs provide support 
for this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications. At this time, it is not known if this RFA will be reissued.
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Domestic or foreign
 
 
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 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:

Suresh Mohla, Ph.D.
Division of Cancer Biology
National Cancer Institute 
6130 Executive Boulevard, EPN 5038
Bethesda, MD  20892
Telephone:  (301) 435-1878
FAX: (301) 480-0864
Email: mohlas@mail.nih.gov

Mehrdad Tondravi, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institutes of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 451-9871
FAX:  (301) 480-3503
Email: mt270t@nih.gov

o Direct your questions about peer review issues to:

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Telephone: (301) 496-3428
FAX: (301) 402-0275 
Email:  ncidearefof@mail.nih.gov

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

Bill Wells
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 242
Rockville, MD 20892
Telephone:  (301) 496-8796
FAX:  301 496-8606
Email: wellsw@mail.nih.gov

Florence Danshes
Grants Management Branch
National Institutes of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Rm 734
Bethesda, MD 20892
Telephone:  (301) 594-8861
email: FD39J@nih.gov

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NCI 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:

Suresh Mohla, Ph.D.
Division of Cancer Biology
National Cancer Institute 
6130 Executive Boulevard, EPN 5038
Bethesda, MD  20892

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title and 
number must be typed on line 2 of the face page of the application form and 
the YES box must be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application must be 
sent to:

Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8041, MSC-8329
Rockville, MD 20852 (express courier)
Bethesda MD 20892-8329

APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE 
WILL NO LONGER BE ACCEPTED.  This policy does not apply to courier deliveries 
(i.e. FEDEX, UPS, DHL, etc.) 
(http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html)  
This change in practice is effective immediately.  
This policy is similar to and consistent with the policy for applications 
addressed to Centers for Scientific Review as published in the NIH Guide 
Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html.

APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  If an application is received 
after that date, it will be returned to the applicant without review.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness by the NCI program staff.  

Incomplete applications will be returned to the applicant without further 
consideration.  And, if the application is not responsive to the RFA, CSR 
staff may contact the applicant to determine whether to return the application 
to the applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the Division of Extramural Activities (DEA) at NCI in accordance with the 
review criteria stated below.  As part of the initial merit review, all 
applications will:

o  Receive a written critique
o  Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score
o  Those that receive a priority score will undergo 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 discuss the following aspects 
of your application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals: 

o  Significance 
o  Approach 
o  Innovation
o  Investigator
o  Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move a 
field forward.

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

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

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

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

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

SPECIFIC CRITERIA FOR REVIEW OF R21 APPLICATIONS:  R21 applications submitted 
to this RFA should be considered to be pilot and feasibility studies with a 
high degree of potential significance and innovation, and for which there may 
be more risk and no preliminary data.

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

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

o INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

o 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:         October 17, 2002
Application Receipt Date:              November 21, 2002
Peer Review Date:                      February/March, 2002
Council Review:                        May 2003
Earliest Anticipated Start Date:       July 1, 2003
 
AWARD CRITERIA

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

o  Scientific merit (as determined by peer review)
o  Availability of funds
o  Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research. This policy results from the NIH Revitalization Act of 1993 (Section 
492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. 
The amended policy incorporates: the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance with the 
new OMB standards; clarification of language governing NIH-defined Phase III 
clinical trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; and 
b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy 
requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  
You will find this policy announcement in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.  A 
continuing education program in the protection of human participants in 
research in now available online at: http://cme.nci.nih.gov/

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research 
on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Guidance 
for investigators and institutional review boards regarding research involving 
human embryonic stem cells, germ cells, and stem cell-derived test articles 
can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-044.html.
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   It is the responsibility of the applicant to provide 
the official NIH identifier(s)for the hESC line(s) to be used in the proposed 
research.  Applications that do not provide this information will be returned 
without review.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA.  
It is important for applicants to understand the basic scope of this 
amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application. 
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving 
the health promotion and disease prevention objectives of "Healthy People 
2010," a PHS-led national activity for setting priority areas. This RFA is 
related to one or more of the priority areas. Potential applicants may obtain 
a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance No. 93.396 for NCI and the Catalog of Federal Domestic 
Assistance No. 93.847 for NIDDK.  The program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, Public 
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care, or early childhood 
development services are provided to children.  This is consistent with the 
PHS mission to protect and advance the physical and mental health of the 
American people.

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	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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