CHEMOPREVENTION OF ESTROGEN RECEPTOR (ER) NEGATIVE BREAST CANCER PRECLINICAL 
STUDIES
 
Release Date:  March 21, 2002

RFA:  CA-03-005
 
National Cancer Institute (NCI)   
 (http://www.nci.nih.gov/)

LETTER OF INTENT RECEIPT DATE:  June 27, 2002
APPLICATION RECEIPT DATE:       July 25, 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 Special Requirements
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 

The initiative will encourage applications focused on 1) validation of 
surrogate biomarkers, which can be modulated by agents which may prevent 
Estrogen Receptor (ER) negative breast cancer in animal models of non-
hormonally responsive mammary cancer.  The experimental protocols in animals 
should parallel potential clinical chemoprevention protocols for breast cancer 
in humans;  2) identification of potential targets found both in hormonally 
non-responsive animal models of breast cancer and in ER negative breast cancer 
in humans and 3) determination of the efficacy of potential chemopreventive 
agents.  Modulatable surrogate biomarkers are broadly defined and might 
include gene or protein expression, specific DNA mutations or chromosomal 
alterations or characteristics associated with imaging (e.g. breast density, 
nuclear morphometry, etc.) which can be quantitatively altered by an effective 
chemopreventive agent.  Modulatable surrogate biomarkers could be examined in 
lesions (preinvasive lesions, invasive lesions), in at risk epithelium or in 
serum.  One should be able to demonstrate a strong correlation between 
alteration of the biomarker and the effects of the chemopreventive agent on 
tumor incidence and multiplicity in the animal model. 

RESEARCH OBJECTIVES

Background  

Preclinical studies using animal models have been critically important for 
identifying a number of chemical agents which are now being applied in the 
prevention of cancer (e.g., tamoxifen , raloxifene, retinoids, COX-2 
inhibitors). Animal models aimed at developing new, specific and potentially 
potent agents for prevention of ER negative breast cancer as well as 
potentially offering modulatable biomarkers should accelerate and drive 
forward the clinical research  on ER negative breast cancer.  These 
developments should help to diminish the risk of ER negative breast cancer 
and, in conjunction with agents which are effective against ER positive breast 
cancer (tamoxifen, raloxifene, aromatase inhibitors) , offer the possibility 
of regimens which will profoundly decrease the overall risk of breast cancer.  
The American Cancer Society estimates that in this year 193,000 new cases of 
breast cancer will be diagnosed and that roughly 40,000 women will die of this 
disease. It is estimated that roughly 30% of breast cancers are ER negative 
and that they represent 12-15,000 of the breast cancer related deaths each 
year. 
  
Short term pilot (Phase II) clinical studies in women at risk of developing ER 
negative breast cancer represent an efficient way of demonstrating potential 
efficacy of preventive agents. These studies depend heavily on the development 
of potential agents and cancer-related surrogate endpoints employing animal 
models. Such endpoints might include: levels of expression of specific genes 
or proteins, incidence or levels of specific genetic alterations (LOH, 
microsatellite alterations, FISH, mutations in suppressor/oncogenes, base 
methylation in certain genes), and or parameters related to image analysis, 
(e.g., nuclear morphometry , breast density, etc.).   Such endpoints could be 
determined in lesions, in epithelial cells at high risk of developing cancer 
or in serum.  These surrogate markers can be validated in animal studies where 
experiments can be followed till the production of invasive tumors.  Surrogate 
endpoints that have already undergone some studies in animal models for breast 
cancer include expression of various genes, proliferation, apoptosis, and 
nuclear imaging.  The incorporation of newer imaging technology into small 
animal cancer prevention assays to validate their future use in clinical 
trials protocols is also encouraged. However it is clear that a larger effort 
is needed to validate surrogate endpoint biomarkers in preclinical models 
employing intermediate endpoints similar to those proposed clinically for 
women at high risk of ER negative tumors. Once validated in animal models with 
a cancer endpoint, these biomarkers could then be rapidly translated into the 
clinical trials effort.  In developing these endpoint biomarkers, the use of 
classes of agents which appear to be promising for ER negative breast cancer 
(e.g. COX-2 inhibitors,  EGFr inhibitors,  RXR agonists , farnesyltransferase 
inhibitors, etc.) might be prime candidates.  Biomarkers developed for these 
drugs could be immediately translated to clinical trials.  In contrast markers 
developed for totally new agents will require significant toxicologic and 
pharmacologic testing of those new agents prior to their use in clinical 
trials.

Further studies with several potential classes of agents warrant further 
evaluation in relevant preclinical animal models before they can be nominated 
for preventive interventions in the population of women at risk for ER 
negative disease. For example, members of the non-steroidal anti-inflammatory 
drug family (NSAIDs) have shown some efficacy in hormonally responsive models 
of breast cancer and their primary target COX-2 is expressed in ER negative 
tumors as well.  Therefore, further investigations of this class of agents in 
ER negative models appears appropriate.  Based on preclinical animal studies 
and limited human studies, other potential agents to consider, include 
inhibitors of Neu and EGFr, rexenoids,  farnesyl transferase inhibitors , etc.  
While these are examples, additional agents based on specific targeting to ER 
negative tumors are encouraged for testing in these applications. One might 
hope that additional targets might be defined by examining genes or proteins 
whose expression is altered in ER negative breast cancer. Thus EGFr and Neu 
have been identified as potential targets.  However, the continued cataloging 
of gene and protein expression changes by RNA or proteomic approaches is 
likely to result in many additional targets. Combination prevention trials 
targeting specific biochemical pathways may also have great potential for 
leading to more effective preventive strategies based on multiple mechanistic 
approaches.  Thus the combination of an antiestrogen/estrogen plus a rexenoid 
appears to have synergistic effects in ER positive breast cancer models in 
animals.

Objectives and Scope:

The development of animal model protocols that can facilitate the discovery 
and development of agents to prevent or diminish the risk of ER negative 
breast cancer in women represents an extraordinary opportunity to reduce 
breast cancer incidence, morbidity, and mortality. The purpose of this 
initiative is to invite investigator-initiated grant applications developing 
and evaluating chemopreventive strategies preclinically which could be rapidly 
translated to clinical studies and are applicable to women at high risk for 
development of ER negative breast cancer.  The range of activities supported 
by this RFA would include preclinical studies to: 1) develop modulatable 
endpoint biomarkers in animal models of hormonally non responsive breast 
cancer employing effective preventive agents.   Such biomarkers might include:  
gene or protein expression, or specific molecular changes, DNA mutations, 
image analysis etc. in specific preclinical models in which relevant cancer 
incidence and multiplicity are decreased by known effective agents. 
Interventions and determinations of endpoints that parallel potential clinical 
protocols are of particular use.  Thus clinical protocols are likely to 
examine preinvasive lesions, at risk epithelia or sera in addition to more 
advanced lesions for modulation of potential endpoints.  However a portion of 
any protocol would be to carry animals to an invasive tumor endpoint to 
determine the correlation of marker modulation and the final tumor endpoint.   
2) test and prioritize agents using preclinical animal models for ER negative 
breast cancer.  It would be expected that >40% of the animals would develop 
hormonally non responsive mammary tumors in any model that is proposed.   In 
addition the model should develop preinvasive and invasive lesions that are 
histologically similar to that observed in human breast cancer.   The purpose 
of this RFA is not primarily to support development of totally new animal 
models for ER negative breast cancer.   However, a grant which includes as a 
component limited alteration or optimization or prevention testing in a 
previously developed model is not precluded.  If one employs a transgenic 
animal model one must determine whether a given chemopreventive agent affects 
expression of the promoter.  3) Further characterize by genomic, proteomic or 
imaging techniques changes associated with hormonally non responsive breast 
cancer in multiple animal models as well as correlating with those seen in 
lesions or serum of humans with ER negative breast cancer or individuals at 
high risk of developing, ER negative breast cancer. In order to facilitate 
these comparative studies NCI will supply grantees funded via this RFA with a 
limited number of animal tumors, normal tissue and serum samples from 3 
different hormonally non responsive tumor models.  The specific models may be 
from rats or mice and will depend on availability.  NCI will not supply 
rodents for the primary chemopreventive studies.  

Applicants are especially encouraged to apply chemopreventive agents directed 
against certain of the recently identified molecular targets found in ER 
negative breast cancer in humans (e.g.  Neu, EGFr, COX-2) .   Although it is 
anticipated that any model would have been characterized for the presence of 
histopathologic lesions it would be useful to do some early characterization 
of any models for gene expression patterns and expression of targets that are 
similar to that observed in humans.  Approaches comparing any animal results 
to known results in humans.  For example, the published published results of  
Perou, et al (Nature 406, 747-752  or results from the CGAP web site 
(http://cgap.nci.nih.gov/) etc., can be employed.  Based on these initial 
characterizations the applicant should identify potential markers, e.g., genes 
or gene products which are over expressed or under expressed in hormonally non 
responsive mammary lesions in their model.  

The investigators funded under this RFA will be encouraged to collaborate with 
scientists involved in the Mouse Models for Human Cancer Consortia (MMHCC) and 
take advantage of animal models developed in the MMHCC.  Transgenic animal 
models for mammary cancer are already under development and might be used with 
the application of drug development.  Similarly newly developed imaging 
techniques that as are being evaluated as part of the MMHCC activities could 
be incorporated.

The total project period for applications submitted in response to the present 
RFA may not exceed 5 years. Because the nature and scope of the research 
proposed in response to this RFA may vary, it is anticipated that the duration 
and sizes of awards will vary also. Therefore applications will be accepted 
for R01, R21/R33, and competitive supplements to existing awards in this area.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  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 April 2003.   

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

FUNDS AVAILABLE  

The NCI intends to commit approximately $3.0 million in FY 2003 to fund 7 to 
10 new and/or competitive continuation grants in response to this RFA.  An 
applicant may request a project period of up to 5 years and a budget for 
direct costs of up to $300,000 per year. Facility and Administrative costs on 
consortium arrangements are not included in direct cost requests greater than 
$250,000.  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 NCI 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 competing renewal applications will be accepted and/or if this RFA will be 
reissued.

ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics:

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

The NIH Grants Policy Statement governs the research grant programs awarded 
under this RFA.  Awards under this RFA to foreign institutions will be made 
only in accordance with NIH policy governing such awards.

SPECIAL REQUIREMENTS

In order to facilitate discussion and cooperation between investigators funded 
under this RFA two meetings among the various investigators funded by this RFA 
will be held.  The first meeting would take place within two months of initial 
funding and the second meeting would be undertaken approximately 24 months 
later.  Therefore, it is a requirement that investigators include the costs of 
these two one day meetings in their submitted budgets. 

An investigator should address the following questions:  

1. Does your study include examination of tissues e.g. at risk epithelia, 
preinvasive lesions and sera which are likely to be obtained in clinical 
cancer prevention trials?  

2. Does your investigation include some agents with known efficacy in the 
proposed or similar models? 

3. Are any technical approaches and techniques proposed likely to be directly 
applicable to clinical cancer chemoprevention trials? 

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:

Dr. Ronald Lubet
Division of Cancer Prevention
Institute or Center, MSC 7322
Executive Plaza North, 2110
Bethesda, MD  20892
Telephone:  (301) 594-0457
FAX:  (301)402-0553
Email:  rl57q@nih.gov

o Direct your questions about peer review issues 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
Telephone (301) 496-3428
Fax: (301) 402-0275
Email: ncidearefof-r@mail.nih.gov

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

Eileen Natoli
Grants Administration Branch
National Cancer Institute
EPS, Room 243
Bethesda, MD  20892
Telephone: (301)  496-8791 
FAX: (301) 496-8601
Email: natolie@gab.nci.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:

Dr. Ronald Lubet
Division of Cancer Prevention
Institute or Center, MSC 7322
Executive Plaza North, 2110
Bethesda, MD  20892
Telephone:  (301) 594-0457
FAX:  (301)402-0553
Email:  rl57q@nih.gov

SUBMITTING AN APPLICATION

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

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title and 
number must be typed on line 2 of the face page of the application form and 
the YES box must be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application 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 Affairs (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  Receive a second level review by the National Cancer Advisory 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?  Does your study address the development of agents and or 
surrogate biomarkers applicable to estrogen receptor negative breast cancer?  
Does your study include examination of tissues e.g. at risk epithelia, 
preinvasive lesions, sera which are most likely to be obtained in clinical 
cancer prevention studies?  Do you propose the use of at least some agents 
with known efficacy in the proposed or similar models?  It will be difficult 
to optimize markers with minimally effective agents.

(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?  Are the approaches employed directly applicable to cancer 
chemoprevention trials?  Are any technical approaches directly applicable to 
clinical cancer chemoprevention trials?

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

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

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

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

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.

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)

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

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:           June 27, 2002
Application Receipt:                July 25, 2002
Peer Review Date:                   November/December 2002
Review by NCAB Advisory Board:      February 2003
Earliest Anticipated Start Date:    April 2003

AWARD CRITERIA
 
Applications recommended by the National Cancer Advisory Board will be 
considered for award based upon the following:  

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities as it relates specifically to this RFA.

REQUIRED FEDERAL CITATIONS 

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.  Reviewers are 
cautioned 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, CHEMOPREVENTION OF ESTROGEN RECEPTOR (ER) NEGATIVE BREAST CANCER 
:PRECLINICAL STUDIES, is related to priority area of  Cancer:  Reduce the 
number of new cancer cases as well as the illness, disability, and death 
caused by cancer.  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. 93.393.  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 and Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92  
(http://grants.nih.gov/grants/policy/policy.htm).  This program is not subject 
to the intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-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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