DIET, EPIGENETIC EVENTS, AND CANCER PREVENTION 

RELEASE DATE:  April 30, 2004

PA NUMBER:  PA-04-099

Updates:
May 16, 2006 (PA-06-412) - This PA has been reissued as PA-06-412 for submission 
of R01 applications as of May 16, 2006.

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date for these 
mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms 
expires on the date indicated below. Other mechanisms relating to this announcement 
will continue to be accepted using paper PHS 398 applications until the stated 
expiration date below, or transition to electronic application submission. 
Replacement R03 (PA-06-414) and R21 (PA-06-413) funding opportunity announcements 
have been issued for the submission date of June 1, 2006 and submission dates 
for AIDS and non-AIDS applications thereafter.

Expiration date extended, see NOT-CA-05-026

EXPIRATION DATE for R21 and R03 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 and R03 AIDS and AIDS-Related Applications: May 2, 2006 
EXPIRATION DATE for All R01 Applications: May 16, 2006

Department of Health and Human Services (DHHS)

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

COMPONENT OF PARTICIPATING ORGANIZATION:
National Cancer Institute (NCI) 
 (http://www.nci.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 
93.393, 93.396

THIS PA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE OF THIS PA 

The NCI invites applications for new R01, R21, and R03 grants which are 
focused on research leading to the elucidation of mechanism(s) by which 
dietary factors influence epigenetic processes as well as increasing the 
understanding of these processes in cancer prevention. The objective is to 
encourage collaboration between nutrition and epigenetic experts to study 
bioactive food components with cancer preventative properties, and to examine 
key epigenetic events in cancer processes (i.e., carcinogen metabolism, cell 
division, differentiation, apoptosis) so that investigators can begin to 
establish linkages between epigenetics, methylation pattern, and tumor 
incidence/behavior. It is anticipated that the information gained will 
provide guidance for the development of dietary intervention strategies for 
cancer prevention.

RESEARCH OBJECTIVES
 
Background

Cancer is a manifestation of both abnormal genetic and epigenetic events.  
Epigenetic events represent important mechanism(s) by which gene function is 
selectively activated or inactivated.  DNA methylation is the covalent 
addition of a methyl group to the 5 position of cytosine within CpG 
dinucleotides and is a fundamental process that not only modulates gene 
expression, but also is key to regulating chromosomal stability. Fluctuations 
in the degree of CpG island methylation are key to regulating functional 
promoters by modifying the binding of transcription factors and methyl-DNA 
binding proteins.  A variety of regulatory proteins including DNA 
methyltransferases, methyl-CpG binding proteins, histone-modifying enzymes, 
chromatin remodeling factors, and their multimolecular complexes are involved 
in the overall epigenetic process.  Since epigenetic events are susceptible 
to change, they represent excellent targets to explain how environmental 
factors, including diet, may modify cancer risk and tumor behavior.  Abnormal 
DNA methylation patterns are a hallmark of most cancers, including those of 
high prevalence in the United States, i.e., colon, lung, prostate, and breast 
cancer.  

Preclinical and clinical studies provide intriguing evidence that part of the 
anticancer properties attributed to several bioactive food components, 
encompassing both essential and non-essential nutrients, may relate to DNA 
methylation patterns.  There are four ways in which nutrients may be 
interrelated with DNA methylation.  The first is that nutrients may influence 
the supply of methyl groups for the formation of S-adenosylmethionine (SAM). 
The second mechanism is that nutrients may modify utilization of methyl 
groups by processes including shifts in DNA methyltransferase activity.  A 
third plausible mechanism may relate to DNA demethylation activity.  Finally, 
the DNA methylation patterns may influence the response to a nutrient. 

Global hypomethylation, accompanied by region-specific hypermethylation, is a 
common characteristic among tumor cells.  Stress, including that resulting 
from dietary methionine/choline, folate, zinc, and/or selenium inadequacies, 
as well as excessive alcohol intake, can lead to global DNA hypomethylation.  
Interestingly, the continuous feeding of a diet deficient in choline and 
methionine is recognized to lead to global DNA hypomethylation and cause 
hepatocellular carcinomas in rats in the absence of any exogenous carcinogen.  
While limitations in the supply of methyl groups appear to be a common 
mechanism, available data suggest that other factors determining DNA 
methylation, including DNA methyltransferase (Dnmt), may be influenced by 
bioactive food components.

Increased selenium concentrations have been found to inhibit Dnmt1 activity 
and protein expression in vitro. Consistent with these data, selenium 
deficiency leads to increased Dnmt1 protein expression in vitro.  Recently, a 
polyphenol occurring in green tea, epigallocatechin-3-gallate (EGCG), has 
been reported to inhibit Dnmt1 activity as well as affect CpG demethylation 
and reactiviation of methylation-silenced genes in esophageal cancer cells.  
The ability of such widely differing dietary components as selenium and EGCG 
to influence Dnmt1 activity suggests that other dietary factors may also 
influence methyl utilization and ultimately modify DNA methylation patterns. 
Neonatal exposure to the phytoestrogens coumestrol and equol has been found 
to lead to specific gene hypermethylation in the c-H-ras proto-oncogene in 
pancreatic DNA.  Data indicating that consumption of high fiber diets is 
accompanied by a reduction in estrogen receptor methylation in colon tissue 
from healthy subjects has also been reported.  Hypermethylation of the 
promoter CpG islands is recognized to contribute to the loss of function of 
several tumor related genes, including estrogen receptor (ER).  Overall, 
several studies illustrate that bioactive food components other than 
essential nutrients can influence DNA methylation processes.

Epigenetic events occurring in utero can lead to persistent changes in gene 
expression and can be modified by the diet.  For example, the diet provided 
to female mice of two strains during pregnancy modified the offsprings' hair 
coat color (increased agouti versus yellow) and DNA methylation patterns.  
Expression of the yellow hair color in these mice is recognized to be 
controlled by hypomethylation of the agouti long terminal repeat (LTR), which 
was hypermethylated by dietary supplementation of the maternal diet with 
zinc, methionine, betaine, choline, folate, and vitamin B12.  Expression of 
this yellow coat color is linked with increased risk of obesity, diabetes, 
and cancer.  While long-term health implications remain to be determined, 
these studies demonstrate that feeding a methyl-supplemented diet to the mice 
increased levels of DNA methylation in the agouti LTR and increased the 
proportion of agouti to yellow mice.  It should be noted that this effect 
occurred with control diets that are considered adequate for meeting 
nutritional needs.  These data point to the likelihood that in utero nutrient 
exposures can lead to genomic imprinting in the offspring and potentially 
modify cancer risk.

Emerging evidence indicates that various chromatin states such as histone 
modifications (acetylation and methylation) and nucleosome positioning 
(modulated by ATP-dependent chromatin remodeling machines) determine DNA 
methylation patterning. Histone modifications have recently generated a great 
deal of excitement in epigenetic research, culminating in the histone code 
hypothesis. Evidence suggests that butyrate may mediate gene expression by 
encouraging interactions between a DNA binding protein and a histone 
acetyltransferase. The zinc-finger binding protein-89 (ZBP-89), a DNA-binding 
protein that binds GC-rich sites, has been found to mediate butyrate gene 
expression of p21waf1. The proposed model of p21waf1 promoter activation by 
butyrate is thought to be through promotion of p300 (a histone 
acetyltransferase) and ZBP-89 interaction with the subsequent recruitment of 
Sp1 to the complex.  More probing studies are needed to characterize 
additional gene-specific acetylation changes brought about by bioactive food 
components.

Objectives and Scope

This initiative is designed to promote innovative preclinical and clinical 
research to determine how diet and dietary factors impact DNA methylation and 
other epigenetic processes involved in cancer prevention.  Although much 
evidence exists that dietary components are linked to cancer prevention, the 
specific nutrients and sites of action remain elusive.  Diet, in fact, has 
been implicated in many of the pathways of cancer, including apoptosis, cell 
cycle control, differentiation, inflammation, angiogenesis, DNA repair, and 
carcinogen metabolism.  These are also processes that are likely regulated by 
DNA methylation and possibly other epigenetic events that impact gene 
function.  The objective of this initiative is to continue to address the 
following issues: how bioactive food components regulate DNA methylation or 
other epigenetic events for cancer prevention, how bioactive food components 
might alter DNA methylation or other aberrant epigenetic events and restore 
gene function, and how these components might circumvent or compensate for 
genes and pathways that are altered by epigenetic events.

Another important aim of this initiative is to encourage collaborations 
between nutrition and epigenetic/ DNA methylation experts to study bioactive 
food components with cancer-preventative properties and to examine key 
epigenetic events in cancer processes (e.g., carcinogen metabolism, cell 
division, differentiation, and apoptosis) in order to begin to establish 
linkages between epigenetics, methylation patterns, and tumor 
incidences/behaviors. Thus, it is expected that each application demonstrate 
experience in nutrition and cancer prevention as well as DNA methylation or 
epigenetics.

Studies should also link phenotypic changes to epigenetic alterations induced 
by specific essential and non-essential nutrients. The resulting information 
will be critical for optimizing effective dietary intervention strategies for 
cancer prevention.  Investigators may choose from the full range of clinical 
and preclinical approaches.  The focus should be on how individual dietary 
components influence DNA methylation and other epigenetic events and how this 
correlates with phenotypic change. Very little information currently exists 
about gene-specific changes in DNA methylation as influenced by bioactive 
food components; furthermore, very little information exists to adequately 
evaluate the specificity of individual nutrients, the impact of 
intakes/exposures, and any acclimation with time and/or tissue specificity.  
This initiative encourages the submission of novel approaches to unravel 
relationships between DNA methylation and other epigenetic events, diet, and 
cancer prevention.

A variety of technologies to assess DNA methylation sequences may be 
utilized.  These can be broadly classified into techniques that measure the 
overall content or distribution patterns of 5-methylcytosine (i.e., 
methylated CpG island amplification, methylation-sensitive restriction 
fingerprinting, differential methylation hybridization, and Restriction 
Landmark Genomic Scanning) and those that examine known gene sequences (i.e., 
methylation-sensitive single nucleotide primer extension, and combined 
bisulfite restriction analysis).  The use of genetically engineered animal 
models, including transgenic or gene knockouts, is appropriate.  Molecular 
resources such as gene databases and bioinformatics may also be used to 
expedite identification of gene-specific methylation targets.   

The following study topics are relevant examples for the development of R01, 
R21, and R03 grant applications in response to this PA. These examples are 
not meant to be all-inclusive.  

o  Gene/region-specific changes in DNA methylation and histone 
acetylation/methylation caused by excesses and limitations in bioactive food 
components or calories. 
o  Relationship between dietary induced global DNA hypomethylation and gene-
specific hypermethylation.
o  Relationship between diet induced changes in DNA methylation and histone 
acetylation/methylation and control of gene function.
o  Temporality in DNA methylation patterns as influenced by bioactive food 
components.
o  Bioactive food component regulation of DNA methylation and epigenetic 
processes, i.e., methylenetetrahydrofolate reductase, methionine synthase, 
DNA methyltransferases, demethylases (or various demethylation processes), 
methylcytosine-binding proteins, histone methyltransferases, histone 
aceyltransferases and deacetylases.
o  Linkages between DNA methylation or other epigenetic pattern as a result 
of environmental exposures, including low-dose radiation, and the anticancer 
properties of bioactive food components.

MECHANISMS OF SUPPORT 

This PA will use the NIH Investigator-initiated Research Project Grant (R01), 
the NIH Exploratory/Developmental grant (R21), and the NIH Small Grants 
Program (R03) as award mechanisms.  As an applicant, you will be solely 
responsible for planning, directing, and executing the proposed project. 

An R21 applicant may request a project period of up to 2-years with a 
combined budget for direct costs of up $275,000 for the 2-year period.  For 
example, the applicant may request $100,000 in the first year and $175,000 in 
the second year. The request should be tailored to the needs of the project.  
Normally, no more than $200,000 may be requested in any single year.  For R03 
applications, the total budget may not exceed $100,000 in direct costs for 
the entire project and the direct costs in any one-year for R03 grant 
applications must not exceed $50,000.  The total project period for R03 
applications submitted in response to this announcement may not exceed 3 
years.  The R21 and R03 grants are not renewable. Investigators are 
encouraged to seek continued support after completing an 
Exploratory/Developmental Grant project or a Small Grant project through a 
Research Project Grant (R01).
 
This PA uses just-in-time concepts.  It also uses the modular and non-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.  Otherwise, follow the instructions 
for non-modular budget research. Otherwise follow the instructions for non-
modular budget research grant applications. This program does not require 
cost sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
   
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government 
o Domestic or foreign institutions/organizations
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

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Sharon A. Ross, PH.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Blvd., EPN Room 3157, MSC 7328
Bethesda, MD  20892-7328
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 594-7547
FAX: (301) 480-3925
Email: rosssha@mail.nih.gov

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

Ms. Debbie Dunn
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, EPS Room 243
Bethesda, MD  20892-7150
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-3154
FAX:  (301) 496-8601
Email: dunned@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The 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.

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

SUPPLEMENTARY INSTRUCTIONS:  All instructions for the PHS 398 (rev. 5/2001) 
must be followed, with these exceptions for R21 applications:
 
o  Research Plan
 
Items a - d of the Research Plan (Specific Aims, Background and Significance, 
Preliminary Studies, and Research Design and Methods) may not exceed a total 
of 15 pages.  No preliminary data is required but may be included if it is 
available.  Please note that a Progress Report is not needed; competing 
continuation applications for an exploratory/developmental grant will not be 
accepted.
 
o Appendix.  Use the instructions for the appendix detailed in the PHS 398 
except that no more than 5 manuscripts, previously accepted for publication, 
may be included. 

All instructions for the PHS 398 (rev. 5/2001) must be followed, with these 
exceptions for R03 applications:

o Research Plan

Items a - d of the Research Plan (Specific Aims, Background and Significance, 
Preliminary Studies, and Research Design and Methods) may not exceed a total 
of 10 pages. Please note that a Progress Report is not needed; competing 
continuation applications for a small grant will not be accepted.

o Appendix.  The appendix may include original, glossy photographs or color 
images of gels, micrographs, etc., provided that a photocopy (may be reduced 
in size) is also included within the page limits of the research plan. No 
publications or other printed material, with the exception of pre-printed 
questionnaires or surveys, may be included in the appendix.

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

SPECIFIC INSTRUCTIONS FOR MODULAR 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.

For the NIH Exploratory/Developmental Grant (R21), applicants may request 
direct costs in $25,000 modules, up to a total direct cost of $275,000 for the 
combined 2-year award period.      

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

Applicants requesting more than $500,000 must carry out the following steps:
   
1. Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

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

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

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

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be mailed on or before the receipt 
dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an unfunded version of an application 
already reviewed, but such an application must include an Introduction 
addressing the previous critique. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

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

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

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the 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 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 these 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 will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below.)

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

ADDITIONAL REVIEW CONSIDERATIONS 

Sharing Research Data

Applicants requesting more than $500,000 in direct costs in any year of the 
proposed research are expected to include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the rationale for 
not sharing research data will be assessed by the reviewers. However, 
reviewers will not factor the proposed data sharing plan into the 
determination of scientific merit or priority score.

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

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

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

REQUIRED FEDERAL CITATIONS 

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

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants.  (See NIH Policy for Data and Safety Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html.)  

Clinical trials supported or performed by NCI require special considerations.  
The method and degree of monitoring should be commensurate with the degree of 
risk involved in participation and the size and complexity of the clinical 
trial.  Monitoring exists on a continuum from monitoring by the principal 
investigator/project manager or NCI program staff or a Data and Safety 
Monitoring Board (DSMB).  These monitoring activities are distinct from the 
requirement for study review and approval by an Institutional review Board 
(IRB).  For details about the Policy for the NCI for Data and Safety 
Monitoring of Clinical trials, see 
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm.  For Phase I and II 
clinical trials, investigators must submit a general description of the data 
and safety monitoring plan as part of the research application.  For 
additional information see NIH Guide Notice on “Further Guidance on a Data 
and Safety Monitoring for Phase I and II Trials” 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.  
Information concerning essential elements of data safety monitoring plans for 
clinical trials funded by the NCI is available at 
http://www.cancer.gov/clinical_trials/.

SHARING RESEARCH DATA:  Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing (http://grants.nih.gov/grants/policy/data_sharing) or 
state why this is not possible.  Investigators should seek guidance from 
their institutions, on issues related to institutional policies, local IRB 
rules, as well as local, State, and Federal laws and regulations, including 
the Privacy Rule. Reviewers will consider the data sharing plan but will not 
factor the plan into the determination of the scientific merit or the 
priority score.

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

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

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

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

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.  A 
continuing education program in the protection of human participants in 
research is 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://stemcells.nih.gov/index.asp and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s) for the hESC line(s) to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

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

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

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The 
Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information”, 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm.

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


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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