CIRCULATING CELLS IN CANCER DETECTION

RELEASE DATE:  December 12, 2003

PA NUMBER:  PA-04-035

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. The 
non-AIDS portion of this funding opportunity expires on the date indicated below. 
A replacement R21 (PA-06-423) funding opportunity announcement has been issued 
for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter.

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

(Expiration date previously extended, see NOT-CA-05-026) 

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/NIH) 
 (http://www.nci.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.393, 93.394

This Program Announcement (PA) replaces PA-02-086, which was published in the 
NIH Guide on March 21, 2002.

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism of Support 
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 Award Criteria
o Receipt and Review Schedule
o Required Federal Citations

PURPOSE OF THIS PA  

The purpose of this PA is to develop novel technologies for capturing, 
enriching, and preserving exfoliated abnormal cells and macromolecules in 
body fluids or effusions and to develop methods for concentrating the 
enriched cells for biomarker studies. In the context of this PA, we have 
extended the definition of exfoliation to include not only the cellular 
materials, but also subcellular materials, such as DNA and proteins. In body 
fluids, such as sputum, the number of exfoliated tumor cells is often small 
compared to the number of non-neoplastic cells. Therefore, the detection of 
exfoliated abnormal cells by routine cytopathology is often limited because 
few atypical cells may be present in the specimen. There may be difficulty in 
separating dysplastic cells from non-specific reactive changes and 
degenerating cells or variation in diagnostic criteria. Furthermore, 
exfoliated cells are frequently contaminated with normal cells, bacteria, and 
other cellular debris, which makes molecular analysis difficult without 
physical separation of the neoplastic cells. Thus, the development of 
enrichment methods becomes prerequisite for the routine detection of small 
numbers of exfoliated cells and small amounts of subcellular materials in 
biological fluids for molecular analysis. Similarly, subcellular materials 
are in amounts that may not be detectable by available technologies and 
therefore the enrichment of such materials is of paramount importance.  
Enrichment will allow exfoliated cells and subcellular molecules, for example 
from urine, to be used for genomic, proteomic, and epigenomic analyses that 
may lead to improvements in the detection of bladder cancer through 
measurements of alterations in expressed genes, peptide profiles, and 
epigenetic markers. 

RESEARCH OBJECTIVES  

Background

The most common human tumors arise from epithelial surfaces (e.g. colon, 
lung, prostate, oral cavity, esophagus, stomach, uterine cervix, bladder). 
Their development often becomes apparent when tumor cells exfoliate 
spontaneously into sputum, urine, or even into various effusions.  The 
molecular and genetic abnormalities within these exfoliated cells could be 
used to detect and identify precancerous lesions or very early stage cancer 
if highly sensitive technologies were clinically available to identify the 
few abnormal cells among millions of normal cells.   For example, detection 
of widespread microsatellite instability (MSI), as demonstrated by expansion 
or deletion of repeat elements of DNA, may be adapted for exfoliated cells in 
general.  With the advent of PCR-based detection of DNA from rare neoplastic 
cells in body fluids, mutations have been detected in ras genes from the 
stools of patients with colorectal cancer, in p53 from the urine of patients 
with bladder cancer, and in p53 genes in the sputum of patients with lung 
cancer.  As these assays are complex and technically challenging, they depend 
on the development of novel technologies for isolating and enriching cells or 
subcellular materials of interest. 

Abnormal exfoliated cells can be routinely identified by cytologic 
examination of brushings and fluids, for instance, from bronchi, pancreatic 
ducts, voided urine, and effusions. Currently, fluids are usually processed 
by centrifugation or membrane filtration. However, the detection of abnormal 
exfoliated cells, for instance, cancer cells by routine cytopathological 
examination may be limited because the number of abnormal cells may be very 
small compared to the number of normal cells, is difficult. Alternatively, 
the cellular and nuclear changes in abnormal cells may be minimal compared to 
normal cells. This is particularly true of cytological examinations of urine 
cytology, where many low-grade papillary lesions are often missed on.  New 
PCR-based technologies may substantially enhance the sensitivity, but current 
technologies for isolating and analyzing exfoliated cells are too cumbersome 
to be of practical utility. The cellular and molecular changes that ensue 
during tumor progression do so over a number of years and in an apparently 
stochastic manner.  This progressive accumulation of genetic and epigenetic 
changes in precancerous cell populations eventually confers the malignant 
phenotype on emerging clonal subpopulations. In human and animal clinical and 
experimental models, the progression of precancer to cancer is known to be 
lengthy.  For example, it takes an average of estimated 15 to 20 years for a 
small adenomatous polyp to become malignant.  Prior to the appearance of a 
morphologically identified precancerous lesion, numerous genetic and 
molecular alterations would have already occurred.  During histological 
progression into a morphologically identifiable lesion, the stochastic 
process of molecular events in different cells confers genetic heterogeneity.  
Finding molecular and genetic biomarkers of malignancy is particularly 
important in detecting the emergence of precancerous cell populations and is 
what the NCI considers to be an “Extraordinary Opportunity.”  In these 
earliest stages of neoplasia, lesions should be amenable to complete 
eradication.  This principle has been well-demonstrated in cervical 
neoplasia, where screening for dysplastic exfoliated cells can result in a 
70% or greater reduction in the cervical cancer mortality.  During the early 
stages of cancer development, there is a window of opportunity to detect 
precancerous cells with genetic or molecular biomarkers that identify and 
characterize their progression towards cancer. Detection of genetic 
abnormalities in preneoplastic lesions poses challenges because of the small 
size of lesions, the heterogeneity of precancerous cells, and their dilution 
by normal cellular constituents.  Therefore, assays should be tailored to 
detect a small number of abnormal cells or molecules among a large number of 
normal cells or molecules in biological fluids – such as, in colonic washes 
of the gastrointestinal tract, in sputa, and in bronchial biopsies. 

In order to detect and analyze precancerous and cancerous cells in biologic 
fluids, there are a variety of approaches.  The most appropriate approach 
depends upon i) the type of biological fluid (sputum, bronchial washing, 
cervical brushing, voided urine, etc.), and ii) the form of analysis to be 
performed (e.g., cytopathological analysis, morphometric analysis, molecular 
biomarkers for specific receptors or genetic changes, FISH-or-PCR based 
analyses).  All of these approaches require an enrichment of atypical 
epithelial cells through selective processing to concentrate the assay target 
of interest.  The enrichment methods currently used can be grouped into the 
following two broad categories: i) mechanical (centrifugation, cytospin, 
sucrose gradients, etc.) and ii) antibody-based selection with mechanical 
separation (FACS - flow assisted cell sorting, MACS - magnetic assisted cell 
sorting, etc.). While one type of enrichment process can be sequentially 
added to another to improve the yield, all of these methods have good but not 
adequate sensitivity or specificity required for detecting precancerous cells 
in body fluids.  Given that the concentration of these cells or molecules can 
be very low compared to other commonly present cell types or molecules, one 
needs enrichment factors of 1 to 10,000 or 1 to million.

More than 80 percent of human tumors originate from epithelial cells, often 
at a mucosal surface, and are clonal in origin.  Precancerous exfoliated 
cells can be routinely identified in pathology departments by cytologic 
examination of washings or brushings from bronchi, oral cavity, esophagus, 
stomach, bile and pancreatic ducts, sputum and urine; however, the detection 
of exfoliated cancer cells by routine cytopathological examination is limited 
because of the presence of few atypical cells in specimens, the difficulty of 
distinguishing low grade dysplasias from non-specific reactive or 
inflammatory changes, and the low sensitivity and specificity of the 
available diagnostic methodology.  These limitations are particularly true of 
urine cytology, where most low-grade papillary lesions are missed on 
cytologic examination of urine.  New PCR-based technologies may substantially 
enhance sensitivity, but current technologies for isolating exfoliated cells 
are too cumbersome to be of practical utility.  For example, exfoliated cells 
are frequently contaminated with normal cells, bacteria, and other cellular 
debris, making molecular analysis difficult without further physical 
separation of neoplastic cells.  Therefore, the development of novel, high-
throughput, sensitive technologies for sample preparation is a prerequisite 
for the successful detection of small numbers of exfoliated cells or small 
amounts of subcellular materials, such as DNA and proteins, in biological. 

There are occasions in which the only biologic materials available from 
patients are stored plasma or serum samples. The amount of DNA in these 
samples are generally very low when they are obtained from normal(healthy) 
individuals, but increased amounts of circulating DNA have been found in 
cancer. The circulating DNA in plasma/serum of cancer patients has been shown 
to reflect the characteristics of the tumor DNA including molecular changes, 
such as methylation, point mutations, and microsatellite instability. 
Fragmented nucleosomal DNA in plasma resulting from apoptotic death of the 
tumor cells may also provide an indication for tumor DNA. There is a need to 
develop high-yield technologies to isolate circulating DNA that can be used 
for early detection of cancer and the follow-up of the disease.
 
Goals and Scope

The primary purpose of this initiative is to encourage the development of 
high-throughput technologies to facilitate the isolation and enrichment of 
exfoliated cells and subcellular materials.  In pursuit of these goals, the 
NCI invites applications that address the following areas:

o Development of high-throughput technologies for identifying abnormal 
exfoliated cells and subcellular materials in body fluids;

o Development of sampling technologies for capturing and preserving 
exfoliated tumor cells and subcellular materials in body fluids;  

o Development of enrichment methods for the isolation of tumor cells and 
subcellular materials;

o Development of sensitive, high-throughput molecular, cytomorphometric, 
immunologic, and other relevant technologies to isolate tumor cells or 
subcellular materials in malignant effusions to help detect low tumor burden 
and distinguish reactive cells from tumor cells.

The long-term goal, to which this initiative will eventually lead, is the 
development of panels of well-characterized biomarkers derived from 
exfoliated cells that can be sampled in the clinical setting. These 
methodologies will be tested and validated in future population-based 
clinical trials, and integrated into a comprehensive information system that 
will be developed under the Early Detection Research Network.

MECHANISM OF SUPPORT 

This PA will use the NIH exploratory/developmental (R21) award mechanism.  As 
an applicant, you will be solely responsible for planning, directing, and 
executing the proposed project.

The applicant may request a project period of up to two years with a combined 
budget for direct costs of up $275,000 for the two year period.  For example, 
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.  These 
grants are non-renewable and continuation of projects developed under this PA 
will be through the traditional unsolicited investigator initiated grant 
program. 

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see http://grants.nih.gov/grants/funding/modular/modular.htm).   
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular format.  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_2001/part_i_1.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

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:

Mukesh Verma, Ph.D.
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, EPN 3144
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-3893
FAX:  (301) 402-8990
Email: mv66j@nih.gov

Or

Sudhir Srivastava, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, EPN 3142
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-3983
FAX:  (301) 402-8990
Email: ss1a@nih.gov

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

Ms. Karen Chuang
Grants Management Specialist
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Blvd. MSC 7148
Bethesda, MD 20892-7150 
Telephone: (301) 496-2784
FAX: (301) 496-8601
Email:  chuangk@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 the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be checked.

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

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 two year award period.      

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 received by or 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 under this 
PA. This does not preclude the submission of a substantial revision of an 
unfunded version of an application already reviewed, but such application 
must include an introduction addressing the previous critique. Unfunded 
applications previously reviewed as investigator-initiated applications under 
a different research grant mechanism may be resubmitted as a new application 
under this PA
(see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-019.html ).   

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 Those that receive a priority score will receive a second level review by 
an appropriate national advisory council or board.  

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate 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 must 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. (See url in Federal Citations, below.)

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.  
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. (NIH Policy for Data and Safety Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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.  See NIH 
Guide Notice on “Further Guidance on a Data and Safety Monitoring for Phase I 
and II Trials” for additional information: 
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:  
http://www.cancer.gov/clinical_trials/

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking more than $500,000 or 
more in direct costs in any single year are expected to include a plan for 
data sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing  Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule. Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

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

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

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

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). Those who must comply with the Privacy Rule (classified 
under the Rule as “covered entities”) must do so by April 14, 2003 (with the 
exception of small health plans which have an extra year to comply).  

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


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


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