RELEASE DATE:  October 3, 2002

PA NUMBER: PA-03-003 (This PA has been reissued, see PA-05-165)

EXPIRATION DATE:  September 16, 2005. 

National Cancer Institute (NCI)

This Program Announcement (PA) replaces PA-01-010, which was published 
in the NIH Guide on October 31, 2000.


o Purpose of the PA
o Research Objectives
o Mechanism(s) 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


The Division of Cancer Treatment and Diagnosis and the Division of 
Cancer Prevention of the National Cancer Institute invite research 
grant applications from interested investigators to explore innovative 
strategies for the early detection of cancer, assessment of cancer 
prognosis or prediction of response to cancer treatment. Advances in 
the understanding of basic cancer biology and the development of 
powerful molecular technologies are leading to the identification of 
many new abnormalities in precancerous and cancer cells. This 
initiative promotes the initial evaluation of molecular or cellular 
characteristics in human specimens and/or the development of assays 
that may result in important advances in the detection, diagnosis and 
treatment of cancers.

The objective of this Program Announcement is to encourage applications 
for exploratory (R21) grants from individuals who are interested in 
testing new ideas that are based on a sound scientific rationale and 
may advance progress in cancer detection and diagnosis. The R21 grant 
mechanism is utilized to support pilot projects or feasibility studies 
that may produce innovative advances in science.

This Program Announcement replaces and supersedes PA-01-010, 
Exploratory Studies in Cancer Detection, Diagnosis and Prognosis. 
Investigators interested in laboratory correlative studies linked to 
clinical trials may also consider two additional Program Announcements 
from the National Cancer Institute: PA-98-099 (Correlative Studies 
Using Specimens from Multi-Institutional Treatment Trials) and PA-00-
047 (Quick-Trials for Novel Cancer Therapies). Exploratory studies 
focused on cancer imaging, including new imaging modalities, agents and 
analysis methods, are more appropriate for PA-01-030 
(Exploratory/Developmental Grants for Diagnostic Cancer Imaging), 
sponsored by the NCI Biomedical Imaging Program.



The National Cancer Institute is interested in the development and 
testing of improved methods for detecting characteristics of cancer 
that are useful for the clinical management of cancer patients or 
individuals at risk for developing cancer. Much of the work in the 
early stages of this development process is exploratory and 
descriptive, focusing on the search for molecular and cellular 
differences between tumors and premalignant or normal tissues. When 
differences are found, an attempt must be made to determine their 
clinical significance by correlating the changes with clinical 
parameters.  The further development of an approach will be driven by 
its potential to answer clinical questions.

It has been difficult for investigators to obtain support for early 
translational studies through the traditional research project 
grant(R01) mechanism. Such studies may not be sufficiently developed 
for a standard R01 grant application, may be more descriptive than 
mechanistic in nature, and may be considered high-risk. The exploratory 
grant (R21) mechanism is more appropriate for these investigations. We 
expect that results generated through these R21 grants will serve as a 
basis for planning futureclinical research project (R01) grant 
applications or NCI cooperative clinicaltrial group studies.

Because the exploratory grant mechanism is designed to support 
innovative ideas, extensive preliminary data as evidence of feasibility 
are not required. However, the applicant must develop a sound research 
plan. The opportunity for discovery of new information about the 
behavior of premalignant or tumor cells in the human body and the 
potentialsignificance of the information to be obtained are major 
considerations in the evaluation.

Research Goals and Scope

The major goal of this initiative is to promote the initial evaluation 
of new molecular or cellular characteristics of premalignant cells or 
tumors or the development of assays that will be useful for cancer 
detection, diagnosis and/or prognosis. New biomarkers and laboratory 
assays are needed for cancer screening and risk assessment, for 
pathologic characterization of malignant tumors and assessment of 
disease prognosis, and for prediction and measurement of response to 
treatments, particularly with novel therapeutic or chemopreventive 
agents. Investigators are encouraged to pursue new clinical 
insights and to consider the full array of potentially informative 
biological characteristics of tumor cells and tissues. The investigator 
shouldprovide a strong rationale for proposing that a particular 
biomarker or assay has the potential to address a significant clinical 

Investigators should propose innovative approaches to clinical 
questions or substantial improvements in existing strategies. For 
example, an investigator might propose to adapt and optimize an 
experimental assay technique for application to clinical specimens. 
Proof-of-principle studies might also include comparisons of assay 
formats (i.e., DNA-based vs. protein-based) in a clinical setting, or 
initial retrospective or prospective studies to correlate assay results 
with patient outcomes. Investigators are encouraged to employ robust 
techniques that could be rapidly and widely adopted. The laboratory 
assays must utilize human specimens. Where applicable, evidence of 
statistical support should be included to ensure proper correlation of 
laboratory measurements with clinical outcomes.

This initiative is intended to support translational studies which 
identify promising new means for cancer detection and diagnosis and 
which provide the initial, critical information necessary to decide 
whether potential clinical utility justifies further investment. 
Applicants should explain the significance of the proposed research in 
terms of its potential for clinical application. Priority will be given 
to well-designed studies that will help us to differentiate those new 
markers and techniques that have potential clinical utility from those 
that do not.

This Program Announcement is sponsored jointly by the Cancer Diagnosis 
Program and the Cancer Therapy Evaluation Program (Division of Cancer 
Diagnosis and Treatment) and the Cancer Biomarkers Research Group 
(Division of Cancer Prevention) of the National Cancer Institute.

The Cancer Diagnosis Program supports research projects to develop 
better clinical tests to improve the assessment of cancer prognosis and 
guide the choice of cancer treatment.  New methods are sought to refine 
the classification and staging of tumors, to clarify the influence of 
germ-line or other genetic mutations on the course of the disease, to 
predict the response of tumors to therapy and to monitor the recurrence 
of cancer. 

The Cancer Therapy Evaluation Program is interested in funding new 
mechanistic or correlative laboratory studies that are relevant 
toclinical studies and trials of cancer therapy and supportive care.  
The correlative studies must have a future clinical application such as 
development of new treatment strategies, predicting response to 
specific therapies, or selection of patients for therapies.  Examples 
of correlative studies include, but are not limited to, analysis of 
predictive markers, pharmacogenetic studies, studies of drug 
resistance, and analysis of immune response.

The Cancer Biomarkers Research Group, Division of Cancer Prevention, 
supports and facilitates a broad spectrum of research activities that 
address early development and initial validation stages of molecular 
biological and genetic biomarkers that can be applied in risk 
prediction, early detection and primary prevention of cancer.

The NCI Tissue Expediter 
(http://www-cdp.ims.nci.nih.gov/expediter.html) can 
assist investigators in locating and determining appropriate human 
tissue resources for their research project. Applicants should remember 
that Federal and local regulations for the protection of human research 
subjects apply to the use of human tissue specimens in research, and 
these issues must be addressed in the application (refer to the 
instructions in the application kit). Additional information is 
available at 
http://www-cdp.ims.nci.nih.gov/brochure.html, and from the Office for 
Human Research Protections (http://www.hhs.gov/ohrp/). Applicants 
proposing research with human subjects must observe NIH policies 
regarding the inclusion of women, minorities and children (see below).

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 total 
project period for an application submitted in response to this PA may 
not exceed two years. These grants are non-renewable. Though the size 
of award may vary with the scope of research proposed, it is expected 
that applications will stay within the budgetary guidelines for an 
exploratory/developmental project; direct costs are limited to $100,000 
(four budget modules) per year unless the application includes 
consortium costs, in which case the limit is $125,000 direct costs 
(five budget modules) per year. 

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format since you are submitting an application with direct costs in 
each year not to exceed a maximum of $125,000. (see 


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
o Faith-based or community based organizations


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.


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

o Direct your questions about scientific/research issues to:

Dr. James V. Tricoli
Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room EPN 6035
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-1591
FAX:  (301) 402-7819
Email: tricolij@mail.nih.gov

Dr. Sudhir Srivastava
Cancer Biomarkers Research Group, Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Room EPN-330 F
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 435-1594
FAX:  (301) 402-0816
Email: srivasts@mail.nih.gov

Dr. Heng Xie
Cancer Therapy Evaluation Program, Division of Cancer Treatment and 
National Cancer Institute
6130 Executive Boulevard, Room EPN 7009
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-8866
FAX:  (301) 480-4663
Email: xieh@ctep.nci.nih.gov

o Direct your questions about financial or grants management matters 

Eileen M. Natoli
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd. – EPS 243
Bethesda, MD  20892
Telephone:  (301) 496-8791
Email:  natolie@gab.nci.nih.gov


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). A letter of intent is 
not required and the page limits for the proposal are the same as those 
stipulated in the PHS 398 form.  The PHS 398 is available at 
https://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.

All application instructions outlined in the PHS 398 application kit 
are to be followed, with the following requirements for R21 

1.  R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" 
concepts, with direct costs requested in $25,000 modules, up to the 
total direct costs limit of $100,000 per year, unless the application 
includes consortium costs, in which case the limit is $125,000 direct 
costs per year.

2.  Although preliminary data are not required for an R21 application, 
they may be included.

3.  Sections a-d of the Research Plan of the R21 application may not 
exceed 25 pages, including tables and figures.

4.  R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to 
circumvent the page limit for the research plan.  Copies of appendix 
material will only be provided to the primary reviewers of the 
application and will not be reproduced for wider distribution.  The 
following materials may be included in the appendix:

o Up to five publications, including manuscripts (submitted or accepted 
for publication), abstracts, patents, or other printed materials 
directly relevant to the project.  These may be stapled as sets.  
o Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.  
o Original glossy photographs or color images of gels, micrographs, 
etc., provided that a photocopy (may be reduced in size) is also 
included within the 25 page limit of items a-d of the research plan.

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

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 
https://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 

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 
https://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 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.


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


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 this study address an important problem? If the 
aims of the 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? In this case, what is the potential for 
translation of basic research to clinical applications?

(2) APPROACH:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project? This includes, where applicable, the statistical 
rationale for the study design and the choice of sample size.  Does the 
applicant acknowledge potential problem areas and consider alternative 

(3) 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 

(4) INVESTIGATOR: Is the investigator 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.


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


components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 

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 concerning essential elements of data safety 
monitoring plans for clinical trials funded by the NCI is available:  

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 

All investigators proposing clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
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 

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, 

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 

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 
A continuing education program in the protection of human participants 
in research in now available online at:  http://cme.nci.nih.gov/

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

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 

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.

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 

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 

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.394 , Cancer Detection and Diagnosis 
Research, and is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.  
Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at 
https://grants.nih.gov/grants/policy/policy.htm  and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

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

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
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