EXPLORATORY STUDIES IN CANCER DETECTION, PROGNOSIS AND PREDICTION
 
Release Date:  October 31, 2000 (see replacement PA-03-003)
 
PA NUMBER:  PA-01-010
 
National Cancer Institute

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

This Program Announcement replaces and supersedes two prior Program 
Announcements, PA-98-022 (Exploratory Studies in Cancer Diagnostics) and PA-
98-042 (Exploratory Grants for Correlative Laboratory Studies and Clinical 
Trials).

This PA will expire on October 2, 2002.
 
PURPOSE

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 two prior Program 
Announcements, PA-98-022 (Exploratory Studies in Cancer Diagnostics) and PA-
98-042 (Exploratory Grants for Correlative Laboratory Studies and Clinical 
Trials). In addition, its scientific scope now includes biomarkers for cancer 
detection and risk assessment. 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) (see below). 
Exploratory studies focused on cancer imaging, including new imaging 
modalities, agents and analysis methods, are more appropriate for PA-98-008 
(Exploratory/Developmental Grants for Diagnostic Cancer Imaging), sponsored 
by the NCI Biomedical Imaging Program.

RESEARCH OBJECTIVES

Background

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 future clinical 
research project (R01) grant applications or NCI cooperative clinical trial 
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 potential significance 
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 should provide a 
strong rationale for proposing that a particular biomarker or assay has the 
potential to address a significant clinical problem.

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 to clinical 
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).

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) 
exploratory/developmental (R21) grant mechanism. 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. Applicants will be responsible 
for the planning, direction and execution of the proposed project. NIH grants 
policies will apply to the applications received and awards made in response 
to this Program Announcement.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by foreign and domestic, for-profit and 
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 
investigators. 

INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Dr. Tracy G. Lugo
Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Blvd., Room EPN 6035
Bethesda, MD  20892
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-1591
FAX:  (301) 402-7819
Email: TL82S@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

Ms. Diane Bronzert
Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 734 MSC 7432
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-8866
FAX:  (301) 480-4663
Email: db85g@nih.gov

 Direct inquiries regarding fiscal matters to:
 
Ms. Sara Stone
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243
Bethesda, MD  20892
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-9927
FAX:  301-496-8601
Email:  Stones@gab.nci.nih.gov

APPLICATION PROCEDURES
 
The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff. The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.  
Application kits are available at most institutional offices of sponsored 
research and may be obtained from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
grantsinfo@nih.gov.  For those applicants with internet access, the 398 kit 
may be found at: http://grants.nih.gov/grants/forms.htm.

Applicants are strongly encouraged to call the program contacts listed in 
INQUIRIES above with any questions regarding the goals of this PA.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $100,000 per year ($125,000 if there are 
consortium/contractual costs). The total direct costs must be requested in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities 
and Administrative (F&A) costs] for the initial budget period.  Items 8a and 
8b should be completed indicating the Direct and Total Costs for the entire 
proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 
4 of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION -  Prepare a Modular Grant Budget Narrative 
page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages). At the top of the page, enter the total direct costs requested for 
each year.  This is not a form page.

o  Under Personnel, list all project personnel, including their names, 
percent of effort, and roles on the project. No individual salary information 
should be provided. However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student compensation in 
developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000. List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project. Indicate whether the collaborating institution 
is domestic or foreign.  The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount. 
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person.  A sample biographical sketch may be 
viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST -  This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.

Applications not conforming to these guidelines will be considered 
unresponsive to this PA and will be returned without further review.

The standard requirements for length and format in PHS 398 application kit 
must be observed.

The title and number of the PA must be typed on line 2 of the face page of 
the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the 
checklist, and five signed, exact, single-sided 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)

Applications must be received by the regular receipt dates indicated in the 
application kit beginning February 1, 2001.  The Center for Scientific Review 
(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 substantial revisions of applications already 
reviewed, but such applications must include an introduction addressing the 
previous critique.
  
REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines. Applications will be evaluated for scientific and technical merit 
by an appropriate scientific review group convened in accordance with the 
standard NIH peer review procedures. As part of the initial merit review, all 
applications will receive a written critique and undergo a process in which 
only those applications deemed to have the highest scientific merit, 
generally the top half of applications under review, will be discussed, 
assigned a priority score, and receive a second level review by the 
appropriate national advisory council or board.  

Review Criteria
 
The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  The 
reviewers will comment on the following aspects of the application in their 
written critiques in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered by the reviewers in assigning the 
overall score weighting them as appropriate for each application.  Note that 
the application does not need to be strong in all categories to be judged 
likely to have a 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.
 
1.  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?  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 tactics?
 
3.  Innovation.  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative? Does the project challenge 
existing paradigms or develop new methodologies or technologies?
 
4.  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)?
 
5.  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?

The initial review group will also examine: the appropriateness of proposed 
project budget and duration; the adequacy of plans to include both genders 
and minorities and their subgroups, and children as appropriate for the 
scientific goals of the research and plans for the recruitment and retention 
of subjects; the provisions for the protection of human and animal subjects; 
and the safety of the research environment.

AWARD CRITERIA
 
Applications will compete for available funds with all other recommended 
applications assigned to that IC.  The following will be considered in making 
funding decisions:  Quality of the proposed project as determined by peer 
review, availability of funds, and program priority.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
 
It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included  in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is provided 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000  
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

It is the policy of NIH 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 clear and compelling 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 was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 

Investigators also may obtain copies of  the policy from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

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

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a 
PHS-led national activity for setting priority areas. This PA, Exploratory 
Studies in Cancer Detection, Prognosis and Prediction, is related to priority 
area of  cancer.  Potential applicants may obtain a copy of "Healthy People 
2010" at http://www.health.gov/healthypeople/.
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic Assistance No. 
93.394 and 93.395.  Awards are made under authorization of the Sections 301 
and 405 of the Public Health Service Act as amended ( 42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 92.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

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


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