Release Date:  November 13, 2000 (see replacement PA-03-064)

PA NUMBER:  PA-01-015

National Cancer Institute

Letter of Intent Date:  Jan. 4, 2001, May 4, 2001, Sep. 3, 2001,
                        Jan. 4, 2002, May 3, 2002, Sep. 3, 2002

Receipt Date:  Regular receipt dates


This Program Announcement (PA) replaces PA-98-099, which was published in NIH 
Guide, August 14, 1999.

This PA will expire on October 2, 2002. 


The Cancer Therapy Evaluation Program and the Cancer Diagnosis Program of the 
Division of Cancer Treatment and Diagnosis and the Cancer Biomarkers Research 
Group of the Division of Cancer Prevention, National Cancer Institute invite 
research grant applications from institutions or consortia capable of 
performing clinical translational research on promising predictive and 
prognostic markers.  These studies should focus on clinical correlative or 
mechanistic studies that will be useful for cancer risk assessment, early 
detection, prognosis, and for predicting response to therapy and to prevention 
interventions.  NCI encourages accessing tissue specimens from the NCI 
Clinical Trials Cooperative Groups (NCI Cooperative Groups) or other large 
multi-institutional treatment and prevention clinical trials that have studied 
well defined patient populations and have outcome data available.  This 
Program Announcement (PA) is intended to support collaborations between 
researchers with promising correlative markers and clinical trials groups with 
access to patient populations essential for validation studies.  Researchers 
who are interested in accessing specimens are encouraged to contact the NCI 
Cooperative Groups or visit the Cancer Diagnosis Program website 
( if ongoing collaborations are not in 

This PA will utilize the investigator-initiated research project grant (R01) 
mechanism for analysis of specimens from large multi-institutional clinical 
trials and the exploratory/pilot grant (R21) mechanism for pilot exploratory 

Investigators interested in conducting laboratory correlative studies on 
single institution trials may also consider two additional Program 
Announcements from the National Cancer Institute: PA-01-010  (Exploratory 
Studies in Detection, Diagnosis, and Prediction) 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-98-008 (Exploratory/Developmental Grants for Diagnostic 
Cancer Imaging), sponsored by the NCI Biomedical Imaging Program.


The NCI supports an extensive network of clinical and laboratory research 
studies related to cancer detection, prevention and therapy through contracts, 
grants and cooperative agreements.  The Cancer Therapy Evaluation Program 
(CTEP), Division of Cancer Treatment and Diagnosis (DCTD) supports a program 
of integrated national networks of clinical investigators and institutions 
(NCI Clinical Trials Cooperative Groups) for the conduct of large scale, 
multi-institutional clinical trials.  The Community Oncology and Prevention 
Trials Research Group, Division of Cancer Prevention (DCP), supports programs 
to improve clinical oncology in community settings and conduct prevention and 
control trials.  Presently, the NCI Cooperative Groups conduct approximately 
400 clinical trials evaluating approximately 20,000 cancer patients per year. 
The Cooperative Groups have established tumor banks that provide access to 
tumor specimens from large numbers of patients with a variety of malignancies. 
The clinical trials organizations maintain statistical databases and are 
capable of correlating laboratory data with clinical outcome.  The Early 
Detection Research Network (EDRN) of the Division of Cancer Prevention has 
created a research platform for collaborating with the clinical trials 
community and appointed liaisons for the various NCI Cooperative Groups.  The 
EDRN is available for assistance in validation studies and researchers may 
form collaborations through its Associate Member Program 

Recently, investigators in molecular genetics and immunobiology have 
discovered new promising biomarkers that may identify patients who would 
benefit from specific therapeutic strategies.  Technological advances in PCR, 
flow cytometry, immunohistochemistry, in situ hybridization and high-
throughput, high yield array technologies will allow laboratory investigators 
to do multiple analyses on tumor specimens and study tumor heterogeneity in a 
variety of tumor types. Many opportunities exist for conducting correlative 
laboratory studies that may be immediately relevant to cancer treatment. In 
addition, opportunities exist for the molecular characterization of precancer 
and early stage cancer through analysis of specimens from treatment and 
prevention trials.

This PA is designed to promote collaborations and interactions between basic 
researchers and clinical investigators to advance research on clinical 
correlations that can improve therapeutic approaches.  NCI is seeking to 
encourage correlative laboratory studies linked to large scale multi-
institutional clinical trials.  In many instances, the laboratory 
investigators are already recipients of R01 or P01 support for their basic 
research.  These laboratory investigators may not have access to patient 
specimens or outcome data for large scale analysis.  The Clinical Trials 
Cooperative Groups have established tumor and specimen banks for specific 
diseases, and reference labs necessary for the diagnosis and monitoring of 
patients.  This initiative proposes to link these peer-approved activities and 
for a relatively small additional investment provide a mechanism to obtain 
definitive data on the relationship of biological features and the clinical 
behavior of the tumors or other human tissues.  Objectives and approaches will 
be investigator-initiated with NCI assisting investigators to assure that 
promising new approaches will be moved rapidly into clinical practice.

Research Goals and Scope

The objectives of this PA are to foster collaborations and interactions 
between basic researchers, private industry, and clinical investigators to 
perform clinical translational research on promising predictive and prognostic 
markers. These studies should focus on clinical correlative or mechanistic 
studies that will be useful for cancer risk assessment, early detection, 
prognosis, and predicting response to therapy and to prevention interventions.   
These studies should focus on correlations between biologic features of tissue 
specimens collected from the NCI Cooperative Groups or other large 
multi-institutional clinical trials and patient outcomes.

This PA will utilize the R01 investigator initiated research grant mechanism 
to support clinical correlative studies on large multi-institutional clinical 
trials for validation of promising predictive or prognostic markers and the 
exploratory/pilot grant mechanisms  (R21) to support pilot exploratory 
studies.  For the R01 grant submissions, preliminary data, including relevant 
animal models or analysis of patient specimens, that supports the hypotheses 
must be provided.  Because the R21 grant mechanism is designed to support 
pilot or feasibility studies, preliminary data as evidence of feasibility are 
not required.  The correlative studies should be based on strong and testable 
hypotheses. A clear rationale should be given for the experimental design and 
technical methodologies selected. The hypotheses tested must relate to 
potential clinical applications such as patient monitoring for preventive or 
therapeutic interventions, development of new therapeutic strategies or 
testing new biomarkers for the identification of patient subsets for specific 
prevention or treatment approaches.  The laboratory assays must use specimens
from patients receiving defined treatments in large clinical trials such as 
phase III clinical trials.  Applications must include a statistical section 
describing the study design and plans for analysis of data designed to test 
the hypotheses.  All investigators are encouraged to work with 
multi-institutional organizations or form a consortium in order to access 
sufficient numbers of patient specimens and clinical information to test the 
proposed hypotheses.

Some examples of therapeutic laboratory correlates may include but are not 
limited to: (1) phenotypic or genotypic alterations which appear to correlate 
with the development of therapy resistance; (2) loss or inactivation of tumor 
suppressor genes related to prognosis; (3) analysis of basal membrane factors 
or genes related to tumor invasion and metastases; (4) studies of chromosomal 
rearrangements or deletions that may be used for risk assessment, early 
detection, or prognosis; (5) correlation of tumor growth factors or oncogenes 
with response to therapies during cancer progression; (6) alterations in cell 
cycle control; (6) characterization of immune response with association to new 
immunotherapies for prevention or treatment; (7) evaluation of  serum or tumor 
biomarkers for risk assessment, early detection, or prognosis; (8) analyses of 
expression of cellular receptors for growth factors or differentiating agents; 
(9) defining and targeting specific populations of cells for therapy; (10) 
analysis of in vitro response of tumor cells to growth factors/differentiating 
agents; and (11) evaluating accessible sites for precancerous changes 
occurring in less accessible sites, for instance the oral cavity as a 
surrogate site for the lung in smokers. Surrogate sites may be anatomically-
associated, such as oral cavity to lung cancer, or may be functionally 
related, such as scalp hair follicles to prostate cancer, both of which have 
androgen receptors.

Researchers who have previously not collaborated with the NCI Cooperative 
Groups or Division of Cancer Prevention Programs are encouraged to contact 
them and discuss potential collaborations to obtain access to NCI-supported 
specimen banks and outcome data for laboratory analysis under this PA.  NCI 
staff (see Inquiries) will be able to provide assistance in identifying NCI 
Cooperative Groups that would be interested in collaborating with basic 
science investigators on laboratory and clinical studies of new markers.  The 
NCI Tissue Expediter is available to assist investigators in determining the 
appropriate tissue resource for their research project 
(  Information on how to access 
NCI-supported specimen banks including contacts for the NCI Cooperative Group 
banks is available at the following web address:   The NCI Cooperative Groups have 
mechanisms in place to review proposals for access to NCI Cooperative Group 
tissue banks from prevention and treatment trials.  A letter from the 
appropriate NCI Group Chair confirming approval to provide specimens in the 
event of NCI funding of the PA grant application should be included in the 
grant application.  For Intergroup tissue banks, a letter from the Intergroup 
tissue bank chair should also be included.   


Support of this program will be through the National Institutes of Health 
(NIH) research project grant (R01) mechanism and the exploratory/developmental 
grant (R21) mechanism.  Applicants will be responsible for the planning, 
direction, and execution of the proposed project.  All PHS and NIH grants 
policies will apply to applications received and awards made in response to 
this PA.  Applicants for the R21 grant mechanism may request up to $100,000 
direct costs (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 and support may not exceed two years.  The R21 grants 
are non-renewable and competitive continuation of projects developed under 
this program will be through the R01 research grant mechanism.  Applications 
for the R01 grant mechanism may not exceed five years. NIH grants policies 
apply to these awards.

Future unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the customary 
peer review procedures.

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


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.  Applications may be from a single 
institution or may include arrangements with one or more institutions (e.g., 
consortia, NCI Groups) if appropriate.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 


Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome. 

Direct inquiries regarding programmatic issues to:

Ms. Diane Bronzert
Cancer Therapy Evaluation Program
National Cancer Institute
6130 Executive Boulevard, Room 734, MSC 7432
Bethesda, MD  20892-7432
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email:  db85g@NIH.GOV

Dr. Tracy Lugo
Cancer Diagnosis Program
National Cancer Institute
6130 Executive Boulevard, Room 6035A, MSC 7388
Bethesda, MD  20892-7388
Telephone:  (301) 496-1591
FAX:  (301) 402-7819
Email:  tl82s@NIH.GOV

Dr. Donald Henson
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Room 305
Bethesda, MD 20892
Telephone: (301) 496-9424
FAX: (301) 496-8667

Direct inquiries regarding NCI supported specimen banks to:

Ms. Marianna Bledsoe
Cancer Diagnosis Program
National Cancer Institute
6130 Executive Boulevard, Room 6035A, MSC 7388
Bethesda, MD  20892-7388
Telephone:  (301) 496-7147
FAX:  (301) 402-7819

Direct inquiries regarding fiscal matters to:

Ms. Sara Stone
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-9927
FAX:  (301) 496-8601
Email: stones@GAB.NCI.NIH.GOV


Prospective applicants are asked to submit, a letter of intent by the dates 
mentioned on the first page of this PA, that includes a descriptive title of 
the proposed research, the name, address, and telephone number of the 
Principal Investigator, the identities of other key personnel and 
participating institutions (including NCI Groups or other tissue banks), and 
the number and title of the PA in response to which the application may be 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of subsequent applications, the information is helpful 
in planning for the review of applications.  It allows staff to estimate the 
potential review workload and plan the review.

The letter of intent is to be sent to Ms. Diane Bronzert listed under INQURIES  
by the letter of intent receipt date. 


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. Applications 
will be accepted at the standard application deadlines as indicated in the 
application kit. Applications 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 301/710-0267, 
email:  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.  For those applicants with internet access, the 398 kit may be found 

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

All clinical trials supported or performed by NCI require some form of 
monitoring. 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 to 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 of the NCI for Data Safety Monitoring of 
Clinical Trials see 
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:



Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $250,000 per year for R01 and, up to a total 
direct cost request of $100,000 per year for R21. (Applications that request 
more than $250,000 direct costs for R01 in any year must follow the 
traditional PHS 398 application instructions.)  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.

of the PHS 398.  It is not required and will not be accepted with 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 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 all 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:

- 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.

Submit a signed, typewritten original of the application, including the 
checklist, and five signed, exact, single-sided photocopies, in one package 

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.


Applications will be assigned on the basis of established Public Health 
Service referral guidelines.  Applications will be evaluated for scientific 
and technical merit 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 five criteria to be used in the evaluation of grant applications are 
listed below.

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?

2.  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?

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, 
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.


Applications will compete for available funds with all other approved 
applications.  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.


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, available on the Internet at:; a complete 
copy of the updated Guidelines are available at    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.


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 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 

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


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.

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, Correlative Studies Using 
Specimens from Mulit-institutional Prevention and Treatment Trials, is related 
to priority area of cancer.  Potential applicants may obtain a copy of 
"Healthy People 2010" at

This program is described in the Catalog of Federal Domestic Assistance No. 
93.395. Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92. This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

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

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