CORRELATIVE STUDIES USING SPECIMENS FROM MULTI-INSTITUTIONAL TREATMENT TRIALS

Release Date:  August 14, 1998

PA NUMBER:  PA-98-099

P.T.

National Cancer Institute

Application Receipt Dates:  November 17, 1998; February 1; June 1; and October
1, each year thereafter

PURPOSE

The Cancer Therapy Evaluation Program (CTEP) and Cancer Diagnosis Program (CDP)
of the Division of Cancer Treatment and Diagnosis, National Cancer Institute
invite research grant applications from institutions or consortia capable of and
interested in performing translational research on promising predictive and
prognostic markers.  These studies should focus on correlations between biologic
features of tissue specimens collected from the NCI Clinical Trials Cooperative
Groups (NCI Groups) or other large multi-institutional clinical trials and
patient outcomes.  The markers should be assessed for their ability to predict
clinical outcomes in the context of therapy or response to particular therapies. 
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 are
encouraged to contact the NCI Groups if ongoing collaborations are not in place.

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
studies.  The R21 grant mechanism is utilized for pilot projects or feasibility
studies to support exploratory research that may produce innovative advances in
science.  The R21 grant mechanism provides limited funds (maximum of $100,000
direct costs per year not including indirect costs of any collaborating
institutions) for short-term (up to two years) research projects.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, Correlative Studies Using
Specimens from Multi-Institutional Treatment Trials, is related to the priority
area of cancer.  Potential applicants may obtain a copy of "Healthy People 2000"
(Full Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-512-1800).

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.  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 investigators.

MECHANISM OF SUPPORT

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 per year in direct costs, not
including indirect costs for collaborating institutions, 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. 
Awards will be administered under PHS grants policy as stated in the Public
Health Service Grants Policy Statement, PHS Publication No. (OASH) 94-50.000
(Rev. April 1, 1994).

RESEARCH OBJECTIVES

Background

Insights into the biologic function and clinical relevance of growth factors,
genes that promote and suppress neoplasia, mechanisms of treatment sensitivity
and resistance and functions of the immune system provide important new clinical
research opportunities for investigators studying patients enrolled on
therapeutic clinical trials.  Historically, clinical prognostic factors have
assisted clinicians in the selection of appropriate therapeutic interventions. 
Recent advances in molecular genetics and immunobiology have identified new
promising markers for the identification of patients who would benefit from
specific therapeutic strategies.  New technological advances in methodologies
such as PCR, flow cytometry, immunohistochemistry, in situ hybridization and
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 can
be expected to be immediately relevant to cancer treatment.

The NCI supports an extensive network of clinical and laboratory research studies
related to cancer 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 primary goal
of these trials is the definitive evaluation of clinical treatment programs. 
Presently, the Groups conduct approximately 400 clinical trials evaluating
approximately 20,000 patients per year.  The Groups have access to tumor
specimens from large numbers of patients with established tumor banks in a
variety of malignancies.  They maintain statistical databases and are capable of
correlating laboratory data with the clinical outcome of patients. These
investigators stand ready and willing to integrate basic laboratory studies with
clinical 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 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 for large scale analysis.  The Clinical Trials
Cooperative Group mechanism (U10) provides support for patient accrual, 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.  Objectives and approaches will be
investigator-initiated with the CTEP and CDP assisting investigators to assure
that promising new approaches will be moved more 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
translational research on promising predictive and prognostic markers.  Theses
studies should focus on correlations between biologic features of tissue
specimens collected from the NCI Clinical Trials Cooperative Groups (NCI Groups)
or other large multi-institutional clinical trials and patient outcomes.  The
markers should be assessed for their ability to predict clinical outcomes in the
context of therapy or response to particular therapies.  Researchers who have
previously not collaborated with the NCI Groups are encouraged to contact them
and discuss potential collaborations to obtain access to patient specimens and
NCI-supported specimen banks for laboratory analysis under this PA.  NCI staff
from CTEP and CDP (see Inquiries) will be able to provide assistance in
identifying NCI Groups that would be interested in collaborating with basic
science investigators on laboratory and clinical studies of new markers.  The NCI
Tissue Expediter (see Inquiries) will be 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 Group banks is available at the following web address:
http://www.specimens.ims.nci.nih.gov.  The NCI Groups have mechanisms in place
to review proposals for access to NCI Group tissue banks.  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.  The grant application will be deferred if
the appropriate letters of support are not received prior to review.

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, extensive 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 therapeutic response, development
of new treatment strategies or identification of patient subsets that may
relapse, or for specific treatment approaches.  The laboratory assays must
utilize 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-center organizations or form a consortium of institutions in order to
access sufficient numbers of patient specimens and clinical information to test
the proposed hypotheses.

Some examples of therapeutic laboratory correlates include, but are not limited
to:

o  Phenotypic or genotypic alterations which appear to correlate with the
development of therapy resistance;

o  Loss or inactivation of tumor suppressor genes related to prognosis;

o  Analysis of basal membrane factors or genes related to tumor invasion or
metastases;

o  Studies of chromosomal rearrangements or deletions that may be used as
prognostic indicators;

o  Correlation of tumor growth factors or oncogenes with response to therapies;

o  Alterations in cell cycle control;

o  Characterization of immune response associated with new immunotherapies;

o  Evaluation of use of serum or tumor markers that correlate with tumor
progression;

o  Analyses of expression of cellular receptors for growth factors or
differentiating agents;

o  Defining and targeting specific populations of cells for therapy.

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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 20, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

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.

NIH POLICY AND GUIDELINES ON THE 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://www.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, one month prior to the application
receipt date, a letter of intent 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 submitted.

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 NCI staff to estimate the
potential review workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

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

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95).  Applications must be received by November 17, 1998, and on the regular
receipt dates indicated in the application kit starting in 1999.  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 301/710-0267, Email: grantsinfo@nih.gov.  The title and
number of the program announcement must be typed in Section 2  on the face page
of the application.

The completed original application and five legible copies must be sent or
delivered 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health Service
referral guidelines.  Applications will be reviewed for scientific and technical
merit by study sections of the Center for Scientific Review (CSR), 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?

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.

AWARD CRITERIA

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.

INQUIRIES

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
Division of Cancer Treatment and Diagnosis
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
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 700, MSC 7388
Bethesda, MD  20892-7388
Telephone:  (301) 496-1591
FAX:  (301) 402-7819
Email:  tl82s@NIH.GOV

Direct inquiries regarding NCI supported specimen banks to:

Ms. Marianna Bledsoe
NCI Tissue Expediter, Cancer Diagnosis Program
National Cancer Institute
6130 Executive Boulevard, Room 700, MSC 7388
Bethesda, MD  20892-7388
Telephone:  (301) 496-7147
FAX:  (301) 402-7819
Email:  mb80s@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Kelli Oster
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 261
FAX:  (301) 496-8601
Email:  OSTERK@GAB.NCI.NIH.GOV

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.395.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241
and 285) and administered under PHS grants policies and Federal Regulations 42
CFR 52 and 45 CFR Part 74 and part 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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