PIVOTAL CLINICAL TRIALS FOR CHEMOPREVENTION AGENT DEVELOPMENT

NIH GUIDE, Volume 26, Number 36, October 24, 1997

RFA:  CA-98-001

P.T. 34

National Cancer Institute

Letter of Intent Receipt Date:  December 2, 1997
Application Receipt Date:  January 13, 1998

PURPOSE

The Division of Cancer Prevention (DCP), National Cancer Institute (NCI) invites
applications to further the drug development efforts of the Chemoprevention
Branch by carrying out intermediate-sized Phase II/III efficacy trials of
promising chemopreventive agents in major cancer target organs, particularly
prostate, breast, lung, colon, and bladder.

Currently, most NCI-sponsored Phase II clinical trials enroll fewer than 100
participants and evaluate a spectrum of potential surrogate endpoint biomarkers
(SEBs) as study endpoints over a relatively brief study period (2 weeks to 6
months).  This is in contrast to the large Phase III clinical chemoprevention
trials with tamoxifen, finasteride (Proscar), and aspirin conducted under the
direction of the Community Oncology & Rehabilitation Branch or the
Chemoprevention Branch which are enrolling 10,000 to 22,000 participants and
evaluating clinical parameters, such as cancer incidence reduction, over many
years. This comparison emphasizes the need for Phase II/III chemoprevention
clinical trials of intermediate size and duration which are designed to establish
the efficacy of promising agents and the validity of the most promising
histopathologic and laboratory-based SEBs currently held to be "reasonably
certain" predictors of cancer prevention. Because of the critical nature of the
biomarkers used in Phases I and IIb clinical trials of clinical chemopreventive
drug development, the careful scientific conduct of these biomarker assessments
is considered essential to progress in chemoprevention. Measurement of these
biomarkers is crucial.  It is anticipated that biomarkers validated through these
intermediate Phase II/III studies could be used in future efficacy evaluations
of new chemopreventive compounds and in clinical and regulatory decision-making.

As described above, the intermediate-sized clinical trials supported through this
RFA are a pivotal decision point in the NCI chemoprevention drug development
program.  The consensus view of a Working Group from the NCI and the FDA
acknowledges that "the interim analysis of a validated surrogate endpoint of
cancer incidence may facilitate the timely and cost-effective marketing of
efficacious drugs (Kelloff et al., Cancer Epidemiol. Biomark. Prev. 4:  1-10,
1995)."  Thus, the efficacy and safety data from these studies potentially
supports FDA marketing approval (NDA applications) for chemoprevention
indications, and certainly facilitates decisions regarding the most appropriate
recommendations for subsequent large, community-based efficacy studies.

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 RFA, Pivotal Clinical Trials for
Chemoprevention Agent Development, 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 domestic and foreign 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 from minority and women investigators are
encouraged. For those respondents affiliated with the Community Clinical Oncology
Program (CCOPs), it is suggested that proposals be submitted through the CCOPs
mechanism.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) mechanism. The cooperative
agreement is an assistance mechanism in which substantial involvement of the NCI
with the recipient is anticipated during the performance of the planned activity. 
The nature of the NCI's involvement is described under SPECIAL REQUIREMENTS, 2. 
Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant/awardee.

The total project period for an application submitted in response to the present
RFA may not exceed five years.  The anticipated award date is July 1998.  This
RFA is a one-time solicitation.  Future unsolicited competitive continuation
applications will compete with all other investigator-initiated research
applications and be peer reviewed by an appropriate study section in the Center
for Scientific Review (CSR) (formerly DRG), NIH.

FUNDS AVAILABLE

Approximately $3 million in total costs for the first year of support will be
committed specifically to fund applications submitted in response to this RFA. 
It is anticipated that three to four awards will be made.  Because the nature and
scope of the research proposed in response to this RFA may vary, it is
anticipated that the size of the awards will vary also.  Awards and the level of
support depend on receipt of a sufficient number of applications of high
scientific merit.

Although this program is provided for in the financial plans of the NCI, awards
made pursuant to this RFA will be contingent on the continued availability of
funds for this purpose.

RESEARCH OBJECTIVES

Background

The purpose of this initiative is to enhance clinical cancer prevention research. 
This RFA seeks to build on information from Chemoprevention Branch contract-
supported agent identification, preclinical testing, and Phase I and early Phase
II clinical studies of promising agents by supporting their continued systematic
development in longer, intermediate-sized Phase II/III clinical trials.

The goals for these pivotal clinical studies comprise (1) expansion and
refinement of information from the smaller Phase II trials on efficacy,
participant recruitment and retention, adverse effects, and acceptability of
treatment over time; (2) validation of surrogate endpoint biomarkers (SEBs)
selected from experience in the Phase II studies; and (3) diversification of the
target populations for the chemopreventive interventions.  Results of these
pivotal clinical trials may support New Drug Applications (NDAs) to the FDA,
where appropriate, for chemoprevention indications and larger community-based
cancer prevention clinical trials with incidence reduction endpoints.

As our understanding of carcinogenesis increases, preventive interventions become
increasingly practical for many primary cancer sites.  While prevention of
carcinogen exposures and lifestyle changes may eventually alter cancer incidence,
pharmacologic interventions offer an attractive approach with the potential for
more immediate results.  The drug development process for these chemopreventive
agents, in contrast to that for cancer therapy drugs, has unique requirements
because of the generally good health status of their target populations, the
anticipated long duration of use, and the low level of acceptable toxicity.

The NCI's chemoprevention drug development program has the mission of identifying
safe and effective chemical agents for preventing human cancer.  This program is
an applied drug development science effort with clinical trials as its endpoint. 
It begins with the identification of candidate agents for development and the
characterization of these candidates for efficacy using in vitro and animal
screens. Promising agents are then further tested in animal models to explore
their potential for clinical application, with regard to both safety and
efficacy.  The most successful agents then progress to clinical trials.  The
ultimate goal of this process is to achieve accurate and reliable information on
long-term efficacy and safety that will support marketing approval and widespread
clinical use.

In contrast to the development of therapeutic agents, the identification and
validation of biomarkers characterizing the neoplastic process are key aspects
of the chemoprevention drug development process.  SEBs are defined as measurable
and modulatable biological or chemical properties that are highly correlated to
cancer incidence and that may serve as indicators of the likely incidence or
progression of cancer.  While traditional Phase I drug development studies focus
on pharmacokinetics and tolerability of the investigational agent, Phase I
chemoprevention studies are designed to develop and evaluate biologic markers of
drug effect and SEBs, besides obtaining required pharmacokinetic and safety
information. Phase II chemoprevention studies characterize dose-biomarker
response and more common chronic toxicities, to identify safe and effective doses
for further studies. When clearly defined and standardized biomarkers are not
known, Phase IIa dose-response studies are undertaken to evaluate the feasibility
of candidate biomarker measurements (for drug effects and/or SEBs) and to
standardize assay conditions and develop quality control procedures.  Phase IIb
chemoprevention studies are done subsequently to establish the dose-response
relationship of SEB modulation and the toxicities associated with chronic
administration in order to select a safe and effective dose for Phase III
clinical trials.

Scope and Objectives

This RFA will support Phase II/III randomized, placebo-controlled clinical trials
to evaluate the chemopreventive efficacy of selected agents or regimens in target
populations consistent with the Clinical Development Plans of the DCP Agent
Development Committee (see Journal of Cellular Biochemistry Supplement 20, 1994
and Supplement 26, 1996).  Investigators may propose any cohort, intervention,
or drug for which justification and developmental support can be provided.  The
following list is provided as an example  for which preclinical, early clinical,
drug supply, and regulatory support may be available:

1. Prevention of colorectal adenomas in patients having a history of colorectal
adenomas or early stage colon carcinoma using selected nonsteroidal
antiinflammatory drugs (NSAIDs, including less toxic derivatives), 2-
difluoromethylornithine (DFMO), Oltipraz, or the combinations of calcium with
vitamin D or an NSAID and of DFMO with an NSAID;

2. Prevention of prostatic intraepithelial neoplasia (PIN), its progression, and
cancer incidence by antiandrogens (e.g., flutamide or bicalutamide), vitamin E,
selenium, the combination of vitamin E with selenium, fluasterone (DHEA analog
8354), selected retinoids [e.g., all-trans-N-(4-hydroxyphenylretinamide) (4-HPR)
or 9-cis-retinoic acid], or 5'-reductase inhibitors (e.g., finasteride);

3. Prevention of bronchial dysplasia, its progression, or second primary upper
aerodigestive cancer in patients with a history of resected early stage non-small
cell lung cancer (NSCLC) or laryngeal cancer by retinoids (e.g., 4-HPR, 9-cis-
retinoic acid or all-trans retinoic acid, possibly in aerosolized formulations),
Oltipraz, N-acetyl-l-cysteine (NAC), or the combinations of Oltipraz with NAC or
4-HPR;

4. Modulation of biomarkers in the breast (including mammographic patterns) and
new proliferative or precancerous lesions in patients with atypical ductal or
lobular hyperplasia or lobular carcinoma in situ by anti-estrogens, retinoids
(e.g., 4-HPR or 9-cis-retinoic acid), fluasterone or low-dose DHEA, DFMO, or the
combination of vitamin E with selenium;

5. Prevention of dysplastic oral leukoplakia, its progression, and oral cancer
by Oltipraz (in chronic smokers), 4-HPR, DFMO or curcumin;

6. Prevention of cervical intraepithelial neoplasia (CIN II/III), its
progression, and cervical cancers by 4-HPR, DFMO, Oltipraz, or selected NSAIDs;

7. Prevention of recurrence or new lesions in patients with Ta/T1 bladder
carcinoma with or without tissue in situ (TIS) (post-BCG) by 4-HPR, DFMO, or
selected NSAIDs;

8. Prevention of precancerous lesions in Barrett's esophagus, their progression,
and esophageal cancers by DFMO, retinoids, or Oltipraz.

9. Progression of precancerous lesions of the skin, their progression, and skin
cancer by DFMO, retinoids or curcumin.

Study endpoints should include changes in the most promising SEBs (such as those
in preinvasive disease or proliferative disease), the development of new
premalignant lesions, and, as appropriate, the occurrence of new invasive
cancers. This emphasis on SEBs requires that the research team include strong
collaborative support from the areas of pathology, biochemistry and molecular
biology, and cancer biology and carcinogenesis.

The clinical trial design should include an adequate number of participants and
should be of sufficient duration to assure statistical power to address the study
questions of chemopreventive efficacy, long-term safety and acceptability, and
SEB validation.  To this end, biostatistics and clinical trial design expertise
should be included from the first efforts in study planning and design.  Study
size and duration will vary according to specific study hypotheses, target
population, agent(s), and SEBs and other endpoints.

SPECIAL REQUIREMENTS

General

Currently, most NCI-sponsored Phase II clinical trials enroll fewer than 100
participants and evaluate a spectrum of potential SEBs as study endpoints over
a relatively brief study period (2 weeks to 6 months).  This is in contrast to
the large Phase III clinical chemoprevention trials with tamoxifen, finasteride
(Proscar), and aspirin conducted under the direction of the Community Oncology
and Rehabilitation Branch or the Chemoprevention Branch which are enrolling
10,000-22,000 participants and evaluating clinical parameters, such as cancer
incidence reduction, over many years. This comparison emphasizes the need for
Phase II/III chemoprevention clinical trials of intermediate size and duration
which are designed to establish the efficacy of promising agents and the validity
of the most promising histopathologic and laboratory-based SEBs currently held
to be "reasonably certain" predictors of cancer prevention. Because of the
critical nature of the biomarkers used in Phases I and IIb of clinical
chemopreventive drug development, the careful scientific conduct of these
biomarker assessments is considered essential to progress in chemoprevention. 
Measurement of these biomarkers is crucial. It is anticipated that biomarkers
validated through these intermediate Phase II/III studies could be used in future
efficacy evaluations of new chemopreventive compounds and in clinical and
regulatory decision-making.

As described above, the intermediate-sized clinical trials supported through this
RFA are a pivotal decision point in the NCI chemoprevention drug development
program.  The consensus view of a Working Group from the NCI and the FDA
acknowledges that "the interim analysis of a validated surrogate endpoint of
cancer incidence may facilitate the timely and cost-effective marketing of
efficacious drugs (Kelloff et al., Cancer Epidemiol.  Biomark. Prev.  4:  1 10,
1995)."  Thus the efficacy and safety data from these studies potentially
supports FDA marketing approval (NDA applications) for chemoprevention
indications, and certainly facilitates decisions regarding the most appropriate
recommendations for subsequent large, community-based efficacy studies.

Applications funded under this RFA will be supported through the cooperative
agreement (U01) mechanism.  An assistance relationship will exist between NCI and
the awardees to accomplish the research objectives.  As described more fully
below, the recipients will have primary responsibility for the development and
performance of the activity.  However, there will be government involvement with
regard to (1) assistance in securing an Investigational New Drug (IND) approval
from the Food and Drug Administration (FDA), (2) coordination and assistance in
obtaining the chemopreventive agent, and (3) monitoring of study safety and
conduct.  If an investigator anticipates requiring considerable assistance in
obtaining the chemopreventive agent and/or in securing an IND permit from the
FDA, such assistance should be sought in writing to and approved by the NCI
Program Director, prior to submitting an application. Awards will not be made
until all arrangements for obtaining the IND and the agent are  completed.  Cost
of agent and necessary formulation should be included in the budget.

Definitions

Program Director - the NCI Program Staff official (see INQUIRIES section of this
RFA) responsible for the stewardship and monitoring of the award.  The Program
Director may also function as the Staff Collaborator.

Staff Collaborator - the NCI Program Staff Individual responsible for
contributing expert advice on the scientific design and conduct of the research.

Data Safety and Monitoring Committee - the committee composed of external, non-
participating scientists appointed by the Principal Investigator to monitor
patient safety, conduct data audits, and document progress to the NCI Program
Director.

Terms and Conditions of Award

A. Applicability.  These special Terms and Conditions of Award are in addition
to and not in lieu of otherwise applicable OMB administrative guidelines, HHS
grant administration regulations in 45 CFR part 74 and 92, and other HHS, PHS and
NIH grant administration policy statements.

The administrative and funding instrument used  will be a cooperative agreement,
an "assistance" mechanism (rather than an "acquisition" mechanism) in which
substantial NCI scientific and/or programmatic involvement with the awardee is
anticipated during performance of the activity.  Under the cooperative agreement,
the NCI purpose is to support and/or stimulate the recipient's activity by
involvement in and otherwise working jointly with the award recipient in a
partner role, but it is not to assume direction, prime responsibility, or a
dominant role in the activity.

Consistent with the above concept, the dominant role and prime responsibility for
the activity reside with the awardee(s) for the project as a whole, although
specific tasks and activities in carrying out the studies will be shared among
the awardees and the NCI Staff Collaborator

Under the cooperative agreement, a relationship will exist between the recipient
of these awards and the NCI, in which the performers of the activities are
responsible for the requirements and conditions described below, and agree to
accept program assistance from a named NCI Staff Collaborator in achieving
project objectives.

Failure of an awardee to meet the performance requirements, including these
special terms and conditions of award, or significant changes in the level of
performance, may result in a reduction of budget, withholding of support,
suspension and/or termination of the award.

B. Awardee Rights and Responsibilities.

The Awardee is responsible for:

1. Research design and protocol development, including definition of objectives
and approaches, planning, implementation, participant recruitment and follow-up,
data collection, quality control, interim data and safety monitoring, final data
analysis and interpretation, and publication of results.

2. Establishing an external Data Safety and Monitoring Committee to review data. 
The Principal Investigator will name external, non-participating investigators
to serve as members on a Data Safety and Monitoring Committee and schedule
meetings periodically.  The NCI Staff Collaborator will be a non-voting member.

3. Designating Protocol Chairs.  The Principal Investigator shall designate a
single Protocol Chairperson (if the P.I. does not assume this role).  The
Protocol Chairperson shall function as the scientific coordinator for the
protocol and shall assume responsibility for developing and monitoring the
protocol.  All proposed protocol modifications will be submitted by the Chair
through the Principal Investigator to the NCI Program Director, for review and
approval, subject to negotiation with the awardee.

4. Implementing the data collection method and strategy.

5. Establishing mechanisms for quality control and monitoring. Awardees are
responsible for ensuring accurate and timely assessment of the progress of each
study, including development of procedures to ensure that data collection and
management are:  (1) adequate for quality control and analysis; (2) for clinical
trials, as simple as appropriate in order to encourage maximum participation of
physicians and patients and to avoid unnecessary expense; and (3) sufficiently
staffed.

6. Submitting interim progress reports, when requested, to the NCI Program
Director including as a minimum, summary data on protocol performance.  The Data
Safety and Monitoring Committee may require additional information. Such reports
are in addition to the annual awardee noncompeting continuation progress report.

7. Establishing procedures, where applicable, to comply with FDA regulations of
21 CFR Part 312 for studies involving investigational agents and to comply with
the requirements of 45 CFR Part 46 for the protection of human subjects.  For
IND's sponsored by the NCI, the Principal Investigator is responsible for
obtaining approval from both the Institutional Review Board and the NCI Program
Director to enroll patients and to change the protocol.  The Principal
Investigator is also responsible for all aspects of investigational drug
acquisition, formulation, distribution, etc.

8. Cooperating in the reporting of the study findings.  The NCI will have access
to and may periodically review all data generated under an award.  Where
warranted by appropriate participation, plans for joint publication with NCI of
pooled data and conclusions are to be developed by the Principal Investigator,
as applicable. NIH policies governing possible co-authorship of publications with
NCI staff will apply in all cases.  In general, to warrant co-authorship, NCI
staff must have contributed to the following areas:  (a) design of the concepts
or experiments being tested; (b) performance of significant portions of the
activity; and (c) preparation and authorship of pertinent manuscripts.  The
awardee(s) will retain custody of and have primary rights to the data developed
under these awards, subject to Government rights of access consistent with
current HHS, PHS and NIH policies.

C. NCI Staff Responsibilities

It is expected that the dominant role and prime responsibility for the activity
will reside with the awardee(s) for the project as a whole, although specific
tasks and activities in carrying out the studies will be shared among the
awardees and the NCI Staff Collaborator who will provide expert advice to the
awardee(s) on specific scientific and/or analytic issues as described below.  The
NCI Staff Collaborator will be named later based upon the subject matter of the
award.  However, the NCI Program Director will retain overall programmatic
responsibility for the award and will be the contact point for all facets of
interaction with the awardee related to stewardship and monitoring of the award.

NCI Program Staff responsibilities will include:

1. Interacting with the Principal Investigator(s) on a regular basis to monitor
study progress.  Monitoring may include:  regular communications with the
Principal Investigator and staff, periodic site visits for discussions with
awardee research team, observation of field data collection and management
techniques, quality control, fiscal review, and other relevant matters; as well
as attendance at Data Safety and Monitoring Committee and related meetings.  The
NCI retains, as an option, the right to act as Sponsor for an IND filed to
support the clinical research and to conduct periodic external review of
progress.

2. Participating in the Data Safety and Monitoring Committee meetings.  The NCI
Staff Collaborator will be an invited attendee and participant of the Data Safety
and Monitoring Committee and, if applicable, subcommittees, but will not have a
vote on any committee.

3. Serving as a resource with respect to other ongoing NCI activities that may
be relevant to the protocol to facilitate compatibility and avoid unnecessary
duplication of effort.

4. Involvement assisting in the design and coordination of research activities
for awardees as elaborated below:

a. Assisting by providing advice in the management and technical performance of
the investigations, coordinating clearances for investigational agents held by
NCI.  The NCI reserves the right to crossfile or independently file an
Investigational New Drug Application form with the FDA.

b. Through participation in meetings/correspondence of the research team, with
the agreement of the Principal Investigator, the NCI Staff Collaborator may
assist in the design, development, and coordination of the research or clinical
protocol, in the statistical evaluations of data, in the preparation of
questionnaires and other data recording forms, and in the publication of results.

c. Reviewing and approving protocols to insure they are within the scope of peer
review and for safety considerations, as required by Federal regulations.  The
NCI Program Director will monitor protocol progress, and may request that a
protocol study be closed to accrual for reasons including:  (a) accrual rate
insufficient to complete study in a timely fashion; (b) accrual goals met early;
(c) poor protocol performance; (d) patient safety and regulatory concerns; (e)
study results that are already conclusive; and (f) emergence of new information
that diminishes the scientific importance of the study question. The NCI will not
permit further expenditures of NCI funds for a study after requesting closure
(except for patients already on-study).

d. Reviewing and providing advice regarding the establishment of mechanisms for
quality control and study monitoring.

5. Making recommendations for continued funding based on: a) overall study
progress, including sufficient patient and/or data accrual; b) cooperation in
carrying out the research (e.g., attendance at Data Safety and Monitoring
Committee meetings, implementation of group decisions, compliance with the terms
of award and reporting requirements); and/or c) maintenance of a high quality of
research, which will allow pooling of data and comparisons across multiple
cooperative agreement awards for common data elements.

D. Collaborative Responsibilities

In addition to the interactions defined above, NCI Staff and Awardees shall share
responsibility for the following activities:

1. Data Safety and Monitoring Committee.  A Committee organized by the Principal
Investigator will be the main oversight body of the clinical trial.  The Data
Safety and Monitoring Committee has primary responsibility to review progress,
monitor patient accrual, data management, and patient safety, and cooperate on
the publication of results. The Data Safety and Monitoring Committee will
document progress in written reports to the NCI Program Director, and will
provide periodic supplementary reports to designated NCI staff upon request.

The Data Safety and Monitoring Committee will be composed of external, non-
participating peer Investigators, including those of data
coordinating/statistical centers, if any, and the NCI Staff Collaborator.  An
initial meeting of the Data Safety and Monitoring Committee will be convened
early after award by the Principal Investigator.  The final structure of the Data
Monitoring Committee will be established at the first meeting; the Principal
Investigator will not be a member or routine attendee of the Committee after the
first meeting.  The NCI Staff Collaborator will have nonvoting membership on the
Committee, and as appropriate, its subcommittees. Such a Committee usually will
meet at least yearly.

A Chairperson, other than the NCI representative, will be selected by a vote of
the members.  The Chairperson is responsible for coordinating the Committee
activities, for preparing meeting agendas, and for scheduling and chairing
meetings.

E. Arbitration

Any disagreement that may arise on scientific/programmatic matters (within the
scope of the award), between award recipients and the NCI may be brought to
arbitration.  An arbitration panel will be composed of three members -- one
selected by the awardee, a second member selected by NCI, and the third member
selected by the two prior selected members.  These special arbitration procedures
in no way affect the awardee's right to appeal an adverse action that is
otherwise appealable in accordance with PHS regulations at 42 CFR Part 50,
Subpart D, and HHS regulations at 45 CFR Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is NIH policy 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.

All investigators proposing research involving human subjects should read the
"NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical
Research," which  has been published in the Federal Register, March 28, 1994 (59
FR 14508-14513)  and in the NIH GUIDE FOR GRANTS AND CONTRACTS, March 18, 1994,
Volume 23, Number 11.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by December 2, 1997, 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, and the number and title of
this RFA.

Although a letter of intent is not required, is not binding, and does not enter
into the review of subsequent applications, it is requested to provide an
indication of the number and scope of applications and to avoid conflict of
interest in the review.

The letter of intent is to be sent to:

Gary J. Kelloff, M.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Suite 201
Bethesda, MD  20892
Rockville, MD 20852 (for express/courier services)
Telephone:  (301) 496-8563
FAX:  (301) 59442943
Email:  [email protected]

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used for these
cooperative agreements.  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:
[email protected].

The RFA label available in PHS-398 must be affixed to the bottom of the face
page.  Failure to use this label could delay processing of the application such
that it may not reach the review committee in time for review.  Additionally, the
title of the RFA, PIVOTAL CLINICAL TRIALS FOR CHEMOPREVENTION AGENT DEVELOPMENT
and the RFA number CA-98-001, must be typed in line 2 of the face page and the
YES box must be marked.

A signed, typewritten original of the application, including the Checklist and
three signed, clear, and single-sided photocopies must be submitted in one
package to:

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the same time, two additional copies of the application must also be sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892
Rockville, MD 20852 (for express/courier service)

Applications must be received by January 13, 1998.  If an application is received
after that date, it will be returned to the applicant without review.  The Center
for Scientific Review (CSR) will not accept any application in response to this
RFA 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.

Preparation of the Application

The general instructions provided in PHS-398 for the preparation of applications
must be used.  Because the Terms and Conditions of Award (discussed in the
SPECIAL REQUIREMENTS Section), will be included in all awards issued as a result
of this RFA, it is critical that each applicant provide specific plans for
responding to the terms and conditions of award and requirements stated in the
RFA. Plans must take into account NCI staff involvement as well as how all the
responsibilities of awardees will be fulfilled.

The following items apply to all applications:

1. Clinical trial designs should include an adequate number of participants and
should be of sufficient duration to assure statistical power to address the study
questions of chemopreventive efficacy, long-term safety and acceptability, and
surrogate endpoint biomarker (SEB) validation.  To this end, biostatistics and
clinical trial design expertise should be included from the first efforts in
study planning and design.

2. A rationale for selection of the target patient cohort and an estimate of the
number of participants required to complete the clinical studies should be
provided.  Criteria and calculations used to estimate sample size should be
included.  The patient cohort should be described and its selection justified. 
The cohort should be defined, as appropriate by age, sex, race, dietary customs,
education, geographic location, occupational or lifestyle risk factors, and
relevance to a specific cancer problem or its prevention by the test agent. 
Accrual rate should be estimated.  If multiple institutions are involved, the
proposal should include verification of the co-investigators' willingness to
participate, and pertinent additional information regarding the cooperating
institutions' staff qualifications, resources, research plans, including patient
availability and data flow, as well as corresponding budget requirements.

3. A discussion of the evaluation of SEBs, including relevance to the test agent
and target population should be provided.

4. A rationale for each test agent should be provided, including relevant
epidemiological and laboratory data. Preclinical and clinical toxicity data
should also be presented.  Where the availability or safety of the agent are in
doubt, the applicant should consult with the NCI Program Director or the
manufacturer prior to preparing the application.  As noted above, applicants
anticipating the need of considerable assistance in obtaining the chemopreventive
agent(s) to be studied or in securing IND approval, e.g. with respect to adequate
preclinical toxicology data, should seek this assistance from the NCI Program
Director in writing.  The request should be made to the Program Director prior
to submission of the application.

5. Clinical chemistry and biologic aspects of the studies should be completely
described, including sample collection, storage, handling, analysis, and quality
control.  The methods and equipment to be used and the technical qualifications
and experience of the personnel involved should be addressed.  If these aspects
of the studies are to be conducted by groups other than at the applicant's
institution, a letter from the cooperating institutions indicating their
willingness to participate should be included.

6. Any known or potential toxicity considerations should be described, along with
the techniques and procedures to monitor any adverse events and dose
modifications to be made based on toxicity.

7. Methods to monitor patient compliance and, as appropriate, methods to document
nutrient intake should be specified.

8. A willingness to work cooperatively with the NCI Program Director in the
implementation and conduct of the study should be indicated.

9. Applicants from institutions which have a General Clinical Research Center
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the GCRC as a resource for conducting the proposed research.  In such
a case, a letter of agreement from either the GCRC Program Director or Principal
Investigator could be included with the application.

REVIEW CONSIDERATIONS

A. Review Procedures

Upon receipt, applications will be reviewed by the Center for Scientific Review
(CSR) for completeness and by the NCI for responsiveness.  Incomplete and/or non-
responsive applications will be returned to the applicant without further
consideration.

Applications that are complete and responsive to the Request for Applications
will be evaluated for scientific and technical merit in accordance with the
review criteria stated below by an appropriate peer review group convened by the
NCI.  As part of the initial merit review, all applications will receive a
written critique and may undergo a process in which only those applications
deemed to have the highest scientific merit will be discussed, assigned a
priority score, and receive a second level review by the National Cancer Advisory
Board.

The review group will assess the scientific merit of the studies using the
following review criteria:

B. Review Criteria

Review Criteria for the Proposed Clinical Trial

--Scientific merit of the proposed research.  This includes design, methodology
(including considerations of toxicity, quality assurance, endpoint analyses, and
power), and the clinical study protocol.

--The significance and importance of the objectives.  Basic and clinical
scientific significance, as well as originality of the proposed research. 
Particularly important are the definition of the high-risk target populations and
the evaluation biomarkers relative to clinical interventions.

--Documentation of relevant prior successful accrual.

--The qualifications of the Principal Investigator to serve as both the
scientific and administrative leader of the proposed research. The Principal
Investigator should be an established scientist with a substantial record of
independent research.

--The adequacy of the commitment (percent effort) of the Principal Investigator
to the proposed research.  There should be a specific commitment to both the
scientific and administrative aspects of the proposed research though it is not
mandatory that the Principal Investigator be a project leader of an individual
research project.

--The qualifications of Co-Investigators and support personnel.

--The presence of an organizational and administrative structure appropriate for
effective attainment of the proposed research objectives.

--The mechanisms for internal quality control of the research.

--The institutional environment in which the research is conducted, including the
availability of space, equipment and patients as well as the physical proximity
of participants.  For applications involving more than one institution, the
mechanisms for assuring close coordination and interaction are evaluated.

--The adequacy of the proposed means for early detection of and protection
against potential adverse effects upon humans and the environment.

--The appropriateness of the statistical design and mechanism for the rigorous
management and verification of research data. Adequacy of methods for data and
tissue collection and analysis. Documentation of validated bioanalytical
procedures (method sensitivity, specificity, quality control, etc.) and of prior
experience with endpoints to-be-evaluated.

--Adequacy of adherence to guidelines for including gender and minority
representation in any study population.

--The appropriateness of the budget.  A realistic budget reflects the project
leader's understanding of the scope of work.

--Adequacy of plans for NCI Program staff involvement with the proposed research.

AWARD CRITERIA

The earliest feasible start date for the initial awards will be July 1998. 
Besides technical merit as determined by peer review, NCI will base funding
decisions on how well the applicant institutions meet the goals and objectives
of the program described in the RFA, as well as on availability of resources at
the applicant institution and study populations.

SCHEDULE

Letter of Intent Receipt:  December 2, 1997
Application Receipt Date:  January 13, 1998
Review by NCAB:            May 1998
Anticipated Award Date:    July 1998

INQUIRIES

Written and telephone inquiries concerning the RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Inquiries regarding programmatic issues such as responsiveness and eligibility
may be directed to:

Gary J. Kelloff, M.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Suite 201
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-8563
FAX:  (301) 594-2943
Email:  [email protected]

Inquiries regarding fiscal matters may be addressed to:

Ms. Carolyn Mason
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Suite 243
Bethesda, MD  20892-7340
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-7800 Ext. 259

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Number
93.399, Cancer Control.  Awards will be made under authority 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 258); and administered under PHS grant policies and
Federal Regulations 42 CFR Parts 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirement 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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