Full Text CA-97-014
 
PIVOTAL CLINICAL TRIALS FOR CHEMOPREVENTION AGENT DEVELOPMENT
 
NIH GUIDE, Volume 26, Number 7, March 7, 1997
 
RFA:  CA-97-014
 
P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Clinical Trial 
  Chemopreventive Agents 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  April 3, 1997
Application Receipt Date:  May 22, 1997
 
PURPOSE
 
The Division of Cancer Prevention and Control (DCPC), 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 SEBs as
study endpoints over a relatively brief study period (2 weeks 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 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 IIb
of clinic al 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 applications submitted in response to
the present RFA may not exceed five years.  The anticipated award
date is September 1997.  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 a study section in the Division of Research Grants (DRG),
NIH.  However, if it is determined that there is a sufficient
continuing need, the NCI will invite recipients of awards made under
this RFA in FY 97 to submit competitive continuing applications for
review according to procedures described below under APPLICATION
PROCEDURES and REVIEW CONSIDERATIONS.
 
FUNDS AVAILABLE
 
Approximately $3 million in total costs for the first year of support
for the program will be committed specifically to fund applications
submitted in response to this RFA.  It is anticipated that 3-4 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 DCPC 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 only but 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 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 (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 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 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 IIb
of clinic al 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 Collaborator 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 shall 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 (Section 492B of Public Law 10-43) and
supersedes and strengthens previous policies (Concerning the
Inclusion of Women in Study Populations), which have been in effect
since 1990.
 
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 was 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.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by April 3, 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 names of other key personnel, the 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 and Control
National Cancer Institute
6130 Executive Boulevard, Suite 201
Bethesda, MD  20892
Rockville, MD 20852 (for express/courier services)
Telephone:  (301) 496-8563
FAX:  (301) 402-0553
Email:  kelloffg@dcpcepn.nih.nci.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 9/95) 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 301/435-0714, email:
ASKNIH@odrockm1.od.nih.gov.
 
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-97-014, 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:
 
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 May 22, 1997.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) 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 DRG 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 discussion of the evaluation of SEBs, including relevance to
the test agent and target population should be provided.
 
3.  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.
 
4.  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.
 
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 Division of
Research Grants (DRG) 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
 
o  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.
 
o  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.
 
o  Documentation of relevant prior successful accrual.
 
o  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.
 
o  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.
 
o  The qualifications of Co-Investigators and support
personnel.
 
o  The presence of an organizational and administrative
structure appropriate for effective attainment of the
proposed research objectives.
 
o  The mechanisms for internal quality control of the
research.
 
o  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.
 
o  The adequacy of the proposed means for early detection of
and protection against potential adverse effects upon humans
and the environment.
 
o  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.
 
o  Adequacy of adherence to guidelines for including gender
and minority representation in any study population.
 
o  The appropriateness of the budget.  A realistic budget
reflects the project leader's understanding of the scope of
work.
 
o  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 September 1997.  Besides technical merit, 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 and study
populations.
 
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 may be directed to:
 
Gary J. Kelloff, M.D.
Division of Cancer Prevention and Control
National Cancer Institute
6130 Executive Boulevard, Suite 201
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-8563
FAX:  (301) 402-0553
Email:  kelloffg@dcpcepn.nih.nci.gov
 
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
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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