CHEMOPREVENTION OF TOBACCO-RELATED CANCERS IN FORMER SMOKERS:  CLINICAL STUDIES
 
Release Date:  April 19, 2001

RFA:  RFA-CA-02-009 (see replacement RFA-CA-03-006)
 
National Cancer Institute
 
Letter of Intent Receipt Date:  June 25, 2001
Application Receipt Date:       July 30, 2001

PURPOSE

The purpose of this initiative is to fund clinical research to develop 
effective chemopreventive strategies that reduce the risk of tobacco-related 
cancers in former smokers.  This initiative will fund pilot clinical trials 
(phase I/II or phase II) evaluating the efficacy of chemopreventive agents in 
specified cohorts of former smokers and translational studies performed on 
specimens (such as tissue, blood, urine, etc.) derived from these clinical 
trials.       

RESEARCH OBJECTIVES
 
Background 

An efficient way of identifying clinically useful chemopreventive agents is to 
perform short term pilot clinical studies examining the effect of 
interventional agents on molecular, imaging, and histologic endpoints in 
populations at high risk for developing invasive cancer.  These studies serve 
to establish the safety and preliminary efficacy of the interventional 
strategies (“proof of principle”) in high risk, but phenotypically normal, 
populations and are crucial in determining which agents/strategies are safe 
and effective enough for further development in phase III clinical trials.  
Since phase III cancer prevention trials require large patient cohorts, major 
resources, and many years to give a definitive answer, it is imperative to 
prioritize promising agents before embarking on such trials.  The purpose of 
this RFA is to stimulate phase I/II or phase II clinical trials that will 
identify agents suitable for definitive testing in the phase III trial context 
for tobacco-related cancers in cohorts of former smokers.

It is estimated that smoking is responsible for more than thirty percent of 
all cancers, particularly cancers arising in the lung, head and neck, bladder, 
esophagus, kidney, pancreas, and cervix.  While the risk of developing cancer 
(i.e., of the lung) in people who quit smoking decreases substantially 
compared with the risk in people who continue to smoke, former smokers 
continue to have significantly elevated cancer risk compared to never smokers 
and this increased risk is maintained for the remainder of their lives.  
Recent data show that genetic damage in tobacco-exposed tissues, such as the 
bronchial epithelium, persists for decades after stopping smoking.  Currently 
almost one-half of all new cases of lung and bladder cancer occur in former 
smokers.  Therefore, the identification of molecular and imaging markers of 
risk and early neoplasia, and the testing of agents that can prevent the 
development of clinical cancer in this group are of high public health 
importance.

Increasing understanding of the lengthy process of human carcinogenesis is 
providing many new opportunities for prevention and early intervention.  The 
identification of genotypic and phenotypic abnormalities that occur frequently 
during tobacco-induced carcinogenesis in the aerodigestive or urothelial 
epithelia, for instance, provides markers for risk of developing cancer as 
well as potential targets for intervention in the process of carcinogenesis.  
For instance, the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 
(COX-2) are frequently expressed in tobacco related malignancies as well as in 
preneoplastic lesions associated with these malignancies, thereby representing 
novel, mechanistic targets for intervention. Similarly, loss of heterozygosity 
at chromosomal loci such as 3p and 9p are frequent early changes occurring in 
lung and upper aerodigestive carcinogenesis, suggesting that the tumor 
suppressor genes found at these loci  (i.e., FHIT at 3p) may have important 
roles in these early phases of carcinogenesis and thereby be reasonable 
mechanistic targets.

Phase II clinical cancer prevention trials depend on intermediate endpoints, 
whether they be histologic preinvasive lesions or molecular endpoints, to 
determine preliminary interventional agent efficacy.  Since these trials are 
intended to evaluate efficacy quickly, it is necessary to identify surrogates 
for cancer incidence/mortality to serve as trial endpoints.  Examples of such 
surrogate or intermediate endpoints include, but are not limited to: 
preneoplastic lesions at high risk for progression to invasive cancer (e.g., 
oral leukoplakia, superficial bladder cancer, bronchial dysplasia, etc.), 
abnormalities in expression of specific proteins associated with cancer (e.g., 
proteins involved in the control of growth, differentiation, and/or 
apoptosis), and specific genetic or epigenetic abnormalities (e.g., 
microsatellite alterations, FISH abnormalities, mutations/deletions in tumor 
suppressor genes or oncogenes, aberrant promoter methylation).  The 
incorporation of newer imaging technologies, such as spiral CT, PET, MRI, or 
combinations, into chemoprevention trials could also provide novel and 
important information.

Several promising agents are already available for chemoprevention studies in 
lung, head and neck, bladder, and other tobacco-damaged organ sites.  For 
example, members of the non-steroidal anti-inflammatory drug family (NSAIDs) 
have shown efficacy in animal models for multiple tobacco-related 
malignancies, including cancers of the lung, upper aerodigestive tract, 
esophagus, and bladder.  Furthermore, the highly specific COX-2 inhibitor 
celecoxib, which has minimal gastrointestinal toxicity compared with other 
NSAIDs, has already been shown to be effective in reducing colorectal polyp 
number in patients with familial adenomatous polyposis.  As mentioned above, 
elevated COX-2 levels have been documented in a variety of tobacco-related 
neoplasms, including cancers of the lung, bladder, and esophagus, as well as 
precursor lesions for lung cancer (atypical adenomatous hyperplasia) and for 
oral malignancy (oral leukoplakia).  Thus, COX-2 may be one reasonable target 
for chemoprevention strategies, although many other targets also exists.  
Based on preclinical animal studies and limited human studies, the list of 
other potential agents to consider includes, but is not limited to, 
glucocorticoids, selenium, lipoxygenase inhibitors, farnesyl transferase 
inhibitors, EGF receptor inhibitors, and myo-inositol.  Given that the same 
carcinogenic exposure (tobacco) is operational in a variety of target organs 
and that several of these agents have potential efficacy in multiple organ 
sites, clinical studies assessing chemopreventive efficacy in multiple tobacco 
damaged organs would also have great appeal.  Alternatively, regional drug 
delivery to  minimize systemic toxicity (such as by inhalation) would 
constitute another important chemopreventive strategy.

Combination prevention trials targeting specific biochemical pathways that are 
relevant to tobacco-induced carcinogenesis represent yet another important 
experimental approach.  Since preclinical data support the use of both COX-2 
and lipoxygenase inhibitors for chemoprevention in various organs, the 
combination of a COX-2 inhibitor with a lipoxygenase inhibitor may prove more 
efficacious than either alone by blocking both major pathways of the 
arachidonic acid metabolism.  Another example of a combination approach is the 
concurrent use of myo-inositol and glucocorticoids delivered by inhalation, as 
has been shown to be highly efficacious in animal lung carcinogenesis models.  
Multiple new agents are also expected to be identified by the companion 
preclinical RFA addressing chemopreventive agent development using animal 
studies that is being issued simultaneously with this RFA 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-02-008.html). The 
appropriate preclinical screening of agents and targeted early clinical trials 
to identify the most promising agents are the crucial foundations for a 
chemopreventive strategy that should ultimately lead to a reduced cancer 
burden for our society.

Objectives and Scope

The purpose of this initiative is to establish multiple pilot short term 
clinical trials (phase I/II or phase II) evaluating the efficacy of 
chemopreventive agents in specified cohorts of former smokers.  These studies 
should integrate the evaluation of multiple biomarkers and surrogate endpoints 
into the clinical trial design.  Given that a significant long term goal of 
the NCI is the identification and validation of intermediate endpoints to 
replace cancer incidence and mortality as endpoints in clinical trials (and 
thereby significantly shorten the duration of such trials), investigators are 
strongly encouraged to collect and save relevant specimens (tissues, blood, 
urine, etc.) for future translational studies as well.  It is anticipated that 
reissuance of this RFA in future years will include funds for independent 
translational studies performed on specimens collected before and after 
chemopreventive intervention in former smokers.

The clinical trials should focus on specified target organs, well defined 
cohorts of former smokers, and particular chemopreventive agents or strategies 
as reflect the interests and expertise of the investigators.  Should they so 
desire, investigators will have access to agents that the Division of Cancer 
Prevention (DCP) already has in supply and for which Investigational New Drug 
(IND) support is available.  Alternatively, DCP will work with investigators 
to provide IND support for agents of their choice.  Examples of clinical 
studies that would be appropriate for this initiative, for the purpose of  
illustration only, might include the following:

1.  Former smokers (30 or more pack year smoking history) with bronchial 
dysplasia on fluorescence bronchoscopy and random bronchial biopsy might be 
randomized to chemopreventive treatment or placebo.  In addition to the 
primary endpoint of treatment (number of sites and grade of bronchial 
dysplasia), investigators might include assessments of several of the 
following:  promoter methylation, apoptosis (TUNEL, bcl-2/bax/bcl-x family), 
LOH at 3p/9p, EGFR, COX-2, Ki-67, cyclin D1, p27, and telomerase.  These 
investigations might be performed on biopsied tissue, bronchoalveolar lavage, 
and induced sputum.  Assessment of some of the markers may be performed on 
buccal smear as well.  Subjects may also be asked to undergo spiral CT at the 
beginning of the study with appropriate follow-up if abnormalities are 
present.

2.  Former smokers with oral leukoplakia might be randomized to 
chemopreventive treatment or placebo.  The primary endpoints of treatment 
would be the size and grade of leukoplakia, but investigators might also 
include assessments of the following: genetic damage such as LOH at 3p, 9p, 
and17p, p53, RAR-beta, Ki-67, cyclin D1, p27, EGFR, COX-2, apoptosis, and 
telomerase.  Assessments would be performed on biopsied normal and involved 
tissue as well as sputum and buccal smears.

3.  Former smokers with superficial bladder cancer who have undergone 
resection and remain at high risk might be randomized to chemopreventive 
intervention or placebo.  The primary endpoint would be recurrence of bladder 
cancer (superficial versus invasive), but investigators might also include 
assessments of the following in the resected superficial bladder cancer as 
well as histologically normal mucosa pre and post treatment:  microsatellite 
instability, p53, EGFR, COX-2, Ki-67, survivin, NMP-22, DNA ploidy, apoptosis, 
and telomerase.  Surveillance would also include marker analysis in urine and 
bladder washings.

4.  Former smokers who have been curatively treated after a stage I or II 
squamous cell carcinoma of the head and neck might be randomized to treatment 
with a chemopreventive agent or placebo.  Patients would be followed up for 
recurrence and development of a second tobacco-related malignancy, 
particularly in the aerodigestive tract.  This would be a pilot study in 100 
or so patients, not a definitive phase III study (for example, see Hong WK et 
al,. N Eng J, 323:795, 1990).  Analysis of the primary tumors for relevant 
markers could be incorporated (i.e., if an NSAID were used, primary tumors 
should be examined for COX-2 expression).  Surveillance could include spiral 
CT of the chest. 

The NCI will conduct a safety and protocol review of the studies prior to 
their initiation.  This review is required to assure that all safety, conduct, 
monitoring, and reporting conform to FDA IND guidelines.  The awardee 
institutions and Pricipal Investigators must agree to comply with the 
recommendations of the review.

SPECIAL REQUIREMENTS

General
 
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.  It is expected that 
each submission will describe plans for a clinical trial using a specified 
chemopreventive agent in a tobacco-damaged target organ in a well-delineated 
cohort of former smokers to meet the objectives of this RFA.  As described 
below, the recipients will have primary responsibility for the development and 
performance of the research activities.  However, there will be government 
involvement in clinical studies, 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, documentation of such 
assistance from the NCI should be obtained 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 Staff official responsible for contributing 
expert advice on the scientific design and conduct of the research

Terms and Conditions of Award 

A.  These special Terms of Award are in addition to and not in lieu of 
otherwise applicable OMB administrative guidelines, HHS Grant Administration 
Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant 
Administration policy statements.  (Part 92 applies when state and local 
governments are eligible to apply as a "domestic organization.")
 
The administrative and funding instrument used for this program is a 
cooperative agreement (U01), an "assistance" mechanism (rather than an 
"acquisition" mechanism) in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during performance of 
the activity. Under the cooperative agreement, the NIH 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 this concept, the dominant role and prime responsibility for 
the activity resides 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 DCP Project Scientist.
 
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.  Implementing the data collection method and strategy.

3.  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)  as 
simple as appropriate in order to encourage maximum participation of 
physicians and patients and to avoid unnecessary expense;  and 3)  
sufficiently staffed.

4.  Submitting interim progress reports (twice a year) to the NCI Program 
Director including summary data on protocol performance.  One of these 
progress reports will be the annual awardee noncompeting continuation progress 
report. 

5.  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 INDs 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 ultimately responsible for all aspects of investigational 
drug acquisition, formulation, distribution, etc., although the NCI will 
provide aid for drug acquisition, IND support, etc. if requested prior to 
submission of application.

6.  Cooperating in the reporting of the study findings.  The NCI will have 
access to and may periodically review all data generated under an award.  
Awardees 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 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 Staff responsibilities will include:

1.  Interacting with the Principal Investigator 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 teams, observation of field data collection and management 
techniques, quality control, fiscal review, and other relevant matters.  The 
NCI retains, as an option, the right to act as Sponsor for an IND filed to 
support the clinical research and conduct periodic external review of 
progress.

2.  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.

3.  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.  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).

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

     d.  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., compliance with the terms of 
the award and reporting requirements).

D.  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. This special arbitration 
procedure in no way affects the awardee's right to appeal an adverse action 
that is otherwise appealable in accordance with the PHS regulations at 42 CFR 
Part 50, Subpart D and HHS regulation at 45 CFR Part 16.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be 
a cooperative agreement (U01) an "assistance" mechanism (rather than an 
"acquisition" mechanism), in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during performance of 
the activity.  Under the cooperative agreement, the NIH 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. 
Details of the responsibilities, relationships and governance of the study to 
be funded under cooperative agreement(s) are discussed in this document under 
the section “Terms and Conditions of Award.” 
 
The total project period for applications submitted in response to the present 
RFA may not exceed 5 years.  The anticipated award date is April 1, 2002.    

Because the nature and scope of the research proposed in response to this RFA 
may vary, it is anticipated that the sizes of awards will vary also. 
 
Awards and 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 Division of Cancer Prevention, awards pursuant 
to this RFA are contingent upon the availability of funds for this purpose. 
 
In addition to the current RFA solicitation, it is anticipated that this RFA 
will be reissued two additional times at one year intervals.  Future issuances 
will have a greater focus on translational biomarker studies on specimens 
collected during the course of the clinical trials supported by this RFA and 
will include independent funding for these translational studies separately 
from funding of clinical trials.  If the Division of Cancer Prevention does 
not continue the program, awardees may submit grant applications through the 
usual investigator-initiated grants program.

FUNDS AVAILABLE

The NCI intends to commit approximately $4,000,000 in FY 2002 to fund 5 to 6 
new and/or competitive supplement grants to existing cooperative agreements in 
response to this RFA.  An applicant may request a project period of up to 5 
years and a budget for direct costs of up to $1,000,000 per year.  Because the 
nature and scope of the research proposed may vary, it is anticipated that the 
size of each award will also vary.  Although the financial plans of the NCI 
provides support for this program, awards pursuant to this RFA are contingent 
upon the availability of funds and the receipt of a sufficient number of 
meritorious applications. 

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 individuals,  
women, and persons with disabilities are encouraged.

INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Eva Szabo, M.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Blvd., Rm 2132, MSC 7341
Bethesda, MD  20892
Phone:  (301) 435-1595
FAX: (301) 480-3924
Email:  szaboe@mail.nih.gov

Direct inquiries regarding review issues to:

Ms. Toby Friedberg 
Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8109, MSC-8326
Rockville, MD 20852 (express courier)
Bethesda MD 20892-8329
Telephone (301) 496-3428
Fax: (301) 402-0275
Email: tf12w@nih.gov

Direct inquiries regarding fiscal matters to: 
 
Ms. Eileen Natoli
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd., EPS, Room 243 
Bethesda, MD  20892 
Telephone:  (301) 496-8791 
Fax:  (301) 496-8601
Email:  natolie@gab.nci.nih.gov

LETTER OF INTENT
 
Prospective applicants are asked to submit, by June 25, 2001, a Letter of 
Intent that includes a descriptive title of the proposed research, the name, 
address, telephone and fax numbers, and email address of the Principal 
Investigator, and the number and title of the RFA 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 a subsequent application, 
it allows NCI staff to estimate the potential review workload and plan the 
review.

The Letter of Intent is to be sent to Eva Szabo, M.D. listed under INQUIRIES 
by the Letter of Intent receipt date.

SCHEDULE
 
Letter of Intent Receipt:         June 25, 2001
Application Receipt Date:         July 30, 2001
Peer Review Date:                 October/November 2001
Review by NCAB Advisory Board:    February 2002
Earliest Anticipated Start Date:  March 1, 2002

APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  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, E-mail: grantsinfo@nih.gov.  For those applicants with internet 
access, the 398 kit may be found at 
http://grants.nih.gov/grants/funding/phs398/phs398.html.  

Additional Materials to Include in the Application
 
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 validation.

2.  Tobacco exposure must contribute to cancers arising in the organ system(s) 
under study.  A discussion reflecting this connection and justification for 
choice of target organ should be provided.   

3.  A discussion of the evaluation of surrogate endpoint biomarkers and their 
relevance to the test agent and target population should be provided.

4.  A rationale for the test agent should be provided, including relevant 
epidemiological and laboratory data.  Preclinical and clinical toxicology 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.  A rationale for selection of the target patient cohort (within the scope 
of this RFA, which requires studies to be performed in former smokers) and an 
estimate of the number of participants required to complete the studies should 
be provided.  The cohort should be defined, as appropriate, by age, sex, race, 
occupational or lifestyle risk, etc.  Accrual rates 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.

6.  Laboratory 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.

7.  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.

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

9.  All clinical trials supported or performed by NCI require some form of 
monitoring. The method and degree of monitoring should be commensurate with 
the degree of risk involved in participation and the size and complexity of 
the clinical trial.  Monitoring exists on a continuum from monitoring by the 
principal investigator/project manager or NCI program staff to a Data and 
Safety Monitoring Board (DSMB). These monitoring activities are distinct from 
the requirement for study review and approval by an Institutional Review Board 
(IRB). For details about the Policy of the NCI for Data Safety Monitoring of 
Clinical Trials see http://deainfo.nci.nih.gov/grantspolicies/   For phase I 
and II clinical trials, investigators must submit a general description of the 
data and safety monitoring plan as part of the research application.  See NIH 
Guide Notice on “Further Guidance on a Data and Safety Monitoring for Phase I 
and II Trials” for additional information: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application. Type the RFA number 
on the label. Failure to use this label could result in delayed processing of 
the application such that it may not reach the review committee in time for 
review. In addition, the RFA title and number must be typed on line 2 of the 
face page of the application form and the YES box must be marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change. Please note this is in pdf format.
 
Submit a signed, typewritten original of the application, including the 
Checklist, and three signed photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive
Room 1040 - MSC 7710
Bethesda, MD  20892-7710
(20817 for express service)
 
At the time of submission, two additional copies of the application must also 
be sent to:

Ms. Toby Friedberg 
Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8109, MSC-8326 
Rockville, MD 20852 (express courier)
Bethesda, MD 20892-8329

Applications must be received by July 30, 2001.  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 announcement 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 a 
substantial revision of an application already reviewed, but such an 
application must include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by the National Cancer Institute.  Incomplete and/or non-
responsive applications will be returned to the applicant without further 
consideration.  

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the Division of Extramural Activities of the National Cancer Institute in 
accordance with the review criteria stated below.  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 the applications under review, will be 
discussed assigned a priority score, and receive a second level review by the 
National Cancer Advisory Board.

Review Criteria

The five criteria to be used in the evaluation of grant applications are 
listed below.
 
The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  The 
reviewers will comment on the following aspects of the application in their 
written critiques in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered by the reviewers in assigning the 
overall score weighting them as appropriate for each application.  Note that 
the application does not need to be strong in all categories to be judged 
likely to have a major scientific impact and thus deserve a high priority 
score.  For example, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a field forward.
 
1.  Significance.  Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?

2.  Approach.  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

3.  Innovation.  Does the project employ novel concepts, approaches, or 
method?  Are the aims original and innovative? Does the project challenge 
existing paradigms or develop new methodologies or technologies?
 
4.  Investigator.  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the Principal Investigator and other researchers (if any)?  Is there 
adequate commitment (percent effort) on the part of the Principal Investigator 
to the proposed research?
 
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?  
Are there adequate patient numbers to meet accrual goals?
 
The initial review group will also examine: the appropriateness of proposed 
project budget and duration; the adequacy of plans to include both genders and 
minorities and their subgroups as appropriate for the scientific goals of the 
research and plans for the recruitment and retention of subjects; the adequacy 
of plans for including children as appropriate for the scientific goals of the 
research, or justification for exclusion; the provisions for the protection of 
human subjects; and the safety of the research environment.

AWARD CRITERIA

Applications recommended by the National Cancer Advisory Board will be 
considered for award based upon (a) scientific and technical merit; (b) 
program balance, including in this instance, sufficient compatibility of 
features to make a successful clinical research program a reasonable 
likelihood; and (c) availability of funds.

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 sub- populations 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 indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000  
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups, if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are clear and compelling scientific and ethical reasons not 
to include them.  This policy applies to all initial (Type 1) applications 
submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
“NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects” that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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

REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS

All investigators proposing research involving human subjects should read the 
policy that was published in the NIH Guide for Grants an Contracts, June 5, 
2000 (Revised August 25, 2000), and is available at the following URL address 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

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

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas. This RFA, Chemoprevention of Tobacco-
Related Cancers in Former Smokers:  Clinical Studies, is related to priority 
area of tobacco use.  Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/.
 
AUTHORITY AND REGULATIONS

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

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


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