Research (OER)
9000 Rockville Pike
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and Human Services (HHS)
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INNOVATIVE TOXICOLOGY MODELS FOR DRUG EVALUATION: EXPLORATORY/DEVELOPMENTAL
GRANTS AND PHASED INNOVATION AWARD
RELEASE DATE: March 12, 2002
PA NUMBER: PAR-02-074
EXPIRATION DATE: December 31, 2003, unless reissued.
National Cancer Institute (NCI)
(http://www.nci.nih.gov/)
Letter of Intent Receipt Dates: July 26, 2002; March 26, 2003;
November 25, 2003
Application Receipt Dates: August 23, 2002; April 23, 2003;
December 23 2003
This Program Announcement (PA) replaces PAR-01-003, which was published in the
NIH Guide on October 25, 2000.
THIS PA CONTAINS THE FOLLOWING INFORMATION
o Purpose of the PA
o Research Objectives
o Mechanisms of Support
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations
PURPOSE
Recent advances in cancer biology, molecular biology, combinatorial chemistry,
and screening technology provide unprecedented opportunities for discovery of
new agents for the treatment and prevention of cancer. Drug discovery can now
be focused on specific molecular or regulatory sites within the cancer cell.
The National Cancer Institute (NCI) considers exploitation of this knowledge
and technology for discovery of new cancer therapies a high priority
(http://plan.cancer.gov/). It is expected that research focused on discovery
and validation of new targets and screening design efforts to identify agents
that affect these targets will result in a multitude of new chemical and
biological agents with potential for clinical benefit. However, before such
agents can be tested and used widely in patients, safety and acceptable
toxicity to critical organs must be demonstrated. Current practices and
procedures for safety evaluations are costly and time consuming utilizing
large amounts of compound and animals. Thus, it is impractical to evaluate
large number of compounds, as well as analogs in a chemical series, identified
from new high throughput molecular target based screening models.
This PA encourages the development, standardization, and validation of new and
innovative assays which determine or predict specific organ toxicities (e.g.,
hematotoxicity, cardiotoxicity, gastrointestinal toxicity, hepatotoxicity,
nephrotoxicity, ototoxicity, bladder toxicity, neurotoxicity, pulmonary
toxicity, and endocrine toxicity, including pancreatic beta cell toxicity) as
well as new methodology for high throughput toxicity screening which involves
the use of molecular endpoints, computer modeling, proteomics and genomics.
The development of these toxicity assays and their incorporation early in the
development process would assist in the evaluation and prediction of human
sensitivity and allow for more cost efficient evaluations of numerous analogs
prior to selection of the ultimate drug development candidate.
Through a separate PA, PA-02-075 (http://grants.nih.gov/grants/guide/pa-
files/PA-02-075.html), the NCI is inviting applications for Small Business
Innovation Research (SBIR) and Small Business Technology Transfer (STTR)
support, focusing on the same research areas as described in the RESEARCH
OBJECTIVES section of this solicitation. This PA is co-sponsored by the
National Institute on Deafness and Other Communication Disorders, the National
Institute of Diabetes, Digestive and Kidney Diseases, the National Institute
on Drug Abuse, and the National Institute of Environmental Health Sciences.
Qualified applicants are strongly encouraged to consider responding to the
SBIR/STTR program announcement. SBIR and STTR application information is
available at the following website:
http://grants.nih.gov/grants/funding/sbir.htm.
Potential applicants who believe that they may be eligible for the SBIR/STTR
program should contact the NCI staff listed under INQUIRIES to discuss this
issue. In addition, potential applicants are encouraged to access the PHS
SBIR and STTR OMNIBUS SOLICITATION for information on eligibility requirements
at the following website:
http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf.
RESEARCH OBJECTIVES
Background
Recent advances in all branches of medical sciences provide new insight into
the underlying mechanisms in malignancy and suggest new targets and approaches
to therapy. Drug discovery can now be focused on targeting key regulatory
pathways or specific macromolecules relevant to cancer. For example, key
growth regulatory pathways and genes mutated in cancer cells are being
identified, and array technology for expression of thousands of genes as well
as computer-assisted evaluation of data are available. New technologies in
chemistry that allow facile synthesis of millions of new chemicals, and high
resolution structures of important target proteins are becoming available.
These advances taken together and coupled with high throughput screening allow
identification of large numbers of agents that could be seriously considered
for clinical evaluation. Translation of these new technological discoveries
and innovations into clinical benefit for the cancer patient through these
newly discovered agents is essential; however, the later stages in this drug
development process are lengthy and costly. Obviously new procedures are
necessary to decide which of the multitude of new agents should be tested in
animals and then in humans. In addition, these scientific advances can be
extremely useful for the development of new toxicity models with novel
endpoints to determine therapeutic agent toxicity.
Investigations focusing on the toxicity of potential cancer, AIDS or other
drugs or biologicals to healthy organs in intact experimental animals are the
final steps in the preclinical stages of new drug development. Data generated
from these studies on each new drug are evaluated in light of potential human
toxicity and form a major portion of the information required by the Food and
Drug Administration (FDA) for an Investigational New Drug (IND) application.
Preclinical toxicology studies are generally conducted in two animal species
with the following objectives: to define the Maximum Tolerated Dose (MTD),
Dose Limiting Toxicities (DLTs), schedule-dependency of toxicity,
reversibility of adverse effects, and a safe clinical Starting Dose (SD). The
animal studies required to obtain such information for an IND application have
significant limitations, both in terms of cost and time requirements as well
as prediction of problems to be encountered when agents are administered to
humans. For example, since animal studies are very expensive and time-
consuming, it is generally impractical to evaluate numerous analogs of a
chemical series or large numbers of possible candidates from a high throughput
screening program. Another concern is the lack of information gained from
animal toxicology studies in regard to molecular mechanisms for observed
toxicities. It cannot be determined if toxicities of new agents designed to
attack a key molecular target are related to actions of inhibition of that
target or to other unknown aspects of the drug's action in various organs.
New technology to improve toxicology approaches and define toxicity at the
molecular level are emerging, but as yet none has been validated and accepted
for common use. New technology will be highly valuable when combined with
other approaches to develop a total toxicological profile of specific organ
toxicity and molecular mechanisms responsible for this toxicity. Data
analysis software programs are being written to predict toxicological
endpoints. Individually, these activities may not be sufficient, but they may
be highly valuable when combined with other approaches to develop a total
toxicological profile of specific organ toxicity and molecular mechanisms
responsible for this toxicity.
Objectives and Scope
The goals of this PA are the discovery, development and validation of new
assays and procedures to determine quickly and cheaply toxicological profiles
of potential therapeutic drugs. It is expected that a molecular definition of
toxicity in the affected organ, tissue or cell would be a component of the
procedure. Approaches for new toxicology assays in response to this
initiative are broad and are determined by the creativity of the applicant.
Genetically modified animals or cell lines, various non-mammalian organisms,
in vitro assays utilizing primary mammalian cells (human cells are of
particular interest), tissue slices, isolated organs, sub-cellular fractions
or purified enzymes could be utilized for the model. Computer modeling
utilizing existing biological and toxicological data bases would be
appropriate. Genomic and proteomic technology could be exploited to profile
total gene activity or protein expression and thereby establish molecular
correlations with specific toxicities. Molecular endpoints to evaluate
toxicity and high throughput toxicity screening could be used to help decide
which agent of a chemical series should be pursued, to allow exploration of
toxicity at an earlier stage in drug development, to define the toxicity
profile of agents selected for clinical trial or to define the toxicity
profile of agents selected for clinical trial.
The NCI, through the Developmental Therapeutics Program:
http://dtp.nci.nih.gov/, on occasion utilizes its internal resources to foster
drug development. For this PA, drugs and toxicology data from previous drug
development sponsored by NCI may be made available to awardees. For
additional information contact Dr. Adaline C. Smith at the address listed
under INQUIRIES.
MECHANISMS OF SUPPORT
This PA will use the NIH R21, R33, and the combined R21/R33 Phased-Innovation
Award mechanisms. Applicants will be solely responsible for planning,
directing, and executing the proposed project.
For R21 submissions only, use the modular format (see
http://grants.nih.gov/grants/funding/modular/modular.htm). For combined
R21/R33 applications, and for R33 only applications, follow the instructions
for non-modular research applications.
For R21 submissions (when submitted without an R33 application), you may
request up to $100,000 direct costs (four budget modules) per year unless your
application includes consortium costs, in which case the limit is $125,000
direct costs (five budget modules) per year. Total project period for an R21
application may not exceed two years.
Specific features of the Phased-Innovation Award mechanism include:
o Single submission and evaluation of both the R21 and R33 as one
application.
o Expedited transition from feasibility phase to development phase.
o Flexible budgets.
o Flexible staging of feasibility and development phases.
The use of multiple award mechanisms will allow projects to be submitted at
various stages of development. The R21 will provide support for projects in
early stages of development where little or no preliminary data are available,
and it is difficult to predict success sufficiently to develop an extended R33
phase. The R33 will provide support for projects in which feasibility has
been demonstrated and thus are ready for extended development. The combined
R21/R33 will provide support for projects that require feasibility
demonstration and for which success of aims and milestones in the R21
component are sufficiently predictable to consider the extended R33 phase.
Under this PA, applicants can submit either an R21, a combined R21/R33, or an
R33 application alone if feasibility can be documented, as described in the
APPLICATION PROCEDURES section of this PA. The total project period for an
application submitted in response to this PA may not exceed the following
duration: R21, 2 years; R33, 3 years; combined R21/R33 application, 4 years.
In the combined application the R21 phase cannot extend beyond 2 years.
The R21 phase, as part of a combined R21/R33 application, may not exceed
$100,000 direct costs per year except to accommodate indirect costs to
subcontracts to the projects. Although the R33 application has no official
budgetary limit, applications requesting in excess of $500,000 dollars direct
costs in any single year of the grant period require prior approval before
submission. It is strongly recommended that applicants contact NCI staff at
an early stage of application development to convey critical information, such
as potentially large budget requests or to discuss programmatic adherence to
the guidelines of the proposed project. Refer to the INQUIRIES sections of
this PA for NCI staff contacts.
The combined R21/R33 application offers two advantages over the regular
application process:
1. Single submission and evaluation of both the R21 and the R33 as one
application.
2. Minimal or no funding gap between R21 and R33. The award of R33 funds
will be based on program priorities, on the availability of funds, and on
successful completion of negotiated scientific milestones as determined by NCI
staff in the context of peer review recommendations.
To be eligible for the Phased Innovation Award, the R21 phase must include
well defined, quantifiable milestones that will be used to judge the success
of the proposed research, as well as a credible plan for the development of
technology for the R33 phase. The Phased Innovation Award must have a section
labeled Milestones at the end of the Research Plan for the R21 phase. This
section must include well-defined quantifiable milestones for completion of
the R21 part of the application, and a discussion of the implications of
successful completion of these milestones for the proposed R33 study.
ELIGIBLE INSTITUTIONS
Application(s) may be submitted if the institution has any of the following
characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to develop
an application for support. Individuals from underrepresented racial and
ethnic groups as well as individuals with disabilities are always encouraged
to apply for NIH programs.
WHERE TO SEND INQUIRIES
We encourage your inquiries concerning this PA and welcome the opportunity
answer questions from potential applicants. Inquiries may fall into three
areas: scientific/research, review, and financial or grants management
issues. Applicants are also encouraged to check the website:
http://dtp.nci.nih.gov/ for additional information.
Direct inquiries regarding scientific/research issues to:
Adaline C. Smith, Ph.D., D.A.B.T.
National Cancer Institute
Division of Cancer Treatment and Diagnosis
Toxicology and Pharmacology Branch
6130 Executive Blvd, Room 8036, MSC 7451
Bethesda, MD 20892-7458
Rockville, MD 20852 (for courier service)
Telephone: (301) 496-8777
FAX: (301) 480-4836
Email: smithad@mail.nih.gov
Direct inquiries regarding fiscal matters to:
Barbara Fisher
National Cancer Institute
Grants Administration Branch
6120 Executive Boulevard, Room 243
Bethesda, MD 20892
Telephone: (301) 846-1015
FAX: (301) 846-5720
Email: fisherb@gab.nci.nih.gov
Direct inquiries regarding review matters to:
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncidearefof-r@mail.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes
the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this PA
Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows NCI staff to estimate the potential review workload and plan
the review.
The letter of intent is to be sent by the date listed at the beginning of this
document. The letter of intent should be sent to:
Adaline C. Smith, Ph.D., D.A.B.T.
National Cancer Institute
Division of Cancer Treatment and Diagnosis
Toxicology and Pharmacology Branch
6130 Executive Blvd, Room 8036, MSC 7451
Bethesda, MD 20892-7458
Rockville, MD 20852 (for courier service)
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). The PHS 398 is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 435-0714,
Email: GrantsInfo@nih.gov.
APPLICATION RECEIPT DATES: Applications submitted in response to this program
announcement will be accepted by the receipt dates listed on the first page of
this program announcement.
SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:
Applications requesting $500,000 or more in direct costs for any year must
include a cover letter identifying that Dr. Adaline Smith has agreed to accept
assignment of the application.
Applicants requesting more than $500,000 must carry out the following steps:
1) Contact Dr. Adaline Smith, listed in INQUIRIES or LETTER OF INTENT, at
least 6 weeks before submitting the application, i.e., as you are developing
plans for the study;
2) Obtain agreement from Dr. Adaline Smith that Dr. Smith will accept your
application for consideration for award; and,
3) In a cover letter sent with the application, mention that Dr. Adaline
Smith agreed to accept assignment of the application, and provide a copy of
the agreement.
This policy applies to all investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended or revised version
of these grant application types. Additional information on this policy is
available in the NIH Guide for Grants and Contracts, October 19, 2001 at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.
I. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION
AWARD APPLICATION:
R21/R33 applications must include specific aims that are relevant to each
phase as well as feasibility milestones that would justify transition to the
R33 phase. Applications must include a specific section labeled Milestones
following the Research Plan of the R21 phase. Milestones should be well
described, quantifiable and scientifically justified and not be simply a
restatement of the R21 specific aims. A discussion of the milestones relative
to demonstration of R21 progress, as well as the implications of successful
completion of the milestones for the R33 phase, should be included. This
section should be indicated in the Table of Contents. Applications lacking
this information, as determined by NCI program staff, will be returned to the
applicant without review. For funded applications, completion of the R21
milestones will elicit an NCI expedited review that will determine whether or
not the R33 should be awarded. The release of R33 funds will be based on
successful completion of negotiated scientific milestones, program priorities,
and on the availability of funds. The expedited review may result in
additional negotiations of award.
R21/R33 Phased-Innovation Award application must be submitted as one
application with one Face Page. Although it is submitted as a single
application, it should be clearly organized into two phases. To accomplish a
clear distinction between the two phases, applicants are directed to complete
Sections a-d of the Research Plan twice: one write-up of Sections a-d and
milestones for the R21 phase and Sections a-d again for the R33 phase. The
Form 398 Table of Contents should be modified to show Sections a-d for each
phase as well as the milestones. There is a page limit of 25 pages for the
composite a-d text. (i.e., Section a-d and milestones for the R21 and Section
a-d for the R33 phase must be contained within the 25 page limit.)
In preparing the R21/R33 application, investigators should consider the fact
that applications will be assigned a single priority score. In addition, as
discussed in the REVIEW CONSIDERATIONS section, the initial review panel has
the option of recommending only the R21 phase for support. However, a Phased-
Innovation Award application with an R33 Phase that is so deficient in merit
that it is not recommended for support will reflect upon the judgment of the
applicant. For these reasons, the clarity and completeness of the R21/R33
application with regard to feasibility milestones and specific goals for each
phase are critical. The presentation of milestones that are not sufficiently
scientifically rigorous to be valid for assessing progress in the R21 phase
will reflect upon the scientific judgment of the applicant.
1. FACE PAGE OF THE APPLICATION:
Item 2. Check the box marked "YES" and type the NUMBER AND TITLE of this PA.
Also, indicate that the application is submitted as an R21/R33.
Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT:
For the R21 phase of the combined R21/R33 application, direct costs are
limited to a maximum of $100,000 per year for up to two years and the award
may not be used to supplement an ongoing project. The requested budgets can
exceed this cap to accommodate indirect costs to subcontracts to the project.
Insert the total costs requested for first year of support in item 7a.
Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:
For the R21 phase, direct costs requested for the proposed period may not
exceed $200,000 for two years of support. The requested budgets can exceed
this cap to accommodate indirect costs to subcontracts to the project. Insert
sum of all years of requested support in item 8a.
2. PAGE 2 - DESCRIPTION:
As part of the description, identify concisely the technology or assay
methodology to be developed, its innovative nature, its relationship to
presently available capabilities, and its expected impact on toxicology
approaches.
3. BUDGET:
The application should provide a DETAILED BUDGET for Initial Budget Period
(form page 4), for each of the initial years of the R21 and R33 phases as well
as a budget for the entire proposed period of support (form page 5). Form
pages should indicate which years are R21 and R33. All budgets should include
a justification for each item requested.
4. RESEARCH PLAN:
Item a, Specific Aims:
The applicants must present specific aims that the applicant considers to be
scientifically appropriate for the relevant phases of the project. The
instructions in the PHS 398 booklet for this section of research grant
applications suggest that the applicant state the hypotheses to be tested.
Since the goal of this PA is to develop new methods for toxicological
analysis, hypothesis testing per se may not be the driving force in developing
such a proposal and, therefore, may not be applicable. Furthermore, for R21
grant applications, preliminary data are not required, although scientifically
sound preliminary data should be included when available.
Item b, Background and Significance:
The applicant should elaborate on the innovative nature of the proposed
research. Clarify how the assay or technology development proposed in this
project is a significant improvement over existing approaches. Explain the
potential of the proposed technology for having a broad impact on cancer
research and toxicological evaluations. Clearly identify how the project, if
successful, would result in new capabilities for toxicology analysis, the
immediacy of the opportunity, and how the proposed assays would differ from
existing approaches.
Item c, Preliminary studies/Progress report:
The R21 phase should provide current thinking or evidence in the field to
substantiate feasibility of the R21 phase. While preliminary data are not
required for the R21 phase, easily understandable data that provide relevant
information to aid review could be included when available. The R33 phase need
not repeat information already provided in the R21 phase.
Applicants are encouraged to include all information required for adequate
review evaluation. However, in the event that assays and technology are not
yet patent protected and the applicant does not wish to include complete
details, the application should at a minimum provide a demonstration (results)
of the capabilities of the proposed approach.
Item d, Research Design and Methods:
Instructions for PHS 398 should be followed. In addition, for the R21 phase
only, the following information must be included as a final section of Item d:
Applications must include a specific section labeled Milestones following the
Research Design and Methods of the R21 phase. Milestones should be well
described, quantifiable, and scientifically justified and not be simply a
restatement of the specific aims. A discussion of the milestones relative to
the success of the R21 phase, as well as implications of successful completion
of the milestones for the R33 phase should be provided. The page number of
the Milestones section should be listed in the Table of Contents.
Applications lacking this information, as determined by program staff, will be
returned to the applicant without review. Completion of the R21 milestones
will elicit an expedited review by NCI program staff that will determine
whether or not the R33 should be awarded. The release of R33 funds will be
based on successful completion of milestones, program priorities, and on
availability of funds. Expedited review may result in additional negotiations
of award.
II. SPECIFIC INSTRUCTIONS FOR SUBMISSION OF THE R21 APPLICATION WHEN SUBMITTED
WITHOUT THE R33 PHASE:
MODULAR GRANT APPLICATION:
R21 only applications must be submitted in a modular grant format. The total
project period for an R21 application may not exceed two years. The modular
grant format simplifies the preparation of the budget in these applications by
limiting the level of budgetary detail. Applicants request direct costs in
$25,000 modules. Section C of the research grant application instructions for
the PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step
guidance for preparing modular grants. Additional information on modular
grants is available at
http://grants.nih.gov/grants/funding/modular/modular.htm.
1. Face page of the application:
Item 2, Check the box marked "YES" and type the NUMBER AND TITLE of this PA.
Also indicate that the application is for an R21.
2. Page 2, Description:
As part of description, identify concisely the technology or assay methodology
to be developed, its innovative nature, its relationship to presently
available capabilities, and its expected impact on toxicology approaches.
3. Research Plan:
Item a, Specific Aims:
The applicant must present specific aims that the applicant considers to be
scientifically appropriate for the project. The instructions in the PHS 398
booklet for this section of research grant applications suggest that the
applicant state the hypothesis to be tested. Since the goal of this PA is to
develop new methods for toxicological analysis, hypothesis testing per se may
not be the driving force in developing such a proposal and, therefore, may not
be applicable. Furthermore, for R21 applications, preliminary data are not
required, although scientifically sound preliminary should be included when
available.
Item b, Background and Significance:
The applicant should elaborate of the innovative nature of the proposed
research. Clarify how the assay or technology development in this project is
a significant improvement over existing approaches. Explain the potential of
the proposed technology for having a broad impact on cancer research and
toxicological evaluations. Clearly identify how the project, if successful,
would result in new capabilities for toxicology analysis, the immediacy of the
opportunity, and how the proposed assays would differ from existing
approaches.
Item c, Preliminary studies/Progress report:
R21 applications should provide current thinking or evidence in the field to
support the project. While preliminary data are not required, easily
understandable data that provide relevant information to aid review could be
included when available.
Applicants are encouraged to include all information required for adequate
review evaluation. However, in the event that assays and technology are not
yet patent protected and the applicant does not wish to include complete
details, the application should at a minimum provide a demonstration (results)
of the capabilities of the proposed approach.
Item d, Research Design and Methods:
Instructions for PHS 398 should be followed.
III. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN
SUBMITTED WITHOUT THE R21 PHASE:
The PHS 398 research and grant application instructions and forms (rev.
5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be
used for application and will be accepted on the dates listed on the first
page of this PA. This version of the PHS 398 is available in an interactive,
searchable PDF format. The NIH will return applications that are not
submitted on the 5/2001 version. For further assistance contact GrantsInfo,
Telephone: 301/435-0714; Email: GrantInfor@nih.gov.
1. FACE PAGE OF THE APPLICATION:
Item 2. Check the box marked "YES" and type the TITLE AND NUMBER of this PA.
Also, indicate that the application is for an R33.
2. DESCRIPTION:
As part of the description, identify concisely the technology or assay
methodology to be developed, its innovative nature, its relationship to
presently available capabilities, and its expected impact on toxicology
approaches.
3. BUDGET:
The application should provide a DETAILED BUDGET for the Initial Budget Period
(form page 4) as well as a budget for the entire proposed period of support
(form page 5). Budget should include a justification of all items requested.
4. RESEARCH PLAN:
Item a, Specific Aims: Instructions in the PHS 398 booklet suggest that the
applicant state the hypothesis to be tested. Since the goal of this PA is to
develop new methods for toxicolgical analysis, hypothesis testing per se may
not be the driving force in developing such a proposal and therefore, may not
be applicable.
Item b, Background and Significance:
The applicant should elaborate on the innovative nature of the proposed
research. Clarify how the assay or technology development proposed in a
significant improvement over existing approaches. Explain the potential of
the proposed technology for having a broad impact on cancer research and
toxicological evaluations. Clearly identify how the project, if successful,
would result in new capabilities for toxicology analysis, the immediacy of the
opportunity, and how the proposed assays would differ from existing
approaches.
Item c, Preliminary studies/Progress Report:
R33 applications should clearly state how feasibility for the project has
already been demonstrated. It would be expected that this demonstration would
include significant data. This section must document that progress has been
achieved which is essentially equivalent to that expected from an R21 grant.
The application must clearly describe how the project is ready for scale up to
an expanded development stage.
Item d, Research Design and Methods:
Instructions for PHS 398 should be followed.
IV. FOR ALL APPLICATIONS:
Appendix: All instructions in the Form 398 kit apply.
SENDING AN APPLICATION TO THE NIH: 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
Bethesda, MD 20817 (for express/courier service)
To expedite the review process, at the time of submission, send two additional
copies of the application to:
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Applications must be received by the receipt dates listed at the beginning of
this PA.
APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE CENTER FOR SCIENTIFIC REVIEW
WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries
(i.e. FEDEX, UPS, DHL, etc.)
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html).
This change in practice is effective immediately.
This policy is similar to and consistent with the policy for applications
addressed to National Cancer Institute as published in the NIH Guide Notice
http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html.
APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE
WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries
(i.e., FEDEX, UPS, DHL, etc.) http://grants.nih.gov/grants/guide/notice-
files/NOT-CA-02-002.html. This change in practice is effective immediately.
This policy is similar to and consistent with the policy for applications
addressed to Centers for Scientific Review (CSR) as published in the NIH Guide
Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html
APPLICATION PROCESSING: Applications must be received by or mailed before the
receipt dates described at
http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not
accept any application in response to this PA that is essentially the same as
one currently pending initial review unless the applicant withdraws the
pending application. The CSR will not accept any application that is
essentially the same as one already reviewed. This does not preclude the
submission of a substantial revision of an application already reviewed, but
such application must include an Introduction addressing the previous
critique.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR and
for adherence to the guidelines of this PA by the NCI program staff.
Applications not adhering to the guidelines of this PA, and those applications
that are incomplete as determined by CSR or by NCI program staff, will be
returned to the applicant without review.
Applications that are complete and adhere to the guidelines of this PA will be
evaluated for scientific and technical merit by an appropriate peer review
group convened by the Division of Extramural Activities of the NCI in
accordance with the review criteria stated below.
As part of the initial merit review, all applications will:
o Receive a written critique
o Undergo a selection process in which only those applications deemed to have
the highest scientific merit, generally the top half of applications under
review, will be discussed and assigned a priority score
o In addition, applications receiving a priority score will undergo a second
level review by National Cancer Advisory Board.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. The
goals of NIH-supported research are to advance our understanding of biological
systems, improve the control of disease, and enhance health. Within this
framework, the specific goals of the PA are the discovery and validation of
new and innovative assays to predict specific toxicities of potential cancer
drugs. Assays developed under this PA would be expected to be effective for a
quick and cost effective determination of toxicity of specific compounds and,
importantly, to reduce the number of animals required. 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 important research effort may be proposed which does not present novel and
innovative technology but which is essential to move the field forward or
develop an innovative model. In the written comments, reviewers will be asked
to discuss the following aspects of the application in order to judge the
likelihood that the proposed research will have a substantial impact on the
pursuit of these goals:
o Significance
o Approach
o Milestones
o Innovation
o Investigator
o Environment
(1) SIGNIFICANCE:
Does the study address an important problem? If the aims of the application
are achieved, how do they advance scientific knowledge? What will be the
effect of these studies on the concepts or methods that drive this field?
What may be the anticipated societal benefit of the proposed activity? Will
the proposed toxicology methodology have a competitive advantage over existing
toxicology procedures?
(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? What is the time frame for developing the proposed technologies and
suitability of this time frame for meeting the scientific community's needs?
What are the throughput and cost effectiveness of the proposed toxicology
assays?
(3) MILESTONES:
How appropriate are the proposed milestones against which to evaluate the
demonstration of feasibility for transition to the R33 development phase?
(4) INNOVATION:
Does the project employ novel concepts, approaches or methods? Are the aims
original and innovative? Does the project challenge existing paradigms or
develop new methodologies or technologies?
(5) INVESTIGATOR:
Are the researchers appropriately trained and well suited to carry out this
work? Is the work proposed appropriate to the experience level of the
principal investigator and to that of other researchers, including consultants
and collaborators (if any)?
(6) 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?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the
application will also be reviewed with respect to the following:
PROTECTIONS:
The adequacy of the proposed protection for humans, animals, or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
INCLUSION:
The adequacy of plans to include subjects from both genders, racial and ethnic
groups (and subgroups), and children as appropriate for the scientific goals
of the research. Plans for the recruitment and retention of subjects will
also be evaluated. (See Inclusion Criteria included in the section on Federal
Citations, below)
BUDGET:
The reasonableness of the proposed budget and the requested period of support
in relation to the proposed research.
For the R21/R33 Application, the initial review group will evaluate the
specific goals for each phase and the feasibility milestones that would
justify expansion to the R33 phase. A single priority score will be assigned
to each scored application. As with any grant application, the initial review
group has the option of recommending support for a shorter duration than that
requested by the applicant and basing the final merit rating on the
recommended portion of the application. For the R21/R33 application, this may
result in a recommendation that only the R21 phase be supported, based on
concerns related to the application's specific goals and the feasibility
milestones justifying expansion to the R33 phase. Deletion of the R33 phase
by the review panel or presentation of inadequate milestones in the
application may affect the merit rating of the application.
AWARD CRITERIA
Applications submitted in response to a PA will compete for available funds
with all other recommended applications. The following will be considered in
making funding decisions:
o Scientific merit of the proposed project as determined by peer review
o Availability of funds
o Relevance to program priorities
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Dates: July 26, 2002; March 26, 2003;
November 25, 2003
Application Receipt Dates: August 23, 2002; April 23, 2003;
December 23, 2003
NCAB Review Dates: February, 2003; September, 2003;
May, 2004
Earliest Anticipated Award Date: April, 2003; December, 2003;
September 2004
REQUIRED FEDERAL CITATIONS
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components
involving Phase I and II clinical trials must include provisions for
assessment of patient eligibility and status, rigorous data management,
quality assurance, and auditing procedures. In addition, it is NIH policy
that all clinical trials require data and safety monitoring, with the method
and degree of monitoring being commensurate with the risks (NIH Policy for
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998:
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Clinical trials supported or performed by NCI require special considerations.
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 or 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 for the NCI for Data and Safety
Monitoring of Clinical trials see:
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. 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. Information concerning essential elements of data
safety monitoring plans for clinical trials funded by the NCI is available:
http://www.cancer.gov/clinical_trials/
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a
clear and compelling 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 clinical research should read the AMENDMENT "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research - Amended, October, 2001," published in the NIH Guide for Grants and
Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are
available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm
. The amended policy incorporates: the use of an NIH definition of
clinical research; updated racial and ethnic categories in compliance with the
new OMB standards; clarification of language governing NIH-defined Phase III
clinical trials consistent with the new PHS Form 398; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a)
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
The NIH maintains a policy 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 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 is available at
http://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject participants for
all investigators submitting NIH proposals for research involving human
subjects. You will find this policy announcement in the NIH Guide for Grants
and Contracts Announcement, dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A
continuing education program in the protection of human participants in
research in now available online at: http://cme.nci.nih.gov/
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research
on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only
research using hESC lines that are registered in the NIH Human Embryonic Stem
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).
It is the responsibility of the applicant to provide the official NIH
identifier(s)for the hESC line(s)to be used in the proposed research.
Applications that do not provide this information will be returned without
review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a
project that is supported in whole or in part with Federal funds and (2) cited
publicly and officially by a Federal agency in support of an action that has
the force and effect of law (i.e., a regulation) may be accessed through FOIA.
It is important for applicants to understand the basic scope of this
amendment. NIH has provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public archive,
which can provide protections for the data and manage the distribution for an
indefinite period of time. If so, the application should include a
description of the archiving plan in the study design and include information
about this in the budget justification section of the application. In
addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.
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. Furthermore,
we caution reviewers 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 PA is
related to one or more of the priority areas. 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. 93.395, and is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.
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 described at http://grants.nih.gov/grants/policy/policy.htm
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and discourage the 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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