INNOVATIVE TOXICOLOGY MODELS FOR DRUG EVALUATION:  EXPLORATORY/DEVELOPMENTAL 
GRANTS (R21, R33) AND PHASED INNOVATION AWARD (R21/R33)

Release Date:  October 25, 2000

PA NUMBER:  PAR-01-003

National Cancer Institute

Letter of Intent Receipt Dates:  December 7, 2000 and October 10, 2001
Application Receipt Dates:       January 11, 2001 and November 14, 2001

THE PA INCLUDES MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST 
BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. THIS PA DOES NOT 
USE THE MODULAR GRANT CONCEPT.

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 as stated 
in its "Bypass Budget" (http://2001.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.  Developments in genomics and proteomics will 
provide new approaches to evaluate quickly and effectively the expected large 
numbers of new agents. 

This Program Announcement (PA) encourages the development, standardization, 
and validation of new and innovative assays which determine or predict 
specific organ toxicities (e.g., cardiotoxicity, gastrointestinal toxicity, 
hepatotoxicity, nephrotoxicity, ototoxicity, bladder toxicity, neurotoxicity, 
pulmonary toxicity, and endocrine toxicity, including pancreatic beta cell 
toxicity) of potential cancer therapeutic agents.  Agents that have been 
evaluated in both animals and man can be utilized retrospectively to validate 
the utility, sensitivity, and reproducibility of the assay and to determine if 
other factors such as agent stability, protein binding, or metabolic 
activation are important parameters for interpretation and validation of the 
assay.

Through a separate PA, PAR-01-004 
(http://grants.nih.gov/grants/guide/pa-files/PAR-01-004.html), 
the NCI is inviting applications for SBIR and STTR 
support, focusing on the same research areas as described in the RESEARCH 
OBJECTIVES section of this solicitation.  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 
award 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.htm

This solicitation will utilize the R21, R33, and the R21/R33 combined Phased 
Innovation Award mechanisms.  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 of feasibility phase to development phase.
o  Flexible budgets.
o  Flexible staging of feasibility and development phases.

The use of the multiple 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 there is little or no preliminary data 
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 which require 
feasibility demonstration, and the aims and milestones of the R21 are 
sufficiently predictable to consider the extended R33 phase.

This PA will expire on November 15, 2001.  NIH Grants policies apply to these 
awards.

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 
for cancer therapy and prevention.  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, array technology for expression of 
thousands of genes as well as computer-assisted evaluation of data are 
available.  New technologies in chemistry which 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 hundreds and maybe 
thousands of agents which 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 
humans.  It is reasonable to consider that new technological advances which 
lead to discovery of the new agents could likewise be exploited to expedite 
the development and decision process.

Investigations focusing on the hazards of potential cancer or AIDS 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).  
Procedures to obtain such information for IND filing have significant 
limitations in aspects such as 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 class 
of compounds in a species prior to selection of the best developmental 
candidate or to decide which of a multitude of "hits" identified from 
screening models should be brought to clinical evaluation.  Another concern is 
the lack of information gained from these toxicological studies in regard to 
molecular or mechanistic 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.  For example, bacterial strains and transgenic mice have been 
engineered to detect mutational activities of agents.  "Toxicogenomics", e.g., 
analysis of the gene transcription profile in a cell or organ following toxic 
agent administration [Molecular Carcinogenesis 24:153-159 (1999)] is under 
development using a variety of approaches, including DNA arrays.  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 goal of this PA is the discovery, development and validation of new assays 
and procedures to determine quickly and cheaply toxicological profiles of 
potential cancer 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, 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, 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, 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.

The overall objective of this PA is to provide a flexible funding mechanism to 
support the research activities required to develop and validate innovative 
toxicology assays.

MECHANISM OF SUPPORT

Support for this program will be through the National Institutes of Health 
(NIH) Exploratory/Developmental Research Grant (R21),  the 
Exploratory/Developmental Research Grant Phase 2 (R33) and the Phased 
Innovation Award (R21/R33 combined).  The R33 is a newly established NIH grant 
mechanism to provide a second phase for the support of innovative exploratory 
and development research initiated under the R21 mechanism.  

Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  Except as otherwise stated in 
this PA, awards will be administered under NIH grants policy as stated in the 
NIH Grants Policy Statement, NIH Publication No. 99-8, October 1998.

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, either as a single application or as part of a combined R21/R33 
application, may not exceed $100,000 direct costs per year except to 
accommodate Facility and Administrative (F&A) 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.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and 
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 
investigators.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.  Applicants are encouraged to check the 
website, http://dtp.nci.nih.gov/, for additional information.
 
Direct inquiries regarding programmatic issues to:

Adaline C. Smith, Ph.D., D.A.B.T.
National Cancer Institute
Division of Cancer Treatment and Diagnosis
Toxicology and Pharmacology Branch
6116 Executive Blvd., Room 5113, MSC 7458
Bethesda, MD 20892-7458
Telephone:  (301) 496-8777
FAX: (301) 480-4836
Email: smithad@mail.nih.gov

Direct inquiries regarding fiscal matters to:

Sara Stone
National Cancer Institute
Grants Administration Branch
6120 Executive Boulevard, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-9927
FAX:  (301) 496-8601
Email:  stones@gab.nci.nih.gov

Direct inquiries regarding review matters to:

Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Telephone:    (301) 496-3428
FAX:    (301) 402-0275

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent by the dates 
listed on the first page of this announcement that includes a descriptive 
title of the proposed research, the name, address, and telephone number of the 
Principal Investigator, the identities of other key personnel and 
participating institutions, and the number and title of the PA in response to 
which the application may be submitted.  Although a letter of intent is not 
required, is not binding, and does not enter into the review of a subsequent 
application, the information that it contains allows NCI staff to discuss 
potential problems or concerns with the applicant as well as estimate the 
potential review workload and plan the review.  

The letter of intent is to be sent to Dr. Adaline C. Smith at the address 
listed under INQUIRIES.

APPLICATION PROCEDURES

1.  SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION 
AWARD APPLICATION:

Applications are to be submitted on the grant application form PHS 398 (rev. 
4/98) and prepared according to the instructions provided unless specified 
otherwise within this SECTION.  Application kits are available at most 
institutional offices of sponsored research and may be obtained from the 
Division of Extramural Outreach and Information Resources, 6701 Rockledge 
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email:  
grantsinfo@nih.gov.  For applicants with internet access, the 398 kit may be 
found at: http://grants.nih.gov/grants/forms.htm.

R21/R33 applications must include the specific aims and clear measurable goals 
(milestones)  that would demonstrate feasibility and 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 specific aims.  It should be clear how the specific aims of 
the R33 continue and expand the R21 study. A discussion of the milestones 
relative to the progress of the R21 phase, as well as the implications of 
successful completion of the milestones for the R33 phase, should be included. 
See Research Plan, item d, listed below for a further discussion of 
milestones.

R21/R33 combined applications should 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, an 
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 specific goals and feasibility milestones 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 F&A costs to subcontracts to the project.  
Insert the first year of support in item 7a. 

Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:

For the R21 phase of the combined R21/R33 application, direct costs requested 
for the proposed period may not exceed $200,000 for two years of support.  The 
statement in item 7a above pertaining to subcontract costs also applies here. 
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) with R21 
and R33 periods listed separately.  All budgets should include a written 
justification for each item requested.

4.  Research Plan (Page 15 in PHS 398 Instructions)

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. 

Item b: Background and significance

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 which 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 in the PHS 398 booklet 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, and the page number of the milestones 
section should be listed.  This 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.

2. SPECIFIC INSTRUCTIONS FOR SUBMISSION OF THE R21 APPLICATION WHEN SUBMITTED 
WITHOUT THE R33 PHASE:

Applications for R21 grants are to be submitted on the grant application form 
PHS 398 (rev. 4/98) and prepared according to instructions provided for R21 
applications in the previous section except that milestones and discussion of 
the implication of the milestones to an R33 phase are not required.  
Application kits are available at most institutional offices of sponsored 
research and may be obtained from the Division of Extramural Outreach and 
Information Resources, 6701 Rockledge Dr. MSC 7910, Bethesda, MD 20892-7910, 
telephone: 301/435-0714, email: grantsinfo@nih.gov.  For applicants with 
internet access, the 398 kit may be found at: 
http://grants.nih.gov/grants/forms.htm.

1.  Face page of the application:

Item 2.  Check the box marked "YES" and type the number of this PA.  Also 
indicate that the application is for an R21.

3.  SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN 
SUBMITTED WITHOUT THE R21 PHASE.

Applications for R33 grants are to be submitted on the grant application for 
PHS 398 (rev. 4/98) and prepared according to the instructions provided unless 
specified otherwise within items 1-5 below.  Application kits are available at 
most institutional offices of sponsored research and may be obtained from the 
Division of Extramural Outreach and Information Resources, 6701 Rockledge Dr. 
MSC 7910, Bethesda, MD 20892-7910, telephone: 301/435-0714, email:    
grantsinfo@nih.gov.  For applicants with internet access, the 398 kit may be 
found at: http://grants.nih.gov/grants/forms.htm.

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 written 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, 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.

FOR ALL APPLICATIONS

A signed, typewritten original of the application, including the checklist, 
and three signed, exact, single-sided photocopies, should be submitted 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:

Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275

Applications must be received by the receipt dates listed at the beginning of 
this PA.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the CSR for completeness and by 
NCI program staff for adherence to the guidelines. Applications not adhering 
to application instructions described above 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 NCI, Division of Extramural Activities in accordance 
with the review criteria stated below.  As part of the initial merit review, 
all applicants will receive a written critique and may undergo a process in 
which only those applications deemed to have the highest scientific merit, 
generally the top half of the applications, will be discussed, assigned a 
priority score, and receive a second level review by the 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.  
Within this framework, the specific goals of the PA are the discovery and 
validation of new and innovative assays which 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 investigator may propose to 
carry out important work that by its nature is not innovative but is essential 
for development of a valuable assay.

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?  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.  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 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 sufficient access to resources 
(equipment, facilities, etc.)?  Is there evidence of institutional support?

Additional Considerations

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.

The initial review group will also examine: the appropriateness of the 
proposed project budget and duration; the adequacy of plans to include both 
genders and minorities and their subgroups, and children as appropriate for 
the scientific goals of the research and plans for the recruitment and 
retention of subjects; the provisions for the protection of human and animal 
subjects; and the safety of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other recommended 
applications. The quality of the proposed project as determined by peer 
review, availability of funds, and program priority will be considered in 
making final funding decisions.

SCHEDULE

Letter of Intent Receipt Dates:   December 7, 2000 and October 10, 2001
Application Receipt Dates:        January 11, 2001 and November 14, 2001
NCAB Review Dates:                May 2001 and May  2002
Earliest Anticipated Award Date:  July 1, 2001 and July 1, 2002

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).
 
All investigators proposing research involving human subjects should read the 
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 are 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 also may obtain copies of the policy from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

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 PA, Innovative Toxicology Models 
for Drug Evaluation, is related to the priority area of cancer.  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.  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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