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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