INNOVATIVE TOXICOLOGY MODELS: SBIR/STTR RELEASE DATE: March 12, 2002 PA NUMBER: PA-02-075 October 8, 2008 - This PA has been replaced by PA-09-006 (SBIR [R43/R44]) and PA-09-007 (STTR [R41/R42]) EXPIRATION DATE: December 31, 2003, unless reissued. National Cancer Institute (NCI) (http://www.nci.nih.gov/) National Institute on Deafness and Other Communication Disorders (http://www.nidcd.nih.gov/) National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov/) National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.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-01-004, 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 Mechanism(s) 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 diseases. Drug discovery can now be focused on specific molecular or regulatory sites within the diseased 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 the 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 using traditional methods. Similarly these scientific advances provide opportunities to develop new and innovative tests to determine the toxicity of environmental chemicals. The National Institute of Environmental Health Sciences (NIEHS) has been directed by Congress to develop and validate alternatives for acute and chronic toxicity testing that will reduce or eliminate the use of animals. In 2000 the NIEHS convened an international workshop on in vitro methods for assessing acute systemic toxicity. The results of this meeting can be found at http://iccvam.niehs.nih.gov/methods/invidocs/finalall.pdf. Recommendations include suggestions for research, development and validation efforts that would further advance the usefulness of in vitro methods especially those directed at specific organ toxicities. This PA encourages the development, standardization, and validation of new and innovative assays that 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 that 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 the selection of the ultimate drug development candidate. This PA must be read in conjunction with the current OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH for SMALL BUSINESS INNOVATION RESEARCH (SBIR) and SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS: http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf. All of the instructions within the OMNIBUS SOLICITATION apply with the following exceptions: o Special receipt dates o Initial review convened by the NCI, Division of Extramural Activities o Additional review considerations For this PA, the Modular Grant format will not be used. This PA will utilize the SBIR and STTR mechanisms, but will be run in parallel with a PA of identical scientific scope that will utilize the Exploratory/Developmental Grants mechanism, http://grants.nih.gov/grants/guide/pa-files/PAR-02-074.html. 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 either therapeutic agent or environmental chemical 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. The National Toxicology Program (NTP) is an interagency program located at NIEHS, whose mission is to evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology. Currently the NTP tests chemicals of environmental or occupational concern using study designs similar to that used in preclinical toxicology studies described above including 30 and 90 day toxicity studies, two year bioassay to determine the carcinogenic potential of chemicals, two generation studies to determine reproductive toxicity and in utero exposure to determine developmental toxicity. The goal of the NTP and NIEHS is in line with the goal of the NCI and the other NIH Institutes participating in this PA: to develop new and novel alternative toxicity tests that could replace or reduce the animal tests and in addition provide mechanistic information on the target environmental agent that would aid in intervention/prevention efforts. 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. In this regard, the NIEHS has recently established the National Center for Toxicogenomics (NCT) (http://www.niehs.nih.gov/nct/home.htm). One of the major goals of the NCT is to determine the usefulness of genomics data in the development of alternative toxicity tests. 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 and environmental agents. 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 or for which there is significant environmental exposure. Applicants should be aware of the activities of the Inter Agency Coordinating Committee for the Validation of Alternative Methods (ICCVAM), a part of the NTP: http://iccvam.niehs.nih.gov. ICCVAM has prepared documents and instructions relating to the validation and regulatory acceptance of alternative methods that will be helpful in writing the application and in proper validation of the methods/tests proposed. 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. Summary The overall objective of this PA is to provide a flexible funding mechanism within the SBIR and STTR programs with regard to budgets and time of funding to support the research activities required to develop and validate innovative toxicology assays by small businesses. MECHANISM OF SUPPORT Support for this PA is through the SBIR and STTR mechanisms that are set-aside programs. This PA is a one-time announcement that may be reissued. 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, March 2001, available at: http://grants.nih.gov/grants/policy/nihgps_2001/ Applications can be submitted for support as Phase I STTR (R41) or Phase I SBIR (R43) grants, Phase II STTR (R42) or Phase II SBIR (R44) grants, or the SBIR/STTR FAST-TRACK option as described in the OMNIBUS SOLICITATION. Phase II applications in response to this PA will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The Phase II application must be a logical extension of the Phase I research. Information on the FAST-TRACK process and the OMNIBUS SOLICITATION are available at: http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf. Hard copies are not available. ELIGIBLE INSTITUTIONS Eligibility requirements are described in the OMNIBUS SOLICITATION for SBIR/STTR grant applications. Any small business, independently owned by United States citizens or permanent resident aliens, and located in the United States may apply. The small business must be organized for-profit, cannot be dominant in its field of expertise, and must have its principal place of business in the United States. For both Phase I and Phase II, the R&D must be performed in its entirety in the United States. Including any affiliates, the company can be the employer of no more than 500 people. 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 to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about 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 20892-7451 Telephone: (301) 496-8777 FAX: (301) 480-4836 Email: smithad@mail.nih.gov James A. Crowell, Ph.D. National Cancer Institute Division of Cancer Prevention Chemopreventive Agent Development Research Group 6130 Executive Blvd., Room 2118 MSC 7322 Bethesda, MD 20892-7322 Telephone: (301) 594-0459 FAX: (301) 594-2943 Email: jcrowell@exchange.nih.gov Lynn E. Luethke, Ph.D. Program Director, Hearing National Institute on Deafness and Other Communication Disorders 6120 Executive Blvd, 400-C Bethesda, MD 20892 Telephone: (301) 402-3458 FAX: (301) 402-6251 Email: lynn_luethke@nih.gov Robert Star, M.D. Senior Scientific Advisor National Institute of Diabetes, Digestive and Kidney Diseases Building 31, Room 9A35 31 Center Drive MSC 2560 Bethesda, MD 20892-2560 Telephone: (301) 594-7715 FAX: (301) 496-2830 Email: robert_star@nih.gov David J. McCann, Ph.D. Chief, Medications Discovery & Toxicology Branch National Institute on Drug Abuse Division of Treatment Research & Development 6001 Executive Boulevard, Room 4123, MSC 9551 Bethesda, MD 20892-9551 Telephone: (301) 443-2999 FAX: (301) 443-2599 Email: dmccann@nih.gov Jerrold J. Heindel, Ph.D. Scientific Program Administrator Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O.Box 12233 Research Triangle Park, NC 27709 Fedex: 79 T.W. Alexander Drive 4401 Research Commons, 3rd Floor Phone: (919) 541-0781 Fax: (919) 541-5064 Email: heindelj@niehs.nih.gov o Direct your questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: ncidearefof@mail.nih.gov o Direct your questions about financial or grants management matters to: Mr. Shane Woodward National Cancer Institute Executive Plaza South, Room 243 6120 Executive Blvd, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-8649 FAX: (301) 496-8601 Email: woodwars@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 20892-7451 SUBMITTING AN APPLICATION The PHS 398 research grant application (rev. 5/2001) must be used. Instructions and forms are available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Refer to Chapter VI for specific instructions for SBIR and STTR applications. Applications will be accepted on the dates listed on the first page of this PA. This version of PHS 398 is available in an interactive, searchable PDF and HTML 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: GrantsInfo@nih.gov. 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. The SBIR/STTR OMNIBUS SOLICITATION is available electronically through the NIH, Office of Extramural Research Small Business Funding Opportunities web site: http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf. Application instructions are also available at this site. Helpful information for preparation of the application can be obtained at: http://grants.nih.gov/grants/grant_tips.htm THE TITLE AND NUMBER OF THIS PA MUST BE TYPED ON LINE 2 OF THE FACE PAGE OF THE APPLICATION. All instructions within the solicitation apply with the following exceptions: - special receipt dates - initial review convened by the NCI Division of Extramural Activities - additional review considerations Applications can be submitted for Phase I or Phase II support, or as a combined Phase I and II (FAST-TRACK). A Phase II application will be accepted only as continuation of a previously funded Phase I grant. The Phase II proposal must be a logical extension of the Phase I research but not necessarily a Phase I project supported in response to this initiative. The OMNIBUS SOLICITATION indicates the normal levels of support and period of time for SBIR and STTR Phase I and Phase II awards. However, some toxicology model discovery and validation projects are likely to require longer time periods and/or larger budgets to accomplish the proposed aims. Therefore, if adequately justified, budgets up to $250,000 total costs per year (direct costs, indirect costs, and profit/fee) and time periods up to 2 years for Phase I and $650,000 total costs per year (direct costs, indirect costs, and profit/fee) and up to 4 years for Phase II can be requested. For FAST-TRACK applications the total duration of Phase I plus Phase II cannot exceed 5 years. PHASE I: Demonstration of feasibility of the innovative approach. Research should be proposed to provide sufficient reason to continue the assay development in Phase II. It would be expected that assay methodology would be established. If two years of support are requested, the goals for the first year should be clearly stated and not simply a reiteration of specific aims. Support for the second year will be contingent upon Institute programmatic evaluation to ensure that investigators are accomplishing the goals presented. PHASE II: Development of approach to a stage at which the assay can be used for toxicology purposes. Extensive studies designed to validate the approach would be expected. Validation should include analysis of compounds with known organ toxicities and should follow the ICCVAM guidelines. Innovative aspects of the research necessary to complete the projects such as development of new in vivo models that may require "surrogate endpoints" should be clearly described. Goals and milestones for each year of support should be clearly presented. Support for years two to four, if requested, is dependent upon Institute programmatic review of progress and achievement of the proposed goals. For example, if a goal such as identification of a known toxicity is not achieved, the continuation years may not be supported. FAST TRACK: Applications may be submitted for combined Phase I and Phase II, FAST TRACK consideration as described in the OMNIBUS SOLICITATION. However, due to the complex nature of toxicological assay development, it is recommended that only well defined and more advanced projects be proposed for support through this mechanism. Phase I, FAST TRACK applications must specify clear, measurable milestones that should be achieved prior to Phase II funding. Failure to provide such information in the Phase I application and/or sufficient detail in the Phase II application may be sufficient reason for the peer review committee to exclude the Phase II from consideration. If so, the applicant may apply later for Phase II support. Such applications will be reviewed by an appropriate scientific review group convened by the NIH. Special provisions described in this PA pertaining to Phase I and Phase II also apply to FAST TRACK applications. An additional requirement of all Phase II and FAST TRACK applications is the Product Development Plan. The small business must submit a Product Development Plan (limited to ten pages) as an Appendix to the Phase II application addressing the four areas described in the instructions for PHS 398, Chapter VI, Section C. 9. j. Potential applicants are encouraged to contact program staff for guidance and to read the advice and information on the web sites. However, responsibility for planning, direction, and execution of the proposed research will be solely that of the applicant. The completed original application and three legible copies must be sent or delivered to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive Room 1040, MSC 7710 Bethesda, MD 20892-7710 (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 express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 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 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 listed at the top of the first page of this PA. 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 by CSR staff for completeness and by NCI or another participating Institute program staff for adherence to guidelines. Incomplete applications and applications not adhering to instructions described above will be returned to the applicant without further review. Applications that are complete and adhere to the guidelines of this PA will be evaluated for scientific and technical merit and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of this PA by an appropriate peer review group convened by the NCI, Division of Extramural Activities, in accordance with the peer review criteria listed 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 Those that receive a priority score undergo a second level review by the appropriate advisory council(s) of NCI, NIDCD, NIDDK, NIDA or NIEHS. REVIEW CRITERIA Review criteria are described in the OMNIBUS SOLICITATION and are as follows: 1. The soundness and technical merit of the proposed research. (Preliminary data are not required for Phase I proposals.) 2. The qualifications of the proposed Principal Investigator, supporting staff, and consultants. 3. The scientific, technical, or technological innovation of the proposed research. 4. The potential of the proposed research for commercial application or societal impact. 5. The appropriateness of the budget requested. 6. The adequacy and suitability of the facilities and research environment. 7. Where applicable, the adequacy of assurances detailing the proposed means for (a) safeguarding human or animal subjects and/or (b) protecting against or minimizing any adverse effect on the environment. For this PA the following points will also be considered during review. The goals of NIH-sponsored research are to advance our understanding of biological systems, improve the control of disease, and enhance health. Within this framework, the specific goals of this PA are the discovery and validation of new and innovative assays which predict specific toxicities of potential drugs and environmental agents. 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 decrease 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 the criteria will be addressed and considered 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 impact and thus deserve a high priority rating. For example, an important research project may be proposed which does not present novel and innovative technology but which is essential to develop an innovative model. SIGNIFICANCE. Does the study address an important problem? Does the proposed project have commercial potential to lead to a marketable product or process? What may be the anticipated commercial and societal benefits of the proposed activity? If the aims of the application are achieved, how will scientific knowledge be advanced? Does the proposal lead to enabling technologies (instrumentation, software, etc.) for further discoveries? Will the technology have a competitive advantage over existing/alternative technologies that can meet the market needs? APPROACH. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Is the proposed plan a sound approach for establishing technical and commercial feasibility? Does the applicant acknowledge potential problem areas and consider alternative strategies? Are the milestones and evaluation procedures appropriate? INNOVATION. Does the project challenge existing paradigms or employ novel technologies, approaches or methodologies? Are the aims original and innovative? INVESTIGATOR. Is the Principal Investigator capable of coordinating and managing the proposed SBIR/STTR? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers including consultants and sub-contractors (if any)? ENVIRONMENT. Is there sufficient access to resources (equipment, facilities, etc.)? Does the scientific and technological 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? For Phase II applications: In addition to the above criteria, to what degree was progress toward the Phase I objectives met and feasibility demonstrated in providing a solid foundation for the proposed Phase II activity? Is there a detailed validation plan? For Phase I/Phase II Fast Track applications, the following additional criteria will be applied: Does the Phase I specify clear, measurable goals (milestones) that should be achieved prior to initiating Phase II? Did the applicant submit a concise Product Development Plan that adequately addresses the four areas described in Section 9.j in the Instructions for the SBIR/STTR applications? To what extent was the applicant able to obtain letters of interest, additional funding commitment and/or resources from private sector or non-SBIR/STTR funding sources that would enhance the likelihood for commercialization? The initial review group will evaluate the specific goals for both the R43 and R44 phase. A single priority score will be assigned to each application. The initial review group has the option of recommending support for a shorter duration than that requested and basing the final merit rating on the recommended portion of the application. For FAST TRACK applications, this may result in a recommendation that only the R43 phase be supported. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 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, all 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. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended SBIR and STTR applications. Portions of the SBIR and STTR allotments will not be designated for this initiative. 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 FAST TRACK, Phase II applications may be funded following submission of the Phase I progress report and other documents necessary for continuation. Phase II applications will be selected for funding based on the initial priority score, grant Program staff"s assessment of the Phase I progress and determination that Phase I goals were achieved, the project"s potential for commercial success, and the availability of funds. 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 Council Review Dates: February, 2003, October, 2003, June, 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.ht m. 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. 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 Nos. 93.395, 93.847, 93.848, 93.849 and 93.115, 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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