INNOVATIONS IN CANCER SAMPLE PREPARATION (SBIR/STTR) RELEASE DATE: January 7, 2004 RFA Number: RFA-CA-05-008 (This RFA has been reissued, see RFA-CA-06-007) (see NOT-CA-04-013) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Cancer Institute (NCI) (http://www.nci.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.393, 93.394, 93.395, 93.396 LETTER OF INTENT RECEIPT DATES: February 10, 2004; May 17, 2004; September 17, 2004. APPLICATION RECEIPT DATES: March 10, 2004; June 17, 2004; October 18, 2004. THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Project Period and Amount of Award o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirement o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations NOTICE: This Request for Application (RFA) must be read in conjunction with the current OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH, CENTERS FOR DISEASE CONTROL AND PREVENTION, and FOOD AND DRUG ADMINISTRATION FOR SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS. The solicitation (see http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf) contains information about the SBIR and STTR programs, regulations governing the programs, and instructional information for submission. All of the instructions within the SBIR/STTR 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; and o In certain cases, larger budgets and longer project periods than statutory guidelines. PURPOSE OF THIS RFA This RFA will utilize the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms, but will be run in parallel with a RFA of identical scientific scope (CA-05-004, http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-004.html) that will utilize the exploratory/developmental research Phase I (R21) mechanism, the exploratory/developmental research Phase II (R33) mechanism, and the phased innovation (R21/R33) mechanisms. The National Cancer Institute (NCI) invites applications for research projects involving the development and significant enhancement or adaptation of sample preparation methodologies and technologies, the development of assays to assess sample quality, and studies designed to elucidate the criteria by which to judge sample quality. The outcome will be products and methods designed to optimize sample utility. Samples may originate from residual material not necessary for patient care or from cell lines, model organisms, or other sources relevant to cancer research. The development of new and/or improved cancer sample preparation methodologies and technologies, the development of assays to assess sample quality, and studies to elucidate the criteria needed to judge sample quality cover a wide range of project sizes and innovation levels. This RFA will allow the submission of applications involving Phase I, Phase II, and Fast- Track mechanisms. Phase I (R41 or R43) applicants may propose small, highly innovative feasibility studies or small, short-term exploratory studies to meet one of the RFA goals. Fast-Track applicants should propose projects that require a small feasibility study followed by a well-defined development plan. Successful completion of the Phase I feasibility study and the resulting transition to Phase II will be judged by NCI staff according to Fast-Track review criteria. Projects for which feasibility has already been established through the award of a Phase I grant (through this or another relevant RFA) may be proposed as Phase II (R42 or R44) applications. Feasibility means that some preliminary experiments have been performed and that sufficient technical data exist to support proof of principle of the technology/hypothesis. This initiative is part of a broader technology development program within the NCI. That program underscores the desire of NCI to develop and integrate novel technologies focused on the molecular analysis of cancers and their micro-environment in support of cancer research, diagnosis, and treatment. In the research continuum of discovery, development, and delivery, this program thus emphasizes the link between development and delivery. This specific initiative aims to foster the development of sample preparation techniques and methodologies that are essential for effective research, technology development, and validation that will eventually lead to clinical applications. This RFA capitalizes on both the success and intent of the original NCI- sponsored Innovative Molecular Analysis Technologies (IMAT) program in bringing together a multi-disciplinary group of scientists and engineers to work on cancer and the expansion of interest in technology development across the NCI and other NIH institutes and centers. This continuation of the IMAT program consists of the following three initiatives: Innovative Technologies for the Molecular Analysis of Cancer; Innovations in Cancer Sample Preparation; and Application of Emerging Technologies for Cancer Research. This RFA is designed to support research focused on sample preparation methods. Projects focused on the development of novel technologies may be most suitable for RFA (CA-05-006), Innovative Technologies for the Molecular Analysis of Cancer SBIR/STTR (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-006.html). Projects focused on evaluating emerging technologies that are ready for initial clinical or biological application in cancer research may be most suitable for RFA (CA-05-007), Application of Emerging Technologies for Cancer Research SBIR/STTR (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-007.html) (see MECHANISM OF SUPPORT). RESEARCH OBJECTIVES Background High quality sample preparations are the foundation for effective technology validation as well as for meaningful biological and clinical research. Sample preparation covers the spectrum from preparation of molecules to cells to tissues. Preparation of the highest quality samples can be hampered by technical issues, lack of standards by which to judge quality, and lack of standard practices. Sample preparation methods vary. Researchers often develop sample preparation methodologies in an ad hoc fashion as part of other projects. This lack of information and standardization affects the quality and comparability of data across all fields of cancer research and across all technological platforms. Objectives and Scope Sample preparation methods and technologies may be developed for sample collection, processing, isolation, storage, purification, preservation, and, in the case of stored tissues, reversal of adverse events resulting from storage and preservation. Methods may be developed for preparation of molecules, fluids, tissues, or any other samples necessary for cancer research. Researchers may propose to develop methods to isolate cells or sub-cellular components, such as classes of molecules, organelles, or sub- cellular structures. They may propose to isolate specific classes of molecules, such as membrane-bound proteins. They may also propose studies to determine the effects of collecting, processing, and storage on molecular components of interest in stored specimens. The goal is to develop products and methodologies that maximize the quality and utility of samples for research and, in the case of human specimens, maximize the quality of the samples for research and clinical needs without compromising patient care. Sample preparation methods may impact the results or interpretation of biological studies. Investigators may apply different methods of sample preparation using the same measurement technology. In many cases of measuring biological response, no gold standard exists by which to compare research results obtained from the different sample preparation methods. There is a need for methods to assess the quality of samples prepared using different methodologies. This RFA will support methods to assess sample quality and studies that elucidate the criteria needed to judge sample quality under different conditions. This RFA will also support the development of technologies to make these assessments, such as the development of sample reference materials that can be used to calibrate the effectiveness of new fixatives or new detection methodologies. It is expected that many investigators who developed successful cancer sample preparation techniques under previous IMAT initiatives or under the new RFA (Innovative Technologies for Molecular Analysis of Cancer, RFA (CA-05-006) will propose projects for this RFA. However, this RFA is not limited to techniques developed under the IMAT program. Investigators are encouraged to use any sample preparation methodologies or techniques relevant to cancer. For all projects proposed, it will be important to substantiate the ultimate value of the innovation for analyzing samples, optimizing analysis, and/or evaluating sample quality for the purpose of research and eventually clinical applications. Also of importance is the potential for ultimately transferring knowledge, technologies, and/or methodologies to other laboratories or the clinic. In the case of technologies intended for use on clinical specimens or in patients, applications from or collaborations with investigators involved in the clinical research of cancer are encouraged. MECHANISMS OF SUPPORT This RFA uses the SBIR and STTR mechanisms, which are set-aside programs. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Future unsolicited, competing-continuation applications based on this project will compete with all SBIR/STTR applications and will be reviewed according to the customary peer review procedures. The anticipated award date is approximately nine months from the respective receipt date. This RFA uses just-in-time concepts. It also uses the modular budgeting format. Specifically, if you are submitting an application budget of $100,000 total costs (direct, F&A, and fee) or less, use the modular budget format and instructions as described in the current SBIR/STTR Omnibus Solicitation. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://odoerdb2-1.od.nih.gov/gmac/nihgps_2003/index.htm. Except as otherwise stated in this RFA, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, December 2003, available at. http://odoerdb2-1.od.nih.gov/gmac/nihgps_2003/index.htm. Applications may 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 SBIR/STTR Omnibus Solicitation. The Phase II application must be a logical extension of previously funded Phase I SBIR/STTR research but not necessarily a Phase I project supported in response to this RFA. Fast Track applications will benefit from expedited evaluation of progress following the Phase I feasibility study for transition to Phase II funding for expanded developmental work. The Phase I portion of the Fast-Track application must contain well-defined quantitative milestones that will be used to judge the success of the proposed research, as well as a credible plan for the pilot application of the proposed technology in Phase II. PROJECT PERIOD AND AMOUNT OF AWARD The SBIR/STTR Omnibus Solicitation indicates the statutory guidelines of funding support and project duration periods for SBIR and STTR Phase I and Phase II awards. Under this RFA, an applicant may request a project period of up to 2 years for Phase I, up to 3 years for Phase II, and up to 4 years for a combined Phase I/Phase II Fast-Track, of which the Phase I portion may be no more than 2 years. An applicant may request a budget for total costs of up to $100,000 per year for Phase I and the Phase I portion of Fast-Track applications. . Phase I budgets can exceed this cap to accommodate indirect costs to subcontracts to the project, but funds for such may not be rebudgeted. Budgets for Phase II and the Phase II portion of Fast-Track grant applications should be appropriate for the science proposed. Because the nature and scope of the proposed research will vary from application to application, NCI will consider budgets that exceed the statutory guidelines. Total costs include direct costs, F&A, and fee/profit. FUNDS AVAILABLE The NCI intends to commit approximately $1,250,000 in FY 2005 to fund 8-12 Phase I, Phase II, and/or Fast-Track applications under the SBIR/STTR set- aside funding mechanism. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. ELIGIBLE INSTITUTIONS Eligibility requirements are described in the SBIR/STTR Omnibus Solicitation. Only small business concerns are eligible to submit SBIR/STTR applications. A small business concern is one that, on the date of award for both Phase I and Phase II agreements, meets ALL of the criteria as described in the current SBIR/STTR Omnibus Solicitation. Also, for eligibility clarification see the July 25, 2003 Notice in the NIH Guide for Grants and Contracts (NOT-OD-03-053) SMALL BUSINESS ELIGIBILITY REQUIREMENTS FOR APPLICANTS TO THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. 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. On an SBIR application, the principal investigator must have his/her primary employment (more than 50%) with the small business at the time of award and for the duration of the project. The PI on an STTR application may be employed with the small business concern or the participating non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant small business concern, which is characterized by an official relationship between the small business concern and that individual. SPECIAL REQUIREMENT An annual meeting of all investigators funded through this program will be held to share progress and research insights that may lead to further progress in the program. Applicants should request travel funds in their budgets for the principal investigator and one additional senior investigator to attend this annual meeting. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into four areas: scientific/research, intellectual property, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Gregory J. Downing, D.O., Ph.D. Office of Technology and Industrial Relations National Cancer Institute Building 31, Room 10A52 Bethesda, MD 20892 Rockville, MD 20652 (or express/courier service) Telephone: (301) 496-1550 FAX: (301) 496-7807 E-mail: downingg@mail.nih.gov o Direct your questions regarding intellectual property management plans to: Wendy Patterson, J.D. Technology Transfer Branch National Cancer Institute, NIH, DHHS 6120 Executive Boulevard, EPS Room 450 Bethesda, MD 20892 Rockville, MD 20652 (or express/courier service) Telephone: (301) 496-0477 E-mail: pattersw@mail.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 E-mail: ncirefof@dea.nci.nih.gov o Direct your questions about financial or grants management matters to: Ted Williams Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, EPS Room 243 Bethesda, MD 20892 (for regular mail) Rockville, MD 20852 (for express mail) Telephone: (301) 496-8785 FAX: (301) 496-8601 E-mail: tw133b@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 RFA. 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 at least one month prior to the targeted receipt date. The receipt dates and respective letter of intent dates are listed at the beginning of this document. The letter of intent should be sent to: Gregory J. Downing, D.O., Ph.D. Office of Technology and Industrial Relations National Cancer Institute Building 31, Room 10A52 Bethesda, MD 20892 Rockville, MD 20652 (or express/courier service) Telephone: (301) 496-1550 FAX: (301) 496-7807 E-mail: downingg@mail.nih.gov SUBMITTING AN APPLICATION The PHS 398 research grant application must be used for all SBIR/STTR Phase I, Phase II and Fast-Track applications (new and revised). Effective October 1, 2003, applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Prepare your application in accordance with the SBIR/STTR Omnibus Solicitation and the PHS 398. Helpful information for advice and preparation of the application can be obtained at: http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf. For further assistance contact GrantsInfo, Telephone: (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS Applications may be submitted for Phase I or Phase II support, or as a combined Phase I and II (Fast-Track). The Phase II proposal must be a logical extension of previously funded Phase I SBIR/STTR research but not necessarily a Phase I project supported in response to this initiative. The total duration for a Phase I/Phase II Fast-Track application cannot exceed 4 years. PHASE I: Demonstration of feasibility of the innovative approach. Research should be proposed with quantitative feasibility milestones that, when accomplished, would provide sufficient reason to continue the technology development in Phase II. It would be expected that technology feasibility would be established. If 2 years of support are requested, the goals for the first year should be clearly stated and not be simply a reiteration of specific aims. Support for the second year will be contingent upon Institute programmatic evaluation to ensure that investigators are reaching milestones and accomplishing the goals presented. PHASE II: Development of approach to a stage at which the sample preparation technology can be piloted for implementation. Extensive studies designed to validate the approach would be expected. Goals and milestones for each year of support should be clearly presented. Support for years 2 and 3, if requested, is dependent upon Institute programmatic review of progress and achievement of the proposed milestones. FAST-TRACK: Applications may be submitted for combined Phase I and Phase II, Fast-Track consideration as described in the OMNIBUS SOLICITATION. The Phase I part of Fast-Track applications must specify clear, quantitative milestones that should be achieved prior to Phase II funding. These must be presented in a section labeled Milestones at the end of the Research Plan. A discussion of the suitability of the proposed milestones for assessing success in Phase I, and a discussion of the implications of successful completion of these milestones for the proposed Phase II, should also be presented in this section. 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, a Phase I grantee 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 RFA pertaining to Phase I and Phase II applications also apply to FAST TRACK applications. All Phase II and Fast-Track applications must include a succinct Commercialization Plan (limited to 15 pages). The Commercialization Plan must be included as part of the Research Plan. Refer to Phase II grant application instructions for more specific details and instructions. See http://grants.nih.gov/grants/funding/sbirsttr2/PhaseII_SBIRSTTR.pdf or http://grants.nih.gov/grants/funding/sbirsttr2/PhaseII_SBIRSTTR.doc. 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. INTELLECTUAL PROPERTY MANAGEMENT PLAN: Certain research plans will require collaboration and coordination between investigators at different institutions, some of whom may not be NIH funding recipients and who may have pre-existing intellectual property (IP) obligations to third parties. It is anticipated that commercial embodiments of the results of such research may incorporate single inventions shared by several institutions, or multiple inventions each from a separate institution. Therefore, prior to funding, Phase II grant applicants must address how they will coordinate patent prosecution and licensing activities, if necessary to enable a licensee to access the bundle of IP needed to take a product to market on commercially viable terms. Suggested strategies include: (1) assigning IP rights to related inventions to an invention management firm; (2) designating one organization to take the lead on patenting and licensing related inventions: (3) agreeing in advance, that if multiple parties are to independently license related inventions, that the total of stacked royalties will not exceed a predetermined percentage rate. The technology transfer/IP management/licensing officer or equivalent at the principal investigator’s institution is to submit an intellectual property (IP) management plan, including at least those elements above. Alternatives to the suggested strategies, which accomplish the same goals, will be considered. IP management plans are a just-in-time requirement; it is not necessary to include the plan in the grant application, but plans will be required before a Phase II grant can be awarded. Applicants institutions should avoid exclusively licensing those inventions that are research tools unless either: (1) the field of use of the exclusive license is restricted to commercial use, or (2) the exclusive licensee will make the research tool available on reasonable terms. Applicants attention is directed to the NIH policy on the dissemination of biological research resources ( research tools ), which can be found at http://www.ott.nih.gov/policy/rt_guide_final.html. USING THE RFA LABEL: The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf. The title and number of this RFA must be typed on line 2 of the face page of the application and the YES box must be marked. 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, two additional copies of the application and all copies of the appendix material must be sent to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) Appendices should be comprised of single-sided, unbound materials, with separators between documents. 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 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. RECEIPT OF APPLICATIONS: Applications must be received on or before the application receipt dates listed in the heading of this RFA. If applications are received after those dates, they will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. This does not preclude the submission of a substantial revision of an unfunded version of an application already reviewed, but such an application must include an Introduction addressing the previous critique. An application through this RFA that is unsuccessful may be resubmitted as amended by the October receipt date. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NCI. Incomplete and non-responsive applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score; o Receive a written critique; o 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. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals within the context of the SBIR/STTR program. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment ALL SBIR/STTR APPLICATIONS 1. Significance: Does this 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 (e.g., instrumentation, software) for further discoveries? Will the technology have a competitive advantage over existing/alternate technologies that can meet the market needs? 2. 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? 3. Innovation: Does the project challenge existing paradigms or employ novel technologies, approaches or methodologies? Are the aims original and innovative? 4. Investigators: 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 subcontractors (if any)? Are the relationships of the key personnel to the small business and to other institutions appropriate for the work proposed? 5. Environment: Is there sufficient access to resources (e.g., equipment, facilities)? 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: MILESTONES: In the case of Phase I or Fast-Track applications, are appropriate and quantitative scientific milestones included that will show, when completed by the end of Phase I, whether or not the project has shown feasibility to pursue Phase II aims? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below.) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 in the sections on Federal Citations, below.) Human Subjects: 1. Protection of Human Subjects from Research Risks - for all studies involving human subjects. See instructions and "Guidance for Preparing the Human Subjects Research Section. If an exemption is claimed, is it appropriate for the work proposed? If no exemption is claimed, are the applicant's responses to the six required points appropriate? Are human subjects placed at risk by the proposed study? If so, are the risks reasonable in relation to the anticipated benefits to the subjects and others? Are the risks reasonable in relation to the importance of the knowledge that reasonably may be expected to be gained? Are the plans proposed for the protection of human subjects adequate? 2. Inclusion of Women Plan - for clinical research only. Does the applicant propose a plan for the inclusion of both genders that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? 3. Inclusion of Minorities Plan - for clinical research only. Does the applicant propose a plan for the inclusion of minorities that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? 4. Inclusion of Children Plan- for all studies involving human subjects. Does the applicant describe an acceptable plan in which the representation of children of all ages (under the age of 21) is scientifically appropriate and recruitment/retention is addressed realistically? If not, does the applicant provide an appropriate justification for their exclusion? 5. Data and Safety Monitoring Plan for clinical trials only. Does the applicant describe a Data and Safety Monitoring Plan that defines the general structure of the monitoring entity and mechanisms for reporting Adverse Events to the NIH and the IRB? CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. BIOHAZARDS: Is the use of materials or procedures that are potentially hazardous to research personnel and/or the environment proposed? Is the proposed protection adequate? ADDITIONAL REVIEW CONSIDERATIONS: The following items may be also be considered by reviewers but will not be included in the determination of scientific merit. SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget may be considered. For all applications, is the percent effort listed for the PI appropriate for the work proposed? On applications requesting up to $100,000 total costs, is the overall budget realistic and justified in terms of the aims and methods proposed? On applications requesting over $100,000 in total costs, is each budget category realistic and justified in terms of the aims and methods? PERIOD OF SUPPORT: The appropriateness of the requested period of support in relation to the proposed research. PHASE II APPLICATIONS: In addition to the above review criteria: 1. How well did the applicant demonstrate progress toward meeting the Phase I objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity? 2. Did the applicant submit a concise Commercialization Plan (formerly Product Development Plan) that adequately addresses the seven areas described in the Research Plan, item J? 3. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? AMENDED APPLICATIONS: In addition to the above criteria, the following criteria will be applied to revised applications. Are the responses to comments from the previous SRG review adequate? Are the improvements in the revised application appropriate? PHASE I/PHASE II FAST-TRACK APPLICATION REVIEW CRITERIA For Phase I/Phase II Fast-Track applications, the following criteria also will be applied: 1. Does the Phase I application specify clear, appropriate, and measurable goals (milestones) that should be achieved prior to initiating Phase II? 2. Did the applicant submit a concise Commercialization Plan (formerly Product Development Plan) that adequately addresses the seven areas described in the Research Plan, item J? 3. To what extent was the applicant able to obtain letters of interest, additional funding commitments, and/or resources from the private sector or non-SBIR/ STTR funding sources that would enhance the likelihood for commercialization? 4. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? Phase I and Phase II Fast-Track applications that satisfy all of the review criteria will receive a single rating. Failure to provide clear, measurable goals may be sufficient reason for the scientific review group to exclude the Phase II application from Fast-Track review. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Dates: February 10, 2004; May 17, 2004; September 17, 2004. Application Receipt Dates: March 10, 2004; June 17, 2004; October 18, 2004. Peer Review Dates: June 2004; November 2004; March 2005. Council Reviews: September 2004; February 2005; June 2005. Earliest Anticipated Start Dates: December 2004; April 2005; July 2005. AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. For FAST-TRACK applications, the Phase II portion may not be funded until a Phase I final report and other documents necessary for continuation have been received and assessed by program staff to determine whether the Phase I milestones have been successfully achieved. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. See http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of Data and Safety Monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety 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 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/. SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing). Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 "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 is 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://stemcells.nih.gov/index.asp 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, in the project description and elsewhere in the application as appropriate, 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 RFA 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as covered entities ) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the internet sites. 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 RFA 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 at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. 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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