PA-01-091: FLEXIBLE SYSTEM TO ADVANCE INNOVATIVE RESEARCH FOR CANCER DRUG DISCOVERY BY SMALL BUSINESSES (FLAIR)

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FLEXIBLE SYSTEM TO ADVANCE INNOVATIVE RESEARCH FOR CANCER DRUG DISCOVERY BY SMALL BUSINESSES (FLAIR) Release Date: May 7, 2001 (see replacement PAR-03-074) PA NUMBER: PA-01-091 National Cancer Institute Letter of Intent Receipt Dates: June 6, 2001, March 6, 2002, October 8, 2002 Application Receipt Dates: July 12, 2001, April 10, 2002, November 12, 2002 This Program Announcement (PA) replaces PAR-00-030, which was published in the NIH Guide, release date December 15, 1999. PURPOSE Discovery and development of new drugs and biologicals for cancer treatment, including gene therapy and drug delivery approaches, normally involve lengthy and costly projects. The multiple components of the overall process including discovery, efficacy testing, development of lead agents, toxicology and pharmacology, Investigational New Drug Application (IND) filing, and clinical evaluation, may require years and several million dollars. The small business community is an active participant in the cancer therapy discovery effort. Thus it is important that their innovative ideas be supported. The Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs were developed to support innovative research with a commercial intent by small businesses. This PA provides a flexible system within the SBIR and STTR programs to accommodate the special needs of the complex discovery and development process, at least partially, from basic discovery through proof of principle demonstration in clinical trials. It is hoped that this initiative will stimulate drug discovery research efforts in the small business community. This PA must be read in conjunction with the OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH, SMALL BUSINESS INNOVATION RESEARCH GRANT (SBIR) APPLICATIONS and SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS 2001. All of the instructions within the OMNIBUS SOLICITATION apply with the following exceptions: o Special receipt dates o Initial review convened by the Division of Extramural Activities, National Cancer Institute (NCI) o Additional review considerations o More flexible time and budget specifications o No modular format. Instructions for detailed budgets will be followed. This PA will expire on November 13, 2002, unless reissued. NIH Grants policies apply to these awards. RESEARCH OBJECTIVES Recent advances in all branches of medical sciences provide new insight into the underlying mechanisms in malignancy and suggest new targets and approaches for therapy. For example, key growth regulatory pathways and genes mutated in cancer cells are being identified, array technology for expression of thousands of genes as well as computer-assisted evaluation of data are available, new technologies in chemistry which allow facile synthesis of millions of new chemicals, and high resolution structures of important target proteins are becoming available. NCI has made approaches for drug discovery based on these directions a high priority: http://plan2002.cancer.gov/. Translation of these new discoveries and innovations into clinical benefit for the cancer patient is essential; however, the process is lengthy and costly. Following initial discovery and lead optimization, potential drugs must undergo a series of rigorous pre-clinical evaluations which may culminate in a clinical trial. The actual procedures for this process vary somewhat with each agent to be tested, and, with innovative approaches often required for new agents, an extensive research effort may be necessary for successful development and eventual commercialization. The objective of this PA is to provide a flexible funding mechanism with regard to budgets and time of award to support the research activities required to enable small businesses to bring their innovative efforts for drug discovery and development to clinical validation. Projects submitted in response to this PA should be focused on discovery and development of a specific agent or class of agents. Applications devoted to topics relating more generally to drug discovery such as technology and model development without direct relevance to development of a specific agent are not appropriate. Flexibility within the PA allows for projects to be presented at all stages of the drug discovery and development process. Projects will be evaluated on OVERALL innovation, strength of the drug discovery approach, and probability of clinical success, with less emphasis on the nature of the specific stage proposed in the application. This latter aspect is especially important if applications are focused on later stages of the drug discovery and evaluation process that may be more routine and often considered less innovative as stand-alone projects. MECHANISM OF SUPPORT Support for this PA is through the SBIR and STTR mechanisms which are set- aside programs. This PA is a one-time announcement which may be reissued. 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 proposal must be a logical extension of the Phase I research. Information on the FAST-TRACK process and the OMNIBUS SOLICITATION is available at http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf. ELIGIBILITY REQUIREMENTS Eligibility requirements are described in the OMNIBUS SOLICITATION. Any small business independently owned by United States citizens or permanent resident aliens and located in the United States may apply. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Frequently Asked Questions relating to this PA are available on the Developmental Therapeutics Program website: http://dtp.nci.nih.gov/, go to Grants and Contracts site: http://dtp.nci.nih.gov/branches/gcob/gcob_index.html. Direct inquiries regarding programmatic issues to: George S. Johnson, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute Executive Plaza North, Room 8152, MSC 7456 6130 Executive Blvd Bethesda, MD 20892-7456 Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: johnsong@exchange.nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathleen Shino National Cancer Institute Executive Plaza South, Room 243 6120 Executive Blvd Bethesda, MD 20892-7150 Telephone: (301) 846-1016 FAX: (301) 846-5720 Email: shinok@gab.nci.nih.gov Direct inquiries regarding review matters to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8326 Bethesda, MD 20892-8326 Telephone: (301) 496 -3428 FAX: (301) 402-0275 Email: tf12w@nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by the dates listed on the first page of this PA, a Letter of Intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the PA in response to which the application may be submitted. Although a Letter of Intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. NCI policy requires that all applicants requesting greater than $500,000 direct costs in any one year must obtain approval from NCI Program staff prior to submission of the application. If greater that $500,000 per year is requested, this fact must be clearly stated and approval requested in the Letter of Intent. The letter of intent is to be sent to Dr. George S. Johnson at the address listed under INQUIRIES by the Letter of Intent receipt dates. APPLICATION PROCEDURES Applications received in response to this PA are to be prepared as described in the OMNIBUS SOLICITATION for the SBIR and STTR programs. The 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. Helpful information for preparation of the application can be obtained at http://grants.nih.gov/grants/grant_tips.htm. Applications will be accepted at the application receipt dates listed on the first page of this PA document. THE TITLE AND NUMBER OF THIS PA MUST BE TYPED IN LINE 2 ON THE FACE PAGE OF THE APPLICATION. For FAST-TRACK, Phase I and Phase II applications must be submitted together for concurrent initial peer review. If an application is received after one of the application receipt dates, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this PA that is essentially the same as one currently pending review, unless the applicant withdraws the pending application. Revised applications may be submitted, but such applications must include an introduction addressing the previous critique. The OMNIBUS SOLICITATION indicates the normal levels of support and period of time for SBIR and STTR Phase I and Phase II awards. However, for this PA budgets up to $250,000 total costs per year (direct costs, indirect costs, and fixed fee) and time periods up to 2 years for Phase I and $650,000 total costs per year (direct costs, indirect costs, and fixed fee) and up to 4 years for Phase II can be requested. The total duration of Phase I plus Phase II cannot exceed 5 years. A detailed budget with appropriate justification of all requested items should be provided in all applications. SBIR Phase I applications will use Budget for Phase I Direct Costs (form page 3 of PHS 6246-1), and justify this request using Budget Justification form page 4 and PHS 62461. STTR Phase I applications will use Budget of Applicant Organization for Phase I - Direct Costs Only (form page 3 of PHS 6246-3) and justify this request using Budget Justification (form page 5). Phase I SBIR and STTR applications requesting a duration of more than one year should follow the following procedures: Photocopy Form page 3, Budget for Phase I - Direct Costs only , and number it Form Page 3a Phase I - 2nd year budget . (This page will not be counted against the 25 page limit.); Provide the appropriate/requested information in the narrative justification (Form Page 4) for years 1 and 2; Indicate on the Phase I Face Page in Field 6, Dates of Project Period, the dates for the ENTIRE project period; Indicate on the Phase I Face Page in Field 7, the requested Direct Costs and Total Costs for the entire project period; The summary statement will reflect the recommended budget for the -01 and -02 years. 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. All Phase II applications and FAST TRACK applications must include a succinct commercialization plan, hereafter referenced as a Product Development Plan . The Product Development Plan must be included as part of the Research Plan. (Note: It is no longer included as appendix material in FAST TRACK applications.) Refer to Phase II grant application instructions for more specific details and instructions. PHASE I: Demonstration of feasibility for proceeding to the next step in the drug discovery and development process. Applicants should emphasize innovative aspects of the agent or approach as well as the potential for clinical relevance. Applications should include a brief plan for development of the agents and clearly state how the proposed Phase I fits into this plan. If two years of support are requested, the goals for the first year must be clearly stated. Support for the second year will be contingent upon NCI programmatic evaluation to ensure that investigators have accomplished the proposed goals. . PHASE II: Continuing support for development of preclinical activities which may include establishment of proof of principle in clinical trials. Support can be requested for preclinical developmental activities including pharmacology, formulation and toxicology. Innovative aspects of the research necessary to complete the projects such as development of new in vivo evaluation models which may require surrogate endpoints should be clearly described. Support for clinical trial evaluation up to the point of establishing proof of principle (or through Phase II development) can be requested to commence following completion of the pre-clinical activities and approval of the IND by the FDA. A brief plan for the clinical trial should be presented in the RESEARCH PLAN section. Also, IN THE HUMAN SUBJECTS SECTION, INCLUDE THE COMPLETE CLINICAL PROTOCOL and DATA AND SAFETY MONITORING PLAN. Informed consent form(s) must be included. NIH will treat as confidential any scientific, preclinical, clinical or formulation data and information that the sponsor deems to be proprietary and confidential. For each trial, provide a Gender and Minority Inclusion Report in the format provided in the 398 form instructions: http://grants.nih.gov/grants/funding/phs398/phs398.html. The goals and milestones for each year of support must be clearly presented. Support for years two to four, if requested, is dependent upon NCI Programmatic review of progress and achievement of the proposed goals. For example, if a goal cannot be achieved such as identification of a more effective analog or demonstration of acceptable toxicity cannot be demonstrated, additional years may not be supported. This PA encourages projects with aims focusing on later stages of drug development such as formulation and toxicology. However, accomplishing these aims may likely require expertise not present in the applicant small business, and a sub-contract site within the award may be required. Information on the drug development process is available: http://dtp.nci.nih.gov/ and http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm. 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 the drug development process, 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 a standing Study Section of CSR or by a special review group convened in response to a re- issuance of this PA, if applicable. Special provisions described in this PA pertaining to Phase I and Phase II also apply to FAST TRACK applications. FAST TRACK applications must include a succinct commercialization plan, hereafter referred to as a Product Development Plan . The Product Development Plan must be included as part of the Research Plan. (Note: It is no longer included as appendix material in FAST TRACK applications). Refer to Phase II grant application instructions for more specific details and instructions. 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 (20817-7710 for express/courier service) Two additional copies of the application must also be sent to: Ms. Toby Friedberg Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8236 Bethesda, MD 20892-8326 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Applications must be received by the receipt dates listed at the beginning of this PA. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by CSR staff for completeness and by NCI program staff for adherence to the guidelines of this PA. Applications not adhering to instructions described above and those applications that are incomplete as determined by CSR or NCI program staff will be returned to the applicant without review. Applications that are complete and adhere to the guidelines of the 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 a scientific review group convened by the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications, will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board (NCAB). Review Criteria: Review criteria are described in the OMNIBUS SOLICITATION and are available at: http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf. 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 include the discovery and development of new cancer therapies within the SBIR and STTR programs. In addition to the standard review criteria described in the OMNIBUS SOLICITATION, 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 criterion 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 highly meritorious. For example, an investigator may propose a development or testing project which alone may not be highly innovative, but is required for successful development of an innovative and potentially important agent. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? What is the potential clinical relevance of the research and agents proposed? 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? Is it likely that the drug or vaccine can be developed in a reasonable time frame? Is the approach feasible and cost effective? For systems intended for clinical research, the following, additional criteria will be considered: to what degree is the analysis appropriate for clinical research and likely to have utility for the analysis of clinical specimens or patients? Milestones. Are the proposed feasibility goals in Phase I, if successful, appropriate and sufficient for transition to a Phase II? Innovation. Does the project employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms? Are the new drugs or vaccines proposed novel? Investigator. Is the investigator appropriately trained and well suited to carry out this research? 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? For FAST TRACK, the initial review group will evaluate the Phase I application for measurable goals to be achieved prior to initiating Phase II. Failure to provide clear, measurable goals may be sufficient reason for the initial review group to judge the application non-competitive. The review group may disapprove the Phase II component and then review and score the Phase I application. The initial review group will also examine: the adequacy of the proposed project budget and duration; the adequacy of plans to recruit and retain both genders, minorities and their sub-groups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; the safety of the research environment; and the Data and Safety Monitoring Plan. AWARD CRITERIA Applications will compete for available funds with all other approved SBIR and STTR applications. A portion of the SBIR/STTR allotment will not be designated for this initiative. Funding decisions for Phase I or Phase II applications will be based on quality of the proposed project as determined by peer review, program priority, potential for clinical success, adequacy of the Data and Safety Monitoring Plan, and availability of funds. 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, NCI’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. SCHEDULE Letter of Intent Receipts: June 6, 2001 March 6, 2002 October 8, 2002 Application Receipt: July 12, 2001 April 10, 2002 Nov. 12, 2002 NCAB Review: Jan/Feb 2002 Sept/Oct 2002 May/June 2003 Earliest Anticipated Award Date: April 2002 December 2002 July 2003 INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 research involving human subjects should read the UPDATED "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html. A complete copy of the updated Guidelines is available at: http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III Clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and /or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at http://grants.nih.gov/grants/guide/notice-files/not98-024.html. DATA AND SAFETY MONITORING OF CLINICAL TRIALS All clinical trials supported or performed by NCI require some form of monitoring. 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 to 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 of 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 plan for Phase I and II Trials for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy published in the NIH Guide for Grants and Contracts, June 5, 2000 (Revised August 25, 2000), available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-036.html. A continuing education program on the protection of human participants in research is now available online at: http://cme.nci.nih.gov/. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2010", a PHS lead national activity for setting priority areas. The PA, Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses (FLAIR) is related to the priority area of cancer. Potential applicants may obtain a copy of Healthy People 2010" at http://www.health.gov/healthypeople/ AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and part 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro- Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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