FLEXIBLE SYSTEM TO ADVANCE INNOVATIVE RESEARCH FOR CANCER DRUG DISCOVERY BY SMALL BUSINESSES (FLAIR) Release Date: December 15, 1999 PA NUMBER: PAR-00-030 National Cancer Institute Letter of Intent Receipt Dates: February 16, 2000, and October 18, 2000 Application Receipt Dates: March 22, 2000, and November 22, 2000 This Program Announcement (PA) replaces RFA: CA-98-022, which was published in the NIH Guide, August 20, 1998. PURPOSE Discovery and development of new cancer therapeutics, including both drugs and biological response modifiers, 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. The Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs have supported these efforts, however, the extent of such support has been limited by the stringent guidelines of the Phase I and Phase II components. For example, feasibility of the approach or of the drug as a potential clinical agent has often been difficult to establish within the limited Phase I time and budget guidelines. This PA provides a flexible system within the SBIR and STTR programs to accommodate the extensive needs of the complex discovery and development process, at least partially, from basic discovery through proof of principle demonstration in clinical trials. This PA must be read in conjunction with the OMNIBUS SOLICITATION OF THE PUBLIC HEALTH SERVICE FOR SMALL BUSINESS INNOVATION RESEARCH GRANT (SBIR) APPLICATIONS (PHS 2000-2) and the OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH FOR SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS (PHS 2000-3). All of the instructions within the omnibus solicitation apply with the following exceptions: -Special receipt dates -Initial review convened by the Division of Extramural Activities, National Cancer Institute (NCI) -Additional review considerations -More flexible time and budget specifications HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PAR, Flexible System to Advance Innovative Research for Cancer Drug Discovery by Small Businesses , is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202- 512-1800), or at http://odphp.osophs.dhhs.gov/pubs/hp2000 ELIGIBILITY REQUIREMENTS Eligibility requirements are described in the OMNIBUS SOLICITATIONS. Any small business independently owned by United States citizens or permanent resident aliens and located in the United States may apply. 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 SOLICITATIONS. 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 SOLICITATIONS are available at http://grants.nih.gov/grants/funding/modular/modular.htm All PHS and NIH grant policies will apply to applications received in response to this program announcement. 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://2001.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 support to support the research activities required to enable small businesses to bring their innovative efforts for drug discovery and development to clinical evaluation. 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 are generally more routine and often considered less innovative as stand-alone projects. 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 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, available at http://grants.nih.gov/grants/guide/notice-files/not94-100.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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 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 avoid conflict of interest in the review. The letter of intent is to be sent to Dr. George S. Johnson at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications received in response to this PA are to be prepared as described in the OMNIBUS SOLICITATIONS for the SBIR and STTR programs. OMNIBUS SOLICITATIONS are available electronically through the NIH, Office of Extramural Research Small Business Funding Opportunities at http://grants.nih.gov/grants/funding/sbir.htm. Hard copies, subject to availability, may be obtained from the PHS SBIR/STTR Solicitation Office, telephone (301) 206-9385, FAX (301) 206-9722, email [email protected]. Helpful information for preparation of the application can be obtained at http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf Phase I applications are to be submitted on the grant application form PHS 6246-1(SBIR) or PHS 6246-3 (STTR), which are located in the back pages of the OMNIBUS SOLICITATIONS. Use PHS 6246-2 for SBIR Phase II, and PHS 6246-3 for STTR Phase II applications. For FAST-TRACK, Phase I and Phase II applications must be submitted together for concurrent initial peer review. Applications will be accepted on March 22, 2000, and November 22, 2000. THE TITLE AND NUMBER OF THIS PA MUST BE TYPED IN LINE 2 ON THE FACE PAGE OF THE APPLICATION. If an application is received after 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 SOLICITATIONS indicate 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, Facilities and Administrative Costs, and fixed fee) and time periods up to 2 years for Phase I and $650,000 total costs per year (direct costs, Facilities and Administrative Costs, and fixed 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. Applications requesting a budget up to $100,000 (direct costs) per year should use the Modular Grant format http://grants.nih.gov/grants/funding/sbir1/modular.htm . Other applications should provide a detailed budget. 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 PHASE I: Demonstration of feasibility for the next step in the drug discovery and development process. It would be expected, but not required, that Phase I would support relatively early discovery and evaluation projects. Phase I projects should focus on research required to advance to the next stage in the development process. Applicants should emphasize innovative aspects of the agent or approach as well as the potential for clinical relevance. Applications should include a 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 should be clearly stated. Support for the second year will be contingent upon NCI programmatic evaluation to ensure that investigators are accomplishing the goals presented. PHASE II: Continuing support for development of preclinical activities and for 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. 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. The goals and milestones for each year of support should 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 acceptable toxicity cannot be demonstrated, additional years may not be supported. The NCI, through the Developmental Therapeutics Program (http://dtp.nci.nih.gov) and the Cancer Therapy Evaluation Program (http://ctep.info.nih.gov), on occasion utilizes its internal resources to foster drug development and clinical trials of agents discovered by small businesses. For additional informational contact Dr. George S. Johnson at the address listed under INQUIRIES. FAST TRACK: Applications may be submitted for combined Phase I and Phase II, FAST TRACK consideration as described in the OMNIBUS SOLICITATIONS. 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. An additional requirement of the FAST TRACK mechanism 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 FAST TRACK applications in the OMNIBUS SOLICITATIONS. 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 one 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 BETHESDA, MD 20817 (for express/courier service) One additional copy of the application must also be sent to: Ms. Toby Friedberg Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8062, MSC 8239 Bethesda, MD 20892-8329 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 responsiveness. Applications not adhering to application instructions described above and those applications that are incomplete or non-responsive will be returned to the applicant without review. Applications that are complete and responsive to the PA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applicants will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit generally the top half of the applications will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board (NCAB). Review Criteria: Review criteria are essentially as described in the OMNIBUS SOLICITATIONS with the additional considerations specified for this PA. Reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged highly meritorious. 1. The soundness and technical merit of the proposed approach (Preliminary data are not required for Phase I applications). 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? 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? 2. The qualifications of the proposed principal investigator, supporting staff, and consultants. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 3. The scientific, technical, or technological innovation of the proposed research. Does the project employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms? 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. 8. Innovative aspects of the overall drug discovery and development plan. 9. Potential clinical relevance of the research and agent proposed. 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 initial review group will also examine 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, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other recommended 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, 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. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: George S. Johnson, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute Executive Plaza North, Room 841 6130 Executive Blvd Bethesda, MD 20892-7456 Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: [email protected] 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) 496-8635 FAX: (301) 496-8601 Email: [email protected] Direct inquiries regarding review matters to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8062 Bethesda, MD 20892-8329 Telephone: (301) 496 -3428 FAX: (301) 402-0275 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395. Awards are made under authorization of the Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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