PAR-01-062: CANCER PROGNOSIS AND PREDICTION: SBIR/STTR INITIATIVE

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CANCER PROGNOSIS AND PREDICTION: SBIR/STTR INITIATIVE Release Date: March 1, 2001 (see replacement PAR-03-099) PA NUMBER: PAR-01-062 National Cancer Institute Letter of Intent Date: May 9, 2001, November 6, 2001, May 2, 2002, and November 7, 2002 Application Receipt Date: June 13, 2001, December 11, 2001, June 11, 2002, and December 11, 2002 PURPOSE The Cancer Diagnosis Program of the National Cancer Institute invites applications for research projects to evaluate the utility and pilot the application of new strategies for determining prognosis or predicting response to therapy. This will provide tools to improve clinical decision-making in the care of cancer patients. This program is intended to accelerate the translation of new discoveries into clinical practice by enabling investigators to apply new diagnostic strategies to clinical problems. The primary objective is to move research quickly and directly from the promising exploratory stage through further assay development into initial confirmatory testing in a clinical setting. This program will utilize the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms, but will be run in parallel with a program of identical scientific scope, http://grants.nih.gov/grants/guide/pa-files/PAR-01-061.html, that will utilize the newly-created Phased Application Award mechanism. The SBIR and STTR applications received in response to this program announcement will undergo initial scientific review convened by the NCI Division of Extramural Activities and will be subject to cost and duration limitations comparable to the parallel Phased Application Award applications. This Program Announcement (PAR) must be read in conjunction with the OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH, SMALL BUSINESS INNOVATION RESEARCH (SBIR) and SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS, available online at http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf All of the instructions within the Omnibus Solicitation apply with the following exceptions: o Special receipt dates o Initial review convened by the NCI Division of Extramural Activities o Additional review considerations RESEARCH OBJECTIVES Background The number of clinical laboratory assays currently in routine use in oncology is very small. For example, estrogen and progesterone receptor status of breast cancers is used to predict response to hormonal therapy. Blood levels of prostate specific antigen and human chorionic gonadotropin in prostate cancer and germ cell cancer, respectively, are used to assess the effectiveness of treatment and to detect recurrence. Patients whose tumor cells exhibit over-expression or amplification of the Her2/neu gene may be offered Herceptin , forerunner of a new class of therapeutic agents directed against specific molecular targets. These markers are the exception, not the rule. During the past five years the College of American Pathologists, ASCO Expert Panels and the American Joint Committee on Cancer have carefully considered many new markers proposed for use in managing breast, colon and prostate cancer, but have found none with proven clinical utility sufficient to justify their adoption for routine practice. Recently the NCI has sought to encourage the rapid appraisal of new candidate prognostic and predictive markers through a series of program announcements soliciting exploratory (R21) studies. An increasing number of publications have described new molecules, new patterns of gene expression and new aspects of tumor cell growth that appear to be correlated with known prognostic factors. However, very few markers progress beyond the stage of an initial promising result. Studies to move the development of a new diagnostic test beyond the exploratory stage require large numbers of patient samples with associated clinical data, a robust, efficient assay format and substantial statistical input. The transition from an exploratory marker study to initial confirmatory testing in a clinical setting may involve additional developmental work. For example, the study design may change from a retrospective to a prospective analysis or from a single institution to a multi-institutional setting. Frequently an assay format must be modified, which may require the generation and characterization of additional reagents. Procedures for standardization between collaborating laboratories may be needed. Research Goals and Scope This program is intended to support projects that test the value of new strategies for predicting the course of the disease or the response to therapy as tools in clinical decision-making. The desired outcome will be studies with sufficient statistical power using efficient assay techniques that are conclusive enough to support the initiation of larger clinical trials designed to influence practice recommendations or to pursue FDA approval of a new device or analytic reagent. Partnerships of appropriate medical institutions with biotechnology companies and medical device manufacturers are encouraged. Phase I applications will be considered exploratory, so that extensive preliminary data from the applicant's own laboratory are not required. However, the project must be based on a strong rationale, and the applicant should provide evidence that the initial clinical evaluation of the proposed diagnostic strategy is promising. Applicants should justify their proposals on the strength of the clinical study proposed for a future Phase II project; the Phase I award provides time for necessary preliminary work such as, for example, the substantial modification of an assay format. Applicants for Fast-Track (combined Phase I/II) projects need to provide information in the application or to propose milestones that will demonstrate the feasibility of the Phase II project. Milestones must be designed to permit a straightforward decision as to whether or not the applicant is ready to initiate Phase II. Milestones should also be provided to show that the assay format to be used in Phase II meets necessary performance standards for sensitivity, specificity and reproducibility. Phase II projects must be described in sufficient detail to permit reviewers to assess the significance and innovation of the proposed work and the strength of the experimental design. Applicants are expected to provide promising evidence of clinical utility for their proposed diagnostic strategy and to show how their new test or procedure will aid the process of clinical decision-making for a specific group of patients. The application should clearly state the clinical question that the new test or procedure is intended to address: for example, diagnosis, prognosis, prediction of response to therapy, disease monitoring, etc. Investigators should plan to report correlations between the new diagnostic test and other measures used in the same clinical setting, and they should describe what additional information beyond standard clinical parameters that the new test is expected to provide. Investigators who propose prospective studies must clearly describe the arrangements for collection and analysis of patient outcome data, especially if follow-up will be required beyond the end of the award period. Proposals will be evaluated on the strength of the scientific rationale, the significance of the problem to be addressed, the adequacy of the proposed statistical design, the feasibility of accrual of study participants or human tissue specimens and the choice of assay format and analytic performance criteria. MECHANISM OF SUPPORT Responsibility for the planning, direction and execution of the proposed project will be solely that of the applicant. Except as otherwise stated in this program announcement, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, rev. March 2001. Support for this PAR is through the SBIR and STTR mechanisms, which are set- aside programs. 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 under the SBIR/STTR FAST-TRACK option as described in the OMNIBUS SOLICITATION (http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf). Phase II applications in response to this PAR 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. Because the length and time of clinical research projects often exceeds that normally awarded for SBIR/STTR grants, NCI will entertain well-justified Phase I applications with a project period up to two years and a budget not to exceed $100,000 per year direct costs, excluding subcontractor indirect costs. Information on the FAST-TRACK process and the OMNIBUS SOLICITATION are available at: http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf Unless otherwise noted, all NIH grants policies apply. ELIGIBILITY REQUIREMENTS Eligibility requirements are described in the OMNIBUS SOLICITATION. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Tracy G. Lugo, Ph.D. Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room 6042 Rockville, MD 20892 Telephone: (301) 496-1591 FAX: (301) 402-7819 Email: TL82S@nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathleen J. Shino Grants Administration Branch National Cancer Institute 6120 Executive Blvd., EPS Room 243 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 Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) 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 PAR, 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 PAR 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Tracy Lugo at the address listed under INQUIRIES by the letter of intent receipt date. APPLICATION PROCEDURES OMNIBUS SOLICITATION for both the SBIR and STTR programs are available electronically through the NIH, Office of Extramural Research small Business Funding Opportunities web site at 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/funding/sbir_policy.htm Applications are to be submitted on the grant application form PHS 398, http://grants.nih.gov/grants/funding/phs398/phs398.html, and will be accepted at the application deadlines as indicated on the first page of this document. THE TITLE AND NUMBER OF THIS PAR MUST BE TYPED IN LINE 2 ON THE FACE PAGE OF THE APPLICATION. The OMNIBUS SOLICITATION gives the normal levels of support and period of time for SBIR and STTR Phase I and II awards. However, these award levels are guidelines and not ceilings. Therefore, larger budgets with longer periods of time may be requested if required to complete the proposed research. As stated under MECHANISM OF SUPPORT section, Phase I applications submitted in response to this PAR can have a project period of up to two years and a budget not to exceed $100,000 per year direct cost excluding subcontractor Facility and Administrative costs. An annual meeting of all investigators funded through this program will be held to share progress and research insights that may 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 Applicants requesting a budget period of more than 1 year for Phase I should follow these procedures: o Photocopy Form Page 3 Budget for Phase I-Direct Costs Only , number it Form Page 3a . o Use Form Page 3 for the first year budget and title Form Page 3a Phase I- 2nd Year budget. This page will not be counted against the 25-page total. o Provide the appropriate/requested information in the narrative justification (Form Page 4) for years 1 and 2 o Indicate on the Phase I Face Page in Field 6, Dates of Project Period, the dates for the ENTIRE project period (e.g., Nov. 15, 2000-Nov. 15, 2002). o Indicate on the Phase I Face Page in Field 7 the requested Direct Costs for the entire project period and the Total Costs for the entire project period (e.g., 2 years). Phase II applications submitted in response to this PAR have no budget limitations. The total duration (Phase I and Phase II application) cannot exceed five years. The SBIR Phase II application and instructions can be obtained at http://grants.nih.gov/grants/funding/sbir2/index.htm In order to apply for the FAST-TRACK option, applications for both Phase I and Phase II must be submitted together according to the instructions for FAST TRACK applications as described in the OMNIBUS SOLICITATION. The Phase I application must specify clear, well-defined quantifiable milestones that should be achieved prior to Phase II funding. Milestones should be located in a separate section at the end of the Research Plan of the Phase I and should be indicated in the Table of Contents. Failure to provide measurable milestones and sufficient detail may be sufficient reason for the peer review committee to exclude the Phase II application from FAST-TRACK review. If so, at a later date, the applicant may apply for Phase II support through normal application procedures. Such applications will be reviewed by a standard Study Section of the Center for Scientific Review or by a special review group convened in response to a re- issuance of this PAR, if applicable. An additional requirement of the FAST-TRACK mechanism is the Product Development Plan. The small business must submit a concise 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 SOLICITATION. In the event that an applicant feels that technology is too proprietary to disclose, applicants at a minimum should provide a demonstration (e.g., results) of the capabilities of the proposed technology. 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 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. Submit a signed, typewritten original of the application, including the Checklist, and one signed, photocopy, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) To expedite the review process, at the time of submission, send one copy of the application to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8239 Bethesda, MD 20892-8239 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 PAR. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the CSR for completeness and by the NCI program staff for adherence to the guidelines. Applications not adhering to application instructions described above and those applications that are incomplete as determined by CSR or by NCI program staff will be returned to the applicant without review. Applications that are complete and adhere to the guidelines of this PAR 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 The review criteria are described in the NIH OMNIBUS SOLICITATION and available on the web at the following URL address: http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf, The reviewers will comment on the six 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 the goals of this PAR. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a technology forward. In considering the scientific and technical merit of each application, the following criteria will be used as described in the OMNIBUS SOLICITATION (PHS 2000-2). 1. Significance. Does this study address an important problem? Does the proposed project have commercial potential to lead to a marketable product or process? If the aims of the application are achieved, how will scientific knowledge be advanced? What may be the anticipated commercial or societal benefits? How is the proposed diagnostic strategy superior to existing alternatives? What will be the impact on the design of future clinical trials or on clinical practice? 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? This includes the statistical rationale for the study design and the choice of sample size. Is the proposed plan a sound approach for establishing technical and commercial feasibility? Does the applicant acknowledge potential problem areas and consider alternative tactics? Has the applicant considered how the Phase II study, if promising, could proceed into eventual definitive testing of the diagnostic strategy? What additional uses can be projected for the proposed assay(s), or what additional groups of patients might benefit from the new diagnostic strategy? 3. Milestones (FAST-TRACK applications only). How appropriate are the proposed milestones against which to evaluate the demonstration of feasibility for transition to Phase II? 4. Innovation. Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methods or technologies? What is the throughput and cost effectiveness of the proposed assay(s)? 5. Investigator. Is the Principal Investigator capable of coordinating and managing the proposed SBIR/STTR project? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 6. Environment. Is there sufficient access to resources (e.g., equipment, facilities)? 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? Are the planned statistical and data management resources adequate? For FAST-TRACK, the Phase I application should specify clear, well defined quantifiable milestones that should be achieved prior to initiating Phase II. Failure to provide clear, measurable milestones may be sufficient reason for the study section to judge the application non-competitive. Additional Considerations For all applications, the initial review group will also examine: the appropriateness of the proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups, 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. Reviewers will comment on the appropriateness of the proposed budget and its duration in relation to the proposed research. AWARD CRITERIA Applications will compete for available funds with all other recommended SBIR and STTR applications. Funding decisions for Phase I or Phase II applications will be based on quality of the proposed project as determined by peer review, availability of funds, and program priority. 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. 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 are 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 the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.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. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants and Contracts, June 5, 2000 (Revised August 25, 2000), available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.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. 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 led national activity for setting priority areas. This PAR, Cancer Prognosis And Prediction: SBIR/STTR Initiative, 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. 93.394, (use appropriate program number). Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies 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 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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