DEVELOPMENT OF HIGH-YIELD TECHNOLOGIES FOR ISOLATING EXFOLIATED CELLS IN BODY FLUIDS Release Date: November 15, 2000 RFA: CA-01-016 National Cancer Institute Letter of Intent Receipt Dates: March 6, 2001 Application Receipt Dates: April 10, 2001 PURPOSE The purpose of this Request for Application (RFA) is to develop novel technologies for capturing, enriching, and preserving exfoliated abnormal cells in body fluids or effusions and to develop methods for concentrating the enriched cells for biomarker studies. In body fluids, such as sputum, the number of exfoliated tumor cells is often small compared to the number of non- neoplastic cells. Therefore, the detection of exfoliated abnormal cells by routine cytopathology is often limited because few atypical cells may be present in the specimen. Furthermore, there may be difficulty in separating dysplastic cells from non-specific reactive changes and degenerating cells or variation in diagnostic criteria. Furthermore, exfoliated cells are frequently contaminated with normal cells, bacteria, and other cellular debris, which makes molecular analysis difficult without physical separation of the neoplastic cells. Thus, the development of enrichment methods is a prerequisite for the routine detection of small numbers of exfoliated cells and small amounts of subcellular materials in biological fluids for molecular analysis. This Request for Application (RFA) 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 (PHS 2001-2). PHS-2001-2 will be issued in January 2001. Therefore, applicants may want to refer to PHS 2000-2 (http://grants.nih.gov/grants/funding/sbir.htm) as a general reference until the Calendar Year 2001 SBIR/STTR Omnibus Solicitation is released 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 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 Program Announcement of identical scientific scope PAR-01-019 that will utilize the exploratory/developmental (R21) grant mechanism. PAR-01-019 is available at (see http://grants.nih.gov/grants/guide/pa-files/PAR-01- 019.html). RESEARCH OBJECTIVES Background The most common human tumors arise from epithelial surfaces (e.g. colon, lung, prostate, oral cavity, esophagus, stomach, uterine cervix, bladder). Their development often becomes apparent when tumor cells exfoliate spontaneously into sputum, urine, or even into various effusions. The molecular and genetic abnormalities within these exfoliated cells could be used to detect and identify precancerous lesions or very early stage cancer if highly sensitive technologies were clinically available to identify the few abnormal cells among millions of normal cells. For example, detection of widespread microsatellite instability (MSI), as demonstrated by expansion or deletion of repeat elements of DNA, may be adapted for exfoliated cells in general. With the advent of PCR-based detection of DNA from rare neoplastic cells in body fluids, mutations have been detected in ras genes from the stool of patients with colorectal cancer, and in p53 from the urine of patients with bladder cancer and in the sputum of patients with lung cancer. As these assays are complex and technically challenging, they depend on the development of novel technologies for isolating and enriching exfoliated cells. Abnormal exfoliated cells can be routinely identified by cytologic examination of brushings and fluids, for instance, from bronchi, pancreatic ducts, voided urine and tapping of effusions. Currently fluids are usually processed by centrifugation or membrane filtration. However, the detection of abnormal exfoliated cells, for instance, cancer cells by routine cytopathological examination may be limited because the number of abnormal cells may be very small compared to the number of normal cells. Alternatively, the cellular and nuclear changes in abnormal cells may be minimal compared to normal cells. This is particularly true of urine cytology, where many low-grade papillary lesions are often missed on cytological examination. New PCR-based technologies may substantially enhance the sensitivity, but current technologies for isolating exfoliated cells are too cumbersome to be of practical utility. Finding molecular and genetic biomarkers of early cancer represents an extraordinary opportunity for the National Cancer Institute (NCI) and is particularly important in detecting the emergence of precancerous cell populations. In these earliest stages of neoplastic development, lesions should be amenable to complete eradication. This has been well demonstrated in cervical neoplasia, where screening for brushed exfoliated cells has resulted in a 70% or greater reduction in cervical cancer mortality. Brushing of the esophagus or stomach is commonly performed during endoscopic examination. Goals and Scope In pursuit of these goals, the NCI invites applications, which address the following areas: o development of novel technologies for identifying abnormal exfoliated cells in body fluids, o development of novel technologies for capturing, enriching, and preserving abnormal exfoliated cells in body fluids, o development of enrichment methods for the isolation of tumor cells, o development of sensitive, high-throughput molecular, cytomorphometric, immunologic, and other relevant technologies to isolate tumor cells in malignant effusions for detection of low tumor burden and to help distinguish reactive cells from tumor cells. Applicants should not only address the technology of enriching and isolating exfoliated cells, but they should also address their viability and usefulness for cytologic and molecular studies. MECHANISM OF SUPPORT Support for the RFA is through the SBIR and STTR mechanisms, which are set- aside programs. Awards will be administered under NIH grants policy stated in the NIH Grants Policy Statement, NIH publication 99-8 October 1998. 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. Phase II applications in response to this RFA 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 are available at: http://grants.nih.gov/grants/funding/sbirsttr1/index.htm FUNDS AVAILABLE $ 1 M to support up to 6 Phase I and/or Phase II applications under the SBIR/STTR set-aside funding mechanism are available. 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. ELIGIBILITY REQUIREMENTS Eligibility requirements are described in the OMNIBUS SOLICITATION. Any small business, independently owned by United States citizens and located in the United States, may apply. INQUIRIES Direct inquiries regarding programmatic issues to: Sudhir Srivastava, Ph.D., M.P.H. Division of Cancer Prevention National Cancer Institute EPN, Room 330F 6130 Executive Boulevard Rockville, MD 20852 Telephone: (301) 435-1594 FAX: (301) 402 -0816 Email: ss1a@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 Direct inquiries regarding fiscal matters to: Ms. Kathleen Shino Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC 7150 Bethesda, MD 20892-7150 Rockville, MD 20852 (express courier) Telephone: (301) 496-8635 Fax: (301) 496-8601 Email: shinok@gab.nci.nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by the date listed on the first page of this RFA, 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 RFA 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. Sudhir Srivastava by the letter of intent receipt date listed. SCHEDULE Letter of Intent Receipt: March 6, 2001 Application Receipt Date: April 10, 2001 Peer Review Date: June 2001 Review by NCAB Advisory Board: September 2001 Earliest Anticipated Start Date: December 2001 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.htm. Only a limited number of hard copies will be available, and they may be obtained from the PHS SBIR/STTR Solicitation Office, phone (301) 206-9385, FAX (301) 206-9722, email a2y@cu.nih.gov. Helpful information for preparation of the application can be obtained: http://grants.nih.gov/grants/funding/sbir.htm. Applications are to be submitted on the grant application form PHS 6246-1 (1/99) (SBIR) and PHS 6246-3 (STTR) (3/99) (in a single document) located in the back pages of the OMNIBUS SOLICITATION, and will be accepted at the application deadlines as indicated on the first page of this document. THE TITLE AND NUMBER OF THIS RFA MUST BE TYPED IN LINE 2 ON THE FACE PAGE OF THE APPLICATION. The OMNIBUS SOLICITATION give 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 RFA can have a project period of up to two years and a budget not to exceed $100,000 per year direct cost excluding subcontractor indirect costs. The second year of the Phase I budget should be included on the Budget Justification page, using categorical totals if costs deviate significantly from the first year of the budget, with narrative justifications for the increase(s). If the second year simply escalates due to cost of living factors, a statement to that effect with the escalation factor should be included rather than categorical totals. Phase II applications submitted to this RFA that exceed the normal levels of support as stated in the OMNIBUS SOLICITATION must be strongly justified. The total duration (Phase I and Phase II application) cannot exceed four years. 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 RFA, 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. 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 additional copy of the application 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 Applications must be received by the receipt date listed at the beginning of this RFA. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the National Cancer Institute. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. 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 receive a written critique and 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, 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 NIH Omnibus Solicitation and available on the web at the following URL address: http://grants.nih.gov/grants/funding/sbirsttr1/index.htm In addition to the standard review criteria as described in the NIH OMNIBUS SOLICITATION, 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 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 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. Significance. Does this study address the objectives of this RFA? If the aims of the application are achieved, how will this project enable the technological application of exfoliated cells? What will be the effect of these studies on the concepts or methods that drive the non-invasive approaches to cancer detection? To what degree does the technology support the needs of the targeted research community? 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? What is the time frame for developing the proposed technologies and suitability of this time frame for meeting the scientific community’s needs? How easy will it be to use the proposed technology? Are the plans for proposed technology dissemination adequate? Milestones. How appropriate are the proposed milestones against which to evaluate the demonstration of feasibility for transition to the Phase II development phase? Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? What is the throughput and cost effectiveness of the proposed technology? What additional uses can be projected for the proposed technology? Investigator. 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)? 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? 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. 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 subpopulations 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 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 are 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. 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 a 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 RFA, Development of High-Yield Technologies for Isolating Exfoliated Cells in Body Fluids, 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. 93.393 Cancer Cause and Prevention Research. 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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