Expired RFA-CA-06-001: SBIR/STTR: CIRCULATING CELLS AND DNA IN CANCER DETECTION

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SBIR/STTR: CIRCULATING CELLS AND DNA IN CANCER DETECTION RELEASE DATE: June 9, 2004 RFA NUMBER: RFA-CA-06-001 - This RFA has been replaced by RFA-CA-07-027(SBIR [R43/R44]) and RFA-CA-07-028(STTR [R41/R42]) EXPIRATION DATE: October 13, 2005 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENT OF PARTICIPATING ORGANIZATION: National Cancer Institute (NCI) (http://www.nci.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.393, 93.394 LETTER OF INTENT RECEIPT DATE: January 17, 2005; May 16, 2005; September 14, 2005 APPLICATION RECEIPT DATE: February 14, 2005; June 13, 2005; October 12, 2005 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Project Period and Amount of Award o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations NOTICE: This Request for Application (RFA) must be read in conjunction with the current OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH, CENTERS FOR DISEASE CONTROL AND PREVENTION, and FOOD AND DRUG ADMINISTRATION FOR SMALL BUSINESS INNOVATION RESEARCH (SBIR) SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS. The solicitation (see http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf [PDF] or http://grants.nih.gov/grants/funding/sbirsttr1/index.doc [MS Word]) contains information about the SBIR and STTR programs, regulations governing the programs, and instructional information for submission. All of the instructions within the SBIR/STTR Omnibus Solicitation apply with the exception of the following. o Special receipt dates; and o Initial review convened by the NCI Division of Extramural Activities. PURPOSE OF THIS RFA The Division of Cancer Prevention of the National Cancer Institute invites small business applications for research projects to develop novel technologies for capturing, enriching, and preserving exfoliated abnormal cells and circulating DNA from body fluids or effusions and to develop methods to concentrate these cells and DNA for cancer biomarker detection. In body fluids, such as sputum, the number of exfoliated tumor cells is often low compared to the number of normal cells, making it difficult to detect these abnormal cells by routine cytopathology. Separation of dysplastic cells from degenerating cells and cells undergoing non-specific reactive changes is problematic. Moreover, exfoliated cells are frequently contaminated with normal cells, bacteria, and cellular debris. Therefore, enrichment methods are needed to allow for routine detection and molecular analysis of small numbers of exfoliated cells. Circulating extracellular DNA was first reported in 1948. It has been shown that the circulating DNA in the blood of cancer patients has genetic characteristics identical to those of the primary tumors. Thus, circulating DNA is an important material that may be useful for cancer detection. Currently available methods for isolating undegraded circulating DNA are limited, and there is a need to develop novel methods which improve the yield of undegraded DNA and to adapt detection assays so that this DNA can be used to detect mutations, microsatellite instabilities, loss of heterozygosity, epigenetic changes, and other molecular genetic changes. 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 (PA-04-035) that will utilize the exploratory/developmental (R21) grant mechanism. RESEARCH OBJECTIVES Background Cellular and molecular changes that ensue during tumor progression occur over a number of years and in an apparently stochastic manner. For example, it takes an average of 15 to 20 years for a small adenomatous polyp to become malignant. Prior to the appearance of a morphologically identified precancerous lesion, numerous genetic and molecular alterations have occurred. During the early stages of cancer development, there is a window of opportunity to detect precancerous cells with genetic or molecular biomarkers that identify and characterize their progression towards cancer. Finding molecular and genetic biomarkers of malignancy is an extraordinary opportunity for the NCI and is particularly important in detecting the emergence of precancerous cell populations. In these earliest stages of neoplasia, lesions are more likely to be amenable to eradication. This principle has been well-demonstrated in cervical neoplasia, where screening for dysplastic exfoliated cells can result in a 70 percent or greater reduction in mortality due to cervical cancer. Detection of genetic abnormalities in preneoplastic lesions poses challenges because of the small size of lesions, the heterogeneity of precancerous cells, and the relatively low number of abnormal cells compared to normal cells. Rationale More than 80 percent of human tumors (e.g. colon, lung, prostate, oral cavity, esophagus, stomach, uterine cervix, and bladder) originate from epithelial cells, often at a mucosal surface, and are clonal in origin. Cells from these tumors exfoliate spontaneously into blood, sputum, urine, and various effusions. Abnormalities within these exfoliated cells could be used to detect and identify precancerous lesions or very early stage cancers if highly sensitive technologies were available to identify the presence of a few abnormal cells among millions of normal cells. For example, PCR has been used to detect mutant DNAs in neoplastic exfoliated cells; mutations have been detected in ras genes present in stool samples obtained from patients with colorectal cancer, and in p53 from the urine of patients with bladder cancer and in the sputa of patients with lung cancer. Assays to detect genetic mutations, microsatellite instability, or hypermethylation may be adapted for use with exfoliated cells. As these assays are complex and technically challenging, their general use will require the development of novel technologies for isolating and enriching abnormal exfoliated cells. Studies performed in the early 1970s showed that increased quantities of DNA are found in the plasma of patients suffering from different malignancies, but it was not until the 1990s that this circulating DNA was shown to exhibit tumor-related alterations. Mutant DNA has been found in the plasma of patients with colorectal, pancreatic, biliary tree, skin, head-and-neck, lung, breast, kidney, ovarian, nasopharyngeal, liver, bladder, gastric, prostate, and cervical cancers as well as in haematologic malignancies. Allelic imbalance (AI), which involves the loss or gain of chromosomal regions, is found in many cancers. AI can be detected in genomic tumor DNA released into the blood after cellular necrosis or apoptosis. These observations indicate that plasma/serum may be a suitable specimen source for noninvasive diagnostic, prognostic, and follow-up tests for cancer Barriers Precancerous exfoliated cells can be identified by cytologic examination of washings or brushings from bronchi, oral cavity, esophagus, stomach, bile and pancreatic ducts, as well as of sputum and urine specimens. However, the detection of these exfoliated cancer cells by routine cytopathological examination is very difficult because the number of abnormal cells in the specimens is usually very low compared to the number of normal cells. It is also difficult to distinguish low grade dysplasia from non-specific reactive or inflammatory changes due to the low sensitivity and specificity of current diagnostic methodologies. This is particularly true of urine cytology, where most low-grade papillary lesions are missed by cytologic examination. Even with new PCR-based technologies with enhanced sensitivity, current technologies for isolating exfoliated cells are too inefficient to be of practical utility. Therefore, the development of novel, high-throughput, sensitive technologies for sample preparations is a prerequisite for the successful detection of the small number of exfoliated cells or of the small amounts of DNA, RNA and proteins in these cells. There are a variety of approaches to detect and analyze precancerous and cancerous cells in body fluids (e.g., cytopathological analysis, morphometric analysis, molecular biomarkers for specific receptors or genetic changes, Fluorescence in Situ Hybridization [FISH] analysis, or PCR-based analysis). The selection of approach, in many instances, depends on the type of biological specimens (sputum, bronchial washing, cervical brushing, voided urine, etc.). Given that the concentration of the atypical epithelial cells can be very low compared to that of normal cells, all of these approaches require between 1 to 10,000 and 1 to million enrichments of the atypical cells. Currently, there are two broad categories of enrichment methods: mechanical (centrifugation, cytospin, sucrose gradients, etc.) and antibody- based selection with mechanical separation (FACS flow-assisted cell sorting, MACS - magnetic assisted cell sorting, etc.). While these two types of enrichment processes can be used in series to improve the yield, none of the currently available methods achieve sufficient enrichment of atypical cells to allow them to be routinely used for cancer detection. The single largest barrier to using circulating DNA for cancer detection is the amount of circulating undegraded DNA that can be isolated is low, making it unsuitable for currently available assay technologies. Several factors affect the yield and purity of circulating DNA. Intracellular nuclease activity in both apoptotic and necrotic cells in a particular organ affect the degree of DNA degradation found in body fluids. Also, the degree to which a particular tissue is represented in the total circulating DNA is dependent on the mechanism and efficiency by which apoptotic cells are eliminated from the tissue. As with any other diagnostic technique, practical application of circulating DNA technology is dependent on concurrent increase in the sensitivity and reproducibility of molecular based-assays. The potential use of circulating DNA for cancer detection could be greatly enhanced by developing isolation methods that result in less degradation and by adapting assay methods to use the low amounts that can be isolated. Because of the limitations of conventional markers, there has been a search for additional sources of specificity so as to expand the target pool of cancer-associated molecules. Circulating cells and DNA offer such opportunity for detection molecular aberrations in plasma/serum, or other body fluids, that accurately reflect the situation in primary tumor. This will, however, require the development of methodological consistencies so as to allow valid comparisons between various assays based on circulating cells or DNA. Objective and Scope The primary purpose of this initiative is to encourage the development of technologies for isolating and characterizing exfoliated cells, circulating cells, and plasma/serum DNA. A secondary purpose is the analytical validation of existing and/or newly developed technologies for their usefulness in cancer detection. Analytical validation refers to the measurement of sensitivity and reproducibility of the proposed assay/technology. The long- term goal of the technology development is to identify a panel of well- characterized biomarkers derived from exfoliated cells and/or circulating DNA that can be sampled in a clinical setting. These methodologies will be tested and validated in future population-based clinical trials, and integrated into a comprehensive information system that will be developed under the Early Detection Research Network (www.cancer.gov/edrn). In pursuit of these goals, the NCI invites applications which address the following areas: o Development of high-throughput, high-yield technologies for isolating exfoliated cells, circulating cells and DNA in body fluids; o Development of methods for enrichment and preservation of exfoliated cells, circulating cells and DNA isolated from body fluids; o Development of sensitive, high-throughput molecular, cytomorphometric, immunologic, and other relevant technologies to isolate and characterize tumor cells in malignant effusions for detection of low tumor burden, to help distinguish reactive cells from tumor cells, and to perform accurate assays on circulating DNA; o Validation of the sensitivity and reproducibility of current technologies for isolating and characterizing exfoliated cells, circulating cells and DNA isolated from body fluids. MECHANISMS OF SUPPORT This RFA uses the SBIR and STTR mechanisms, which are set-aside programs. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Future unsolicited, competing-continuation applications based on this project will compete with all SBIR/STTR applications and will be reviewed according to the customary peer review procedures. The anticipated award date is approximately 9-11 months from the respective receipt date. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW SBIR/STTR applications using the standard receipt dates for NEW applications described in the current SBIR/STTR Omnibus Solicitation. As there are multiple receipt dates, it is possible that an unfunded application can be resubmitted under this RFA as a revised application. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats. Specifically, if you are submitting an application budget of $100,000 total costs (direct, F&A and fee) or less, use the modular budget format. For applications requesting more than $100,000, use the non-modular budget format. Instructions for both are described in the current SBIR/STTR Omnibus Solicitation. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. Except as otherwise stated in this RFA, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, December 2003, available at http://grants.nih.gov/grants/policy/nihgps_2003/. Applications may be submitted for support as Phase I STTR (R41) or Phase I SBIR (R43) grants; Phase II STTR (R42) or Phase II SBIR (R44) grants; or the SBIR/STTR FAST-TRACK option as described in the SBIR/STTR Omnibus Solicitation. Phase II applications in response to this RFA will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. A Phase II application must be a logical extension of the Phase I research but not necessarily a Phase I project supported in response to this RFA. Fast Track applications will benefit from expedited evaluation of progress following the Phase I feasibility study for transition to Phase II funding for expanded developmental work. PROJECT PERIOD AND AMOUNT OF AWARD The SBIR/STTR Omnibus Solicitation indicates the statutory guidelines of funding support and project duration periods for SBIR and STTR Phase I and Phase II awards. For this RFA budgets up to $100,000 in total costs and time periods up to 1 year for Phase I can be requested. Budgets up to $500,000 in total costs per year and time periods of up to 2 years may be requested for Phase II. Total costs include direct costs, F&A, and fee/profit. FUNDS AVAILABLE The NCI intends to commit approximately $1 million a year for two years to fund a total of two to five Phase I and/or Phase II applications under the SBIR/STTR set-aside funding mechanism. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. ELIGIBLE INSTITUTIONS: Eligibility requirements are described in the SBIR/STTR Omnibus Solicitation. Only small business concerns are eligible to submit SBIR/STTR applications. A small business concern is one that, on the date of award for both Phase I and Phase II agreements, meets ALL of the criteria as described in the current SBIR/STTR Omnibus Solicitation. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. On an SBIR application, the principal investigator must have his/her primary employment (more than 50 percent) with the small business at the time of award and for the duration of the project. The PI on an STTR application may be employed with the small business concern or the participating non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant small business concern, which is characterized by an official relationship between the small business concern and that individual. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct questions about scientific/research issues to: Sudhir Srivastava, Ph.D., M.P.H. Division of Cancer Prevention National Cancer Institute 6130 Executive Boulevard, EPN Room 3144 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3983 FAX: (301) 402-8990 Email: [email protected] o Direct your questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: [email protected] o Direct questions about financial or grants management matters to: Shane Woodward Grants Administration Branch National Cancer Institute Fairview Center Building, Suite 300 1003 West 7th St. Frederick, MD 21701-4106 Telephone: (301) 846-1017 FAX: (301) 846-5720 Email: [email protected] LETTER OF INTENT Prospective applicants are asked to submit a letter-of-intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Sudhir Srivastava, Ph.D., M.P.H. Division of Cancer Prevention National Cancer Institute 6130 Executive Boulevard, EPN Room 3144 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3983 FAX: (301) 402-8990 Email: [email protected] SUBMITTING AN APPLICATION The PHS 398 research grant application must be used for all SBIR/STTR Phase I, Phase II, and Fast-Track applications (new and revised). Effective October 1, 2003, applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Prepare your application in accordance with the SBIR/STTR Omnibus Solicitation and the PHS 398. Helpful information for advice and preparation of the application can be obtained at http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf. The NIH will return applications that are not submitted on the 5/2001 version of the PHS 398. For further assistance, contact GrantsInfo; Telephone: (301) 710-0267; Email: [email protected]. SUPPLEMENTARY INSTRUCTIONS Support for the second year will be contingent upon Institute programmatic evaluation to ensure that investigators are accomplishing the goals presented. USING THE RFA LABEL: The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. The RFA label is also available at http://grants.nih.gov/grants/funding/phs398/labels.doc or http://grants.nih.gov/grants/funding/phs398/labels.pdf. The title and number of this RFA must be typed on line 2 of the face page of the application and the YES box must be marked. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) To expedite the review process, at the time of submission, send two additional copies of the application and all five copies of the appendix materials to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) Appendices should be comprised of unbound materials, with separators between documents. APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e., FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html). This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. RECEIPT OF APPLICATIONS. Applications must be received on or before the receipt dates listed on the first page of this announcement. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Research (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NCI. Incomplete and/or non-responsive applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Cancer Advisory Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals within the context of the SBIR/STTR Program. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score: o Significance o Approach o Innovation o Investigator o Environment ALL SBIR/STTR APPLICATIONS 1. Significance: Does the proposed project have commercial potential to lead to a marketable product or process? Does this study address an important problem? What may be the anticipated commercial and societal benefits of the proposed activity? If the aims of the application are achieved, how will scientific knowledge be advanced? Does the proposal lead to enabling technologies (e.g., instrumentation, software) for further discoveries? Will the technology have a competitive advantage over existing/alternate technologies that can meet the market needs? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Is the proposed plan a sound approach for establishing technical and commercial feasibility? Does the applicant acknowledge potential problem areas and consider alternative strategies? Are the milestones and evaluation procedures appropriate? 3. Innovation: Does the project challenge existing paradigms or employ novel technologies, approaches or methodologies? Are the aims original and innovative? 4. Investigators: Is the Principal Investigator capable of coordinating and managing the proposed SBIR/STTR? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers, including consultants and subcontractors (if any)? Are the relationships of the key personnel to the small business and to other institutions appropriate for the work proposed? 5. Environment: Is there sufficient access to resources (e.g., equipment, facilities)? Does the scientific and technological environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See additional information and criteria included in the section on Federal Citations, below.) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See additional information and Inclusion Criteria in the sections on Federal Citations, below.) Human Subjects: 1. Protection of Human Subjects from Research Risks - for all studies involving human subjects. See instructions and "Guidance for Preparing the Human Subjects Research Section. If an exemption is claimed, is it appropriate for the work proposed? If no exemption is claimed, are the applicant's responses to the six required points appropriate? Are human subjects placed at risk by the proposed study? If so, are the risks reasonable in relation to the anticipated benefits to the subjects and others? Are the risks reasonable in relation to the importance of the knowledge that reasonably may be expected to be gained? Are the plans proposed for the protection of human subjects adequate? 2. Inclusion of Women Plan - for clinical research only. Does the applicant propose a plan for the inclusion of both genders that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? 3. Inclusion of Minorities Plan - for clinical research only. Does the applicant propose a plan for the inclusion of minorities that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? 4. Inclusion of Children Plan - for all studies involving human subjects. Does the applicant describe an acceptable plan in which the representation of children of all ages (under the age of 21 years) is scientifically appropriate and recruitment/retention is addressed realistically? If not, does the applicant provide an appropriate justification for their exclusion? 5. Data and Safety Monitoring Plan - for clinical trials only. Does the applicant describe a Data and Safety Monitoring Plan that defines the general structure of the monitoring entity and mechanisms for reporting Adverse Events to the NIH and the IRB? CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the required five items described under Vertebrate Animals (section f of the Research Plan instructions) will be assessed. BIOHAZARDS: Is the use of materials or procedures that are potentially hazardous to research personnel and/or the environment proposed? Is the proposed protection adequate? ADDITIONAL REVIEW CONSIDERATIONS: The following items may be also be considered by reviewers but will not be included in the determination of scientific merit. SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget may be considered. For all applications, is the percent effort listed for the PI appropriate for the work proposed? On applications requesting up to $100,000 total costs, is the overall budget realistic and justified in terms of the aims and methods proposed? On applications requesting over $100,000 in total costs, is each budget category realistic and justified in terms of the aims and methods? PERIOD OF SUPPORT: The appropriateness of the requested period of support in relation to the proposed research. PHASE II APPLICATIONS In addition to the above review criteria: 1. How well did the applicant demonstrate progress toward meeting the Phase I objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity? 2. Did the applicant submit a concise Commercialization Plan that adequately addresses the seven areas described in the Research Plan item J? 3. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? AMENDED APPLICATIONS In addition to the above criteria, the following criteria will be applied to revised applications. 1. Are the responses to comments from the previous SRG review adequate? 2. Are the improvements in the revised application appropriate? PHASE I/PHASE II FAST-TRACK APPLICATION REVIEW CRITERIA For Phase I/Phase II Fast Track applications, the following criteria also will be applied: 1. Does the Phase I application specify clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II? 2. Did the applicant submit a concise Commercialization Plan that adequately addresses the seven areas described in the Research Plan, item J? 3. To what extent was the applicant able to obtain letters of interest, additional funding commitments, and/or resources from the private sector or non-SBIR/ STTR funding sources that would enhance the likelihood for commercialization? 4. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? Phase I and Phase II Fast-Track applications that satisfy all of the review criteria will receive a single rating. Failure to provide clear, measurable goals may be sufficient reason for the scientific review group to exclude the Phase II application from Fast-Track review. RECEIPT AND REVIEW SCHEDULE Letter-of Intent-Receipt Dates: January 17, 2005; May 16, 2005; September 14, 2005 Application Receipt Dates: February 14, 2005; June 13, 2005; October 12, 2005 Peer Review Dates: June/July 2005; October/November 2005; February/March 2006 Council Reviews: September 2005; February 2006; June 2006 Earliest Anticipated Start Dates: January 1, 2006; April 2006; July 2006 AWARD CRITERIA Applications submitted in response to an RFA will compete for available funds with all other recommended SBIR and STTR applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review; o Availability of funds; and o Relevance to program priorities. For FAST-TRACK applications, the Phase II portion may not be funded until a Phase I final report and other documents necessary for continuation have been received and assessed by program staff that the Phase I milestones have been successfully achieved. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. See http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); and efficacy, effectiveness, and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (See NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998, at http://grants.nih.gov/grants/guide/notice-files/not98-084.html.) Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a 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 for the NCI for Data and Safety Monitoring of Clinical trials, see http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. For additional information, see NIH Guide Notice on Further Guidance on a Data and Safety Monitoring for Phase I and II Trials at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available at http://www.cancer.gov/clinical_trials/. SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing (http://grants.nih.gov/grants/policy/data_sharing) or state why this is not possible. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: (a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and (b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research is available online at http://cme.nci.nih.gov/. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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