EXPLORATORY STUDIES IN CANCER DETECTION, PROGNOSIS AND PREDICTION Release Date: October 31, 2000 (see replacement PA-03-003) PA NUMBER: PA-01-010 National Cancer Institute THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. This Program Announcement replaces and supersedes two prior Program Announcements, PA-98-022 (Exploratory Studies in Cancer Diagnostics) and PA- 98-042 (Exploratory Grants for Correlative Laboratory Studies and Clinical Trials). This PA will expire on October 2, 2002. PURPOSE The Division of Cancer Treatment and Diagnosis and the Division of Cancer Prevention of the National Cancer Institute invite research grant applications from interested investigators to explore innovative strategies for the early detection of cancer, assessment of cancer prognosis or prediction of response to cancer treatment. Advances in the understanding of basic cancer biology and the development of powerful molecular technologies are leading to the identification of many new abnormalities in precancerous and cancer cells. This initiative promotes the initial evaluation of molecular or cellular characteristics in human specimens and/or the development of assays that may result in important advances in the detection, diagnosis and treatment of cancers. The objective of this Program Announcement is to encourage applications for exploratory (R21) grants from individuals who are interested in testing new ideas that are based on a sound scientific rationale and may advance progress in cancer detection and diagnosis. The R21 grant mechanism is utilized to support pilot projects or feasibility studies that may produce innovative advances in science. This Program Announcement replaces and supersedes two prior Program Announcements, PA-98-022 (Exploratory Studies in Cancer Diagnostics) and PA- 98-042 (Exploratory Grants for Correlative Laboratory Studies and Clinical Trials). In addition, its scientific scope now includes biomarkers for cancer detection and risk assessment. Investigators interested in laboratory correlative studies linked to clinical trials may also consider two additional Program Announcements from the National Cancer Institute: PA-98- 099 (Correlative Studies Using Specimens from Multi-Institutional Treatment Trials) and PA-00-047 (Quick-Trials for Novel Cancer Therapies) (see below). Exploratory studies focused on cancer imaging, including new imaging modalities, agents and analysis methods, are more appropriate for PA-98-008 (Exploratory/Developmental Grants for Diagnostic Cancer Imaging), sponsored by the NCI Biomedical Imaging Program. RESEARCH OBJECTIVES Background The National Cancer Institute is interested in the development and testing of improved methods for detecting characteristics of cancer that are useful for the clinical management of cancer patients or individuals at risk for developing cancer. Much of the work in the early stages of this development process is exploratory and descriptive, focusing on the search for molecular and cellular differences between tumors and premalignant or normal tissues. When differences are found, an attempt must be made to determine their clinical significance by correlating the changes with clinical parameters. The further development of an approach will be driven by its potential to answer clinical questions. It has been difficult for investigators to obtain support for early translational studies through the traditional research project grant (R01) mechanism. Such studies may not be sufficiently developed for a standard R01 grant application, may be more descriptive than mechanistic in nature, and may be considered high-risk. The exploratory grant (R21) mechanism is more appropriate for these investigations. We expect that results generated through these R21 grants will serve as a basis for planning future clinical research project (R01) grant applications or NCI cooperative clinical trial group studies. Because the exploratory grant mechanism is designed to support innovative ideas, extensive preliminary data as evidence of feasibility are not required. However, the applicant must develop a sound research plan. The opportunity for discovery of new information about the behavior of premalignant or tumor cells in the human body and the potential significance of the information to be obtained are major considerations in the evaluation. Research Goals and Scope The major goal of this initiative is to promote the initial evaluation of new molecular or cellular characteristics of premalignant cells or tumors or the development of assays that will be useful for cancer detection, diagnosis and/or prognosis. New biomarkers and laboratory assays are needed for cancer screening and risk assessment, for pathologic characterization of malignant tumors and assessment of disease prognosis, and for prediction and measurement of response to treatments, particularly with novel therapeutic or chemopreventive agents. Investigators are encouraged to pursue new clinical insights and to consider the full array of potentially informative biological characteristics of tumor cells and tissues. The investigator should provide a strong rationale for proposing that a particular biomarker or assay has the potential to address a significant clinical problem. Investigators should propose innovative approaches to clinical questions or substantial improvements in existing strategies. For example, an investigator might propose to adapt and optimize an experimental assay technique for application to clinical specimens. Proof-of-principle studies might also include comparisons of assay formats (i.e., DNA-based vs. protein-based) in a clinical setting, or initial retrospective or prospective studies to correlate assay results with patient outcomes. Investigators are encouraged to employ robust techniques that could be rapidly and widely adopted. The laboratory assays must utilize human specimens. Where applicable, evidence of statistical support should be included to ensure proper correlation of laboratory measurements with clinical outcomes. This initiative is intended to support translational studies which identify promising new means for cancer detection and diagnosis and which provide the initial, critical information necessary to decide whether potential clinical utility justifies further investment. Applicants should explain the significance of the proposed research in terms of its potential for clinical application. Priority will be given to well-designed studies that will help us to differentiate those new markers and techniques that have potential clinical utility from those that do not. This Program Announcement is sponsored jointly by the Cancer Diagnosis Program and the Cancer Therapy Evaluation Program (Division of Cancer Diagnosis and Treatment) and the Cancer Biomarkers Research Group (Division of Cancer Prevention) of the National Cancer Institute. The Cancer Diagnosis Program supports research projects to develop better clinical tests to improve the assessment of cancer prognosis and guide the choice of cancer treatment. New methods are sought to refine the classification and staging of tumors, to clarify the influence of germ-line or other genetic mutations on the course of the disease, to predict the response of tumors to therapy and to monitor the recurrence of cancer. The Cancer Therapy Evaluation Program is interested in funding new mechanistic or correlative laboratory studies that are relevant to clinical studies and trials of cancer therapy and supportive care. The correlative studies must have a future clinical application such as development of new treatment strategies, predicting response to specific therapies, or selection of patients for therapies. Examples of correlative studies include, but are not limited to, analysis of predictive markers, pharmacogenetic studies, studies of drug resistance, and analysis of immune response. The Cancer Biomarkers Research Group, Division of Cancer Prevention, supports and facilitates a broad spectrum of research activities that address early development and initial validation stages of molecular biological and genetic biomarkers that can be applied in risk prediction, early detection and primary prevention of cancer. The NCI Tissue Expediter (http://www-cdp.ims.nci.nih.gov/expediter.html) can assist investigators in locating and determining appropriate human tissue resources for their research project. Applicants should remember that Federal and local regulations for the protection of human research subjects apply to the use of human tissue specimens in research, and these issues must be addressed in the application (refer to the instructions in the application kit). Additional information is available at http://www-cdp.ims.nci.nih.gov/brochure.html, and from the Office for Human Research Protections (http://www.hhs.gov/ohrp/). Applicants proposing research with human subjects must observe NIH policies regarding the inclusion of women, minorities and children (see below). MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) exploratory/developmental (R21) grant mechanism. The total project period for an application submitted in response to this PA may not exceed two years. These grants are non-renewable. Though the size of award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/developmental project; direct costs are limited to $100,000 (four budget modules) per year unless the application includes consortium costs, in which case the limit is $125,000 direct costs (five budget modules) per year. Applicants will be responsible for the planning, direction and execution of the proposed project. NIH grants policies will apply to the applications received and awards made in response to this Program Announcement. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Tracy G. Lugo Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-1591 FAX: (301) 402-7819 Email: TL82S@nih.gov Dr. Sudhir Srivastava Cancer Biomarkers Research Group, Division of Cancer Prevention National Cancer Institute 6130 Executive Boulevard, Room EPN-330 F Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 435-1594 FAX: (301) 402-0816 Email: srivasts@mail.nih.gov Ms. Diane Bronzert Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Room 734 MSC 7432 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: db85g@nih.gov Direct inquiries regarding fiscal matters to: Ms. Sara Stone Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-9927 FAX: 301-496-8601 Email: Stones@gab.nci.nih.gov APPLICATION PROCEDURES The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov. For those applicants with internet access, the 398 kit may be found at: http://grants.nih.gov/grants/forms.htm. Applicants are strongly encouraged to call the program contacts listed in INQUIRIES above with any questions regarding the goals of this PA. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $100,000 per year ($125,000 if there are consortium/contractual costs). The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). At the top of the page, enter the total direct costs requested for each year. This is not a form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is domestic or foreign. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years; - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this PA and will be returned without further review. The standard requirements for length and format in PHS 398 application kit must be observed. The title and number of the PA must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the checklist, and five signed, exact, single-sided 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) Applications must be received by the regular receipt dates indicated in the application kit beginning February 1, 2001. The Center for Scientific Review (CSR) will not accept any application in response to this PA that is essentially the same as one currently pending 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. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or 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. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged 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 field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? In this case, what is the potential for translation of basic research to clinical applications? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? This includes, where applicable, the statistical rationale for the study design and the choice of sample size. Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. 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? 4. 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)? 5. 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 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 applications assigned to that IC. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. 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 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 PA, Exploratory Studies in Cancer Detection, Prognosis and Prediction, is related to 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 and 93.395. Awards are made under authorization of the Sections 301 and 405 of the Public Health Service Act as amended ( 42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro- Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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