CORRELATIVE STUDIES USING SPECIMENS FROM MULTI-INSTITUTIONAL PREVENTION AND TREATMENT TRIALS Release Date: November 13, 2000 (see replacement PA-03-064) PA NUMBER: PA-01-015 National Cancer Institute Letter of Intent Date: Jan. 4, 2001, May 4, 2001, Sep. 3, 2001, Jan. 4, 2002, May 3, 2002, Sep. 3, 2002 Receipt Date: Regular receipt dates 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 (PA) replaces PA-98-099, which was published in NIH Guide, August 14, 1999. This PA will expire on October 2, 2002. PURPOSE The Cancer Therapy Evaluation Program and the Cancer Diagnosis Program of the Division of Cancer Treatment and Diagnosis and the Cancer Biomarkers Research Group of the Division of Cancer Prevention, National Cancer Institute invite research grant applications from institutions or consortia capable of performing clinical translational research on promising predictive and prognostic markers. These studies should focus on clinical correlative or mechanistic studies that will be useful for cancer risk assessment, early detection, prognosis, and for predicting response to therapy and to prevention interventions. NCI encourages accessing tissue specimens from the NCI Clinical Trials Cooperative Groups (NCI Cooperative Groups) or other large multi-institutional treatment and prevention clinical trials that have studied well defined patient populations and have outcome data available. This Program Announcement (PA) is intended to support collaborations between researchers with promising correlative markers and clinical trials groups with access to patient populations essential for validation studies. Researchers who are interested in accessing specimens are encouraged to contact the NCI Cooperative Groups or visit the Cancer Diagnosis Program website (http://www.specimens.ims.nci.nih.gov) if ongoing collaborations are not in place. This PA will utilize the investigator-initiated research project grant (R01) mechanism for analysis of specimens from large multi-institutional clinical trials and the exploratory/pilot grant (R21) mechanism for pilot exploratory studies. Investigators interested in conducting laboratory correlative studies on single institution trials may also consider two additional Program Announcements from the National Cancer Institute: PA-01-010 (Exploratory Studies in Detection, Diagnosis, and Prediction) and PA-00-047 (Quick-Trials for Novel Cancer Therapies). 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 NCI supports an extensive network of clinical and laboratory research studies related to cancer detection, prevention and therapy through contracts, grants and cooperative agreements. The Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD) supports a program of integrated national networks of clinical investigators and institutions (NCI Clinical Trials Cooperative Groups) for the conduct of large scale, multi-institutional clinical trials. The Community Oncology and Prevention Trials Research Group, Division of Cancer Prevention (DCP), supports programs to improve clinical oncology in community settings and conduct prevention and control trials. Presently, the NCI Cooperative Groups conduct approximately 400 clinical trials evaluating approximately 20,000 cancer patients per year. The Cooperative Groups have established tumor banks that provide access to tumor specimens from large numbers of patients with a variety of malignancies. The clinical trials organizations maintain statistical databases and are capable of correlating laboratory data with clinical outcome. The Early Detection Research Network (EDRN) of the Division of Cancer Prevention has created a research platform for collaborating with the clinical trials community and appointed liaisons for the various NCI Cooperative Groups. The EDRN is available for assistance in validation studies and researchers may form collaborations through its Associate Member Program (http://edrn.nci.nih.gov). Recently, investigators in molecular genetics and immunobiology have discovered new promising biomarkers that may identify patients who would benefit from specific therapeutic strategies. Technological advances in PCR, flow cytometry, immunohistochemistry, in situ hybridization and high- throughput, high yield array technologies will allow laboratory investigators to do multiple analyses on tumor specimens and study tumor heterogeneity in a variety of tumor types. Many opportunities exist for conducting correlative laboratory studies that may be immediately relevant to cancer treatment. In addition, opportunities exist for the molecular characterization of precancer and early stage cancer through analysis of specimens from treatment and prevention trials. This PA is designed to promote collaborations and interactions between basic researchers and clinical investigators to advance research on clinical correlations that can improve therapeutic approaches. NCI is seeking to encourage correlative laboratory studies linked to large scale multi- institutional clinical trials. In many instances, the laboratory investigators are already recipients of R01 or P01 support for their basic research. These laboratory investigators may not have access to patient specimens or outcome data for large scale analysis. The Clinical Trials Cooperative Groups have established tumor and specimen banks for specific diseases, and reference labs necessary for the diagnosis and monitoring of patients. This initiative proposes to link these peer-approved activities and for a relatively small additional investment provide a mechanism to obtain definitive data on the relationship of biological features and the clinical behavior of the tumors or other human tissues. Objectives and approaches will be investigator-initiated with NCI assisting investigators to assure that promising new approaches will be moved rapidly into clinical practice. Research Goals and Scope The objectives of this PA are to foster collaborations and interactions between basic researchers, private industry, and clinical investigators to perform clinical translational research on promising predictive and prognostic markers. These studies should focus on clinical correlative or mechanistic studies that will be useful for cancer risk assessment, early detection, prognosis, and predicting response to therapy and to prevention interventions. These studies should focus on correlations between biologic features of tissue specimens collected from the NCI Cooperative Groups or other large multi-institutional clinical trials and patient outcomes. This PA will utilize the R01 investigator initiated research grant mechanism to support clinical correlative studies on large multi-institutional clinical trials for validation of promising predictive or prognostic markers and the exploratory/pilot grant mechanisms (R21) to support pilot exploratory studies. For the R01 grant submissions, preliminary data, including relevant animal models or analysis of patient specimens, that supports the hypotheses must be provided. Because the R21 grant mechanism is designed to support pilot or feasibility studies, preliminary data as evidence of feasibility are not required. The correlative studies should be based on strong and testable hypotheses. A clear rationale should be given for the experimental design and technical methodologies selected. The hypotheses tested must relate to potential clinical applications such as patient monitoring for preventive or therapeutic interventions, development of new therapeutic strategies or testing new biomarkers for the identification of patient subsets for specific prevention or treatment approaches. The laboratory assays must use specimens from patients receiving defined treatments in large clinical trials such as phase III clinical trials. Applications must include a statistical section describing the study design and plans for analysis of data designed to test the hypotheses. All investigators are encouraged to work with multi-institutional organizations or form a consortium in order to access sufficient numbers of patient specimens and clinical information to test the proposed hypotheses. Some examples of therapeutic laboratory correlates may include but are not limited to: (1) phenotypic or genotypic alterations which appear to correlate with the development of therapy resistance; (2) loss or inactivation of tumor suppressor genes related to prognosis; (3) analysis of basal membrane factors or genes related to tumor invasion and metastases; (4) studies of chromosomal rearrangements or deletions that may be used for risk assessment, early detection, or prognosis; (5) correlation of tumor growth factors or oncogenes with response to therapies during cancer progression; (6) alterations in cell cycle control; (6) characterization of immune response with association to new immunotherapies for prevention or treatment; (7) evaluation of serum or tumor biomarkers for risk assessment, early detection, or prognosis; (8) analyses of expression of cellular receptors for growth factors or differentiating agents; (9) defining and targeting specific populations of cells for therapy; (10) analysis of in vitro response of tumor cells to growth factors/differentiating agents; and (11) evaluating accessible sites for precancerous changes occurring in less accessible sites, for instance the oral cavity as a surrogate site for the lung in smokers. Surrogate sites may be anatomically- associated, such as oral cavity to lung cancer, or may be functionally related, such as scalp hair follicles to prostate cancer, both of which have androgen receptors. Researchers who have previously not collaborated with the NCI Cooperative Groups or Division of Cancer Prevention Programs are encouraged to contact them and discuss potential collaborations to obtain access to NCI-supported specimen banks and outcome data for laboratory analysis under this PA. NCI staff (see Inquiries) will be able to provide assistance in identifying NCI Cooperative Groups that would be interested in collaborating with basic science investigators on laboratory and clinical studies of new markers. The NCI Tissue Expediter is available to assist investigators in determining the appropriate tissue resource for their research project (http://www.cdp.ims.nci.nih.gov/expediter.html). Information on how to access NCI-supported specimen banks including contacts for the NCI Cooperative Group banks is available at the following web address: http://www.specimens.ims.nci.nih.gov. The NCI Cooperative Groups have mechanisms in place to review proposals for access to NCI Cooperative Group tissue banks from prevention and treatment trials. A letter from the appropriate NCI Group Chair confirming approval to provide specimens in the event of NCI funding of the PA grant application should be included in the grant application. For Intergroup tissue banks, a letter from the Intergroup tissue bank chair should also be included. MECHANISM OF SUPPORT Support of this program will be through the National Institutes of Health (NIH) research project grant (R01) mechanism and the exploratory/developmental grant (R21) mechanism. Applicants will be responsible for the planning, direction, and execution of the proposed project. All PHS and NIH grants policies will apply to applications received and awards made in response to this PA. Applicants for the R21 grant mechanism may request up to $100,000 direct costs (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 and support may not exceed two years. The R21 grants are non-renewable and competitive continuation of projects developed under this program will be through the R01 research grant mechanism. Applications for the R01 grant mechanism may not exceed five years. NIH grants policies apply to these awards. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. 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. Applications may be from a single institution or may include arrangements with one or more institutions (e.g., consortia, NCI Groups) if appropriate. 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: Ms. Diane Bronzert Cancer Therapy Evaluation Program National Cancer Institute 6130 Executive Boulevard, Room 734, MSC 7432 Bethesda, MD 20892-7432 Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: db85g@NIH.GOV Dr. Tracy Lugo Cancer Diagnosis Program National Cancer Institute 6130 Executive Boulevard, Room 6035A, MSC 7388 Bethesda, MD 20892-7388 Telephone: (301) 496-1591 FAX: (301) 402-7819 Email: tl82s@NIH.GOV Dr. Donald Henson Division of Cancer Prevention National Cancer Institute 6130 Executive Boulevard, Room 305 Bethesda, MD 20892 Telephone: (301) 496-9424 FAX: (301) 496-8667 Email: deh@helix.nih.gov Direct inquiries regarding NCI supported specimen banks to: Ms. Marianna Bledsoe Cancer Diagnosis Program National Cancer Institute 6130 Executive Boulevard, Room 6035A, MSC 7388 Bethesda, MD 20892-7388 Telephone: (301) 496-7147 FAX: (301) 402-7819 Email: mb80s@nih.gov Direct inquiries regarding fiscal matters to: Ms. Sara Stone Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-9927 FAX: (301) 496-8601 Email: stones@GAB.NCI.NIH.GOV LETTER OF INTENT Prospective applicants are asked to submit, a letter of intent by the dates mentioned on the first page of this PA, 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 (including NCI Groups or other tissue banks), and the number and title of the PA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information is helpful in planning for the review of applications. It allows staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Ms. Diane Bronzert listed under INQURIES by the letter of intent receipt date. 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. Applications will be accepted at the standard application deadlines as indicated in the application kit. Applications 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. 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. For those applicants with internet access, the 398 kit may be found at: http://grants.nih.gov/grants/funding/phs398/phs398.html. Applicants are encouraged to call the program contacts listed in INQUIRIES above with any questions regarding the goals of this PA. All clinical trials supported or performed by NCI require some form of monitoring. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff to a data and safety monitoring board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional Review Board (IRB). For details about the Policy of the NCI for Data Safety Monitoring of Clinical Trials see http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on Further Guidance on a Data and Safety Monitoring for Phase I and II Trials for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html 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 $250,000 per year for R01 and, up to a total direct cost request of $100,000 per year for R21. (Applications that request more than $250,000 direct costs for R01 in any year must follow the traditional PHS 398 application instructions.) 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 all 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. 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 Public Health Service referral guidelines. Applications will be evaluated for scientific and technical merit 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 five criteria to be used in the evaluation of grant applications are listed below. 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? 2. 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? 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, 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 approved applications. 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, available on the Internet at: 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 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 these policies 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, Correlative Studies Using Specimens from Mulit-institutional Prevention and Treatment Trials, 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. 93.395. 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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