CORRELATIVE STUDIES USING SPECIMENS FROM MULTI-INSTITUTIONAL TREATMENT TRIALS Release Date: August 14, 1998 PA NUMBER: PA-98-099 P.T. National Cancer Institute Application Receipt Dates: November 17, 1998; February 1; June 1; and October 1, each year thereafter PURPOSE The Cancer Therapy Evaluation Program (CTEP) and Cancer Diagnosis Program (CDP) of the Division of Cancer Treatment and Diagnosis, National Cancer Institute invite research grant applications from institutions or consortia capable of and interested in performing translational research on promising predictive and prognostic markers. These studies should focus on correlations between biologic features of tissue specimens collected from the NCI Clinical Trials Cooperative Groups (NCI Groups) or other large multi-institutional clinical trials and patient outcomes. The markers should be assessed for their ability to predict clinical outcomes in the context of therapy or response to particular therapies. 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 are encouraged to contact the NCI Groups 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. The R21 grant mechanism is utilized for pilot projects or feasibility studies to support exploratory research that may produce innovative advances in science. The R21 grant mechanism provides limited funds (maximum of $100,000 direct costs per year not including indirect costs of any collaborating institutions) for short-term (up to two years) research projects. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA, Correlative Studies Using Specimens from Multi-Institutional Treatment Trials, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). 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. 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 per year in direct costs, not including indirect costs for collaborating institutions, 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. Awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, PHS Publication No. (OASH) 94-50.000 (Rev. April 1, 1994). RESEARCH OBJECTIVES Background Insights into the biologic function and clinical relevance of growth factors, genes that promote and suppress neoplasia, mechanisms of treatment sensitivity and resistance and functions of the immune system provide important new clinical research opportunities for investigators studying patients enrolled on therapeutic clinical trials. Historically, clinical prognostic factors have assisted clinicians in the selection of appropriate therapeutic interventions. Recent advances in molecular genetics and immunobiology have identified new promising markers for the identification of patients who would benefit from specific therapeutic strategies. New technological advances in methodologies such as PCR, flow cytometry, immunohistochemistry, in situ hybridization and 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 can be expected to be immediately relevant to cancer treatment. The NCI supports an extensive network of clinical and laboratory research studies related to cancer 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 primary goal of these trials is the definitive evaluation of clinical treatment programs. Presently, the Groups conduct approximately 400 clinical trials evaluating approximately 20,000 patients per year. The Groups have access to tumor specimens from large numbers of patients with established tumor banks in a variety of malignancies. They maintain statistical databases and are capable of correlating laboratory data with the clinical outcome of patients. These investigators stand ready and willing to integrate basic laboratory studies with clinical 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 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 for large scale analysis. The Clinical Trials Cooperative Group mechanism (U10) provides support for patient accrual, 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. Objectives and approaches will be investigator-initiated with the CTEP and CDP assisting investigators to assure that promising new approaches will be moved more 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 translational research on promising predictive and prognostic markers. Theses studies should focus on correlations between biologic features of tissue specimens collected from the NCI Clinical Trials Cooperative Groups (NCI Groups) or other large multi-institutional clinical trials and patient outcomes. The markers should be assessed for their ability to predict clinical outcomes in the context of therapy or response to particular therapies. Researchers who have previously not collaborated with the NCI Groups are encouraged to contact them and discuss potential collaborations to obtain access to patient specimens and NCI-supported specimen banks for laboratory analysis under this PA. NCI staff from CTEP and CDP (see Inquiries) will be able to provide assistance in identifying NCI Groups that would be interested in collaborating with basic science investigators on laboratory and clinical studies of new markers. The NCI Tissue Expediter (see Inquiries) will be available to assist investigators in determining the appropriate tissue resource for their research project. Information on how to access NCI-supported specimen banks including contacts for the NCI Group banks is available at the following web address: http://www.specimens.ims.nci.nih.gov. The NCI Groups have mechanisms in place to review proposals for access to NCI Group tissue banks. 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. The grant application will be deferred if the appropriate letters of support are not received prior to review. 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, extensive 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 therapeutic response, development of new treatment strategies or identification of patient subsets that may relapse, or for specific treatment approaches. The laboratory assays must utilize 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-center organizations or form a consortium of institutions in order to access sufficient numbers of patient specimens and clinical information to test the proposed hypotheses. Some examples of therapeutic laboratory correlates include, but are not limited to: o Phenotypic or genotypic alterations which appear to correlate with the development of therapy resistance; o Loss or inactivation of tumor suppressor genes related to prognosis; o Analysis of basal membrane factors or genes related to tumor invasion or metastases; o Studies of chromosomal rearrangements or deletions that may be used as prognostic indicators; o Correlation of tumor growth factors or oncogenes with response to therapies; o Alterations in cell cycle control; o Characterization of immune response associated with new immunotherapies; o Evaluation of use of serum or tumor markers that correlate with tumor progression; o Analyses of expression of cellular receptors for growth factors or differentiating agents; o Defining and targeting specific populations of cells for therapy. 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. 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. NIH POLICY AND GUIDELINES ON THE 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://www.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit, one month prior to the application receipt date, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions (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 NCI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Ms. Diane Bronzert Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Room 734, MSC 7432 Bethesda, MD 20892-7432 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: db85g@NIH.GOV APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). Applications must be received by November 17, 1998, and on the regular receipt dates indicated in the application kit starting in 1999. 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. The title and number of the program announcement must be typed in Section 2 on the face page of the application. The completed original application and five legible copies must be sent or delivered 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by study sections of the Center for Scientific Review (CSR), 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? 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. 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 Division of Cancer Treatment and Diagnosis 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 Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Room 700, MSC 7388 Bethesda, MD 20892-7388 Telephone: (301) 496-1591 FAX: (301) 402-7819 Email: tl82s@NIH.GOV Direct inquiries regarding NCI supported specimen banks to: Ms. Marianna Bledsoe NCI Tissue Expediter, Cancer Diagnosis Program National Cancer Institute 6130 Executive Boulevard, Room 700, 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. Kelli Oster Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, ext. 261 FAX: (301) 496-8601 Email: OSTERK@GAB.NCI.NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and part 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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