NIH Cancer Biomarkers Research Network (CBRN) Program

NIH Cancer Biomarkers Research Network (CBRN) Program is sponsored by National Institutes of Health (NIH). Supports research on cancer biomarkers, including those relevant to lymphoma and rare cancers.

NIH Guide: THE EARLY DETECTION RESEARCH NETWORK: BIOMARKERS DEVELOPMENTAL LABORATORIES THE EARLY DETECTION RESEARCH NETWORK: BIOMARKERS DEVELOPMENTAL LABORATORIES Release Date: January 20, 1999 (see reissuance RFA-CA-04-006 ) National Cancer Institute Letter of Intent Receipt Date: March 11, 1999 Application Receipt Date: April 26, 1999 The Division of Cancer Prevention (DCP), National Cancer Institute (NCI), invites applications for cooperative agreements to establish a national Network that will have responsibility for the development, evaluation, and validation of biomarkers for earlier cancer detection and risk assessment.

Biomarkers are defined as cellular, biochemical, molecular, or genetic alterations by which a normal, abnormal, or simply biologic process can be recognized, or monitored. Biomarkers are measurable in biological media, such as in tissues, cells, or fluids. The purpose of the Network is to establish a scientific consortium of investigators, academic as well as industrial, with resources for basic, translational, and clinical research.

The consortium will have three main components -- Biomarkers Developmental Laboratories, Biomarkers Validation Laboratories and Clinical/Epidemiologic Centers.

The Biomarkers Developmental Laboratories will have responsibility for the development and characterization of new, or refinement of existing biomarkers, the Biomarkers Validation Laboratories will serve as a Network resource for clinical and laboratory validation of biomarkers, which include technological development and refinement, and the Clinical/Epidemiology Centers will conduct clinical and epidemiological research regarding the wide clinical application of biomarkers.

A Steering Committee composed of the Principal Investigators in the Network and appropriate NCI staff will coordinate the work of the consortium. Logistic support and informatics will be provided through an auxiliary Data Management and Coordinating Center. The purpose of this Request for Applications (RFA) is to establish the Biomarkers Developmental Laboratories.

Subsequent RFAs will be issued to establish the Biomarkers Validation Laboratories, Clinical/Epidemiologic Centers, and the Data Management and Coordinating Center. Applicants are encouraged to seek funding to participate in more than one component, because it is recognized that collaboration already exists in individual institutions for clinical testing and validation of biomarkers/reagents.

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 RFA, Early Detection Research Network: Biomarkers Developmental Laboratories, is related to the priority area of cancer prevention.

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), or at http://www. crisny. org/health/us/health7.

html . Applications may be submitted by 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. Domestic institutions may propose collaborations/consortia with foreign institutions.

Applications will not be accepted from foreign For this RFA, teams composed of NIH intramural investigators may submit project applications to become components of the Network, but they may not request or receive funds from this program.

The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity.

Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity.

Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award." The total project period for applications submitted in response to this RFA may not exceed five years. The anticipated award date is September 30, 1999.

Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. At this time the NCI anticipates that there will be a renewed competition after five years.

If the NCI does not continue the program, awardees may submit grant applications through the usual investigator-initiated grants program. However, before submitting such an application, applicants are advised to contact the program director listed under INQUIRIES. An estimated $4.

6 million will be available for the first year. It is anticipated that 8 to 10 awards will be made. Because the nature and scope of the research proposed may vary, it is anticipated that the size of the awards will also vary.

Funding beyond the initial budget period will be contingent on the continued availability of funds for this purpose, the continued progress of the awardees, and the Network as a whole. At the present time, the NCI has not determined whether or how this solicitation will be continued beyond the present RFA and related RFAs for the Network.

In addition, the NCI anticipates incorporating up to two NIH intramural projects as components of the Consortium. Although no funds from the amount set aside for this RFA will be used to support intramural projects, NIH intramural project applicants must verify that the amount of the resources allocated from intramural sources does not exceed $500,000 direct costs.

For further budget information pertaining specifically to NIH intramural applications, see the "APPLICATION PROCEDURES" "Additional Instructions for NIH Intramural Project Applicants." Funding for the NIH intramural projects will be derived from existing intramural Although the primary tumor can usually be controlled by local therapy, most cancer deaths are caused by metastatic disease.

The goal of early detection and screening is therefore the diagnosis and treatment of cancer before it spreads beyond the organ of origin, perhaps even in its pre-invasive state. Unfortunately, available early detection and screening techniques pick up many tumors at a relatively late stage in their natural history. As a result, decrements in mortality with the current available detection modalities are likely to be modest.

New technologies coming from the field of molecular and cellular biology are able to identify genetic as well as antigenic changes during the early stages of malignant progression. Some of these changes show promise as biomarkers for preneoplastic development or for early malignant transformation.

The application of these emerging technologies in the field of early detection and risk assessment is a high priority in the National Cancer Institute's strategy for reducing mortality from cancer.

Detection of early cancer has been identified as an area of extraordinary opportunity for investment in the NCI 2000 Data show that detection and prompt treatment of pre-malignant or small lesions can reduce mortality, for instance, from mammography and Pap screening.

Therefore, it seems reasonable to explore the application of the new molecular- based technologies for earlier and more specific detection and even for risk assessment, that is, before the cancer physically develops in order to institute chemoprevention. These are the overarching goals of the research Network.

The continued acceleration of scientific progress is no doubt faster than it has ever been; consequently, the need for clinical application is now greater than ever. Research in molecular genetics, cell biology, protein chemistry and immunology has found that cells undergo many changes during neoplastic progression.

Often occurring early in the malignant process, these changes include, for example, production of novel proteins, growth factors, cytokines, etc., in addition to multiple genetic alterations. Because these changes have been associated with malignant transformation, they are now recognized as biomarkers for cancer.

Such biomarkers, whether present in tissue, serum, urine, etc., could serve as indicators of early cancer or as markers of risk for Early detection technologies are also rapidly evolving while existing technologies are undergoing progressive refinement in their sensitivity, specificity, and throughput.

Improved analytic tools have allowed a more detailed examination of the molecular basis of carcinogenesis and provided the ability to identify the molecular and cellular signatures of cancer and to explore the gene- environment interaction relevant to early detection.

To explore fully the application of molecular profiles for earlier detection and risk assessment, it is essential to understand the molecular pathogenesis of cancer, that is, the natural history of tumor progression at the molecular level, so that the biological behavior of an evolving lesion (for example, dysplasia or field change) can be predicted with greater accuracy.

Current observations indicate that cancers usually evolve through many complex cellular processes, pathways, and networks. A better understanding of the circuits in these pathways is critical if we are to successfully apply these molecular-based technologies to Progress in the field, however, is currently impeded by some practical hurdles.

The systematic application of biomarkers for earlier cancer detection or even for risk assessment has been fragmented and not well coordinated. While studies conducted by individual investigators have been useful in advancing our understanding of carcinogenesis, there has been a lack of research emphasis on the continuum of preclinical tumor development, early evaluation of new techniques and their clinical application.

In many of these reported studies the investigators have not been able to explore fully the biological implications or to test systematically the clinical application of these molecular markers. This has resulted, in part, from the lack of a stable connection between basic laboratory research and the opportunity for rapid clinical evaluation.

Other factors contributing to the lack of systematic evaluation include the non- availability of high quality matched specimens from normal, suspicious, preneoplastic and multistage neoplastic lesions along with demographic and follow-up data. As a consequence, much work in this area has been fragmented into numerous small and disconnected studies without complete evaluation.

Usually, the results of these studies cannot even be generalized to the population as a whole. Objectives (applicable to Network as a Whole) This initiative will support the creation of a national Network for early cancer detection with resources for translational research that will include the laboratory sciences, clinical sciences, public health, biostatistics, informatics, and computer sciences.

The goals of the Network will be to discover and to coordinate the evaluation of biomarkers/reagents for the earlier detection of cancer and for the assessment of risk.

Specifically, the objectives of the o the development and testing of promising biomarkers or technologies in institutions having the scientific and clinical expertise, in order to obtain preliminary information that will guide further testing; o the timely and early phase evaluation of promising, analytically proven biomarkers or technologies.

Evaluation will include measures of diagnostic predictive accuracy, sensitivity, specificity, and whenever possible, medical benefits, such as predictors of clinical outcome or as surrogate endpoints for early detection and for prevention intervention clinical trials; o the timely development of biomarkers and expression patterns, sometimes of multiple markers simultaneously, which will serve as background information for subsequent large definitive validation studies in the field of cancer detection o collaboration among academic and industrial leaders in molecular biology, molecular genetics, clinical oncology, computer science, public health, etc., for the development of high throughput, sensitive assay methods for biomarkers from an early detection and risk assessment viewpoint; o conducting early phases of clinical/epidemiological studies, e.g. cross- sectional, retrospective, to evaluate predictive value of biomarkers; and o encourage collaboration and rapid dissemination of information among awardees to ensure progress and avoid fragmentation of effort.

The ultimate impact of new technology on prolonging survival and reducing mortality will not be felt until highly predictive biomarkers are developed for earlier cancer detection or for risk assessment. The success of this effort depends in large measure on exploring the concordance between genetic or molecular markers and the morphologic changes associated with premalignant and pre-invasive lesions that have life-threatening potential.

In other words, we need to identify biomarkers that are predictive of clinical outcomes. Because early detection and treatment issues are often related, the Network will need meaningful participation from the various medical organizations.

In some of its activities, the Network may need to relate programmatically to the research infrastructures supported by NCI (e.g., Specialized Programs of Research Excellence [SPOREs], Cancer Genetics Network, Breast and Colon Cancer Family Registries, Cooperative Human Tissue Network, Cancer Genome Anatomy Project), with ongoing NCI clinical research programs/trials (e.g., Clinical Community Oncology Program, Prostate, Lung, Colon, and Ovarian Trial); or with other health agencies, such as Food and Drug Affairs, Department of Defense, and Veteran Administration.

Certain types of trials in earlier detection, especially those involving treatment, may best be conducted as intergroup studies with treatment- oriented cooperative groups, such as the NCI Clinical Cooperative Groups, NCI designated Cancer Centers, international collaborators, clinical epidemiologists, and health maintenance organizations. The need for such cooperation should be anticipated and provided by the Network leadership.

Scope (applies to this RFA) The scope of this RFA is to establish the Biomarkers Developmental Laboratories (BDL) which will form one of the three scientific components within the Consortium for the Network.

The BDL will conduct translational research in the biology of incipient neoplasia encompassing the development, characterization and testing of biomarkers of early cancer or risk, development of relevant technologies for biomarker detection, and analytical tools for the evaluation of biomarkers.

Translational research in this context is defined as the movement of discoveries from the laboratories into patient or population research settings or the movement of observations from patient settings back to the laboratory.

Biological, morphological, and clinical alterations occurring in premalignant and malignant lesions offer the opportunity to delineate the early stages of tumor progression, thereby providing a wider window of opportunity for intervention.

The National Cancer Institute has identified several high priority research opportunities in early detection and risk assessment: o Determine secreted proteins that correlate with the presence of pre-cancerous o Develop highly sensitive and specific assays to detect cancer related proteins o Develop highly specific and sensitive assays to detect tumor cells in body o Develop highly specific and sensitive assays to detect molecular products of tumor cells in body fluids with emphasis on the identification of molecular determinants (risk factors) in accessible surrogate anatomic sites for the less accessible major cancer sites This initiative encourages the submission of applications in broad categories of translational studies on complex cellular pathways, processes, and networks to identify the molecular and cellular signatures of cells, which can be used for earlier detection or for risk assessment.

The scope of the BDL is limited to translational research leading to identification and/or characterization of biomarkers or to a panel of biomarkers. Special emphasis should be placed on cancers of the prostate, breast, colon, lung, ovary, upper-respiratory tract and other epithelial cancers, which are the major causes of cancer-related mortality and have yet to be controlled with screening and prevention.

The search for new markers should reflect new information about key points in cancer biology (i.e. apoptosis, cell cycle control). However, this initiative will not support research of a fundamental nature, such as studies on growth regulation, cell cycle control, or other basic studies that are not explicitly focused on tumor target systems.

To expedite clinical application, the validation of the biomarkers will be performed in collaboration with the other scientific components of the Consortium. The Early Detection Research Network will consist of four components: 1) the Consortium, 2) a Steering Committee (SC), 3) an Advisory Committee (AC), and (4) a Data Management and Coordinating Center.

Consortium: The Consortium will consist of three scientific components: i) the Biomarkers Developmental Laboratories (BDL), ii) the Biomarkers Validation Laboratories (BVL), and iii) the Clinical/Epidemiologic Centers (CEC). These three components jointly will be known as the Consortium for Biomarkers in Early Detection Research (CBEDR). Each component will be funded through a separate Request-for-Application.

An applicant, however, may seek funding to participate in more than one component.

The awardee will conduct independent research using their U01 funds and the collaborative research using the Core Funds from the Headquarters (see definition of "Headquarters" below) and from the set-aside funds in their U01 pending approval by the Steering Committee and release by the Each laboratory/center, which will be managed by a Principal Investigator, may include academic and industrial biotechnology investigators who are involved in cancer detection and diagnostic research.

In order to expedite the translational research, the Consortium will be supplemented by the ad hoc participation of additional investigators (academic or community-based) who are able to validate the results of laboratory studies through patient accrual. It is anticipated that the CBEDR will consist of experts in basic molecular science, laboratory technology, clinical studies, biometry, and in epidemiology.

The expertise in laboratory science should include conducting research in the biology of incipient neoplasia encompassing the development, characterization and testing of biomarkers of early cancer and risk, development of relevant technologies for biomarker detection, and analytical tools for the evaluation of biomarkers for detection and risk assessment.

The expertise in laboratory validation should include knowledge and practice of Standard Operating Procedures (SOPs), and experience in the statistical evaluation of accuracy, precision, reproducibility and performance characteristics of tests in multi-center settings. Expertise in patient accrual and associated clinical issues for pilot studies will be needed to apply basic science discoveries to clinical settings.

Computational and informatic needs of the Consortium will be provided by a Data Management and Coordinating Center. Therefore, the Consortium, in concert with the Steering Committee, the Advisory Committee, and the Data Management and Coordinating Center will constitute the Network (see definition of "Network" NIH intramural laboratory may be one of the research members in the Consortium.

Steering Committee: The Steering Committee will have major scientific management oversight, including monitoring the activities of the Data Management and Coordinating Center. For administrative structure, and responsibilities of the Steering Committee, see "Collaborative Responsibilities."

Advisory Committee: A separate Advisory Committee will be established by the NCI to ensure that the overall Network is adequately responsive to promising opportunities, exhibits the desired degree of flexibility in composition and decision-making and makes prioritization decisions free from conflicts of interest. For further details, see "Collaborative Responsibilities."

Data Management and Coordinating Center: The Data Management and Coordinating Center will provide logistic support for the conduct of the Steering and Advisory Committee meetings, provide statistical and data management support for protocol development, conduct analysis of clinical data, and informatics. It will study applied and theoretical approaches to the simultaneous analysis of multiple markers.

In addition, the Data Management and Coordinating Center will develop common informatic and analytical tools for the interpretation of data and instruments for checking uniformity, consistency, accuracy, timelessness, reproducibility and privacy of the data. Headquarters: The institution of the Chair of the Steering Committee will serve as the Headquarters of the Network.

The Chair of the Steering Committee can be any Principal Investigator involved in the Network. The Chair serves as the Principal Investigator of the Headquarters awards and implements the scientific, operational and organizational policies of the Network. The headquarters provides the executive leadership, scientific direction, and management for the Network.

It serves as a center for information dissemination to investigators and institutions in the Network as well as to others outside the Network.

Funds will reside with 1) the Consortium For Biomarkers in Early Detection Research, 2) the Data Management and Coordinating Center, and 3) the Consortium for Biomarkers in Early Detection Research: The Principal Investigators will have funds available through the individual U01 awards to support the development of the scientific program and clinical protocols.

All investigators will be encouraged to seek supplemental funding through the Small Business Innovation Award (SBIR, R43 and/or R44), Small Business Technology Transfer (STTR, R41 and/or R42), Exploratory/Developmental grants (R21/R33), and other research support mechanisms. Data Management and Coordinating Center: The Data Management and Coordinating Center will be funded through a separate RFA.

Core Funds for the Headquarters: Core funds will be available to the Chair of the Steering Committee. Applicants under this RFA need not apply for the Core Funds in their U01 applications. Core funds are reserved for post-award collaborative research and for a variety of other functions: 1.

Core funds would be used to expand participation within the Consortium through supplemental funding to an investigator, not part of the Consortium. However, receipt of these supplemental funds does not, in and of itself imply membership on the Steering Committee. Core Funds that are provided for these supplements will represent direct cost only.

Facilities and administrative costs will not be provided for research activities supported by the Core supplemental funds. 2. Funds will often be needed in moving a new marker test to the point at which it can be validated at multiple centers and in larger populations.

Test reagents will require scale-up at this point, and the Steering Committee will require sufficient funding to contract to laboratories or companies that can scale up production and maintain quality of the reagents (e.g., monoclonal antibodies, labels, etc.) and to Clinical/Epidemiologic Centers for subject accrual. Funds will also be required for data management, travel, meetings, and other collaborative activities of the Network.

The above activities will be supported by the funds that will be added to the Chair's award (The Core Funds) and the use of this fund will be restricted The Steering Committee will be responsible for coordinating the research effort across the Consortium, including the Data Management and Coordinating Center, and will formulate policy and procedures for the operations and management of the The following example illustrates the functions of the Network and the support it offers for moving basic research findings into clinical practice.

An investigator within the Consortium identifies a putative biomarker through original laboratory research. Based on the pilot research findings, the putative marker seems to be useful for early cancer detection. The investigator can then approach the Steering Committee for additional evaluation of the marker and possible support for further testing.

The Steering Committee then has the responsibility to review the data on the potential marker using its standing formal criteria as a guide. The Steering Committee can consult the Advisory Committee to obtain information on the requirements and need for additional research on the marker.

It also can consult the Biomarkers Validation Laboratories and the Clinical Centers regarding requirements for laboratory tests, needs for quality assurance, and the availability of patient groups for clinical validation. If necessary, scientific resources from other Centers can be pooled to conduct studies. Concurrently, the informatic team in the Data Management and Coordinating Center can develop tools for the analysis of results.

There will also be flexibility so that investigators outside the Consortium could form a collaboration with one of the existing centers, or directly bring their discoveries to the Steering Committee (e.g., By Letter of Intent). To support such efforts, the Steering Committee will be able to use core funds to supplement the investigator's ongoing research.

The investigator, in turn, will agree to share his research findings and become part of the Consortium . Awardee: The institution to which a cooperative agreement (U01) is awarded. Principal Investigator (PI): The investigator who is designated by the applicant organization to direct the project to be supported by the U01 grant or NIH intramural project in response to the RFA.

The PI will assume the responsibility and accountability to the applicant organization officials and to the NCI for the performance and the proper conduct of the research supported by the U01 mechanism or the NIH intramural project in accordance with the terms and conditions that are stated in the RFA. The PI will be a voting member of the Steering Committee.

NCI Program Director: A scientist administrator from the NCI extramural staff, the Program Director will not only provide normal stewardship for the U01 grants awarded under this RFA, but will also be substantially involved in the scientific coordination and collaboration within the Network, will have responsibilities in broad scientific and programmatic issues and serve as a voting member of the Steering Committee, as defined under the "Terms and Conditions of Award."

Terms and Conditions of Award These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. [Part 92 applies when state and local governments are eligible to apply as a "domestic organization."]

Additionally, the following terms and conditions will be incorporated into the U01 award statement, and will be provided to the PI and the awardee institutional official at the time of award. For NIH Intramural Projects, these terms and conditions will be provided to the PI of the NIH Intramural Project and the NIH Institute Scientific Director at the time of selection to be a Network component.

Under the cooperative agreement, the NCI purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity.

Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Program A.

Awardee Rights and Responsibilities: Extramural and NIH Intramural Projects The PI of a U01 or NIH Intramural project will have the primary authority and responsibility to define objectives and approaches, including research design and protocol development; participant recruitment and follow-up, if applicable, data collection, quality control, interim data and safety monitoring, and to plan, conduct, analyze, and publish results.

The PI of a U01 or NIH Intramural project will assume responsibility for managing individual protocols/research and collaborative projects approved by the Steering The PI of a U01 or NIH Intramural project will assume responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the research supported by the U01 or the NIH intramural project in accordance with the terms and conditions of the award.

The PI of a U01 or NIH Intramural project will serve as a voting member of the steering committee, will attend the Planning meeting and two Steering Committee meetings in the first year and two Steering Committee meetings a year in The PI of a U01 or NIH Intramural project will be responsible for accepting and implementing the goals, priorities, common protocols, procedures, and policies agreed upon by the Steering Committee.

The PI of a U01 or NIH Intramural project will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

The PI of a U01 or NIH Intramural project will be responsible for collaborating on common research designs or protocols, including methods and requirements for joint participation and collaboration as directed by the Steering Committee, and handling of data, including appropriate sharing of methods and data among collaborating organizations. B.

NCI Extramural Staff Responsibilities There will be only one NCI Program Director for the Network.

However, the Program Director may be assisted by other NCI staff on specific scientific The NCI Program Director will have substantial scientific programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship for grants as Because of the Network's diverse research agenda and the number of tasks that have to be accomplished to achieve its goals, a number of NCI staff members may interact with the Network as needed.

The NCI Program Director (a staff member in the Division of Cancer Prevention) will assist the Network on scientific and programmatic issues, and advise the Network on the availability of other resources. A member from the Chemoprevention Branch, NCI, will be available to assist the Network on intermediate endpoints and on any ongoing chemoprevention trials relevant to the Network studies.

A member from the Biometry Branch, NCI, will be available to assist the Network on the issues of study design, sample size, and other statistical computations.

The other NCI staff may assist and advise the Network on relevant programmatic and scientific issues through the NCI The Program Director will convene the initial meeting of the Steering Committee, have voting membership on the Steering Committee, and, as determined by that committee, its subcommittees.

Although the PI will have lead responsibilities in all collaborative tasks and activities, it is anticipated that the NCI Program Director will have lead responsibilities in sharing the broad programmatic issues among awardees.

The NCI reserves the right to adjust funding, withhold support, suspend, terminate or curtail the study or an individual award in the event of a failure to comply with the Terms and Conditions of Award, substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, or human subject ethical issues, whenever C: Collaborative Responsibilities o The Steering Committee will have major scientific management oversight and responsibility for developing collaborative research designs, protocols and manuals, facilitating the conduct and monitoring of studies, and reporting study results.

The Steering Committee will be composed of the Principal Investigators from each member of the Consortium, the Principal Investigator of the Data Management and Coordinating Center, and the NCI Program Director. Each member will have one vote. The Chair (non-NIH person) will be selected by the Steering Committee.

The institution of the Chair of the Steering Committee will serve as the Headquarters (for definition see "Network Organization"). Subcommittees will be established by the Steering Committee, as it deems appropriate; the NCI Program Director will serve on subcommittees as he/she deems appropriate. o After all the Network components have been funded, the Steering Committee will convene its first Planning Meeting.

Initial responsibilities of the Steering - establish Network policies and procedures; - establish policies and procedures for collaborative projects, protocols, and Network-defined projects; - establish policies and procedures for reviewing changes in projects not showing translational significance at the request of the laboratories/centers, and making recommendations to the NCI for replacing the project with more promising ones with revised scope and adjusted budget (increase in the budget will