CANCER INTERVENTION AND SURVEILLANCE MODELING NETWORK (CISNET) RELEASE DATE: May 14, 2004 RFA: RFA-CA-05-018 Update: The following update relating to this announcement has been issued: June 25, 2009 - This RFA has been reissued as (RFA-CA-09-025). EXPIRATION DATE: October 15, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Cancer Institute (NCI) (http://www.nci.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.393, 93.394 LETTER OF INTENT RECEIPT DATE: September 14, 2004 APPLICATION RECEIPT DATE: October 14, 2004 This RFA is a reissue of RFA-CA-99-013 and RFA-CA-02-010, which were published in NIH Guide on August 18, 1999 and July 9, 2001. THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute (NCI), invites applications from domestic and foreign applicants to support collaborative research using simulation and other modeling techniques to describe the impact of interventions (i.e., primary prevention, screening, and treatment) in population- based settings in the United States or in non-US settings that will shed light on US population-based trends. It is well known that great progress in the war against cancer is possible by the complete use and adequate delivery of existing modalities of cancer control. The primary goals of this research are: 1) to determine the impact of cancer control interventions on observed trends in incidence and/or mortality; and 2) to determine if recommended interventions are having their expected population impact by examining discrepancies between controlled cancer intervention study results and the population experience. Once a general understanding of the various factors influencing current trends has been achieved, a number of secondary goals may be addressed. Applicants may propose secondary goals of modeling the potential impact of new interventions on future national trends, and/or determining the impact of targeted cancer control interventions on population outcome (i.e. evaluating optimal cancer control strategies). Prior to the first issuance of CISNET most models of cancer interventions had been developed to describe hypothetical cohorts in a trial or other limited clinical settings. It is not the purpose of this RFA to focus on the analysis of hypothetical or trial-based cohorts and/or cost-effectiveness analyses, but rather to support analyses based on realistic scenarios of population impact. Projects will focus on models describing the population impact of the observed dissemination of cancer control interventions as well as other factors on observed national incidence and/or mortality trends. CISNET was originally funded as a cooperative agreement (U01) for two phased-in rounds of funding. In September 2000, CA-99-013 funded seven grants in breast cancer and one in prostate and one in colorectal cancer. A second round, funded under CA-02-010 in August 2002, funded 5 grants in lung cancer as well as two additional grants for colorectal cancer and one in prostate cancer. The first round of funding will end in September 2004, and the second round in summer/fall 2006. For a summary of currently funded CISNET projects from the first and second rounds of funding (which started in FY 2000 and 2002 respectively) cancer see http://www.cisnet.cancer.gov. This reissuance of CISNET will be limited to modeling applications focusing on breast, prostate, lung, and colorectal cancer. While the reissuance of CISNET will not be limited to grantees previously or currently funded, CISNET will no longer fund models that are either starting from scratch or have not been previously applied to the analysis of population trends. This means that models should have been applied to multiple real birth cohorts representing the actual population experience. Models that have been applied only to hypothetical cohorts, as is sometimes done to model trial data or estimate cost effectiveness, will not be considered. The emphasis in this reissuance is in the application of already developed models to study the population impact of existing or emerging cancer control interventions. Applicants who were funded by either CA-99-013 or CA- 02-010 are eligible to apply for funding, as well as those who have never been funded under a CISNET RFA. In addition, applications are being solicited for cancer site-specific coordinating centers for all four of the cancer sites covered in CISNET (i.e. breast, prostate, colorectal and lung cancer). To keep applications focused, each will be limited to a single cancer site. The CISNET project requirements call for the development of site-specific working groups that will: (1) facilitate comparative analyses, (2) allow modeling groups’ access to a broader array of data resources and interdisciplinary expertise and (3) provide a forum for discussions of validation and other methodologic issues. The CISNET will allow for diversity and originality of modeling approaches that can be compared using uniform criteria. New investigators will be expected to join in the ongoing collaborative activities already underway. The Division of Cancer Control and Population Sciences, which fulfills a federal-level function to respond to evolving surveillance questions of national policy relevance, helps focus research questions and acts as a conduit to national data resources necessary for parameter estimation, model calibration, validation and population trends. An emergent property of this collaborative agreement is progress towards a comprehensive understanding of the determinants of cancer site-specific trends at the population level and a better understanding of the science of modeling. RESEARCH OBJECTIVES Background Modeling is the use of mathematical and statistical techniques within a logical framework to integrate and synthesize known biological, epidemiological, clinical, behavioral, genetic and economic information. Prior to CISNET much of the simulation and other modeling techniques had been utilized to describe the impact of cancer interventions (i.e., primary prevention, screening, and treatment) for hypothetical cohorts or in trial and other clinical settings. The goal of this RFA is to promote the application and extension of these models to population-based settings in order to ascertain determinants of cancer trends. This information is critical to the NCI because of the necessity of understanding if recommended interventions are having their expected population impact, and predicting the potential impact of new interventions on national trends. These studies will often involve extrapolation of results of controlled cancer intervention studies to estimates of U.S. population and community effectiveness. This type of modeling addresses issues of population-based policies and programs, and is distinct from individual level models of risk and models of clinical decision making used at the individual patient- physician level. An additional goal of this concept is to advance methodology for modeling and to develop more uniform criteria for model validation in the population setting. The NCI has a longstanding need to provide answers to critical policy questions, which can only be answered through an indirect synthesis of available information and assumptions. A commitment to modeling of this type will allow NCI to bring the most sophisticated tools available for evidence-based planning in order to: 1. Be responsive to challenges due to the increasing pace of technology, and to provide short-term answers while randomized controlled trials (RCT’s) are still in progress. In the future we will be increasingly faced with new interventions, biomarkers, diagnostic and genetic tests that will become widely disseminated prior to rigorous testing in controlled settings, and therefore the evaluation of population impact will become even more important. 2. Address emerging questions while they are still being debated in the policy forum. For example, new smokeless tobacco products are coming on the market, and modeling of their potential impact can benefit the FTC and other policy makers. 3. Translate RCT evidence of quantities to the population setting. 4. Provide estimates of quantities that will never be derived from RCT’s. For example, half of Americans alive today who ever smoked are ex-smokers. It is important to understand the patterns of quitting, the process of carcinogenesis for ex-smokers, and the implications for future lung cancer trends. Prior to the CISNET, NCI had supported a variety of small efforts in this area through in-house work, contracts and grants. The majority of extramural efforts have been directed at the analysis of specified cancer control interventions using a variety of modeling approaches applied to a hypothetical cohort or in the context of a trial or other limited settings, while the in-house work has mainly been directed toward addressing cancer surveillance issues at the national level. There has been growing recognition that much can be gained by integration of these two approaches. Models have increasingly been used in recent years to inform public health policy decisions at the national level. In Europe, the cervical and breast cancer screening models have been used to design, monitor and evaluate national screening programs in several countries . Models have been used in the United States to understand the implications of dramatic changes in national cancer statistics, such as patterns of increasing incidence related to screening for breast and prostate cancer [2-4], and improving survival due to the dissemination of breakthrough treatment approaches in Hodgkin's Disease and testicular cancer [5-6]. One of the major accomplishments of CISNET to date has been building an infrastructure for the comparative analysis of population-based models to answer important policy-based questions. This infrastructure has included the following components: 1. Model Development: Prior to the initiation of CISNET approximately 3 years ago, there were only a few models that were available to study population trends in incidence and mortality as a function of cancer control interventions. Some grantees had existing models that had been developed for other purposes, e.g. cost-effectiveness analysis of hypothetical cohorts, design of randomized controlled trials, etc. These models have been retooled to support multiple cohorts, which incorporate the full complement of intervention types (i.e. treatment, screening, and prevention). Other models have been built from scratch. The development, calibration, and validation of these models has been a major infrastructure building activity, and those models funded in the first round are now coming “online” to start to address important cancer control issues. In the process of model development, CISNET has achieved the stated goal of making outside investigators more aware and interested in cancer surveillance and control issues. 2. CISNET Web Sites: There are three CISNET related web sites: Model Profiler: One major hindrance to understanding differences between disparate model results is the lack of comparable documentation on model structure. The CISNET collaborative group has developed a state-of-the-art interactive web site, called the Model Profiler, which allows modelers to put components of their models into templates to facilitate comparisons of model structure. Each CISNET team is given a private model profile web site on which to maintain their model profile information. Since the core documentation format is the same for each group, the published profile information is readily comparable among models. After the documentation has matured, each CISNET member group can "publish" selected documents on the main CISNET interactive web site. All of the grantees funded in the first round have published at least the core documents to the CISNET site. This site is accessible to all CISNET members and allows them to view and compare model profile documents over a range of different models. Talks comparing a particular model component across the various grantees are held at the CISNET meetings and rely on information from the model profiler. A user will, in the future, be able to "publish" a portion of their model profiler so that it is available to the general public and can be used as a link to be cited in publications. Providing such details is responsive to suggestions that published models provide enough details to allow for better understanding and model comparisons . CISNET Interactive Web Site: This interactive web site is available only to CISNET members, and serves as the main “message board”. It includes places to post meeting talks and agendas and host discussion groups, a home page for each cancer site and grantee and a section on data resources. CISNET Public Web Site (http://cisnet.cancer.gov/): This is a public site that includes a list of the grantees and recent developments within the CISNET group. It serves as a place for those outside CISNET to learn about the group, and has a contact e-mail address for inquiries and for posing policy relevant issues for the CISNET group to consider. 3. Organizational Structure and Meetings: CISNET has instituted an organizational structure, which allows for efficient working relationships (http://cisnet.cancer.gov/about/orgchart.html). There are four working groups, one for each of the cancer sites, and a methodology group. Each group has a rotating Principal Investigator (PI) leader and one or more NCI scientific coordinators. The PI leaders for each working group serve on the steering committee along with the NCI program director, and the chair of the steering committee is chosen from among the PI’s. There are two meetings a year. At the annual meeting (in November) approximately one day is devoted to general issues with all groups meeting together, one day to methodologic issues, and one day to cancer site-specific meetings. At the mid-year meetings (May - June), each cancer site group meets separately. Recently, a computer programmers’ support group was formed as a forum for discussion of issues of importance to those programming statistical simulation models (e.g. random number generation and management). 4. Development of Additional Mechanisms for Scientific Exchange: In addition to the web sites and meetings discussed above, the CISNET publication policy provides a mechanism for groups to comment on each others articles prior to submission. In addition, a CISNET journal club has been instituted, where relevant articles are discussed on phone-in conference calls. 5. Affiliate Member Policy: CISNET allows interested modeling groups that share CISNET objectives to apply for affiliate membership, which provides access to the web site, the ability to attend meetings and participate in discussion groups, etc. There is no funding associated with affiliate membership status. 6. Data Resources: One advantage of the CISNET collaboration is the ability to gain access to data resources that otherwise may not have been available. This is accomplished through joint requests using the imprimatur of the NCI when necessary. In some cases additional sources of funding have been necessary to support both data management and scientific staff to assist in utilizing the data. Requests stress collaboration rather than data access. Each modeling group has posted information on data resources to which they have access on the web site, and conditions for their use. Scientific Questions Being Addressed: CISNET investigators are engaged in a wide range of policy-relevant modeling studies including: 1. Development of Base Case Questions: A major strength of having a consortium of modelers is the ability to employ a comparative modeling approach. While each modeler has areas of individual focus, whenever possible, common "base" questions have been developed that allow for comparisons across models. Sometimes widely different results from models are often difficult to resolve, and base cases provide a chance to reach common consensus on important questions, and to better understand differences between models. In these base case questions, a set of common population inputs is used across all models (e.g., dissemination patterns of screening and treatment, mortality from non- cancer causes), and a common set of intermediate and final outputs is developed to help understand differences and similarities across models. In breast cancer, all seven grantees are addressing the question “What is the Impact of Adjuvant Therapy and Mammography on US Breast Cancer Mortality: 1975-2000?" This is a timely issue, especially given the recent controversy, which arose from the publication of meta-analyses of randomized controlled trials of mammography screening [8-9]. As part of the collaboration, the NCI staff has brought together disparate data sources to model the dissemination of adjuvant therapy  and screening mammography in the US. The plan is to publish a summary of these analyses in high-profile journal article(s), and the Journal of the National Cancer Institute (JNCI) Monograph Series has agreed to publish a complete authoritative report on this analysis. For prostate cancer, the grantees are focusing on the impact of Prostate Specific Antigen (PSA) screening on US incidence and mortality trends, and then will add the impact of treatment. Prostate cancer poses an interesting contrast to breast cancer because, despite the widespread dissemination of PSA screening and various treatment modalities, the RCT’s evidence is considerably spottier. In colorectal cancer, the group is embarking on a series of base case questions, the first of which represents a hypothetical test scenario to better understand the implications of how each group is modeling the natural history of disease, especially the development of adenomas into cancer. In lung cancer, the focus will be on modeling the impact of smoking on lung cancer mortality from 1975-2000. While the impact of smoking on lung cancer is generally well understood, there are certain aspects of this modeling which are still a major challenge, e.g., gaining a better understanding of the process of carcinogenesis for those who have quit smoking, understanding the role of changing tobacco products on population trends, and understanding trends in lung cancer among non- smokers. 2. Breast Base Case Spin-Off Questions: The breast base case serves as a “jumping off” point for each grantee as they vary the basic formulation to focus on areas of individual interest. Spin-off issues that are actively being pursued include: modeling the impact of using alternative more biologically-based natural disease history formulations, especially continuous time tumor growth models which include microscopic fatal metastases which are initially undetectable; analyses for different racial/ethnic uninsured/underinsured groups; a unique Bayesian approach to update its prior estimates of treatment efficacy to obtain posterior estimates of community effectiveness of adjuvant therapy and mammography which best reproduce national mortality trends; geographically based analyses, the role of risk factors in breast cancer trends; and the potential impact of optimal screening intervals. 3. Prostate Cancer: CISNET researchers have published an analysis of trends in the use of the PSA test , for modeling prostate cancer incidence trends to obtain estimates of overdiagnoses associated with PSA screening . In addition, these researchers are investigating the use of modeling to better understand the results of ecologic analyses of the effectiveness of PSA screening. 4. Special Issue of Statistical Methods in Medical Research (SMMR): CISNET was invited to sponsor a special issue of SMMR entitled “Uses of Stochastic Models for the Early Detection of Cancer,” with articles to be submitted in spring 2003. Articles in the issue include: (1) Distribution of Clinical Covariates at Detection of Cancer; Stochastic Modeling and Statistical Inference, (2) Planning Public Health Programs and Scheduling: Breast Cancer, (3) Planning of Randomized Trials (4) The Use of Modeling to Understand the Impact of Screening on US Mortality: Examples from Mammography and PSA Screening, (5) Parameter Estimation for Stochastic Models via Simulation, and (6) Diversity of Model Approaches. 5. Linkages with other Cancer Surveillance and Control Activities: CISNET has sought linkages to be integrated with and responsive to situations where modeling may play an important role. Examples include: Immunochemical Fecal Occult Blood Test (iFOBT): The Agency for Health Research and Quality (AHRQ) and the Center for Medicare and Medicaid Studies (CMS) approached NCI for assistance in studying a reimbursement decision related to the immunochemical FOBT test (http://cisnet.cancer.gov/reports/medicare.html ). Healthy People 2010 Mid-Course Correction Studies: Healthy People 2010 (HP2010) is the DHHS blueprint for achieving the Nation’s health goals to increase quality and years of healthy life, and eliminate health disparities. CISNET modelers have been asked to aid in a mid-course (2005) evaluation to help us determine if reaching HP 2010 upstream goals for cancer treatment, screening, and prevention will enable us to fall short/meet/exceed the downstream 2010 cancer mortality goals, and retarget our efforts if necessary. Impact of Harm Reduction Tobacco Products: Discussions with the Tobacco Control Research Branch, DCCPS, have indicated that modeling the potential public health impact of new smokeless tobacco products can benefit the FTC and other policy makers. Objectives and Scope The objective of this RFA is to take models that have been developed in the first rounds of funding or independently and enhance their areas of application. Investigators will apply these models to specific high priority, policy-relevant questions in a comparative fashion. This reissue will capitalize and expand upon model development work already completed. While the reissuance of CISNET will not be limited to grantees previously funded, it will no longer fund models that are either starting from scratch or have not been previously applied to the analysis of population trends. Instead the components of population models will be refined and applied. Areas of application will include more refined analyses of current trends, and a renewed emphasis on future trends and optimal cancer control planning. While the original issuance focused primarily on discovery (i.e. basic mathematical and statistical relationships necessary for the development of multi-cohort population models) and development (i.e. data sources and realistic scenarios to evaluate past intervention impact in the population setting and project future impact), the reissuance will continue development efforts and will greatly enhance the delivery element (i.e. synthesizing relevant scenarios for informing policy decisions and cancer control planning implementation). While some new mathematical and statistical derivations may be necessary, they should not be the center-piece of these applications. Instead the focus of the application should be on identifying important cancer surveillance and control questions, obtaining the data sources and making model modifications as necessary to run the model, and producing results that are meaningful and packaged in a way that policy makers and cancer control planners can understand. Inclusion of interdisciplinary expertise will be essential in this phase of CISNET. Applications should demonstrate modeling capability, and propose a specific research plan. However, applicants should be flexible enough to accommodate further refinement and integration with other efforts. The purpose of these efforts is to model the impact of the observed dissemination of cancer control interventions in the population, rather than using observed population trends to postulate new etiologic factors. However, these models can include components which model the impact of population changes in both modifiable and non-modifiable risk factors. Models, which include the synergistic impact of multiple interventions simultaneously, are desirable. Models can be of the entire US population, a region of the country, or some specific identified population where unique data exists on the implementation of an intervention, or in a subpopulation of specific interest (e.g., rural poor). However, whenever possible, inference should relate to the US as a whole. Models can be developed for non-US populations, but should be justified based on their applicability to understanding US cancer trends. It is not the primary purpose of this RFA to support analysis of hypothetical or trial-based cohorts and/or cost effectiveness analysis (even though there may be secondary analyses of this type), but rather to support analysis based on realistic scenarios of population impact. Examples of areas of interest and types of questions are given below. Note that these are examples only, and applicants should not feel constrained to choose areas of application from this list only. Natural History: What new quantifiable statements can be made concerning estimates and uncertainty in the adenoma-colorectal cancer sequence? What is the range of natural history models associated with in situ breast cancer, and what are the implications of these natural history models for the overdiagnosis of disease? Treatment: What is the contribution of treatment to observed declines in prostate cancer mortality, especially the transition from the use of androgen deprivation therapy after biochemical failure (i.e. rising PSA levels) to use in the adjuvant setting? How can future improvements in the quality of care and the general health status of older individuals result in increased use and responsiveness to treatment? Screening: What is the impact on incidence and mortality of both the increased dissemination of currently established screening modalities (e.g. FOBT and sigmoidoscopy) and the potential dissemination of new or more novel modalities (e.g. screening colonoscopy, advanced imaging modalities, immunochemical FOBT, fecal mutagen tests and other innovative biomarkers)? As screening trial results for PSA, flexible sigmoidoscopy, chest x-ray, and spiral computed tomography (CT) start to become available over the next decade; how do these results alter our understanding of population trends in incidence and mortality? Risk Factors/Prevention: Given that obesity is a major problem that is getting worse, what are the implications for projections of breast and colorectal cancer mortality? What is the expected dissemination of the use of Tamoxifen for women with different risk profiles, and what is the projected mortality reduction associated with these levels of dissemination? Resources/Tradeoffs: How would resource requirements be affected by the use of risk stratification models (e.g. [14-15]) or biomarkers that would allow selective screening and/or selective surveillance monitoring of higher risk individuals? What is the national burden of iatrogenic morbidity from prostate cancer treatment among screen detected men and how do we weigh this against the potential mortality gains? Health Disparities: Can we use population trends to better understand differences in the natural history of prostate cancer between white and black men, and how can we use this information to better target interventions? How do racial disparities in obesity impact future trends? What is the impact of racial, economic, and insurance status disparities in the use of adjuvant therapy and mammography on breast cancer mortality? System Modeling: What is the impact of changing Medicare reimbursement policies on screening, treatment, and cancer mortality? Current Events: CISNET models should be able to help translate (in a timely manner) the impact of specific emergent results from epidemiologic, genetic, treatment, prevention, and screening studies to the population setting. Recent examples include how the mutation of a gene involved in non-small cell lung cancer (NSCLC) increases the likelihood that the drug, gefitinib, will show a beneficial response , the prevention trial which showed that although finasteride reduced the risk of developing prostate cancer, those who developed the cancer had had higher grade tumors , the international clinical trial which found that post-menopausal survivors of early-stage breast cancer who took the drug letrozole after completing an initial five years of tamoxifen therapy had a significantly reduced risk of cancer  . Healthy People 2010, NCI’s 2015 Goals, and Emerging Technologies: CISNET models can help translate the relationship between upstream (e.g. screening, modifiable risk factors) and downstream (e.g. mortality) goals. It can also help target the upstream factors which have the most potential for influencing mortality. In addition, CISNET models can help target what types of emerging technologies have the largest potential to help us reach NCI’s 2015 goal of eliminating suffering from cancer. Is enough known about these technologies to have confidence in these projections? Can modeling point to the most important studies that could be conducted to gain more confidence with respect to their operating characteristics? Coordinating Centers In the first issuance of CISNET no funds were specifically allocated for coordination activities. In this reissuance we have set aside funds for coordinating centers for all four cancer sites, i.e., breast, prostate, colorectal and lung cancer. Coordinating centers should be site specific because each center needs to be totally conversant with the data sources, modeling issues, and policy questions specific to that cancer site. Coordination activities, under the general direction and consensus of the NCI and PI's, will include: (1) formulating, prioritizing, and coordinating work on base case and other questions (including outside requests), (2) negotiating common requests for outside data sources, (3) consensus building and coordinating critical evaluation of disparate results, (4) preparing inputs and collecting and processing common outputs for model comparisons, and (5) coordinating synthesis papers and group responses bringing together disparate information to inform policy makers. Through the coordinating center, each CISNET cancer site group will constitute an established expert knowledge base that can provide technical advice on evolving policy-relevant surveillance questions. Because all of the expertise necessary to accomplish these goals are not likely to exist in one place, the coordinating center would have discretionary funds to tap outside expertise for particular tasks, pay for access to data sources, and provide funds to modeling groups to mount intensive efforts to provide technical advice while issues are still relevant in the policy area. Even though one group would be tasked with being the coordinating center, CISNET would be run through consensus, as it has in the past. Coordinating center grant applications could come from current CISNET grantees, current applicants for modeling grants, or other applicants with population-based modeling experience. Budget Funds can be allocated towards adapting existing models to address new issues and for the development of data sources to inform these models. First and early years budgets should be directed at improving the use of these models to answer a well-developed list of specified questions. Later years should increasingly focus on delivery and synthesis of results into formats which are directly usable by policy makers. Funds should also be allocated for making models more accessible for use by others. No funds should be allocated to creating new population based- models or the basic mathematical structure of new models. Modeling groups will be required to attend the following two meetings: (1) An annual meeting (approximately 3 days) in which all four cancer sites will meet together. (2) Mid-year meetings (approximately 2 days) when each cancer site meets separately. For purposes of budgeting, funds should be requested for up to three persons to travel to each of these two meetings. If a PI, or an institution wishes to submit several applications, which share a common structure (e.g., models for breast and prostate cancer which share a similar computing framework), funds to develop or enhance that common structure should be included separately in each application, and duplication of funding activities will be negotiated at the time of award. Likewise, travel funds for each application should be considered separately, and overlapping funding will be negotiated at the time of award. Finally, a submission from one institution may contain subcontracts for consultation from another institution, which may be unnecessary if both institutions are funded under CISNET. Areas of potential duplication of funds across multiple applications should be clearly identified. Applicants who were funded under CA-02-010 may have a remaining period of funding still available when they are funded by this RFA. In that circumstance, they may be asked to terminate their remaining funding under CA-02-010 in order to initiate their funding under this RFA. It is anticipated that the budgets for the modeling grants will range between approximately $100,000 - $250,000 total costs for the first year, with only modest changes in funding after that. We expect the average budget to be approximately $200,000 total costs in the first year. The budget for the modeling grants will be limited to a cap of $250,000 total cost for the first year, with suggested maximum increases of 3 percent for each year after the first year. If increases are larger than 3 percent, strong scientific justification must be given. The budgets for the coordinating centers will be capped at $150,000 direct costs, excluding third party indirect costs. In the award, it is expected that approximately $50,000 will be restricted for a Discretionary Fund used to pay for expertise and programming time to gain access to data sources that model specific input components of interest to the entire group, and that address timely issues/questions that were not anticipated in the original application, etc. The budget for the coordinating center should include substantial involvement of the PI (suggested minimum of at least 15% time however a larger commitment is preferable) to provide leadership and coordinate questions to be addressed and synthesis of results. Additional personnel could include statisticians, programmers, administrative assistants, and others with multi-disciplinary expertise as needed. Coordinating centers should include funds to send up to four persons to both the mid-year and annual meetings. If a grantee has a coordinating center and a modeling grant, travel funds should be reduced to eliminate overlap. Budgets for both the modeling grants and the coordinating center should not be in modular format. MECHANISM OF SUPPORT This RFA will use the NIH (U01) is a cooperative agreement award mechanism. As an applicant, you will be primarily responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator- initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July 2005. This RFA uses just-in-time concepts. It also uses the non-modular budgeting formats (see https://grants.nih.gov/grants/funding/modular/modular.htm). Follow the instructions for non-modular budget research grant applicants. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm. The NIH (U01) is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award FUNDS AVAILABLE The NCI intends to commit approximately $1,800,000 in total costs (direct and Facilities and Administrative (F&A) costs) in FY 2005 to fund 6 to 9 new modeling grants in response to this RFA. In addition, NCI intends to commit approximately $950,000 (direct and Facilities and Administrative (F&A) costs) in FY 2005 to fund 4 coordinating centers (one each in breast, prostate, colorectal, and lung cancer. An applicant may request a project period of up to five years. Although an applicant can submit applications for more than one cancer site (either for modeling grants or coordinating centers), each individual application must be limited to one cancer site. Coordinating center grants must be submitted separately from modeling grants, even if one applicant submits both. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. The final awards will reflect the quality of the technical aspects and proposed staff of the applications, adherence to the spirit of intent of this RFA, and a balance of the number of funded applications across the four cancer sites. ELIGIBILE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. Since there are many unique aspects specific to each cancer site, each modeling grant application is limited to a single cancer site. If a PI, or an institution, is submitting several applications that share a common structure (e.g., models for lung and prostate cancer which share a similar computing framework), funds to develop or enhance that common structure should be included separately in each application, and overlapping funding of activities will be considered at the time of award (see Special Requirements - Budget). Similarly, each Principal Investigator (PI) is limited to only one coordinating center grant application per cancer site, and thus up to four applications are possible by one PI. If a PI, or an institution, is submitting a coordinating center applications and a modeling grant application or several coordinating center applications they should submit any potential areas of overlap between the applications, and overlapping funding of activities will be eliminated at the time of award. SPECIAL REQUIREMENTS Separate applications must be made for modeling grants and coordinating centers, even if the same PI is applying for both. Applications must clearly be labeled as either a "Modeling Application" or "Coordinating Center Application". Research Plan Modeling applications in response to the RFA must address the following areas: Specific Aims and Significance: The application must clearly state the surveillance/cancer control research questions which this application is designed to address and the importance of these issues for understanding current or future trends in incidence or mortality trends and/or cancer control strategies in the US. The plan should demonstrate a general understanding of the various factors influencing observed trends before investigating secondary goals of future trends and optimal cancer controls strategies. If the application includes the modeling of trends outside of the US or in subpopulations of the US, justification must be given as to what special insights or understanding this will yield. Applicants should demonstrate the flexibility of their model to estimate the potential population impact of emerging cancer control technologies. Methods: For each research question the applicant should specify data sources for model building, calibration and validation, any additional model components that must be built, and the overall approach to the problem. Background/Work to Date: Applicants should describe in detail work completed to date and work in progress for developing and applying their model. It should be clear to the reviewers of these applications that the models are working population-based surveillance models that have been applied in situations beyond that of hypothetical cohorts or trial- based situations. They should describe the model structure, substantive questions that have been addressed, data sources used for model construction, calibration and validation. They should describe the practical importance of questions that have been addressed, and how their results will help advance informed decision making. In addition they should describe the types of collaborations they have engaged in with others (either within CISNET or outside of CISNET), and the role they have played in these collaborations. Synthesis/Coordination/Collaboration: Applicants should describe ideas for collaborative projects that could be undertaken. These joint projects could involve “base cases” where common model inputs (e.g. dissemination of screening in the US population) and outputs would be mutually agreed upon by cancer site working group participants, sharing of methods and data resources, or synthesis of existing results. While it will be a group decision to actually engage in any particular proposed collaborative activities, applicants will be judged on the soundness of their ideas and understanding of how joint collaborative activities can be conducted in a consortium of this type. Investigators should state their willingness to participate in joint meetings, to share methods and data resources, and to embark on collaborative efforts to decide overall research direction. Investigators will be asked to post project descriptions and pre- submission publications on the CISNET grantees web site for comment and review by the cooperative group. Contractual Arrangements: The application should describe contractual arrangements necessary for acquisition and/or consolidation of data necessary for parameter estimation. Any other contractual arrangements should also be described. Model Sharing: In this reissuance, the NCI requires each applicant to propose a concrete plan for making their models more accessible to those outside the consortium. Ideally, this plan should endeavor to address aspects of the following four components: (1) enhancing understanding of model structure by requiring at least the basic templates of the Model Profiler to be posted on a public website, (2) allow those outside CISNET to pose questions or scenarios (possibly based on national or regional issues of interest) which would lead to specific sets of runs to be conducted by the modelers, (3) enhancing the ability of others to run the models directly by developing public versions of executable programs of model or model subcomponents when feasible, and (4) enhancing access to source code by releasing code in the context of collaborations or other specified scenarios. Applicants should describe how each of these components will be achieved, and can add other components as well. For some aspects of this plan, it is reasonable to assume that interested users may need to provide funding. Coordinating centers applications in response to this RFA must address the following areas: Background and Qualifications: The applicant should describe their knowledge of data sources, policy issues, and modeling issues relevant to the specific cancer site. The applicant should have prior modeling experience with this cancer site, and should describe how this experience is relevant to CISNET activities. Cooperation/Coordination with Modeling Grantees and NCI Scientific Coordinators: Decisions concerning the scientific priorities of the site specific working group, use of discretionary funds, etc. will be made through consensus of the coordinating center, NCI program staff, and the modeling grantees. The coordinating center will be responsible for building group consensus and moving the agenda forward. The applicant should describe general plans for these types of activities. Prioritizing Questions to Be Addressed: The coordinating center should lay out a process for identifying and synthesizing: the set of questions to be addressed by the site specific working group, the timelines for these efforts, which questions are best answered using collaborative or single efforts, and any gaps in the set of questions and how best to fill those gaps. In addition, the coordinating center should work out a general process for handling outside requests to address specific questions/issues including when to seek additional funding or to fit the work within existing support of either the coordinating center (including the use of discretionary funds) or individual grantees. Cooperation with Model Profiler / CISNET Web Site Contractor: NCI has a contract to support the development and use of the model profiler and CISNET members’ only web site. One aspect of the contract involves the use of the model profiler to develop a comparative synthesis of particular aspect of the models (e.g., how they model the improvement in survival associated with screen detection). The applicant should indicate a willingness to work cooperatively with the NCI contractor who maintains the Model Profiler/CISNET Web Site. For more information on the contract for the Model Profiler/CISNET Web site, please contact Dr. Eric Feuer, the NCI Program Director (contact information listed below). Base Cases: The coordinating center will be responsible for managing the development and analysis of base cases. The applicant should specify the role of the coordinating center in managing this process, as well as specific ideas for future base cases. The applicant may state in what type of situations they feel that base cases are appropriate. Synthesis of Results: As CISNET work moves more into the delivery phase, the agenda will shift more to the synthesis of modeling results. Synthesis involves resolving differences when possible, or coming to a clear understanding, differences which remain. Often the problem in comparing disparate modeling results is that many variables are changing simultaneously, which makes isolating differences difficult. Synthesis efforts could involve comparing results entirely within CISNET (e.g. a base case) or a comparison of results between CISNET and outside groups. Applicants should describe their approach to synthesis activities, and ideas for specific issues to be addressed. Current Events: The coordinating center should have a plan for keeping abreast of current policy related controversies, and the latest research results across the spectrum of treatment, screening and prevention for the cancer site. The plan should make use of the models, if appropriate, to help synthesize population-level results related to these controversies and results. Applicants should develop a plan to prioritize analyses related to estimating the population impact of emerging cancer control technologies. Cooperative Agreement Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official at the time of award. Under this cooperative agreement, a partnership will exist between the recipient of the award and the NCI. 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, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. 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 Scientific Staff as described below. 1. Definitions: AWARDEES: Institutions receiving cooperative agreements through this RFA. NCI PROGRAM DIRECTOR: A scientist administrator from the NCI extramural staff, the Program Director, will provide normal stewardship for the U01 grants awarded under this RFA. NCI PROJECT SCIENTIST: A project scientist from NCI who will coordinate the overall scientific efforts and collaborations within the CISNET Network. The NCI Program Director may also serve as the NCI Project Scientist. PRINCIPAL INVESTIGATOR (PI): The investigator who is designated by the applicant organization to direct the project to be supported by the U01 grant. The PI will assume the 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 mechanism. Each institution may have more than one CISNET PI, and a single person may be the PI for applications for more than one cancer site. NCI SCIENTIFIC COORDINATORS: Scientists from the NCI extramural staff designated by the Program Director to coordinate the activities for one of the four cancer sites and the methodology-working group. NCI scientific coordinators will have substantial scientific involvement with the working groups and will help refine research questions. NCI SCIENTIFIC STAFF: Scientific staff from NCI's extramural and intramural programs called upon to provide their expertise to the CISNET efforts. EXTRAMURAL SCIENTIFIC INVESTIGATORS: Scientific staff named in the application from the participating institutions and their subcontractors. CANCER-SITE WORKING GROUPS: There will be four cancer site-specific working groups (breast, prostate, colorectal, and lung cancer). Voting members of each working groups will be the PI's of the modeling grants, the designated NCI Scientific Coordinator, and the PI of the coordinating center. The co-chairs of the working groups will be the NCI Scientific Coordinator and the PI of the coordinating center. METHODOLOGY WORKING GROUP: A group comprised of interested methodologists among the extramural scientific investigators and NCI Scientific Staff. The chairs of the methodology working group will be one Extramural Scientific Investigator (chosen by mutual consent of the Extramural Scientific Investigators on the Methodology Working Group) and an NCI Scientific Coordinator designated by the NCI Program Director. Other subcommittees will be formed by the working group as needed. STEERING COMMITTEE: The steering committee will consist of the four PI's of the site-specific coordinating centers, the NCI Project Scientist, and one NCI Scientific Coordinator as designated by the NCI Program Director. The Chair of the Steering Committee will be one of the PI's as selected by the Steering Committee. The Steering Committee will provide overall direction for the CISNET project and provide oversight to procedures and policies. 2. Awardee Rights and Responsibilities The award recipients must join the NCI CISNET project for the purpose of planning, developing, and conducting collaborative projects to address high priority surveillance research objectives. Within this framework, awardees have primary authorities and responsibilities to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of their studies. Awardees will be required to attend working group meetings and are obligated to adhere to joint decisions for publication and research direction decided on by the Steering Committee and the Working Groups. Awardees will be expected to share information about model structure and assumptions at working group meetings, as well as strategies and data resources for parameter estimation. Awardees will be expected to engage in efforts coordinated by the Working Groups for calibration, validation, and comparison of model results. Awardees will retain custody of and have primary rights to the models and model results developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Awardees are expected to develop and implement a set of procedures for making their models accessible to interested parties. 3. NCI Staff Responsibilities The NCI Program Director will provide review progress reports and perform other administrative duties related to the normal stewardship for the U01 grants awarded under this RFA. The NCI Program Director recommends: reductions to the budget, withholding support, or suspending, terminating or curtailing a study or an award in the event of substantial lack of collaborative participation, failure to make satisfactory progress in fulfilling the stated goals of the project, refusal to carry out the recommendations of the Working Groups or the Steering Committee, or substantial failure to comply with the terms of award. The NCI Project Scientist and his designees 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. The NCI Project Scientist will serve as a member of the Steering Committee. The NCI Project Scientist will designate an NCI Scientific Coordinator for each cancer site and for the methodology group who will serve as a co-chair of the Working Groups. The NCI Scientific Coordinators will provide information about a wide range of data resources, which will be used for parameter estimation and population trends, and will serve as a conduit to the potential utility and access to these resources. In addition, the NCI Scientific Coordinators will call upon other NCI Scientific Staff to provide advice on specific scientific and technical issues as needed. NCI will provide support for a Model Profiler/CISNET Web Site for the CISNET project through a separate contract for use by the awardees. 4. Collaborative Responsibilities A. Steering Committee The Steering Committee will: Be the ultimate decision making body for CISNET, unless a disagreement is brought to arbitration. Review, approve, and provide comments on the written reports and recommendations of the Cancer Site-Specific Working Groups. This approval process should ensure that the proposed activities are consistent with the objectives and scope as specified in the RFA. Review, approve, comment on, and provide directives for implementation based on the written recommendations from the Methodology Working Group. Set publication procedures and policies. Coordinate communication between the Working Groups. Schedule additional meetings and conference calls as needed. B. Working Groups Meet at least twice a year. Refine research questions that are consistent with high priority surveillance research needs. Identify key potential determinants and confounders of population based trends, and to identify useful data resources to inform these models. Collaborate to identify and select common data resources for conducting calibration and independent model validation. Consider the development of common modules that supply intermediate inputs to the central simulation models (e.g., screening histories supplied by a dissemination module, survival improvements in a screening model supplied by a treatment dissemination module). Consider the use of common input data for dissemination, costs, and other parameters based on the best available national estimates. Facilitate comparative analyses, which will improve the credibility of individual models. Evolve into an expert knowledge base to provide technical advice on policy relevant surveillance questions. C. The Methodology Working Group will: Meet once a year, mainly for the purpose of scientific presentation and exchange of ideas, and to coordinate research plans where necessary. Provide a forum for the discussion of methods development associated with the application of micro simulation and other models to population-based questions. At the discretion of the group, provide written recommendations to the steering committee for common methodologic approaches and validation strategies and development of common model components. D. The Coordinating Center will: Coordinate the agendas of the cancer site-specific meetings. Formulate, prioritize, and coordinate work on base case and other questions. Negotiate common requests for outside data sources. Build consensus and coordinate critical evaluation of disparate results. Prepare inputs and collect and process common outputs for model comparisons. Coordinate synthesis papers and group responses bringing together disparate information to inform policy makers. Field outside requests and work with the modeling grantees to determine priorities. Coordinate conference calls and communication within the cancer-site specific working groups. Be required to work cooperatively with the contractor who maintains the Model Profiler/Interactive Web Site. E. Responsibilities of the PI's of the coordinating centers will be to: Convene working meetings. Set meeting agendas. Coordinate communication within the Working Group. Set (in consultation with the working group) the publication agenda and schedule. Serve as a voting member of the Steering Committee, and represent their Working Group to the Steering Committee. 5. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NCI may be brought to arbitration. An arbitration panel will be composed of three members; one selected by the recipient group, a second member selected by the NCI, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. The NCI will be holding a series of phone conference calls (probably one for each cancer site and one for coordinating centers) for applicants to hear more about the existing CISNET work, and to discuss the scope of potential applications. For more information about the schedule for these calls see http://cisnet.cancer.gov. Summaries of the calls and/or tapes will be available for those unable to participate directly. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Dr. Eric Feuer Division of Cancer Control and Population Sciences National Cancer Institute 6116 Executive Boulevard, Room 5041, MSC 8317 Bethesda, MD 20892-8317 Rockville, MD 20852 (express courier) Telephone: (301) 496-5029 Fax: (301) 480-2046 Email: firstname.lastname@example.org o Direct your questions about peer review issues to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 Telephone (301) 496-3428 Fax: (301) 402-0275 Email: email@example.com o Direct your questions about financial or grants management matters to: Ms. Crystal Wolfrey Grants Administration Branch National Cancer Institute 6120 Executive Plaza South, Suite 243 Bethesda, MD 20892 Rockville, MD 20852 (express courier) Telephone: (301) 496-8634 FAX: (301) 496-8601 Email: firstname.lastname@example.org LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Dr. Eric Feuer Division of Cancer Control and Population Sciences National Cancer Institute 6116 Executive Boulevard, Room 5041, MSC 8317 Bethesda, MD 20892-8317 Rockville, MD 20852 (express courier) Telephone: (301) 496-5029 Fax: (301) 480-2046 Email: email@example.com SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo; Telephone (301) 710-0267; Email: GrantsInfo@nih.gov. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at https://grants.nih.gov/grants/funding/phs398/labels.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all five copies of the appendices must be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 Appendices should be comprised of unbound materials, with separators between documents. APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (https://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html). This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version or the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NCI. Incomplete applications will not be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Cancer Advisory Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of these criteria in assigning the application’s overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have 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. Criteria for Modeling Grants SIGNIFICANCE: Does this study propose to address important population- based surveillance and cancer control problems, rather than an emphasis on new mathematical/statistical derivations? If the aims of the application are achieved, how will surveillance research and cancer control be advanced? What will be the potential effect of these studies on policy of health care practices that could ultimately improve the health of the American public? Does the application address realistic strategies and issues which have a real chance of being implemented in the population? Will the results be packaged in a way that policy makers and cancer control planners can understand? WORK TO DATE: Does the applicant have a working multi-cohort population-based model, which can be used to address cancer surveillance and control issues? Has the model been employed to address important cancer surveillance and control issues, and how successfully has the model performed? Is the model appropriate to address practical issues associated with the aims of the application? APPROACH: Are the nature and characteristics of the model to be employed adequate? Is there evidence that the model proposed is currently being used for multiple cohort population-based studies? Are the plans for adapting the model to address the specific aims of this application adequate (e.g. adding a new module to address prevention strategies)? Does the applicant have a plan for demonstrating a general understanding of the various factors influencing observed trends before investigating secondary goals of future trends and optimal cancer controls strategies? Are the strategies for identifying and characterizing differences between modeled and observed population trends, and general approach towards developing a comprehensive understanding of the determinants of cancer site-specific trends at the population level adequately addressed? 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? Does the applicant lay out a specific and reasonable plan for making the model accessible to others? INVESTIGATORS: Do the investigators comprise an interdisciplinary team that is adequate to present the results for use by policy makers and cancer control planners? Is appropriate interdisciplinary expertise included? Is the principal investigator appropriately trained and well suited to carry out this work? Do the investigators have extensive modeling experience? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the applicant’s prior work demonstrate an understanding of the problems inherent in working with population-based data? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Are modeling activities an established element of the research environment? Do the proposed modeling efforts take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? COLLABORATION: Do the investigators state their willingness to participate in joint meetings, share methods and data resources, and embark on collaborative efforts to decide overall research direction? Is the research plan flexible enough to accommodate further refinement and integration with other efforts? While it will be a group decision to actually engage in any particular proposed collaborative activities, do the applicants show an understanding of how joint collaborative activities can be conducted in a consortium of this type? Criteria for Coordinating Centers RESEARCH TEAM: Does the proposed research team have experience with population-based modeling, data sources, and policy issues for the specific cancer site? Does the PI indicate a sufficient commitment of time (suggested minimum of at least 15%, but more may be necessary) to devote the time and energy to help focus the research efforts? Has the PI demonstrated leadership abilities? PLANS FOR COORDINATION: Does the coordinating center lay out a proposed set of plans that are flexible to incorporate group input? Does the coordinating center plan recognize that the activities of the coordinating center will be dictated by group consensus? Does the plan include creative options for comparing models, reaching group consensus, and synthesizing results for use by cancer control planners and policymakers? Does the coordinating center have plans for conducting base cases, fielding outside inquiries, and other group activities? Does the application recognize that coordination with the contractor for the Model Profiler/Interactive Web Site will be necessary? DATA SOURCES/MODELING INPUTS: Is the coordinating center knowledgeable about data sources, and do they have unique access or knowledge of particular data sources? Does the coordinating center have plans for gaining access to important data sources as they are released (e.g. trial results)? Does the coordinating center have plans and capabilities to model specific inputs that are of common interest across the models? CURRENT EVENTS: Does the coordinating center have a plan for keeping abreast of current policy related controversies, and the latest research results across the spectrum of treatment, screening and prevention for their cancer site? Is there a plan to make use of the models, if appropriate, to help synthesize population-level results related to these controversies and results? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: September 14, 2004 Application Receipt Date: October 14, 2004 Peer Review Date: February/March 2005 Council Review: June 2005 Earliest Anticipated Start Date: July 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities The final awards will reflect the scientific merit of the applications, adherence to the spirit of intent of this RFA, and a balance of the number of funded applications across the four cancer sites. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. See http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (See the NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998 at https://grants.nih.gov/grants/guide/notice-files/not98-084.html.) SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing (https://grants.nih.gov/grants/policy/data_sharing) or state why this is not possible. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that:(a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and (b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects’ research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research in now available online at: http://cme.nci.nih.gov/. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at https://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. REFERENCES 1. van den Akker-van Marle E, de Koning H, Boer R, van der Maas P. Reduction in breast cancer mortality due to the introduction of mass screening in the Netherlands: comparison with the United Kingdom. J Med Screen 1999; 6:30-34. 2. Feuer, E.J., Wun, L.M. "How Much of the Recent Rise in Breast Cancer Incidence Can be Explained by Increases in Mammography Utilization: A Dynamic Population Approach," American Journal of Epidemiology, 1992; 136, 1423-1436. 3. Wun, L.M. Feuer, E.J., Miller, B.A. "Are Increases in Mammographic Screening Still a Valid Explanation for Trends in Breast Cancer Incidence in the United States?" Cancer Causes and Control, 1995; 6, 135-144. 4. Legler, J.M., Feuer, E.J., Potosky, A.L., Merrill, R.M., Kramer, B.S., "The Role of Prostate-Specific Antigen Testing Patterns in the Recent Prostate Cancer Incidence Decline," Cancer Causes and Control, 1998; 9, 519-527. 5. Feuer, E.J., Kessler, L.G., Triolo, H.E., Baker, S.G., Green, D.T. "The Impact of Breakthrough Clinical Trials on Survival in Population Based Tumor Registries," Journal of Clinical Epidemiology, 1991; 44, 141-153. 6. Weller, E.A., Feuer, E.J., Frey, C.M., Wesley, M.N., "Parametric Relative Survival Modeling Using Generalized Linear Models with Application to Hodgkin's Lymphoma,” Applied Statistics, 1999; 48, 79- 89. 7. Siegel, JE, Weinstein MC, Torrance GW: Reporting Cost-Effectiveness Studies and Results, Cost-Effectiveness in Heath and Medicine. Gold, MR, Siegel JE, Russel LB, Weinstein MC (editors) Ch 9 p276-303, 1996. 8. Olsen O and Gotzsche P. Cochrane review on screening for breast cancer with mammography. Lancet 2001 358:1340-2, 2001. 9. Humprey L, Chan BKS, Detlefsen, S, Helfland M, Screening for breast cancer, Systematic Evidence Review Number 15, Prepared for Agency for Healthcare Research and Quality (ahrq.gov), 2002. 10. Mariotto A., Feuer EJ, Harlan LC, Wun LM, Johnson KA, Abrams J., Trends in the use of adjuvant multi-agent chemotheapy and Tamoxifen for breast cancer in the United States, 1975-1999, JNCI, 94: 1626-1634, 2002. 11. Etzioni R, Berry K, Legler J, Shaw P. PSA Testing in black and white men: An analysis of Medicare claims from 1991-1998. Urology. 2002, 59:251-5, 2002. 12. Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R, Gann PH, Feuer EJ. Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incident trends. JNCI, 94:981-90, 2002. 13. Levin B, Brooks D, Smith RA, Stone A, Emerging technologies in screening for colorectal cancer: CT colonography, immunochemical fecal occult blood tests, and stool screening using molecular markers, CA Cancer J Clin 53: 44-55, 2003. 14. Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al.; Projecting individualized probabilities of developing cancer for white females who are being examined annually. JNCI, 81: 1879-1886, 1989. 15. Bach PB, Katton MW, Thornquist MD, Fris MG, Tate RC, Barnett MJ, Hseih LJ, Begg CB, Variations in lung cancer risk among smokers., JNCI, 95: 470-478, 2003. 16. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson, BE, Meyerson M. EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science, Online publication, April 29, 2004. 17. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr., The influence of finasteride on the development of prostate cancer., N Engl J Med., 349(3):215-24, 2003. 18. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. Obstet Gynecol Surv. Mar;59(3):201-3, 2004.
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