ANCILLARY STUDIES TO OBESITY-RELATED CLINICAL TRIALS RELEASE DATE: October 22, 2003 RFA Number: RFA DK-03-022 (see addenda NOT-DK-04-007 and NOT-DK-04-002) February 4, 2011 - This RFA has been reissued as RFA-DK-10-503. Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATIONS: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATIONS: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) National Institute on Aging (NIA) (http://www.nia.nih.gov/) National Center for Complementary and Alternative Medicine (NCCAM) (http://nccam.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.847 and 93.848; NIA 93.866; NCCAM 93.213 LETTER OF INTENT RECEIPT DATE: February 19, 2004; October 19, 2004; June 17, 2005. APPLICATION RECEIPT DATE: March 19, 2004; November 19, 2004; July 19, 2005. THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) 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 Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The goal of this initiative is to solicit research grant applications for ancillary studies investigating obesity-related research questions in conjunction with six NIDDK-sponsored cooperative agreement clinical trials and consortia and one NIA-sponsored cooperative agreement. These ancillary study proposals may utilize patients and/or patient materials from the seven clinical cooperative agreements cited below, subject to study- specific restrictions. Acceptable studies will vary depending upon the parent cooperative agreement and may include investigation of the genetic and environmental factors underlying obesity, of the pathogenesis of obesity and associated co-morbidities, of surrogate markers or biomarkers for obesity- related disease and therapeutic effects of interventions, and of new technologies for measurement of diet, physical activity and energy balance. The NIA is particularly interested in ancillary projects elucidating the relationships of aging changes to the above topics. Potential applicants are encouraged to consider any of the cooperative agreements included in this RFA as a resource for addressing aging-relevant research questions. The NCCAM is interested in supporting investigations of complementary or alternative approaches to weight maintenance and the prevention and treatment of overweight or obesity. The following seven major cooperative agreement clinical trials or networks qualify for submission of ancillary studies under this announcement: o Look AHEAD: Action for Health in Diabetes o Diabetes Prevention Program Outcomes Study (DPPOS) o Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) o Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) o Bariatric Surgery Clinical Research Consortium (BSCRC). o Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) Studies o Weight Reduction for Incontinence Network (WIN) These cooperative agreements are the only trials or networks for which ancillary study applications will be accepted under this announcement. The first two of these cooperative agreements are currently in progress and can accommodate applications for all receipt dates. The NASH CRN, the TODAY study, the Bariatric Surgery Clinical Research Consortium, and the WIN study are still in the design phase and CALERIE is in the pilot testing phase. These five studies will not be ready to accept ancillary study proposals until the later receipt dates. RESEARCH OBJECTIVES Background The obesity epidemic has been well documented in the scientific literature and in the lay press. Recent data from the National Health and Nutrition Examination Survey demonstrate that almost two thirds of Americans now are overweight, and over 30% now are obese (BMI ? 30). Obesity is associated with a host of comorbid conditions, including diabetes, cardiovascular disease, certain cancers, osteoarthritis, and gallbladder disease. Despite the enormous health impact of obesity and recent progress in our understanding of the condition at the molecular level, many aspects of the basic pathophysiology and genetics of obesity remain to be investigated. In addition, interrelationships of factors that contribute to energy balance and to difficulties associated with weight loss over the long term are not well- understood. The NIDDK has made a substantial investment in six cooperative agreements to investigate obesity-related diseases and conditions in large numbers of well- characterized participants. In addition, the NIA is supporting a set of obesity-related intervention studies supported via a cooperative agreement. These trials and networks can provide access to participants who have been screened for a range of obesity-associated phenotypes and for whom various associated biological samples have been collected. Thus, ancillary studies to the seven unique parent agreements represent a cost-effective way to capitalize on these major clinical research investments. In addition, ancillary studies to the trials and networks will encourage basic scientists and clinical investigators to work together, enabling more in-depth studies of pathogenesis mechanisms during ongoing clinical protocols. Finally, this announcement offers the potential for access to existing NIDDK and NIA- supported cooperative agreements by a wider community of investigators from outside the parent study sites. The seven cooperative agreements eligible for ancillary studies funded under this announcement are briefly described below, along with links to more detailed information on study websites: 1) Look AHEAD: Action for Health in Diabetes. Look AHEAD is a sixteen center randomized clinical trial investigating the long-term health consequences of weight loss. The Look AHEAD cohort will comprise 5000 overweight or obese participants with type 2 diabetes, aged 45-75. Participants are randomized to one of two interventions: an intensive lifestyle intervention designed to produce and sustain weight loss over the long term, or a diabetes support and education condition. The study will complete enrollment of subjects in April, 2004. Currently the Look AHEAD population is comprised of approximately 35% minority individuals and 59% females, with an average age of 58 years. Due to heavy existing ancillary study burden, Look AHEAD will be open primarily to ancillary studies that propose using existing stored serum, plasma or DNA samples or involve little additional burden to participants. The study has a well-defined ancillary study policy and process for submission of ancillary studies to be approved by the ancillary studies committee. The policy and online proposal submission site may be found at: http://lookahead.phs.wfubmc.edu/index.cfm?fuseaction=public_sitemap Please note that Look AHEAD requires applicants to prepare an online summary of the proposed research 60 days before the NIH receipt date and to obtain a letter indicating willingness to collaborate from at least one Look AHEAD principal investigator before an application can be approved by the ancillary studies committee for submission to this RFA. Applications may be submitted for all three receipt dates. 2) The Diabetes Prevention Program Outcomes Study (DPPOS). The Diabetes Prevention Program Outcomes Study or DPPOS is the follow-up study to the DPP that initiated interventions in 1996 and was ended one year early (May 2001) as a result of highly significant and positive study outcomes as reported in the New England Journal of Medicine (The DPP Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002 Feb 7;346 (6):393-403). These results demonstrated that lifestyle and drug interventions could markedly reduce the risk for developing type 2 diabetes in a group at high risk due to the presence of impaired glucose tolerance, by 58% for lifestyle and 31% for metformin, regardless of ethnicity. The DPP included 45 percent of the study cohort from African American, Hispanic American, Asian American, Pacific Islander, and American Indian populations. In addition, 20 percent of our study population was greater than age 60 and 68% of participants were women. While the primary goal of the DPP was to prevent the development of diabetes, an important secondary goal was to decrease the rate of cardiovascular disease and its risk factors. These clinically important outcomes were considered as secondary during the DPP due to a lack of sufficient power to detect potential differences between the treatment groups. The DPPOS will provide insights regarding the clinical course of newly diagnosed type 2 diabetes and the persistence of the delay of diabetes onset seen in the DPP. In addition, the DPP is the longest follow-up study of sustained weight loss ever conducted. Of major interest is the outcome of continued lifestyle and long-term weight loss, and metformin intervention in the gender specific and minority sub-groups randomized to the DPP and enrolled in the DPPOS. The DPPOS website may be found at: http://www.bsc.gwu.edu/dpp/index.htmlvdoc Studies may be submitted for all three receipt dates. 3) The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). The NASH CRN was constituted to focus on the etiology, contributing factors, natural history, complications, and therapy of nonalcoholic steatohepatitis. Eight clinical centers and a data coordinating center make up the network. Approximately 1500 pediatric and adult participants with nonalcoholic liver disease will be included in both retrospective and prospective databases beginning in late 2003. A three-arm randomized, placebo-controlled clinical trial (RCT) of an insulin sensitizing agent or vitamin E will be conducted in 250 non-diabetic adult participants with documented NASH. A trial in pediatric NASH patients will randomize 180 children to receive treatment with vitamin E, metformin, or placebo. All patients in both clinical trials will have liver biopsies taken pre- and post-treatment. Treatment will be for two years. Enrollment into both trials will begin in early 2004. The NASH CRN will be open to ancillary studies that involve limited additional burden to study participants. The NASH CRN ancillary study policy is posted on the NASH CRN website: http://www.nashcrn.com. Ancillary study proposals utilizing the NASH CRN may be submitted for the second and third receipt dates under this announcement. 4) Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) The TODAY study is a 12-site clinical trial to assess the best treatment for type 2 diabetes in the pediatric population. The TODAY cohort will consist of 750 youth between the ages of 10 and 17 years, who will be randomized to one of three arms: 1) metformin alone; 2) metformin plus rosiglitazone; and 3) metformin plus an intensive lifestyle intervention. All participants will receive standardized diabetes education. The primary outcome will be time to rescue, defined as a hemoglobin A1c < 8.5% for 6 months. Secondary outcomes include beta cell function, comorbidities (dyslipidemia, hypertension), microvascular complications, side effects/QOL, and cost analysis. The protocol has been finalized and is awaiting IRB approval. We expect that enrollment will begin in late fall 2003. The TODAY ancillary studies policy is in the process of being finalized and will be placed on the study website at http://www.todaystudy.org when it becomes available. A link to study information also will be posted on the FAQ site for this RFA at: http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm. We anticipate that investigators will need to submit a 3-5 page proposal to the TODAY ancillary studies committee as part of the review process. Ancillary studies will be considered if they do not significantly add to participant burden and require the unique characteristics of the TODAY cohort. Investigators outside of the trial who wish to conduct an ancillary study will need to have a TODAY study member as a co-investigator. Ancillary study proposals to the TODAY trial may be submitted for the second and third receipt dates under this announcement. 5) Bariatric Surgery Clinical Research Consortium (BSCRC). The goal of the BSCRC is to facilitate coordinated clinical, epidemiological, and behavioral research in the field of bariatric surgery, through the cooperative development of common clinical protocols and a bariatric surgery database to collect information from participating CCs. The BSCRC will help pool the necessary clinical expertise and administrative resources to facilitate the conduct of multiple clinical studies in a timely, efficient manner. Also, the use of standardized definitions, clinical protocols, and data collection instruments will enhance our ability to provide meaningful evidence-based recommendations for patient evaluation, selection, and follow-up care. The consortium was funded in September 2003. During the first 10-12 months after funding, investigators will collaboratively develop protocols, with IRB and other approvals to be obtained by September 2004. Additional information about the BSCRC will be posted on the FAQ site for this RFA at: http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm. Ancillary study proposals to the BSCRC may be submitted for the second and third receipt dates under this announcement. 6) Weight Reduction for Incontinence Network (WIN). The WIN includes two clinical centers (recruiting sites) and a data coordinating center. The purpose of the Network is to examine the effects of an intensive behavioral weight control program compared to usual care to determine the short-term effect of weight loss on frequency of urinary incontinence and quality of life. A total of 330 overweight and obese women with urinary incontinence will be recruited beginning in 2004. After completing the intensive weight reduction program, a second randomization will be done to test whether an enhanced weight maintenance program results in better long-term weight loss through 18 months compared to a standard maintenance program. Urodynamic studies will also be performed in the study cohort. Procedures for the conduct of ancillary studies are under development. Additional information about the WIN will be posted when available on the FAQ site for this RFA at: http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm. Ancillary study proposals to the WIN may be submitted for the second and third receipt dates under this announcement. 7) Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) Studies. The NIA-supported CALERIE studies consist of three clinical site cooperative agreements testing different interventions of sustained caloric restriction (CR) in non-obese (but mostly overweight) individuals. Locations of the CALERIE clinical sites include the Washington University in St. Louis, Tufts University in Boston, and the Pennington Biomedical Research Center in Baton Rouge. The Coordinating Center is located at Duke Clinical Research Institute. The primary goals of CALERIE are to gain knowledge: 1) about CR effects in humans on physiology, metabolism, body composition, and risk factors for age-related pathologies, and 2) of similarities, differences and interactions between the effects of CR and physical activity on the physiological outcomes of interest (e.g., changes in energy metabolism, surrogate markers of oxidative stress, endocrine function). Initiated in early 2002, the CALERIE clinical sites are presently conducting pilot projects of different CR interventions involving 20-30% restriction of energy intake. Some of the feasibility studies also include physical activity interventions designed to achieve similar levels of negative energy balance as with CR. The CALERIE study participants are between 25-60 years old and most have BMI values between 25-29.9. The results of these feasibility studies will be subsequently used to design full-scale clinical trial(s) of CR sustained for at least two years. The NIA invites potential applicants to propose ancillary projects to the full-scale CALERIE projects, which are expected to begin mid 2004. Further details of the CALERIE studies and ancillary study policy can be found at: http://calerie.dcri.duke.edu. Since the CALERIE studies are still in the pilot testing phase, ancillary study proposals to CALERIE will not be accepted until the second receipt date. Those proposing ancillary studies must submit a 3-4 page proposal to the CALERIE ancillary studies committee, and secure CALERIE’s permission for the study, as a prerequisite for submitting an application in response to this RFA. Ancillary studies may be permitted by CALERIE if they do not significantly add to participant burden, do not compromise achievement of CALERIE goals, do not duplicate currently planned CALERIE studies, and require the unique characteristics of the CALERIE study population. The following are examples of research topics that might be pursued through ancillary projects to CALERIE studies. This list is not intended to be all- inclusive: o Metabolic, physiologic and body composition adaptations to sustained caloric restriction (CR) during early weight loss and during weight stability on CR. o Effects of sustained caloric restriction on processes that may affect rates of aging in humans (e.g., cell death, oxidative damage, mitochondrial functions) and on risk factors for age-related diseases. o Differences between effects of sustained caloric restriction and effects of increased physical activity on physiologic functions, body composition, and disease risk factors. Research Scope The link between obesity, especially visceral obesity, and a number of associated conditions, such as diabetes, cardiovascular disease, cancer and osteoarthritis, continues to be a critical research question. The application of powerful new genetics tools to samples from well-characterized obese individuals may identify genes that lead to the development of obesity and its comorbidities as well as those that influence responses to obesity treatment. Studies to identify biomarkers of obesity-associated disease risk should yield new targets for therapeutics to disrupt the development of obesity and its comorbidities and to help to identify those in whom preventive strategies might be implemented. Environmental, behavioral and societal factors that contribute to the development of obesity and the ability to lose weight and sustain weight loss also need to be explored, as do physiologic pathways of the neuroendocrine and endocrine systems, GI function, adipocytes, liver, muscle biology, appetite, and energy expenditure. Studies of innovative methodologies for measuring dietary intake or energy expenditure would also be encouraged. Ancillary studies consist of measurements not being conducted as part of the parent clinical trial or network. They may be done on the entire participant cohort or on subsets of participants, depending on the sample size required to answer the research questions. They may involve physiologic or behavioral measures, imaging techniques or analyses of biological specimens from participants. The following are examples of research activities that might be pursued through ancillary studies in collaboration with one or more of the seven cooperative agreements. These are examples only and are not meant to be limiting. However, each of the seven cooperative agreements has its own unique restrictions on what types of investigations are acceptable, based on burden to participants and study staff. o Identification of genetic variants associated with short-term and/or longer-term weight loss in response to lifestyle, CAM practices, or other therapeutic interventions o Identification of genes associated with increased or decreased risk for obesity in metabolically well-characterized populations from diverse racial and ethnic groups. o Use of weight loss models (e.g., diet, surgery, physical activity, CAM) to understand biological and psychological factors contributing to weight regain in humans. o Determination of the relationship between inflammatory markers and obesity. o Identification of serum, urine and/or various depot specific markers of obesity phenotypes across diverse racial and ethnic groups. o Evaluation of the short-term impact of bariatric surgery, behavioral interventions, or CAM practices (including mind-body therapies)on an obesity- related co-morbid condition, such as non-alcoholic steatohepatitis or insulin resistance. o Investigation of the impact of bariatric surgery on long-term energy balance, including factors such as appetite, nutrient absorption, nutrient metabolism, energy expenditure, fitness, or body composition. o Development of tools to improve assessment of diet, caloric intake and physical activity. o Study of the role of microsomal oxidative stress in the pathogenesis of obesity-associated liver disease. o Investigation of behavioral and environmental correlates of weight maintenance. o Identification age-related differences in clinical and physiologic outcomes of interventions affecting weight, and factors responsible for these differences. o Relationships of comorbid conditions in older persons (e.g., osteoporosis, osteoarthritis) to risks and benefits of interventions affecting body weight The NCCAM is interested in the efficacy and safety of, patterns and prevalence of, use of, cost benefit of, and professional and patient attitudes towards complementary and alternative medicines (CAM) for weight loss and maintenance of weight loss, as well as for amelioration of side effects of bariatric surgery or pharmaceutical interventions. In addition, the NCCAM is interested in interactions of CAM with other interventions. NCCAM groups CAM practices within five major domains, acknowledging that other groupings are possible: (1) alternative medical systems; 2) mind-body interventions; (3) biologically-based interventions; (4) (manipulative and body-based methods; (5) energy therapies (http://nccam.nih.gov/about/plans/fiveyear/fiveyear.pdf). Limitations: Please note that each of the seven cooperative agreements for which ancillary study proposals may be submitted has limitations on the type of investigations permissible and each has specific requirements for partnership with study investigators. In general, the following types of investigations are permitted under this announcement, subject to the limitations set by each study's leadership: o Assay of archived biological samples from completed and ongoing studies; and o Collection of new data and samples from ongoing studies. You may NOT propose to fund the activities that are part of the core protocol for the parent trial through this announcement. Likewise, you may NOT seek funds for analysis of existing data or for studies that substantially duplicate ongoing ancillary studies to the parent trials. In most cases, modification of intervention protocols will not be permitted; however, in certain limited circumstances, this might be considered acceptable by the parent study. MECHANISM OF SUPPORT This RFA will use the NIH research project grant (R01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA will be active for portions of three fiscal years (FY 2004 - FY 2006) contingent on the availability of funds. 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 dates are September 30, 2004, July 1, 2005, and April 1, 2006. Applications that are not funded in the first two rounds of competition described in this RFA may be revised and resubmitted under this RFA. Applications submitted for the third receipt date will not have the opportunity to revise and resubmit under this RFA. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE The participating ICs intend to commit at least $3.5 million to fund 7 to 11 new grants in response to this RFA. Given the multiple receipt dates, funding could be significantly more if applications of sufficient quality and institute priority are received. Because the nature and scope of the proposed research will vary from application to application, we anticipate that the size and duration of each award also will vary. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $1 million per year, including fiscal and administrative costs on subcontracts. You are strongly encouraged to discuss proposed budgets with the IC program official for the parent trial or network prior to extensive preparation of your application. Although the financial plans of the ICs 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 meritorious applications. ELIGIBLE 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 o Foreign institutions are not eligible to apply. 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. You may respond to this announcement even if you are not an investigator who currently is part of the seven trials or networks. However, you will be required to obtain appropriate approvals from the trial or network proposed in your ancillary study. SPECIAL REQUIREMENTS To be responsive to the requirements of this announcement, you must propose studies using the seven ongoing NIDDK- or NIA-funded cooperative agreements cited above. Ancillary studies associated with major clinical trials provide a valuable opportunity to gain insights into the origins and pathogenesis of obesity. However, the potential value of such studies must be balanced against the need to ensure that the main trial outcomes are not compromised by the burden of additional studies. Hence, you must provide documentation at the time of grant submission that you have received approval from the appropriate governing body of the parent trial or network to conduct your proposed ancillary study. Each clinical trial or network covered by this announcement has provided guidelines for which types of ancillary studies are currently acceptable and for the process of obtaining approval. These study-specific guidelines either are currently posted on each study's website (provided in Background) or links will be provided as they become available via the FAQ website for this RFA at: http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm. Please note that study-specific restrictions may limit the types of ancillary proposals that are acceptable. Applications not containing documentation of preliminary approval from the appropriate governing body (such as the Steering Committee) will be considered non-responsive to this announcement and will be returned to the Investigator without having undergone peer review. You must include a statement of your willingness to work collaboratively with the parent study and to abide by all parent study policies, publication restrictions, data access provisions, etc. You may be required by specific trials or networks to include funds in your application to travel to national Steering Committee meetings and/or to cover the cost of access to samples and data at held by the parent study Coordinating Center or by central repositories. This RFA applies only to NEW applications, not to competing renewals of ongoing ancillary studies. Data Sharing Plan Due to the collaborative nature of the parent trials, all applicants will be required to submit a data sharing plan, regardless of the dollar amount of their application. Reviewers will assess the adequacy of the proposed plan. Ancillary studies also will be required to abide by the data sharing policies of the parent trial or network. NIH policy requires that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication [Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice (http://www.ott.nih.gov/policy/rt_guide_final.html)]. Therefore, it is expected that the specimens and data collected in projects funded by this RFA will be made available to the broader scientific community, after a proprietary period, at no charge other than the costs of reproduction and distribution. This RFA has a special requirement that applicants include a "Sharing Plan" in the application that describes how they will share the specimens and data collected with the wider scientific community. For NIDDK-funded studies, the Plan must include the eventual transfer of these materials to the NIDDK Central Biosample and Data Repositories or another archival storage facility designated by NIDDK. Approval of the data sharing plan will be a condition of the award. The effectiveness of the resource sharing will be evaluated as part of administrative review of each Non-competing Grant Progress Report (PHS 2590). Data and Safety Monitoring Plan All applicants must include a data and safety monitoring plan for the ancillary study activities even when the parent trial already has a central Data and Safety Monitoring Board and even if the study is of minimal risk. In addition, each applicant should include $10,000 in the budget to provide for Coordinating Center tracking of ancillary study participants and any additional data management functions required for the parent trial because of the ancillary study activities. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. A website on the NIDDK homepage containing information pertaining to this RFA is located at http://www.niddk.nih.gov/fund/crfo/ancillariesFAQ.htm. Answers to frequently asked questions and other information updates concerning this RFA will be posted on the site as they are developed. Applicants are strongly encouraged to visit this website on a regular basis in the course of preparing their applications. 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: Barbara Harrison, M.S. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 661 Bethesda, MD 20892-5450 (for express/courier service: Bethesda, MD 20817) Telephone: (301)594-8858 FAX: (301)480-8300 E-mail: email@example.com Chhanda Dutta, PhD Geriatrics and Clinical Gerontology Program National Institute on Aging Gateway Building, Suite 3C-307 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301)435-3048 FAX: (301)402-1784 E-mail: firstname.lastname@example.org Marguerite Klein National Center for Complementary and Alternative Medicine 6707 Democracy Blvd., Suite 401 Bethesda, MD 20892-5475 (for express mail, use 20817) Telephone: (301)402-5860 Fax: (301)480-3621 E-mail: email@example.com o Direct your questions about peer review issues to: Francisco O. Calvo, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301)594-8897 FAX: (301)480-3505 Email: firstname.lastname@example.org o Direct your questions about financial or grants management matters to: Sharon Bourque Grants Management Specialist National Institute f Diabetes and Digestive and Kidney 6707 Democracy Boulevard, Room 719 Bethesda, MD 20892 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8846 FAX: (301)480-3504 Email: email@example.com Grace Poe Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Room 2N212 Bethesda, MD 20892-9205 Phone: (301)402-1472 Fax: (301)402-3672 E-mail: firstname.lastname@example.org Marc Milton Pitts, M.B.A. Grants Management Specialist National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Blvd., Suite 401 Bethesda, MD 20892 Phone: (301)594-9095 Fax: (301)480-1552 E-mail: email@example.com 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: Francisco O. Calvo, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: firstname.lastname@example.org 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 http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: You must submit a letter documenting the preliminary approval of your proposed ancillary study by the parent trial or network. The required documentation varies somewhat between the parent studies, so be sure to follow the procedures provided by the parent trial or network of interest to you. In addition, you must explicitly state your willingness to abide by the policies of the parent trial or network. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs, including indirect costs on subcontracts, must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. 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: http://grants.nih.gov/grants/funding/phs398/label-bk.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 copies of the appendix material must be sent to: Francisco Calvo, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 752 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 Email: email@example.com 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 of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete applications will not be reviewed. 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 NIDDK 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 an appropriate national advisory council or board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. 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 the following criteria in assigning the application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment 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. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? 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: o Importance of the proposed topic to advancement of obesity research. o Justification of the need for access to a large trial or network as opposed to a simpler research setting. 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: All applicants 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 Dates: February 19, 2004; October 19, 2004; June 17, 2005. Application Receipt Dates: March 19, 2004; November 19, 2004; July 19, 2005. Peer Review Dates: June/July 2004, February/March 2005, October/November 2005. Council Review: September 2004, May 2005, January/February 2006 Earliest Anticipated Start Date: September 30, 2004, July 1, 2005, April 1, 2006. 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: Only very meritorious applications within the scientific interests and scope of the NIDDK mission will be supported. o Cumulative burden: The cumulative burden to the parent trial or network of all ancillary studies ongoing and proposed for funding under this RFA may become a limiting factor. For example, if small quantities of biological samples are available, not all studies rated as highly meritorious may be able to access them. Likewise, the cumulative burden of studies already approved for funding may be such that those of lower priority cannot be funded, regardless of priority score. 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. 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. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking more than $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing. 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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://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. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFAPA 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). Those who must comply with the Privacy Rule (classified under the Rule as “covered entities”) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). 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 http://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.healthypeople.gov/. 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) 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 http://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.
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