EXPLORATORY STUDIES OF SUSTAINED CALORIC RESTRICTION IN NON-OBESE PERSONS: PHYSIOLOGIC EFFECTS AND COMPARISONS/INTERACTIONS WITH PHYSICAL ACTIVITY Release Date: October 12, 2000 RFA: AG-01-001 National Institute on Aging (http://www.nih.gov/nia/) Letter of Intent Receipt Date: January 12, 2001 Application Receipt Date: April 25, 2001 PURPOSE The National Institute on Aging (NIA) invites applications for cooperative agreements (U01s) for exploratory controlled human intervention studies on the effects of caloric restriction (CR) interventions on physiology, body composition, and risk factors for age-related pathologies in non-obese persons. Applications are also invited for studies of similarities, differences and/or potential interactions between the effects of CR and of physical activity (PA) on these outcomes. Studies in young adults and/or middle-aged persons up to age 60 may be proposed. Subject populations of interest are overweight persons (Body Mass Index of 25.0-29.9), other individuals at high risk for becoming overweight or obese, and formerly obese persons at risk for recurrence of obesity. Proposals for studies of interventions in persons currently obese will be considered non- responsive to this Request for Applications (RFA). The use of reliable techniques for tracking caloric intake and expenditure (especially doubly-labeled water techniques), and level of physical activity are considered essential features of these exploratory studies. The results from these studies will be valuable in guiding the design of possible subsequent studies or clinical trials to determine the long-term effects of CR and PA on the development of age-related pathologies. 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 Request for Applications (RFA), Sustained Caloric Restriction in Non-Obese Persons: Physiologic Effects and Comparisons/Interactions with Physical Activity , 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/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) mechanism. The cooperative agreement is an assistance mechanism in which substantial involvement of the NIA with the recipient is anticipated during the performance of the planned activity. The nature of the NIA's involvement is described under Terms and Conditions of Award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant/awardee. The total project period for an application submitted in response to the present RFA may not exceed seven years. The anticipated award date is September, 2001. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE For the initial year of funding, the amount of funds available to support projects submitted in response to this RFA is approximately $2,500,000, plus funds for the purchase of doubly labeled water (see Research Goals and Scope section). Total funding for the second year of awards will be at approximately the same level. Depending on the requirements for Phase 2 of funded projects (see Special Requirements section), a larger amount may be available for years 3-7 of the project period. It is anticipated that 2-4 awards will be made. However, awards will be contingent upon availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. The number and size of awards made, may vary given the potential variation in the nature and scope of the research projects submitted in response to this RFA. RESEARCH OBJECTIVES Background Numerous studies in laboratory animals have shown that chronic caloric restriction (CR), i.e., limiting caloric intake below ad libitum levels, extends maximum and average life span by as much as 40% and delays age-related pathologies correspondingly. CR increases life span whether initiated in early adult life or middle age, but its effects diminish with increasing age of onset of CR. The amount of life span extension increases with the degree of caloric restriction (up to approximately 40% restriction; substantial effects have occurred with 20% restriction. Among the aging changes slowed by these regimens are declines in glucose tolerance and insulin sensitivity, and increases in body weight. (These regimens do not produce sustained weight loss: After transient weight loss, weight either remains stable or increases more slowly than in controls.) Chronic CR in nonhuman primates has been found to produce parallel physiologic changes to those seen in rodents. Studies of its effects on nonhuman primate life span have not been completed. An important question is whether these effects on life span and development of age-related pathologies can be explained by CR’s effects on weight, body composition, or physical activity. CR prevents most or all of the weight gain and increase in fat mass over adult life in laboratory rodents, and increases spontaneous physical activity. Though the issue is not fully resolved, experimental animal data indicate that these factors may not fully explain CR’s effect on longevity and age- related pathologies. Much of the evidence supporting this inference comes from studies of effects of chronic exercise in experimental animals. In studies in which chronic exercise affected body weight and body fat comparably to CR, it had significantly less effect on mean life span. In particular, though both interventions increased mean life span in the animals studied, only CR consistently increased maximum life span. These findings have raised the possibility that either CR may have some beneficial effect on aging processes, not mediated by body weight, that exercise may lack, or that exercise may have some adverse effect that counteracts some of the benefits it may share with CR. The implications of these findings regarding effects of voluntary CR on life span and development of age-related diseases in humans are unknown. There are essentially no data from epidemiologic studies on the relationship of caloric intake or voluntary caloric restraint over the life span to these outcomes. Human weight-loss intervention studies (primarily in obese or overweight persons) have included regimens for sustained reduction of caloric intake, but the duration of interventions has been at most only a few years. In most of these studies, the interventions have combined CR with other interventions such as physical activity. In addition, caloric intake of individuals in these studies (as well as in epidemiologic studies) cannot be estimated well because of limitations in the accuracy of self-reported data on food intake. As a result of these factors, a clear determination of the effects of sustained caloric restriction per se on life span, development of age-related pathologies, or on risk factors for these pathologies, is not possible from existing data. Hence, it is also not possible to draw firm conclusions from existing data about similarities, differences, or interactions between sustained CR and PA in their effects on these outcomes in humans. In March 1999, the NIA and NIDDK (National Institute on Diabetes Digestive Diseases and Kidney) co-sponsored the Caloric Restriction Clinical Implications Advisory Group. The Advisory Group reviewed data and made recommendations for epidemiologic, experimental therapeutic, mechanistic, and human intervention studies relating to the relationships of caloric intake, energy balance, and weight gain over the lifespan with longevity and morbidity. The proceedings from this Advisory Group meeting will be published in the Journals of Gerontology: Series A Biological and Medical Sciences, with an anticipated publication date in late 2000. Notice of publication will be posted on the NIA Website at http://www.nih.gov/nia/news/. The Advisory Group recommended studies of human CR interventions in non-obese persons lasting for at least two years, to determine effects on a variety of physiologic and psychological factors and disease risk factors. The Advisory Group noted that an effective initial target range for weight reduction in CR interventions in non-obese persons could be tentatively set at 15-20% of initial body weight, and also noted that several caloric restriction studies at different levels of dietary restriction will be needed to assess the potential benefits and disadvantages of CR in human populations. The Advisory Group also recommended studies comparing effects of chronic exercise with those of CR, and interactions between the effects of exercise and CR. This Request for Applications solicits projects that will address these topics. Research Goals and Scope The primary goals of this RFA are: 1) to gain knowledge about the effects in humans of sustained CR on physiology, metabolism, body composition, risk factors for age-related pathologies, progression of age-related changes (where feasible), and its potential adverse effects 2) to gain knowledge of similarities, differences and interactions between the effects of CR and PA on the above outcomes when employed in interventions to prevent weight gain. Projects submitted in response to this RFA should consist of controlled human intervention studies of: 1) the effects of reduced calorie intake alone, or 2) comparison of the effects of CR to those of physical activity interventions that have the same effects on weight as the CR intervention, and/or 3) determining interactions between the effects of reduced calorie intake and increased physical activity, e.g., through factorial-design studies. Proposed projects that include only physical activity interventions will be considered non-responsive to this RFA. Studies in young adults, and/or middle-aged persons up to age 60 years at the time of the start of interventions, may be proposed. Participants should be free of major chronic diseases (e.g., diabetes, cardiovascular disease, osteoporosis). Participants in the study should be non-obese (Body Mass Index below 30.0). Subject populations of interest are overweight persons (Body Mass Index 25.0-29.9), or other individuals at high risk for becoming overweight or obese, and previously obese persons at risk for recurrence of obesity. Proposals for studies of interventions in obese persons will be considered non- responsive to this RFA. The intervention(s) should be at least 2 years in duration. Studies that propose to carry out the intervention(s) for greater than two years must include plans for an interim analysis at two years. As described below, projects should include a pilot phase in which to acquire data on which to refine the selection of the CR regimen (and PA regimens, if these are proposed) to be tested. Proposed CR interventions to be tested should consist of a specified percentage reduction in individuals caloric intake below their pre- study levels. CR interventions should be designed to be maintained over the duration of the study, subject to periodic review of participant safety, protocol adherence, and other issues. The degree of CR should produce no more than a 20% reduction in body weight over the course of the study. (Applicants are reminded that focus of this RFA is on CR rather than weight loss per se. CR interventions which may result in weight stability over the study interval may be proposed.) CR protocols should be designed to assure that intake of micronutrients in subjects in the intervention groups and control groups is maintained at adequate levels, and is not diminished from baseline levels in subjects in the control groups. If comparisons between the effects of CR and PA (or studies of their interactions) are proposed, the type and/or intensity of the proposed PA intervention (or combined CR/PA intervention) should be designed to result in the same pattern and extent of weight change expected from the CR regimen selected. Proposals for studies should include study protocols, with clearly defined eligibility and exclusion criteria, and information on proposed subject recruitment, outcome measures/endpoints, sample size/power calculations, as well as baseline measures and follow-up examinations. Study design should include appropriate control group(s) and appropriate measures to blind study personnel to the intervention assignment of the study participants (e.g., studies may be single- blinded). It is also important that potential applicants consider the methods they may use to assess/monitor the behavioral and quality of life aspects of their proposed interventions. Potential influences of behavioral and social factors on recruitment and retention into the studies should be considered in the study design. Study endpoints must include: o Energy intake and expenditure (see below for requirement of doubly- labeled water technique) o Physical activity o Body composition (as measured by DEXA or MRI; other techniques available and proposed for body composition will be in addition to DEXA or MRI) Other outcome measures may include but are not limited to the following: o Endocrine responses, including reproductive hormones o Insulin sensitivity and glucose metabolism o Cardiovascular/respiratory measures o Bone density/metabolism o Immune function o Quality of life o Potential adverse effects The use of the most valid and reliable techniques for tracking caloric intake and expenditure (e.g., doubly-labeled water) and level of physical activity (e.g., accelerometers) are considered essential features of these exploratory studies. Proposals must include plans for tracking energy intake and expenditure using the doubly-labeled water technique unless they include a rationale for use of another method that provides equal or greater accuracy. Applications should request funding for enough doubly-labeled water to assess energy expenditure at time intervals deemed optimal and appropriate within their study designs. The NIA recognizes the current limitations in availability, price uncertainty, and cost constraints of using doubly-labeled water, and is presently exploring possibilities to lessen or offset costs of doubly-labeled water for projects submitted in response to this RFA. Nevertheless, applicants should budget fully for the doubly-labeled water needed in their proposed projects, using their best estimates for prices at the time of the study. Applicants are also encouraged to consider including related data collection and analyses in their proposed studies, on topics such as the following: o Factors affecting ability to identify and recruit appropriate subjects for CR interventions, and improved measures to identify non- obese subjects at high risk for significant weight gain (to guide recruitment for future studies) o Factors affecting adherence to CR and combined CR-PA interventions o Feasibility and differences in effects of alternative CR and PA intervention strategies. o Dose-response and time-course of effects of CR, and combinations of CR and PA (including effects during the weight-stable phase of the interventions) on weight, physiologic function, disease risk factors, and potential short-term adverse effects o Potential gender differences in the response to CR and PA o Effects of physical activity interventions on caloric intake, and/or effects of calorie restriction interventions on levels of physical activity o Correlation of questionnaires with more laboratory-based measures for caloric consumption/expenditure (e.g., doubly-labeled water) and physical activity (e.g., three-dimensional accelerometers) o Genetic factors predicting/influencing responses to CR, or combination of CR and PA interventions Potential applicants are encouraged to use interdisciplinary approaches in developing their study designs, including expertise (where appropriate) in such areas as nutrition, physiology, endocrinology, metabolism, body composition, clinical trials, behavioral sciences, biostatistics, and gerontology. Potential applicants interested in conducting research on molecular and neural aspects of caloric restriction in experimental animals are encouraged to review the concurrent NIA RFA, Molecular And Neural Mechanisms Underlying The Effects of Caloric Restriction on Health and Longevity, http://grants.nih.gov/grants/guide/rfa-files/RFA-AG-01-002.html. SPECIAL REQUIREMENTS Under the terms of the cooperative agreement, the awardee defines the details of the project within the guidelines of the RFA, retains primary responsibility for the performance of the activity and for the analysis and publication of the results. The awardee agrees to accept assistance, close coordination and participation of the designated NIA program administrator in all aspects of the scientific and technical management of the project in accordance with the terms of this RFA. The NIH will have the option of halting the study or individual study sites if the program objectives are not being met, or have been met prior to the full 7-year period. After the scientific merit, personnel and resources of proposals have been assessed by peer review, modification of the individual study site protocols may be necessary. This may include use of common lab measures, instrumentation, and methods of specimen collection and storage (including arrangements to make the specimens available to outside investigators), in order to maximize achievement of the objectives of this RFA. Needs for such modifications may arise both before and during implementation of protocols, and cannot always be foreseen before the intervention begins. The maximum duration of proposed studies may not exceed 7 years. The variations in project length will be due to differences in time needed for subject recruitment, duration of intervention (must be at least 2 years) and period of follow-up. Studies supported through this RFA will consist of three phases: Phase 1: Protocol Refinement (up to 2 years) Applicants should describe Phase 1 activities in detail in their proposals. Activities during this phase may include but are not limited to: o recruitment and screening of subjects o identification of improved predictors of risk for weight gain, to guide recruitment o racial/ethnic and cultural appropriateness of protocols o determination of optimal recruitment strategies o verification of interventions feasibility o verification of techniques to determine protocol adherence o measurement of short-term effects of the intervention o potential adverse effects and tolerability o dose-response and time-course studies testing differing levels of CR and PA (the type and/or intensity of the PA intervention selected should match the magnitude of an effect(s) achieved through CR) o protocol refinement based on results during this phase Studies in this phase may be conducted in a clinical research center environment and/or with community-dwelling subjects. In order to proceed to Phase 2, the study sites must demonstrate: o valid and reliable measurement of physical activity levels and energy intake o participants adherence to intervention protocol(s) o safety and tolerability of CR and PA interventions o successful recruitment strategies Phase 2. Protocol Implementation (at least two years). Activities under this phase include the conduct of intervention activities, continued screening and recruitment of subjects (if necessary), and preliminary data analysis. It is recognized that protocols for Phase 2 may be substantially modified from those described in the application, based on results of Phase 1. Applicants should nonetheless describe their proposed Phase 2 intervention in detail, indicating what aspects are still to be finalized based on results of Phase 1 studies, and describing the resources available to implement protocol modifications based on Phase 1 results. (Examples include potential other population sources and/or clinical sites if additional participants are needed, or other facilities and equipment for determining body composition, if proposed methods prove infeasible.) By the end of Phase 2, all study subjects should have completed the intervention protocol(s), and data analysis plans should be clearly established by the study sites. Phase 3. Data analysis and reporting (approximately one year). Applicants should also state their willingness to participate in meetings to track the progress of their studies and to promote exchange of experiences and ideas. A workshop may be convened at the end of the project period, to discuss future directions. It is anticipated that the awardees may meet more frequently than once a year during the first and last year of their project periods. In addition, awardees from this RFA may meet periodically with the awardees of the NIA RFA, Molecular And Neural Mechanisms Underlying The Effects of Caloric Restriction on Health and Longevity, http://grants.nih.gov/grants/guide/rfa-files/RFA-AG-01-002.html. An exchange of data and ideas between researchers conducting basic/molecular studies and clinical research on the effects of caloric restriction will be invaluable in guiding future studies in this area. Funds for travel to the Washington D.C. area for the principal investigator (and up to two co-investigators, if appropriate) for two one-day meetings should be included in the budgets for each year. Applicants should also review the NIA document, Policies For Human Intervention Studies at http://www.nih.gov/nia/funding/policy/humint.htm for specific requirements for the safety of participants in intervention studies. This NIA policy does not replace existing NIH regulations on protection of human subjects, policies and guidelines for conduct of clinical research, inclusion of women and minorities, research project administration, reporting, and financial management, or requirements of local Institutional Review Boards (IRBs). DHHS regulations for the protection of human subjects are described in 45 CFR46. The implementation of these regulations for PHS research grants involving human subjects is found in the PHS 398 form (rev. 4/98) available on the NIH home page http://grants.nih.gov/grants/forms.htm. Organizational Components 1. Study Sites A study site is the Institution that receives an award for conducting the investigations under this RFA. There should be evidence of strong Institutional support for the site and a stated willingness to follow common aspects of study design, lab measures and analyses as approved by the Steering Committee. 2. Steering Committee A Steering Committee will serve as the main decision-making body for the shared aspects of the exploratory studies. The Steering Committee will have the overall responsibility for the development and finalization of standard definitions/lab measures common to the protocols of the study sites. The principal investigators of the study sites and the designated NIA Program Administrator will comprise the voting members of the Steering Committee. The studies will proceed into the next phase only after approval by the Steering Committee of the site protocols, review and approval by the Monitoring Board, and acceptance by the NIA. The Steering Committee will meet every three to six months, or as needed. 3. Monitoring Board A Monitoring Board will be formed to advise the study sites by periodically reviewing their research progress and the safety of the study subjects, as well as resolve any serious conflicts over how the overall study should proceed. The Monitoring Board will be comprised of experts in relevant medical, statistical and bioethical fields. The Board’s approval will be required before initiation of Phase 1 study protocols, and before transition to Phase 2. The Chairperson of the Steering Committee and the NIA Program Administrator will participate as non-voting members of this Board. Terms and Conditions of Award The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92 and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (UO1), an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardees is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient’s activity by 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 awardees for the project as a whole, although specific tasks and activities in carrying out the collaborative aspects will be shared among the awardees and the designated NIA Program Administrator. 1. Awardee Responsibilities Awardees will have primary authorities and responsibilities to define objectives and approaches, and for participant recruitment and follow- up, quality control, data analysis and interpretation, and for preparation of publications from their projects. Awardees at the study sites shall retain custody of, and primary rights to, the site-specific data developed under their award, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. In addition, awardees will engage in collaborative activities through participation in Steering Committee meetings and potential conference calls in the development and implementation of common measures across study sites. The Steering Committee will define the rules regarding access to and publication of findings from analysis of common data. 2. Staff Responsibilities The designated NIA Program Administrator will have substantial scientific/programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship of grants. The awardee agrees to accept assistance from the designated NIA Program Administrator, as described below: o Participate in the monitoring of issues relating to recruitment, treatment, follow-up, quality control, and adherence to protocols. o Assist in the development and/or adjustment of study protocols. o In conjunction with the Steering Committee, approve the transition of study sites from Phase 2 to Phase 3. After approval from the Monitoring Board, the NIA must accept (approval by the Director, NIA) the protocol before it can be implemented. The NIA reserves the right to terminate or curtail the study (or an individual award) in the event of substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breech of the protocol; if human subject safety or ethical issues dictate a premature termination; or if there is failure to develop or implement mutually agreeable collaborative protocols. o Assistance in data analyses 3. Collaborative Responsibilities A Steering Committee will serve as the main decision-making body for the shared aspects of the exploratory studies. The Steering Committee will have the overall responsibility for developing and finalizing standard definitions/lab measures common to the protocols of the study sites. The principal investigators of the study sites and the designated NIA Program Administrator will comprise the voting members of the Steering Committee. The studies will proceed into the next phase only after approval by the Steering Committee of the site protocols, review and approval by the Monitoring Board, and acceptance by the NIA. The Steering Committee will meet every three to six months, or as needed. A Monitoring Board will be formed to advise the study sites by periodically reviewing their research progress and the safety of the study subjects, as well as resolve any serious conflicts over how the overall study should proceed. The Monitoring Board will be comprised of experts in relevant medical, statistical and bioethical fields. The Board’s approval will be required before initiation of Phase 1 study protocols, and before transition to Phase 2. The Chairperson of the Steering Committee and the NIA Program Administrator will participate as non-voting members of this Board. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the U01 award), between U01 awardees and the NIA may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (without NIH representatives voting) or by the individual U01 awardee in the event of an individual disagreement; a second member selected by the NIA; and, the third member selected by the two prior selected members. For U01 awardees, this special arbitration procedure will in no way affect the awardee’s right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning this policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to the program staff listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: GrantsInfo@nih.gov. Applications are also available on the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html. The RFA label available in the PHS 398 (rev. 4/98) 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note that this sample label is in pdf format. Submit a signed, original of the application, including the Checklist, and three signed photocopies of the application 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, send two additional copies of the application to: Chhanda Dutta, Ph.D. Director, Musculoskeletal Research and Nutrition, Metabolism and Gastroenterology Research Geriatrics Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3E-327 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 435-3048 FAX: (301) 402-1784 Email: cd23z@nih.gov These copies are used to identify conflicts and to help ensure the appropriate and timely review of the application. Applications must be received by 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. 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. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the NIA. Incomplete and/or nonresponsive applications will 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 NIH in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council on Aging. 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 discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Schedule: Letter of Intent Receipt Date: January 12, 2001 Application Receipt Date: April 25, 2001 Date of Initial Review: July 2001 Review by Advisory Council: September 2001 Anticipated Award Date: September 2001 AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priorities INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Chhanda Dutta, Ph.D. Director, Musculoskeletal Research and Nutrition, Metabolism and Gastroenterology Research Geriatrics Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3E-327 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 435-3048 FAX: (301) 402-1784 Email: cd23z@nih.gov Direct inquiries regarding fiscal matters to: Ms. Cynthia Riddick Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: riddickc@exmur.nia.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.866. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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