DEVELOPING INTERVENTIONS FOR MULTIPLE MORBIDITIES RELEASE DATE: August 27, 2004 RFA Number: RFA-AG-05-007 EXPIRATION DATE: January 14, 2005 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATIONS: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATIONS: National Institute on Aging (NIA) (http://www.nia.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.866 LETTER OF INTENT RECEIPT DATE: December 14, 2004 APPLICATION RECEIPT DATE: January 13, 2005 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute on Aging (NIA) requests R34 and R21 applications exploring potential interventions to decreasing morbidity, mortality, and disability associated with multiple, co-occurring diseases in elderly patients. This initiative supports (1) planning projects for clinical trials to design and test interventions supported by current epidemiologic and clinical evidence (R34 applications), and (2) exploratory studies to establish a scientific basis for future interventions (R21 applications). The focus of both types of activities should be on improving health outcomes related to interactions of multiple co-occurring diseases or conditions in elderly patients. The coexistence of multiple chronic conditions ( multiple morbidity ) is more common among older patients than younger ones and confers a special burden in its compound effects on overall health status, functional ability, and quality of life. This initiative builds on our understanding of the epidemiology and pathophysiology of co-occurring disease processes to decrease the complex and interacting morbidities and disabilities associated with multiple coexisting chronic medical conditions. Its goal is, ultimately, to improve overall health status of elders with coexisting diseases and to decrease the associated disabilities through evidence-based medical care that takes into account their complex interactions. RESEARCH OBJECTIVES BACKGROUND The co-occurrence of diseases and/or disease processes ( multiple morbidity or multimorbidity ) is a highly prevalent problem in clinical medicine, particularly among older patients. Multiple medical diagnoses have been reported as frequently as 78% among people age 80 years and older, a marked increase from the 10% baseline observed for children and teenagers (ages 0-19 years) in the same general practice population (1). In a recent population-based survey of men and women 55 -84 years of age, 65% of participants reported 1-3 diagnoses of common medical problems ( e.g., heart disease, hypertension, diabetes, arthritis, cancer, stroke, pulmonary disease) and 19% reported 4 or more coexisting diagnoses. (2). Gender-specific age differences in the number of diagnoses were statistically significant (p<0.01): women ages 65-84 reported more numerous diagnoses than their younger counterparts and than men of the same ages. Similarly, 81% of community dwelling women ages 65 years and older screened for participation in the Women’s Health and Aging Study reported two or more chronic medical problems, and 18% reported five or more (3); although health was considered excellent or good by 71% of this population, only 5% reported having none of the 14 chronic conditions assessed in the study. An increasing body of research demonstrates that the coexistence of multiple diseases increases the likelihood of disability. Several studies demonstrate an increased risk of impaired mobility associated with increasing number of diagnoses (1, 4-6), while others show increased difficulty with activities of daily living (1, 7, 8). Related research suggests that combinations of certain diseases may have a synergistic impact on functional status, both in general activities of daily life and in specific activities or functions (3). The association of multimorbidity with increasing age and functional compromise suggests that, as the general population ages, the public health burden of co-occurring diseases will increase significantly. Diseases that are common in elders, such as hypertension and arthritis, may occur together by chance alone. However, the impact of co- occurrence on functional status is often greater than the sum of the impacts of the individual chronic diseases. For example, Fried et al. show that the combination of arthritis and hypertension are associated with a much greater increase in risk of disability in higher function and self care (OR 7.5) than either condition alone (arthritis OR 2.4, hypertension OR 0.9) (3). The co-occurrence of disease processes more frequently than predicted by chance alone suggests common risk factors and/or overlapping pathophysiology. Recognition and exploration of common pathways of these co-occurring conditions offers the potential for improved medical management as well as for targeted interventions to decrease the synergistic interactions of impairment and disability. KNOWEDGE TO BE ACHIEVED Despite the implications of multiple morbidity for geriatric care, relatively little attention has been given to the complex clinical interactions and interrelationships of the co-occurring chronic diseases. This initiative supports preliminary research and planning activities that will provide a basis for clinical studies addressing the management of health and/or functional problems related to multiple morbidity. Ultimately, this research and its subsequent intervention studies should contribute to the development of evidence-based treatment strategies for patients with multiple medical problems, demonstrating efficacy and safety in the presence of co-occurring diseases, and/or improving functional outcomes in elderly patients with multiple morbidities. The preliminary studies supported through this initiative should provide the knowledge required to give a scientifically sound basis for clinical intervention studies targeting co-occurring conditions. In this RFA, the term condition refers to diseases, disabilities, or physiologic impairments. The knowledge to be achieved includes but is not limited to the following: 1. Identifying important health issues related to the coexistence in older persons of two or more specific conditions for which the optimal choice from currently available interventions is unknown, or for which new treatments might improve outcomes. Examples are issues related to: o a combination of conditions in which one or more condition aggravates one or more of the other conditions, o a combination of conditions for which currently available treatments for one condition have adverse effects on one or more of the others, o a combination of co-existing conditions that have overlapping etiologies or risk factors; o a combination of conditions that synergistically increases risk for other conditions or adverse outcomes, o a combination of conditions in which one or more condition confounds the diagnosis or clinical evaluation of one or more other conditions; or o interactions of treatments for more than one condition produce adverse effects or outcomes. 2. For each important health issue - identifying one or more possible interventions that might be tested in a clinical trial or trials to address this health issue. Possible types of interventions include: o single therapies, o combinations of therapies, or o treatment algorithms for individualizing therapy. 3. For each important health issue and possible intervention - identifying potential outcomes that might be measured in a trial or trials to address this health issue. Outcomes to be considered include: o effects of the intervention on each of the selected coexisting conditions, o outcomes such as morbidity, mortality, disability, and/or o the rate of progression of the study conditions and their associated functional limitations. 4. For each important health issue, possible intervention, and set of potential outcome measures to: o critically examine the State-of-the-Science regarding the combination of conditions; o determine whether the State-of-the-Science is adequate to support a trial of the intervention under consideration; and o if the state-of-the-Science is adequate, design an appropriate clinical trial. Relevant considerations include but are not limited to(a) Do epidemiologic, pathophysiologic, and/or clinical data provide a sufficient rationale for the trial and indicate its feasibility? (b) Given the prevalence of combinations of conditions in the older population and current patterns of usual care, is the trial under consideration practicable? (c) Are established methods and criteria for diagnosing or assessing the conditions under study, and for grading their severity, adequate for a clinical trial of the intervention under consideration? (d) Are existing outcome assessment tools appropriate for use in participants with the proposed conditions? If not, can existing tools be adapted to meet the needs of the study, or is the development of new assessment instruments required? (e) Are current statistical approaches suitable for exploring the interactions of multiple morbidities within the context of the prospective study? Are innovative approaches needed to address specific questions in the proposed prospective clinical trial? REFERENCES 1. Van den Akker M, Buntinx F, Metsemakers JFM, et al. Multimorbidity in general practice: Prevalence, incidence, and determinants of co- occurring chronic and recurrent diseases. J Clin Epidemiol 1998; 51(5) 367-375. 2. Foley D, Ancoli-Israel S, Britz P, Walsh J. Sleep disturbances and chronic disease in older adults: Results of the 2003 National Sleep Foundation Sleep in America Survey. (In press). 3. Fried LP, Bandeen-Roche K, Kasper JD, et al. Association of Comorbidity with disability in older women: The Women’s Health and Aging Study. J Clin Epidemiol 1999; 52(1):27-37. 4. Guralnik JM, LaCroix AZ, Abbott RD, et al. Maintaining mobility in late life: Demographic characteristics and chronic conditions. Am J Epidemiol 1993; 137:845-857. 5. Ettinger WH, Davis MA, Neuhaus JM, et al. Long-term physical functioning in persons with knee osteoarthritis from NHANES-I: Effects of comorbid medical conditions. J Clin Epidemiol 1994; 47:809-815. 6. Campbell AJ, Busby WJ, Robertson MC, et al. Disease, impairment, disability, and social handicap: A community-based study of people aged 70 years and older. Disabil Rehabil 1994; 16:72-79. 7. Guralnik JM, LaCroix AZ, Everett DF, et al. Aging in the Eighties: The Prevalence of Comorbidity and its Association with Disability. Advanced Data from Vital and Health Statistics (No. 170), 1989; National Center for Health Statistics, Hyattsville, MD. 8. Mor V, Murphy J, Masterson-Allen S, et al. Risk of functional decline among well elders. J Clin Epidemiol 1989; 42:895-904. MECHANISM OF SUPPORT This RFA will use both the NIH (R21) Exploratory/Developmental Research Grant and the NIH (R34) Clinical Trial Planning Grant award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 15, 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular budgeting format (see http://grants.nih.gov/grants/funding/modular/modular.htm). 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. Depending on the degree to which available data address the KNOWLEDGE TO BE ACHIEVED for a specific health issue and possible intervention, applicants may choose to apply for either the R21 or the R34 awards. Exploratory/developmental research grants (R21) Exploratory/developmental research grants may be proposed when preliminary information suggests that a health problem related to specific coexisting conditions might be addressed by a clinical trial, but there are insufficient data to support the rationale for such a trial, to evaluate its feasibility, or to plan it appropriately. Such applications should identify the crucial gaps in necessary data, describe how the data could be obtained, and explain how they would be used in regard to a possible trial. Examples of needed studies and data that could be obtained in such exploratory studies include but are not limited to(a) epidemiologic, pathophysiologic, or clinical data to evaluate the impact of the clinical problem to be addressed, and/or the potential effects of interventions under consideration for a trial; (b) the development and validation of new diagnostic methods and criteria for the conditions, and for grading their severity, that are appropriate for the type of intervention study being considered; (c) the development and validation of new outcome assessment tools needed for the type of trial under consideration; and/or (d) the development of new statistical approaches needed to analyze interactions of multiple morbidities within and treatment effects in the type of trial under consideration. Exploratory/developmental research grant applications use the NIH R21 mechanism as described in the program announcement PA-03-107: NIH Exploratory/Developmental Research Grant Award (R21). This program announcement is available online at http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html . This mechanism allows a project period of up to two years and a combined budget (both years) up to $275,000 direct costs. No more than $200,000 direct costs may be requested in a single year. Clinical Trial Planning grants (R34) Planning grants for clinical trials may be proposed when current data provide strong support for the importance of the health problem to be addressed, the likelihood of efficacy of the intervention to be tested, the ability to assess conditions and outcomes appropriately, and the feasibility of conducting a trial. Applicants for planning grants may request funds for activities such as (a) preparing a detailed protocol and a Manual of Procedures; (b) analyzing existing data needed to refine the study design and protocols (e.g., power calculations, dosage or intensity of intervention, budget estimates); (c) conducting preliminary studies to guide selection of, and/or refine, study procedures and instruments, to estimate recruitment and retention potential, and to plan collection and analysis of biological specimens; and/or (d) providing travel expenses for individuals from multiple sites to planning meetings for the project. Planning grant applications use the NIH R34 mechanism as in the program announcement PA-04-008: NIH Clinical Trial Planning Grant (R34) Program. This program announcement is available online at http://grants.nih.gov/grants/guide/pa-files/PA-04-008.html. This mechanism allows a project period of one year and a budget for direct costs up to $100,000. However, because of the additional complexities of studying multiple coexisting conditions, responses to this RFA may request direct costs up to $150,000. FUNDS AVAILABLE The NIA intends to commit approximately $1,000,000 in FY 2005 to fund 3 to 5 new awards in response to this RFA. For clinical trial planning grants (R34 mechanism), an applicant may request a project period of one year and a budget for direct costs of up to $150,000. For exploratory/developmental studies (R21 mechanism), an applicant may request a project period of up to two years and a budget for direct costs of up to $275,000 for the total project period, not to exceed $200,000 in any one year. NIH no longer counts consortium F&A costs as a direct cost when determining if an applicant is in compliance with a direct cost limitation on a solicited application. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html for further details.) Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIA 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 or foreign institutions/organizations o Faith-based or community-based organizations. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS All applications should include travel expenses for the Principal Investigator to attend a 1-2 day annual meeting of awardees in Bethesda, MD, in Year 01 of the proposal budget. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. 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: Susan G. Nayfield, M.D., M.Sc. Chief, Geriatrics Branch Geriatrics and Clinical Gerontology Program National Institute on Aging Gateway Building, Suite 3C307 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-6761 FAX: (301) 402-1784 Email: nayfiels@mail.nih.gov o Direct your questions about peer review issues to: Michael Micklin, Ph.D. Chief Risk, Prevention, & Health Behavior Integrated Review Group Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Rm. 3136 MSC 7759 Bethesda, MD 20892 (20817 for overnight delivery) Tel: 301-435-1258 FAX: 301-594-6363 E-mail: MicklinM@mail.nih.gov o Direct your questions about financial or grants management matters to: Ms. Cynthia Riddick Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: riddickc@nia.nih.gov 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: Susan G. Nayfield, M.D., M.Sc. Chief, Geriatrics Branch Geriatrics and Clinical Gerontology Program National Institute on Aging Gateway Building, Suite 3C307 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-6761 FAX: (301) 402-1784 Email: nayfiels@mail.nih.gov 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 D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B 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) 710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs 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/labels.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and five 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) 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 NIA. Incomplete applications will not be reviewed. If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. 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 CSR in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National 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 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 Are the preliminary research projects or research planning activities consistent with the overall goals and specific aims of the RFA? o Will theses preliminary projects or activities support the design and implementation of an intervention study that addresses the medical management and associated medical and functional outcomes of co- occurring diseases and/or disease proceses in older adults? 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 AND MINORITIES IN RESEARCH: The adequacy of plans to include subjects from both genders, and all racial and ethnic groups (and subgroups) 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 BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: December 14, 2004 Application Receipt Date: January 13, 2005 Peer Review Date: June 2005 Council Review: September 2005 Earliest Anticipated Start Date: September 15, 2005 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. 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 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. 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 RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at 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) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at 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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