RFA-AG-04-005

THE ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE RELEASE DATE:  October 2, 2003   RFA Number:  RFA-AG-04-005 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 16, 2003   APPLICATION RECEIPT DATE:  January 16, 2004  THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support  o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements  o Where to Send Inquiries o Letter of Intent o Submitting an Application o 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 National Institute on Aging (NIA) invites applications from  qualified institutions for a Cooperative Agreement (UO1) to establish a  Coordinating Center (CC) together with a Neuroimaging Center (NC) and a  consortium of clinical sites for the NIA Neuroimaging Initiative. The  purpose of this Initiative, planned as a public-private partnership, is  to develop a multi-site, longitudinal, prospective, naturalistic study  of normal cognitive aging, mild cognitive impairment (MCI), and early  Alzheimer's disease (AD) as a public domain research resource to  facilitate the scientific evaluation of neuroimaging (magnetic  resonance imaging [MRI], positron emission tomography [PET]), and other  biomarkers for the onset and progression of MCI and AD. A primary goal  is to identify the biomarkers of disease progression that are most  promising for use as surrogate endpoints in phase 2 and 3 clinical  trials for the prevention and treatment of AD.  An essential feature of this initiative is that the clinical,  neuropsychological, imaging, and biological data and samples will be  made available to all qualified scientific investigators at time  intervals to be determined by the Steering Committee and estimated to  be every 3-6 months, with raw data available more frequently. The  period of support for the Neuroimaging Initiative will be five years.   RESEARCH OBJECTIVES Advances in the understanding of the pathophysiology and genetics of AD  are providing opportunities for developing disease-modifying therapies.  A number of neuroimaging technologies and biological substances in the  blood and cerebrospinal fluid (CSF) now appear to have considerable  potential for measuring progression in this disease (Frank, R.A., et  al., Neurobiology of Aging 24:521-36, 2003). A number of studies in AD  and MCI have demonstrated that imaging parameters are more sensitive  and consistent measures of disease progression than cognitive  assessment. Some studies have shown that imaging measures correlate  with cognitive test performance in MCI and AD — an initial step in the  validation of markers that accurately predict the course of disease and  that could be used as surrogate endpoints to establish claims for  disease-modifying treatment. The technical feasibility of using  structural MRI measures as a surrogate endpoint of disease progression  in multi-center clinical trials has been demonstrated (Jack, C.R., et  al., Neurology 60:253-260, 2003).  A slowed rate of atrophy in a structure known to be affected by AD  together with neuropsychological test data indicating that cognitive  function was stabilizing or improving, would be strong evidence for a  disease-modifying effect. In phase 2 trials, imaging and other markers  can help to rapidly identify appropriate doses, assess safety, and  compare drugs in early development. Biomarkers decrease the time and  cost of phase 2 and 3 clinical trials, increasing the safety and  efficiency of drug development.      Collaborating with the Food and Drug Administration (FDA) on projects  such as the Initiative helps the NIH bridge the gap between research  and the regulatory process, speeding the fruits of research into  treatments for disease, a priority for both agencies. The FDA is  increasingly accepting of surrogate endpoints based on imaging, which  are not yet fully validated, including as primary endpoints in pivotal  trials (recent examples include Etanercept, Eloxatin), given the marker  is reasonably likely to predict clinical benefit (CFR 314.510), a  condition that the Initiative can help demonstrate.    A group of cognitively normal older subjects will be studied in order  to document changes in neuropsychological, imaging, and biochemical  parameters that occur with normal aging. This will allow comparison  with the changes occurring in the MCI and early AD groups. A fraction  of the normal group would also be expected to develop MCI and possibly  AD over the time period studied, so data may also be collected on very  early measurable changes in the course of illness. Primary objectives:   1.Collect serial clinical, neuropsychological, biological, and imaging  data (1.5T structural MRI on all subjects with a bridging study to 3T  at a subset of sites, and 18fluoro-deoxyglucose (FDG) PET at a subset of  sites) on subjects with MCI (followed for three years), normal controls  (followed for three years), and subjects with early AD (followed for 2  years), in order to define the rate and variance of change of  neuroimaging and other markers of disease onset and progression for  comparison with clinical and neuropsychological measures, using  relatively frequent sampling points. The primary goal of these efforts  is to identify useful surrogate markers of disease progression that  will decrease the time and sample size needed to document disease- modifying efficacy in clinical trials.    2.Collect, process, and store serial blood, CSF, and urine samples in  the three groups of subjects for analyses for potential biomarkers of  disease progression, including genomic, proteomic, and metabolomic  markers that can be correlated with clinical, neuropsychological, and  imaging data. Immortalized cell lines will also be established. 3.Establish methodologies for the multi-site collection, quality  assurance/quality control, and distribution/sharing of neuroimaging and  other biological data, in conjunction with clinical and  neuropsychological data.  4.Place the longitudinal databases in the public domain and make the  data available to all qualified investigators at time intervals to be  determined by the Steering Committee (estimated to be every 3-6 months,  with raw data available more frequently) for a variety of analyses that  will provide insight into the natural history of MCI and AD, evaluate  the ability of biomarkers to predict the onset and rates of progression  of MCI and AD, including conversion from MCI to AD, and evaluate which  methods provide the greatest statistical power for distinguishing  pathological changes from normal aging.   Initial MRI images will need to be evaluated as per inclusion/exclusion  criteria, for example, ruling out potential participants with multiple  lacunes in a critical memory structure. Calculation of measures such as  hippocampal, entorhinal cortex, and temporal horn volumes for  incorporation into the database is anticipated as being fundable  through this Initiative. As such, applicants to the Initiative should  use the anticipated rates of change in these or other potential  biomarkers to generate primary hypotheses on how these measures relate  to cognitive decline and conversion to AD. Using estimates of sources  of variance and magnitude of treatment benefit, applicants are  encouraged to generate hypothetical power calculations for clinical  trial design. Minimal data analyses are included as part of this RFA,  but funding for more extensive analyses will be encouraged through  other mechanisms such as RO1, RO3, and R21 grants. Applicants for the Neuroimaging Initiative will need to establish three  components for the Initiative: (1) a CC for delineating protocols,  organizing and monitoring data and sample collection, storage, and  distribution, and other administrative functions such as organizing  Steering Committee meetings; (2) a strong NC or Core for delineating  imaging protocols, establishing and monitoring quality assurance (QA)  and quality control(QC) procedures for the collection of imaging data  among the sites, storage and distribution of imaging data, and image  processing; and (3) clinical sites, each providing a core team of  researchers skilled in the recruitment and clinical evaluation of  subjects with normal cognition, MCI, and AD, and the implementation of  assessment tools for MCI and AD. All sites must also have MRI (1.5T)  capability and access to adequate time on an MRI scanner; a subset of  sites must have capability and access to adequate time on a PET  scanner; and a subset of sites, on a 3T MRI scanner.  Individual potential clinical sites may be included in more than one  application. A Steering Committee, comprised of the principal investigator (PI) of  the cooperative agreement, the leaders of the CC, NC, and each of the  clinical sites, the NIA Program Administrator, representatives from  partnering pharmaceutical and/or medical imaging companies, and the  FDA, will have primary responsibility for finalizing standard  definitions, procedures, and laboratory measures common to the  protocols of the study sites.  The Steering Committee will also  encourage and consider proposals for ancillary studies. These studies  will most likely require funding from sources outside of this  cooperative agreement. The criteria for MCI should follow those discussed as amnestic and  multiple-domain MCI in Petersen (2003), so may include subjects who  have mild cognitive deficits outside of the domain of memory in  addition to memory impairment (Petersen RC, Nature Reviews 2:646-653,  2003). Inclusion of subjects with symptoms of depression or who are  being treated with anti-depressant medications that do not have strong  anti-cholinergic actions is encouraged, as many studies establish  depression as a risk factor for AD. Applicants should include  inclusion/exclusion criteria that will be uniform across all sites for  each of the subject groups, although final details will be determined  by the Steering Committee.    NIA staff, in conjunction with four working groups of experts,  discussed how to achieve the goals of the Initiative. Reports on the  findings of these groups are posted on the NIA web site  (http://www.nia.nih.gov). Suggested time points for assessment were as  follows:  o HEALTHY CONTROLS: Baseline, 12, 24, & 36 months;  o MCI: Baseline, 3, 6, 12, 18, 24, 30, & 36 months;  o MILD AD GROUP: Baseline, 3, 6, 12, 18, & 24 months.    All subjects would complete clinical, neuropsychological, 3D volumetric  MRI (1.5T) evaluations, and blood sampling at each time point. At less  frequent time points, in a sub-set of subjects, CSF samples would be  collected and at those sites with the capability, PET scanning and 3T  MRI.   Blood samples will be collected, processed and stored for the  establishment of immortalized cell lines. The findings of a working  group on promising biomarkers in blood, CSF, and urine, which are  feasible to collect in a multi-center study are published in Frank,  R.A., et al., Neurobiology of Aging 24:521-36, 2003. Applicants may  propose other measures as well, and should also plan for the  collection, shipment, and storage of aliquots of samples for analyses  of substances to be determined by future research including proteomic  and metabolomic studies. The results of all analyses will need to be  submitted for inclusion in the centralized dataset, consistent with the  data-sharing plans of the Initiative.  Funding for the analysis of substances in the specimens collected is  not anticipated to be available from the funds for this Initiative,  with the exception of Apolipoprotein E alleles and standard clinical  laboratory assessments. Funding for the establishment of cell lines is  anticipated.     To advise the Steering Committee, applicants should also plan to  recruit an external advisory committee, consisting of scientists from  outside the institutions awarded funding for the Initiative. External  advisory committee members should not be recruited until the NIH review  is complete. This committee will be used to evaluate the progress of  the Initiative, ensure that data monitoring procedures are sufficient  and that quality data are being collected to the highest standards  possible, evaluate the effectiveness of communications among the CC,  NC, and clinical sites, and any other activities for which outside  expertise is required or desirable. The NIA project coordinator, who  will also serve as the program administrator, will attend each meeting  of this committee as an observer.  The CC is expected to work in collaboration with its NC, the clinical  sites, and the NIA project coordinator to assist in protocol  development and planning, subject recruitment, project administration,  and close-out.  MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01) award mechanism.  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 not later than  September 30, 2004.   The NIH U01 is a cooperative agreement award mechanism. In the  cooperative agreement mechanism, the Principal Investigator retains the  primary responsibility and dominant role for planning, directing, and  executing the proposed project, with NIH staff being substantially  involved as a partner with the Principal Investigator, as described  under the section "Cooperative Agreement Terms and Conditions of  Award." The total project period for an application submitted in  response to the present RFA may not exceed 5 years.  FUNDS AVAILABLE  The NIA intends to commit up to $12 million in FY 2004 for the initial  year of funding for the Neuroimaging Inititative. An applicant may  request a project period of up to 5 years and a budget for total costs  of up to $12 million per year. The size of the proposed budget for each  year should be appropriate for the phase being conducted in that year.  No more than one award will be made as a result of this RFA and funding  of this award is contingent upon availability of funds. ELIGIBLE INSTITUTIONS  You may submit an application 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 institutions o Foreign institutions are eligible to serve as clinical sites but not  as the CC or NC. 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 The CC and the clinical sites should obtain IRB approvals consistent  with the guidance on repositories from the NIH Office of Human Research  Protections (OHRP):  http://ohrp.osophs.dhhs.gov/humansubjects/guidance/reposit.htm. The NIH  brochure on research on human specimens may also be useful and can be  found at: http://www.cdp.ims.nci.nih.gov/policy.html   1. (A) Special requirements for the Neuroimaging Initiative CC are as  follows: o  The applicant should state the willingness and ability to cooperate  with the Neuroimaging Initiative clinical sites and NC and NIA staff in  all design, data collection, management and distribution functions. The  applicant should provide a plan for developing a cooperative  relationship among the clinical sites and between the various  organizational components. o  A formal data-sharing plan must be included in the application,  including a plan for a system that allows databases to be queried, in  conjunction with CC staff, by investigators not directly associated  with the Initiative.  (B) Special requirements for the NC or Core are as follows: o  Images should be centrally archived for centralized analysis for  those comparisons that address the primary aims of the study.  Applicants should describe procedures that will allow investigators  from different organizations to analyze data using other methods (e.g.,  different image reconstruction, image deformation, or normalization  techniques) in order to optimize the study of imaging measures as  putative surrogate markers of AD.  Data should be stored in the  original and in any modified formats. o  The NC applicant should state the willingness and ability to  cooperate with the Neuroimaging Initiative CC and clinical sites and  NIA staff in all design, data collection, management and distribution  functions. (C) Special requirements for clinical sites are as follows: o  Site applicants should state the willingness and ability to  cooperate with the Neuroimaging Initiative CC and Neuroimaging Center  and NIA staff in all design, data collection, management and  distribution functions. 2. Cooperative Agreement 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 project administrator. A. Awardee Responsibilities The Coordinating Center (CC) awardee agrees to work cooperatively with  the Neuroimaging Initiative Neuroimaging Center (NC) and clinical sites  and will have the primary responsibility for developing and  implementing systems necessary for communications among the various  Neuroimaging Initiative organizational components. The CC will  facilitate the design and refinement of all protocols, manuals of  operation, and forms.  The awardee institution will retain custody of, and primary rights to,  the data developed under this award, subject to Government rights of  access consistent with current HHS, PHS, and NIH policies, with the  added stipulation that all primary data shall be shared within time  periods to be specified, as a fundamental purpose of this Initiative is  the establishment of an unrestricted public database.  The primary governing body of the study will be the Steering Committee,  which will have responsibility for the final details of study design  and policy decisions and will define the rules regarding access to  common data. B.  Staff Responsibilities The designated NIA Project Administrator will serve as a member of the  Steering Committee and have substantial scientific/programmatic  involvement during conduct of this cooperative agreement, through  technical assistance, advice and coordination above and beyond normal  program stewardship of grants. The awardee agrees to accept assistance  from the designated NIA Project Administrator, as described below: o  Participation, through the Steering Committee, in the monitoring of  issues relating to recruitment, follow-up, QA/QC, and adherence to  protocols. o  Assistance in the development and/or adjustment of study protocols. An NIA Program Director will be responsible for the normal program  stewardship on this award. The Program Director may also be designated  as the NIA Project Administrator described above.  C. Collaborative Responsibilities The Steering Committee, comprised of the PI of the cooperative  agreement, the leaders of the CC, NC, and each of the clinical sites,  the NIA project administrator, representatives from partnering  pharmaceutical and/or medical imaging companies, and the FDA, will have  primary responsibility for finalizing standard definitions, procedures,  and laboratory measures common to the protocols of the study sites. The  SC will meet every three to six months, or as dictated by the needs of  the Neuroimaging Initiative. Each member of the Steering Committee will  have one vote, and all major scientific decisions will be determined by  majority vote of the Steering Committee. Subcommittees appointed by the  Steering Committee, comprised of appropriate staff from the CC, NC, and  clinical sites, will be involved in the design of protocols and manuals  of operations, and in ongoing functions of the Neuroimaging Initiative,  such as consideration of potential ancillary studies and preparation of  publications.  To oversee the allocation and distribution of biological specimens  generated from the Neuroimaging Initiative, the Steering Committee will  select a Resource Allocation Review Committee (RARC). This group will  review applications for use of the biological specimens. The format of  the application and criteria for the use of repository biological  specimens will be developed by the RARC with advice and approval from  the Steering Committee and made available to all potential users. The  RARC will be made up of individuals not directly involved in the  Neuroimaging Initiative and without conflicts of interest. Membership  on this committee will rotate periodically according to a procedure  developed by the RARC.   D.  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, nor will it affect the government's rights with regards to  grants enforcement. 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 inquiries regarding programmatic issues to: Susan Molchan, M.D. Program Director, Alzheimer's Disease Clinical Trials Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Bldg., Suite 350 7201 Wisconsin Ave. Bethesda, MD 20892-9205 Telephone:(301)496-9350; FAX:(301)496-1494 E-mail:  molchans@mail.nih.gov o Direct inquiries regarding peer review issues to: Mary Nekola, Ph.D. Chief, Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C-212 Bethesda, Maryland 20892-9205 Express Mail Zip Code:  20814 Telephone:  301/496-9666; FAX:  301/402-0066 E-mail:  nekolam@nia.nih.gov o Direct inquiries regarding financial or grants management matters to: Linda Whipp Grants Management Officer National Institute on Aging 7201 Wisconsin Avenue, Suite 2N-212 Bethesda, Maryland  20892-9205 Express Mail Zip Code:  20814 Telephone:  301/496-1472; FAX:  301/402-3672 E-mail: whippl@nia.nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by December 16, 2003, 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 for the CC, NC, and the clinical sites 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 Molchan, M.D. Program Director, Alzheimer's Disease Clinical Trials Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Bldg., Suite 350 7201 Wisconsin Ave. Bethesda, MD 20892-9205 Telephone:(301)496-9350; FAX:(301)496-1494 E-mail:  molchans@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 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 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 Introduction and Background sections should be provided for the  application as a whole. Following those sections three separate  sections should be prepared, one for the CC (up to 25 pages), one for  the NC or Core (up to 25 pages), and one for the clinical sites (3-4  pages/site). In addition, please include a chart of the clinical sites  summarizing patient (MCI and early AD) recruiting experience and  potential, neuropsychological and clinical experience with MCI and AD  patients, experience as part of multi-site studies, MRI (1.5T)  experience, MRI scanner availability and access, and if applicable, PET  experience and PET scanner availability and access, and/or 3T MRI  experience, availability, and access.  Individual potential clinical sites may be included in more than one  application.   Provide a flow chart or time line of the evaluations and procedures  planned for subjects. Plans for ensuring compliance with HIPAA, data  integrity, quality control, and data sharing should be discussed. Personnel: For each of the three components of the Initiative, the  application must describe the expertise of key scientific, technical  and administrative personnel and include a mechanism for replacing key  professional or technical personnel should the need arise.  Budget:  The budgets should be based on the applicant's best judgment  of activities likely to be involved during the different phases of the  Initiative as delineated under the section on Research Objectives.  Budgets should include costs of organizing at least two Steering  Committee meetings annually and for attendance of necessary CC, NC, and  clinical site staff to these meetings. Budgets should include costs of  at least two external scientific advisory committee meetings annually.  Budgets should include projected data handling costs, reporting  functions, meetings, and other communications costs. Funding for  extensive analyses will be encouraged through other mechanisms such as  research grants but budgets for evaluation of scans for exclusion  criteria, for example, ruling out potential participants who have  multiple lacunes in a critical memory structure, and determination of  measures such as hippocampal, entorhinal cortex, and temporal horn  volumes for incorporation into the database will be needed. Clinical  sites will be reimbursed for costs on a per visit/per protocol basis.  Attempts should be made by the applicant institution to utilize  existing clinical facilities, such as General Clinical Research Centers  and AD Centers. Costs relating to the clinical efforts for the  Neuroimaging Initiative may be funded through the Initiative, provided  there is no overlap of funding. Only those research patient costs  directly related to Initiative activities may be charged to the  Initiative. Include an explanation of the programmatic, fiscal, and administrative  arrangements made between the grantee administration and the  collaborating institutions. 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 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: Mary Nekola, Ph.D. Chief, Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C-212 Bethesda, Maryland 20892-9205 Express Mail Zip Code:  20814 Telephone:  301/496-9666; FAX:  301/402-0066 E-mail:  nekolam@nia.nih.gov Material included in appendices must follow the instructions in PHS  398.  APPLICATION PROCESSING: 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. 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 Aging. 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 the NIA 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 Approach o Investigator o Environment APPROACH: Are the conceptual framework, hypotheses, design, and methods  adequately developed, well-integrated, and appropriate to the aims of  the project?  Are potential problem areas acknowledged and alternative  tactics considered? Does the proposed approach in managing the  logistical and data coordination have scientific and technical merit?  Are the proposed plans and experience relating to subject recruitment  and retention, staff training, data collection, monitoring, management,  editing, processing, and reporting adequate? Has justification for  specific acquisition parameters been provided? Are plans for the  collection, shipment, and storage of biological samples adequate? Are  the plans for coordination with the study site investigators adequate?  Is the approach to developing a cooperative relationship among the  study sites and between the various Neuroimaging Initiative  organizational components adequate? Are the plans for exercising  appropriate leadership in matters of study design, data acquisition,  data management, and data distribution demonstrated?  INVESTIGATOR: Are the applicant and his/her staff appropriately trained  and well-suited to carry out this work? Is the work proposed  appropriate to the applicant's experience level as the PI? Does the  application provide evidence of specific competence and relevant  experience of professional, technical, and administrative staff  pertinent to the operation of a CC and NC for multi-site studies?   Prior experience collecting data and patient specimens from multiple  clinical sites and monitoring data quality should be demonstrated. Do  NC applicants have experience with quality-controlled collecting,  cleaning, processing, and analysis of MRI and FDG-PET scans of the  brain, including studies of AD? Is there evidence of experience in and  willingness to participate appropriately in a collaborative study as  described in this RFA? Are there adequate assurances that the CC  personnel have experience in utilizing procedures that insure the  safety and confidentiality of medical records? These questions should  also be addressed with reference to the lead investigator and staff of  the NC. Investigators and staff at the clinical sites should document  experience and capabilities as noted above under Special Requirements,  and document experience recruiting and evaluating normal elderly, MCI,  and early AD subjects, MRI (and if applicable PET) experience/access,  and collecting blood and CSF for scientific protocols.  ENVIRONMENT: For the CC, the NC, and the clinical sites, does the  scientific environment in which the work will be done contribute to the  probability of success? Is there evidence of institutional support? Has  the application documented the adequacy of the proposed facility,  technical hardware, and space for the CC/NC/clinical sites?  Is there  an appropriate organizational and administrative structure to the  proposed CC/NC?  Evidence of institutional support and commitment  should be provided. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the  application will also be reviewed with respect to the following:   o The capability of recruiting an appropriate number of subjects during  an approximately 18 month recruitment period. For clinical sites, a  documented record of past success of recruiting efforts for MCI, normal  control, and AD subjects.    o All sites must also have 1.5T MRI capability and access to adequate  time on an MRI scanner. Subsets of sites must have capability and  access to adequate time on a PET scanner and 3T MRI. For clinical  sites, a documented record of previous MRI (and PET if applicable)  research experience. 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). The Neuroimaging Initiative CC will be setting up a repository of  samples from human subjects. Therefore, the CC must comply with current  human subjects protection policies regarding potential patient  identifier information that are associated with these stored samples.  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). Plans for recruitment and retention of subjects will  also be evaluated. (See Inclusion Criteria in the sections on Federal  Citations, below). ADDITIONAL REVIEW CONSIDERATIONS SHARING RESEARCH DATA:  Applicants requesting more than $500,000 in  direct costs in any year of the proposed research must include a data  sharing plan in their application. The reasonableness of the data  sharing plan or the rationale for not sharing research data will be  assessed by the reviewers. However, reviewers will not factor the  proposed data sharing plan into the determination of scientific merit  or priority score. BUDGET:  The reasonableness of the proposed budget in relation to the  proposed research. RECEIPT AND REVIEW SCHEDULE  Letter of Intent Receipt Date:     December 16, 2003 Application Receipt Date:        January 16, 2004 Peer Review Date:           April-May, 2004                        Council Review:                         August, 2004 Earliest Anticipated Start Date:        September 1, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific/technical merit (as determined by peer review) o Availability of funds o Programmatic priorities 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 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://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm 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.   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 will be placing data collected under this RFA in a public  archive, which must provide protections for the data. 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.health.gov/healthypeople/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of  Federal Domestic Assistance at http://www.cfda.gov/ and is not subject  to the intergovernmental review requirements of Executive Order 12372  or Health Systems Agency review.  Awards are made under 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 to 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.