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NHLBI PROGRAMS OF EXCELLENCE IN NANOTECHNOLOGY RELEASE DATE: March 22, 2004 RFA Number: RFA-HL-04-020 EXPIRATION DATE: July 22, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENT OF PARTICIPATING ORGANIZATION: National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S) 93.937, 93.838, 93.839 LETTER OF INTENT RECEIPT DATE: June 23, 2004 APPLICATION RECEIPT DATE: July 21, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA This RFA will create multidisciplinary teams capable of developing and applying nanotechnology and nanoscience solutions to the diagnosis and treatment of cardiovascular, pulmonary, hematopoietic and sleep disorders. In recent years, rapid advances in science and technology have opened up the burgeoning new field of nanotechnology, bringing a myriad of opportunities and possibilities for advancing medical science and disease treatment. Nanotechnology and nanoscience focus on materials at the atomic, molecular, and supramolecular levels. The goal is to control and manipulate these new materials by precisely configuring atoms and molecules, producing novel molecular assemblies and designing systems of self- assembly to create supramolecular devices on the scale of an individual cell and smaller. Investigators with skills in nanotechnology rarely focus on heart, lung, blood, and sleep (HLBS) research and investigators focused on HLBS disorders are generally not oriented to the development and use of nanomaterials and nanotechnologies. Therefore, a crucial need exists to foster partnerships between the two communities and to establish shared goals and resources. Creating multidisciplinary teams will be essential to realizing the potential of nanotechnology and applying it to HLBS disorders. RESEARCH OBJECTIVES Background Cardiovascular, pulmonary, and blood diseases are responsible for 50% of all deaths in the US, killing almost 1.2 million Americans in 1999. An estimated 61.8 million Americans suffer from heart, lung, and blood diseases, resulting in an enormous total economic burden of more than $450 billion dollars in 1999. Nanotechnology and nanoscience have the potential to make very significant contributions to the diagnosis and therapy of HLBS disorders, mitigating the huge social and economic costs of these diseases. However, the pace of application of nanotechnology and nanoscience to HLBS disorders has been slow. To accelerate the use of nanotechnology and nanoscience to solve problems in HLBS disease, the NHLBI developed a Request for Information (RFI), with advice from scientists and physicians with interests in nanotechnology. This RFI canvassed the broader scientific community for approaches to developing and applying nanotechnology to HLBS disorders. A Working Group consisting of scientists, engineers, and physicians with expertise across nanotechnology, nanoscience, and HLBS diseases used the RFI responses as the starting point for their discussions, assessing the field of nanotechnology, and suggesting appropriate directions for research. Nanotechnology was broadly construed as research and technology development at the atomic and molecular levels intended to create, understand, and use nano-scale (i.e., typically less than 100nm) structures, devices, and systems having novel properties and functions associated with their size and structure. In addition, the Working Group cautioned against overly rigid or restrictive definition of nanotechnology, emphasizing the continuum of scale from the nano- to the micro- scale. Nanocomponents will also be important in microscale devices, which are therefore included under the nanotechnology rubric. The “top down” approach, encompassing miniaturization of current technology, and the “bottom up” approach, taking advantage of self-assembly or directed assembly of molecules into nanostructures, offer complementary routes for addressing biomedical problems. The primary recommendation of the Working Group was to facilitate interdisciplinary research between the nanotechnology and nanoscience communities and researchers working on HLBS disorders. Therefore this initiative aims to create programs that bring together scientists from complementary disciplines through NHLBI Programs of Excellence in Nanotechnology (PENs). The PENs will have three goals; i) Perform cutting edge research to develop and apply nanotechnology and nanoscience solutions to HLBS research and medicine; ii) Develop a cadre of investigators with the ability to apply nanotechnology and nanoscience to clinically-oriented HLBS research; iii) Disseminate techniques and applications to HLBS research and medicine through program websites. Team members may not necessarily be located in the same geographical location, and team size will be determined by the proposed scientific problems. The PENs should be dynamic and able to change and adapt as research and the field progress. Inclusion of industrial partners is encouraged in order to access the large reserve of expertise available. The overriding goal of these multidisciplinary programs will be to create nanotechnology applications for HLBS medicine. Research Scope The potential applications of nanotechnology and nanoscience to clinically relevant problems in heart, lung, blood, and sleep disorder research encompass a wealth of opportunities. The diagnosis and treatment of vulnerable atherosclerotic plaque represents an area where targeted nanoparticles and nanodevices have great potential. Possible applications include noninvasive diagnosis, targeted therapy, plaque stabilization by removal of material such as oxidized lipoprotein, and nanodevices attaching to unstable plaque and broadcasting external warnings of plaque rupture. Tissue repair and regeneration is another area with broad implications for public health where nanotechnology could have great impact, for example providing superior scaffoldings for the generation of heart or lung tissue or the production of vascular grafts. Biodegradable nano- and microparticles releasing cytokines, growth factors and angiogenic factors have potential for guiding tissue repair in vivo. Lung inflammatory disease represents another likely target for diagnosis and therapy utilizing nanotechnology. Therapeutic nanoparticles capable of sensing alveolar function could release drugs only when needed, restricting drug delivery to affected areas in heterogeneous disease conditions. Devices to monitor thrombotic and hemorrhagic events are another potential target for nanotechnology and nanoscience. Multifunctional devices could detect events, transmit real-time biological data externally, and deliver anticoagulants or clotting factors while the patient seeks treatment. An essential component of developing nanotechnology and nanoscience for HLBS medicine will be ensuring that the novel technology is safe to apply. Biosafety (e.g. toxicity, immune responses) should be considered in all applications. Hence, the following areas would represent appropriate topics for proposed projects. This list is not intended to be all-inclusive, and other topics should be considered. o Apply nano- and micro-scaffoldings as the basis for tissue repair and cellular replacement in vessels and organs. o Develop multifunctional sensors to detect thrombotic events, transmit real- time biologic data outside the body and deliver therapeutic agents such as anticoagulants as needed. o Utilize targeted probes for the detection of vulnerable atherosclerotic plaque and targeted delivery of therapy. o Develop inhaled nanoscale biosensors capable of interrogating lung microenvironments, enabling diagnosis of pro-inflammatory signals at an early stage. o Develop nanoparticle-based in vivo sensors to monitor O2 blood concentrations and heart functions to detect problems during sleep. o Utilize lipid-based nanoparticles for site-specific delivery of antifungal or other antimicrobial therapy, allowing targeting to the pulmonary epithelium and mitigating nephrotoxicity, or directing therapy into bacterial biofilm collections. o Rationally design genetically engineered proteins for inorganics (GEPIs) – proteins engineered to recognize and bind to inorganic molecules, enhancing biocompatibility of therapeutic devices. o Utilize self-assembling peptide nanotubes to form artificial ion channels with regulated function. It is important to emphasize that the PENs are expected to bring together investigators with expertise in nanotechnology and in HLBS research to form collaborative programs. Projects outside the scope of this RFA include; o Studies that are not focused on the use of nanotechnology or nanoscience to address clinically relevant problems. While the inclusion of clinical studies is not a requirement of the program, technology-driven applications which do not include the application of this technology to HLBS biology or disease will not be considered responsive. o Studies that do not address heart, lung, blood, or sleep disorders. Program for Skills Development Full implementation of a nationwide effort in translational research for nanotechnology and nanoscience requires availability of trained M.D., M.D./Ph.D. and Ph.D. scientists. These individuals must be knowledgeable about the molecular aspects of nanotechnology and nanoscience and able to integrate the translational and clinical concepts necessary for the application of the technology to HLBS disorders. One unique feature of the PENs will be a requirement to function as a program for advanced skills development to produce M.D., M.D./Ph.D and Ph.D. scientists capable of translational research to apply nanotechnology to HLBS disorders. MECHANISM OF SUPPORT This RFA will use the NIH U01 award mechanism. 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". 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 FUNDS AVAILABLE The NHLBI intends to commit approximately $6 million (total costs) in FY 2005 and approximately $12 million per year (total costs) in FY2006-9 to fund 3 to 4 new grants in response to this RFA. An applicant may request a project period of up to 5 years, and it is anticipated that a budget for direct costs of up to $1 million for FY 2005 and $2 million per year for FY 2006-9 would be appropriate. An additional $50,000 per year (direct costs) will be available for the PEN selected to be the Administrative Center. 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 NHLBI 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 institutions/organizations o Foreign institutions are not eligible to apply as Principal Investigators. However, PEN collaborative projects may include work at a foreign site when the expertise at the foreign site is not present in the United States. 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 Investigator Meetings: Investigators from the individual PENs will meet annually to present updates on progress, to exchange ideas, and to discuss problems encountered. The agenda for the meetings will be determined by an Executive Committee comprised of the Principal Investigators of the PENs and the NHLBI Program Coordinator. The annual meeting will include poster presentations by postdoctoral fellows as part of the skills development program. The PEN budget should include provisions for 5-10 investigators to attend the Investigator Meetings. Executive Committee: The Executive Committee, comprised of the Principal Investigators of the PENs and the NHLBI Program Coordinator, will meet quarterly by conference call. The Executive Committee will plan Investigator Meetings, and designate and determine areas of shared interest and potential for collaboration in order to further the goals of the program. The Executive Committee will also oversee the Skills Development programs. Administrative Center: The Administrative Center will serve a range of functions common to each PEN such as organizing Investigator Meetings and External Advisory Panel meetings, arranging conference calls, and designing and maintaining a website to support the PENs. The Administrative Center site will be selected from the PENs, and will receive additional funds to support these activities. Applicants should indicate whether they wish to be considered for the Administrative Center site. Internal Operating Committee: Each PEN will have an Internal Operating Committee to facilitate internal governance and operations, and to oversee the collaborative arrangements among investigators. This Committee should be comprised of the PEN Director and component leaders. The Internal Operating Committee will meet in person twice annually, and an NHLBI Program Officer should be present at these meetings. External Advisory Panel: The External Advisory Panel will consist of non-PEN affiliated scientists appointed by the NHLBI. The panel will meet during the second and fourth years of the PEN program to review the progress of each PEN, and to assess the overall programmatic goals of the initiative. Responsiveness: Technology-driven applications that do not include the application of this technology to HLBS biology or disease will not be considered responsive. In order to be responsive to the RFA, PENs are required to bring together investigators with expertise in nanotechnology and in HLBS research to form collaborative programs. Terms and Conditions of Award The cooperative agreement is an award instrument establishing an Assistance relationship (in contrast to an Acquisition relationship) between NHLBI and a recipient, in which substantial NHLBI scientific and/or programmatic involvement with the recipient is anticipated during performance of the activity. The NHLBI purpose is to support and/or stimulate the recipients’ activity by involvement in and otherwise facilitating the activity in a partner role, but avoiding a dominant role, direction, or prime responsibility. The terms and conditions below, elaborate on these actions and responsibilities, and the awardee agrees to these collaborative actions with the NHLBI Project Scientist toward achieving the project objectives. It is anticipated that these terms and conditions will enhance the relationship between the NHLBI staff and the principal investigator(s), and will facilitate the successful conduct and completion of the study. These agreements will be in addition to, and not in lieu of, the relevant NIH procedures for grants administration. The terms will be as follows: 1. The awardee(s) will have lead responsibilities in all aspects of the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Internal Operating Committee and External Advisory Panel. Internal Operating Committee: Each PEN will have an Internal Operating Committee to facilitate internal governance and operations, and to oversee the collaborative arrangements among investigators. This Committee should be comprised of the PEN Director and component leaders. The Internal Operating Committee will meet in person twice annually, and an NHLBI Program Officer should be present at these meetings. External Advisory Panel: The External Advisory Panel will consist of non-PEN affiliated scientists appointed by the NHLBI. The panel will meet during the second and fourth years of the PEN program to review the progress of each PEN, and to assess the overall programmatic goals of the initiative. Administrative Center: The Administrative Center will serve a range of functions common to each PEN such as organizing Investigator Meetings and External Advisory Panel meetings, arranging conference calls, and designing and maintaining a website to support the PENs. 2. The NHLBI Project Scientist will participate in Investigator Meetings; he/she or another NHLBI scientist may serve on other study committees, when appropriate. 3. Awardee(s) agree to oversight by the Executive Committee, comprised of the Principal Investigators of the PENs and the NHLBI Program Coordinator. The Executive Committee will plan Investigator Meetings, and designate and determine areas of shared interest and potential for collaboration in order to further the goals of the program. The Executive Committee will also oversee the Skills Development programs. 4. For applications which include clinical components, awardee(s) will submit a data and safety monitoring plan. 5. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. 6. Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NHLBI support; or special access to study results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI. 7. The NHLBI reserves the right to terminate or curtail the study (or an individual award) in the event of (a) substantive changes in the agreed-upon workscope with which NHLBI cannot concur, (b) human subject ethical issues that may dictate a premature termination. 8. Any disagreement that may arise in scientific/programmatic matters (within the scope of the award, between award recipients and the NHLBI) may be brought to arbitration. An arbitration panel will be composed of three members--one selected by the Executive Committee (with the NHLBI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NHLBI, and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NHLBI under applicable statutes, regulations and terms of the award. 9. These special terms of award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant administration policy statements. 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: Denis Buxton, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9044-7940 Bethesda, MD 20892-7940 Bethesda MD 20817 (for express delivery) Telephone: (301)435-0516 FAX: (301)480-1454 Email: buxtond@nhlbi.nih.gov o Direct your questions about peer review issues to: Anne P. Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute National Institutes of Health 6701 Rockledge Drive, Room 7214, MSC 7924 Bethesda, MD 20892-7924 Bethesda, MD 20817 (for express delivery) Telephone: 301-435-0270 Fax: 301-480-0730 Email: clarka@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Norma DeGuzman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7167 Bethesda, MD 20892-7926 Telephone: (301) 496-6740 FAX: (301) 480-3310 Email: deguzman@nhlbi.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 by mail or email to Dr. Anne Clark at the address listed under Where to Send Inquiries. SUBMITTING AN APPLICATION Applications must have a DUN and Bradstreet (D&B;) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS 1. Page limitations for PEN applications have been increased to a maximum of 40 pages from the usual 25-page limit for sections A-D of the "Research Plan". This 40- page limit is an absolute maximum; standard type size and format specifications must be adhered to. Applicants are encouraged to be concise and use fewer pages. 2. Description page - In addition to the information requested on Form Page 2, identify in the Description the name(s) of the institution(s) leading the PEN and other participating institutions. The Description should clearly indicate the area(s) of nanotechnology research that will be the focus of the PEN, the planned multi-disciplinary approach, and the specific objective of the project. The description of the roles of Lead Investigators should be provided in greater detail in the narrative for personnel in the budget section. The Lead Investigators will usually include the Principal Investigator and a subset of the Key Personnel. The following information is provided to clarify the roles of the various individuals who are to be named on this page. NIH grants policy requires that each application designate a single Principal Investigator (PI) who (1) is responsible for the overall scientific and technical direction of the effort and (2) serves as the contact person with whom NIH staff will interact. Lead Investigators provide essential scientific, engineering, technical, and visionary leadership to the effort. Key Personnel are those individuals who contribute in a substantive way to the scientific or engineering development or execution of the project. 3. An organization chart that clearly defines the partnership and relationships among its various components must be included with the application. A program plan should accompany the organization chart and list major tasks with a timeline of quantitative milestones for the entire project period. The structure and function of the Internal Operating Committee should be described in this section. The organization chart and program plan must not exceed one page each. This information should be included in the Research Design and Methods section of the application. 4. PEN Budget Items - A separate budget for each partner at a subcontract/consortium institution, and when appropriate for clarity, for each partner within the grantee institution must be included. Include a summary budget for all PEN participants with partners at non-grantee institutions shown as consortium arrangements. It is understood that this is an initial budget, and that the PI has the responsibility, upon approval from NHLBI, to reallocate funds during the project to accomplish the PEN goals. The PI is expected to devote a minimum of 25% effort to the PEN. The percent effort requested for all personnel should be limited to time devoted specifically to PEN activities and not to other research projects. Information documenting the level of effort on PEN activities should be included in the application. The need for all requested personnel costs should be thoroughly justified. There will be an annual PEN Investigator Meeting at a date and location to be determined by NHLBI staff and the Administrative Center. Applicants should include travel funds for 5-10 investigators, including participants in the Skills Development Programs, specifically for these meetings in the PEN budget request. Applicants may request and justify additional travel funds. Travel funds could be used to promote collaboration among PEN partners at different institutions or at a distant site, for travel of external advisors to the PEN site, and/or for PEN partners to attend scientific meetings essential to the progress of the project and for which other funds are not available. Other expenses can be requested including costs necessary for the central administration and fiscal management of the PEN including relevant and reasonable costs for reprints, graphics, and publications. Administrative support (a secretary or an administrative assistant) may be requested only for matters directly pertaining to the PEN. With regard to projected funding by source, some PEN applicants may anticipate or receive commitments for significant funding from sources other than the NIH; e.g., from a collaborating company. In this case, applications should describe the source, annual amount, and use of the other funding. 5. Resources - The application should describe the equipment and facilities available for the proposed PEN. If the PEN entails an institutional commitment of resources across boundaries in the institution or anticipates the provision of institutional resources, letters from appropriate senior-level individuals describing their agreements to support those commitments must be included. Where appropriate, describe the shared facilities to be established including specific major research instruments and plans for the development of instruments. Describe plans for maintaining and operating the facilities including staffing, provisions for user fees, and plans for ensuring access to outside users. Distinguish between existing facilities and those still to be developed. 6. Research Design and Methods (Section D of the Research Plan) - A PEN should focus on a systems approach for nanotechnology research aimed at a significant advance in HLBS medicine. The research goals should be sufficiently long term and comprehensive to justify organizing a PEN and adaptable enough to permit change as the research proceeds. The integrative systems approach and its appropriateness for the proposed project should be described including plans for collecting, analyzing, and interpreting data. Plans for enhancing the abilities and opportunities for investigators to work across disciplinary boundaries should also be included. 7. Skills Development Plan – The Research Design and Methods section of the application must include a description of plans to develop interdisciplinary skills in postdoctoral fellows and other investigators, and should contain plans for mentoring. The goal of the skills development plan should be to produce independent investigators capable of applying nanotechnology and nanoscience to HLBS research and medicine. An investigator with responsibility for overseeing the skills development plan should be identified, and the budget for the skills development plan should be indicated. A minimum of 5% of the budget should be allocated to the skills development plan. This section is included in the 40 page limit for Sections A-D of the Research Plan. 8. Administrative Center – The application should indicate in the Research Design and Methods section of the application whether the PEN would be interested in serving as the Administrative Center. The Administrative Center will be selected administratively after PEN awards are made, and no application materials are required at this time. 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 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 must be sent to send to Dr. Anne Clark at the address listed under Where to Send Inquiries. APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or nonresponsive applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI 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 NHLBI Advisory Council. 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The score should reflect the overall impact that the PEN award could have on the selected area of HLBS research based on consideration of the five criteria given below. The emphasis on each criterion can vary from one application to another depending on the nature of the application and its relative strengths. An application need not be strong in all categories to be judged likely to have major technical or scientific impact and thus deserve a high priority score. For example, an investigative partnership may propose to perform important work that by its nature is not innovative but is essential to advance a field. A PEN may propose design-directed, developmental, discovery-driven, or hypothesis-driven research at universities, national laboratories, medical schools, large or small businesses, or other public and private entities. The review criteria include: 1. Significance. If the specific aims of the PEN are achieved, will they provide significant advances in the selected area of nanotechnology research? Is the research likely to have a significant impact on other areas of research? Will the technological advances have a significant impact on human health? 2. Approach. Are the PEN engineering, scientific, and clinical approaches and methods adequately developed, well-integrated, and appropriate to the aims of the project? Does the application address potential problem areas and consider alternative strategies? Is a timetable with adequate research milestones proposed? Are appropriate specifications and evaluation procedures provided for assessing technological progress? Is the plan for sharing or disseminating technologies developed or enhanced under this program announcement adequate? Is the plan for technology transfer involving each partnering organization adequate? If partnership with industry or small business is included, does this positively affect the research goals and technology dissemination? 3. Innovation. Does the PEN propose new approaches, explore new research paradigms, or represent new concepts that combine engineering, physical, and clinical sciences? Will the proposed approaches or concepts solve current scientific or technical problems in novel ways? 4. Investigators. Is the PI capable of coordinating and managing the proposed PEN? Are the investigators (partners) appropriately trained in their disciplines and capable of conducting and contributing to the management of the proposed interdisciplinary work? 5. Environment. Does the scientific and technological environment in which the work will be done contribute to the probability of success? Does the proposed research take advantage of unique features of the scientific environment or employ useful collaborative arrangements within the program? Is there evidence of institutional support? Does the program create potential opportunities to foster trans- disciplinary communication and training across traditional scientific and technical boundaries? 6. Synergy. Does the he synergy of aims contribute to the overall goals of the project, and are the plans for collaboration between investigators to achieve these overall goals adequate? 7. Skills Development Plan. Are the skills development plans for developing independent investigators who can apply nanotechnology and nanoscience to HLBS research and medicine likely to succeed? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o BIOSAFETY Adequacy of plans to address biosafety considerations in order to translate the novel technology to the clinical setting. o DATA SHARING: 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 in the determination of scientific merit or priority score. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. o 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). o INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). o 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. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: June 23, 2004 Application Receipt Date: July 21, 2004 Peer Review Date: October/November 2004 Council Review: February 2005 Earliest Anticipated Start Date: April 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 HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: (if applicable) 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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the “Standards for Privacy of Individually Identifiable Health Information”, the “Privacy Rule,” on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as “covered entities”) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on “Am I a covered entity?” Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance Nos. 93.937, 93.838, 93.839, 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 administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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