DEVELOPMENT AND APPLICATION OF PET AND SPECT LIGANDS FOR BRAIN IMAGING STUDIES (PHASED INNOVATION AWARD) RELEASE DATE: April 21, 2003 PA NUMBER: PA-03-112 Update: This PA has been reissued as PA-06-462 for submission of R33 applications, PA-06-461 for R21 and PA-06-463 for R21/R33 as of August 7, 2006 March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through Grants.gov using the electronic SF424 (R&R) application. Replacement R21/R33 (PA-06-463) and R21 (PA-06-461) funding opportunity announcements have been issued for the submission date of June 1, 2006 and submission dates thereafter. EXPIRATION DATE: March 2006, unless reissued. National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov/) National Institute on Aging (NIA) (http://www.nia.nih.gov/) National Institute of Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov/) National Institute of Biomedical Imaging and Bioengineering (NIBIB) (http://www.nibib.nih.gov/) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov/) National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.242 (NIMH), 93.866 (NIA), 93.273 (NIAAA), 93.286, 93.287 (NIBIB), 93.279 (NIDA), and 93.853 (NINDS). THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA This PA is a reissue of RFA MH-02-003. The National Institute of Mental Health (NIMH), the National Institute on Aging (NIA), National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Biomedical Imaging and Bioengineering (NIBIB), the National Institute on Drug Abuse (NIDA), and National Institute of Neurological Disorders and Stroke (NINDS) request research grant applications for the development of novel radioligands for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging in human brain, and that incorporate pilot or clinical feasibility evaluation in pre-clinical studies, model development, or clinical studies. This initiative is intended to facilitate the development of: 1) PET and SPECT probes for molecular targets (e.g., receptors, intracellular messengers, disease-related proteins) that are of broad interest to the neuroscience research community, and 2) new technologies for radiotracer development. The primary motivation for this initiative is the lack of versatile agonist and antagonist PET and SPECT radiotracers for molecular targets that are implicated in brain disorders. The use of radiotracers for imaging molecular events in preclinical and clinical studies is essential for understanding the circuitry that underlies normal brain function and the pathophysiology of brain disorders. It is the intent of this initiative to foster the development of NIH partnerships with scientists from pharmaceutical industry and academic nuclear medicine research centers to develop ligands for PET and SPECT brain imaging with the goal of making new radioligands accessible to the research community as essential research tools for central nervous system (CNS) imaging, and as potential biological markers and surrogate endpoints for translational and clinical research, drug discovery and development, and clinical trials. This solicitation will utilize the Phased Innovation Award Mechanism that is intended to encourage the development and application of technology in neurobiological research. Specific features of this mechanism include: o Single submission and evaluation of both the R21 and R33 phases as one application. An R33 application alone may be submitted. o Expedited transition from the feasibility phase (R21) to the development phase (R33) based on successful completion of negotiated quantitative Milestones. o Flexible staging of feasibility (R21) and development (R33) phases. o Applications from industry or industry partnerships with other groups are encouraged. o Review of submissions by the Center for Scientific Review (CSR) and expedited NIH programmatic review for transition from the R21 to the R33 phase. Small businesses are encouraged to respond to the parallel PA, PA-02-028, Development of PET and SPECT Ligands for Brain Imaging (SBIR Award) http://grants.nih.gov/grants/guide/pa-files/PA-02-028.html. Its objectives are identical; however, it will use the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms. The same expedited review and transition from Phase I to Phase II funding are expected to apply, as will the same cost and time limitations as this PA for Phased Innovation Awards. RESEARCH OBJECTIVES Background Tremendous opportunities exist for the application of PET and SPECT imaging in studies of the pathophysiology and treatment of brain disorders, but relatively few radioligands are currently available for functional imaging of target molecules implicated in normal brain function, aging, and in brain and behavioral disorders. A recent workshop, "Consortium for the Development of Novel PET and SPECT Ligands for Brain Imaging," organized by the National Institute of Mental Health (NIMH) together with six other National Institutes of Health (NIH) Institutes, explored opportunities to work collaboratively across academia, industry, the Food and Drug Administration (FDA), and NIH Institutes to accelerate radiotracer development. The participants proposed several ways in which the NIH could foster radioligand development: a) partnering with industry, including possible means to address intellectual property rights issues; b) implementing targeted research initiatives specifically for the development of radioligands; and c) establishing an annual meeting of a consortium (industry, academia, NIH, and the FDA) to continue exploring ways to stimulate radioligand development. A detailed summary of the workshop is available at http://www.nimh.nih.gov/research/imagingsummary.cfm. Participants at a recent NIH-supported forum stressed the need for the NIH to encourage effective partnering with industry on radioligand development [PET Tracers as Intellectual Property, Society of NonInvasive Imaging in Drug Development (SNIDD), October, 2000; NIMH Strategic Plan for Mood Disorders Research Working Groups, March 2001]. Both groups proposed that NIH's intramural and extramural programs work together to develop new ligands and foster their dissemination to the scientific community. The NIMH working groups endorsed that radioligand development would be immensely valuable for several purposes: a) understanding the abnormal biological processes which underlie mood disorders and other brain disorders; b) determining the interaction of a drug or drug candidate with a specified target; c) guiding initial dosing of new therapeutic agents; and d) as central biomarkers of the illness, with the potential to predict symptom onset, monitor the progression of the disease, and assess the efficacy of therapeutic compounds. The NIMH Strategic Plan for Mood Disorders Research is available at http://www.nimh.nih.gov/strategic/stplan_mooddisorders.cfm. SCOPE This initiative is intended to stimulate the development of radioligands for molecular targets (e.g., receptors, cell adhesion molecules, intracellular messengers, and disease related proteins) that are of broad interest to the scientific community. The widespread availability and use of these radioligands are expected to: 1) accelerate research on identifying and characterizing the neural circuits and pathways implicated in the pathophysiology of brain disorders (especially mental and behavioral disorders, substance abuse, neurodegenerative disorders, and pediatric brain disorders) and brain changes with age, and 2) facilitate the identification of new therapeutic targets and the development of new compounds as potential therapeutic agents. Exploratory studies on the identification of novel targets or the identification of base compounds for specific molecular targets are not appropriate topics for this initiative. Molecular targets for which radioligands are needed include, but are not limited to, the following. Please contact program staff listed under Inquiries to determine program priorities and molecular targets of interest to specific NIH institutes or refer to the internet addresses listed above for each of the participating NIH institutes. o Receptors: adenosine; adrenergic: alpha 1, alpha 2; cannabinoid: CB1, CB2; corticotropin releasing hormone: CRH R1, CRH R2; dopamine: D1, D3, D4, D5, and low affinity DA receptors; estrogen; GABA A subunits; GABA ion channel; GABA B; glutaminergic; glycine site; metabotropic glutamate subtypes; muscarinic subunits; neurokinin receptors: NK1, NK2, NK3; nicotinic receptor subunits: alpha 7 & alpha 4 beta 2; NMDA subunits; opioid receptors: mu, delta, kappa; serotonin: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT5, 5-HT6, 5-HT7; sigma ligand; substance P; voltage gated ion channels: Ca, Na, K M current proteins. o Transporters: vesicular ACh; GABA glutamate; NET; SERT. o Enzymes: choline acetyltransferase; dopamine beta-hydroxylase; GABA transaminase; glutamic acid decarboxylase; glutaminergic; phosphodiesterases;tyrosine hydroxylase. o Intracellular targets: abnormal protein aggregates including amyloid or tau deposition; diacylglycerol; gene expression markers; lipid metabolism; neuroinflammatory markers: cytokines, COX inhibitors; peptidases; phosphatases; phospholipases; protein kinases; stem cells. The following objectives would make appropriate topics for proposed R21/R33 projects. This list is not meant to be all-inclusive. o Lead compound identification/development and syntheses of chemicals with suitable binding affinity, biodistribution, pharmacokinetics, and physio-chemical properties allowing radiochemical synthesis. o Pre-clinical studies, including: initial pharmacology and toxicology to screen out compounds that are unlikely to be promising candidates for PET or SPECT imaging; radiolabeling procedures; in vitro and ex vivo autoradiography; in vivo imaging including micro PET (rodent and/or primate); and studies of pharmacological specificity, biodistribution, and pharmacokinetics. o Model development for quantitation, including development and evaluation of pharmacokinetic models and use of animal models of gradient of binding sites/enzymes to assess sensitivity to changes. o Determination of toxicology/pathology (FDA approved) for submission of a Radioactive Drug Research Committee (RDRC) or Investigational New Drug (IND) application. o IND application development and submission to the FDA prior to pilot human studies. o Pilot human imaging studies with normal controls, pharmacological challenges with analyses of radiometabolites under the auspices of IRB approval (i.e., RDRC or IND development and submission). o Clinical studies in patient/disease populations or experimental manipulations. The NIBIB is interested in more fundamental research and technology development related to the design and use of probes to study structure and function at the molecular and subcellular level. MECHANISM OF SUPPORT This mechanism of support will use the National Institutes of Health (NIH) Phased Innovation Award (R21/R33). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed 5 years. o This PA does NOT use the "Modular Grant" and "Just-in-time" concepts. o Awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, March 2001, available at http://grants.nih.gov/grants/policy/nihgps_2001/index.htm. (Printed copies of this document are not available.) o Support for this program will be through the National Institutes of Health (NIH) Exploratory/Developmental Research Grant (R21) and the Exploratory/Developmental Research Grant Phase 2 (R33). The R33 is an NIH granting mechanism that provides a second phase of support to continue innovative exploratory and developmental research initiated under the R21 mechanism. Transition from the R21 to R33 phase will be based on an expedited programmatic review by NIH staff and will depend on satisfactory completion of negotiated, quantitative R21 Milestones. o Under this PA, applicants can submit either a combined R21/R33 application (Phased Innovation Award application) or an R33 application alone if feasibility can be documented, as described in the APPLICATION PROCEDURES section, below. o Applications for R21 support alone will not be accepted under this PA but may be eligible for submission under the NIH Exploratory/Developmental Grant (R21) Program. o The total project period for an application submitted in response to this PA may not exceed 5 years. Its components are limited as follows: R21, up to 3 years; R33, up to 3 years; combined R21/R33 application, up to 5 years. o The R21 phase may not exceed $150,000 direct costs per year. For the purpose of accomplishing the goals of this PA, subcontracts may be included in the budget to support investigators at sites other than the awardee organization. Facilities and Administrative costs for subcontracts will not be counted toward the $150,000 direct costs maximum. The combined R21/R33 application offers two advantages over the regular application process: 1. Single submission and evaluation of both the R21 and R33 components as one application; and 2. Minimal or no funding gap between the R21 and R33 budget awards. The amount of R33 funding will depend upon program priorities, availability of funds, and successful completion of negotiated, quantitative Milestones, as determined by NIH staff, who will take peer review recommendations into consideration. The R21 phase of the Phased Innovation Award must include: (1) well-defined, quantifiable Milestones that will be used to judge the success of the proposed development of novel PET or SPECT ligands; and (2) a credible plan for the validation and/or application of novel PET or SPECT radioligands in human brain imaging studies. The proposed clinical studies should have the potential to inform about normal brain function, brain aging, pathophysiology, pharmacologic treatment of brain disorders, or validation of imaging biomarkers as surrogate markers of disease course and/or clinical response to treatment. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign 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 Data Sharing Plan It is the NIH policy that the research resources developed through this PA become readily available to the research community for further research, development, and application, in the expectation that this will lead to knowledge of benefit to the public. Applications must include a plan to share protocols, procedures, unlabeled PET and SPECT ligands, analytical tools, IND filing information, and other materials that may be developed in the course of the project with the scientific community. It is expected that the principal investigator's data sharing plan will include the following elements: (1) mechanisms by which all protocols, procedures, methodologies, toxicology information, unlabeled PET or SPECT precursors, IND filing info are widely distributed to qualified investigators in the scientific community; (2) a protocol and criteria for wide dissemination of these data, information, and materials and (3) a timetable for distribution. Applicants are invited to utilize NIH supported repositories such as the NIMH Chemical Synthesis and Drug Supply Program (http://www.sri.com/biosciences/ nimh/) or the NIDA Drug Supply Program to make unlabeled PET and SPECT ligands widely available to the scientific community. Reviewers will assess the adequacy of the proposed plan as detailed in the review criteria section. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. A separate section labeled "Milestones" should be included at the end of the Research Plan of the R21 application. The Milestones will be used as criteria to make objective evaluations of progress at the end of the R21 phase. In addition to well-defined, quantifiable Milestones, the suitability of the proposed Milestones for assessing the success of the R21 phase and the implications of successful completion of these Milestones for the proposed R33 study should also be discussed. Examples of quantifiable Milestones could include: identification and synthesis of a lead compound with characteristics suitable for PET or SPECT imaging; radiolabeling of lead compound(s) for in vivo imaging; in vivo imaging in rodents and/or primates to assess biodistribution and physicochemical properties of the radioligand; use of animal models to assess pharmacokinetic properties of the radioligand (binding potential, sensitivity to displacement by agonists or antagonists at the target site); determination of preclinical toxicology and pathology for the submission of an IND (Investigational New Drug) application to the Food and Drug Administration (FDA); or IRB approval for clinical studies. Annual Meetings An annual meeting of all investigators funded through this program will be held to share progress and research insights that may further progress in the program. For this purpose, applicants should request travel funds for the principal investigator and one additional senior investigator to attend a two-day meeting each year, the location of which will be announced. Applicants should also include a statement in their applications indicating their willingness to participate in such meetings and to cooperate with other researchers. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Linda Brady, Ph.D. Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7185 Bethesda, MD 20892 Telephone: (301) 443-5288 FAX: (301) 402-4740 Email: lb@helix.nih.gov Molly Wagster, Ph.D. and Neil Buckholtz, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 350 Bethesda, MD 20892 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: wagsterm@nia.nih.gov; buckholn@nia.nih.gov Antonio Noronha, Ph.D. Neuroscience Branch, Division of Basic Research National Institute of Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 409, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-7722 FAX: (301) 594-0673 Email: anoronha@willco.niaaa.nih.gov Brenda Korte, Ph.D. Division of Biomedical Imaging National Institute of Biomedical Imaging and Bioengineering 6707 Democracy Boulevard, Suite 200 Bethesda, MD 20892 Telephone: (301) 451-4774 FAX: (301) 480-4973 Email: kortebr@mail.nih.gov Steven Grant, Ph.D. Division of Treatment Research and Development National Institute on Drug Abuse 6001 Executive Boulevard, Room 4238 Bethesda, MD 20892 Telephone: (301) 443-4877 FAX: (301) 443-6814 Email: sgrant@nida.nih.gov Emmeline Edwards, Ph.D. Systems and Cognitive Neuroscience National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2109 Bethesda, MD 20892-9521 Telephone: (301) 496-9964 FAX: (301) 402-2060 Email: edwardse@ninds.nih.gov o Direct your questions about financial or grants management matters to: Ms. Carol J. Robinson Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6118 Bethesda, MD 20892 Telephone: (301) 443-3858 FAX: (301) 443-6885 Email: crobinso@mail.nih.gov Ms. Linda Whipp Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: whippl@nia.nih.gov Ms. Judy Fox Simons Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6001 Executive Boulevard, Suite 505, MSC-7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2434 Email: jsimons@willco.niaaa.nih.gov Ms. Lisa Moeller Grants Management Specialist National Institute of Biomedical Imaging and Biomedical Engineering 6707 Democracy Boulevard, Room 983, MSC 5469 Bethesda, MD 20892-5469 Telephone: (301) 451-4793 FAX: (301) 480-4974 Email: lm236j@nih.gov Gary Flemming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131 Bethesda, MD 20892 Telephone: (301) 443-6710 FAX: (301) 594-6847 Email: gf6s@mail.nih.gov Mr. Aaron Kinchen Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3271 Bethesda, MD 20892 Telephone: (301) 496-7386 FAX: (301) 402-0219 Email: kinchena@ninds.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). 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) 710-0267, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD APPLICATION: Applications for R21/R33 grants are to be submitted on the grant application form PHS 398 and prepared according to the instructions provided unless specified otherwise within this section. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, 6701 Rockledge Drive, MSC 7910, Bethesda MD 20892-7910, telephone 301 710-0267, email: grantsinfo@nih.gov. See also the website for PHS 398: http://grants.nih.gov/grants/funding/phs398/phs398.html. The R21/R33 application must include specific aims for each phase and quantitative Milestones for the R21 component that would later help justify transition to the R33 phase. See below, Item d., "Research Design and Methods" for directions for including Milestones in the application. After funding and completion of the R21 phase, a comparison of progress with the R21 Milestones in an NIH expedited review will determine whether or not the R33 continuation grant should be awarded. Funds for R33 developments are contingent on program priorities, the availability of funds, and satisfactory completion of the negotiated Milestones. The expedited review may result in additional negotiations of award. The R21/R33 Phased Innovation Award application must be submitted as a single application, with one face page. Although it is submitted as a single application, it should be clearly organized into two phases. To provide a clear distinction between the two phases, applicants are directed to complete Sections a-d of the Research Plan twice: one write-up of Sections a-d and Milestones for the R21 phase, and Sections a-d again for the R33 phase. The Form 398 Table of Contents should be modified to show Sections a-d for each phase as well as the Milestones. There is a page limit of 25 pages for the composite a-d text (i.e., Sections a-d and Milestones for the R21 and Sections a-d for the R33 phase all must be contained within the 25-page limit). The initial review group will assign a single priority score to the combined R21/R33 application. Therefore, the clarity and completeness of the R21/R33 application with regard to the R21 feasibility Milestones and the specific goals of each phase are crucial. A weak R33 component will impact the evaluation of both phases of the R21/R33 application. Presentation of Milestones that are not sufficiently rigorous, and not quantitative, such as procedural research plans, may not permit adequate validation of the R21 feasibility studies and adversely affect reviewer opinions of the merit of the application. Face Page of the application: Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT: Insert the amount requested for first year R21 support in Item 7a. This PA does NOT use the "Modular Grant" and "Just-in-time" concepts. For the R21 phase of the combined R21/R33 application, direct costs are limited to a maximum of $150,000 per year for a maximum of 3 years. The award may not be used to supplement an ongoing project. The requested budget may exceed this cap to accommodate for Facilities and Administrative costs to subcontracts of the project. Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT: Insert the sum of all years of requested support for direct costs in Item 8a. The statement in item 7a above pertaining to subcontract costs also applies here. Budget: The application should provide a detailed budget on Form Page 4, Initial Budget Period, for each of the initial years of the R21 and R33 phases (use two Form Page 4s, one for each phase) as well as a budget on Form Page 5 for the entire proposed period of support. Indicate on the Form pages which years are for R21 and which are for R33 support. All budgets should include written justifications for line items requested. An annual meeting of all investigators funded through this program will be held to share progress and research insights that may further progress in the program. Applicants should request travel funds in their budgets for the principal investigator and one additional senior investigator to attend this annual meeting. Research Plan: A combined R21/R33 application should present two sets of research plans (items a through d), one of them for R21 feasibility studies, and the other for R33 developmental work. The entire Research Plan, consisting of two sets of items a through d, must fit within a 25-page limit. Item a., Specific Aims. The application must present specific aims that the applicant considers technically or scientifically appropriate for the relevant phases of the project. The PHS 398 instructions for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Since the goal of the R21 phase of this PA is the development of novel radioligands for PET and SPECT imaging in preclinical and clinical studies or innovative technologies for radioligand development, hypothesis testing per se may not be the driving force in developing such a proposal, and therefore, may not be applicable. For the R21 portion of the grant application, preliminary data are not required, although they should be included when available. Item d., Research Design and Methods. Follow the PHS 398 instructions. In addition, for the R21 phase only, the following information must be included as a final section of Item d: Applications must include a specific section labeled Milestones following the Research Design and Methods section of the R21 component of the application. Milestones are to be appropriate measures of whether the specific aims have been accomplished and proof of principle established upon completion of the R21 phase of work. Milestones should be well described, quantifiable, and technically or scientifically justified. They are not to be simply a restatement of the specific aims or be procedural in nature. A discussion of the Milestones relative to the success of the R21 phase, as well as the implications for successful completion of the Milestones for the R33 phase, should be provided. The page number of the Milestones section should be listed on the Table of Contents page. Applications lacking adequate Milestone information, as determined by the NIH program staff, will be returned to the applicant without review. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED WITHOUT THE R21 PHASE Applications for R33 grants are to be submitted on the grant application form PHS 398 and prepared according to the instructions provided unless specified otherwise within the items listed below. Budget: The application should provide a detailed budget on Form Page 4, Initial Budget Period, for the initial year of the R33 phase as well as a budget on Form Page 5 for the entire proposed period of support. All budgets should include written justifications for line items requested. Research Plan: Item a., Specific Aims. The PHS 398 instructions for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Because the goal of the R33 phase of this PA is to evaluate and/or validate the utility of novel radioligands for PET and SPECT imaging in preclinical or clinical studies or innovative technologies for radioligand development, hypothesis testing per se may not be the driving force in developing such a proposal, and therefore, may not be applicable. Item c., Preliminary Studies/Progress report This section must document that feasibility (proof of principle) studies have been completed, and progress achieved that is equivalent to that expected through the support of an R21 project. The application must clearly describe how the exploratory/developmental work already performed is ready to scale up to an expanded developmental stage. Quantitative performance capabilities of the novel PET or SPECT ligands or performance capabilities of the novel radiotracer technology that may be objectively evaluated should be provided, and compared with the published literature. Item d., Research Design and Methods Follow the PHS 398 instructions. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. 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. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the appropriate national advisory council or board REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to 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 scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: ADDITIONAL CONSIDERATIONS DATA SHARING PLAN: How appropriate are the proposed plans for making novel PET or SPECT radioligands, radioligand development technology, IND filing information, or other resources generated under the project widely available to the scientific community? Are the plans adequate for effective dissemination of the proposed radiotracers, technology, data, or other resources? MILESTONES (for R21/R33 applications) and PROOF OF PRINCIPLE (for R33 applications): For the R21/R33 applications, how appropriate are the proposed Milestones against which to evaluate the demonstration of feasibility for transition to the R33 development phase? For the R33 applications, how well has feasibility or proof of principle been demonstrated? For the R21/R33 Phased Innovation Award Application, the initial review group will evaluate the specific goals for each phase and the feasibility Milestones that would justify progression to the R33 phase. A single priority score will be assigned to each scored application. As with any grant application, the initial review group has the option of recommending support for a shorter duration than that requested by the applicant, and basing the final merit rating on the recommended portion of the application. This may result in a recommendation that only the R21 phase of the combined R21/R33 application be supported, based on the relative merit of the two research plans, adequacy of the milestones for determining the success of Phase I feasibility studies and capacity to provide easily assessed justification for progression to the R33 phase without further peer review. The Initial Review Group may recommend modifications to or the addition of Milestones. Deletion of the R33 phase by the review panel or inadequate Milestones may affect the merit rating of the application. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001 .html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this 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 PA 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 the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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