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.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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