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/archive/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) 435-0714, 
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 301 435 0714, 
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


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.