DEVELOPMENT OF PET AND SPECT LIGANDS FOR BRAIN IMAGING (PHASED INNOVATION AWARD)

Release Date:  September 27, 2001 (see reissuance PA-03-112)

RFA:  RFA-MH-02-003

National Institute of Mental Health
 (http://www.nimh.nih.gov/)
National Institute on Drug Abuse
 (http://www.nida.nih.gov/)
National Institute on Aging
 (http://www.nih.gov/nia/)

Letter of Intent Receipt Date:  November 12, 2001
Application Receipt Date:       December 11, 2001

PURPOSE

The intent of this solicitation is to invite 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-01-151, 
Development of PET and SPECT Ligands for Brain Imaging (SBIR Award) 
that will be issued shortly.  Its objectives will be 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 RFA for Phased Innovation Awards. 

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS 
led national activity for setting priority areas. This RFA, Development of 
Novel PET and SPECT Ligands for Brain Imaging (Phased Innovation Award), 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/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, companies, units of State and local governments, and 
eligible agencies of the Federal government.  Racial/ethnic minority 
individuals, women, and persons with disabilities are encouraged to apply as 
Principal Investigators.

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 RFA may not exceed 5 years.  This RFA is a one-time solicitation.  
Future unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the 
customary peer review procedures.  The anticipated award date is July 1, 
2002.

o  This RFA 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 a 
relatively new 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 RFA, 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 RFA, 
but may be eligible for submission under PA-00-073 NIMH 
Exploratory/Developmental Grant (R21) Program 
http://grants.nih.gov/grants/guide/pa-files/PA-00-073.html or other PAs 
supporting the R21 mechanism.

o  The total project period for an application submitted in response to this 
RFA 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 RFA, subcontracts may be included 
in the budget to support investigators at sites other than the awardee 
organization.  Facilities and administrative subcontracts costs in a given 
year will not be counted toward the maximum of $150,000 direct costs 
requested by the awardee organization that year.  

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, the 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.  

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.  

FUNDS AVAILABLE

The participating ICs intend to commit approximately $2,500,000 (NIMH: 
$1,500,000; NIDA: $750,000; NIA: $250,000) in FY 2002 to fund 10 to 15 new 
grants in response to this RFA.   Because the nature and scope of the 
research proposed may vary, it is anticipated that the size of each award 
will also vary.  Although the financial plans of the IC(s) provide support 
for this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications.  Funding of the second R33 phase of the grant will be 
contingent upon the satisfactory completion of quantifiable Milestones during 
the first R21 phase of the project.
 
Although the National Institute of Neurological Diseases and Stroke (NINDS), 
http://www.ninds.nih.gov/, is not providing funds to this RFA, the Institute 
may consider supporting meritorious applications received in response to this 
RFA that are relevant to its mission. 

Although the National Institute on Alcohol Abuse and Alcoholism (NIAAA), 
http://www.niaaa.nih.gov/, is not currently providing funds to this RFA, the 
Institute is willing to support meritorious applications received in response 
to this RFA that are relevant to its mission.

Although the National Institute of Biomedical Imaging and Bioengineering 
(NIBIB), http://www.nibib.nih.gov/, is not formally 
participating in this solicitation, the Institute has strong interests in 
studies of novel radioligands for PET and SPECT imaging and other issues 
dealing with contrast agents.  Applications addressing the development of 
novel contrast agents that are not organ or disease specific may be 
considered by NIBIB for support. 

For the purpose of accomplishing the goals of this RFA, subcontracts may be 
included in the budget to support investigations at sites other than the 
awardee institution.  The requested budget may exceed the $150,000 cap to 
accommodate for Facilities and Administrative costs to subcontracts of the 
project. 

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 several recent NIH-supported forums 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, October, 2000; NIMH Mood Disorders Strategic 
Plan 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.

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, & 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.

SPECIAL REQUIREMENTS 

Data Sharing Plan

The NIH is interested in ensuring that the research resources developed 
through this RFA 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.  The sharing plan will be considered part of the 
scientific methodology for carrying out the research and, as such, the 
adequacy of the plan will be considered in determining whether the project 
shall be funded.  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. 

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.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.  The 
revisions relate to NIH defined Phase III clinical trials and require:  a) 
all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH 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 was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address:  http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

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.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

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 RFA 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.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, budgetary information for the R21 and R33 
phases, and the number and title of the RFA in response to which the 
application may be submitted.  Although a letter of intent is not required, 
is not binding, and does not enter into the review of a subsequent 
application, the information that it contains allows IC staff to estimate the 
potential review workload and plan the review.

The letter of intent is to be sent by November 12, 2001 to:

Dr. Linda Brady
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:  [email protected]

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 8/8/2001) 
at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants.  This version of the PHS 398 is available in an 
interactive, searchable PDF format.  Although applicants are strongly 
encouraged to begin using the 8/8/2001 revision of the PHS 398 as soon as 
possible, the NIH will continue to accept applications prepared using the 
4/1998 revision until January 9, 2002.  Beginning January 10, 2002, however, 
the NIH will return applications that are not submitted on the 8/8/2001 
version.  For further assistance contact GrantsInfo, Telephone 301/710-0267, 
Email: [email protected].

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: 
[email protected].  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 RFA 
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.  
For the R21 phase, direct costs requested for the proposed period may not 
exceed $150,000 per year for any year of the phase one R21 feasibility study 
support.  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 RFA 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 RFA 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.

FOR ALL APPLICATIONS

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be 
sent to:

Dr. Linda Brady
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:  [email protected]

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.  Appendices should be sent to 
CSR.
  
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an Introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the CSR for completeness, and 
by NIH program staff for adherence to the guidelines of this RFA.  
Applications not adhering to application instructions described above and 
those applications that are incomplete as determined by CSR or by NIH program 
staff will be returned to the applicant without review. 

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the CSR in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will receive a written 
critique and undergo a process in which only those applications deemed to 
have the highest scientific merit, generally the top half of the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by the 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 the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judge likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator 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 this study address an important problem?  If the aims 
of the application are achieved, how will in vivo PET or SPECT imaging 
technology or scientific knowledge be advanced?  What will be the effect of 
these studies on the concepts or methods that drive this field?  To what 
degree does the development of novel PET or SPECT radioligands or radiotracer 
technology support the needs for the targeted disease? 

2.  Approach.  Are the conceptual framework, design, and methods adequately 
developed, well integrated, and appropriate to the aims of the project?  Does 
the applicant acknowledge potential problem areas and consider alternative 
tactics?  What is the time frame for developing and evaluating the utility of 
the proposed PET or SPECT radioligands or technologies, and suitability of 
this time frame for meeting the community's needs?  If industrial 
partnerships are proposed, how will they facilitate the development and 
evaluation of radioligands or technologies?

3.   Innovation.  Does the project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new tools, methodologies, or technologies?  
What additional uses can be projected for the proposed radioligands or 
technology?

4.   Investigator.  Is the principal investigator appropriately trained and 
well suited to direct or carry out this work?  Is the work proposed 
appropriate to the experience level of the principal investigator and other 
researchers (if any)?

5.   Environment.  Does the technical and scientific environment in which the 
work will be performed contribute to the probability of success?  Does the 
proposed work take advantage of unique features of the technical and 
scientific environment or employ useful collaborative arrangements?  Is there 
evidence of institutional support?

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.

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include genders, minorities and their subgroups, 
and children as appropriate for the scientific goals of the research.  Plans 
for the recruitment and retention of subjects will also be evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

SCHEDULE

Letter of Intent Receipt Date:    November 12, 2001
Application Receipt Date:         December 11, 2001
Peer Review Date:                 February/March 2002
Council Review:                   May 2002
Earliest Anticipated Start Date:  July 1, 2002

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic 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:  [email protected]

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:  [email protected]

Molly Wagster, Ph.D. and Neil Buckholtz, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 3C307
7201 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  [email protected]; [email protected]

Direct inquiries regarding fiscal 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:  [email protected]

Gary Flemming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Blvd, R00m 3131
Bethesda, MD  20892
Telephone:  (301) 443-6710
FAX:  (301) 594-6847
Email:  [email protected]

Ms. Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.242 (NIMH), 93.279 (NIDA), and  93.866 (NIA).  Awards are made 
under authorization of Sections 301 and 405 of the Public Health 
Service Act as amended (42 USC 241 and 284) and administered under NIH 
grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 
and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

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