RELEASE DATE:  November 5, 2003
PA NUMBER:  PAR-04-018

EXPIRATION DATE:  February 1, 2007, unless reissued

Department of Health and Human Services (DHHS)

National Institutes of Health (NIH) 

National Institute of Neurological Disorders and Stroke (NINDS) 
National Institute of Deafness and Other Communication Disorders (NIDCD)



o Purpose of this 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


The National Institute of Neurological Disorders and Stroke (NINDS) and 
the National Institute of Deafness and Other Communication Disorders 
(NIDCD) invite qualified investigators to submit grant applications for 
the establishment of National Centers for Neurofibromatosis Research.  
Recent discoveries have created important opportunities for basic, 
translational, and clinical research on the neurofibromatoses.  The 
purpose of this Program Announcement (PA) is to encourage the formation 
and development of research centers that can capitalize on these 
opportunities, and ultimately develop therapeutic interventions for 
neurofibromatosis patients.  These centers are intended to provide 
focused expertise and resources, and establish a multi-disciplinary 
environment that will accelerate research progress.



The neurofibromatoses (NF) are autosomal dominant genetic disorders that 
cause tumors to grow along peripheral nerves.  NF also often affects the 
development of other tissues (including bones, skin, heart, blood, and 
brain) and causes learning disabilities in approximately one-third of 
patients.  There are three distinct forms of NF - NF1, NF2, and the 
recently identified subtype schwannomatosis.  Patients with these 
disorders experience a wide range of symptoms, which range from mild to 

Over a decade ago, investigators identified the genes that cause NF1 and 
NF2 (neurofibromin and merlin/schwannomin respectively) and began to 
characterize their protein products.  NF has served as an important 
paradigm for understanding how mutations in single genes can affect the 
development of multiple tissues. A great deal of information is now 
available regarding the functions of the NF1 and NF2 gene products, as 
well as about the signaling pathways in which they participate.  These 
advances in basic research are providing hope that rational therapeutics 
will be developed to block the aberrant cell proliferation and other 
abnormalities associated with these diseases.  In addition, 
sophisticated cell and animal models now exist that can be used to test 
candidate therapeutics.

The goal of NF research is the development of more effective therapies 
for patients with these disorders. Current treatment modalities, such as 
surgery and radiation, are at best designed to ameliorate specific 
symptoms. Developing more effective pharmaceutical or biological 
interventions will require further basic research, pre-clinical therapy 
development, and clinical studies and trials.  Much of this research 
will require centralized resources and interdisciplinary collaborations. 
For example, testing candidate therapeutics can be done more efficiently 
in an environment where the appropriate cell and animal models are 
assembled, and screening technologies are optimized.  Centralized tissue 
repositories, clinical databases, and other resources will greatly 
facilitate genetic and epidemiological studies. Effective clinical 
trials require both infrastructure and sufficient numbers of well-
characterized patients. Interaction between basic scientists and 
clinicians will also be critical for translating research discoveries 
into interventions that can be tested in the clinic.  


NF centers are intended to provide an interdisciplinary, interactive 
environment that will accelerate research progress and permit studies 
that could not be done as effectively in individual laboratories.  
Proposals should include a minimum of three research projects, which can 
be basic, translational, or clinical in focus.  However, at least one 
project in each center application should focus specifically on 
preclinical therapy development or clinical research, and all centers 
should be designed to enhance progress towards the goal of treating NF. 
Projects should be designed to take advantage of the interactive, 
centralized facilities provided by the proposed center.  In addition, a 
strong case must be made that the individual projects are synergistic in 
nature.  Finally, every center should include at least one project 
focusing on NF1, the most common of the three forms of NF. 

Proposed research projects should relate directly to the etiology, 
pathogenesis or treatment of NF.  Examples of possible projects include:

o  Molecular and cell biological studies of NF1, NF2, or schwannomatosis 
that will be accelerated by the centralized availability of research and 
clinical expertise, patient DNAs and tissues, or other resources.
o  Investigation of the pathogenesis of neurofibromas, gliomas, 
malignant peripheral nerve sheath tumors, skeletal and cardiovascular 
abnormalities, learning disabilities, and other manifestations of NF.
o  High-throughput preclinical screening of candidate NF therapeutics.
o  Development of improved cell and animal models for preclinical 
o  Genotype-phenotype studies of NF patients. 
o  Identification of NF modifier genes and analysis of their effects on 
patient phenotype.
o  Natural History studies, particularly those that will guide 
therapeutic interventions or establish a baseline for future clinical 
o  Phase I or II Clinical Trials of potential therapeutic interventions 
for NF.
o  Development of improved and standardized methods for assessing 
outcome in NF clinical trials  and clinical research (e.g. measurement 
tools for tumors, NF-specific microarrays, cognitive measures).

In addition to describing the proposed research projects, applicants 
must explain how establishing a research center will either accelerate 
research progress or permit research that would be difficult or 
impossible in an individual laboratory.  Such justification could, for 
example, include how a center will permit:

o Centralization of resources (e.g. tissues, DNAs, genotypic or 
phenotypic information derived from patients) required for the proposed 
research projects.
o More efficient preclinical testing of potential therapeutics.
o Pooling of patient populations, without which a specific clinical 
study or trial could not be achieved.
o Interaction between basic researchers and clinicians.
o Training of potential NF researchers directly involved in center 
activities or visiting the center from other sites. 

Applicants can propose the establishment of core facilities necessary 
for the proposed research.  For example, cores designed to collect 
tissue or DNA samples, store genotypic or phenotypic information, 
facilitate clinical studies or trials, or coordinate administrative 
functions can be included within each center proposal.  Applicants must 
describe in detail why each core facility is required for the research 
described in the application.


The mechanism of support for this solicitation will be the Research 
Center Grant (P50).  Responsibility for planning, direction, and 
execution of the proposed research centers will rest solely with the 
applicant.  Because the nature and scope of the research proposed in 
response to this PA may vary, it is anticipated that the size of the 
award may also vary.

NINDS P50 grants are generally limited to $1 million dollars per year 
direct costs for five years.  However, high quality patient-oriented 
research requires resources devoted to training personnel, ensuring 
appropriate inclusion and follow-up of subjects, monitoring patient 
safety, and coordinating activities among participating sites (see Therefore, NINDS 
recently published a notice raising the budget ceiling for specific 
solicited P50 applications to $1.5 million per year direct costs (see 
This increased ceiling will also apply to center applications received 
through this PA that have significant clinical components.  Applicants 
requesting additional funds must explain clearly why they are required 
for the proposed clinical studies.

Any future unsolicited competing continuation applications based on this 
project will compete with all NIH investigator-initiated applications 
and be reviewed according to the customary peer review procedures.

This PA uses just-in-time concepts. Investigators seeking to carry out 
pilot studies of therapies in preparation for a clinical trial should 
apply under the auspices of the Preliminary Investigations Leading to 
Optimal Trials in Neurology program announcement PAR-03-174.  Since such 
applications must conform to the intent of both program announcements, 
including the additional review criteria of PAR-03-174  
(, potential 
applicants are strongly encouraged to contact NINDS program staff for 
guidance.  Close collaboration and integration between research center 
activities and clinical trials is encouraged.


You may submit (an) application(s) if your institution has any of the 
following characteristics:
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic institutions/organizations
o Foreign institutions are not eligible to apply
o Faith-based or community based organizations 


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.


We encourage inquiries concerning this PA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

Direct your questions about scientific/research issues to:

Robert Finkelstein, Ph.D.
Neurogenetics Cluster
National Institute of Neurological Disorders and Stroke
Neuroscience Center, RM 2143
6001 Executive Blvd MSC 9525
Bethesda, MD  20892-9525
Phone: 301-496-5745
FAX:  301-402-1501

Amy M. Donahue, Ph.D.
Division of Scientific Programs
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard RM 400C, MSC-7180
Bethesda, MD  20892-7180
Phone:  301-402-3458
FAX:  301-402-6251

Direct your questions about peer review issues to:

Alan Willard, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, RM 3208
6001 Executive Blvd MSC 9529
Bethesda, MD 20892-9529
Phone: 301-496-9223
FAX: 301-402-0182

Direct your questions about financial or grants management matters to:

Kathleen Howe
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3266
Bethesda, MD  20892
Phone:  (301) 496-9231
FAX:  (301) 402-0219

Sara Stone 
Division of Extramural Activities
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400B, MSC-7180
Bethesda, MD  20892-7180
Telephone:  301-402-0909
FAX:  301-402-1758


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). Applications must 
have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements. The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form. The PHS 398 is available 
at in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:

The title and number of this PAR must be typed in line 2 of the face 
page of the application form and the YES box must be checked.

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at  Application deadlines are also 
indicated in the PHS 398 application kit.

YEAR: Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIH staff member within 
one of NIH institutes or centers who has agreed to accept assignment of 
the application.   

Applicants requesting more than $500,000 must carry out the following 
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist, and three signed, 
photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

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

Alan Willard, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, RM 3208
6001 Executive Blvd MSC 9529
Bethesda, MD 20892-9529
Phone: 301-496-9223
FAX: 301-402-0182

APPLICATION PROCESSING: Applications must be received by or mailed on 
or before the receipt dates described at  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.

The NINDS Guidelines for the development of Program Project and Center 
Applications should be followed when preparing the application.  They 
are available on the NINDS home page at: 

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.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened by NINDS in accordance with the standard NIH peer review 
procedures will evaluate 
applications for scientific and technical merit.

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of the 
applications under review, will be discussed and assigned a priority 
o Receive a written critique
o Receive a second level review by an appropriate National Advisory 
Council or Board. 


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. 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.  

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The 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 

(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, your 
application will also be reviewed with respect to the following:

INTEGRATION AND COLLABORATION:  The ability of the proposed Center 
to promote integration across research projects and collaboration across 
laboratories including basic, translational, and clinical approaches.  
Activities in each project should inform and advance the others and the 
proposed collaborative activities should provide synergy to the proposed 

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).

of plans to include subjects from both genders, all racial and ethnic 
groups (and subgroups), and children as appropriate for the scientific 
goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

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.


SHARING RESEARCH DATA: Applicants requesting more than $500,000 in 
direct costs in any year of the proposed research are expected to 
include a data sharing plan in their application. The reasonableness of 
the data sharing plan or the rationale for not sharing research data 
will be assessed by the reviewers. However, reviewers will not factor 
the proposed data sharing plan into the determination of scientific 
merit or priority score. 

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.


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


HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated 
with reference to the risks to the subjects, the adequacy of protection 
against these risks, the potential benefits of the research to the 
subjects and others, and the importance of the knowledge gained or to be 

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required 
for all types of clinical trials, including physiologic, toxicity, and 
dose-finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of 
data and safety monitoring boards (DSMBs) is required for multi-site 
clinical trials involving interventions that entail potential risk to 
the participants.  (NIH Policy for Data and Safety Monitoring, NIH Guide 
for Grants and Contracts, June 12, 1998:  

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible.  Investigators should 
seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule. Reviewers will 
consider the data sharing plan but will not factor the plan into the 
determination of the scientific merit or the priority score.

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 

All investigators proposing clinical research should read the AMENDMENT 
"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 
a complete copy of the updated Guidelines are available at  
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 

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 

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

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at and at  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see  It is the responsibility of the applicant to 
provide, in the project description and elsewhere in the application as 
appropriate, the official NIH identifier(s) for the hESC line(s)to be 
used in the proposed research.  Applications that do not provide this 
information will be returned without review. 

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

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.  

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 
( 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

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 

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at 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

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

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