RARE DISEASES CLINICAL RESEARCH NETWORK

RELEASE DATE:  February 27, 2003 (see addendum NOT-RR-03-005)
 
RFA:  RR-03-008  (This RFA has been replaced by RFA-OD-08-001 and RFA-OD-08-002) 

 National Center for Research Resources (NCRR)
 (http://www.ncrr.nih.gov)
Office of Rare Diseases, NIH (ORD, NIH)
 (http://rarediseases.info.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
 (http://www.niams.nih.gov/)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov) 

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER:  93.389
 
LETTER OF INTENT RECEIPT DATE:  April 1, 2003

APPLICATION RECEIPT DATE:  April 29, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The National Center for Research Resources (NCRR) the Office of Rare 
Diseases, National Institutes of Health (ORD, NIH), the National 
Institute of Neurological Disorders and Stroke (NINDS), the National 
Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), and the National Institute of Child Health and Human 
Development (NICHD) invite applications for Rare Diseases Clinical 
Research Centers (RDCRCs) and a Data and Technology Coordinating Center 
(DTCC), which together will form the Rare Diseases Clinical Research 
Network.  The purpose of this cooperative research network is to 
facilitate clinical research in rare diseases through support for 1) 
collaborative clinical research in rare diseases, including 
longitudinal studies of individuals with rare diseases, clinical 
studies, phase one and two trials, and/or pilot and demonstration 
projects; 2) training of clinical investigators in rare diseases 
research; 3) a test bed for distributed clinical data management that 
incorporates novel approaches and technologies for data management, 
data mining, and data sharing across rare diseases, data types, and 
platforms; and 4) access to information related to rare diseases for 
basic and clinical researchers, academic and practicing physicians, 
patients, and the lay public. Each RDCRC must include a consortium of 
clinical investigators, institutions, GCRCs, and relevant 
organizations, including patient support organizations, for the study 
of a subgroup of rare diseases. The DTCC, a collaboration between data 
base and computational/computer science innovators, will provide a 
scalable coordinated clinical data management system for collection, 
storage, and analysis of data of RDCRCs, a portal and tools for 
integration of developed and publicly available datasets for data 
mining at RDCRCs, web based recruitment and referral, and a user 
friendly resource site for the public, research scientists, and 
clinicians.  This cooperative program should facilitate identification 
of biomarkers for disease risk, disease severity/activity, and clinical 
outcome and encourage development of new approaches to diagnosis, 
prevention, and treatment of rare diseases.

RESEARCH OBJECTIVES

Background

Approximately 25 million people in the United States are affected by an 
estimated 6,000 rare diseases or conditions leading to significant 
morbidity and mortality.  'Rare disease' is defined through an 
Amendment to the Orphan Drug Act of 1983 (Orphan Drug Act, P.L. 97-414; 
Health Promotion and Disease Prevention Amendments, P.L. 98-551) as a 
condition affecting fewer than 200,000 Americans or a disease with a 
greater prevalence but for which no reasonable expectation exists that 
the costs of developing or distributing a drug can be recovered from 
the sale of the drug in the United States. 

An NIH ORD Special Emphasis Panel, composed of academic scientists, 
representatives of voluntary patient support groups, pharmaceutical, 
biotechnology and device industries, and other Federal agencies, made 
recommendations on the special research and health care issues posed by 
rare diseases.  These recommendations encompassed four major areas: 1) 
Stimulating Research on Rare Diseases and Conditions, with specific 
emphasis on clinical research and training of clinical research 
scientists, establishing diagnostic and treatment centers with 
informatics support, and promoting the collaboration of the voluntary 
patient support groups, health care systems, and industry; 2) Utilizing 
Research Resources, with the NIH supported GCRCs, the development of a 
centralized information database containing research resources, made 
available to research investigators, physicians, and patients for their 
use; 3) Coordination of Rare Diseases Research and Development 
Activities, with a primary responsibility of ORD to coordinate 
activities and act as a liaison between the rare diseases community and 
the NIH, including the public, and intramural and extramural 
investigators at the NIH ICs and other Federal agencies, manufacturers, 
and voluntary organizations; and 4) Identifying Emerging Opportunities 
in Rare Diseases Research, specifically through the establishment of 
specialized research and diagnostic centers to attract the interests of 
industry to promote advances and products for the prevention, 
diagnosis, and treatment of rare diseases.  These recommendations are 
contained within the Department of Health and Human Services National 
Institute of Health Report on Steps to Coordinate Rare Diseases 
Research Programs," January 2001 
(http://rarediseases.info.nih.gov/news-reports/reports.html)

In November 2002, the Rare Disease Act of 2002 (Public Law 107-280) 
directed ORD, NIH to support regional centers of excellence for 
clinical research into, training in, and demonstration of diagnostic, 
prevention, control, and treatment methods for rare diseases.  This law 
provides the legislated mandate for this solicitation to address the 
needs of rare disease clinical research. 

Rare diseases offer promising leads for scientific advancement.  Many 
rare diseases represent single gene defects whose abnormalities in 
specific genes or proteins offer insight into normal biologic function.  
Other rare diseases are complex resulting from the interaction of two 
or more genes. Understanding the pathogenesis of rare diseases may 
advance our understanding of more common medical disorders.  

Despite the advances and opportunities for research in rare diseases, 
there remain difficulties in clinical diagnosis and management.  
Diagnosis may be straightforward with well-described phenotypes or 
difficult with poorly defined criteria. There is insufficient 
characterization of the course of many rare diseases.  Treatment can be 
equally challenging with many questions concerning appropriate and best 
clinical management.  Rare diseases pose unique challenges to 
identification and coordination of resources and expertise for small 
populations dispersed over wide geographic areas.  Rare diseases 
research requires collaboration of scientists from multiple disciplines 
sharing research resources and patient populations.   Rigorous 
characterization and longitudinal assessment is needed to facilitate 
discovery of biomarkers of disease risk, disease activity, and response 
to therapy. In addition, controversies concerning current treatment 
strategies could be resolved by systematic assessment.  Well described 
patient populations will be important to bring promising therapies to 
the clinic.

This initiative will establish a collaborative and coordinated network 
of investigators and patient groups committed to investigation of rare 
diseases working in partnership with leaders in technology to enhance 
communication and sharing of resources in a multidisciplinary approach. 
The Rare Diseases Clinical Research Network will focus on the 
collection of clinical information to develop biomarkers and new 
approaches to diagnosis, prevention, and treatment and promote the 
training of new clinical investigators in rare diseases research.  The 
Network will support a comprehensive and integrated approach to data 
collection, storage, and management, and the integration of clinical 
data with other unique data, including genetic, imaging, pathologic, 
laboratory. The Data and Technology Coordinating Center will 
incorporate new approaches to distributed computing and federated 
databases. 

Organization of the Rare Diseases Clinical Research Network

The Rare Diseases Clinical Research Network is a cooperative network 
composed of several Rare Diseases Clinical Research Centers (RDCRCs) and 
a single Data and Technology Coordinating Center (DTCC) to facilitate 
clinical research in rare diseases.  A Steering Committee, composed at a 
minimum of the Director of each RDCRC, the Director of the DTCC, the 
Office of Rare Diseases Program Coordinator, and the NCRR Program 
Coordinator will establish the procedures for the function of the RDCR 
Network, as outlined in section "Steering Committee."  An independent 
Scientific Advisory Board (SAB), established by the NIH, will provide 
independent oversight of the network and each component. 

Rare Disease Clinical Research Centers.  Each RDCRC will perform 
collaborative clinical research in rare diseases, train new 
investigators in rare diseases research, and provide content for an 
internet resource site on rare diseases.  Each RDCRC will consist of a 
consortium of clinical investigators, institutions, and relevant 
organizations, including patient support organizations, focused on a 
subgroup of rare diseases.  Use of the resources available at General 
Clinical Research Centers must be incorporated into each RDCRC.  The 
focus of each Center can be on particular defects, i.e., lysosomal 
storage diseases, amino acid metabolism defects; particular organ 
systems, i.e., primary immune deficiencies, mental retardation 
syndromes; or other groupings.  Since rare diseases are diverse, the 
nature of clinical research that is feasible varies.  The application 
must describe the group of rare diseases to be included, the rationale 
for this grouping, and the relevant expertise available in the 
consortium Center.  

Each application must include:

o a description and rationale for the planned clinical studies and 
longitudinal assessment of subjects.  Strategies for recruitment, 
retention, assessment, and analysis must be included. Depending on the 
state of knowledge of the particular diseases, the clinical studies 
could include strategies for assessing current therapeutic 
interventions, phase 1 or 2 clinical trials, or pilot and demonstration 
projects.  Examples of demonstration/pilot studies include development 
of novel laboratory assays and clinical instruments. 

o a plan for training of new investigator(s) for clinical research in 
rare diseases within their consortium. 

o a description of resources to be included in a web site for education 
and research in rare diseases.  These resources should include links or 
materials for lay public, patients, basic and clinical researchers, and 
clinicians. Examples include but are not limited to: contacts for 
animal models; tissue, serum, specimens, DNA, etc; antibodies and 
research reagents; genetic resources; registries; education materials; 
and/or diagnostic flow charts.  The actual design and implementation of 
the site will be a collaborative activity of the DTCC and all the 
RDCRCs through the Steering Committee (see below). The Center must 
agree to work cooperatively to develop the web site resource and 
provide content related to its focused rare diseases. 

The Data and Technology Coordinating Center (DTCC). The Data and 
Technology Coordinating Center will develop and make available a secure, 
customizable coordinated clinical data management system for collection, 
storage, and analysis of diverse data types from multiple diseases and 
geographically disparate locations. The DTCC should develop and provide 
a user friendly system for web based recruitment and referral, tools for 
cross disease data mining, and a portal for access and integration of 
publicly available data resources.  The DTCC should have computational 
sophistication for scaling the systems and tools to allow incorporation 
into a distributed, national clinical information network.  The DTCC 
must address privacy and confidentiality issues related to database 
management and distributed computing and allow multiple levels of data 
sharing. The Steering Committee will provide scientific and technical 
assistance and guidelines with respect to quality control, uniformity of 
data collection, management of the collective rare diseases database, 
and data analysis.

Scientific Advisory Board (SAB).  The NIH will establish an independent 
SAB to assist NIH in the evaluation of the Rare Diseases Clinical 
Research Network.  The SAB will provide review of any new research 
activity that is developed in subsequent years of funding.

MECHANISM OF SUPPORT
 
This Request for Applications (RFA) will use NIH U54 award mechanism.  
As an applicant you will be solely responsible for planning, directing, 
and executing the proposed project.  This RFA is a one-time 
solicitation.  The anticipated award date is September 28, 2003.  

This RFA uses just-in-time concepts.  It also uses the non-modular 
budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  

The NIH U54 is a cooperative agreement award mechanism in which the 
Principal Investigator retains the primary responsibility and dominant 
role for planning, directing, and executing the proposed project, with 
NIH staff being substantially involved as a partner with the Principal 
Investigator, as described under the section "Cooperative Agreement 
Terms and Conditions of Award."

FUNDS AVAILABLE 

The participating ICs intend to commit approximately $7.0 M in FY 2003 
to fund 4 RDCRCs ($5 M) and 1 DTCC ($2 M) to new grants in response to 
this RFA. An applicant must request a project period of five years.  
Each RDCRC may request a budget for direct costs of up to $900,000 per 
year, but total cost may not exceed $1.25 M. Because the nature and 
scope of the proposed research will vary from application to 
application, it is anticipated that the size of each award will also 
vary. Although the financial plans of the ICs 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.  It is anticipated that this RFA will be 
reissued in future years dependent on the availability of funds to the
ORD.

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

Foreign institutions are not eligible to apply.

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

These cooperative agreements (U54s) will require cooperation among the 
ORD Program Coordinator, NCRR Program Coordinator, the participating IC 
Program Officers, and Directors of the Rare Disease Clinical Research 
Centers, and the Director of the Data and Technology Coordinating 
Center to maximize their effectiveness.  A number of issues need to be 
addressed in their applications including those highlighted in 
Organization of the Rare Diseases Clinical Research Network and below 
under Cooperative Agreement Terms and Conditions.

Cooperative Agreement Terms And Conditions Of Award

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator as well as the 
institutional official at the time of award.

These special Terms of Award are in addition to, and not in lieu of, 
otherwise applicable OMB administrative guidelines, HHS Grant 
Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, 
and NIH Grant Administration policy statements.

The administrative and funding instrument used for this program is the 
multiproject cooperative agreement (U54), an "assistance" mechanism 
rather than an "acquisition" mechanism, in which substantial NIH 
scientific and/or programmatic involvement with the awardee is 
anticipated during the performance of the activity.  Under the 
cooperative agreement, the NIH purpose is to support and/or stimulate 
the recipient's activity by involvement in and otherwise working jointly 
with the award recipient in a partner role, but it is not to assume 
direction, prime responsibility, or a dominant role in the activity.  
Consistent with this concept, the dominant role and prime responsibility 
for the activity resides with the awardees for the project as a whole, 
although specific tasks and activities in carrying out the research will 
be shared among the awardees and the NIH Research Coordinators.

1.  Awardee Rights and Responsibilities 

Awardees will have primary responsibility for defining the details of 
the project within the guidelines of the RFA RR 03-008 and for 
performing the scientific activity, and agree to accept close 
coordination, cooperation, and participation of the NIH staff in those 
aspects of the scientific and technical management of the project 
described below.  Specifically, awardees have primary responsibility as 
described below.

RDCRC Director and the DTCC Director

The Rare Diseases Clinical Research Center Directors and Data and 
Technology Coordinating Center Director are the persons responsible for 
the overall management of their Centers and coordination with the other 
Centers.  The relationship between the Clinical Centers and the Data and 
Technology Center should be one of equal partners in the Network. Each 
Center Director must devote at least 20% effort to this program. 

Collaboration and Coordination 

The collaboration of investigators between Centers is highly encouraged 
based on shared interests and complementary talents. The planned 
collaborating sites within the Center must be ongoing and active.  Plans 
for evaluating and removing or replacing non-productive members of a 
Center consortium must be in place for each Center. 

Steering Committee Membership and Meeting Attendance

Each Center Principal Investigator will be designated the Center 
Director.  Each Center Director will be a voting member of the Network 
Steering Committee and participate in all Committee activities and 
decisions including, but not limited to, conference calls and special 
subcommittees as may be necessary.  The Steering Committee shall be 
responsible for determining the frequency of meetings and scheduling the 
time and location.  The Steering committee will establish the procedures 
for the function of the Centers network, as outlined in section 
"Steering Committee."

Data Coordination and Management and Sharing 

The awardees will have primary rights to all data developed under these 
awards, subject to Government rights of access consistent with HHS and 
NIH policies.  The DTCC will develop with the input of the Steering 
Committee a data management system.  All Centers will place their data 
at the DTCC who will also offer analysis expertise for Network 
investigators.  The intention of the NIH is that the data collected 
within this Network will be become a resource for the Rare Disease 
Community and will be made available to the scientific community.  
Criteria and mechanisms for data sharing among investigators within the 
Network and with the scientific community will be developed by the 
Steering Committee. 

Publication and Presentation of Study Findings

Early publication of major findings is encouraged.  Publications and 
oral presentations of work performed under this agreement will require 
appropriate acknowledgment of the Rare Disease Clinical Research Network 
and NIH support.  The Steering Committee will establish the procedures 
and criteria for presentation and publication of data developed within 
the Centers network.

Federally Mandated Regulatory Requirements

Each institution participating in the Rare Diseases Clinical Research 
Network is required to meet DHHS regulations for the protection of human 
subjects and FDA requirements for the conduct of research using 
investigational agents.  At a minimum, these include:

o methods for assuring that each institution at which Rare Diseases 
Clinical Research Network investigators are conducting clinical studies 
has registered with the Office of Human Research Protections (OHRP; 
http://www.hhs.gov/ohrp/) and has a Federalwide Assurance; that 
study protocols are reviewed and approved by the responsible 
Institutional Review Board (IRB) prior to patient entry; that active 
protocols are reviewed at least annually by the IRB, and that amendments 
are approved by the IRB.

o methods for assuring or documenting that each patient, or patient's 
parent/legal guardian, gives fully informed consent to participation in 
a research protocol prior to the initiation of the clinical study.

2.  NIH Staff Responsibilities

One representative from ORD and one representative from the NCRR will be 
designated to serve as the Program Coordinators for this cooperative 
agreement.  The ORD and NCRR Program Coordinators and one Program 
Officer from each participating IC will have substantial 
scientific/programmatic involvement during the conduct of this activity 
through technical assistance, advice and coordination above and beyond 
normal program stewardship for grants, as described below.

Steering Committee Membership and Meeting Attendance

The ORD and NCRR Program Coordinators and one Program Officer from each 
participating IC will serve on the Steering Committee and will 
participate in all Committee activities, including, but not limited to, 
meetings, conference calls, subcommittees, and special committees.  They 
will assist in development of operating policies, quality control 
procedures, and policies that require cooperative action.  However, 
while the ORD and the NCRR Program Coordinators and participating IC 
Program Officers will attend Steering Committee Meetings, their 
cumulative votes may never exceed 40 percent. 

Monitoring Performance

The ORD and NCRR Program Coordinators and IC Program Officers will 
assist the Steering Committee in the development of procedures for 
monitoring the performance of the clinical studies. This includes 
participation in periodic on-site monitoring with respect to compliance 
with protocol specifications, quality control and accuracy of data 
recording, and accrual.  The NIH will also provide assistance to the 
DTCC in identifying technology resources, provide oversight of 
activities, including security and privacy issues. 

Publication and Presentation of Clinical Studies Findings

The NIH staff may contribute, through review, comment, analysis, and/or 
co-authorship, to reporting results of the clinical studies and 
trials/studies to the investigator community and other interested 
scientific and lay organizations.  Co-authorship by the NIH staff will 
be subject to approval in accordance with the NIH policies regarding 
staff authorship of publications resulting from extramural awards.

The Government, via the ORD Program Coordinator and the NCRR Program 
Coordinator, will have access to data generated under this Cooperative 
Agreement and may periodically review the data and progress reports.  
Information obtained from the data may be used by NIH staff for the 
preparation of internal reports on the activities of the clinical 
studies.  However, awardees will retain custody of and have primary 
rights to all data developed under these awards.

Program Stewardship

The assigned Program Directors will be responsible for normal 
programmatic stewardship and monitoring of this award and approval of 
new pilot studies.  The Program Directors may also serve as the NCRR 
Program Coordinator and the substantively involved IC Program officers.  
They may receive input and recommendations from other NIH staff in 
monitoring the awards. 

3.  Collaborative Responsibilities

All investigators within each Center and the Coordinating Center must 
be willing to work cooperatively and collaboratively both within their 
Center consortium and with other Centers.  Each Center is expected to 
send two Center participants to three 2 day meetings in the first year 
to the Washington, D.C. area and biannually thereafter. 

Steering Committee

A Steering Committee will be established to serve as the main governing 
body of the cooperative network.  At a minimum, the Steering Committee 
will be composed of one representative from each of the RDCR Centers, 
one representative from the DTCC, the ORD Program Coordinator, the NCRR 
Program Coordinator, and other participating IC Program Officers.  All 
members are expected to actively participate in all Steering Committee 
activities. The combined vote of NIH membership may never exceed 40 
percent. 

The Chairperson of the Steering Committee will be selected by the 
Steering Committee from among the non-Federal members during one of the 
early meetings of the Committee to be convened by the NIH Research 
Coordinators.  All major decisions will be determined by the Steering 
Committee.  The Committee will meet at least three times during the 
first 12 months of the program and at least semi-annually thereafter. As 
needed, the Steering Committee may establish subcommittees for special 
purposes.  It is expected that most of the work of the Steering 
Committee will be performed in these subcommittees.  All Centers must 
abide by decisions of the Steering Committee.

The Steering Committee will have responsibility for facilitating the 
conduct of the clinical studies, promoting trans-Center collaboration, 
establishing and updating the content of the web resource site, and 
establishing procedures for reporting results of Center studies. The NIH 
may provide additional funds in future years for new pilot projects. The 
Steering Committee should develop procedure for reviewing proposals for 
such projects. The Steering Committee will provide scientific and 
technical assistance and guidelines with respect to quality control, 
uniformity of data collection, management of the collective rare 
diseases database, and data analysis.  

4.  Arbitration

Any disagreement that may arise on scientific or programmatic matters 
(within the scope of the award) between award recipients and the NIH may 
be brought to arbitration.  An arbitration panel will be formed to 
review any scientific or programmatic issue that is significantly 
restricting progress. This panel will be composed of three members -- 
one selected by the Steering Committee or by the individual awardee in 
the event of an individual disagreement, a second member selected by the 
NIH, and a third member with expertise in the relevant area and selected 
by the two prior members.  While the decisions of the Arbitration Panel 
are binding, these special arbitration procedures will in no way affect 
the awardee's right to appeal an adverse action in accordance with PHS 
regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR 
Part 16.

PRE-APPLICATION MEETING 

The ORD and NCRR anticipate holding a pre-application meeting in March 
2003 to which all interested prospective applicants are invited. 
Program and review staff will make presentations that explain their 
goals and objectives for the Rare Diseases Clinical Research Network 
and answer questions from the attendees.  A Grants Management 
Specialist will be available to answer financial questions. Prospective 
applicants are urged to monitor the NIH Guide Notice for the date and 
time of the meeting at http://grants.nih.gov/grants/guide/index.html. 
Additionally, consult the following website, established as an 
information resource for this RFA: 
http://rarediseases.info.nih.gov/news-reports/reports.html

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA 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:

o Direct your questions about scientific/research issues to:

Giovanna M. Spinella, M.D.
Office of Rare Diseases
National Institutes of Health
6100 Executive Blvd., Room 3B01 MSC 7518 
Bethesda, MD 20892-7518
Telephone: (301) 402-4336
FAX: (301) 480-9655
Email: spinellg@od.nih.gov

or

Elaine Collier, M.D.
Division of Clinical Research
National Center for Research Resources
6705 Rockledge Drive, Room 6122 MSC 7965
Bethesda, MD  20892-7965
Telephone: (301) 435-0794
FAX: (301) 480-3661
Email: CollierE@ncrr.nih.gov

o Direct your questions about peer review issues to:

Robert Weller, Ph.D.
Division of Clinical and Population Based Studies
Center for Scientific Review
6701 Rockledge Drive Room 3160
Rockville, MD 20892-7770
Telephone: (301) 435-0694
FAX: (301) 480-3962
Email: wellerr@csr.nih.gov

o Direct your questions about financial or grants management matters 
to: 

Mary V. Niemiec
Lead Grants Management Specialist
Office of Grants Management
National Center for Research Resources
One Rockledge Centre, Room 6086
6705 Rockledge Drive  MSC 7965
Bethesda, MD  20892-7965
Tel: (301) 435-0842
FAX: (301) 480-3777
email: mn20z@nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 the date listed at the beginning 
of this document.  The letter of intent should be sent to:

Giovanna M. Spinella, M.D.
Office of Rare Diseases
National Institutes of Health
6100 Executive Blvd., Room 3B01 MSC 7518 
Bethesda, MD 20892-7518
Telephone: (301) 402-4336
FAX: (301) 480-9655
Email: spinellg@od.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.

SUPPLEMENTAL INSTRUCTIONS

See additional application instructions under the sections RESEARCH 
OBJECTIVES and SPECIAL REQUIREMENTS.

USING THE RFA LABEL: 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.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist, and four signed, 
photocopies, in one package, including appendices 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, one additional copy of the application must 
be sent to:

Elaine Collier, M.D.
Division of Clinical Research
National Center for Research Resources
6701 Democracy Boulevard, Suite 619, MSC 7965
Bethesda, MD  20892-4874 
 
APPLICATION PROCESSING: Applications must be received on or before 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. 

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.
 
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.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes.  While the investigator may 
still benefit from the previous review, the RFA application is not to 
state explicitly how.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the ORD and NCRR program coordinators.  

Incomplete and/or non-responsive applications will be returned to the 
applicant without further consideration.

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 Center for Scientific Review in accordance 
with the review criteria stated below.  As part of the initial merit 
review, all applications will:

o Receive a written critique
o 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 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 the 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 the application's overall score, weighting them 
as appropriate for each application.  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, 
an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

SIGNIFICANCE: Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be 
advanced? What will be the effect of these studies on the concepts or 
methods that drive this field?  

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of 
the project? Does the applicant acknowledge potential problem areas and 
consider alternative tactics?  Is the plan for training new 
investigators adequate and appropriate?  For the DTCC, does the 
proposed approach incorporate scalable and secure technology?

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 methodologies or 
technologies?  Are there novel methods for recruitment and outreach to 
health professionals?

INVESTIGATOR: Is the investigator appropriately trained and well suited 
to carry out this work? Is the work proposed appropriate to the 
experience level of the principal investigator and other researchers 
(if any)? Are the investigators committed to collaborative and 
cooperative nature of this program?

ENVIRONMENT: Does the scientific environment in which the 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?  Is there active participation of 
relevant patient support organizations? 

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:

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.  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.  

ADDITIONAL CONSIDERATIONS 

DATA SHARING:  The adequacy of the proposed plan to share data. 

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.  Budgets must 
include funds for travel of the Center Director to Bethesda, MD for a 2 
day meeting three times in the first year, and semiannually in 
subsequent years. 

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  April 1, 2003
Application Receipt Date:  April 29, 2003
Peer Review Date:  July 2003
Council Review:  September 2003
Earliest Anticipated Start Date:  September 2003

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.
 
REQUIRED FEDERAL CITATIONS 

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 gained.

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.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   It is the responsibility of the applicant to 
provide 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. 

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.

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 RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92. All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at http://grants.nih.gov/grants/policy/policy.htm.

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


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