HIGH THROUGHPUT GENOTYPING CENTERS FOR HUMAN AND ANIMAL DNA

RELEASE DATE:  September 24, 2003 (see addendum NOT-RR-04-002)
 
RFA Number:  RFA-RR-03-012
 
Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATIONS:

National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATIONS:

National Center for Research Resources (NCRR)
 (http://www.ncrr.nih.gov)
National Cancer Institute (NCI)
 (http://www.nci.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:  93.389, 93.393, 
93.394, 93.399
 
LETTER OF INTENT RECEIPT DATE: November 18, 2003
APPLICATION RECEIPT DATE: December 18, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism 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) invites applications 
to develop and operate High Throughput Genotyping Centers. The purpose 
of this Request for Applications (RFA) is to increase the research 
resource capacity that provides for the genotyping of polymorphic 
markers in human and animal DNA. The research proposed under this RFA 
will expand the nation's resources for high-throughput genotyping under 
conditions that allow for economies of scale, quality assurance and 
data sharing. The program should facilitate identification of 
biomarkers for disease risk, disease severity/activity, and clinical 
outcome as well as animal genetic loci related to human disease, and 
should encourage development of new approaches to diagnosis, 
prevention, and treatment of human diseases.

RESEARCH OBJECTIVES

Background

Many disorders are known to occur in families but lack the simple 
inheritance pattern that allows a single gene to be identified as the 
causative agent. The identification, two decades ago, of polymorphic 
markers spanning all 24 human chromosomes made linkage studies 
possible, and led to the conclusion that multiple genes could act 
together to increase or reduce the risk of numerous common disorders. 
The cost to society of these diseases, whether assessed in economic 
terms or as burden of care, is enormous and justifies research that 
will lead to strategies for prevention or cure. Genotyping describes 
the characterization of inheritable characteristics and is widely used 
for studies that seek to identify genes that contribute to disease. The 
contribution is generally in the form of susceptibility to a disorder 
or, conversely, to protection. Genotyping studies play an increasingly 
important role in our understanding of the pathogenesis of a wide range 
of diseases, encompassing immune as well as vascular, neuropsychiatric, 
metabolic, malignant and gastrointestinal etiologies. Studies of 
siblings who differ in disease expression have pointed to 
susceptibility genes in many disorders (such as histocompatibility 
antigens for type 1 diabetes). The identification of genes contributing 
to other common disorders (such as multiple sclerosis) will likely 
require comparisons between unrelated individuals with and without the 
disorder (association studies) in order to understand the familial 
trends. 

When multiple human genes that contribute to a disease phenotype are 
identified, it is likely that animal models will be required to 
understand the separate contribution that each gene makes and to 
identify points at which a medical intervention might serve to prevent 
the disorder.  In addition, animal models have proven useful for 
identifying Quantitative Trait Loci (QTLs), regions of the genome 
containing genes that contribute to a disease phenotype.  
Identification of candidate genes within animal QTLs can then be used 
to identify the cognate human genes that contribute to the particular 
condition.  This process should be enhanced with the completion of 
whole genome sequences, e.g., for humans, mice and rats.
 
Human genotyping studies in recent years have identified chromosomal 
regions that associate with susceptibility to common (and therefore 
economically important) disorders such as autism, schizophrenia and 
celiac disease. Many animal QTLS influencing, for example, body weight, 
cholesterol metabolism and cardiovascular physiology, have been 
identified.  The methods currently in widest use do not identify 
individual genes – often large numbers of subjects must be studied 
before this critical step can be reached. With the increasing 
refinement of genotyping methods it seems likely that some common 
disorders will be separated into sub-types, for which different 
approaches may be required for prevention. The need for genotyping will 
grow through the foreseeable future as investigators come to prioritize 
potential targets for treatment interventions and as the members of 
afflicted families wish to estimate their risk for a particular 
condition. The use of association studies themselves will enormously 
strain presently available genotyping facilities as the number of 
subjects to be tested increases exponentially. 

In terms of technologies, whole genome scans of polymorphic 
microsatellite markers have been the mainstay of human linkage studies 
in the past decade.  The higher resolution afforded by single 
nucleotide polymorphism (SNP) typing seems likely to dominate the 
demands of clinical investigators in the future while, for many animal 
species, microsatellite-based techniques will be needed.  However, SNP 
maps will probably also be expanded for the most commonly studied 
animals, particularly the mouse.

The considerations discussed above are the impetus to this initiative 
by the Divisions of Clinical Research (DCR) and Comparative Medicine 
(DCM) at the National Center for Research Resources that will increase 
capacity for genotyping. 

Research Objectives

  Applicants will be expected to meet the following objectives:

o  Equip and run a facility that can accession bar coded DNA samples 
that will be supplied by investigators approved by the Steering 
Committee. The accession database must be web accessible and, where 
appropriate, compliant with the Privacy Rule of the Health Insurance 
Portability and Accountability Act (HIPAA). In addition to testing 
these samples for polymorphic markers, the scope of activity shall 
extend to the organization of the polymorphic markers identified into a 
user-interpretable format and to the posting of de-identified data on a 
web server in a form compatible with the requirements of the NIH Data 
Sharing plan http://grants.nih.gov/grants/policy/data_sharing/). For 
animal studies, applicants will be expected to genotype samples using 
existing markers, to develop new markers, as needed, and to integrate 
new markers into extant maps.  Components of these activities are 
described in the following paragraphs.

o  Implement and support a Laboratory Information Management System 
along with other database platforms that will allow for the input, 
storage and retrieval of clinical, genotypic, laboratory, and 
phenotypic data. The laboratory will employ electronic worksheets with 
on line and bar-coded data entry. Facilities for secure storage of data 
prior to establishing HIPAA-compliance and/or web posting are required 
along with the generation of anonymized unique patient numbers to allow 
clinical and phenotypic data to be cross-referenced to any DNA samples 
and genotype data. 

o  Develop a web site on which they publish their standard operating 
procedures for the collection, processing and storage of DNA by 
investigators whose projects are approved by the Steering Committee 
(defined below) for Center Resources. They will advise approved 
investigators concerning the quality control of samples to be 
accessioned for testing, written procedural manuals for collecting, 
transporting and storing biological specimens together with protocols 
for extracting DNA and troubleshooting common problems.

o  Develop a web site to include additional resources for education of 
the lay public, patients, basic and clinical researchers and 
clinicians. Examples include but are not limited to: contacts for 
advice concerning animal genotyping together with links to relevant 
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 Genotyping Center, the Steering Committee 
and the NCRR. 

o  Test accessioned DNA samples for quality and notify investigators of 
failures. Subject variables must be accessioned and stored in a HIPAA-
compliant format such that the results of genotyping can be made 
available to the requestors in a web-compliant form. Current estimates 
are that over 6,000 samples will be accessioned in year 1, increasing 
to about 20,000/year in subsequent years.

o  State the approach they will take to type for polymorphisms (for 
example, micro-satellite typing, SNP typing or any combinations of the 
two) and the internal review mechanisms that will operate to determine 
what approaches to genotyping should be available to approved 
investigators. Applicants should describe their approaches and 
laboratory methods in sufficient detail for their review.

o  10-20% of the budget should be committed to the research and 
development components of genotyping. These components might, for 
example, encompass the development of high-throughput chip approaches 
to SNP typing or alternative methodologic advances. Progress with the 
HapMap and characterization of different block sizes will, for example, 
likely accelerate the use of SNP-based genotyping. Other possible areas 
for research and development include the refinement of polymorphic 
markers for non-human primates and other animal models, and/or the 
enhancement of statistical methods for analyzing clinical and 
epidemiological data and their relationship to co-inheritance of DNA 
markers and complex traits.

A Steering Committee (see below) will meet twice-yearly, and travel and 
per diem funds for the Center Director and two external members should 
be included in the budget.

MECHANISM OF SUPPORT

This RFA will use the 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.  Future 
unsolicited, competing-continuation applications based on this project 
will compete with all investigator-initiated applications and will be 
reviewed according to the customary peer review procedures.  The 
anticipated award date is July 28, 2004.  

The NIH U54 is a cooperative agreement award mechanism. In the 
cooperative agreement mechanism, 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." Plans for possible continuation of the cooperative agreement 
project beyond the initially awarded period of performance, or reissue 
an RFA or other announcement beyond the current RFA, are indefinite.

FUNDS AVAILABLE 

NCRR intends to commit approximately $3.5 M in direct costs in FY 2004 
to equip and support one or two Genotyping Centers. An applicant may 
request a project period of up to five years and a budget for direct 
costs of up to $2M per year in years 2-5. Although the financial plans 
of the NCRR and NCI provide support for this program, awards pursuant 
to this RFA are contingent upon the availability of funds and the 
receipt of meritorious applications.  

ELIGIBLE INSTITUTIONS

You may submit an application 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.

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

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-03-012 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.  Awardees will accept the role of the Steering 
Committee as described below. Specifically, awardees have primary 
responsibility as described below.

Genotyping Center Director.

The Genotyping Center Director should commit at least 20% time to this 
project. The Genotyping Center Director will be a member of 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 NCRR.

Awardees will retain custody of and have primary rights to all data 
developed under these awards; the NIH will have access as described 
below. 

Federally Mandated Regulatory Requirements

All institutions participating in the High Throughput Genotyping Center 
must meet DHHS regulations for the protection of human subjects and 
their confidentiality as well as any applicable FDA requirements. These 
include assuring that each institution from which DNA is received 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. OHRP guidance for repositories may 
be found at 
http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm and 
additional NIH guidance is available from the NIH Brochure on Research 
Involving Human Specimens at http://www.cdp.ims.nci.nih.gov/policy.html

Where animal samples are used, they must have been collected under the 
contributing institution's IACUC-approved protocols.

2.  NIH Staff Responsibilities  

NIH staff assistance will be provided by the NCRR Program Coordinator, 
who shall represent the DCR, NCRR and also by a representative of the 
DCM, NCRR. The Program Coordinator 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.

The NCRR Program Coordinator will serve as a voting member of the 
Steering Committee, will attend all SC meetings, and will participate 
in other Committee activities, including, but not limited to, 
conference calls, subcommittees, and special committees.  The DCM 
representative will also attend all SC Meetings and will provide advice 
to the center regarding animal studies.  He/she will not be a voting 
member of the Committee.

The NCRR Program Coordinator 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 in identifying technology resources, 
provide oversight of activities, including security and privacy issues.

The NCRR, via Program Coordinator, will have access to data generated 
under this Cooperative Agreement and may periodically review the data 
and progress reports consistent with current DHHS, PHS and NIH 
policies.  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.

The NCRR will assign a program director that is responsible for normal 
program monitoring and stewardship of the award.  The program director 
may also serve as the NCRR Program Coordinator.

3. Collaborative Responsibilities

Steering Committee. The Genotyping Center in collaboration with the 
NCRR will establish an independent Steering Committee (SC) to review 
and approve requests for access to the resources of the high throughput 
genotyping center. The SC shall comprise one member each from the 
Divisions of Clinical Research and Comparative Medicine at NCRR and the 
Genotyping Center Director. These three individuals shall select two 
additional and appropriately qualified members from outside the 
recipient institution. The SC shall be responsible for scheduling the 
time and location of meetings that shall be held at least twice yearly.  
The SC will establish the procedures for the function of the Center. 
Requests for access that are approved by the SC will be prioritized on 
the basis of their scientific merit.

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 (with the NIH members not 
voting) 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 

NCRR anticipates holding a pre-application meeting with videoconference 
in October 2003 to which all interested prospective applicants are 
invited. Program staff will make presentations that explain their goals 
and objectives for the High Throughput Genotyping Center 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. 

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:

Anthony R. Hayward, M.D., Ph.D.
Division of Clinical Research
National Center for Research Resources
6701 Democracy Boulevard Room 906 – MSC 4874
Bethesda, MD  20892-4874
Telephone:  (301) 435-0790
FAX:  (301) 480-3661
Email: haywarda@mail.nih.gov

Or

John Harding Ph.D.
Division of Comparative Medicine
National Center for Research Resources
6701 Democracy Boulevard Room 906 – MSC 4874
Bethesda, MD  20892-4874
Telephone:  (301) 435-0776
Fax:  (301) 480-3819
Email: hardingj@mail.nih.gov

Or

Wendy Wang, Ph.D. M.Sc.
Cancer Biomarkers Research Group 
Division of Cancer Prevention 
National Cancer Institute 
6130 Executive Boulevard, EPN 3138 
Rockville, MD 20852 
Telephone:  (301) 594-7607 
Fax:  (301) 402-8990 
E-mail: wangw@mail.nih.gov

o Direct your questions about peer review issues to:

Sheryl Brining Ph.D.
National Center for Research Resources
6701 Democracy Blvd, Room 1074 MSV 4874
Bethesda MD 20892-4874
Telephone: (301) 435-0809
Fax: (301) 480-3660
Email: brinings@mail.nih.gov 

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

Judy Musgrave
Office of Grants Management, NCRR
6701 Democracy Blvd., Room 1048 MSC 4874
Bethesda, MD  20892 
Telephone: (301) 435-0841
Fax: (301) 480-3777
Email: musgravj@mail.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:

Anthony R. Hayward, M.D., Ph.D.
Division of Clinical Research
National Center for Research Resources
6701 Democracy Boulevard Room 906 – MSC 4874
Bethesda, MD  20892-4874

SUBMITTING AN APPLICATION

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 
http://www.dunandbradstreet.com/. The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form. 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.

SUPPLEMENTARY INSTRUCTIONS.  See the Research Objectives section for 
additional application instructions. 

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/labels.pdf.
 
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 and 
all copies of the appendix material must be sent to:

Anthony R. Hayward, M.D., Ph.D.
Division of Clinical Research
National Center for Research Resources
6701 Democracy Boulevard Room 906 – MSC 4874
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 from the previous unfunded 
version of the application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by NCRR. Incomplete and/or unresponsive applications 
will not be reviewed.  

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 NCRR in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

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 written critique
o Receive a second level review by the NCRR National Advisory Council.
 
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 evaluate the 
application in order to judge the likelihood that the proposed research 
resource will have a substantial impact on the pursuit of these goals. 
The scientific review group will address and consider each of the 
following criteria in assigning the 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, 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 the Genotyping Center provide a cost efficient 
resource for human and animal samples? Do the research and development 
components of the application 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 data 
handling components adequately developed, well-integrated, and 
appropriate to the aims of the project? Does the applicant acknowledge 
potential problem areas and consider alternative tactics?

INNOVATION: Does the project extend currently available genotyping 
resources or employ novel concepts, approaches or methods to increase 
capacity? Does the project develop new methodologies or technologies?

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, 
responsiveness to the Research Objectives listed in that section of 
this RFA 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 REVIEW CONSIDERATIONS

Sharing Research Data

Applicants requesting more than $500,000 in direct costs in any year of 
the proposed research must include a data sharing plan in their 
application. The reviewers will assess the reasonableness of the data 
sharing plan or the rationale for not sharing research data. However, 
reviewers will not factor the proposed data sharing plan into the 
determination of scientific merit or priority score. Details of the NIH 
data sharing requirements may be found at: 
http://grants.nih.gov/grants/policy/data_sharing/).

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

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: November 18, 2003
Application Receipt Date: December 18, 2003
Peer Review Date: March 2004
Council Review: May 2004
Earliest Anticipated Start Date: July 28, 2004

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.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 

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: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking more than $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. 
http://grants.nih.gov/grants/policy/data_sharing  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.

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://stemcells.nih.gov/index.asp 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, 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. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom of 
Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  
The Department of Health and Human Services (DHHS) issued final 
modification to the "Standards for Privacy of Individually Identifiable 
Health Information", the "Privacy Rule," on August 14, 2002.  The 
Privacy Rule is a federal regulation under the Health Insurance 
Portability and Accountability Act (HIPAA) of 1996 that governs the 
protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR). 
Those who must comply with the Privacy Rule (classified under the Rule 
as "covered entities") must do so by April 14, 2003 (with the exception 
of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule 
reside with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, 
including a complete Regulation Text and a set of decision tools on "Am 
I a covered entity?"  Information on the impact of the HIPAA Privacy 
Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts 
can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, Internet 
addresses (URLs) should not be used to provide information necessary to 
the review because reviewers are under no obligation to view the 
Internet sites.   Furthermore, we caution reviewers that their anonymity 
may be compromised when they directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas. This RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.healthypeople.gov/.

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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