HYPERACCELERATED AWARD/MECHANISMS IN IMMUNOMODULATION TRIALS

RELEASE DATE:  March 11, 2002

RFA:  AI-02-003 (see also RFA-AI-04-001)

National Institute of Allergy and Infectious Diseases (NIAID)
 http://www.niaid.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/
National Institute of Neurological Disorders and Stroke (NINDS)
 http://www.ninds.nih.gov/
National Institute of Dental and Craniofacial Research (NIDCR)
 http://www.nidcr.nih.gov/ 

LETTER OF INTENT RECEIPT DATE:  One month prior to application receipt date.  

APPLICATION RECEIPT DATE:  Applications will be accepted MONTHLY on the 9th 
of each month.

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

The National Institute of Allergy and Infectious Diseases (NIAID), the 
National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS), the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), the National Institute of Neurological Disorders and Stroke (NINDS), 
and the National Institute of Dental and Craniofacial Research (NIDCR) of the 
National Institutes of Health (NIH) invite investigator-initiated research 
applications for mechanistic studies in clinical trials of immunomodulatory 
interventions for immune system mediated diseases, including, but not limited 
to, asthma and allergy, graft failure in solid organ, tissue, cell and stem 
cell transplantation, and chronic inflammatory, immunodeficiency and 
autoimmune diseases. This Request for Applications (RFA) is a continuation 
and modification of RFA AI-01-001.  

Specifically, this RFA calls for the inclusion of patients and utilization of 
patient samples for the evaluation of immunologic and other relevant 
parameters to facilitate the study and definition of immunological mechanisms 
underlying the intervention, the mechanisms of disease pathogenesis, 
surrogate/biomarkers markers of disease activity and therapeutic effect, and 
mechanisms of human immunologic function. The parent or core clinical trial 
must have independent financial support and will NOT receive support under 
this RFA.  Proposed mechanistic studies associated with clinical trials 
supported by industry are particularly encouraged but clinical trials 
supported by any source, public or private, are eligible.

In order to review and confer awards to applications received in 
response to this RFA in a timely fashion, without delay of the parent or core 
clinical trial, NIAID has developed a pilot project in collaboration with the 
Center for Scientific Review (CSR): NIAID/CSR PILOT OF HYPERACCELERATED 
REVIEW/AWARD.  All applications responding to this RFA will be subject to 
this hyperaccelerated review/award process.  Highly meritorious applications 
selected for funding under this RFA will receive their awards thirteen weeks 
after the application receipt date.  Holidays and other circumstances may 
alter this schedule slightly.

RESEARCH OBJECTIVES

Background

In December 1996, NIAID convened a workshop at which leading basic and 
clinical immunologists discussed the role the NIH should play in current and 
projected clinical trials for various immune mediated diseases.  It was 
considered likely that clinical trials of many new immunologic interventions 
would be supported by the pharmaceutical/biotechnology industry.  However, 
gaps in both knowledge and in research effort were identified which represent 
opportunities for the NIH to contribute to progress in this area.

There was agreement that the mechanisms underlying immunologic interventions 
are poorly understood even in cases where efficacy has been shown (e.g., 
allergen immunotherapy, in treatment of multiple sclerosis with interferons, 
Copolymer-I, and in other immunomodulatory regimens under development).  In 
addition, clinical trials supported by industry and other sources including 
NIH often do not include studies of underlying mechanisms.  There was 
consensus that high priority should be given to the utilization of patient 
samples from clinical trials in immunologic diseases for studies of the basic 
underlying mechanisms of therapeutic effect, immunologic function, and 
disease pathogenesis.

There was also agreement that the usual time required for grant review and 
funding is often incompatible with the time line of a clinical trial.  
Specifically, when a clinical protocol is finalized (which is required for 
applications submitted under this RFA), investigators are often ready to 
begin as soon as Institutional Review Board approval is obtained.  NIAID was 
encouraged to develop a means of responding rapidly to opportunities to study 
underlying mechanisms in order to facilitate collaborations with industry-
supported clinical trials.

These recommendations were strongly supported by a large number of 
investigators who participated in NIAID focus groups in the winter/spring of 
1997.  The RFA AI-98-006 and the NIAID/CSR PILOT OF HYPERACCELERATED 
REVIEW/AWARD were developed in order to implement these recommendations and 
exploit the research opportunities identified.  Based on the successful 
implementation of RFA AI-98-006, the follow-up RFAs AI-00-005 and AI-01-001 
and the Pilot, the current RFA is being issued to continue this effort.

Research Objectives and Scope

The objective of this RFA is to support mechanistic research studies in 
clinical trials of immunomodulatory interventions for immune system mediated 
diseases, including asthma and allergy, graft failure in solid organ and stem 
cell transplantation, and autoimmune diseases, and of vaccines for the 
prevention and treatment of infectious diseases. Specifically, the goal is to 
utilize patients and patient materials from such trials for the evaluation of 
immunologic and other relevant parameters in order to study the underlying 
mechanisms of the intervention, the mechanisms of disease pathogenesis, 
surrogate markers of disease activity and therapeutic effect, and mechanisms 
of human immunologic function.  Such studies are not part of the parent or 
core clinical trial, and are commonly referred to as substudies or ancillary 
studies.  The parent or core clinical trial must have independent financial 
support and will NOT receive support under this RFA. Clinical trials 
supported by any source, public or private, are eligible.  Clinical trials of 
any phase (i.e. I-IV) are eligible.  Examples of relevant research include, 
but are not limited to, the following:

o  Quantitation of disease-related, autoreactive or alloreactive lymphocytes 
using methods such as MHC/peptide tetramers, chimeric antibodies, or very 
early activation antigens.

o  Analysis of autoreactive or alloreactive cells by PCR for expression of 
genes implicated in immunity or inflammation, or by FACS for cell surface 
markers that identify functions (e.g., cytokine receptors that distinguish 
TH1 from TH2 or chemokine receptors or integrins that indicate preferential 
patterns of homing).

o  Assessment of reagents that can identify newly recognized populations of 
regulatory T cells (e.g., Valpha24JalphaQ bearing invariant T cells) which 
appear to be altered in autoimmune disease.

o  Identification and evaluation of cytokine and cytokine receptor 
polymorphisms and analysis for genetic linkage to disease. 

o  Use of high throughput technologies (e.g. chip technology using expressed 
sequence tags) to identify and evaluate genes activated in disease sites.

o  Identification of useful surrogate markers by correlation of the above 
parameters with disease activity and/or response to intervention.

o  Comparison of samples from peripheral blood with those from sites of 
disease, i.e., do peripheral blood samples provide useful information?

o  Assessment for the presence of molecular evidence (e.g. using PCR probes) 
of potential causative environmental agents.

o   The molecular and cellular mechanisms by which lymphocytes, macrophages, 
neutrophils, antibodies, cytokines and complement contribute to successful 
immunotherapy for chronic inflammatory diseases.

o  Immune mechanisms of vaccines. Studies to define the underlying mechanisms 
of protection induced by vaccines against infectious diseases, including 
investigation of the specificity and kinetics of cellular and antibody 
responses, Th1/Th2 and cytotoxic T cell characterization, and immune memory.

The areas outlined above are not intended to be all-inclusive.

NOTE: Clinical trials of drug (ex. antibiotics or antiviral drugs) treatments 
of infectious diseases (e.g. AIDS and Lyme Disease) are NOT eligible for this 
RFA.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01) award 
mechanism.  As an applicant you will be solely responsible for the planning, 
direction, and execution of the proposed project. 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 total requested project period for an 
application submitted in response to this RFA may not exceed four years.  
Some sponsoring Institutes may administratively limit the duration of award. 
Applicants for the R01 mechanism must not exceed a first-year limit of 
$250,000 direct costs.  Modular grant procedures should be used.

This RFA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see https://grants.nih.gov/grants/funding/modular/modular.htm).   
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular format.

FUNDS AVAILABLE 

The participating ICs intend to commit approximately $1,900,000 in FY 2003 to 
fund 8 to 10 new grants in response to this RFA.  An applicant may request a 
project period of up to 4 years and a budget for direct costs of up to 
$250,000 per year.  Because the nature and scope of the proposed research 
will vary from application to application, it is anticipated that the size 
and duration 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. At this time, it is not known if this RFA 
will be reissued.

ELIGIBLE INSTITUTIONS

You may submit (an) application(s) if your institution has any of the 
following characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS

To assist in the overall evaluation of this RFA, the Principal Investigators 
of grants funded under this RFA will be asked to provide brief (1-2 pages) 
summary report one year following the end of the funding period.  The reports 
will summarize the major scientific knowledge gained and identify other 
substantive outcomes such as publications, patents, and new grants, 
contracts, or research studies based on this mechanistic research.

The research plan in the application should be limited to 15 pages.  The 
research plan includes specific aims, background and significance, 
preliminary studies, and research design and methods (Sections A to D). In 
the research plan, include a justification for why the proposed studies 
require the use of patients in this clinical trial as opposed to using 
patients with the same disease state but not in a trial. 

Methods of data analysis and power calculations must be included.  
Include a justification for the required sample size.  A restatement of the 
sample size calculations from the parent clinical trial is insufficient.  If 
appropriate to your application, discuss whether it is necessary to perform 
the mechanistic studies on all patients enrolled in the parent trial or 
whether a sub-sample would be sufficient.  There must be a discussion of the 
statistical procedures that will be used to analyze the data.  The manner in 
which immunological parameters will be related to the clinical outcomes in 
the main study should also be discussed. 

The protocol and the investigators' brochure for the parent or core clinical 
trial should be included with the application as part of the human subjects' 
section. Inclusion of the complete clinical protocol within the PHS 398 grant 
application is intended to simplify the application process by eliminating 
the need to duplicate protocol details in the Research Plan section. Informed 
Consent form(s) must also be included as part of this section.  While drafts 
of the consent forms at participating sites are not required, it would be 
useful to include them if they are available.  NIH will treat as confidential 
any scientific, preclinical, clinical, or formulation data and information 
that the sponsor deems to be proprietary and confidential.

Amended applications will be accepted for Hyperaccelerated Review/Award ONLY 
if invited by NIH.  Applicants with minor or easily corrected problems will 
be invited to submit an abbreviated amendment (5 page limit and one time 
only), which directly addresses the questions and concerns raised in the 
initial review.

In order to ensure coordination between the mechanistic studies and the 
parent or core clinical trial, the principal investigator and the sponsor of 
the parent or core clinical trial must provide written agreement for the 
conduct of the mechanistic studies as presented in the application.

Prior to award, the applicant must provide to the funding institute a 
memorandum of understanding signed by the applicant, an appropriate 
representative of the applicant institution, the principal investigator of 
the parent or core clinical trial, and an appropriate representative of the 
sponsor of the parent or core clinical trial.  This memorandum will indicate 
agreement and will outline the specifics of the agreement for the following 
areas: 1) data from the mechanistic studies (including ownership, analysis, 
access, and release), 2) access to the data from the parent or core clinical 
trial (how/when) which is needed to analyze the mechanistic studies, 
including procedures for prevention of unblinding of the parent trial, 3) 
documentation of quality assurance procedures for both the parent trial and 
the mechanistic studies, and documentation of Data Safety Monitoring 
procedures for the parent trial, especially for efficacy trials, 4) ownership 
of intellectual property developed during the mechanistic studies, and 5) 
publication of the results of the mechanistic studies.

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:

Kristy Kraemer, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Room 5124, MSC-7640
6700-B Rockledge Drive
Bethesda, MD 20892-7640
(Express Mail: 20817)
Phone: 301-496-5598
Fax:   301-402-0175
e-mail: kk187y@nih.gov

Susana A. Serrate-Sztein, M.D.
Rheumatic Diseases Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Room 5AS-25E, MSC-6500
45 Center Drive
Bethesda, MD  20892-6500
Phone: 301-594-5032
FAX:   301-480-4543
e-mail: ss86e@nih.gov

Beena Akolkar, Ph.D.
Program Director, Immunopathogenesis and Genetics of Type 1 Diabetes
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Room 681
6707 Democracy Boulevard
Bethesda, MD 20892
Phone: 301-594-8812
FAX:   301-480-3503
e-mail: ba92i@nih.gov

A. P. Kerza-Kwiatecki, Ph.D.
Program Director, NE
National Institute of Neurological Disorders and Stroke
NSC, Room 2115
6001 Executive Boulevard
Bethesda, MD 20892
Phone: 301-496-1431
FAX:   301-402-2060
e-mail: ak45w@nih.gov

Dennis F. Mangan, Ph.D.
Immunology and Immunotherapy Program
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-Suite 18
Bethesda, MD  20892-6402
Phone: (301) 594-2421
FAX: (301) 480-8318
e-mail: Dennis.Mangan@nih.gov 

o Direct your questions about peer review issues to:

Alexander D. Politis, Ph.D.
Center for Scientific Review
National Institutes of Health
Room 4204, MSC-7812
6701 Rockledge Drive
Bethesda, MD  20892-7812
(Express Mail: 20817)
Phone: 301-435-1225
FAX:   301-480-4042
e-mail: ap147h@nih.gov

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

Ann White-Devine
Division of Extramural Activities  
National Institute of Allergy and Infectious Diseases  
Room 2118, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614  
Phone: 301-402-5601
FAX:   301-480-3780
e-mail: adevine@niaid.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit, one month prior to the 
application receipt date, a letter of intent that includes the following 
information:

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

Although the 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 NIH staff to estimate the potential review workload and to 
plan the review. 

The letter of intent is to be sent one month prior to the application receipt 
date to Dr. Politis at the address listed under INQUIRIES.

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 
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email: GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

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 "AI-02-003" 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: "HYPERACCELERATED AWARD/MECHANISMS IN IMMUNOMODULATORY TRIALS" and RFA 
number "AI-02-003" 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: https://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 five signed, photocopies, in 
one package to:
     
Center For Scientific Review  
National Institutes Of Health  
6701 Rockledge Drive, Room 1040, MSC 7710  
Bethesda, MD  20892-7710  
Bethesda, MD  20817 (for express/courier service) 

Applications must be received by the 9th of each month. If the ninth of the 
month falls on a weekend day or Federal Holiday, then the receipt date is 
advanced to the next business day. The application must not arrive more than 
two days prior to the receipt date. Applications, 
which are received after the 9th, will automatically be processed the 
following month.  Applications not received as a single package on the 
receipt date or not conforming to the instructions contained in PHS 398 (rev. 
5/2001) Application Kit (as modified in, and superseded by, the special 
instructions below, for the purposes of this RFA), will be judged non-
responsive and will be returned to the applicant.  
  
APPLICATION PROCESSING: The Center for Scientific Review (CSR) will not 
accept any application in response to this RFA that is essentially the same 
as one currently pending initial review, unless the applicant withdraws the 
pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed. This does not preclude the 
submission of substantial revisions of applications already reviewed, but 
such applications must include an Introduction addressing the previous 
critique.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the ICs.

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 NIH 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 National Advisory Council or Board of 
the assigned Institutes. 

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 judge the likelihood that 
the proposed research will have a substantial impact on the pursuit of these 
goals:

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move 
a field forward.

1.  Significance.  Does 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?

2.  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?
 
3.  Innovation.  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 
technologies? 

4.  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)?

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

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

o INCLUSION:  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 
included in the section on Federal Citations, below)

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

o 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:       One month before application receipt date.
Application Receipt Date:            9th of each month.
Peer Review Date:                    4-6 weeks after receipt date
Council Review Date:                 Special Electronic Council
Earliest Anticipated Start Date:     13 weeks after receipt of application.

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 

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: https://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 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 (https://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 
available at 
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.ht
m.   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 
https://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 
https://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 https://grants.nih.gov/grants/stem_cells.htm and at 
https://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 
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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

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 Catalogue of 
Federal Domestic Assistance in the following citations: NIAID No. 93.855, and 
No. 93.856; NIDDK No. 93.847, No. 93.848 and No. 93.849; NIAMS No. 93.866; 
Oral Diseases and Disorders Research Awards No. 93.121; NINDS No.93.853; and 
is not subject to the intergovernmental review requirements of Executive 
Order 12372 or Health Systems Agency review. Awards are made under 
authorization of Sections 301 and 405 of the Public Health Service Act as 
amended (42 USC 241 and 284) and administered under NIH grants policies 
described at https://grants.nih.gov/grants/policy/policy.htm and Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The Public Health Service 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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