HEPATITIS C: NATURAL HISTORY, PATHOGENESIS, THERAPY AND PREVENTION

RELEASE DATE:  January 6, 2003 (see amendment NOT-DK-03-003)
 
RFA:  DK-03-011
 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov/)
National Cancer Institute (NCI)
 (http://www.nci.nih.gov/)
National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov/)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
 (http://www.niaaa.nih.gov/)
National Institute of Allergy and Infectious Diseases (NIAID)
 (http://www.niaid.nih.gov/)
National Institute on Drug Abuse (NIDA)
 (http://www.nida.nih.gov/)

LETTER OF INTENT RECEIPT DATE:  March 11, 2003

APPLICATION RECEIPT DATE:  April 15, 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 Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Specific instructions for R21 applications
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 Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute 
(NHLBI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National 
Institute of Allergy and Infectious Diseases (NIAID), and National Institute 
on Drug Abuse (NIDA), invite grant applications for both basic and clinical 
research in the areas of pathogenesis, natural history, therapy and 
prevention of hepatitis C. 

According to the National Health and Nutrition Examination Survey (NHANES) of 
1988–1994, 3.9 million Americans were infected with hepatitis C, and of this 
group, 2.7 million are estimated to have chronic infection. These estimates 
likely under represent the true prevalence of HCV infection since NHANES was 
a population-based household survey that excluded several groups with a 
substantially increased prevalence of infection, such as persons who are 
incarcerated, homeless, or institutionalized due to disability or mental 
illness. 

HCV is the most common blood-borne infection in the United States. HCV 
transmission occurs primarily through exposure to infected blood. 
Transmission risk factors include injection drug use, blood transfusion prior 
to 1992, solid organ transplantation from infected donors, unsafe medical 
practices, occupational exposure to infected blood, birth to an infected 
mother, multiple heterosexual partners, and high-risk sexual practices. High 
HCV seroprevalence rates (from 15 to 50 percent) have been observed in 
specific subpopulations, such as the homeless, incarcerated persons, veterans 
being followed at Veterans Affairs Medical Centers, and hemophiliacs, with 
the highest rates (70 percent to 90 percent) reported in injection drug 
users. In the general population, persons aged 40 to 59 years have the 
highest prevalence of HCV infection, and in this age group, the prevalence is 
highest in African-Americans (6.1 percent). Because of the high rate of 
persistent infection long-term complications of chronic HCV infection are 
projected to increase in the next 15 years. 

Acute hepatitis C leads to chronic infection in approximately 75 percent of 
cases. Age at the time of infection appears to be an important contributing 
factor, spontaneous remission occurring more frequently in younger infected 
individuals.  Chronic hepatitis C is often asymptomatic and can be mild; but 
in 20 percent of patients, the chronic infection leads to progressive liver 
disease and ultimately cirrhosis and end stage-liver disease. These 
conditions increase the risk of developing hepatocellular carcinoma (HCC). 
There is little evidence that the risk of progression of liver disease is 
affected significantly by virologic factors, including viral levels in the 
serum, viral genotype, and quasispecies diversity. However, many host factors 
have been found to increase this risk, including older age, male gender, and 
an immune suppressed state, such as HIV co-infection. Environmental factors 
that may complicate or worsen the course of chronic hepatitis C are alcohol, 
iron overload, obesity, nonalcoholic fatty liver disease, schistosomal co-
infection, hepatotoxic medications, and possibly environmental contaminants.

The incidence of HCV-related liver cancer is continuing to rise in the United 
States and worldwide, in part because of the increasing numbers of persons 
who have been chronically infected for decades, the presence of comorbid 
factors, and the longer survival of persons with advanced liver disease due 
to improved management of complications.  Although significant advances have 
been made in the development of treatments for chronic hepatitis C, their 
efficacy is not universal, and outcome of treatment is considerably affected 
by viral and host factors.  In optimally selected patients, the best current 
therapies are effective in 40 to 50 percent of cases infected with viral 
genotype 1 and in 70 to 80 percent of those infected with genotype 2 and 3. 
Thus, the focus of the RFA is to elucidate the mechanism(s) responsible for 
the acute and chronic injury caused by hepatitis C, define the factors that 
determine the course and long-term outcome of chronic infection, including a 
search for markers of fibrosis progression, and establish the basis for 
resistance to the current therapeutic regimens followed by focused efforts to 
improve the response rate with better and less toxic drugs.  Since the most 
effective way to prevent the liver disease caused by hepatitis C is through 
the development of a preventive vaccine, this RFA also supports the 
submission of applications that aim at generating a vaccine for hepatitis C.
 
RESEARCH OBJECTIVES

A recent NIH Consensus Development Conference entitled "the Management of 
Hepatitis C: 2002"(http://consensus.nih.gov/cons/116/116cdc_intro.htm) 
summarized the current knowledge about hepatitis C and made recommendations 
regarding management and therapy. The Conference also provided key 
recommendations of areas for future research studies on the epidemiology, 
natural history, pathogenesis treatment and prevention of acute and chronic 
HCV infection and its sequelae, in all affected populations.

Research Areas of Focus for this RFA

1. Characterization of the mechanisms of viral replication, chronicity of 
infection, and resistance to host-determined antiviral factors as well as 
administered antiviral agents:

Definition of the viral replication cycle from entry though production of new 
virions, including definition of key viral functions, analysis of structure-
function relationships of viral enzymes/proteins, host-cell interactions and 
mechanisms both in vitro and in vivo.  

Identification of the molecular mechanism(s)and predictor(s) of sustained 
response to antiviral therapy and characterization of mechanisms of non-
responsiveness and development of resistance to therapy.

Determination of the impact of genetics and co-factors, e.g., other viruses 
and their therapies, drug and alcohol use, metabolism errors, etc., on viral 
replication and its response to anti-viral therapies.

2. Characterization of the host's immune responses to infection:

Definition of the immunological phenomena that accompany the early natural 
history, i.e., acute infection and the first 5 years of chronic infection.

Studies on the mechanisms by which HCV evades the immune system and sets up 
chronic infection as well as studies on the mechanisms for maintenance of 
chronic infection.

Characterization of the mechanisms of protective immunity, the specific 
epitopes of HCV involved in protective immune responses, and surrogate 
markers of protective efficacy. Characterization of the factors that are 
deficient in protecting against reinfection.

Definition of protective as well as injurious cellular mediated immune-
responses and the balance between them.

Identification of immunological mechanisms associated with chronic infection, 
as well as how these are modulated by co-infections with hepatitis B virus 
(HBV), human immunodeficiency virus (HIV) and other viral agents.  

Assessment of the effects of drug and alcohol use on immunological mechanisms 
associated with recovery from hepatitis C as well as evolution to chronicity.

Characterization of the unique role of the intrahepatic immune system in 
determining the course and outcome of HCV infection, as well as the role of 
modulating factors on this system.  

3. The understanding of the pathogenic mechanisms and disease progression:

Definition of viral and host factors that contribute to the pathogenesis of 
HCV infection and to each of the stages of disease progression: acute 
infection, chronic infection, progression of fibrosis, evolution to cirrhosis 
and development of HCC.

Identification of biomarkers for disease progression, as well as non-invasive 
markers for fibrosis, cirrhosis and cancer. 

Characterization of the impact of factors such as age, race/ethnicity, and 
gender and co-factors such as HIV, immune suppression, environmental factors, 
obesity, drug and alcohol use on the establishment of the disease as well as 
the mechanisms by which they contribute to progression of chronic liver 
disease. 

Definition of the mechanisms for spontaneous recovery from chronic infection 
with HCV.

Characterization of the molecular pathogenesis of cancer secondary to HCV 
infection.

Studies on the pathogenesis of clinical and biochemical manifestations of  
both hepatic and extrahepatic disease, including cryoglobulinemia, 
glomerulonephritis, keratoconjunctivitis sicca, and arthritis.  

Studies on the molecular and cell biologic mechanisms by which hepatitis C 
causes symptoms of fatigue.

Analysis of the molecular basis for efficacy of novel drugs and active and 
passive immune-therapies.

4. The development of research resources and approaches to characterize the 
pathophysiology of HCV infection: 

Development of fully permissive tissue culture systems that supports the 
viral life cycle.

Development of characterized, representative small animal models: to support 
experimental studies of the pathogenesis of HCV from infection through 
cancer, in liver and extra-hepatic organs and to evaluate the safety and 
efficacy of proposed antiviral therapies, immunotherapies, and disease-based 
therapies and vaccines to prevent or eradicate disease including HCC.

5. The development of novel vaccines and therapies against HCV. 

Development of vaccines using conventional as well as innnovative approaches 
to inducing humoral and cellular immune responses to HCV.

Evaluation of efficacy of novel vaccines in animal models of HCV infection.

Development of molecular approaches to therapy of hepatitis C, including use 
of antisense molecules, siRNAs, and gene therapeutic approaches.

Development of small molecules with activity against HCV and related viruses 
that might be later evaluated in man.

MECHANISM OF SUPPORT
 
This RFA will use NIH R01 and R21 award mechanism(s). 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, 
R01 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 
September 2003. 

The exploratory/developmental grant (R21) mechanism provides short-duration 
support for preliminary studies of a highly speculative or innovative nature 
which are expected to yield, within the 2 year time frame, sufficient 
information upon which to base a well-planned and rigorously defined series 
of further investigations.

Projects will be limited to $100,000 direct costs per year and are limited to 
two years duration.  These grants will not be renewable; competing 
continuation applications will not be accepted. Continuation of projects 
developed under this program will be through the regular research grant 
mechanism (for example, R01).

This RFA uses just-in-time concepts. It also uses the modular budgeting 
format. (see http://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 IC(s) intend to commit approximately $6 million in FY 2003 
to fund 17 to 22 new and continuing grants in response to this RFA. An 
applicant may request a project period of up to 5 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 IC(s) provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds and the 
receipt of a sufficient number of meritorious applications. 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
o Faith-based or community-based organizations 
 
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.   

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Jose Serrano M.D., Ph.D.
Director, Liver and Biliary Programs
Division of Digestive Diseases and Nutrition
National Institute of  Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Rm. 657
Bethesda, MD 20892-5450
Telephone 301  594-8871 
FAX: 301 480-8300
Email: js362q@nih.gov

John S. Cole, III, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Suite 5000
Bethesda, MD  20892-7398
Telephone:  (301) 496-1718
FAX: 301-496-2025
Email: jc121b@nih.gov

Luiz H. Barbosa, D.V.M.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
7601 Rockledge Drive, Rm. 10146
Bethesda, MD  20817
Telephone: 301-435-0075
FAX: 301-480-0868
Email: barbosal@nih.gov 

Diane L. Lucas, Ph.D.
Program Director
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Blvd., Rm. 402
Bethesda, MD  20892-7003
Telephone: 301-443-8744
Fax: 301-594-0673
Email: dlucas@nih.gov 

Leslye D. Johnson, Ph.D.
Chief, Enteric and Hepatitis Diseases Branch
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6610 Rockledge Dr., Rm. 4015
Bethesda, MD  20892
Telephone: 301-496-7051
FAX:  301-402-1456
Email: ljohnson@niaid.nih.gov 

Tom Kresina, Ph.D. 
Deputy Director
Center on AIDS and Other Consequences of Drug Abuse 
National Institute on Drug Abuse
6001 Executive Blvd., Rm. 5200
Bethesda, MD 20892
Telephone: 301-402-1913
FAX 301 594-6566
Email: tk13v@nih.gov

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

Ms. Donna Huggins
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Rm. 711 
Bethesda, MD  20892-5456
Telephone: 301-594-8848
FAX:  301-480-3504
Email:  dh48v@nih.gov

Mr. Bill Wells
Grants Management Specialist
National Cancer Institute
6120 Executive Blvd. Rm. 243
Bethesda, MD  20892
Telephone: 301-496-8796
FAX: 301-496-8601
Email: ww14j@nih.gov

Ms. Shelia Ortiz
Grants Management Specialist
Division of Extramural Affairs
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Rm. 7171
Bethesda, MD  20817
Telephone: 301-435-0166
FAX: 301-480-3310
Email: ortizs@nih.gov 

Mr. Judy Fox
Chief, Grants Management Branch
National Institute of Alcohol Abuse and Alcoholism
6000 Executive Blvd., Suite 504
Bethesda, MD  20892-7003
Telephone: 301-443-4704
FAX: 301-443-3891
Email: jsimons@nih.gov
 
Lesia A. Norwood 
Grants Management Officer 
Grants Management Branch 
Division of Extramural Activities 
National Institute of Allergy and Infectious Disease, NIH 
6700-B Rockledge Drive, MSC 7614, Room 2117 
Bethesda, MD  20892-7614 (Express Zip 20817)
Telephone: 301-402-7146 
FAX:  301-480-3780
Email:  ln5t@nih.gov

Gary Fleming, J.D., M.A.
Chief, Grants Management Branch
National Institute on Drug Abuse/NIH/DHHS
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD  20892-9541
Telephone:  (301) 443-6710
FAX:  (301) 594-6849
Email:  gf6s@nih.gov

LETTER OF INTENT
 
Prospective applicants are asked to submit, by March 11, 2003, 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 to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch 
Division of Extramural Activities
National Institute of Diabetes, Digestive and Kidney Diseases
6707 Democracy Blvd., Rm. 752
Bethesda, MD 20892-5452 
Telephone: 301-594-8897
FAX: 301-480-3505

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.
 
SPECIFIC INSTRUCTIONS FOR R21 APPLICATIONS

All application instructions outlined in the PHS 398 application kit are to 
be followed, with the following requirements for R21 applications:  

1.  R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" 
concepts, with direct costs requested in $25,000 modules, up to the total 
direct costs limit of $100,000 per year. 

2. Although preliminary data are not required for an R21 application, they 
may be included.

3.  Sections a-d of the Research Plan of the R21 application may not exceed 
15 pages, including tables and figures.  

4.  R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to circumvent 
the page limit for the research plan.  Copies of appendix material will only 
be provided to the primary reviewers of the application and will not be 
reproduced for wider distribution.  The following materials may be included 
in the appendix:

o Up to five publications, including manuscripts (submitted or accepted for 
publication), abstracts, patents, or other printed materials directly 
relevant to the project.  These may be stapled as sets.
o Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.
o Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included within 
the 15 page limit of items a-d of the research plan
 
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 
http://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 
http://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 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, appendix material 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)
 
APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  If an application is 
received after that date, it will be returned to the applicant without 
review.
 
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 NIDDK.

Incomplete applications will be returned to the applicant without further 
consideration.  If the application is not responsive to the RFA, CSR staff 
will contact the applicant to determine whether to return the application to 
the applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the CSR in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will:

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 an 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 your 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 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 your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 
tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

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:  March 11, 2003
Application Receipt Date:  April 15, 2003
Peer Review Date:  June/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 

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 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
(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 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 Catalog of 
Federal Domestic Assistance No. 93.848 (NIDDK), 93.396 (NCI), 93.839 (NHLBI), 
93.273 (NIAAA), 93.856 (NIAID), and 93.279 (NIDA) 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) 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. 

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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