HEPATOTOXICITY CLINICAL RESEARCH NETWORK 
 
RELEASE DATE:  July 12, 2002 (see amendment NOT-DK-02-007)

RFA:  RFA-DK-02-033
 
National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK  
 (http://www.niddk.nih.gov/)
 
LETTER OF INTENT RECEIPT DATE:  October 11, 2002
APPLICATION RECEIPT DATE:  November 13, 2002
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Organization of the Hepatotoxicity Clinical Research Network
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 Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) invites applications for the establishment of a Clinical 
Research Network that will focus upon the elucidation of the clinical 
features and pathogenesis of drug and toxin-induced liver injury, a 
common cause of acute liver disease, morbidity and mortality. Drug and 
toxin-induced liver injury can be mild and transient, resulting merely 
in a transient elevation in serum aminotransferase levels, but also can 
be severe, protracted and even life-threatening, resulting in acute 
liver failure. Most severe adverse hepatic toxic reactions are 
unpredictable, idiosyncratic and uncommon. In addition, attribution of 
the hepatic injury to the medication can be unclear and complicated by 
the presence other possible causes of liver disease. Liver injury from 
drugs is often not predicted by pre-clinical testing in laboratory 
animals and most medications that cause severe liver disease in humans 
cause little or no hepatic injury in animals.  Furthermore, the 
increasing use of complementary and alternative medicines (CAM) has led 
to additional cases of toxin-induced liver disease that are often more 
challenging and confusing to evaluate.  Complementary medications often 
consist  of mixtures of herbs and other active compounds that may not 
be well characterized or studied.    

These features make diagnosis of drug and toxin-induced liver injury 
difficult and analysis of the causes of hepatotoxicity limited.  Yet 
drug-induced liver disease is becoming an increasing important problem 
in medicine.  With an increasing proportion of the U.S. population 
taking medications as well as CAM therapies, the clinical burden of 
hepatotoxicity is only going to worsen. Hepatotoxicity is the single, 
most common adverse drug reaction that leads to drug withdrawal and or 
refusal of approval by the Food and Drug Administration (FDA). Such 
withdrawals or refusals have enormous financial implications for the 
pharmaceutical industry and can result in the loss of availability of 
an effective therapy because of a rare occurrence of toxicity in a 
small proportion of patients who take the medication.  The intent of 
this Request for Applications (RFA) is to establish and maintain the 
infrastructure required for a Hepatotoxicity Clinical Research Network 
consisting of a group of interactive Clinical Centers (CCs) and a Data 
Coordinating Center (DCC). The primary objective of the Hepatotoxicity 
Clinical Research Network is to develop standardized instruments to 
identify and fully characterize bona fide cases of drug, CAM and toxin-
induced liver injury to allow for analysis of the epidemiology and 
clinical spectrum of hepatotoxicity and to obtain biological samples 
for study of the pathogenesis of hepatotoxicity using biochemical, 
serological and genetic techniques.  The recent development of powerful 
methods of genetic analysis and pharmacogenomics promises to provide 
important insights into the mechanisms of drug actions and drug 
toxicities. These techniques requires the availability of carefully 
defined cases of liver injury to both create and test hypothesis on 
metabolic pathways that predispose to liver injury.  This initiative 
will expand our understanding of the mechanisms of drug and toxin-
induced liver injury and provide the basis for  more effective and safe  
medical therapies. This is a one-time solicitation to support a 
feasibility phase of a Hepatotoxicity Clinical Research Network for 3 
years.
 
RESEARCH OBJECTIVES

A. Background 

Adverse drug reactions (ADRs) are an increasingly important clinical 
problem in medicine. ADRs are estimated to cause more than 100,000 
deaths per year in the United States and, therefore, rank among the ten 
most common causes of death.Up to 5% of all hospital admissions may be 
attributable to ADRs. Increased length of stay in hospital due to ADRs 
by two days can cost as much as $2500 per patient.  Drug-induced liver 
injury has been the most common type of ADR that has lead to drug 
withdrawal or refusal of approval by the FDA. In surveys of acute liver 
failure in the United States, drug-induced hepatotoxicity is the single 
leading cause.

The cause of acute liver injury due to medications, CAM therapies and 
toxins is often unknown, but in many situations genetic predisposition 
appears to play a leading role.  The role of inheritable variations in 
predisposing to ADRs was shown by the correlation between drug 
responses and inherited deficiencies of metabolic enzymes such as 
pseudocholinesterase (butyrylcholinesterase) and glucose-6-phosphate 
dehydrogenase (G6PD).Genetic polymorphisms (variants alleles present at 
least in 1% of the normal population) are a source of  genetic 
variation to  drug responses.

Although the study of drug-induced liver abnormalities has centered on 
the involvement of pharmacokinetic factors (absorption, distribution, 
metabolism and excretion) there is increasing evidence that genetic 
variation in drug targets (pharmacodynamic factors: receptors, 
channels, enzymes, immune factors) might also predispose to 
hepatotoxicity.  In addition, environmental factors such as disease, 
alcohol, smoking and diet might also be significant sources of 
variability, interacting with genetic factors. 

Thus, predisposition to hepatotoxicity is likely to be multi-factorial, 
involving genes that interact with environmental factors. In a similar 
fashion to complex diseases, heterogeneity of gene variants may also 
interact to give rise to a similar pattern of injury. These factors of 
pathogenesis, coupled with the absence of predictable animal models, 
the lack of specific diagnostic tests, the inaccuracies of scoring 
scales for drug-induced liver toxicity and the unpredictable, 
idiosyncratic nature of most drug-induced liver toxicity, has hampered 
the systematic analysis and study of hepatotoxicity.  

To begin to analyze the pathogenesis and genetic basis of drug and 
toxin-induced liver disease, it is first important to have 
unambiguously characterized cases of hepatotoxicity (phenotype) and 
carefully selected control subjects. Collection of well defined cases 
of hepatotoxicity are needed to engage in genetic profiling to 
establish phenotype-genotype correlations which might predict drug and 
toxin-induced hepatic injury. To address these issues and to determine 
the feasibility of prospectively  collecting cases of drug, CAM and 
toxin-induced liver toxicity, a Hepatotoxicity Clinical Research 
Network is proposed. The primary objective of the Network is to develop 
operational diagnostic criteria, causality assessment instruments and 
strategies to identify and collect well defined cases of toxin-induced 
liver injury in a prospective manner that will permit careful 
collection of clinical information as well as serum, DNA and 
tissue/samples for biochemical, pharmacological and genetic analyses.  

B. Research Scope  

The objective of this RFA is to establish a Hepatotoxicity Clinical 
Research Network that will accelerate advances in the understanding and 
prevention of drug, CAM and toxin-induced liver toxicities. This RFA 
will fund the development of a protocol and study design and a 
feasibility phase of the implementation of the study. The Network will 
have two phases. The first phase will be the development of working 
definitions for drug-induced liver toxicity, diagnostic algorithms, a 
causality assessment protocol or instrument, an overall study design to 
identify cases, a manual of operations for clinical data and specimen 
collection, and an adequate patient consent form. This phase will 
extend for up to 12 months from the award start date and will conclude 
when there is a full-scale study design, data collection forms, a 
manual of operations and patient consent forms that have been approved 
by local Institutional Review Boards.  

The second phase will start with the implementation of the operating 
procedures and enrollment of patients and control subjects and the 
capture of data and samples. This phase will last for 24 months.  
During this phase, patients will be identified and studied, data 
collected and serum, DNA and tissue specimens collected.  During this 
phase the NIDDK will assess the progress of the primary objectives of 
the Network and if appropriate, a second RFA will be issued to continue 
the Hepatotoxicity Clinical Research Network in a fully operational 
form, with proposals to initiate the genetic profiling studies aimed to 
determine the role of genetic variability in drug, CAM and toxin-
induced liver toxicity. 

As the Network accumulates clinical information it would provide the 
preliminary data and background for further investigator-initiated 
research in both clinical and laboratory areas of interest by providing 
reagents, specimens or opportunities to assess hypotheses on the 
pathogenesis, prevention or treatment of drug, CAM and toxin-induced 
hepatotoxicity. 

The Network can also provide a focus of learning in hepatotoxicity and 
serve as a regional and national clinical resource for advice on 
hepatotoxicity.

ORGANIZATION OF THE HEPATOTOXICITY CLINICAL RESEARCH NETWORK

The Network will consist of a data coordinating center (DCC) and as 
many as four to five clinical centers (CC) to collect cases of drug 
induced liver toxicities and appropriate controls in a standardized and 
prospective manner. 

The Hepatotoxicity Clinical Research Network will be a cooperative 
network of up to five CCs and one DCC.  CCs will be responsible for 
proposing protocols for patient and control identification and accrual, 
definition of hepatotoxicity, causality assessment and participating in 
their overall development, conducting the research, and disseminating 
research findings. 

All individual CCs will be required to participate in a cooperative and 
interactive manner with one another and with the DCC in all aspects of 
the Hepatotoxicity Clinical Research Network.  The DCC will support 
protocol development, provide sample size calculations, statistical 
advice, questionnaires, and data analysis, support manuscript 
preparation, and provide overall study coordination and quality 
assurance, including coordination of the activities of the Steering 
Committee and other standing committees.  

It is anticipated that the NIDDK  Biosample Repository 
(http://www.niddk.nih.gov/fund/repository/repository.htm) will be used 
as the specimen repository for the Network.  This  repository is not 
part of this RFA and will be funded independently.

Study Governance

A Steering Committee will be the main governing body of the 
Hepatotoxicity Clinical Research Network. At a minimum, the Steering 
Committee will be composed of  the principal investigators of each CC 
in the Network, the principal  investigator of the DCC, and the NIDDK 
Project Scientist.  The first meeting of the Steering Committee will be 
convened by the NIDDK Project Scientist with assistance from the DCC.  
The logistics and agenda of subsequent meetings will be determined by 
the Steering Committee and arranged by the DCC. By the end of the 
second meeting of the Committee, the NIDDK will name a study 
Chairperson from one of the CCs to oversee and guide Steering Committee 
activities.  The Steering Committee will meet as often as three to  
four times during the first 12 months of the study, and two to three 
times yearly thereafter.  All major scientific decisions will be 
determined by a majority vote of the Steering Committee. Each CC, the 
DCC, and the NIDDK Project Scientist will have one vote.  

The Steering Committee will have primary responsibility for the general 
organization of the Hepatotoxicity Clinical Research Network, 
finalizing common clinical protocols, facilitating the development of a 
standardized nomenclature, diagnostic criteria, histological 
definitions, and necessary components to the common database on 
patients. The Steering Committee will be responsible for the conduct 
and monitoring of studies and reporting study results.Topics for 
investigational and treatment protocols will be proposed and 
prioritized by the Steering Committee.

Other subcommittees of the Steering Committee will be established as 
necessary. For example, a Genetic Profiling Committee with additional 
expert advice could be formed to assess the different genome screening 
strategies and proposed a method suitable for future implementation. A 
Publications Committee would be helpful to facilitate the process for 
authorship selection and to supervise preparation of manuscripts. 
 
Clinical protocols must be approved by local Institutional Review 
Boards and the Hepatotoxicity Clinical Research Network Steering 
Committee before initiation. 
 
The Hepatotoxicity Clinical Research Network investigators will be  
encouraged to seek out separate funding for special projects and to 
develop collaboration with laboratory and basic research investigators 
to draw upon the resources (clinical data, serum, tissue, DNA) made 
available by the Hepatotoxicity Clinical Research Network Database.  
Any specific collaboration involving the resources of the 
Hepatotoxicity Clinical Research Network will require approval by the 
Steering Committee.

MECHANISM OF SUPPORT
 
The NIH (U01)is a cooperative agreement award mechanism in which the 
Principal Investigator retains the primary responsibility and dominant 
role for planning, directing, and executing the proposed project, with 
NIH staff being substantially involved as a partner with the Principal 
Investigator, as described under the section "Cooperative Agreement 
Terms and Conditions of Award"  

The total project period for applications submitted in response to this 
RFA will be three years.  This RFA is a one-time solicitation. Although 
not co-sponsoring this RFA, other Institutes with interest in the 
research area discussed in this RFA are the National Institute of 
General Medical Sciences (NIGMS) and the National Institute of 
Environmental Health Sciences (NIEHS). The NIGMS Pharmacogenetics 
Research Network (PGRN) wants to interact cooperatively with this 
program, which complements the aims of the PGRN.  NIGMS will encourage 
deposition of biological samples into an NIDDK Tissue Repository where 
this is feasible and matches the protocols developed here, for the 
study of mechanisms of hepatotoxicity.  The institute invites those 
considering submissions to this RFA for the Hepatotoxicity Clinical 
Research Network to consider developing collaborative connections with 
the PGRN research sites listed at www.nigms.nih.gov/pharmacogenetics, 
where significant expertise and resources are devoted to research into drug 
biotransformation and the therapeutic actions of drugs, with a goal of 
uncovering clinically significant variation in those pathways. 
Applicants are encouraged to exchange information, definitions, and 
standards with the Pharmacogenetics and Pharmacogenomics Knowledge 
Base, PharmGKB, for the ultimate purpose of making robust correlations 
between genotypes and phenotypes.  The anticipated award date is July 
1, 2003.

This RFA uses just-in-time concepts. 

FUNDS AVAILABLE 
 
A maximum of five awards for CCs and one award for a DCC will be made 
under this RFA. It is anticipated that the award for the DCC will be 
approximately $400,000 direct costs (no more than $600,000 total costs) 
per year.  The amount awarded to each CC per year will vary between 
$200,000 to $250,000 direct costs (no more than $350,000 total costs) 
per year.  The total costs for the Network will be limited to $2.25 
million total costs per year.  Because the nature and scope of the 
research proposed in response to this RFA may vary, it is anticipated 
that the size of an award will also vary in all years. Funds to support 
a NIDDK Tissue/sample repository center will be provided independently 
of this RFA.

Although the financial plans of the NIDDK 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 
applications of outstanding scientific and technical merit.  Designated 
funding levels are subject to change at any time prior to final award, 
due to unforeseen budgetary, administrative, or scientific 
developments. 
 
ELIGIBLE INSTITUTIONS

Applications may be submitted only from domestic institutions.  This geographic 
constraint will be necessary because of the need for close communication among 
members of the program, the requirement for frequent steering committee 
meetings, and site visits for data verification. For-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State and local governments, and eligible agencies of the 
federal government may apply.
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.

All current policies and requirements that govern the research grant 
programs of the National Institutes of Health (NIH) will apply to 
grants awarded under this RFA. Among the disciplines and expertise that 
may be appropriate for this program are gastroenterology, hepatology, 
internal medicine, pediatrics, epidemiology, toxicology, clinical 
pharmacology, public health and clinical database management.

A DCC will be a part of this Hepatotoxicity Clinical Research Network.  
In order to ensure that data analysis is done independently of data 
acquisition, the DCC cannot have the same Principal Investigator as a 
CC. Within the Network an institution may apply for both a CC and the 
DCC, but each must have separate principal investigators and submit a 
separate application with a specific plan of how the independent 
operation (i.e., confidentiality of the study-wide data) of each unit 
of the CC and DCC will be maintained. 
 
SPECIAL REQUIREMENTS 

A. Cooperative Agreement Terms and Conditions of Award

The cooperative agreement is an award instrument establishing an 
"assistance" relationship (in contrast to an "acquisition" 
relationship) between NIDDK and a recipient, in which substantial NIDDK 
scientific and/or programmatic involvement with the recipient is 
anticipated during performance of the activity. The NIDDK purpose is to 
support and/or stimulate the recipient"s activity by involvement in and 
facilitation of the activity in a "partner" role. The dominant role and 
prime responsibility for the planned activity reside with the awardees 
for the project as a whole, although specific tasks and activities in 
carrying out the activity will be shared among the awardees and NIDDK 
Project Scientist.  The terms and conditions below elaborate on these 
interactions and responsibilities, and the awardee agrees to these 
collaborative actions toward achieving the project objectives.  It is 
anticipated that these terms and conditions will enhance the 
relationships among the awardees and with the NIDDK Project Scientist, 
and will facilitate the successful conduct and completion of the study.  
These agreements will be in addition to those outlined in 45 CFR Parts 
74 and 92, and not in lieu of, the relevant NIH procedures for grants 
administration.  The terms will be as follows:

1) Awardees Rights and Responsibilities

The awardee(s) will have lead responsibilities in all aspects of their 
protocols, including any modification of study design, conduct of the 
study, quality control, data analysis and interpretation, preparation 
of publications, and collaboration with other investigators, unless 
otherwise provided for in these terms or by action of the Steering 
Committee. Modifications and ancillary protocols will be approved by 
the Steering Committee and the Data and Safety Monitoring Board.

Awardees will retain custody of and have primary rights to their data 
developed under these awards, subject to Government rights of access 
consistent with current HHS, PHS, and NIH policies.  The collaborative 
protocol and governance policies will call for the continued submission 
of data centrally to the DCC for a collaborative database, the 
submission of copies of the collaborative data sets to each principal 
investigator upon completion of the study, procedures for data 
analysis, reporting and publication, and procedures to protect and 
ensure the privacy of medical and genetic data (if any) and records of 
individuals.  The NIDDK Project Scientist, on behalf of the NIDDK, will 
have the same access, privileges and responsibilities regarding the 
collaborative data as the other members of the Steering Committee.

The Data Coordinating Center will be involved in collaborations with 
the NIDDK and the Clinical Centers during all phases of the study.  
Thus, the awardee is expected to work cooperatively with Clinical 
Centers and sponsoring organizations in a multicenter study  and 
oversee the implementation of and adherence to a common protocol, as 
well as assure quality control of the data collected. In addition to 
organizing and attending regular meetings, the Data Coordinating Center 
will be expected to maintain close communications with the NIDDK 
Project Scientist and the Principal Investigators of the Clinical 
Centers.
 
Awardees are encouraged to publish and to publicly release and 
disseminate results, data and other products of the study, concordant 
with the study protocol and governance and the approved plan for making 
data and materials available to the scientific community and the NIDDK. 
However, during or within three years beyond the end date of the 
project period of NIDDK support, unpublished data, unpublished results, 
data sets not previously released, or other study materials or products 
are to be made available to any third party only with the approval of 
the Steering Committee.

Support or other involvement of industry or any other third party in 
any study performed by the Network-- e.g., participation by the third 
party, involvement of project resources or citing the name of the 
project or the NIDDK support, or special access to project results, 
data, findings or resources-- may be advantageous and 
appropriate.However, except for licensing of patents or copyrights, 
support or involvement of any third party will occur only following 
notification to, and concurrence by, NIDDK.

Upon completion of the project, the DCC is expected to put all study 
intervention materials and procedure manuals into the public domain 
and/or make them available to other investigators, according to the 
approved plan for making data and materials available to the scientific 
community and the NIDDK, for the conduct of research at no charge other 
than the costs of reproduction and distribution.

2) NIDDK Staff Responsibilities

The NIDDK will name a Project Scientist from within the Division of 
Digestive Diseases and Nutrition whose function will be to assist the 
Steering Committee in carrying out the study. The Project Scientist 
will have one vote for all key study group subcommittees. The Project 
Scientist will have substantial scientific-programmatic involvement in 
quality control, interim data analysis, safety monitoring, and final 
data analysis and interpretation, preparation of publications, and 
coordination and performance monitoring. The substantial involvement by 
the Project Scientist is above and beyond the normal program 
stewardship and monitoring provided by the Program Official who is 
assigned to administer the award.

The dominant role and prime responsibility for these activities resides 
with the awardees for the project as a whole, although specific tasks 
and activities in carrying out the studies will be shared among the 
awardees and the NIDDK Project Scientist.

The NIDDK reserves the right to terminate or curtail the study (or an 
individual award) in the event of (a) failure to develop or implement a 
mutually agreeable collaborative protocol, (b) substantial shortfall in 
participant recruitment, follow-up, data reporting, quality control, or 
other major breach of the protocol,(c) substantive changes in the 
agreed-upon protocol with which NIDDK cannot concur, (d) reaching a 
major study endpoint substantially before schedule with persuasive 
statistical significance,or (e) human subject ethical issues that may 
dictate a premature termination.  

3) Collaborative Responsibilities

The Steering Committee, composed of each of the Principal Investigators 
of the DCC and the CCs, the NIDDK Project Scientist, and the Chairman 
of the Steering Committee, will be the main governing board of the 
studies.  This committee will have the primary responsibility for 
approval of the common protocols,facilitating the conduct of 
participant follow-up, monitoring completeness of data collection and 
timely transmission of data to the DCC, and reporting the study 
results.  It will also be responsible for establishing study policies 
in such areas as access to patient data, ancillary studies, 
publications and presentations, and performance standards. Each member 
of the Steering Committee will have one vote and all major scientific 
decisions will be determined by a majority vote of the Steering 
Committee.  A Chairperson will be chosen from among the Steering 
Committee members (but not the NIDDK Project Scientist or Data 
Coordinating Center Principal Investigator), or alternatively, from 
among experts in the field of liver diseases who are not participating 
directly in the study.  Subcommittees will be established on topics 
such as ancillary studies, publications and presentations, quality 
control, recruitment, protocol adherence, among others.  

Each Network CC awardee and the DCC awardee must agree to the 
governance of the study through the Steering Committee.  The Steering 
Committee voting membership shall consist of the Principal 
Investigators of the CCs and the DCC, and the NIDDK Project Scientist.  
Meetings of the Steering Committee will ordinarily be held by telephone 
conference calls or in the Washington DC Metropolitan Area. 

The NIDDK Project Scientist (and the other cited NIDDK scientists) may 
work with awardees on issues coming before the Steering Committee and, 
as appropriate, other committees, e.g., issues of recruitment, follow-
up, quality control, standards and methods, adherence to protocol, 
assessment of problems affecting the study and potential changes in the 
protocol, interim data and safety monitoring, final data analysis and 
interpretation, preparation of publications, and development of 
solutions to major problems such as insufficient participant 
enrollment.  Regardless of the number of NIH staff participating in 
technical advisory roles, the NIDDK will be limited to one vote on the 
Steering Committee.

It is anticipated that the NIDDK Biosample Repository will be used as 
the specimen repository for the Network.

4) Arbitration

Any disagreement that may arise in scientific/programmatic matters 
(within the scope of the award), between award recipients and the NIDDK 
may be brought to arbitration. An arbitration panel will be composed of 
three members--one selected by the Steering Committee (with the NIDDK 
member not voting) or by the individual awardee in the event of an 
individual disagreement, a second member selected by NIDDK, and the 
third member selected by the two prior members. This special 
arbitration procedure in no way affects the awardee"s right to appeal 
an adverse action that is otherwise subject to appeal in accordance 
with the PHS regulations at 42 CFR part 50, Subpart D and HHS 
regulation at 45 CFR part 16, or the rights of NIDDK under applicable 
statutes, regulations and terms of the award.

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:

Jose Serrano M.D., Ph.D.
Director, Liver, Biliary and Pancreas Programs
Division of  Digestive Diseases and Nutrition
National Institute of  Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Room 657, MSC 5450
BETHESDA MD 20892-5450

Phone 301  594-8871 
FAX    301 480-8300
E-mail:  js362q@nih.gov

For Courier service use:
6707 Democracy Blvd, Room 657
BETHESDA MD 20817

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Blvd.
Room 752, MSC 5452
Bethesda, MD  20892-5452
Telephone:(301) 594-8897
FAX:(301) 480-3505
Email:  fc15y@nih.gov

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

Ms. Donita Marconi
Grants Management Specialist
Division of Extramural Affairs, NIDDK
6707 Democracy Blvd.
Room  710, MSC 5456
Bethesda, MD  20892-5456
Telephone:(301) 594-8860
FAX:(301) 480-3504
Email: dm150h@nih.gov

LETTER OF INTENT

Prospective applicants are requested 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 plan for a technical assistance 
workshop, 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, and should be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch 
Division of Extramural Activities, NIDDK
6707 Democracy Blvd.
Room 752, MSC 5452
Bethesda, MD 20892-5452 
Telephone:(301) 594-8897
FAX:(301) 480-3505

SUBMITTING AN APPLICATION

A.  Submission Instructions

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.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist, and three signed, 
photocopies, in one package to:
 
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application 
must be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)

Applications must be received by the application receipt date listed in 
the heading of the RFA.  If an application is received after that date, 
it will be returned to the applicant without review. Supplemental 
documents containing significant revision or additions will not be 
accepted, unless applicants are notified by the Scientific Review 
Administrator.  

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 previously 
reviewed, but such applications must include an introduction addressing 
the previous critique.

B.  Application Requirements

1.  Clinical Center and Data Coordinating Center Applications

Applicants must describe plans to accommodate the stated program 
requirements, criteria, and staff involvement.  Applicants must 
describe plans to achieve the RESEARCH OBJECTIVES and SPECIAL 
REQUIREMENTS stated in this RFA.  In addition, applicants should 
address the following issues that are important to the successful 
development of a collaborative program:  willingness to participate on 
the Steering Committee and appropriate subcommittees, to work 
cooperatively with other members of the Steering Committee, and to 
follow the common protocols established cooperatively by the Steering 
Committee.  

The research plan should follow the instructions in the PHS 398 
application form 
(http://grants.nih.gov/grants/funding/phs398/phs398.html).  
Applications may not exceed 25 pages for sections a - d, excluding 
appendices, which may contain copies of pertinent forms or examples of 
correspondence useful for required tasks.

2.  Clinical  Center Applications 

o Each CC within the Network should propose a plan for identifying and 
characterizing cases of drug-induced liver disease in a prospective and 
defined fashion. The plan should demonstrate knowledge of 
hepatotoxicity and its pathogenesis. 

o The application should define how patients will be screened and 
identified, how hepatotoxicity will be defined, a basis for developing 
diagnostic criteria and an algorithm to define and grade causality 
between the drugs(s), CAM therapies or toxins and the hepatotoxic 
event.  

o A strategy to identify and recruit appropriate clinical controls, 
should be discussed. If necessary, strategies to reach out to 
physicians in the community  for the  identification and recruitment of 
patients and controls should be proposed.

o The CC principal investigator should define an overall structure for 
the hepatotoxicity network database and outline features and clinical 
information that should be included in the common database of patients 
and controls. The plans should include a justification for the 
necessary information to be accrued on patients. The PI should indicate 
how many patients meeting proposed criteria are likely to be identified 
at his/her CC and provide any historical data on cases of 
hepatotoxicity seen at their institution  between September 1, 2001 and  
August 31 2002.  The research plan should follow the instructions in 
the PHS 398 application form (revised 5/01, 
http://grants.nih.gov/grants/forms.htm.   

o  The CC principal investigator should propose  an  informed consent  
which  explains the collection, use and storage of samples  suitable 
for  current and future genetic analysis. The Office of Human Subjects 
Research (OHSR), NIH has developed  points to consider in the 
development of informed consent documents that include the collection 
and research use of human biological materials 
http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm. The proposed consent form 
will be considered in the elaboration of the final informed consent 
form.

o  The CC principal investigator might propose effective genetic 
profiling strategies and the samples needed for the identification of 
genetic variations associated to  hepatotoxicity events.

To promote development of a collaborative program, the issues discussed 
below need to be addressed in each application for a CC within the 
Hepatotoxicity Clinical Research Network.  

o Qualifications and experience. Applicants for CCs should provide 
information on their experience with the diagnosis and clinical 
management of acute drug-induced liver diseases.

o Study population. CC applicants should discuss the number of patients 
with possible drug-induced, CAM therapy-associated or toxin-induced 
liver toxicities seen and followed at the center who might be eligible 
to enroll. Inclusion of all eligible candidates is expected.  The 
applicant for a CC in the Network must include a description of the 
pool of potential study participants by sex, age categories, and 
ethnic/racial distribution, as well as the recruitment source. Patient 
access may be developed by establishing links with other groups outside 
the CC"s institution. If outside links are proposed, there must be a 
well described plan to link the individual CCs with community health 
care providers such as HMOs, clinics, or private practice physicians to 
ensure adequate numbers patients for clinical studies of therapeutic 
agents and management strategies. Documentation with letters of support 
are needed in any consortium arrangement.

o Applicants for a CC from institutions that have a General Clinical 
Research Center (GCRC) funded by the NIH National Center for Research 
Resources are encouraged to identify the GCRC as a resource for 
conducting the proposed research. If so, a letter of agreement from 
either the GCRC Project Coordinator or Principal Investigator should be 
included with the application.    

o Willingness to participate in a Hepatotoxicity Clinical Research 
Network.  The principal investigator should state his/her general 
support of collaborative research and interaction with the NIDDK, the 
other CCs, and the DCC through the Network concept.  Applicants should 
discuss their willingness, and that of the institutions involved, to 
pursue a per patient basis (capitation) of operational costs for each 
protocol. CCs must be able to interact with the DCC to transmit and 
edit data and should discuss their capability to participate in a 
distributed data entry system.

3.  Applications for a DCC:

A separate complete application is required from institutions applying 
to be the DCC for the Hepatotoxicity Clinical Research Network. 
Applicants for the DCC component are not required to be a Clinical 
Center within the study, though applicants for Clinical Centers sites 
may also submit an application to be the DCC. 

The Data Coordinating Center, collects, organizes and maintains all the 
clinical information (clinical data, laboratory and other diagnostics). 
The Database should be accurate, stable, and comprehensive. The 
Database must be flexible, adaptable, and responsive to the changing 
needs of the scientific community. The interface must be simple and 
easy to understand while the output should allow easy access to 
different levels of information.  This output should include Web-based 
links to other databases to facilitate the rapid exploration of 
additional information.

Applicants must address the following responsibilities of the DCC:  

o Participation in the design of the final protocol and development of 
the manual of operation, data collection forms, and questionnaires, 

o Development and implementation of systems for communication among 
Steering Committee members, and among study sites, 

o Data collection, editing, processing, analysis, and reporting, 

o Monitoring of adherence to the protocol and of data quality, 

o  Establishment of procedures that insure the safety and 
confidentiality of all records

The following specific criteria should be addressed:.  

o Qualifications and experience.  The applicant for a DCC must 
demonstrate experience in the area of in coordinating multi-center 
clinical and epidemiological studies in all phases: protocol and manual 
of operations development, staff training in study procedures, research 
instrument development, data collection and management, quality 
assurance, data analysis, distributed data entry, electronic 
communications, administrative management and coordination. Specific 
experience in coordinating or monitoring studies of liver disease or  
toxicities  is not required, but the applicant may wish to include a 
hepatologist with expertise in the area of hepatotoxicity in the 
application as a key collaborator and advisor.

o Study design and management. DCC applications should discuss the 
applicant"s familiarity and experience with various aspects of study 
design that would be important in developing clinical studies, for 
example: eligibility criteria, important considerations for making 
sample size and power calculations, methods and frequency of data 
collection and entry, monitoring accuracy of data collection, quality 
control procedures and plans for statistical analysis. 

o The applicant for the DCC should delineate how serum, DNA and tissue 
specimens will be handled. Laboratories responsible to the DCC will 
manage specimens and laboratory studies as required by the Steering 
Committee.  The costs of performing specific laboratory tests will be 
budgeted as a part of  the per patient costs of each CC. The costs of 
specimen shipment as well as laboratory data acquisition and management 
will be a part of the budget of the DCC.  The NIDDK Biosample 
Repository (http://www.niddk.nih.gov/fund/repository/repository.htm)  
will be used as the specimen repository for the Network and its funding 
is not included in this RFA. Estimated shipping and handling costs of 
$25,000 for specimens should be included in the budget of DCC. 

o The application should discuss strategies for the future acquisition 
of genetic profiling data to be incorporated in the centralized 
Database  and the annotation methods used to  perform computational 
analyses and extraction of information from the literature regarding 
the clinical events as well as include information on genes, cDNAs, 
SNPs protein sequences.

C.  Budget and Related Issues

Applicants should complete the budget information as directed in the 
PHS 398 (5/01 rev) application form. The applicants shall not submit 
budget information in modular format and cost projections should 
adequately correspond to the scope of research proposed.

Applications for CCs:
 
CCs should consider the following additional issues regarding budgets.  
The underlying concept of the Hepatotoxicity Clinical Research Network 
is that a core effort is essential to maintain the infrastructure 
required to perform screening identification  and characterization of 
bona fide cases of  drug-induced liver toxicity, possibly from several 
regional institutions.  Based on this approach, it is estimated that 
the individual CCs will require a minimum level of effort to sustain 
the organizational aspects of the Network.  Therefore, individual CCs 
should submit requests for a CORE BUDGET not to exceed $150,000 total 
costs per year.  It is anticipated that this core budget will cover a 
minimum twenty percent effort for the investigator (principal and any 
co-investigators), fifty percent  effort for a clinical  coordinator 
and a small percent effort for other key personnel (assistants, 
secretary) to collect core study data. Tasks conducted by these 
personnel include study recruitment, data entry, specimen shipment and 
quality control.

Equipment costs, such as computers for data-entry and printers, should 
be included. Include travel costs for two people to attend three one 
and one-half day Hepatotoxicity Clinical Research Network Steering 
Committee meetings a year in Bethesda, MD (three to four  in the first 
year). These costs should be justified appropriately in budgets and may 
be distributed into subcontracts. Escalation is allowed at three 
percent for future years.

In addition to the core budget, each CC will be provided funds for 
implementation of the hepatotoxicity diagnostic criteria. This amount 
should be placed in the patient enrollment category.  Patient care 
costs may be escalated at three percent for future years. Once the CC 
has been awarded and the Hepatotoxicity Clinical Research Network 
Steering Committee members have been selected, a common diagnostic 
protocol will be established and funds will be allocated to CC on a per 
patient enrolled basis. Allowable total costs for each CC (core costs, 
costs per patient to conduct the protocols, and indirect costs) will 
vary.  However, the maximum total costs for each Clinical Center in the 
Network to implement the protocols are $350,000 per year.  

The CCs are requested to present the following information:

o For each year, each CC should include the core budget costs (not to 
exceed $150,000 total costs) and patient enrollment costs.  Estimated 
protocol implementation costs for Year 1 should be based per patient 
for conducting each protocol.

The budget for each diagnostic protocol should be developed on a cost 
per patient basis and include all direct and any applicable facilities 
and administrative costs. Laboratory tests should be part of the per 
patient cost of conducting a protocol.  A budget based on the costs per 
patient for recruiting and maintaining the specified number of subjects 
at the applicant"s center should be included for each protocol. 

Note that ongoing annual budgets for protocols will be based on the 
diagnostic algorithm approved by the Hepatotoxicity Clinical Research 
Network Steering Committee and will be funded through a per patient 
basis (capitation) funding mechanism.  The individual CCs will be 
expected to project patient enrollment for a specific protocol during a 
specified time frame, continuation and level of funding for each CC 
will be based on actual recruitment and overall performance. 

The Hepatotoxicity Clinical Research Network awards will be subject to 
administrative review annually.

DCC Budget:

Applicants for the DCC should prepare budgets for three 12-month 
periods (not to exceed600,000 total cost per year)that roughly 
correspond with the standard coordinating center responsibilities 
outlined in other sections of this RFA.  In the first year, DCC 
applicants should include all costs associated with the organization of 
all administrative aspects of the Hepatotoxicity Clinical Research 
Network to be developed.

The DCC will be subject to administrative review annually. 

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED 
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.
 
PEER REVIEW PROCESS  
 
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 NIDDK 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 NDDK National Advisory Council.
 
REVIEW CRITERIA

A. Criteria for CCs and for DCC

In the written comments reviewers will be asked to evaluate the 
following aspects of the application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals.  Each of these criteria will be addressed and 
considered in assigning the overall score, weighting them as 
appropriate for each application.  Note that 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.

o Significance:  Does the application  address the problem outlined in 
the RFA.  If the aims of the applications 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?  

o Approach: Are the conceptual framework, design, and methods 
adequately developed, well integrated, and appropriate to the aims of 
the project? Does the applicant acknowledge potential problem areas and 
consider alternative tactics?

Since the final study design will be developed collaboratively by the 
Steering Committee, the peer review group will focus on evidence that 
the applicant has carefully thought about the issues involved and 
possesses the knowledge necessary to contribute meaningfully to the 
final design, including understanding of the scientific, ethical, and 
practical issues underlying the proposed study.

o Innovation: Does the project employ novel concepts, approaches or 
methods?  Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 
technologies?

o 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)?  Does the Principal Investigator  have experience in working 
collaboratively to carry out a clinical study or standard protocol? Is 
the Investigator willing to work cooperatively on the Steering 
Committee to develop and follow a unified protocol?

o Environment: Does the scientific environment in which the work will 
be done contribute to the probability of success?  Is there evidence of 
institutional support and commitment for the proposed program?

B.  Review of CC applicants also will be based on the following 
specific criteria:

o Scientific and technical merit of the proposed approach to managing 
the requirements of the study as outlined in the RFA.

o Staff Qualifications: Specific competence and previous experience of 
professional, technical, and administrative staff relevant to the 
operation of a CC in the proposed study. 

o Recruitment Capability: Evidence of successful experience in 
recruitment and retention of research subjects in multicenter clinical 
trials. This includes documentation of access to an adequate patient 
population for the proposed protocols. 

o Resources: Documented adequacy of the proposed facility, space, and 
resources for the work proposed. This includes evidence of an 
appropriate organizational structure and institutional support.

o Data and Sample Management: Adequacy of plans to ensure accurate 
collection and timely transmission of study data to the DCC and patient 
samples to the specimen repository. Documented experience in meticulous 
and expeditious handling of laboratory specimens and study data.

o Knowledge of Problems: Demonstrable knowledge of the potential 
problems associated with the conduct of this study and possible 
solutions.

o Cooperative Experience: Evidence of prior experience in working 
collaboratively in carrying out a developed study protocol.  Evidence 
of willingness to work cooperatively in this study.

o Collaborations between CCs within the Hepatotoxicity Research 
Network: For those applicants that propose collaborative efforts 
between two groups to form a single CC, additional factors to be 
considered would include the advantages of the collaboration in terms 
of cost, recruitment, or facilities, the commitment of the participants 
to the collaboration, and the adequacy of plans to coordinate efforts.

C. Review of DCC  applicants also will be based on the following:

Considerations for the review of applications for the DCC for the 
Hepatotoxicity Research Network include the following issues:

o Understanding of the scientific, statistical, logistical, and 
technical issues underlying multi-center studies, including issues 
relating to treatment and management of liver disease, and knowledge 
necessary to resume a leadership role in the area of study design, 
statistics, logistics, data acquisition and management, handling of 
laboratory specimens, quality control, data analysis, and network 
coordination.

o Evaluation of the comprehensiveness, stability, adaptability  and 
accessibility of the database. The schema used by the database should 
be described along with the capacity of the database to expand to 
accommodate an increase in database entries and information.

o Evaluation of plans for a user support service to provide 
consultation and technical assistance in the use of the database.

o Evaluation of the plans for  future  inclusion of genetic information 
(genes, cDNAs, SNPs protein sequences) and annotation. Annotation 
methods should include computational analyses and extraction of 
information from the literature 

o Plans to coordinate with related databases, including agreeing on 
controlled vocabularies and common data exchange formats. The output 
should include links to information in related databases. 

o Adequacy of the proposed plans for acquisition, transfer, management, 
and analysis of data, quality control of data collection and 
monitoring, and overall coordination of the Hepatotoxicity Research 
Network activities.

o The expertise, training, and experience of the investigators and 
staff, including the administrative abilities of the Principal 
Investigator and co-investigators, and the time they plan to devote to 
the effective coordination of the Hepatotoxicity Clinical Research 
Network.

o The administrative, supervisory, and collaborative arrangements for 
achieving the goals of the program, including willingness to cooperate 
with the principal investigator of the CCs and the NIDDK.

o Facilities, equipment, and organizational structure to effectively 
coordinate the Hepatotoxicity Research Network activities.

o Appropriateness of the budget for the work proposed.

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups as appropriate for the scientific goals of the research.Plans 
for the recruitment and retention of subjects will also be evaluated.

o The reasonableness of the proposed budget and duration in relation to 
the proposed research

o The adequacy of the proposed protection for humans or the 
environment, to the extent they may be adversely affected by the 
project proposed in the application. The initial review group will also 
examine the safety of the research environment.  

Applicants are encouraged to submit and describe their own ideas on how 
best to meet the goals of the Hepatotoxicity Research Network, but they 
are expected to address issues identified under APPLICATION PROCEDURES 
of the RFA. Applications will be judged primarily on the scientific 
quality of the application, however, the scientific merit of the 
proposed research plan will not be the sole criterion for selection of 
a CC. Further considerations for the review include: access to patients 
including children and minority individuals, multi disciplinary nature 
of the proposed studies, the discussion of considerations relevant to 
this RFA, and a demonstrated willingness on the part of the 
investigators to work as part of the Hepatotoxicity Research Network 
and with the NIDDK Project Scientist.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:      October 11, 2002
Application Receipt Date:           November 13, 2002
Peer Review Date:                   March 2003
Council Review:                     May 2003
Earliest Anticipated Start Date:    July 2003

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific and technical merit of the application for a Clinical 
Center or a Data Coordinating Center.

o The multi-disciplinary nature of the proposed studies (CC).

o Demonstration of expertise to manage, design and coordinate 
multicenter clinical trials that include handling and storage of 
laboratory specimens 
(DCC).

o The multi-disciplinary nature of the proposed studies.

o The quality of response to the special requirements stated in this 
RFA. 

o Relevance to the overall programmatic balance and priorities of the 
NIDDK and sufficient compatibility of features proposed in the research 
plan and qualifications of the investigators to make a collaborative 
program within the Hepatotoxicity Research Network a reasonable 
likelihood. 

o Availability of funds

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.

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

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

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

HEALTHY PEOPLE 2010:The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas.  This RFA, Clinical Research Network in Drug induced liver 
toxicity  is related to the priority areas of Medical Product Safety.  
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.  Awards are made under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public 
Law 99-158, 42 USC 241 and 285) and administered under PHS grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This 
program is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to 
provide a smoke-free workplace and promote the non-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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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