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 https://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
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:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and 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
(https://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,
https://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:
https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the
policy of the NIH that women and members of minority groups and their
sub-populations must be included in all NIH-supported clinical research
projects unless a clear and compelling justification is provided
indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43).
All investigators proposing clinical research should read the AMENDMENT
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research - Amended, October, 2001," published in the NIH Guide
for Grants and Contracts on October 9, 2001
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a
complete copy of the updated Guidelines are available at
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.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
https://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject
participants for all investigators submitting NIH proposals for
research involving human subjects. You will find this policy
announcement in the NIH Guide for Grants and Contracts Announcement,
dated June 5, 2000, at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this 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.