STUDY OF VIRAL RESISTANCE TO ANTIVIRAL THERAPY OF CHRONIC HEPATITIS C 
(VIRAHEP-C): CLINICAL CENTERS, DATA COORDINATING CENTER, ANCILLARY STUDIES

Release Date:  September 6, 2000

RFA:  DK-01-007

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov/)

Letter of Intent Receipt Date:  November 15, 2000
Application Receipt Date:       December 15, 2000

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) invites cooperative agreement applications from investigators 
to design and implement a multicenter, clinical trial to study viral 
resistance to interferon alpha therapy in patients with chronic 
hepatitis C, specifically focusing upon African Americans among whom 
such viral resistance is common.  The study will examine several issues 
surrounding viral resistance to interferon in hepatitis C, including 
the following specific clinical research questions: 1) What are the 
differences in sustained virological response rates to optimal 
combination antiviral therapy of hepatitis C among African Americans in 
comparison to non-Hispanic whites?  2) For both racial groups, what 
clinical, biochemical, or virological factors are most reliable in 
predicting a beneficial long-term response to antiviral therapy?  3) 
Does a sustained response correlate with the decrease in hepatitis C 
viral (HCV) RNA in serum that occurs within the first few days of 
antiviral therapy (viral kinetics)?  4) Can monitoring of HCV RNA 
levels reliably predict a lack of sustained virological response to 
interferon-based antiviral therapy? 5) What are the virological, 
cellular, immunological and genetic factors that underlie the response 
to antiviral therapy in hepatitis C? 

The Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis 
C (Virahep-C) is expected to recruit 400 patients at eight 
geographically distributed Clinical Centers over a one-year period with 
two additional years of treatment and follow-up.  The 400 patients will 
include approximately equal numbers of African Americans and non-
Hispanic whites all of whom have chronic hepatitis C and are infected 
with HCV genotype 1. Patients will undergo an extensive initial medical 
evaluation including liver biopsy.  All patients will then receive what 
is judged to be the current optimal therapy of chronic hepatitis C.  
Special emphasis will be placed on determination of the viral kinetics 
of HCV RNA during the first four weeks of treatment and laboratory 
analysis of virological and host factors that might explain the 
diversity in clinical outcome of therapy of hepatitis C. 

The study will be coordinated by a Data Coordinating Center and will be 
complemented by three to four ancillary studies on the biological basis 
of antiviral resistance in hepatitis C.  This RFA requests three 
separate types of applications: for a single Data Coordinating Center, 
for eight Clinical Centers, and for three to four ancillary studies on 
serum, tissue or cells from patients participating in this study.     

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 Request for 
Applications (RFA), Study of Viral Resistance to Antiviral Therapy of 
Chronic Hepatitis C (Virahep-C) is related to one or more of the 
priority areas. Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit domestic 
organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and 
eligible agencies of the Federal government.  Foreign institutions are 
not eligible for this award. Racial/ethnic minority individuals, women, 
and persons with disabilities are encouraged to apply as Principal 
Investigators.

For Clinical Center applications, the expertise appropriate for this 
research program includes knowledge of the clinical and virological 
aspects of hepatitis C and liver disease, expertise in the conduct of 
clinical investigation, and experience in the conduct of multicenter 
clinical trials.  Clinical centers must also have a demonstrated 
experience in enrolling and retaining African American subjects in 
clinical trials.
 
For Data Coordinating Center applications, the expertise appropriate 
for this research program includes biostatistics, knowledge of the 
clinical and epidemiological aspects of hepatitis C and liver disease 
and expertise in data coordination and analysis for multi-center 
clinical trials.

For Ancillary Studies applications, the expertise appropriate for this 
research program includes knowledge of the virology or immunology of 
hepatitis C or of cellular and molecular biology of liver disease or 
the interferon system.  

A single institution may apply for more than one component of the RFA, 
such as for a Clinical Center, the Data Coordinating Center and one or 
more Ancillary Study awards.  However, separate applications are 
required for each component Center and for each separate Ancillary 
Study, if applying for more than one.  In addition, a specific plan of 
how the independent operation of each unit will be maintained is 
required in each application.  Each study should have a separate 
principal investigator and must be administratively and fiscally 
distinct.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this 
project will be the cooperative agreement (U01), which is an assistance 
mechanism rather than an acquisition mechanism.  Under the cooperative 
agreement, the NIDDK’s purpose is to support and/or stimulate the 
recipient’s activity by collaborating and otherwise working jointly 
with the award recipient in a partnership role, but it is not to assume 
direction, prime responsibility, or a dominant role in the activity.  
Consistent with this concept, the tasks and activities in carrying out 
the studies will be shared among the awardees and the NIDDK Project 
Scientist.  Details of the responsibilities, relationships and 
governance of this study funded under a cooperative agreement are 
discussed under the section “Terms and Conditions of Award.”  Except as 
otherwise stated in this announcement, awards will be administered 
under NIH grants policy as stated in the NIH Grants Policy Statement.
 
Applications from institutions that have a General Clinical Research 
Center (GCRC) funded by the NIH National Center for Research Resources 
are encouraged and should identify the GCRC as a resource for 
conducting the proposed research.  In such a case, a letter of 
agreement from either the GCRC program director or Principal 
Investigator should be included with the application.  

The total project period for applications submitted in response to this 
RFA will be five years.  The first year will be used to design the 
trial and develop a detailed protocol and manual of operations for the 
study. Patients will be enrolled during the second year and treated for 
up to one year.  A twelve month follow up period after therapy will be 
needed.  There will then be a twelve month final period of data 
analysis and close out of the clinical trial.  
 
The anticipated award date is July 1, 2001.  It is anticipated that the 
awards for the Clinical Centers will average approximately $150,000 in 
direct costs per year in Fiscal Year (FY) 2001 during the planning 
phase.  Direct costs at the Clinical Centers are expected to gradually 
increase as the protocol is implemented, to a maximum of $250,000 per 
center (direct costs) by the end of recruitment.  In post-treatment 
years, this level of effort is anticipated to decline to approximately 
$150,000 in direct costs, in keeping with reduced Clinical Center 
effort after treatment has been completed and patients are followed on 
no therapy.   

The award for the Data Coordinating Center is anticipated to be 
$700,000 (direct costs) during the planning phase.  Direct costs are 
expected to gradually increase as the protocol is implemented to a 
maximum of approximately $1,000,000 (direct costs) per year for the 
Data Coordinating Center activities and another $500,000 in 
subcontracts for a serum repository and virological testing laboratory. 
In the final analysis year, the level of effort is anticipated to 
decline to approximately $700,000 in direct costs, in keeping with 
reduced effort after treatment and follow up have been completed.  
Funds to support the subcontract aspects of the trial will largely 
cease during the final year of closeout, data analysis, and reporting.

The awards for the Ancillary Studies are anticipated to average 
approximately $100,000 in direct costs per year in Fiscal Year (FY) 
2001, during the planning phase while the collaborations and protocol 
are being developed.  Direct costs are expected to gradually increase 
as the protocol is implemented, to a maximum of $250,000 (direct costs) 
by the end of the enrollment and during the years of treatment and 
follow up.     

Because the nature and scope of the research proposed in Ancillary 
Studies in response to this RFA may vary, it is anticipated that the 
sizes of awards will vary also.

Awards and level of support depend upon receipt of a sufficient number 
of applications of high scientific merit.  Although this program is 
provided for in the financial plans of the NIDDK, awards pursuant to 
this RFA are contingent upon the availability of funds for this 
purpose.

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
R01 applications and be reviewed according to the customary peer review 
procedures.

FUNDS AVAILABLE

For FY 2001, during planning of the trial, $4 million (total costs) 
will be committed to fund the Data Coordinating Center, the Clinical 
Centers, and the Ancillary Study applications submitted in response to 
this RFA.  It is anticipated that one award will be made for the Data 
Coordinating Center, eight for Clinical Centers, and three to four for 
Ancillary Studies.  

NIDDK also has planned for the projected fiscal requirements of the 
study beyond FY 2001, consistent with the direct costs of Clinical 
Centers, the Data Coordinating Center and the Ancillary Studies as 
described above.

The National Institute of Allergy and Infectious Diseases (NIAID) also 
funds research on therapy and viral resistance in hepatitis C and may 
provide funding for applications that are appropriate to areas of 
interest and focus to NIAID.  

Although this program is provided for in the financial plans of the 
NIDDK, the awards pursuant to this RFA are also contingent upon the 
availability of funds and receipt of a sufficient number of 
applications of outstanding scientific and technical merit.

RESEARCH OBJECTIVES

A. Background

Population based studies indicate that 1.8% of the United States 
population have antibody to hepatitis C virus (anti-HCV) and that 
three-fourths of these or approximately 2.7 million Americans are 
chronically infected with this virus.  Rates of anti-HCV are higher 
among African Americans (3.2%) than among the non-Hispanic white 
population (1.8%).  The major long-term consequences of hepatitis C are 
the development of chronic liver disease, cirrhosis and hepatocellular 
carcinoma.  These complications of chronic hepatitis C are also more 
common among African Americans than Caucasians.   At present, chronic 
hepatitis C is estimated to cause 10,000 deaths from end-stage liver 
disease yearly in the United States.  Hepatitis C is also the single 
major reason for liver transplantation.  Furthermore, HCV infection 
accounts for at least half of cases of liver cancer.  Distressingly, 
the mortality rates for hepatitis C-related cirrhosis, the proportions 
of liver transplantations done for hepatitis C, and the incidence of 
hepatocellular carcinoma due to HCV all appear to be increasing, and 
these increases are expected to disproportionally affect African 
Americans.  Mathematical models based upon the age-specific frequency 
of anti-HCV in the population and the natural history of the disease 
suggest that deaths from this disease may double or triple in the next 
decade.  
  
At present, therapies for hepatitis C are problematical.  Alpha 
interferon was first shown to have beneficial effects in this disease 
in the middle 1980s and was approved for use as therapy of hepatitis C 
in the United States in 1991. Yet, a six- or twelve-month course of 
alpha interferon led to sustained remissions in only a minority of 
patients (6-16%).  In 1998, several large randomized controlled trials 
showed that a 24- or 48-week course of the combination of alpha 
interferon with the oral antiviral agent ribavirin led to long-term 
sustained loss of hepatitis C viral (HCV) RNA from the serum and 
improvement in the underlying liver disease in 35-40% of patients.  
Combination therapy was approved for use in chronic hepatitis C in 
1998.  Despite its promise, combination therapy with interferon and 
ribavirin remains difficult and far from satisfactory.  Therapy is 
expensive and associated with many side effects that often limit 
therapy and make therapy contraindicated in some patients.  
Furthermore, even the optimal regimen is effective in less than half of 
patients.

Attempts have been made to identify factors that predict a response to 
interferon and ribavirin therapy.  Retrospective analyses of trials have 
identified that the most important predictors of a higher rate of 
response are viral factors: HCV genotype (rates of response are higher 
with genotypes 2 and 3 than with genotype 1) and viral levels (rates of 
response are higher with lower initial levels of serum HCV RNA).  
Other, less reliable predictors of a higher rate of response are young 
age, female sex and absence of severe fibrosis on pre-treatment liver 
biopsy.  Algorithms using these factors have been created to provide an 
estimate of a response to treatment for individual patients.  
Unfortunately, the large clinical trials of antiviral therapy in 
hepatitis C have been carried out largely in non-Hispanic white 
populations, and the applicability of these findings or any such 
algorithm to minority populations in the United States is unclear.
 
Recently, retrospective analyses of large clinical trials have shown 
that rates of response to interferon differ by race or ethnicity.  
Thus, in virtually all clinical trials that have been analyzed, African 
American patients have had a lower rate of response to alpha interferon 
therapy than Caucasian, Hispanic white and Asian patients.  Indeed, in 
several studies, the long-term response rate to interferon monotherapy 
among African American patients has been nil. The combination of alpha 
interferon with ribavirin led to higher response rates than monotherapy 
in African Americans, but the rates with combination therapy were still 
one-third to one-half those observed in Caucasians.  

The reasons for the relative lack of response to antiviral therapy 
among African Americans are not clear.  Preliminary studies indicate 
that part of the poor response rate among African Americans relates to 
viral genotype.  Patients infected with HCV genotype 1 (either 1a or 
1b) typically have a two- to threefold lower rate of response to 
interferon or combination therapy than patients infected with genotypes 
2 or 3.   While genotype 1 accounts for 70% of HCV infections among 
Caucasians, it is found in over 90% of cases among African Americans. 

Nevertheless, genotype does not appear to account completely for the 
lack of response to antiviral therapy among African Americans.  
Controlling for genotype, African Americans still have a lower rate of 
response to interferon therapy than Caucasians with hepatitis C.  
Racial differences were most clearly evident from analyses of serial 
determinations of HCV RNA levels during antiviral therapy.  African 
Americans often demonstrated minimal or no decrease in viral levels 
with interferon treatment, even when doses were escalated to maximally 
tolerated levels.  These findings suggest that the viral strains of HCV 
that are commonly found among African Americans with hepatitis C are 
more resistant to antiviral therapy using interferon or the combination 
of interferon and ribavirin.  While previous studies have indicated a 
lower response rate among African Americans with hepatitis C, these 
studies have had several shortcomings.  The major problem was that 
virtually all large clinical trials of antiviral therapy in hepatitis C 
have included too few African Americans for meaningful analysis.  Thus, 
African Americans who are estimated to represent 22% of persons with 
chronic hepatitis C, represented 5% or less of patients enrolled in 
many of these large published trials.  The lack of sufficient numbers 
of African American patients makes it difficult to accurately estimate 
response rates and predictors of response in this population.   
Furthermore, the causes of the lack of response and relative resistance 
to interferon action cannot be adequately investigated without 
inclusion of these populations.  

B. Research Goal and Scope of the Activity

The goal of this RFA is to select a Data Coordinating Center, eight 
Clinical Centers, and three to four Ancillary Studies to participate in 
planning and implementing a multicenter clinical trial and clinical 
investigation into combination antiviral therapy of patients with 
chronic hepatitis C infected with HCV genotype 1. 

The primary goal of this study will be to establish the response rates 
of optimal antiviral therapy among African Americans in comparison to 
non-Hispanic whites and to evaluate predictive factors of response.  
The results of this study should help in clinical management of 
patients, in providing accurate estimates of likelihood of response, as 
well as providing insights and reagents and materials for better 
investigation of the nature of resistance to interferon based antiviral 
therapy of hepatitis C.

Several anticipated features of this study are cited below so that 
applicants have a common understanding of factors necessary for the 
collaborative effort.

All patients will undergo a careful medical evaluation and liver biopsy 
before therapy along with extensive characterization of hepatitis C 
virology.  Patients will then start therapy with what is considered at 
the time of this trial the optimal antiviral therapy for hepatitis C 
(genotype 1).  While it is impossible to predict exactly what this 
regimen will be, it is likely to be the combination of alpha interferon 
(either regular or pegylated interferon) with ribavirin given for 48 
weeks.  Initially, patients will be followed with regular 
determinations of HCV RNA levels to characterize the early viral 
kinetics during therapy.  Thereafter, patients will have at least 
monthly determinations of HCV RNA presence (qualitative assays) and/or 
level (quantitative assays).  Symptoms and side effects will be 
carefully and objectively analyzed.  After stopping therapy, patients 
will be followed for one year to establish whether responses were 
sustained.  The exact details of the protocol will be established by 
the steering committee of this trial whose composition is defined 
below.  

A total of 400 patients will be enrolled into this trial, approximately 
50 at each of 8 Clinical Centers.  An equal number of African American 
and non-Hispanic whites will be enrolled averaged across all Centers.  
Thus, a total of 200 African Americans and 200 Caucasian patients will 
be enrolled.   Applicants for the Clinical Centers and Data 
Coordinating Center should propose a detailed design that follows the 
outline given above. Applicants for the Ancillary Studies should 
propose a research plan that is based upon samples and data from the 
clinical study and that helps to elucidate underlying mechanisms of 
antiviral responses to therapy.

This trial will aim to achieve the following five major research 
objectives. 

(1) Establish rates of sustained virological response to a 48-week 
course of combination antiviral therapy among African-Americans along 
with a comparable rate in non-Hispanic whites.  The sample size of this 
trial is based upon this goal.  The estimated rate of sustained 
virological response from previous trials of a 48 week course of 
combination therapy in Caucasian patients with genotype 1 is 30%.  It 
is reasonable to estimate that the response rate among African 
Americans is 15%, approximately half of that among whites.  To 
demonstrate a difference of 50% in African Americans with a p value of 
0.05 and a power of 0.80 would require sample sizes of 176 per group.  
This study should also establish rates of end-of-treatment virological 
response as well as sustained and end-of-treatment biochemical 
responses.     

(2) Establish what factors are most predictive of a response to 
combination therapy in each of the two racial groups of patients 
infected with genotype 1 HCV.  Thus, age, sex, hepatic fibrosis, viral 
level, duration of disease, and other factors have been identified as 
important predictors of a response in Caucasians with hepatitis C who 
are treated with alpha interferon based therapy.  The reliability of 
these predictive factors in African American subjects needs to be 
assessed and how these factors differ from those among whites.  Special 
attention will be focused upon the role of initial viral levels of HCV 
RNA and to developing a simple, clinically useful algorithm that could 
be used to advise patients on the likelihood of a response.

(3) Establish the frequency of different patterns of viral kinetics in 
response to antiviral therapy in the two racial groups of patients.  In 
preliminary analyses, measurements of HCV RNA levels after a few days, 
weeks or a month of therapy with combination alpha interferon and 
ribavirin clearly separates patients who will have a virological 
response by the end of treatment and possibly a high likelihood of a 
sustained virological response (that persists for at least six months 
after stopping all therapy).  The frequency of different levels of 
response (log decreases in HCV RNA levels at different times) in 
different racial groups and the predictive factors for the different 
patterns of response require definition.  This study should also define 
the minimal number and timing of points that will accurately reflect 
viral kinetic responses to therapy.

(4) Establish whether early viral kinetics accurately reflect the 
eventual outcome of therapy and can be used clinically to guide 
management of individual patients being treated.  Thus, lack of 
decrease or a minimal decrease in HCV RNA levels during the first weeks 
or month of therapy may reliably demonstrate that therapy is 
ineffective and futile and can be terminated early.  A reliable guide 
to early termination of therapy would clearly be helpful in reducing 
costs and side effects of treatment in patients who have no chance for 
a beneficial response.  The reliability of these measurements needs to 
be assessed in the two racial groups. These studies will help to define 
the clinical usefulness of measuring HCV RNA levels during antiviral 
therapy. 

(5) Develop and test research hypotheses regarding the viral or host 
factors that determine virological and biochemical responses to 
combination therapy of hepatitis C.   This goal should be the major 
focus of the Ancillary Studies and need not be dealt with in detail in 
applications for the Data Coordinating Center or the Clinical Centers.  
Thus, the lack of a virological response to optimal antiviral therapy 
in hepatitis C requires investigation using virological, immunological, 
genetic and cellular biological methods.  To aid in this goal, 
applications for Ancillary Studies on virological, immunological and 
host genetic factors are requested.  

3. Study Components

(a) Clinical Centers

Clinical Centers in the Virahep-C trial will be expected to:

o Design the study protocol and help write the manual of operations.

o Develop operational plans for the Recruitment phase and the Treatment 
and Follow-up phase of the trial in close collaboration with the 
communities they serve. 

o Participate in a full-scale clinical trial.

o Participate in ancillary studies of trial subjects, as appropriate.

A Clinical Center is an institution that is actively involved in the 
recruitment, evaluation, treatment, and follow-up of study 
participants.  For this trial it will consist of a core team of 
clinical investigators who are skilled in delivery of antiviral therapy 
of patients with chronic hepatitis C and have experience in 
collaborative clinical investigation.  

(b) Data Coordinating Center

The Data Coordinating Center will participate with the Clinical Centers 
and Institute staff during the entire clinical trial.  The Data 
Coordinating Center will have primary responsibility for the 
biostatistical analyses and data management aspects of the trial.  It 
also will manage the central Virological Testing Laboratory and 
Serum/Tissue Repository of this trial through a subcontract.  The 
Coordinating Center will also arrange and manage the interactions of 
the Ancillary Study investigators with the Clinical Centers.  The Data 
Coordinating Center will also be responsible for arrangements made with 
industry or sponsors of the medications to be used and any virological 
testing reagents. The Coordinating Center will also be responsible for 
drug distribution and developing contracts to facilitate the shipping 
of specimens.  Preparation of interim and final reports will be 
collaborative undertakings by all participating Centers, the Data 
Coordinating Center, and the NIDDK.

The Data Coordinating Center will have a central role in statistical 
aspects of the trial, including sample size determination, estimates of 
event rates, interim  analyses for quality control, analyses of trial 
outcomes, and full statistical oversight.  The application should 
include a discussion of statistical issues and potential problems 
likely to arise in the design and conduct of this clinical trial.  The 
Data Coordinating Center will provide the support and guidance 
necessary to maintain the scientific integrity of the trial through 
Coordinating Center staff or procurement of consultants as necessary.

The Data Coordinating Center will have the primary responsibility for 
developing and implementing systems necessary for intra-study 
communications. The Center will facilitate the design and refinement of 
all protocols, manuals of operation, and forms.  The Center will 
establish a system for electronic submission of data in a standard 
format from the clinical centers, process all data transmitted, monitor 
the quality of the data and the performance of the Clinical Centers in 
the implementation of the protocols, and prepare periodic reports to 
Clinical Centers on data quality problems identified.  The Data 
Coordinating Center will be responsible for developing plans for the 
Data Monitoring Committee.  The Center will perform analyses necessary 
for interim publications and presentations, and prepare appropriately 
detailed reports to the NIDDK, the Steering Committee, and to the Data 
Monitoring Committee at regular intervals and as dictated by the study 
needs.  During Phase 4, the Data Coordinating Center will prepare 
outcome analyses of the data from the clinical trial and will 
collaborate with the investigators of the Clinical Centers and the 
NIDDK to prepare final reports of the study for publication.

The Data Coordinating Center will be responsible for acquiring and 
administering subcontracts for a central Virological Testing Laboratory 
and Serum/Tissue Repository.    The virological testing will be the 
routine and necessary assays for the clinical trial.  Examples of the 
types of centralized routine virological testing required include HCV 
RNA testing by polymerase chain reaction, quantitation of HCV RNA in 
serum by polymerase chain reaction or other amplification methods, 
genotyping of HCV sequencing analysis, restriction fragment length 
polymorphism analysis or genotype specific hybridization. The Data 
Coordinating Center will be responsible for assuring the quality of the 
testing and justification of the methods used. The NIDDK also intends 
that a central Serum/Tissue Repository contracted by the Data 
Coordinating Center will store patient samples in a manner suitable for 
future DNA and molecular analyses particularly with the collaboration 
of the Principal Investigators of the ancillary studies.  The contract 
for a Serum/Tissue Repository may be combined with or made a separate 
contract from the Virology Testing Laboratory.  The Coordinating Center 
will also arrange for transport of samples to the Principal 
Investigators of the ancillary studies and arrange for integration of 
data from ancillary studies into the overall study data.  A central 
laboratory supported by a subcontract from the Data Coordinating Center 
must adhere to all NIH policies and procedures governing consortium 
grants.

Staff of the Data Coordinating Center will be required to travel to 
meetings during the planning phase for the development of study design, 
protocols, manuals, and forms.  Phases 2 and 3 will require personnel 
to attend Steering committee meetings, to travel to the Clinical 
Centers as necessary to monitor quality control procedures, and to 
conduct training programs for clinic staff. Additionally, the Data 
Coordinating Center will be required to assist in managing the 
logistics of all committee and sub-committee meetings during the course 
of the trial and will be responsible for taking minutes of the various 
meetings.  The Data Coordinating Center also will make logistical 
arrangements for meetings of the Data Monitoring Committee, but the 
NIDDK Project Scientist will serve as executive secretary of this 
group.

The Data Coordinating Center will assist the NIDDK Project Scientist in 
written, telephone, and electronic communications with Clinical Centers 
and with various committees as requested.

(c) Ancillary Studies

Applicants for Ancillary Studies should propose a detailed research 
plan focused upon elucidation of the biological and virological basis 
for a lack of response to antiviral therapy in hepatitis C in the 
patient population studied in Virahep-C.   

Applicants should develop a research plan to test research hypotheses 
regarding the viral or host factors that determine virological and 
biochemical responses to combination therapy of hepatitis C.  Thus, the 
lack of an on-treatment virological response to optimal antiviral 
therapy in hepatitis C occurs in 30-50% of Caucasians, but in 50-75% of 
African Americans with hepatitis C.  The nature of this viral 
resistance requires investigation using virological, cellular, and 
molecular biological methods.  These investigations will be based upon 
serum and peripheral blood mononuclear cells from patients 
participating in the Virahep-C trial on whom information from careful 
clinical characterization and viral kinetics in response to combination 
therapy will be available.   Patients will be clearly identified with 
antiviral (largely interferon) resistant strains of HCV, and the degree 
of resistance will be carefully defined.   In elucidating the nature 
and cause of antiviral resistance, at least four major areas of 
investigation are important: (1) virological, (2) immunological, (3) 
interferon pharmacokinetics, cell signaling and intracellular effects, 
and (4) host genetic biology.   It is expected that one ancillary study 
will be awarded in each of these areas.  Each ancillary study should 
focus on only one of these areas.  

Investigations appropriate to this RFA include (but are not limited to) 
comparison of different cohorts of patients or interferon-sensitive 
versus interferon-resistant patients for:

o Characterization of major circulating strains of HCV
Nucleotide sequences of HCV RNA of these strains

o Phylogenetic analyses of different strains and inter-isolate 
comparisons 

o Quasispecies complexity and diversity of circulating HCV 

o Changes in quasispecies complexity and diversity with therapy

o Enzymatic and replicative activity of predominant circulating virus 
strain

o Binding of intracellular proteins of expressed antigens from 
different HCV strains

o Inhibition of constitutively expressed as well as interferon-induced 
proteins by HCV antigens from different isolates and strains

o Levels of serum antibodies to different components of HCV and change 
of antibody levels with treatment

o T cell immune responses to different areas of the genome from 
lymphocytes taken before and at different times during therapy

o T cell immune responses to specific epitopes identified from 
resistant and sensitive HCV RNA strains

o Innate immunity and non-specific immune reactivity
Pharmacokinetics of interferon and time course of appearance and 
disappearance of serum interferon levels

o Kinetics of cellular expression of interferon induced genes

o Cell signaling pathways in response to interferon 

o Polymorphisms of interferon responsive gene products

o Cytokine levels and changes in expression before and during 
interferon therapy

o Differences in numbers and proportions of CD4 and CD8 cells and 
circulating lymphocyte subpopulations before and during therapy

o In vitro response of peripheral blood monocytes to interferon actions

o Polymorphisms of major immune response and cytokine genes
Changes in gene expression during interferon therapy as assessed by 
microassay technology.

A liver biopsy will be required on all patients before initiation of 
therapy.  However, it is unlikely that liver tissue will be available 
for virological and immunological studies from most patients.  Thus, 
Ancillary Studies should focus more on serum, plasma and peripheral 
blood mononuclear cell studies rather than analyses of liver tissue.

4. Study Phases

Phase 1 (Planning phase, 12 months: Year 1):  This phase will encompass 
collaborative development of the protocol and the manual of operations 
by a Steering Committee composed of the Principal Investigators of the 
Clinical Centers, the Chairperson of the study, the Principal 
Investigators of the Ancillary Studies, the Principal Investigator of 
the Data Coordinating Center, and the NIDDK Project Scientist.  The 
Steering Committee-approved protocol and manual of operations will be 
subject to review by an NIDDK-appointed group of non-federal experts, 
the Data Monitoring Committee, that will serve to advise the Institute 
on subject safety, data quality and other issues. The Data Coordinating 
Center will solicit and award a subcontract for a virology testing 
laboratory and for a serum/tissue repository either as a combined or 
separate contract.  The Steering Committee will choose a central 
pathologist for the trial during the planning phase.  The pathologist 
may be a member of one of the clinical centers or be located at another 
institution.  The pathologist will be funded through the Data 
Coordinating Center.  The study will move into its operational phase 
only following the recommendation of the Data Monitoring Committee and 
the final approval of the NIDDK. 

Phase 2 (Enrollment phase, 12 months: Year 2): The protocol for the 
study will be initiated in Phase Two.  Each Clinical Center will 
recruit and enroll 50 participants over this period, implement the 
protocol according to the manual of operations, collect the outcome 
data specified in the protocol, and provide study data to the Data 
Coordinating Center.  Clinical Centers also will be responsible for 
collecting and shipping patient specimens to central facilities for 
evaluation and collaborating with the Principal Investigators of the 
ancillary studies in elucidating the nature of viral resistance in the 
treated patients.  The Data Coordinating Center will coordinate these 
activities, and will manage the collection, editing, storage and 
analysis of data.  During this phase, the Ancillary Studies will begin 
evaluation of serum, DNA and peripheral blood mononuclear cells from 
patients receiving antiviral therapy as designated in the protocol 
developed during phase 1.  

Phase 3 (Treatment and Follow-up phase, 24 months: Years 3 and 4):  
Clinical Centers will no longer recruit patients, but will continue to 
implement the protocol, collect outcome data, ship specimens, and 
provide study data to the Data Coordinating Center during this period.  
Patients will be treated for 48 weeks, and all will be followed off of 
therapy for another 48 weeks.  Thus, follow up will conclude 96 weeks 
after enrollment of all patients.  During this period, the Data 
Coordinating Center will continue to coordinate these activities, and 
will manage the collection, editing, storage and analysis of data.  
Ancillary Studies will continue during this phase.

Phase 4 (Analysis phase, 12 months: Year 5):  The final phase of the 
study will be for close-out of Clinical Center activities, final data 
analysis, and reporting of results.   Ancillary Studies are likely to 
need to be continued at reduced activity during this phase and results 
of these studies added to the clinical database.

SPECIAL REQUIREMENTS

1. Participation in a Collaborative Program

To promote the development of a collaborative program among the 
awardees, the applicant should present evidence of experience in 
working cooperatively with other Clinical, Ancillary Study and Data 
Coordinating Centers and of ability to follow common protocols that are 
collaboratively developed.  

(a) Clinical Centers will be expected to communicate with the Data 
Coordinating Center and the NIDDK Project Scientist on a regular basis 
and work closely with the Principal Investigators on the Ancillary 
Studies.

All Clinical Centers in the Virahep-C trial must agree to implement the 
protocol and manual of operations that will be developed cooperatively 
during Phase 1 and agree to electronically transmit all study data in a 
timely fashion to a central Data Coordinating Center for combination 
and analysis.  An explicit statement of willingness to participate in a 
collaborative program should be included in the application.

(b) The Data Coordinating Center will be involved in collaborations 
with the NIDDK, the ancillary studies and the Clinical Centers during 
all phases of the trial.  Thus, the applicant is expected to 
demonstrate experience in working cooperatively with Clinical Centers 
and sponsoring organizations in a multicenter trial and in overseeing 
the implementation of and adherence to a common protocol, as well as 
assuring 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, the Principal Investigators of the 
Ancillary Studies, and the Clinical Centers.

(c) Principal Investigators of the Ancillary Studies will be expected 
to communicate with the Data Coordinating Center and the NIDDK Project 
Scientist on a regular basis.   All Principal Investigators must agree 
to implement the protocol and manual of operations that will be 
developed cooperatively during Phase 1 and agree to electronically 
transmit all study data to the central Data Coordinating Center for 
combination and analysis.  These ancillary studies will address 
virological, immunological, pharmacological and host genetic factors 
that might explain the nature and cause of viral resistance in chronic 
hepatitis C.  The Principal Investigators on these ancillary studies 
will participate in the protocol design and set up the important 
collaborations and arrangements with the Clinical Centers that will be 
needed to carry out the analyses of viral and host factors that 
correlate with response and lack of response to interferon-based 
therapy of hepatitis C.  
 
Principal Investigators on the Ancillary Studies will be expected to 
perform hypothesis-driven laboratory research on serum and/or tissue 
samples from patients participating in the Virahep-C trial.  The 
Investigators will direct all technical help and participate in the 
completion of planned experiments focusing on the mechanism of 
antiviral action of combination therapy against HCV and the possible 
mechanisms of antiviral resistance.  The Investigator will be expected 
to report results regularly and provide results to the Data 
Coordinating Center for analysis in respect to the clinical and other 
virological features of individual patients.

The Principal Investigators of the Ancillary Studies are expected to 
complete the planned experiments in a timely fashion and help analyze 
and prepare the findings for publication.  

(d) Steering Committee.  The primary governing body of the study will 
be the Steering Committee, which will have responsibility for overall 
study design and policy decisions (described in more detail under Terms 
and Conditions).

(e) Executive Committee.  An Executive Committee also will be convened 
to facilitate the monitoring and conduct of the study between meetings 
of the Steering Committee (described in more detail under Terms and 
Conditions).

(f) Data Monitoring Committee.  An independent committee will be 
established by the Director, NIDDK, to review the progress of the study 
on a regular basis (described in more detail under Terms and 
Conditions).
 
(g) NIDDK Project Scientist.   The NIDDK will name an NIDDK Project 
Scientist whose function will be to assist the components as 
appropriate in all aspects of the study (described in more detail under 
Terms and Conditions).

2. Terms and Conditions of Award

The following special terms of award (1-4) are in addition to, and not 
in lieu of, otherwise applicable OMB administrative guidelines, HHS 
grant administration regulations at 45 CFR Parts 74  and 92, and other 
HHS and NIH grant administration policies.

The administrative and funding mechanism to be used to undertake this 
project will be the cooperative agreement (U01), which is an assistance 
mechanism (rather than an acquisition mechanism) in which substantial 
NIH scientific and/or programmatic involvement with the awardee is 
anticipated during the performance of the activity.  Under the 
cooperative agreement, the NIDDK’s purpose is to support and/or 
stimulate the recipient’s activity by collaborating and otherwise 
working jointly with the award recipient in a partner role, but it is 
not to assume direction, prime responsibility, or a dominant role in 
the activity.  Consistent with this concept, the tasks and activities 
in carrying out the studies will be shared among the awardees, the 
Principal Investigators of the Clinical Centers, the Ancillary Studies, 
the Data Coordinating Center, and the NIDDK Project Scientist.

(a) Awardee Rights and Responsibilities.  The tasks or activities in 
which awardees for the Clinical Centers, the Ancillary Studies and the 
Data Coordinating Center of the Virahep-C trial will have substantial 
and lead responsibilities include protocol development, patient 
recruitment and follow-up, data collection, quality control, 
investigation of patient samples, final data analysis and 
interpretation, and preparation of publications.  The awardee agrees to 
work cooperatively with the other Clinical Centers, other Ancillary 
Study investigators and the Data Coordinating Center and agrees to 
follow the common protocol and manual of operations developed in Phase 
1 of the study by the Steering Committee.

Awardees will retain custody of and have primary rights to their data 
developed under these awards, subject to Government policies regarding 
rights of access.

(b) NIDDK Staff Responsibilities.  The NIDDK will name the Project 
Scientist.  The Project Scientist’s function will be to provide 
technical assistance to the Steering Committee, Executive Committee, 
Data Monitoring Committee, and other subcommittees in carrying out the 
study, including quality control, interim data and safety monitoring, 
final data analysis and interpretation, preparation of publications, 
and coordination and performance monitoring.  The NIDDK Project 
Scientist will have voting membership on the Steering Committee, the 
Executive Committee, and, as appropriate, other subcommittees of the 
Steering Committee.  The NIDDK Project Scientist also will serve as 
executive secretary of the independent Data Monitoring Committee.

Other NIDDK scientists may, as appropriate, serve on study committees 
and work with awardees on issues coming before the Steering Committee 
or its subcommittees; however, in all cases, the NIDDK will have only a 
single vote on study committees, either of the whole or on 
subcommittees.  In addition, the NIDDK may invite non-voting 
representatives from other sponsoring Institutes and agencies, as 
appropriate, to attend meetings.  The NIDDK will name a Program 
Officer, separate from the Program Scientist, who will be responsible 
for administering the awards.

The NIDDK reserves the right to terminate or curtail the study (or an 
individual award) in the event of (a) a major breach in the protocol or 
substantial changes in the agreed-upon protocol with which the 
Institute does not agree or (b) human subject ethical issues that may 
dictate a premature termination or (c) substantial shortfall in 
recruitment and/or retention of subjects.

(c) Collaborative Responsibilities and Governance.

(1) The Steering Committee, comprised of each of the Principal 
Investigators of the Clinical Centers, the Study Chairperson, the 
Principal Investigators of each of the Ancillary Studies, the Principal 
Investigator of the Data Coordinating Center, and the NIDDK Project 
Scientist, will have primary responsibility for developing common 
clinical protocols, facilitating the conduct and monitoring of the 
studies, and reporting the study results.  Each member of the Steering 
Committee will have one vote, and all major scientific decisions will 
be determined by majority vote of the Steering Committee.  A 
Chairperson will be chosen from among the Principal Investigators of 
the Clinical Centers.  Subcommittees appointed by the Steering 
Committee and comprised of Principal Investigators and appropriate 
staff from the Clinical Centers, the Ancillary Studies and the Data 
Coordinating Center will be involved in design of the protocol and the 
manual of operations, and in ongoing functions of the trial, such as 
review of ancillary studies and preparation of publications.  Not all 
Clinical Centers will necessarily be represented on all subcommittees.
 
(2) An Executive Committee comprised of the Study Chairperson, the 
Principal Investigator of the Data Coordinating Center and the NIDDK 
Project Scientist also will be convened to effect management decisions 
required between Steering Committee meetings, as needed for efficient 
progress of the trial.  The Executive Committee will report its actions 
to the Steering Committee on a regular basis.   Meetings of the 
Executive Committee will generally be held in the Washington, D.C. 
metropolitan area or by conference call.

(3) An independent Data Monitoring Committee will be appointed by the 
Director, NIDDK, to review periodically the progress of the Virahep-C 
trial.  It will be comprised of experts in relevant medical, 
statistical, operational, and bioethical fields who are not otherwise 
involved in the study.  The Data Monitoring Committee will oversee 
participant safety, evaluate results, monitor data quality, and provide 
operational and policy advice to the Steering Committee and to the 
NIDDK regarding the status of the study.  The Principal Investigator of 
the Data Coordinating Center, the NIDDK Project Scientist, and the 
Director of the Division of Digestive Diseases and Nutrition (or 
representative) may participate as ex-officio, non-voting members of 
the Committee. The NIDDK Project Scientist will serve as executive 
secretary of the Data Monitoring Committee.  The Data Monitoring 
Committee will review progress and report to the NIDDK at least once 
per year.

(d)  Arbitration.  Any disagreement that may arise in scientific-
programmatic matters (within the scope of the award) between award 
recipients and 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 
awardees in the event of an individual disagreement, a second member 
selected by NIDDK, and a third member selected by the two prior 
selected members.  The special arbitration procedure in no way affects 
the awardee’s right to appeal an adverse action that is otherwise 
appealable in accordance with the PHS regulations at 42 CFR Part 50, 
Subpart D and HHS regulations at 45 CFR Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
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 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are 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 research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: 
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

This study will recruit equal numbers of African American and non-
Hispanic white patients.  The focus of the study is on African 
Americans who have a high rate of resistance to antiviral therapy with 
alpha interferon.  The non-Hispanic whites are to be used as a control 
and reference group to analyze response rates by racial group to alpha 
interferon therapy and viral kinetics.  Other minority groups such as 
Asians, Hispanic whites and native Americans will not be included in 
this trial.  Asian Americans will not be included because hepatitis C 
appears to be less frequent in this group than in whites, and because 
data from the United States as well as Asian countries indicate that 
the sustained virological response rates to alpha interferon therapy 
are equal or higher in Asians compared to Caucasians.  Hispanic whites 
will not be included in this trial because response rates to antiviral 
therapy in this group has been similar to that among non-Hispanic 
whites.  Furthermore, studies from Spain report response rates that are 
similar to those from other European countries.  Thus, viral resistance 
does not appear to be common in the Hispanic groups enrolled in 
published clinical trials. Native Americans have not been included in 
this trial because there is little or no information on the frequency 
of hepatitis C in this group and no data on the frequency of response 
to antiviral therapy.  Most studies indicate that hepatitis C is not 
common in Native American populations.  

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.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit, by November 15, 2000, a 
letter of intent that includes a descriptive title of the proposed 
research; the name, address, and telephone number of the Principal 
Investigator; the identities of other key personnel and participating 
institutions; and the number and title of the RFA in response to which 
the application may be submitted; and whether the application is for a 
Clinical Center, Data Coordinating Center or Ancillary Study.

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 NIDDK staff to estimate the potential review 
workload and to plan the review.

The letter of intent is to be sent to:

Ann A. Hagan, Ph.D.
Chief, Review Branch 
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 653 MSC 5452
Bethesda, MD 20892-5452 
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants.  These forms are available at most 
institutional offices of sponsored research and from the Division of 
Extramural Outreach and Information Resources, National Institutes of 
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, 
telephone 301/435-0714, email: GrantsInfo@nih.gov.

The RFA label available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of the application.  
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 2a 
of the face page of the application form, and the YES box must be 
marked.

The sample RFA label available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf  has been 
modified to allow for this change.  Please note this is in pdf format.
  
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
(for express/courier service: Bethesda, MD 20817)

At time of submission, two additional copies of the application must be 
sent to:

Ann A. Hagan, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 653 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8885
FAX: (301) 480-3505

Applications must be received by December 15, 2000.  If an application 
is received after that date, it will be returned to the applicant 
without review.  The Center for Scientific Review (CSR) will not accept 
any application in response to this RFA that is essentially the same as 
one currently pending initial review, unless the applicant withdraws 
the pending application.  The CSR will not accept any application that 
is essentially the same as one already reviewed.  This does not 
preclude the submission of substantial revisions of applications 
previously reviewed, but such applications must include an introduction 
addressing the previous critique.

Instructions to Prospective Applicants

(1) Clinical Centers

The applicants for the Clinical Centers should discuss the important 
design considerations for a clinical trial to investigate viral 
resistance to antiviral therapy of chronic hepatitis C.  While the 
final design for the Virahep-C trial will be determined by the Steering 
Committee, applicants should address the potential requirements of the 
study by providing a description of projected tasks likely to be 
performed by the Clinical Centers.  Solutions should be suggested for 
likely problems.  The applicant's study design should propose 
eligibility requirements for study participation, including patient 
age, gender, and racial/ethnic background.  In addition, exclusion 
criteria should be specified, along with a rationale.  Applicants 
should provide a justification for the subject selection criteria, 
including discussion of statistical considerations, an estimate of the 
number of subjects in the source population, and projected necessary 
time for recruitment.

The overall racial composition of the recruited patient populations in 
this study will be equally divided between African Americans and non-
Hispanic whites.  Plans should include methods and criteria for 
assigning racial and ethnic background.  Plans should include racially 
and ethnically sensitive strategies for recruitment, screening, 
enrollment and retention in the study protocol.

Each applicant should propose the study design he or she believes best 
addresses the objectives of this project as described in RESEARCH 
OBJECTIVES and is most appropriate to the proposed patient population. 
The potential differential effectiveness of antiviral therapy with 
respect to racial/ethnic background of study participants should be 
discussed.  The applicant should propose one specific antiviral therapy 
(not a comparison of two treatments) that would be considered optimal 
therapy for genotype 1 infected patients with hepatitis C. The 
applicant should discuss the components of the initial evaluation, 
inclusion and exclusion criteria.  The applicant should propose a 
schedule of evaluations during therapy with a table showing timing of 
evaluations and assessments and tests to be applied at each point 
before, during and after therapy. 

In addition to the primary and secondary outcome measures listed in 
RESEARCH OBJECTIVES, which should be included in the study design, 
applicants should indicate other outcome measures proposed for 
assessment (e.g., quality of life instruments, symptom scales and 
measurements, virological assays, other measures of liver function) 
identifying those they consider the highest priority that can be 
accommodated within the funds available.  The applicant should clearly 
define endpoints of therapy (virological and biochemical).

Methods to monitor and encourage patient adherence to the trial 
protocol should be clearly defined.  Plans for collection and handling 
of data and samples should be discussed.  Part of the proposed study 
design also should address the means for communicating results of 
patient laboratory tests and guidelines for treatment of comorbidities 
to primary care physicians.

Clinical Centers should describe their experience in recruiting and 
studying patients with liver disease, and in minimizing losses of 
patients to follow-up during long-term clinical studies.  The Clinical 
Center should include a pathologist with experience in reading hepatic 
pathology who will read liver biopsies from patients in the trial.   
Clinical Centers also should document prior involvement in multi-center 
clinical trials and success in recruiting from minority populations.

Applicants should provide evidence that the Clinical Center will be 
capable of recruiting a sufficient number of patients with hepatitis C 
with the proposed inclusion criteria.  The NIDDK expects that the 
average number of patients per center will be approximately 50 and that 
half of the patients will be African Americans and half non-Hispanic 
whites.

An organizational structure for the Clinical Center should be provided 
in the application, delineating lines of authority and responsibility 
for dealing with problems in all general areas.  There should be 
evidence of strong institutional support for the Clinical Center, 
including documentation of adequate space in which to conduct clinic 
activities and office space for staff.  

Personnel: The application for a Clinical Center must describe the 
expertise of key scientific, technical and administrative personnel and 
include a mechanism for replacing key professional or technical 
personnel should the need arise.  Overall, the staff of a Clinical 
Center should include expertise in liver disease and clinical 
investigation. The study team is anticipated to include members who 
perform in roles similar to those cited below.  Members may be full or 
part-time and may serve in more than one capacity, as appropriate.  The 
following suggested roles are intended to be illustrative, not 
prescriptive:

o Principal Investigator to provide overall scientific guidance.

o Project Coordinator who can provide full-time attention to 
administration and management of the trial.

o Physician(s) with expertise in the clinical management of hepatitis C 
and liver disease to help enroll and maintain the patients in this 
study and to oversee the use of antiviral therapy.

o Pathologist with expertise in liver histology and interpretation of 
liver histology in chronic hepatitis. 

o Research nurse(s) or other allied health professional(s) to assist in 
case management and data collection procedures (e.g., phlebotomy, and 
patient assessments).

o Individual(s) for clerical and technical support, including 
administrative tasks, data entry, laboratory sample handling, 
assistance with recruitment and other tasks.

Budget: Applicants for a Clinical Center should submit adequately 
justified budgets for each 12-month period of the trial, reflecting the 
major changes in proposed activities projected to occur as the trial 
progresses through its phases.

During Phase 1 (Year 1), the budget will be for development of the 
protocol and manual of operations, staff recruitment and training, and 
staff certification.  The travel budget for Phase 1 should be estimated 
on the basis of six meetings at regular intervals during the first year 
of award.

During Phase 2 (Year 2), the budget should reflect subject recruitment 
and randomization, implementation of the proposed interventions, 
collection of outcome data proposed by the applicant, and provision of 
study data to the Data Coordinating Center.  Phase 2 budgets should 
include three meetings per year.

During Phase 3 (Years 3 and 4), the budget should reflect the end of 
recruitment and the continued implementation of the proposed 
interventions, collection of proposed outcome data, and provision of 
study data to the Data Coordinating Center.  Phase 3 budgets should 
include three meetings per year.

The Phase 4 budget (Year 5) will be concerned with study close-out, 
analysis of study data, and reporting of results.  Phase 4 budgets 
should include three meetings.

NOTE:

o Detailed budget estimates for years in Phases 2, 3, and 4 should be 
based on the applicant's proposed plan.  Actual budgets for these 
phases will be based on the final protocol developed collaboratively 
during Phase 1.

o It is the intention of the NIDDK that the Data Coordinating Center 
will establish central resource units for the standardized performance 
of key laboratory and clinical parameters.  These costs will be 
included in the Data Coordinating Center funding and should not be 
budgeted by the Clinical Centers.   Clinical Center budgets should also 
not include costs for medications, drug distribution or specimen 
shipping costs.    

o Budgets should allow travel and lodging costs for approximately two 
persons, including the Principal Investigator, to attend Steering 
Committee and Subcommittee meetings.  Since actual meeting locations 
have not been selected, each meeting may be assumed to cost $1500 per 
person for budget purposes.  It is anticipated that about one-half of 
the meetings will be held in the Washington, DC area or Bethesda, MD.

(2) Data Coordinating Center

Applicants for the Data Coordinating Center should address the 
potential requirements of the study by providing a description of 
projected tasks likely to be performed by the Data Coordinating Center 
and the centralized facilities, consistent with resources projected to 
be available for this study.

The application should be structured around the requirements of a 
projected study design that addresses likely outcomes to be determined 
and likely eligibility requirements for study participation, including 
patient age, gender, and exclusion criteria.  

Plans for collection and handling of data and samples consistent with 
the projected needs of the study should be discussed.  Part of the 
proposed study design also should address the means for communicating 
results of patient laboratory tests.  Plans for integration of results 
from the Clinical Centers and the Ancillary Studies should be 
discussed.  Plans for ensuring data integrity and quality control 
should be discussed.

Personnel: The application for the Data Coordinating Center must 
describe the expertise of key scientific, technical and administrative 
personnel and include a mechanism for replacing key professional or 
technical personnel should the need arise.  A Director and a Deputy 
Director for the Data Coordinating Center must be designated.  The 
Director of the Data Coordinating Center should be a biostatistician, 
epidemiologist, or other professional with experience in directing a 
coordinating center for a large scale collaborative multicenter 
clinical trial or other large scale epidemiological research project 
involving multiple institutions.   The Deputy Director should be fully 
qualified to carry out the responsibilities of the Director.  Staff 
needs may be modified as the trial progresses; however, adequate 
support staff should be designated to manage routine tasks.  It is 
expected that senior statistical staff will devote time to developing 
data analysis methods for use in the trial.  

o Director of Data Coordinating Center to provide overall scientific 
and biostatistical guidance.

o Deputy Director qualified to replace the Director.

o Project Manager to attend to day-to-day details of the trial and 
communicate necessary information to clinical centers, repository, 
virology testing laboratory and ancillary studies sites.  Staff 
training is also a responsibility of the Project Manager.

o Statisticians to help in data analysis.

o System analysts to help with developing and managing the database 
programs.

o Computer programmers to develop computer database.

o Clerks and administrative assistants to help in administrative work 
and data entry.

Budget: Applicants for the Data Coordinating Center should submit 
adequately justified budgets for each 12-month period of the trial, 
reflecting the major changes in proposed activities that occur as the 
trial progresses through its phases.

NOTE:  Budgets for this application should be based on the applicant's 
best judgment of likely activities projected to be included in a final 
protocol.  Final budgets will be determined following the design of the 
study protocol and writing of the manual of operations during Phase 1.

The Phase 1 budget (Year 1) should include costs of establishing the 
Data Coordinating Center staff, as required to carry out the 
Coordinating Center's functions.  Phase 1 also will involve development 
of the protocol and manual of operations in conjunction with the 
Steering Committee for the study and creation of a database for the 
trial.  During this phase, the collaborating centralized Virological 
Testing Laboratory and a Serum/Tissue Repository will be identified.  
Coordination will be established with the ancillary studies 
investigators to obtain serum and tissue specimens.  Budgets should 
include the costs of organizing six Steering Committee meetings and 
providing for attendance of necessary Data Coordinating Center staff.

During Phase 2 and 3 (Years 2, 3, and 4), the budgets should include 
projected data handling costs, reporting functions, meetings and other 
communications costs, and the projected expense of performing interim 
analyses requested by the Data Monitoring Committee.  The applicant 
also should address the potential requirements of the study by 
budgeting for tasks likely to be performed by the central virological 
testing facility.  These should include development of a
repository to store patient samples.  It should, however, be understood 
that the specific centralized facilities required and their final 
budgets will be determined following the design of the study protocol 
and the writing of the manual of operations by the Steering Committee.  
The Budget should include funding for a central hepatic pathologist for 
reading liver biopsies for the study. Budgets should include costs of 
organizing three Steering Committee meetings per year and providing for 
attendance of necessary Data Coordinating Center staff.

The Phase 4 budget (Year 5) should be concerned with study close-out, 
analysis of study data, and reporting of results in collaboration with 
the Clinical Centers.  Budgets should include the costs of organizing 
three meetings of the Steering Committee and providing for attendance 
of necessary Data Coordinating Center staff.

NOTE:  Since actual meeting locations have not been selected, each 
meeting may be assumed to cost $1,500 per person.  Each Clinical Center 
will budget for the travel of its own staff members.  It is estimated 
that approximately one-third of the meetings will be held in the 
Washington D.C. area.  The Data Coordinating Center also will be 
responsible for organizing meetings of the Data Monitoring Committee at 
least once a year and for supporting the travel of these individuals to 
meeting sites and their lodging. These costs should be included in the 
budget.

(3) Ancillary Studies

The applicants for an Ancillary Study should discuss how their proposal 
would be integrated into the design of the clinical trial and relate to 
the trial protocol.  These applications need to discuss the design 
considerations for the clinical trial only in relationship to the 
laboratory investigations that are planned.  Thus, if repeated measures 
of virological, immunological or interferon-related responses are 
necessary, it would be important to define the time points necessary 
and what special therapy, data or provisions would be necessary to 
collect the specimens and clinical information.  The plan should also 
discuss any deviation from standard medical practice that would be 
needed for the investigations, such as extra blood drawings, 
lymphopheresis or special procedures.  The investigator should be 
careful not to propose studies that would interfere significantly with 
the recruitment and retention of patients or the course of optimal 
therapy of hepatitis C or interfere with the primary goals of this 
study detailed above under research objectives #1-4.

Personnel: The application for an Ancillary Study must describe the 
expertise of key scientific, technical and administrative personnel and 
include a mechanism for replacing key professional or technical 
personnel should the need arise.  

o Principal Investigator to provide overall scientific guidance.

o Laboratory technicians with expertise in the laboratory 
investigations that are planned.  

o Post-doctoral or other professionals to help direct and conduct the 
laboratory investigations.  

Budget: Applicants for an Ancillary Study should submit adequately 
justified budgets for each 12-month period of the trial, reflecting the 
major changes in proposed activities projected to occur as the trial 
progresses through its phases.

During Phase 1 (Year 1), the budget will be for development of research 
protocol along with techniques and reagents, and staff recruitment and 
training.  The travel budget for Phase 1 should be estimated on the 
basis of six meetings at regular intervals during the first year of 
award.

During Phase 2 (Year 2), the budget should reflect full implementation 
of the research project.  Phase 2 budgets should include three meetings 
per year.

During Phase 3 (Years 3 and 4), the budget should reflect the end of 
recruitment and the continued implementation of the proposed 
interventions, collection of samples and testing, and provision of 
study data to the Data Coordinating Center.  Phase 3 budgets should 
include three meetings per year.

The Phase 4 budget (Year 5) will be concerned with completing final 
studies on patients at the end of the trial, study close-out, analysis 
of study data, and reporting of results.  Phase 4 budgets should 
include three meetings.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDDK. Incomplete and/or non-responsive 
applications will be returned to the applicant without further 
consideration.
Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NIDDK in accordance with the review 
criteria stated below. As part of the initial merit review, all 
applications will receive a written critique and 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, assigned a priority score, and receive a second level review 
by the National Diabetes and Digestive and Kidney Diseases Advisory 
Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas about 
how best to meet the goals of the cooperative study as outlined in this 
RFA and are expected to address the points discussed under SPECIAL 
REQUIREMENTS.  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 and will be weighted 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.  Furthermore, 
the focus of these criteria will depend upon whether the application is 
for a Clinical Center, Data Coordinating Center or Ancillary Study.

(1) For the Clinical Centers of the Virahep-C trial, review will focus 
on the following issues which are listed under the five major review 
criteria: 

o Significance:  Does this study address an important problem?  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?

The final study design will be developed collaboratively by the 
Steering Committee for the trial. In assessing applications for 
Clinical Centers, the peer review group will focus on evidence that the 
applicant recognizes the significance of 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 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?

Does the proposed approach in managing the clinical requirements of the 
study as outlined in the RFA have scientific and technical merit?  Has 
the Principal Investigator proposed an adequate and practical plan to 
recruit, evaluate, enroll, and monitor patients, particularly African 
American subjects?  Does the application provide evidence of successful 
experience in recruitment and retention of research subjects in 
multicenter clinical trials, and particularly experience in the 
recruitment and retention of African American individuals with chronic 
hepatitis C or other liver diseases?  Does the application include 
documentation of access to an adequate patient population from which to 
recruit 50 eligible patients over a one-year period?  At least half of 
patients (25) should be African American.

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?

The final protocol will be developed by the Steering Committee.  Does 
the Principal Investigator offer innovative ideas on means to achieve 
the goals of the study in its design and clinical components?   Does 
the proposal address problems that may arise during the study and 
provide innovative solutions to such problems?  

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 demonstrated knowledge of clinical 
and epidemiological aspects of liver disease and hepatitis C, 
particularly among African American patients?  Does the investigator 
have documented expertise in management and monitoring of therapy of 
patients with hepatitis C? Does the other professional, technical, and 
administrative staff have specific competence and previous experience 
relevant to the operation of a Clinical Center in the proposed study?
    
o Environment: Does the scientific environment in which the work will 
be done contribute to the probability of success?  Do the proposed 
studies take advantage of unique features of the scientific environment 
or employ useful collaborative agreements?  Is there evidence of 
institutional support and commitment for the proposed program?

Has the applicant provided evidence for adequacy of the proposed 
facility, space, and resources for the work proposed?  This includes 
evidence of an appropriate organizational structure and institutional 
support for the Clinical Center.  For those applications that propose 
collaborative efforts between two applicants to form a single Clinical 
Center, 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.  Is there evidence of 
successful collaborative interactions with other investigators under a 
common protocol in a multicenter clinical trial?   

(2)  Review of applications for the Data Coordinating Center will be 
based on the following specific issues which are listed under the five 
major review criteria:

o Significance:  Does this study address an important problem?  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?

The final study design will be developed collaboratively by the 
Steering Committee for the trial. In assessing applications for a Data 
Coordinating Center, the peer review group will focus on whether the 
applicant recognizes the significance of 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 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?

Does the proposed approach in managing the data coordination and 
conduct of the study as outlined in the RFA have scientific and 
technical merit?   Are the proposed plans and experience relating to 
data collection, management, editing, processing, analysis, and 
reporting adequate?  Is there a demonstrated ability to identify, 
enlist, recruit and coordinate the efforts of central Virological 
Testing Laboratory and Serum/Tissue Repository?  Are the plans for 
management of biological samples and coordination with the Ancillary 
Study investigators adequate?  Is the approach to developing a 
cooperative relationship among the participating clinical centers and 
principal investigators on the ancillary studies adequate?  Are the 
plans for exercising appropriate leadership in matters of study design, 
data acquisition, data management, and data analysis demonstrated?   

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?

The final protocol will be developed by the Steering Committee.  Does 
the applicant for the Data Coordinating Center offer innovative ideas 
on how to achieve the goals of the study in its design and 
administration?   Does the proposal address problems that may arise 
during the study and provide innovative solutions to such problems?  

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 application provide evidence of specific competence and 
relevant experience of professional, technical, and administrative 
staff pertinent to the operation of a Data Coordinating Center for a 
collaborative clinical trial?  Prior experience collecting data and 
patient specimens from multiple clinical sites, monitoring the data 
quality, and developing and utilizing statistical methods for analysis 
of data should be demonstrated. Is there evidence of experience in and 
willingness to participate appropriately in a collaborative study as 
described in this RFA?   Are there adequate assurances that Data Center 
personnel have experience in utilizing procedures that insure the 
safety and confidentiality of medical records? 

o Environment: Does the scientific environment in which the work will 
be done contribute to the probability of success?  Do the proposed 
studies take advantage of unique features of the scientific environment 
or employ useful collaborative agreements?  Is there evidence of 
institutional support and commitment for the proposed program?

Has the application documented the adequacy of the proposed facility, 
technical hardware, and space for the Data Coordinating Center?  Is 
there an appropriate organizational and administrative structure to the 
Center?  Evidence of institutional support and commitment for the 
proposed program should be provided.

(3) Review of applications for Ancillary Study awards will be based on 
the following specific questions which are listed under the five major 
review criteria:

o Significance:  Does this study address an important problem?  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?

The final study design will be developed collaboratively by the 
Steering Committee for the trial. In assessing applications for an 
Ancillary Study, the peer review group will address whether the 
application addresses an important and relevant issue in regard to 
viral resistance and possible genetic, host or environmental 
determinants of response to antiviral therapy.   Will the findings from 
the studies add to understanding of the pathogenesis of hepatitis C and 
the determinants of outcome of therapy?  Will the results ultimately be 
applicable to clinical management of patients?   

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?

Does the application have scientific and technical merit and relevance 
to the research objective of elucidating the mechanisms of antiviral 
effects of alpha interferon and other antivirals in hepatitis C or in 
possible racial or ethnic differences in antiviral responses?   Has the 
investigator adequately demonstrated the plan and methods of the 
laboratory studies and integrated these studies into the general design 
of the clinical study?  Does the applicant recognize the practical 
problems in acquiring the required samples from the patients in the 
trial and propose means of correcting these problems?  Does the 
applicant recognize problems in the laboratory results and their 
interpretation and provide possible solutions?  

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?

Does the project suggest novel mechanisms and offer new insights into 
the activity of antiviral agents in hepatitis C?  Does the project 
suggest new approaches to analysis and understanding of clinical 
responses to treatment in hepatitis C and possible racial or ethnic 
differences in these responses?     

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 investigator and supporting research staff have adequate 
training and experience in laboratory investigation of virology or 
immunology of hepatitis C or the cellular biological and antiviral 
activity of interferon or in host genetic markers of disease outcome?   
Is there evidence of prior experience and willingness in working 
collaboratively in carrying out a developed study protocol and sharing 
data?

o Environment: Does the scientific environment in which the work will 
be done contribute to the probability of success?  Do the proposed 
studies take advantage of unique features of the scientific environment 
or employ useful collaborative agreements?  Is there evidence of 
institutional support and commitment for the proposed program?

Is the adequacy of the proposed facility, space, and resources for the 
work proposed documented in the application?  This includes evidence of 
an appropriate organizational structure and institutional support.
 
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 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.

Schedule

Letter of Intent Receipt Date:    November 15, 2000.
Application Receipt Date:         December 15, 2000.
Peer Review Date:                 March-April, 2001.
Council Review:                   May 2001.
Earliest Anticipated Start Date:  July 1, 2001.

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, Data Coordinating Center or Ancillary Study

o Availability of funds

o Cost

o Availability of appropriate study populations and especially the 
racial and ethnic balance among the populations to be accessed by the 
potential awardees

o Geographical distribution of the applicant organizations

o Program balance, including, in this instance, sufficient 
compatibility of features to make a successful collaborative program a 
reasonable likelihood.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to 
clarify any issues or questions from potential applicants is welcome.

The NIDDK will host a meeting of potential applicants for the Virahep-C 
study at the time of the Annual Meeting of the American Association for 
the Study of Liver Disease in Dallas, Texas October 27, 2000.  At that 
time NIDDK staff will be available to discuss the proposal and answer 
questions from applicants.  For the exact time and place of the meeting 
and for other inquires regarding programmatic issues that are not 
addressed in this announcement, contact:

Tommie Tralka
Director, Clinical Trials Program
Division of Digestive Diseases and Nutrition
6707 Democracy Boulevard, Room  675
Bethesda, MD 20892
Telephone: (301) 594-8879
FAX: (301) 480-8300
Email: TralkaT@extra.niddk.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

George Tucker
Division of Extramural Activities
6707 Democracy Boulevard, Room 635
Bethesda, MD 20892
Telephone: (301) 594-8853
FAX: (301) 480-3504
E-mail: tuckerg@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.847 and 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 
Parts 74 and 92.  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.

REFERENCES

Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao FX, Moyer LA, 
Kaslow RA, Margolis HS.  The prevalence of hepatitis C virus infection 
in the United States, 1988 through 1994.  N Engl J Med 1999;341:556-62.

Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH.  Hepatitis C.  Ann 
Intern Med 2000; 132: 296-305.

McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, 
et al.  Interferon alfa-2b alone or in combination with riabvrin as 
initial treatment for chronic hepatitis C.  Hepatitis Interventional 
Therapy Group.  N Engl J Med 1998;339:1485-92.

Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al.  
Randomised trial of itnerferon alpha-2b plus ribavirin for 48 weeks or 
for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for 
treatment of chronic infection with hepatitis C virus.  International 
hepatitis Interventional Therapy Group.  Lancet 1998;352:1426-32.

Reddy KR, Hoofnagle JH, Tong MJ, Lee WM, Pockros P, Heathcote EJ, 
Albert D, John T, Consensus Interferon Study Group.  Racial differences 
in responses to therapy with interferon in chronic hepatitis C.  
Hepatology 1999;30:787-93.

Howell C, Jeffers L, Hoofnagle JH.  Hepatitis C in African Americans.  
Summary of a Workshop.  Gastroenterology 2000; 119: in press.

Newman AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. 
Hepatitis C viral dynamics in vivo and the antiviral effiacy of 
interferon-alpha therapy. Science 1998;282:103-7.


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