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 301/710-0267, 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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