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TB Notes Newsletter
No. 4, 2005
TB Trials Consortium (TBTC) Update
Introducing the TB Trials Network – Enhancing
the U.S. Public Health System’s Willingness and Capacity to Engage
in Clinical Research
In 2002, Elias A. Zerhouni, MD, Director of the National Institutes
of Health (NIH), held meetings with leaders and scientific researchers
from NIH and around the country to develop a “roadmap” for medical
research in the 21st century. Opportunities to make medical
research more efficient and productive were identified. The third
of three NIH Roadmap themes established from this process is “re-engineering
the clinical research enterprise” (http://nihroadmap.nih.gov/).
NIH has funded projects that will contribute to the development
of a systematic infrastructure for expanded clinical research networks
which will have the capacity to “rapidly conduct high-quality clinical
studies that address multiple research questions.” These projects,
or feasibility studies, were selected through a Broad Agency Announcement
(BAA). In response to the BAA, Dr. Carol Dukes Hamilton, Principal
Investigator of TB Trials Consortium (TBTC) site #54 at Duke University,
and TB Controller for North Carolina, put together a successful
application titled “Enhancing the U.S. Public Health System’s Willingness
and Capacity to Engage in Clinical Research.” In October 2004 the
TB Trials Network (TBTN) was launched.
Why are clinical research networks needed? Clinical research
questions can be answered most clearly and definitively when large
numbers of patients are enrolled in a study. And, if a very large
number of patients are enrolled, multiple research questions can
sometimes be answered in a single study. For some research questions,
it may not be possible to even identify the needed number of patients
in one location. Even when the number needed can be found in one
area, it can take such a long time for one site to enroll enough
patients and then more time for the last patient enrolled to complete
the study that over 10 to 20 years could pass before the research
question would be answered. Additionally, there are occasions when
a study has taken so long to be completed that the answer is no
longer relevant by the time the study is completed. If the answer
can be reached sooner, more patients can be helped with the knowledge
gained, and more lives can be saved.
Bringing researchers from multiple locations together in a network
makes it possible to recruit large numbers of patients for a clinical
study very quickly. Additionally, the studies conducted by a group
of researchers will benefit from a broad range of shared expertise.
Study subjects recruited from multiple areas will often be more
heterogeneous and the study conclusions will thus be applicable
to a broader range of patients. Thus, clinical research networks
offer the promise of rapidly answering relevant clinical questions.
Diseases of public health importance (like TB and STDs) are usually
diagnosed and treated at public health clinics. Clinical research
questions that address diseases like TB and STDs can best be studied
in a network of public health clinics.
Though the advantages of a research network are easy to appreciate,
it can be quite challenging to establish the infrastructure needed
for such a network to be formed and to be functional. The TBTC is
such a network and will serve in a way as the “laboratory” for the
TBTN to explore the reasons behind the successes and the opportunities
for greater success of clinical research within the U.S.
public health system.
The TBTN is a collaboration between TBTC and the Duke Clinical
Research Institute (DCRI), which has an established infrastructure,
clinical trials expertise, and tools and training programs. Over
40 public health researchers from TBTC, CDC, and DCRI, representing
nearly 20 academic and research institutions, are contributing to
the effort. The major focus of the proposed TBTN projects will be
to enhance the willingness and capacity for clinics within the U.S.
public health system to engage in clinical research. Though the
specific long-term goal for TBTC is progress toward worldwide TB
control and elimination, the process, connections, and products
developed by TBTN work will have broad application among clinical
research networks in the United States.
Specific aims of the TBTN are as follows:
- Aim 1: Engage public health leaders in the clinical research
enterprise in general, and TB clinical research in particular,
by investing them in priority-setting forums that will also help
the TBTC to create a relevant, timely, and dynamic future scientific
agenda. The first “think-tank” meeting took place September
30, 2005, in Atlanta, Georgia
- Aim 2: Identify and reduce barriers to clinical trials research
public health clinics. We will work with representative TBTC-associated
public health clinics to identify the most significant barriers
to conducting clinical research in their setting and develop a
responsive strategy to reduce the barriers. In August, teams began
conducting site visits (at TBTC recruiting sites in North Carolina,
New York City, Louisiana, Georgia, and Texas) to identify barriers
to research in public health clinics. The visiting teams will
gather observational data, develop interventions, and measure
impact on enrollment over time.
- Aim 3: Under the leadership of William Burman, MD, develop
a model for improving the process of human subjects protection
review in multicenter trials. We will explore the impediments
to expanded use of central institutional review boards (IRBs)
in multicenter trials, and address the complexities associated
with informed consent among subjects who do not speak English.
The TBTN IRB team is currently contacting over 100 IRBs which
oversee multicenter clinical research to determine policies or
barriers against use of a central IRB and the use of the short
form for people who do not speak English.
- Aim 4: To improve interoperability between TBTC sites and
with public health clinics by 1) standardizing data elements and
definitions used in TB-related clinical research, 2) creating
a secure Web-based electronic data capture system for adverse
events reporting in TBTC Study 26, 3) developing a TBTC website,
and 4) determining the feasibility of connecting to NEDSS.
Connection to NEDSS would allow us to take advantage of ongoing
surveillance data collection to improve our ability to recruit
subjects to clinical trials, as well as compare trial populations
with the population at large, so we will have a measure of the
applicability of our findings. As of August 2005, the TBTN informatics
- Nearly completed development of an electronic data capture
adverse event reporting system for a very large multicenter
study (Study 26; enrollment goal, 8000 patients).
- Created a query tracking system (approximately 750 query
rules) for TBTC Study 26
- Developed a fully functional TBTC secure, members-only website
- Created TB Trials Network website www.tbtrialsnetwork.org
- Planned a data standards stakeholders meeting for fall 2005
In the first year of funding, the TBTN has already made significant
progress toward project goals. Through TBTN’s work, the U.S. public
health system can make important contributions to Dr. Zerhouni’s
roadmap initiative and ensure long-term support for programmatically
relevant clinical research carried out in public health settings.
Study enrollment updates:
Study 24 is a single-arm study of largely intermittent,
short-course therapy for patients with INH-resistant TB or INH intolerance.
Enrollment closed December 2004 with a total of 98 patients. By
mid 2007, all patients will have reached the end of follow-up for
study outcomes (treatment failure and relapse).
Study 26 is a trial of short-course treatment of latent
TB infection among contacts of active cases, using a 3-month once-weekly
regimen of isoniazid 900 mg and rifapentine 900 mg, compared to
standard 9-month therapy with isoniazid 300 mg. As of October 26,
2005, Study 26 enrollment was up to 5,178, over half the intended
subjects for total enrollment.
Study 27 is a double-blind, placebo-controlled comparison
of 2-month culture conversion rates when substituting moxifloxacin
for ethambutol in the initiation phase of treatment of pulmonary
TB. Enrollment began in July 2003 and was completed in March 2005,
with a total of 337 patients. Over 50% of patients were enrolled
from two African study sites. Preliminary results were presented
in May 2005 and showed there was no difference between study arms
in terms of time to sputum conversion. There were differences, however,
between North American sites and African sites, with significantly
more North American patients converting their sputum to negative
by 2 months (84%) compared to African patients (60%). Further analyses
Study 28 is a double-blind, placebo-controlled comparison
of 2-month culture conversion rates when substituting moxifloxacin
for isoniazid in the initiation phase of treatment of pulmonary
TB. This isoniazid-sparing regimen for TB treatment is based on
data from the murine model of tuberculosis; in this model, the substitution
of moxifloxacin for isoniazid resulted in significant reductions
in the time to culture conversion and the time to sterilization
when compared to the standard combination of rifampin, isoniazid,
and pyrazinamide. Improved sputum culture conversion after 2 months
of treatment with a moxifloxacin-containing regimen would support
phase 3 clinical trials of moxifloxacin-based treatment regimens
of less than the current 6-month standard regimens. The plan is
to enroll 410 patients from both domestic and international TBTC
sites. Enrollment is expected to begin in late 2005.
—Submitted by Susan M. Ray, MD
Emory Univ. School of Medicine
Member, Advocacy & External Relations Committee, TBTC