Tuberculosis Trials Consortium (TBTC)
Since the 1940s the U.S. Public Health Service (USPHS), and the Department of Veterans Affairs have been part of TB control history because of their role in conducting drug studies for all anti-TB drugs still in use today. In 1960, the USPHS TB control and clinical research program was transferred to CDC from the National Institutes of Health in Maryland. At this time, the CDC began a series of clinical trials of rifampin that helped establish the recommendations for 6 month short-course outpatient therapy for TB. By comparison, TB patients in the early 1960s and before rifampin, had to endure treatment for 18-24 months, part of it in a hospital, and had to take an imposing total of over 600 doses of medication.
In the 1980s, when a declining TB trend led to declining TB funding, and shorter treatment had become the norm, support for TB drug trials slowed. Such was the lack of support for CDC’s clinical trials program that one of CDC’s studies (USPHS Study 21) was nearly terminated several times for lack of adequate funding. With the resurgence of TB, federal support for TB control was restored in the early 1990s. In 1993, CDC conducted the first open competition for a group of TB researchers whose study sites were capable of conducting TB clinical trials, and proceeded to fund them for a period of 5 years (1993–1998). CDC chose sites that met strict readiness criteria: access to TB patients, experience with clinical trials, demonstrated qualifications of the clinical team, and a good plan for recruitment, management, and follow-up of patients. The researchers and CDC decided to conduct first a randomized clinical trial comparing a once-weekly rifapentine-based regimen against the standard twice-weekly rifampin-based regimen, given after the first 2 months of intensive treatment for TB. This trial became USPHS-TBTC Study 22, the first clinical trial conducted by the TBTC: 1,075 TB patients from the US and Canada volunteered as participants.
In 1997 CDC and the investigators from the funded study sites formalized their collaboration, and the TBTC was thus officially created, with formal by-laws adopted in 1998. Several working committees were established. One committee (Core Science Group) develops the scientific program of research, a second (Implementation and Quality Group) supervises the conduct and quality of ongoing studies, and a third (External Relations Group) represents the TBTC to outside entities. The Executive Affairs Group serves as the executive arm of the Steering Committee. The Data Coordinating Center of the TBTC is housed in the Clinical and Health Systems Research Branch of CDC’s Division of Tuberculosis Elimination (DTBE). The TBTC CDC team is composed of medical officers, epidemiologists, trialist, data analysts, data managers, programmers, data clerks, multiple public health students and various administrative support staff, including an administrator for Institutional Review Board approvals.
In 1999 the TBTC underwent its second formal competitive process, to select the clinical trial sites that would comprise the TBTC during the most recent period of CDC-funded research: 1999–2009. The selection of sites at that time resulted in a consortium of 23 centers located in the United States and Canada. In 2003, the consortium gained an international presence by adding sites in Brazil, Spain, and Sub-Saharan Africa.
Since its inception, the TBTC has undertaken nine major trials and 15 sub-studies. The completed TBTC studies have resulted in 25 publications in peer-reviewed journals, as well as over 100 presentations, posters, and abstracts at major medical or scientific meetings. The results of TBTC Study 22 significantly influenced the most recent American Thoracic Society (ATS)/CDC guidelines for treatment of TB (published in 2003); other TBTC study results have led to modification of CDC’s recommendations for treatment of TB and HIV.
In 2009 the TBTC underwent its third formal external re-competition. In the next decade (2010–2020), TBTC patient enrollment will shift from clinical sites located mostly in North America to sites which are predominantly international. The recent recompetition has expanded TBTC’s international presence from a few clinical study sites located outside of North America, to sites in Brazil (two sites), Peru, Spain, South Africa (two sites), Uganda, Kenya, Vietnam, and China (Hong Kong). The TBTC 2010–2020 research group also includes U.S. sites in New Jersey, New York, Washington DC, Texas (four sites), Colorado, Tennessee, and North Carolina. Some of the TBTC sites in and outside North America are linked, in that CDC awarded funds for the international study sites to the U.S.-based institutions that proposed them as partners in the competitive process.
TBTC Study Sites and Partner Institutions 2010-2020
The infrastructure of the TB Trials Consortium includes:
- A network of clinical sites worldwide whose principal investigators are recognized experts in tuberculosis treatment and prevention
- Experienced clinical coordinators and outreach workers at each of the funded sites
- Extensive communications systems, including biannual conferences
- Close and collaborative relationships with local TB control programs to facilitate the recruitment and management of trial patients
- An expert Data & Safety Monitoring Board, which reviews active protocols
- Coordination with the CDC IRB and local IRBs, and support for a CDC-based Central IRB process
- A Data and Coordinating Center at the Centers for Disease Control and Prevention (CDC) in Atlanta
- Cooperative relationships with key manufacturers of TB drugs
- Support for monitoring, training, and protocol development from a leading international contract research organization
- Laboratory support from the national reference laboratory housed in the Mycobacteriology Laboratory Branch at CDC
TBTC clinical trials have enrolled more than 12,000 patients and volunteers over the past 15 years. The consortium's annual operating budget is approximately $11,000,000.00. Confronting the many challenges to the successful development of new TB drugs and treatment regimens, the TBTC looks forward with optimism. The late pipeline of new anti-TB drug candidates is the most promising in 40 years, and advances in TB clinical trials science have fostered the progress of these agents. With commitment and support from CDC, the TBTC provides a unique resource for these clinical studies, and will continue to play an important role in improving TB treatment, prevention and control. Currently the TBTC is concluding a study of an innovative ultra-short-course treatment for latent tuberculosis infection (i.e., TB preventive therapy, results expected in mid-2011), and has begun its first clinical trial in patients with multidrug-resistant TB.
Developing new TB treatment and prevention strategies depends upon collaboration among academic, private sector and government researchers and non-governmental organizations. CDC works closely with such organizations as the Food and Drug Administration, the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID), the Global Alliance for TB Drug Development (TB Alliance), the Foundation for Innovative New Diagnostics (FIND), the Johns Hopkins Center for Tuberculosis Research, the TB Research Unit at Case Western Reserve University, commercial drug manufacturers, and others within and outside the United States.