Leonard Sacks, M.D., Associate Director for Clinical Methodology, Office of Medical Policy, Center for Drug Evaluation and Research
Tuberculosis (TB) remains a major public health concern. It continues to affect millions of people worldwide each year, and a significant portion of these cases are resistant to first-line treatment. Moreover, current TB treatment is burdensome. Patients must take several drugs over the course of at least six months, and then be monitored for relapse for up to 18 months. In about one in 20 patients, the disease will return, but it is difficult to predict who is most at risk for relapse.
Measuring biological markers, or biomarkers, to track the course of a disease or a patient’s response to a drug is common in basic and clinical research, as well as in clinical practice. Biomarkers may allow for the evaluation of the effect of drugs more quickly without having to wait months or years for a measurable clinical outcome.
Currently, patients undergoing treatment for TB are tested for the presence of TB bacilli remaining in sputum after two months of treatment. At this point, bacilli are no longer detectable in about 85 percent of patients. This is called the “two-month conversion rate,” and it usually suggests a low risk for relapse. However, it is not always highly accurate, and therefore cannot be used as a biomarker for measuring the efficacy of new drugs being tested to treat TB.
Reliable biomarkers to assess treatment outcome are critical tools that would revitalize TB drug development. In particular, there is a need to identify better biomarkers that will more precisely predict risk of relapse. Such biomarkers may include lingering byproducts of the bacteria we have not yet been able to detect, or immunological biomarkers produced by patients with TB indicating whether or not they have been cured. Identifying biomarkers that predict the course of a disease is a costly and difficult undertaking. A major obstacle to this type of research has been access to complete patient samples taken throughout the course of treatment.
Overcoming the Obstacles to Identifying TB Biomarkers
The development of new TB drugs has been hampered by the lack of biomarkers that could be used to predict which patients are permanently cured and which patients are at risk for a relapse. The TB Biorepository Project, first established in 2010 with a grant from the FDA, offers prospectively collected, sequential biospecimens from TB patients to researchers and drug developers who are working to identify biomarkers that can be used in clinical trials of new drugs. The Biorepository, which now receives funding from the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation, is managed by the Consortium for TB Biomarkers (CTB2) . The CTB2 is a collaboration among the TB Alliance, the TB Trials Consortium within the Centers for Disease Control and Prevention, and the AIDS Clinical Trials Group, which is funded by the NIH’s National Institute of Allergy and Infectious Diseases.
The TB Biorepository stores de-identified samples of blood, urine and sputum from patients with drug-sensitive TB who have participated in clinical trials or national treatment programs around the world. Multiple samples are taken over 52 weeks from the time that patients start treatment. Corresponding clinical data are collected with each specimen, and data on the long-term outcome of treatment are taken 18 months after starting treatment. The first patient samples in the biobank were obtained from the TB Alliance’s international REMoxTB clinical trial, which was concluded in 2013. Additional samples are now being collected in collaboration with ongoing clinical trials, studies or treatment programs in the United States, South Africa and other parts of the world. The Biorepository, which currently holds multiple sequential samples from about 500 patients, aims to collect samples from 1,000 patients—both those who have been cured and those who have experienced a relapse during follow-up.
The Biorepository can provide qualified investigators with complete, well-categorized biospecimens to develop or validate potential biomarkers, and determine whether what is being measured is actually predicting disease outcome.