Advances in clinical trial design for development of new TB treatments: A call for innovation
Authors: Christian Lienhardt, Payam Nahid
Journal: PLoS Medicine (2019)

After decades of stagnation, research in tuberculosis (TB) therapeutics is experiencing a renaissance, with an increasing number of new and repurposed compounds undergoing evaluation as part of novel treatment regimens.This is much welcome progress, since current regimens are not ideal due to the long duration of treatment required, toxicities, drug-drug interactions, and high costs-particularly for treatment of the various forms of drug-resistant TB (DR-TB).The development of new TB drugs is, however, complex, lengthy, and costly [1], and the pathway to proven new TB treatment regimens is fraught with numerous obstacles and uncertainties [2].In this PLOS Medicine Collection, "Advances in Clinical Trial Design for Development of New Tuberculosis Treatments," we highlight key obstacles and identify potential solutions that will help avoid misadventures and in turn maximize the likelihood of success in identifying new drugs and regimens through a rejuvenated global interest in TB therapeutics.With the emergence of several new chemical entities expected to transition into clinical testing in the next 5 years, the possibility of ultrashort (i.e., requiring treatment for weeks rather than months) regimens for active TB is no longer fanciful.Investigators in the field have learned much from recent TB clinical studies, and we anticipate that well-designed and conducted clinical trials evaluating the next generation of drugs and regimens will, with some good fortune, lead to identification of the ultrashort, safe, and effective regimens so desperately needed.Treatment of TB relies on a synergistic combination of drugs (traditionally categorized as bactericidal or sterilizing) administered for sufficient time to achieve definitive nonrelapsing cure and to prevent selection of drug-resistant mutants [3].The treatment of drug-susceptible TB (DS-TB) is well codified, with a standard combination of 4 drugs given for a duration of 6 months [4].This regimen is the result of a series of clinical studies conducted in several countries, which demonstrated the efficacy of short-course regimens of 6-8 months' duration in patients with pulmonary disease [5].These trials played a key role in the establishment of short-course chemotherapy worldwide, allowing treatment of DS-TB to be based on the best available evidence [6].Since then, clinical trials and programmatic experience have shown that the standard 6-month isoniazid/rifampicin-based regimen, when adhered to, performs consistently well in a wide variety of settings and can serve as a reliable control regimen against which investigational regimens can be compared [4].The situation is, however, more complicated for DR-TB.In the absence of controlled trials comparing different regimens to a recognized "gold standard" treatment, the current recommendations for therapy rely on early-phase culture-conversion results, observational studies, and a few late-phase clinical trials [7].The number and type of drugs required to treat patients with DR-TB has long been a matter of