title: Challenges in the clinical assessment of novel tuberculosis drugs.
abstract: To tackle the global TB epidemic effectively, novel treatment strategies are critically needed to shorten the duration of TB therapy and treat drug-resistant TB. Drug development for TB, stymied for decades, has enjoyed a renaissance over the past several years. However, the development of new TB regimens is hindered by the limitations in our understanding and use of preclinical models; the paucity of accurate, early surrogate markers of cure, and challenges in untangling the individual contributions of drugs to multidrug regimens in a complex, multi-compartment disease. Lack of profit motive, advocacy, and imagination has contributed mightily to the dearth of drugs we have on the shelf to treat this ancient disease. Areas that will speed the development of new regimens for TB include novel murine and in vitro pharmacodynamics models, clinical endpoints that are not culture-based, innovative clinical trial designs, and an infusion of much-needed funding.
authors.affiliation: Divisions of Clinical Pharmacology & Infectious Diseases, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Osler 527, Baltimore, MD, 2187, USA. Electronic address: kdooley1@jhmi.edu.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.affiliation: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC1B 6NH, UK. Electronic address: Patrick.phillips@ucl.ac.uk.
authors.forename: Patrick P J
authors.initials: PP
authors.lastname: Phillips
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, at San Francisco General Hospital, 1001 Potrero Ave., 5K1, San Francisco, CA, USA. Electronic address: pnahid@ucsf.edu.
authors.forename: Payam
authors.initials: P
authors.lastname: Nahid
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Leopoldstrasse 5, 80802 Munich, Germany; German Centre for Infection Research (DZIF), Leopoldstrasse 5, 80802 Munich, Germany; German Centre for Infection Research, Leopoldstrasse 5, 80802 Munich, Germany. Electronic address: hoelscher@lrz.uni-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
mesh_terms: D000818:Animals; D000995:Antitubercular Agents; D055808:Drug Discovery; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D009169:Mycobacterium tuberculosis; D014376:Tuberculosis / Q000188:drug therapy; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents
keywords: Hollow fiber model; Mouse model; Pharmacokinetic/pharmacodynamic; Translational science; Trial design; Tuberculosis
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