FDA approval of bedaquiline--the benefit-risk balance for drug-resistant tuberculosis.

n engl j med 371;8 nejm.org august 21, 2014 689 regimen is not otherwise available.1 One complexity facing the FDA in reviewing the bedaquiline marketing application was that in one of the phase 2 studies, there were more deaths among patients who had bedaquiline added to a background antimycobacterial drug regimen than among those who had placebo added to the same regimen, despite relatively clear evidence of bedaquiline’s efficacy in clearing Mycobacterium tuberculosis from sputum. Given this imbalance in mortality, the approval of bedaquiline has appeared paradoxical to some.2 But marketing applications that are reviewed by the FDA often rely on complex risk–benefit evaluations. (The 120-week final results of the aforementioned phase 2 study are reported by Diacon et al. in this is sue of the Journal [pages 723–732]; the marketing application, however, contained only efficacy data that were available at week 72.) According to the World Health Organization (WHO), the global burden of tuberculosis remains enormous, with an estimated 8.6 million new cases in 2012.3 Without effective treatment, tuberculosis is associated with substantial morbidity and mortality. Among sputum-smear–positive cases of pulmonary tuberculosis in HIVnegative patients, the estimated 10-year case fatality rate is 70%.4 The 27 countries with a high burden of multidrug-resistant pulmonary tuberculosis have been reporting increasing numbers of such cases to the WHO; the estimated incidence reached nearly 450,000 worldwide in 2012.3 Bedaquiline is an antimycobacterial drug that operates by a new mechanism of action: it inhibits mycobacterial ATP synthetase and depletes cellular energy stores. Since its mechanism differs from those of other available antimycobacterial drugs, it has the capacity to retain activity against some M. tuberculosis isolates that are resistant to other drugs and hence may provide an important treatment option for patients with multidrug-resistant pulmonary tuberculosis when an effective multidrug treatment regimen cannot otherwise be constructed. Bedaquiline was approved under the FDA’s accelerated-approval regulations, which allow for the approval of drugs for serious or lifethreatening conditions that provide FDA Approval of Bedaquiline — The Benefit–Risk Balance for Drug-Resistant Tuberculosis