1Background

The emergence of drug-resistant tuberculosis is a major threat to global tuberculosis care and control. WHO estimates that around 480,000 new multidrug-resistant tuberculosis (MDR-TB)¹ cases occurred in the world in 2013 (5). Current treatment regimens for drug-resistant TB are far from satisfactory. Whereas most patients with drug-susceptible TB can usually be cured with a six-month course of treatment, in most MDR-TB cases a treatment length of 20 months or more is used, requiring the daily administration of drugs that are more toxic, more expensive and less effective than those used to treat drug-susceptible TB. Only about half of MDR-TB patients started on treatment globally are treated successfully, as a result of loss to follow-up (28%), commonly associated with adverse drug reactions and high costs associated with treatment, and high frequency of death (15%). In addition, it is estimated that up to a third of MDR-TB cases may have strains with additional resistance to fluoroquinolones and/or injectable second-line drugs (aminoglycosides or capreomycin), rendering their treatment even more difficult, with recourse only to highly toxic drugs. Finally, the global deployment of rapid diagnostics for drug resistance, such as the Xpert MTB/RIF assay, has increased the demand for treatment of MDR-TB patients, and this has not been matched by a similar expansion in the provision of appropriate treatment for diagnosed cases. The increased global scale-up of rapid tests to diagnose MDR-TB cases is bound to make this gap even wider in the coming years. The lack of effective and affordable drugs for the treatment of MDR-TB is a critical factor in the inability of programmes to scale-up their treatment efforts to meet national and global targets.

The landscape of drug development for treatment of TB has evolved dramatically over the last ten years, and novel drugs are presently or soon entering Phase III trials for the treatment of MDR-TB. Dossiers have been submitted to stringent regulatory authorities (SRAs) under procedures of “accelerated” or “conditional” approval for marketing these new drugs. Among these, bedaquiline, a diarylquinoline, was approved by the US Food and Drug Administration (FDA) in December 2012, and WHO issued interim guidance for its use in the treatment of MDR-TB in June 2013(6). Delamanid, a nitro-imidazole, another new compound, has been granted a conditional marketing authorisation by the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) on the 28th April 2014 (7). Dossiers are currently being submitted to several national regulatory authorities and are being evaluated under procedures of “accelerated” or “conditional” approval based on early (Phase IIb) clinical data, and Member States have expressed the need for WHO to provide interim advice on the use of delamanid in MDR-TB treatment.

Considering the global MDR-TB crisis, the limited therapeutic options available for this life-threatening condition, and the need to promote safe and responsible use of TB drugs, WHO has evaluated the added value of delamanid within the context of existing guidelines on programmatic management of MDR-TB. An Expert Group Meeting was convened in April 2014 in Geneva to review the available evidence on the efficacy, safety and effectiveness of this new drug for the treatment of MDR-TB, and to recommend whether WHO interim guidance on the use of this drug in treatment of MDR-TB is warranted. As in the case of bedaquiline (6), it is acknowledged that issuing interim guidance carries the responsibility to ensure that this guidance provides specific recommendations on the conditions for the use of the drug that reflect the limited data currently available. WHO will review, revise or update the interim guidance as additional substantive data on efficacy and safety become available. Acceleration of Phase III trials and completion at the earliest opportunity is imperative, as is timely analysis of emerging operational data on the use of the drug. It should also be noted that, in the absence of interim guidance from WHO, uncontrolled and potentially irresponsible use of the new drug may adversely affect TB care and control efforts overall – with emergence of additional drug resistance and the possible loss of a new drug for TB chemotherapy.