Challenges of Phase III study design for trials of new drug regimens for the treatment of TB.

The standard WHO-recommended 6-month four-drug regimen for the treatment of tuberculosis is highly effective in clinical trial settings, but this level of efficacy is not always achieved in practice. Shorter, simpler regimens that promote better treatment adherence are urgently needed. In addition, it will be necessary to demonstrate noninferiority rather than superiority over the 6-month regimen. There are considerable challenges in designing and conducting noninferiority Phase III trials of new drug regimens. These include the choice of the margin of noninferiority, the primary outcome measure and strategies for handling nonassessable patients and reinfected patients in the analysis. Most of these trials are likely to be large and expensive and public-private partnerships will be required to conduct them.