Advances in clinical trial design: Weaving tomorrow’s TB treatments

points• The development process for new tuberculosis (TB) regimens remains slow and costly.In this concluding paper of the PLOS Medicine Special Collection, we highlight the key suggestions made at a WHO Technical Consultation on "Advances in Clinical Trial Design for Development of New TB Treatments" held in 2018 to address this challenge.• Pharmacokinetics and pharmacodynamics (PK-PD) properties of candidate drugs are critical for constructing effective combination regimens.Bridging PK-PD methods to the analysis of Phase II studies and integrating longitudinal culture results would help with clarifying dose-response relationships and to link drug exposure to bactericidal activity; this would provide valuable insights for the identification of the components of suitable regimens.• New adaptive designs can accelerate Phase II and III trials and improve our ability to select regimens early for further investigation.Among these, the integration of extended posttreatment follow-up with collection of real-time treatment outcomes in the new hybrid Phase IIC design, with features drawn from both Phase II and Phase III trials, permits earlier identification of candidate regimens likely to succeed in Phase III.• Once the efficacy of a regimen is demonstrated in high-quality randomized controlled trial(s), the assessment of its effectiveness under programmatic conditions may permit an estimation of the amount of nonadherence that could substantially alter the likelihood of treatment success.• Vulnerable populations, such as children, pregnant women, and people with HIV infection, should be included in clinical trials from the outset, as these groups have unique characteristics regarding PK, safety, and efficacy, which necessitate special attention in drug and regimen development.• We advocate here for a better systematization and harmonization of the approaches taken internationally to ensure that best practices and novel research designs are used to accelerate development of new TB regimens.