Accelerating the transition of new tuberculosis drug combinations from Phase II to Phase III trials: New technologies and innovative designs

Abstract

Geraint Davies and colleagues discuss the potential for innovative early-phase clinical trial methods and technologies to reduce risk and speed up drug development for tuberculosis.

Development of new TB regimens: Harmonizing trial design, product registration requirements, and public health guidance

“…In addition, combination of bacterial (e.g., minimum inhibitory concentration [MIC]) and host (e.g., pharmacokinetic characteristics, adherence, and perhaps genetic or other features) factors would be of value in dose selection and for predicting outcome [24, 25]. Relevant surrogate markers providing highly reliable estimates of treatment outcome, once realized, could provide sufficient evidence for guideline development beyond market approval [4], but until then, the TB therapeutics field has to look to novel trial designs, long-term endpoint definitions, and other trial features as a means to generating data pertinent to policy decisions [3].…”

“…Under the paradigm of adding a new drug to a regimen or substituting single drugs in a regimen one at a time, it would take 15–20 years to develop an entirely new tuberculosis (TB) regimen comprising three to four new drugs [1]. As has been noted in the papers of this Special Collection on Advances in Clinical Trial Design for Development of New TB Treatments [2–4], the major challenges in the development of new TB treatments include the long developmental pathway to identify best regimens, the uncertainties around the correlation between the treatment effect and existing surrogate endpoints, and uncertainties around the predictive quantitative relationships between Phase II and Phase III trial outcomes. Beyond measures of efficacy, the development of shorter, simpler regimens combining new and existing drugs also requires detailed information on their respective safety and toxicity, their potential for drug–drug interactions, their propensity for development of drug resistance while on therapy, and their use in specific patient populations such as persons infected with human immunodeficiency virus (HIV), pregnant women, and children [5].…”

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

“…Phase IIB studies test more stringently the efficacy of new drug regimens, using generally sputum culture conversion at 8 weeks as an endpoint [30]. Unhappily, as shown with the fluoroquinolone trials, Phase IIB studies are insufficient for predicting long-term outcomes and may fail to identify the degree of improved culture conversion necessary to achieve substantial treatment shortening [31].…”

TB Elimination Requires Discovery and Development of Transformational Agents

“…In this design, named "selection trial with extended post-treatment follow-up" (STEP), limited long-term follow-up data on relapse are collected, together with data on culture conversion, permitting estimation of a Bayesian prediction interval for the likely results of a future Phase III trial [23]. Such Phase IIB/C studies, with arms testing different doses and durations, coupled with the use of novel biomarkers for sterilising cures-these being either RNA expression, cytokine, bacterial or radiological markers-would strengthen and accelerate the process for identifying candidate regimens likely to succeed in Phase III [24], as well as prospectively validating novel biomarkers against the relapse endpoint.…”