Strategy and Aims
Developing even a single drug for tuberculosis is challenging but identifying the most effective treatment regimens is a completely new paradigm in the field. We need a way to facilitate the complex decisions around which doses and combinations of new drugs should enter clinical trials.PreDiCT-TB is pioneering a novel integrated methodology for preclinical systems capable of supporting effective development of TB combination regimens.We believe that only by adopting a more comprehensive and multidisciplinary scientific strategy can these problems be solved.
PreDiCT-TB aims to define the role of preclinical assays and models in the context of their performance in predicting clinical results.This goal can only be achieved by ensuring that the results obtained from these experiments retain their usefulness across the widest possible range of proven agents. In order to achieve this, the consortium will conduct the most comprehensive evaluation of combinations of existing and novel drugs to date using a broad and well-defined panel of preclinical systems.
These results will be replicated internally by multiple partners within the individual work packages while retaining some capability to evaluate a limited number of key experimental parameters.During the period of the project, however, we also aim to augment and improve the characteristics of these systems using novel technologies. Most prominent among these will be methods directed to understanding heterogeneity of pharmacodynamic response among which maybe included enhanced culture techniques, novel molecular mycobacteriological approaches and single cell imaging technologies.
The assembly of a comprehensive repository of pharmacokinetic, pharmacodynamic and clinical trial data will be the key calibrator of the preclinical results, in conjunction with more conventional criteria of assay or model cost, feasibility and reproducibility. Using a mathematical and statistical modelling approach we will formally propagate preclinical information into clinical trial simulation scenarios to make predictions of clinical performance which can compared with existing data.
Our overarching aims are three-fold:
To systematically evaluate two successive panels of representative anti-tuberculosis drugs (licensed and novel) using a suite of standard, novel and enhanced preclinical model systems, with respect to performance in clinical trials
To refine the set of preclinical systems on the basis of these results in order to identify and define the currently optimal critical path in discovery and pre-clinical development for tuberculosis.
To develop an integrated PK-PD/Disease modelling and simulation framework for tuberculosis which will facilitate prediction of optimal combinations and design of clinical studies.