Advances in clinical trial design: Weaving tomorrow's TB treatments.

Christian Lienhardt and co-authors discuss the conclusions of the PLOS Medicine Collection on advances in clinical trial design for development of new tuberculosis treatments.

Analysis of the clinical antibacterial and antituberculosis pipeline.

This analysis of the global clinical antibacterial pipeline was done in support of the Global Action Plan on Antimicrobial Resistance. The study analysed to what extent antibacterial and antimycobacterial drugs for systemic human use as well as oral non-systemic antibacterial drugs for Clostridium difficile infections were active against pathogens included in the WHO priority pathogen list and their innovativeness measured by their absence of cross-resistance (new class, target, mode of action). As of July 1, 2018, 30 new chemical entity (NCE) antibacterial drugs, ten biologics, ten NCEs against Mycobacterium tuberculosis, and four NCEs against C difficile were identified. Of the 30 NCEs, 11 are expected to have some activity against at least one critical priority pathogen expressing carbapenem resistance. The clinical pipeline is dominated by derivatives of established classes and most development candidates display limited innovation. New antibacterial drugs without pre-existing cross-resistance are under-represented and are urgently needed, especially for geographical regions with high resistance rates among Gram-negative bacteria and M tuberculosis.

New drugs for the treatment of tuberculosis: needs, challenges, promise, and prospects for the future.

For the first time in 40 years, a portfolio of promising new compounds for the treatment of tuberculosis is on the horizon. The introduction of new drugs in combination treatment for all forms of tuberculosis raises several issues related to patients' access to novel treatments, programmatic feasibility, cost effectiveness, and implications for monitoring and surveillance, particularly with regard to the development of drug resistance. Particular attention should be given to the identification of optimal drug combination(s) for the treatment of all forms of tuberculosis, particularly in high-risk and vulnerable groups, such as human immunodeficiency virus-coinfected persons and children, and to the rational use of new drugs. Addressing these issues adequately requires the establishment of clear guidelines to assist countries in the development of policies for the proper use of tuberculosis drugs in a way that guarantees access to best treatments for all those in need and avoids inappropriate use of new drugs. After a description of these various challenges, we present activities that will be carried out by the World Health Organization in collaboration with key stakeholders for the development of policy guidelines for optimal treatment of tuberculosis.

New drugs and new regimens for the treatment of tuberculosis: review of the drug development pipeline and implications for national programmes.

PURPOSE OF REVIEW: The aim is to review briefly the problems related to treatment of drug-susceptible and drug-resistant tuberculosis (TB), describe recent advances in the development of new drugs and new regimens, and discuss implications for control programmes. RECENT FINDINGS: Encouraging advances in TB drug research and development have been made since the turn of the century, resulting in a large number of new products introduced into the global portfolio. SUMMARY: Currently, nine compounds at least have advanced to clinical development, including four existing drugs redeveloped for TB indication and five new chemical entities. Present clinical trials are testing new combinations of drugs for a shortened treatment of drug-susceptible TB (<6 months duration) or the safety and efficacy of new drugs in addition to an optimized background therapy for the treatment of multidrug-resistant TB. There are at least 34 compounds or projects in the discovery and preclinical stages, including eight compounds in preclinical development. This increasing development of single compounds underscores the needs for a novel approach to test for optimal drug combinations that would be proposed for treatment of TB in all its forms, and the necessary collaboration of pharmaceutical companies, academia, research institutions, donors, and regulatory authorities.

Toward an optimized therapy for tuberculosis? Drugs in clinical trials and in preclinical development.

Tuberculosis (TB) continues to be one of the greatest challenges in the global public health arena. Current therapeutic agents against TB are old and inadequate, particularly in the face of many new challenges. Multidrug-resistant TB (MDR-TB) has become prevalent in many parts of the world and extensively drug-resistant TB (XDR-TB) is rapidly emerging. There are few or essentially no effective drugs available to treat these drug-resistant forms of TB. TB and human immunodeficiency virus (HIV) coinfection has become another major problem in areas with high prevalence of HIV infection. Simultaneous treatment of TB and HIV is difficult due to the severe drug-drug interactions between the first-line rifamycin-containing TB therapy and antiretroviral agents. However, there have been some encouraging developments in TB drug research and development within the past decade. At present there are 6 compounds, including 3 novel agents, in late stages of clinical development. There are even larger numbers of compounds and projects in the TB drug pipeline at the discovery stage and in early stages of clinical development, mainly targeting treatment shortening and drug resistance. Despite these encouraging developments, the current TB drug pipeline is not sufficient to address the multitude of challenges inherent in the current standard of TB therapy. A stronger TB drug pipeline and a new paradigm for the development of novel TB drug combinations are needed.