What Research Is Needed to Stop TB? Introducing the TB Research Movement

With 9.4 million new cases and 1.7 million deaths worldwide in 2009, tuberculosis (TB) constitutes an unacceptable burden of human suffering and loss [1]. The tools available for TB control are old, lack effectiveness, and are not readily accessible in many settings: the diagnosis of pulmonary TB still relies in most high-burden countries on sputum microscopy, a century old technology; treatment of tuberculosis is based on drugs that are over 40 years old and requires direct supervision to ensure full treatment adherence and prevent drug resistance; and the only TB vaccine (BCG), first used in 1922, has a variable protective efficacy in adults. Novel tools are needed for better TB care and control worldwide [2]. Research has a key role to play in meeting health and development goals. Based on the World Health Organization's (WHO) Stop TB Strategy, the Stop TB Partnership has developed the Global Plan to Stop TB 2011–2015, which lays out the activities to be achieved by 2015 towards elimination of TB (defined as ≤1 TB case per million population per year) by 2050 [3]. The plan sets out a roadmap for halving TB prevalence and deaths globally by 2015, compared with 1990 levels. However, while it is estimated that the incidence rate of TB has been falling globally since 2004, the present rate of decline (less than 1% per year) is insufficient to reach the elimination goal by 2050 [1]. Any realistic prospect of achieving this goal depends both on the better and wider use of existing technologies and the development of revolutionary new technologies for TB control. This would be possible only through an acceleration of research across the continuum, from basic to implementation [4]. Recognizing this, the Stop TB Partnership and the WHO Stop TB Department have launched the TB Research Movement, with the aim of boosting TB research and accelerating progress in TB control towards international targets [5],[6]. We describe here the strategy developed to address the objectives (Box 1) of the Research Movement and the progress made over the last 2 years. Box 1. The TB Research Movement Objectives Objectives of the Research Movement: To provide leadership and advocacy to mobilize increased resources in support of a coherent and comprehensive global TB research agenda to meet the Stop TB goals and targets; and To provide a forum for funders and implementers of TB research to coordinate plans and actions, with the result of ensuring that research needs are addressed, opportunities identified, and gaps filled. The Research Movement Strategic Plan The TB Research Movement is based at the Stop TB Partnership secretariat, housed by the WHO in Geneva, and works in close collaboration with the WHO Stop TB Department and with the Working Groups of the Stop TB Partnership. It operates as an umbrella for research-related issues at the Partnership, and receives advice from the Partnership Coordinating Board and the WHO. The strategy plan developed to address the main objectives of the Research Movement has two major components: (1) the analysis of global TB research funding (aimed at estimating the funding gap); and (2) the development of a global TB research roadmap (representing a consensus on global needs across the TB research spectrum). To this end, the Research Movement has mobilized a broad alliance of stakeholders involved in TB research and development, including scientists involved in basic, applied, and operational research, TB control managers and public health officers, donors and aid agencies, and patients and community representatives. Analysis of Global TB Research Funding Mapping the research funding environment involves answering the questions “who is funding TB research and development (R&D)?”, “what is being funded?”, and “how much is being granted?”. For this, the Research Movement has joined with the Treatment Action Group's (TAG) efforts in evaluating the global landscape of funding in TB R&D, through a worldwide survey of funders and donors. This survey has been carried out regularly since 2005 and brings elements of responses to the questions above and helps monitor the trends in funding TB R&D internationally [7] (Figure 1). Figure 1 Investment in TB R&D by research category: 2005–2009 (from TAG report 2010). The revised Global Plan to Stop TB 2011–2015 estimates that at least US$9.8 billion are needed in TB R&D over the next 5 years to reach the targets of 50% reduction in TB prevalence and mortality by 2015, more than twice those estimated in the initial Global Plan to Stop TB 2006–2015 (Table 1) [8]. Importantly, this updated Global Plan includes target investments for fundamental and operationalresearch, on top of the R&D for new drugs, diagnostics, and vaccines. Table 1 Global Plan to Stop TB 2011–2015: total needs (US$ billion). From the above, the research funding gap can be estimated by comparing the results of the R&D funding survey to the research needs outlined in the Global Plan to Stop TB 2011–2015. Based on TAG Report 2010 [7], assuming that 2009 funding estimates are maintained throughout 2011–2015, and adjusting for inflation, the total funding gap for the next 5 years (2011–2015) is estimated at US$6.4 billion (64%) (Figure 2). The biggest gap in absolute terms is in R&D of new drugs, but the largest in relative terms (as a percentage of total funding required for that component) is R&D of new diagnostics. Remarkably, despite a significant boost in funding R&D for new tools in the past few years, TB research globally remains grossly underfunded, with a funding gap that is disproportionately greater for TB research (60%) than for implementation (35%) (Table 2). Figure 2 Funding required and available by research component 2011–2015. Table 2 Funding required and funding available under two possible scenarios and likely funding gaps (US$ billions). The Global TB Research Roadmap In compiling a global TB research agenda, the fundamental question is “what research is required to stop TB?” This involves answering the questions of “what are we researching in TB?” and “are we trying to answer the right questions?”, i.e., “are we doing studies in areas where evidence is lacking?”. In addressing these questions, we needed to identify critical gaps in research that represent bottlenecks for development of new tools. This allowed the development of a coherent and comprehensive global TB research roadmap towards TB elimination that encompasses all aspects of research, from basic science for discovery, to development of new tools, and their optimal uptake for better TB control. The steps in developing the global TB research roadmap include a series of consecutive activities that are described below: (1) an inventory of the research agendas; (2) the development of key research questions; and (3) the prioritization of research questions. Inventory of TB research agendas Over the past decade, a variety of research agendas has been developed by various groups. A systematic review of these TB research agendas was carried out to evaluate the main research questions and themes, assess the methods used to select priorities, and identify any consistent message emerging from these agendas [9]. The review identified 33 papers. The priority areas for research were: drug development (28 articles), diagnosis (27), epidemiology (20), health services research (16), basic research (13), and vaccine development (13) (Table 3). Research questions were usually quite broad in scope. The most focused questions were on treatment and prevention of multidrug-resistant TB and TB/HIV co-infection, reflecting the inefficiencies of sputum-smear microscopy and the limits of the currently recommended short-course chemotherapy, which is inefficient against drug-resistant forms of the disease and is difficult to combine with standard antiretroviral therapy. The importance of epidemiology and health system research probably reflects the need for studies to optimize the availability and cost-effectiveness of interventions for TB control. The relatively low priority assigned to basic research may indicate the difficulty of establishing an agenda in a field that is mostly investigator driven. Table 3 Number of studies identifying priority topics for TB research in a systematic review of 33 articles with TB research priorities. The methods used to identify priorities in these various agendas varied greatly. Most of these relied on expert meetings with consensus seeking, but few used objectively measurable criteria to select research priorities. Increased recourse to systematic reviews and use of clearly described and reproducible criteria to assess the importance of the research questions would greatly help in the establishment of research priorities.