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

Date Published: September 6, 2019

Publisher: Public Library of Science

Author(s): Christian Lienhardt, Andrew A. Vernon, Marco Cavaleri, Sumati Nambiar, Payam Nahid

Abstract: Christian Lienhardt and colleagues discuss the importance of communication and coordination between regulators, researchers, and policy makers to ensure tuberculosis trials provide high-quality evidence for policy decisions.

Partial Text: 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].

In principle, regulatory authorities overseeing drug development have the primary responsibility of ensuring that the quality, efficacy, and safety of marketed medicinal products are adequate, conforming to currently defined standards. A key role of the regulatory authorities is to determine whether there is a positive benefit–risk balance to support use of the drug for the proposed indication and patient population.

Countries, technical agencies, donors, and other TB stakeholders, routinely seek guidance and advice from WHO on optimal disease management practices to be adopted based on the evidence available. Over the last decade, WHO has published a series of normative guidance documents for the diagnosis and treatment of all forms of TB, with a particular focus on the needs of low- and middle-income countries [13]. In 2007, WHO adopted a procedure to guarantee that guidelines are based on the best available evidence and meet the highest international standards. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, which relies on the use of systematic reviews and meta-analyses, the findings of these reviews are then considered in the context of implementation and feasibility issues of stakeholder countries [14, 15]. The GRADE framework provides an explicit and transparent approach to assess the level of certainty in the evidence across relevant studies and outcomes and to translate that evidence to recommendations. This framework incorporates multiple processes to minimize bias and optimize usability and requires rigor, fairness, and transparency in all judgments and decision-making.

Could outcome definitions in clinical trials be redesigned to satisfy both regulatory and programmatic decision-making needs? We argue that this is feasible, and WHO Technical Consultation on Advances in Clinical Trials Design for TB Treatment Regimen proposed features and designs that could address this need in greater detail and that are described in relevant papers of this Collection [2, 20].

For TB program managers and policy makers at the country level, the successful registration of a candidate drug is only one component of the decision-making process around adoption and use. Feasibility, acceptability, resource use, equity, and quality of life are also considered when formulating public health recommendations, and these rely on qualitative data that need to be collected in parallel to quantitative assessment of evidence.

Given the recent enthusiasm for pursuing novel trial designs in TB therapeutics [37, 39], more interactions will be needed between researchers responsible for designing the next generation of TB trials, regulators, and policy makers. This will allow better harmonization across the research pipeline and subsequent policies on access to TB medicines. Further, stakeholders, including donors and funders, need to acknowledge that both explanatory and pragmatic trials are needed to answer questions about efficacy and safety (explanatory) as well as expected effectiveness in programmatic conditions (pragmatic). In all cases, endpoints should be specific to the purposes. Late-phase clinical trial outputs that serve the objective of registration of a new TB drug or regimen can indeed meet the needs for development of public health guidelines, provided that data on long-term, patient-relevant, and population-relevant outcomes are being collected. Additionally, public health factors such as feasibility, acceptability, resource use, equity, and quality of life should be part of data collections, as these are necessary when formulating public health recommendations. The existing dialogue between drug developers and regulators should be expanded to policy makers under formal mechanisms of consultation, such as the one offered by WHO Task Forces [19]. More effective input from policy makers could greatly streamline and strengthen the value of TB clinical trial data in clinical settings. Such interactions with policy makers can be invaluable at the design stages and would result in better harmonization between the research pipeline and policies on access to TB medicines. The broad discussions that we propose would also ensure that secondary pooled analyses performed by WHO (or other policy-recommending bodies) are reliable and that the risk of conflicting interpretation and messaging provided by investigators and policy makers is reduced and usefully contribute to the generation of reliable and relevant data for further policy guidance on the treatment of all forms of TB [2].



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