Advances In Clinical Trial Design For

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Advances in Clinical Trial Design forDevelopment of New Treatments forTuberculosisAbout this PLOS CollectionWith recent opportunities to test combinations of new and repurposed drugs for the treatment ofTB, new questions arise for optimal clinical trial design. To address these, in March 2018 WHOorganized a consultation on “Advances in Clinical Trial Design for New TB Treatments” to identifyand outline the optimal characteristics of clinical trial designs to inform policy guidance for newTB regimens. This PLOS Medicine Special Collection assembles a series of articles on currentreflections and describes essential new steps in clinical research that will pave the way for thedevelopment of tomorrow’s optimal treatment for all forms of TB.To read the Special Collection online, visit OS Special Collection PartnersFrench National Research Institute for Sustainable Development World Health Organization

Table of ContentsIntroductionAdvances in clinical trial design for development of new TB treatments: A call forinnovationChristian Lienhardt, Payam NahidPLOS MedicinePublished: March 22, 2019 DOI: 10.1371/journal.pmed.1002769 . . . 1Definition of new regimens: early clinical developmentAdvancing the development of new tuberculosis treatment regimens: The essential role oftranslational and clinical pharmacology and microbiologyKelly E. Dooley, Debra Hanna, Vidya Mave, Kathleen Eisenach, Radojka M. SavicPLOS MedicinePublished: July 5, 2019 DOI: 10.1371/journal.pmed.1002842. . . . 6Accelerating the transition of new tuberculosis drug combinations from Phase II toPhase III trials: New technologies and innovative designsGeraint Davies, Martin Boeree, Dave Hermann, Michael HoelscherPLOS MedicinePublished: July 9, 2019 DOI: 10.1371/journal.pmed.1002851 . . . . . 20New trial designs and how they may facilitate regimen developmentKeeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscapePatrick P. J. Phillips, Carole D. Mitnick, James D. Neaton, Payam Nahid, Christian Lienhardt, Andrew J. NunnPLOS MedicinePublished: March 22, 2019 DOI: 10.1371/journal.pmed.1002767 . . . 3 0Designing noninferiority tuberculosis treatment trials: Identifying practical advantagesfor drug regimens with acceptable effectivenessPiero L. Olliaro, Michel VaillantPLOS MedicinePublished: July 12, 2019 DOI: 10.1371/journal.pmed.1002850 . . . 45

Considering subjects: trial adherence and special populationsThe importance of adherence in tuberculosis treatment clinical trials and its relevance inexplanatory and pragmatic trialsAndrew Vernon, Katherine Fielding, Rada Savic, Lori Dodd, Payam NahidPLOS MedicinePublished: December 10, 2019 10.1371/journal.pmed.1002884 . . . 5 9Inclusion of key populations in clinical trials of new antituberculosis treatments: Currentbarriers and recommendations for pregnant and lactating women, children, and HIVinfected personsAmita Gupta, Michael D. Hughes, Anthony J. Garcia-Prats, Katherine McIntire, Anneke C. HesselingPLOS MedicinePublished: August 15, 2019 10.1371/journal.pmed.1002882 . 6 9From trials to guidance: bringing evidence to best programme and practiceDevelopment of new TB regimens: Harmonizing trial design, product registrationrequirements, and public health guidanceChristian Lienhardt, Andrew A. Vernon, Marco Cavaleri, Sumati Nambiar, Payam NahidPLOS MedicinePublished: September 6, 2019 10.1371/journal.pmed.1002915 . 9 5Advances in clinical trial design for development of new TB treatments—Translatinginternational tuberculosis treatment guidelines into national strategic plans: Experiencesfrom Belarus, South Africa, and VietnamGrania Brigden, Nguyen Viet Nhung, Alena Skrahina, Norbert Ndjeka, Dennis Falzon, Matteo ZignolPLOS MedicinePublished: October 18, 2019 10.1371/journal.pmed.1002896 . 10 8ConclusionAdvances in clinical trial design: Weaving tomorrow’s TB treatmentsChristian Lienhardt, Andrew Nunn, Richard Chaisson, Andrew A. Vernon, Matteo Zignol, Payam Nahid, Eric Delaporte,Tereza KasaevaPLOS MedicinePublished: February 27, 2020 10.1371/journal.pmed.1003059. 12 0

PERSPECTIVEAdvances in clinical trial design fordevelopment of new TB treatments: A call forinnovationChristian Lienhardt ID1*, Payam Nahid ID21 Unité Mixte Internationale TransVIHMI (UMI 233 IRD–U1175 INSERM, Université de Montpellier), Institutde Recherche pour le Développement (IRD), Montpellier, France, 2 Division of Pulmonary and Critical CareMedicine, University of California San Francisco, San Francisco, California, United States of America* 111111111a1111111111a1111111111OPEN ACCESSCitation: Lienhardt C, Nahid P (2019) Advances inclinical trial design for development of new TBtreatments: A call for innovation. PLoS Med 16(3):e1002769. hed: March 22, 2019Copyright: 2019 World Health Organization.Licensee Public Library of Science. This is an openaccess article distributed under the CreativeCommons Attribution IGO License, which permitsunrestricted use, distribution, and reproduction inany medium, provided the original work is properlycited. http://creativecommons.org/licenses/by/3.0/igo/. In any use of this article, there should be nosuggestion that WHO endorses any specificorganization, products or services. The use of theWHO logo is not permitted. This notice should bepreserved along with the article’s original URL.Funding: The authors received no specific fundingfor this work.Competing interests: The authors have declaredthat no competing interests exist.Abbreviations: DR-TB, drug-resistant TB; DS-TB,drug-susceptible TB; TB, tuberculosis; TPP, targetproduct profile; TRP, target regimen profile.Provenance: Not commissioned; part of aCollection; not externally peer reviewed.After decades of stagnation, research in tuberculosis (TB) therapeutics is experiencing a renaissance, with an increasing number of new and repurposed compounds undergoing evaluationas part of novel treatment regimens. This is much welcome progress, since current regimensare not ideal due to the long duration of treatment required, toxicities, drug–drug interactions,and high costs—particularly for treatment of the various forms of drug-resistant TB (DR-TB).The development of new TB drugs is, however, complex, lengthy, and costly [1], and thepathway to proven new TB treatment regimens is fraught with numerous obstacles and uncertainties [2]. In this PLOS Medicine Collection, “Advances in Clinical Trial Design for Development of New Tuberculosis Treatments,” we highlight key obstacles and identify potentialsolutions that will help avoid misadventures and in turn maximize the likelihood of success inidentifying new drugs and regimens through a rejuvenated global interest in TB therapeutics.With the emergence of several new chemical entities expected to transition into clinical testingin the next 5 years, the possibility of ultrashort (i.e., requiring treatment for weeks rather thanmonths) regimens for active TB is no longer fanciful. Investigators in the field have learnedmuch from recent TB clinical studies, and we anticipate that well-designed and conductedclinical trials evaluating the next generation of drugs and regimens will, with some good fortune, lead to identification of the ultrashort, safe, and effective regimens so desperately needed.Treatment of TB relies on a synergistic combination of drugs (traditionally categorized asbactericidal or sterilizing) administered for sufficient time to achieve definitive nonrelapsingcure and to prevent selection of drug-resistant mutants [3]. The treatment of drug-susceptibleTB (DS-TB) is well codified, with a standard combination of 4 drugs given for a duration of 6months [4]. This regimen is the result of a series of clinical studies conducted in several countries, which demonstrated the efficacy of short-course regimens of 6–8 months’ duration inpatients with pulmonary disease [5]. These trials played a key role in the establishment ofshort-course chemotherapy worldwide, allowing treatment of DS-TB to be based on the bestavailable evidence [6]. Since then, clinical trials and programmatic experience have shown thatthe standard 6-month isoniazid/rifampicin-based regimen, when adhered to, performs consistently well in a wide variety of settings and can serve as a reliable control regimen againstwhich investigational regimens can be compared [4]. The situation is, however, more complicated for DR-TB. In the absence of controlled trials comparing different regimens to a recognized “gold standard” treatment, the current recommendations for therapy rely on early-phaseculture-conversion results, observational studies, and a few late-phase clinical trials [7]. Thenumber and type of drugs required to treat patients with DR-TB has long been a matter ofPLOS Medicine https://doi.org/10.1371/journal.pmed.1002769 March 22, 20191

debate and controversy despite agreement on basic principles such as the minimum numberof drugs to use and minimum duration of treatment. As a result, the efficacy of recommendedDR-TB treatment regimens has been shown to vary widely in clinical studies and programs[8,9].The need for solid evidence from randomized controlled trials has led the TB research community to adopt a design widely used in HIV research for the development of new antiretrovirals, in which patients are randomized to receive either a new drug or placebo in addition to adefined “optimized background regimen,” usually the best available standard of care [10]. Thisapproach has been used in the development of bedaquiline [11] and delamanid [12], the firsttwo new drugs approved for TB treatment since the late 1980s. While this research designassesses the added value, if any, of a given investigational drug, the approach leaves unresolvedthe question of the optimal drug combination in which to include the new agent [13]. As aresult, additional clinical trials are then needed to identify the best options for treatment usingnew drugs in variable combinations, resulting in additional years of delay in producing thebest evidence for global policy-making decisions. In parallel, practical recommendations areneeded for the use of any newly approved drugs, along with guidance for countries and programs as to which combinations are safe, tolerable, and efficacious, an endeavor that requiressystematic reviews and meta-analyses of observational cohort studies and programmatic data,which carry significant limitations. This approach is not sustainable, practical, or efficient andraises the need for a shift to a more efficient and seamless development process that allows thetesting of novel treatment regimens, including one or more promising new or repurposedmedicines, early in the clinical development pathway. Some stakeholders, such as the TB Alliance, therefore proposed a “unified approach to TB regimen development” addressing thejoint development of new drugs and regimens for both DS-TB and DR-TB [14]. Also, theInternational Union against Tuberculosis and Lung Diseases opted to investigate the safetyand efficacy of a set combination regimen of 9–12-months’ duration for the treatment ofDR-TB in parallel through a randomized controlled trial [15] and observational studies undertaken within programmatic research conditions [16]. However, the availability of results fromthese various studies at different points in time and questions arising from the challenge ofinterpreting and integrating data from various methodologies were found to limit the adequacy of these complementary approaches for development of therapies [17].Duly concerned with the need to base its normative treatment recommendation on the bestavailable evidence [18], and to produce guidelines that would be readily usable in daily practicein all settings, WHO opted to establish minimal and optimal benchmarks for TB regimendevelopment using industry-accepted target product profile (TPP) principles [19]. These TPPsfor new anti-TB regimens, referred to as “target regimen profiles” (TRPs), describe the minimum and optimal attributes and characteristics of future TB regimens to guide the development process [20]. A population-level modeling analysis evaluating the potential impact ofvarious regimen characteristics on the TB epidemic highlighted the paramount importance ofregimen efficacy to exert the largest impact on reduction of TB cases and deaths, both forDS-TB and DR-TB [21]. Other characteristics such as shorter duration of, or increased adherence to, treatment were shown to have important effects by enabling more people with TB toreceive appropriate and timely therapy. Most importantly, this model highlighted the difficultyof improving all potential characteristics simultaneously in a single regimen, leading developers to consider weighing in inevitable trade-offs (e.g., higher cure rates may be difficult toachieve simultaneously with shorter treatment duration, and simpler or better-tolerated regimens may be less robust to emergence of drug resistance) that are duly addressed in the TRPs.Given the recommended regimen characteristics, the implementation of TRPs stimulatedthe question of which clinical trial designs and features should be optimally used for thePLOS Medicine https://doi.org/10.1371/journal.pmed.1002769 March 22, 20192

development of new anti-TB regimens. Major challenges