Impact case study database

Tuberculosis (TB) is a major global killer responsible for approximately 9,000,000 new cases and between 1,000,000 and 2,000,000 deaths per year. Gillespie was a speaker at the seminal meeting at which the Cape Town Declaration was made, that described the increasing TB burden as “a blot on the consciousness of human-kind” and called for funding and renewed emphasis on tuberculosis drug development. The St Andrews group’s critical impact is a result of their research as described in section 2, and a body of work stretching back to 2010, when Gillespie moved to the University of St Andrews from UCL. This has encompassed the development of global TB networks, treatment methodologies and clinical capacity. The research has led to changes in treatment practice, and improved diagnostics for monitoring treatment, which led to development and commercialisation of an assay for real-time antibiotic treatment monitoring in TB patients in 2018.

Development of TB networks, treatment trial methodologies and clinical capacity

When this work first started, there were only a few sites capable of delivering TB trials data to regulatory standards. Since 2014, and through a program of clinical trials research (REMoxTB, STAND, SimpliciTB and PanACEA), the St Andrews group has helped develop capacity capable of delivering registration studies in over 50 sites in 9 countries, across 4 continents.

Multiple global collaborative consortia have been developed following Gillespie’s creation of the Infection and Global Health Division at the University of St Andrews in 2010. The St Andrews group have worked with the Global Alliance for TB Drug Development as the clinical lead. Specifically, the group have built and developed 2 international collaborative networks with major studies REMoxTB (started in 2008, expanded from 2013, and completed in 2018), STAND (started in 2015 completed in 2018) and SimpliciTB (started 2018 and ongoing).

In collaboration with the Global Alliance for TB Drug Development, since 2014/15, we have added 5 African sites, and trial capacity has grown to over 50 sites in 9 countries, across 4 continents and is capable of delivering registration studies rapidly, and has recruited over 2,670 people (participants) across these studies (S1). Specifically, since 2014, we have developed the PanACEA consortium (Pan African Consortium for the Evaluation of Antituberculosis agents; Gillespie is one of three principal investigators), one of the largest collaborations of European and African partners with a wide range of skills (PanACEA I, 2008-2015, and PanACEA II, refunded in 2017), which has grown from 11 institutions in 6 countries to 16 institutions, recruiting patients into commercial and other studies (S2). Through the PANBIOME, STAND, SimpliciTB and PanACEA consortia led by Gillespie since 1 August 2014, the following results have been accomplished. PANBIOME in 2015 resulted in 4 additional sites implementing the MBLA as part of the Biomarkers expansion programme in PanACEA. STAND in 2018 successfully increased trial capacity from 16 sites to 26 sites in 8 countries spanning over 4 continents, Europe, Africa, South America and Asia. SimpliciTB has added over 26 sites, in 8 countries also covering 4 continents. This combined success has resulted (between 2017 and 2020) in an increase, from approximately 10 to over 50, in the number of sites able to perform trials to regulatory standard from 2016/2017.

The building of site capability has been a continuous process starting with REMoxTB and continuing after 2014, with 5 new sites being engaged in Africa since 2015. The Executive Director of European and Developing Countries Clinical Trial Partnership (EDCTP) stated “ As part of the REMoxTB trial running from 2008 to 2014 and as part of the groups continued research, sites in high TB Burden countries were identified, personnel were trained and the facilities were outfitted to conduct the phase 3 TB drug trial. Since 2014, this has had a lasting impact. South African sites, for example, that were part of this early effort now represent the epicentre of cutting-edge TB research, with the capacity to play a central role in the funding of new TB cures” (S2). Further, the Executive Director of EDCTP commented on the benefit of the consortium and development of trial capabilities in sub-Saharan Africa: “ the research and professional development support of St Andrews TB research group and the consortium has formed key players, and the consortium transformed the ability of African scientists to conduct research by increasing trial site capacity and expanded TB expertise” (S2). The PanACEA sites have “ *contributed to the development of critical diagnostic, treatment and research infrastructure in low- and middle-income countries from 2014-2020. This research has resulted in the number of sites increasing in Tanzania from 3 to 5.*”, as evidenced and corroborated by the Director General of NIMR-Mbeya (S3).

Through their research, St Andrews and the Global Alliance consortium have supported and mentored female scientists and made significant progress in addressing the gender imbalance in Global Health clinical scientists in East Africa. Before the St Andrews research collaboration with Tanzania, there were no female African science leaders in the area of TB; as of 2020, there were 5 and this number is rising (S4). Providing evidence of this change, one of those leaders says: “ through mentorship of Professor Stephen Gillespie and Dr Derek Sloan and resources support, and as part of collaborating on (STAND, SimpliciTB and PanBIOME from 2014 to 2020) I mastered a steep learning curve and achieved leadership in the TB field. Currently, I have established a functional clinical trial unit at my institute capable of conducting phase 2 and 3 studies. Also, I have developed a TB research group in my country and systematised research in two sub-categories: health system and clinical research. The group has 5 PhDs, including 2 female and the group continues to benefit mentorship and collaborations with St Andrews experts” (S4).

The work of the St Andrews research group has delivered new tuberculosis clinical trials: PanACEA Multi-Arm Multi-Stage-TB Trial and STAND/SimpliciTB have played a central role in finding new and improved cures for TB (R1, R4 and R5). For these trials, it was necessary to develop all the methodologies needed to deliver a regulatory standard study. After the completion of the REMoxTB trial (2014), we used the extensive dataset to establish many of the tools and protocols that underpin subsequent clinical trials, e.g. STAND and SimpliciTB, which Gillespie led (R2 and R3). “ *The methodologies developed and the network have contributed greatly to the registration of our novel drug pretomanid in 2019 by the US Food and Drugs Administration (FDA) and in 2020 by the European Medicines Agency (EMA)*” according to the Global Alliance (S1). This included many of the methods for the day-to-day management of tuberculosis clinical trials that have become the standard for how TB clinical trials should be managed. Gillespie, and colleagues from his collaborations, provided these details to the European Medicines Agency when revising TB regulatory guidelines in 2018, and members of our consortium presented evidence that formed the basis of the revisions of the advice that has now been published (S5). The TB Alliance, sponsors of the clinical trials, have acknowledged that: “ St Andrews and the consortium have made ground-breaking contributions to develop methodologies that have resulted in the generation of evidence for new drugs for tuberculosis” (S1).

Changed treatment practice and guidelines

We have challenged conventional wisdom about the dosage of the most important drug (rifampicin) in tuberculosis regimens performing a series of studies indicating that higher doses of this antibiotic are more effective (PanACEA - RUNMC, conducted 2010 to 2018, described in R4) (PanACEA MAMS-TB trial, and HighRif studies conducted 2013 to 2020, described in R5). PanACEA has identified the rifampicin dose in World Health Organisation (WHO) guidelines was underdosed and have completed a series of studies to show that the optimal dose was 4 times higher than that in the WHO guidelines (was 10 mg/kg but was increased to 40mg/kg). This development has entered clinical practice in the national treatment centres in Germany and the Netherlands for the treatment of pulmonary and meningeal tuberculosis (S6). In addition, our research (R1) has been used to inform 2018 WHO clinical guidelines for treatment of patients infected with isoniazid resistant strains (S7, p. 31).

Development and commercialization of a real-time antibiotic treatment monitoring assay

Improvements in therapeutic treatment regimens are only one side of the coin when it comes to translating this impact into improved patient outcomes. The other is the ability to monitor the effect of treatments to inform patient management. Classically, it has been difficult to monitor the response to tuberculosis treatment due to the slow growth of the organism in culture. Our research addressed this problem and produced a molecular assay which has been commercialised and is now being used for real-time antibiotic treatment monitoring TB patients in 6 countries.

Since 2011, we have developed a unique molecular tool, the tuberculosis Molecular Bacterial Load Assay (TB-MBLA), which overcomes this problem by detecting the number of live organisms in four hours compared to current methods that take up to 42 days. Working with patients from the PanACEA MAMS-TB trial (conducted between 2013 and 2018), our research provided evidence that the use of TB-MBLA could inform clinical decision making in real-time, and that its use could expedite drug TB clinical trials (R6).

The assay has been commercialised between University of St Andrews spinout enterprise, SOI Ltd in 2018, under the trademark of “VitalBacteria”. As of 1^st December 2020, the assay has been bought and distributed in 6 countries (UK, Germany, Ghana, Zambia, Tanzania and Singapore), has been used to monitor treatment in over 600 people (patients) and had sales of GBP56,957 (S8). The assay is the world’s only rapid and effective custom-designed molecular test for TB treatment monitoring. An independent medical research charity, LifeArc, are developing this further for implementation into clinical practice.

Through a TB Stakeholder conference held in 2018, which brought together health professionals and policy makers from 16 countries across the globe, and a 2-day training of 17 experts in TB-MBLA technology transfer, St Andrews created an international TB-MBLA users’ group consisting of 30 groups in 18 countries for TB diagnostics and treatment management. Through this engagement activity and global reach, the impact that TB-MBLA has for real-time antibiotic treatment monitoring has been recognised by the Treatment Action Group, stating, “ In as little as three days, 16S ribosomal RNA that is detected by MBLA is able to indicate the bactericidal effect of TB drugs and to provide a long-term assessment of treatment response for slow responders” (S9, p. 15). Moreover, the World Health Organisation, included it as an important new diagnostic for TB in their Global Tuberculosis Report 2018, stating “ St Andrews University, Scotland has developed a novel approach for real-time monitoring of a patient’s response to TB treatment. The Molecular Bacterial Load Assay (MBLA) is a real-time reverse transcriptase quantitative PCR (RT-qPCR) that uses 16S-ribosomal RNA (rRNA) targets to quantify the M. tuberculosis bacillary load over the course of treatment” (S10, p. 155).