Implementing Clinical Trials

Designing and implementing an MDR-TB clinical trial is complex and requires team members (centrally and locally) with a unique combination of skills and training. Beyond the obvious clinical, laboratory and statistical expertise required, successful trial implementation requires deep regulatory knowledge and strong project management skills to address the wide variety of implementation challenges that inevitably arise in multi-site trials. Key aspects to address range from site selection and training, to regulatory compliance, procurement, logistics, and community engagement. When added to the complex partner relationships typical for regulatory trials, this breadth of implementation issues demands careful site and study team selection, targeted capacity building, systematization of key trial processes, and structured and continuous stakeholder communication and coordination.

A wide range of partners collaborated in the implementation of STREAM, including the MRC CTU at UCL (which oversees overall trial implementation), technical partners for microbiology, health economics and community engagement, a central safety lab, and a contract research organization for onsite monitoring.

Learn more about the STREAM implementing partners

The principal implementing partners and their roles for the STREAM trial are:

Technical partners

  • Medical Research Council Clinical Trials Unit at University College London is responsible for overall trial implementation, including trial design, statistical analysis, clinical oversight of sites, and data management.

  • Institute for Tropical Medicine is responsible for all microbiology-related aspects of the trial, including initial site assessments and ongoing site monitoring. Additionally, ITM is the central microbiology laboratory for the trial.

  • Liverpool School of Tropical Medicine is responsible for all aspects of the health economics study for the trial.

Contract Research Organization

  • IQVIA is the clinical research organization contracted in Stage 2 to oversee onsite monitoring at all sites and coordination of submissions to some local ethics committees and regulatory authorities.

Central Safety Assessments

  • Q2 Solutions and QCSS are contracted in Stage 2 to provide central laboratory testing and central ECG reviews for participant safety assessments in the trial.

Community engagement

  • REDE-TB is an advocacy expert that provides technical assistance for STREAM community engagement, as detailed in the companion practical recommendations guide.

The scope and scale of the STREAM trial offered an excellent opportunity to identify successes and areas for improvement for future trials. Read a case study here. And to learn about all lessons learned click on the boxes below.

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Download the Implementing Clinical Trials Guide →

Trial implementation in Mongolia: Collaboration for successful clinical trials

In 2013, when the National Center for Communicable Diseases (NCCD) was approached to participate in STREAM, it was the first international trial of such scope and complexity implemented in Mongolia. Despite this, the site was keen to conduct the trial, given the burden of MDR-TB in the country. The site has now participated in both stages of STREAM, recruiting more than 160 participants, and is well-placed to conduct future regulatory TB trials. This was only possible because the site envisioned the trial as a collaboration among stakeholders.

The site’s commitment to collaboration applied well before participant enrollment began, with initial approvals requiring the site to build understanding and support for the trial across stakeholders. The trial allocated adequate time for this work (about seven months) so sensitization meetings with all key stakeholders could be held, including the Ministry of Health (MoH), the national ethics committee, directors of the NCCD, decentralized health facilities, front line health workers, non-profit organizations supporting TB patients, and donors supporting the national TB program (NTP). The trial team’s long-standing relationships with the MoH and the NTP were essential to the success of those initial meetings and achieving buy-in for the trial.

As the site moved closer to enrolling participants, study team members collaborated amongst themselves to ensure they understood each other’s roles and responsibilities, and were thoroughly familiar with the protocol, as well as logistics and regulatory requirements for the trial. Study team members participated in internal role plays that covered key trial processes like screening and enrollment of participants in line with the protocol, randomization to the trial, packaging and dispensing trial medications, ECG and audiometry assessments, and completing case reporting forms. The study team also trained directly observed therapy (DOT) volunteers, who would play an important role in supporting participants during the trial. This upfront investment to clarify roles and responsibilities and to train the study team helped ensure efficient trial implementation and a positive experience for trial participants.

Collaboration between the trial team and the NTP was important at nearly every stage. Site study staff were drawn from the NTP, helping ensure the trial fully understood patient referral patterns and designed effective recruitment processes. Cooperation was also important for patient management – in particular, arranging DOT options for trial participants that met their needs. The study’s experience with clinical aspects of the shorter regimen, community-based support for participants and retention were shared regularly with NTP colleagues. This conscious focus on knowledge sharing strengthened the relationship between the study and the NTP and helped improve coordinated patient management.

The [NTP] appreciates the STREAM trial not only because we contributed to the shorter MDR-TB regimen, but also STREAM’s capacity building initiative has helped to ensure all staff are well-situated to work on other large-scale clinical trials.

STREAM Site Coordinator

The site took a similar approach to managing regulatory issues collaboratively. Given the country’s history with clinical trials, Mongolia’s regulatory institutions had limited experience with oversight of clinical trials like STREAM. In response, the site invested in regular communications with the ethics committee and regulators to strengthen their working relationship. Regulators were invited to visit the trial site for regular updates and the study team often presented protocol amendments in person to facilitate Q&A. The trial protocol has now been amended five times and regulatory approvals have always been obtained in adequate time to permit uninterrupted trial implementation.

STREAM trial staff with the former Minister of Health, Sarangerel Davaajantsan, at the NCCD in Ulaanbaatar, Mongolia (2019).
STREAM trial staff with the former Minister of Health, Sarangerel Davaajantsan, at the NCCD in Ulaanbaatar, Mongolia (2019).

Perhaps the most important collaboration in the trial has been between the study team, and trial participants and family members. For example, the study worked closely with participants to adapt follow up options to participants’ needs. Instead of requiring participants to return to district TB dispensaries for all treatment, participants were offered different options for DOT (at home, at lunch breaks, at family health centers and (in some cases) using video-DOT). The study team credits this flexible approach with ensuring high participant retention at the site.

The final collaboration was between the trial site and the community. With the support of the trial, a community advisory board (CAB) was formed as a coordinating mechanism. The CAB – whose members included people affected by TB and a diverse range of representatives from NGOs and community-based organizations – served as an important bridge between the study and the community. Through the CAB’s work, the study remained aware of the community’s concerns and questions about STREAM, and the community was informed about study progress. This helped build the community’s trust in both the STREAM trial and clinical research generally.

More than seven years after joining STREAM, Mongolia has gained important experience and strengthened critical relationships needed to participate in future clinical trials. This underscores the gains that can be made when stakeholders collaborate with a common purpose.