Building clinical trial capacity to develop a new treatment for multidrug-resistant tuberculosis

Abstract Problem New drugs for infectious diseases often need to be evaluated in low-resource settings. While people working in such settings often provide high-quality care and perform operational research activities, they generally have less experience in conducting clinical trials designed for drug approval by stringent regulatory authorities. Approach We carried out a capacity-building programme during a multi-centre randomized controlled trial of delamanid, a new drug for the treatment of multidrug-resistant tuberculosis. The programme included: (i) site identification and needs assessment; (ii) achieving International Conference on Harmonization – Good Clinical Practice (ICH-GCP) standards; (iii) establishing trial management; and (iv) increasing knowledge of global and local regulatory issues. Local setting Trials were conducted at 17 sites in nine countries (China, Egypt, Estonia, Japan, Latvia, Peru, the Philippines, the Republic of Korea and the United States of America). Eight of the 10 sites in low-resource settings had no experience in conducting the requisite clinical trials. Relevant changes Extensive capacity-building was done in all 10 sites. The programme resulted in improved local capacity in key areas such as trial design, data safety and monitoring, trial conduct and laboratory services. Lessons learnt Clinical trials designed to generate data for regulatory approval require additional efforts beyond traditional research-capacity strengthening. Such capacity-building approaches provide an opportunity for product development partnerships to improve health systems beyond the direct conduct of the specific trial.


Introduction
Traditional research capacity-building efforts tend to focus on post-approval clinical studies and operational research, 1 rather than initial regulatory approval of new medicines. 2,3 New medicines are needed for multidrug-resistant (MDR) tuberculosis 4 and most of the people infected with MDR tuberculosis live in low-income countries, where there is often insufficient capacity to conduct clinical trials that meet the International Conference on Harmonization -Good Clinical Practice (ICH-GCP) standards. [5][6][7][8] We describe a global clinical trial capacity-building programme done in the context of trials for delamanid conducted to achieve approval by a stringent regulatory authority.

Programme design
The clinical development programme for delamanid was sponsored by Otsuka Pharmaceutical Development and Commercialization, Inc., conducted in partnership with national tuberculosis programmes and nongovernmental organizations.
The programme consisted of three connected clinical trials: trial 204 was a three-month randomized, placebo-controlled trial (including a two-month hospitalization period). 9 This was followed by trial 208, a six-month open-label extension of trial 204 in which participants had early access to delamanid. 10 Finally, trial 116 followed all patients enrolled in trial 204 for 24 months. The trials were conducted from May 2008 to May 2012 at 17 sites in nine countries (China, Egypt, Estonia, Japan, Latvia, Peru, the Philippines, the Republic of Korea and the United States of America) with 481 participants completing trial 204 and 421 of these continuing into trial 116.

Identification of programme sites
To identify and qualify clinical trial sites for participation in the delamanid programme, the partnership formed a multi-disciplinary site assessment team. The team consisted of experts in clinical trial management, public health and clinical aspects of MDR tuberculosis, including laboratory microbiology, diagnostics, data recording and reporting and disease management. The goals of the assessment team were to: Problem New drugs for infectious diseases often need to be evaluated in low-resource settings. While people working in such settings often provide high-quality care and perform operational research activities, they generally have less experience in conducting clinical trials designed for drug approval by stringent regulatory authorities. Approach We carried out a capacity-building programme during a multi-centre randomized controlled trial of delamanid, a new drug for the treatment of multidrug-resistant tuberculosis. The programme included: (i) site identification and needs assessment; (ii) achieving International Conference on Harmonization -Good Clinical Practice (ICH-GCP) standards; (iii) establishing trial management; and (iv) increasing knowledge of global and local regulatory issues. Local setting Trials were conducted at 17 sites in nine countries (China, Egypt, Estonia, Japan, Latvia, Peru, the Philippines, the Republic of Korea and the United States of America). Eight of the 10 sites in low-resource settings had no experience in conducting the requisite clinical trials. Relevant changes Extensive capacity-building was done in all 10 sites. The programme resulted in improved local capacity in key areas such as trial design, data safety and monitoring, trial conduct and laboratory services. Lessons learnt Clinical trials designed to generate data for regulatory approval require additional efforts beyond traditional researchcapacity strengthening. Such capacity-building approaches provide an opportunity for product development partnerships to improve health systems beyond the direct conduct of the specific trial.
Lessons from the field  Third, additional staff were hired to do laboratory procedures that were standardized with the use of a single laboratory manual. We improved hospital capacity by establishing better infection control measures and providing laboratory equipment and supplies. We invested in facility renovations and purchased equipment that was loaned to the site with an option to purchase at reduced cost once the trial was complete. All local staff were trained in the use of N95 or equivalent respirators and provided with essential personal equipment.

Investing in key activities
Finally, procurement of second-line drugs varied by location, but included a two-year course of second-line drugs for all participating patients. We ensured that specific second-line drugs required per protocol were obtained if they were locally unavailable and purchased the necessary storage equipment.

Trial management
Staffing investments were made to ensure proper and consistent trial conduct according to ICH-GCP guidelines. The management structure was designed to allow consistent guidance and close Lessons from the field Research capacity: multidrug-resistant tuberculosis Thelma Tupasi et al. oversight (Fig. 1). The trial management team was multidisciplinary and included representatives from the sponsor and local CROs. Sponsor team members were responsible for providing global oversight of the trial sites and direction to clinical research associates and personnel; face-to-face meetings were held with each clinical research associate throughout the trial. The training and re-training of CRO and site staff helped ensure comparability of data across countries. Each CRO was also assigned a regional lead person with extensive trial monitoring and project management expertise who was responsible for ensuring all operational requirements were met. Regional lead staff held bi-weekly teleconferences with their local counterparts throughout the trial. This approach fostered a higher level of communication between the trial management team and the local site staff than would have been possible with traditional outsourcing models.

Regulatory processes
Three main regulatory issues needed to be considered: the protocol review and approval process, customs clearance and adherence to ICH-GCP standards. All sites required at least one institutional review board and government authority review but some settings required approvals from several groups. Often, these reviews needed to be conducted in series. The timelines for approval (from protocol submission for ethics review to final approval) for four countries comprising more than 75% of enrolled patients were as follows for trial 204: country 1, 8 weeks; country 2, 20 weeks; country 3, 41 weeks; and country 4, 32 weeks. Timelines were shorter for the second trial, due to acquired familiarity with regulatory processes and the existing approval of the first trial. Accordingly, the approval timelines for trial 208 were: country 1, 1 week; country 2, 9 weeks; country 3, 26 weeks; and country 4, 1 week. Import permits and customs clearance were straightforward given that all settings had existing regulations. Maintenance of ICH-GCP standards throughout the studies was ensured through a continuous independent auditing process.

Lessons learnt
Several insights arise from our experience. First, sites reviewed and shown to meet international standards for MDR tuberculosis management were deemed well suited for clinical trials. Second, considerable capacity-building efforts were required, including training on the monitoring and management of adverse events, the maintenance of complete, accurate and confidential medical records and ensuring that all doses of study medication were taken (Table 1). Third, capacity-building activities helped address clinical and operational research priorities for drug-resistant tuberculosis, including validation of second-line drug testing, implementation and assessment of rapid diagnostic methods and implementation of monthly drug-susceptibility testing for optimization of treatment regimens. 12 Fourth, institutional review board times were generally faster for the second trial, suggesting an advantage for conducting additional clinical trials in the same settings.

Conclusion
Evaluating new products to meet regulatory approval standards requires additional efforts beyond traditional research capacity strengthening. Improving local capacity in key areas such as trial design, data safety and monitoring, trial conduct and laboratory services allows such settings to achieve ICH-GCP standards, to improve delivery of services to patients and establish a more permanent product evaluation infrastructure (Box 1). Indeed, all sites involved in this capacity-building programme are now equipped to assess new global health products targeting regulatory approval. However, it remains to be seen how these lessons can be translated on a wider scale. We suggest that private-sector partners, donors, governments and nongovernmental agencies create product evaluation centres-of-excellence. Such centres would generate local expertise in developing and evaluating products at all levels of pre-clinical and clinical development, with the intent of achieving approval by regulatory authorities. An array of stakeholders could ensure that global treatment priorities are being targeted. Pooled financing coupled with economies of scale would make such centres more financially feasible,

Fig. 1. Management of the clinical development programme for a new tuberculosis medication, nine countries, 2008-2012
Sponsor management team Note: The sponsor management team included specialists in MDR tuberculosis, clinical management and laboratory microbiology. Each geographical area was assigned two sponsor-based regional leads, specializing in clinical management and laboratory microbiology. Sponsor affiliates located in China, Japan and the Republic of Korea performed monitoring and site management responsibilities within these countries in lieu of the contract research organization.
Lessons from the field Research capacity: multidrug-resistant tuberculosis Thelma Tupasi et al.
potentially translating into reduced post-development prices. Building research capacity in lowresource settings is key for improving health systems and developing new medicines. 13 Perceived challenges in successfully navigating research requirements in such settings often result in obstacles for product development partnerships. 14,15 But as demonstrated here, incorporating appropriate capacity-building efforts into product development plans for novel therapeutics may offer a unique opportunity to reverse this trend and establish a longterm basis for similar future work. This includes using innovative approaches to evaluate drugs and optimize their use. 16 The strategies described here for MDR tuberculosis drugs could serve as a practical roadmap for the development of high-quality clinical trial sites in lowresource settings. ■ Competing interests: None declared. Good Clinical Practice (ICH-GCP) standards may differ from WHO approaches recommended for national tuberculosis programmes; thus, additional efforts may be required to achieve the standards. • Product development partnerships that improve local capacity in key areas such as trial design, data safety and monitoring, allow such settings to achieve ICH-GCP standards, improve delivery of services to patients and foster the ability to conduct future product evaluation trials in other therapeutic areas.
Lessons from the field Research capacity: multidrug-resistant tuberculosis Thelma Tupasi et al.