Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis

May 01, 2021

Contemporary Clinical Trials, May 2021

The Tuberculosis Trials Consortium Study 31/study A5349 is a large (n=2500) international, multi-site (n=34), randomized, open-label, controlled, three-arm, non-inferiority phase 3 clinical trial comparing two four-month regimens to a standard six-month regimen for treatment of drug-susceptible tuberculosis among adolescents and adults. Due to the number of study sites worldwide, complexities inherent in TB diagnosis and treatment, and the major potential impact of this trial, a strong and timely quality assurance program was critical. In response to these demands, the study team developed interventions to improve study conduct and strengthen study quality. Our central monitoring processes included quality control, quality assurance, and monitoring of real-time data. Specifically, we created a novel, five-tiered methodology for quality management at the central level:

  1. Performance of “real-time” data checks on submitted data, and development of topic-specific intervention reports
  2. Production of site-specific missing forms reports based on the expected study schedule for each participant at the site
  3. Evaluation of protocol compliance according to study-specific quality assurance metrics
  4. Production of critical data reports
  5. Identification and notification of protocol deviations

The use of primary study data to identify data issues promptly allowed CDC, as the study sponsor, to focus quality assurance and data cleaning activities on prioritized data related to protocol compliance and accurate determination of study endpoints. Our approach enabled us to inform sites about protocol deviations, resolve missing or inconsistent data, and gain a deeper understanding of challenges experienced at clinical trial sites. We anticipate the utility of this method will be seen beyond the world of TB, for any clinical trial sponsor with access to their data in real time. We will continue to build upon the central monitoring process in future studies, with a focus on these approaches.

Summary and Implications: It is very important to have the best science in every study so that we can trust the results. One of the key challenges in multi-site studies is ensuring that each site performs well. The lessons from this study’s team management plan may help future studies be more successful.

Bryant, K. E., Yuan, Y., Engle, M., Kurbatova, E. V., Allen-Blige, C., Batra, K., Brown, N. E., Chiu, K. W., Davis, H., Elskamp, M., Fagley, M., Fedrick, P., Hedges, K., Narunsky, K., Nassali, J., Phan, M., Phan, H., Purfield, A. E., Ricaldi, J. N., Robergeau-Hunt, K., ACTG; Tuberculosis Trials Consortium (2021). Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis. Contemporary clinical trials, 104, 106355. Advance online publication. https://doi.org/10.1016/j.cct.2021.106355