Clinical trials during the Ebola crisis (2016)

The articles in this Special Issue describe clinical trials and perspectives of those involved in research efforts during the world’s most catastrophic Ebola outbreak recorded. The 2014–2015 crisis resulted in nearly 29,000 cases and over 11,000 deaths, primarily affecting Guinea, Liberia, and Sierra Leone, three of the world’s least developed countries. The few cases that spread to outside regions revealed global vulnerabilities to threats that decades ago may have remained isolated. Major humanitarian and research efforts were mounted and faced enormous challenges, including a highly transmissible infectious disease with rapidly changing epidemiology, no proven interventions, poor local infrastructure, and cultural beliefs that hindered disease control and research. The epidemic presented the first opportunity to evaluate candidate therapies, vaccines, and diagnostics in human studies with clinical endpoints. Previous efforts had prioritized interventions, but at the start of the outbreak all were at different stages of early pre-clinical and clinical development. A further complexity was that a great divide existed about what constituted appropriate research in the midst of such tragedy. Much debate focused on the acceptability of randomization. Some argued that comparisons of infection rates (for vaccine evaluations) or mortality rates (for treatment evaluations) could be based on historical rates, with the view that the exigent circumstances justified administration of experimental interventions to all affected. The unpredictable dynamics of transmission and mortality in this and previous outbreaks raised questions about the validity of this approach. Among those favoring randomization, a further issue was the unit to be randomized, particularly in vaccine studies. Some argued in favor of randomizing clusters (e.g. villages), which could facilitate enrollment based on infection risk and/or more naturally track immunization campaigns. Others expressed concern about inefficiencies of clustered randomization relative to individual randomization, which sets a sample size based primarily on number of clusters, rather than individuals. Each study team faced similar dilemmas about whether (and how) to randomize, making decisions about the trade-off between what was most ethically acceptable, operationally practical, and what provided the greatest scientific validity. These questions, and many others related to appropriate clinical trial design, required careful navigation, all at a record-setting pace. The design articles included in this Special Issue represent very different approaches to these challenges. The perspective pieces provide greater background about the individuals and organizations who contributed to research efforts. While a broad group of contributors was solicited, a complete set of designs and perspectives was not possible. Rather, the collection is a representative slice of a broader research effort. Further contributions and collaborations are needed to advance the science of how to conduct clinical research during an epidemic crisis. Ideally, we will be able to borrow aspects from the different study designs and experiences to forge a consensus on how to proceed with research during the next inevitable epidemic.