Experts Back Randomized Trials to Address Pandemic Outbreaks

Despite ethical and practical concerns, a panel of U.S. and international health and research leaders has concluded that randomized, controlled clinical trials provide the fastest and most reliable way to identify the risks and benefits of treatment candidates for infectious disease outbreaks. Based on a review of efforts to identify and test therapies and vaccines during the Ebola outbreak of 2014-2015, the committee assembled by the National Academies of Sciences, Engineering and Medicine finds that randomized trials may be the most ethical design because timely identification of beneficial treatments minimizes the risk of exposing populations to potentially harmful investigational agents.

Because of difficulties and delays in trying to design and implement trials during a dangerous and spreading epidemic, the report on Integrating Clinical Research into Epidemic Response [see https://www.nap.edu/catalog/24739/integrating-clinical-research-into-epidemic-response-the-ebola-experience] recommends that research authorities from all over the world address important logistical, ethical and policy issues in advance of the next outbreak. World health authorities should take steps during this “inter-epidemic” period to strengthen the capacity of national and local health systems and research operations and to develop mechanisms for rapid ethics reviews and legal agreements for future research. An independent coalition of experts, perhaps based on the model adopted by the new Coalition for Epidemic Preparedness Innovations (CEPI), should set priorities for pathogens to target, develop clinical trial design templates, and identify teams of clinical research experts who could be deployed to help design and conduct research during an outbreak.

Panel co-chair Gerald Keusch, professor at the Boston University Schools of Medicine & Public Health, explained at a briefing how difficulties in launching clinical trials during the Ebola outbreak hindered efforts to find effective treatments or vaccines. Research was delayed initially by faulty identification of the disease, and further by disagreement over whether it was ethical and feasible to conduct randomized studies during a health crisis. There was poor coordination among multiple research groups and competition to obtain approval of research and access to study sites. As a result, the results were “inconclusive” from five studies of possible therapeutics using non-randomized single-arm trials with historic controls, and only one of four vaccine trials provided evidence of protective effect.

To improve the process, the panel emphasizes the need to strengthen the capacity of local and national health care systems, to engage communities in advance on research processes and practices, and to set basic policies for international coordination and collaboration on research during a disease outbreak. The goal, Keusch emphasized, is to be able to launch clinical studies on the “upslope” of an epidemic, instead of after the disease is diminishing and fewer patients are available to study for response to treatment or protection from a vaccine. Clinical research, he emphasized, should be considered “a critical part of response from the beginning.”

In addition to randomization, the panel emphasized the need for researchers to apply rigorous standards to all aspects of clinical trials, such as inclusion and exclusion criteria and data reporting. Adaptive protocols may be useful in some situations, but appropriate and reliable control groups are preferred. Such collaborative efforts now can define research study designs that can be deployed rapidly when an outbreak occurs, depending on the disease involved, and is key for well-designed trials to be implemented in the future.

Training of young investigators in developing nations also is essential during this inter-epidemic period, the panel added, noting the work of the Fogarty International Center at the National Institutes of Health (NIH) in training ethicists and in building local health capacity in low- and middle-income countries.

The report was requested and funded in 2015 by the HHS Assistant Secretary for Preparedness and Response, NIH’s National Institute of Allergy and Infectious Disease, and the Food and Drug Administration in hopes of improving the ability of the global health community to respond to and conduct ethical research during the next infectious disease outbreak.

Jill Wechsler is the Washington Correspondent for Applied Clinical Trials