A new approach to clinical trials during infectious disease outbreaks, such as the coronavirus disease 2019 (COVID-19), could help researchers overcome the myriad challenges they currently face when attempting to test vaccines and treatments during an epidemic.
This comes from a group of scientists developing a work plan for the design of clinical trials during public health emergences. The group is sponsored by the World Health Organization (WHO) and includes Thomas Fleming, a professor of biostatistics at the University of Washington School of Public Health.
The approach is outlined in an article published April 1 in the New England Journal of Medicine.
Outbreaks of infectious diseases such as COVID-19, Ebola Virus Disease (EVD), and Middle Eastern Respiratory Syndrome (MERS), are unpredictable. They vary in size, emerge in different geographic locations, appear months or even years apart, and often don’t last long enough for clinical trials to be designed and conducted in a manner that will provide conclusive results.
With such characteristics, outbreaks do not lend themselves to the traditional double-blind, placebo-controlled, individually randomized clinical trial model. Yet researchers know that in order to determine the efficacy of potential vaccines and therapies, there is an important need for trials to be conducted during infectious disease emergencies.
Enter the WHO core protocol concept, an approach that allows a clinical trial to extend across multiple infectious disease outbreaks. Instead of starting new independent trials for each successive outbreak, study teams can collaborate on existing, ongoing protocols. This consistency in protocol allows data from many sites and different outbreaks to be merged into one clinical trial.
Fleming points out that it was work conducted during the Ebola outbreaks that helped facilitate the idea of a core protocol. During the Ebola outbreak in the Democratic Republic of Congo, Fleming chaired a patient oversight committee for a WHO program that monitored emergency use of unregistered and investigational treatments.
“The scientific and ethical insights from the EVD experiences are now being used by the WHO R&D Working Group to develop scientific processes to evaluate prevention and treatment interventions to address the current outbreak of the novel coronavirus,” Fleming says.
Those interventions include authoring core protocols for COVID-19 vaccine and treatment trials.
“During recent weeks, in collaboration with WHO colleagues, I served as a co-author of core protocols in the nCoV vaccine trial setting and in the nCoV therapeutics trial setting. Our current efforts are focused on finalizing the full protocols for both of these settings, with the hope that randomized clinical trials can be initiated in the near future,” he says.
In addition to bringing multiple outbreaks under a unified clinical trial umbrella, the article notes that core protocols can alleviate the pressure to release inconclusive results from clinical trials, a practice that can make it more difficult to determine the effectiveness and safety of interventions, as illustrated by an examination of two Ebola trials.
From 2014 to2016, a clinical trial in West Africa with an optimized standard-of-care control arm evaluated a cocktail of monoclonal antibodies called ZMapp as a potential treatment for Ebola. But the outbreak waned and the trial was terminated without reaching its specified stopping criteria. The results looked promising; ZMapp appeared to be beneficial in treating Ebola. However, these results did not meet conventional standards for being reliable evidence to support ZMapp as an effective treatment. Despite this, given the importance of reporting the results of completed trials in order to avoid publication bias, the trial’s inconclusive data were released.
Two years later, when an outbreak of Ebola occurred in the Democratic Republic of Congo (DRC), it was determined that the clinical trial initiated in that setting would use ZMapp instead of optimized standard of care as the control against which other treatments would be compared. This decision impacted the interpretability of results of the DRC trial. While the trial successfully identified two promising new treatments, because results were compared to ZMapp, the evidence supporting these promising regimens was not as strong as it could have been had they been evaluated against a standard-of-care group or a control arm with known efficacy. Questions also remain as to whether ZMapp and another regimen having similar mortality really had any effect. These challenges could have been avoided if the 2014-2016 trial had been designed under a core protocol which would have called for that trial to be paused instead of terminated.
Deb Nelson, Biostatistics communications and event manager