In this randomized, controlled trial of a new treatment for acute EVD, the posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%. The overall 28-day crude mortality was 15 percentage points lower among those assigned to ZMapp plus the current standard of care than among those assigned to the current standard of care alone (22% vs. 37%), which corresponds to a 40% lower relative risk of death with ZMapp. If sustained, a mortality difference of 15 percentage points would translate to approximately 15 lives saved for every 100 patients treated. However, this outcome fell short of the prespecified 97.5% probability for superiority.

Although the trial was launched within weeks after the trial drug became available, the notable successes of numerous public health measures in reducing and aiming to extinguish EVD in the affected countries resulted in our not being able to attain the desired enrollment of 100 participants per group. As a consequence of early termination, the 95% credible intervals for the absolute difference in mortality and for the relative risk of death are wide: −34 to 6 percentage points and 0.29 to 1.24, respectively. In addition, although mortality differences according to the age of enrollees (<18 vs. ≥18 years of age), location of enrollment (country), and baseline viral load (cycle-threshold value) all favored the ZMapp group, credible intervals were even wider for these subgroups.

If ZMapp did indeed confer some degree of therapeutic benefit, at least two main factors may have limited the magnitude of the mortality trend that we observed. Although trial patients were clinically symptomatic for only a few days before randomization, at enrollment they were probably 1 week or longer past their date of actual infection. This delay in initiating therapy exceeded the 5-day window within which ZMapp had been shown to provide 90% or greater survival in the nonhuman primate lethal-challenge model.8 In addition, seven of the eight deaths recorded in ZMapp recipients occurred before day 4, which was before administration of the second of three planned infusions. Thus, theoretically, if the full potential efficacy of ZMapp is realized only after the completion of multiple infusions, most of the patients dying from EVD in that group would have died before full dosing was achieved.

Stratification according to country was included because of the concern that access to the types of supportive measures generally available in North America might be limited in West Africa or unevenly distributed among the three involved West African countries. In this regard, certain, but not all, Ebola treatment units (e.g., the Emergency Ebola Treatment Unit in Sierra Leone) were able to provide care at the level of an intensive care unit. Too few patients were enrolled in Guinea to determine whether inclusion of favipiravir further enhanced survival in that country.

Stratification according to baseline cycle-threshold value was instituted because of the perception that patients with very high viral loads at presentation might die despite the use of generally effective medical countermeasures. This was one of the conclusions drawn from the JIKI trial of favipiravir in Guinea, for example, and was raised by several other studies as well.14-20

No major safety concerns were identified with the use of ZMapp. Despite the drawback of an intravenous infusion that had to be given three times over the course of a week, the full course of ZMapp was successfully administered 91% of the time to recipients who survived that first week of the trial.

In considering both the choice of investigational drugs and the most appropriate trial design in which to study them, each group testing clinical research interventions during the 2014–2016 epidemic faced the unenviable task of having to weigh numerous exigencies accompanying the study of potential therapeutic interventions for a highly lethal infection, their own proper sense of the moral imperatives imposed on trial design by a humanitarian crisis, and the evolving cultural milieu in which those considerations arose. In the case of this trial, which was launched during the second half of the epidemic, we believed that a randomized, controlled design would be the most expedient and definitive means of establishing the absence of a harmful effect and of determining whether the very favorable preclinical data in support of ZMapp might actually translate directly into lives saved. The advantages of randomized studies have been discussed extensively by others.5,21-23 True confidence in the findings of studies of treatments with potentially small-to-moderate effects on mortality is often enhanced by well-performed randomized trials; in their absence, there is a greater risk that such treatment effects may be masked by selection bias and confounding. Although a major strength of the PREVAIL II trial was its randomized design, its weaknesses include an open-label as opposed to double-blind design (i.e., potentially influencing observational bias at the bedside) and the early termination owing to the dramatic decline in the number of infected patients.

The laudable and rapid decline in eligible new cases of EVD was a factor that no trial design could anticipate, and it affected our ability to reach definitive conclusions. Despite the concerted efforts of many dedicated researchers domestically and internationally who participated in this and other trials, the outbreak appears to have ended with no incontrovertible evidence that any single treatment intervention, or combination of interventions, was unequivocally superior to the types of supportive medical care typically provided.24

In another sense, however, the trial did succeed in establishing that it is indeed feasible to conduct a randomized, controlled trial in the context of a major public health emergency despite the challenges involved. Furthermore, with a 91.2% probability favoring a treatment effect for ZMapp, arguably this inconclusive but suggestive outcome has altered the sense of equipoise that accompanied this particular product at the start of the trial. How far from neutral this equipoise has shifted may be a matter of judgment. However, in the event of another outbreak, that experimental niche should probably be filled by one of a small number of other promising, but unproven, treatments that have emerged since the beginning of the recent crisis.25-27 As new epidemics emerge, undoubtedly coupled with their own set of challenges, it is important that any experimental interventions be evaluated in as rigorous a manner as possible so that their success or failure can be declared with the confidence that public health policy demands.