As members of the R&D Blueprint,9 a work plan for designing clinical trials during public health emergencies, sponsored by the World Health Organization (WHO), we advocate the use of a “core protocol” in such cases. Core protocols (also called master protocols) have been described for simultaneous evaluation of multiple interventions or of a single intervention targeting multiple diseases.10 We propose a core-protocol concept that allows a clinical trial to extend across multiple infectious disease outbreaks. This approach accommodates the changing and unpredictable features of an epidemic and incorporates new investigative team members into the trial over time.
To avoid a premature release of data, core protocols would specify that efficacy data from a trial that has not yet been completed because of insufficient enrollment should not be released. After an outbreak has ended at a given site, the trial would be paused. If so specified in the core protocol, an independent monitoring committee could review results from an interim analysis of trial data to make recommendations regarding whether the trial should continue or stop for efficacy, futility, or safety, as guided by a prespecified monitoring plan.11 Under the core protocol, the investigators would remain unaware of any results of the analyses; the trial data would be released only if the trial was stopped on the basis of a recommendation from the monitoring committee or had reached its targeted number of end-point events or amount of participant follow-up.
Vaccine trials that are conducted for 2 years or more are commonly performed to combat diseases with predictable seasonality, such as Lyme disease12 and Argentine hemorrhagic fever,13 with results withheld until the requisite numbers of events have been observed. Such studies provide some precedent, albeit imperfect, for our proposal, which differs in that it focuses on diseases with outbreaks that are less predictable, may not be observed every year, and may reemerge in a different location. Such diseases include those targeted by the R&D Blueprint — including Ebola virus infection, Middle East respiratory syndrome, Lassa fever, and Nipah virus infection — that occur irregularly but nonetheless relatively frequently. For pathogens that may emerge only once a decade or even less frequently, this approach may not be practical.
The use of core protocols can facilitate the implementation of clinical research across successive outbreaks. The PALM trial included a core-protocol framework to guard against the release of inconclusive data. If the outbreak in the DRC had waned before the conclusion of the trial, the trial would have continued without a release of the results, unless the data monitoring committee had recommended termination. Ultimately, the PALM trial was terminated during the DRC outbreak on the advice of the data monitoring committee when an interim analysis revealed that REGN-EB3 (another cocktail of three monoclonal antibodies) was superior to ZMapp; improved survival was also associated with the monoclonal antibody mAb114 but not with the nucleotide analogue prodrug remdesivir.
Although the PALM trial was successful in identifying two promising therapeutics, there were limitations resulting from the use of ZMapp as the comparator group because its clinical benefit had not been definitively established during the PREVAIL II trial. The overall evidence in support of REGN-EB3 and especially mAb114 would have been stronger if the drugs had been evaluated against a standard-of-care group, as in the PREVAIL II trial, or a drug with known efficacy. Furthermore, the question remains whether ZMapp and remdesivir have any effect. Such findings would have been particularly valuable in settings in which the monoclonal antibody drugs were not available and would have had implications for the development of combination regimens. Finally, it is not clear how data from the PALM trial would have been interpreted if survival had been similar in patients receiving the other drugs and in those receiving ZMapp. These challenges could have been largely avoided if the PREVAIL II trial had been designed under a core protocol. It is likely that the results of the PREVAIL II trial would not have been published at the end of the epidemic, since they did not meet the prespecified level of evidence required, and the trial would have been restarted in the DRC with a standard-of-care group in place plus ZMapp and additional investigational treatments. With accrued data from the DRC, the question of whether ZMapp was effective could have been answered, thus establishing a clearer benchmark for all candidate products. Such a framework could also have eliminated the need for a new protocol altogether.