The scale of the 2014-2016 West African Ebola outbreak was unprecedented, and led to a global response. As part of this response, clinical trials of the most promising candidate Ebola prophylactic vaccines were fast-tracked for testing in both affected and non-affected countries. Through the EBOVAC1 consortium of global health and research institutions, a collaboration between the London School of Hygiene & Tropical Medicine, the College of Medicine and Allied Health Sciences (Sierra Leone), and Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen) was established to coordinate the EBOVAC-Salone clinical trial of a prime-boost Ebola vaccine regimen developed by Janssen. Operating in a compressed timeframe, and with the epidemic still claiming lives across Sierra Leone, the team met significant challenges particularly in the fields of regulation, operationalizing the trial, and community mobilisation.
Regulation and Trial Design
A critical success factor for accelerated vaccine development to address the Ebola emergency was a highly supportive regulatory environment. A significant challenge was the fact that regulatory authorities in most Ebola affected countries had limited experience in reviewing large clinical trial protocols, and lacked the resources to do so expeditiously.
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In order to address this challenge, systems such as the joint African Vaccine Regulatory Forum (AVAREF) review, facilitated by the World Health Organization (WHO), were established in order to expedite this process. In general, if all concerned national regulatory authorities (NRAs) and ethics committees (ECs) participate in the AVAREF process and commitments can be met, it is likely to be a faster route to approval than local sequential processes.
For the EBOVAC-Salone trial, review timelines were more or less achieved even though the review took place at a time when the workload for both the Pharmacy Board of Sierra Leone (PBSL) – the country's medicines regulatory agency – and the Sierra Leone Ethics Committee (SLEC) had increased dramatically because of a surge in proposals for various therapeutic and vaccine trials related to the outbreak. In the end, the time from submission to approval was approximately 10 and 21 weeks for the SLEC and PBSL respectively. Documents were provided on a rolling basis following subsequent discussions with the authorities. The delay associated with the final PBSL approval pertained to issues getting the clinical trial site operational with all necessary infrastructure, standard operating procedures and staff in place, which we will discuss later.
Another challenge encountered has been the necessity to modify the clinical development programme strategy and EBOVAC-Salone trial design based on the evolution of the epidemic. The initial planning and trial design were done based on the status of the epidemic at that time. It was, however, acknowledged from the start that if the epidemic declined the design would need to change. Modelling allowed the trial design team to think about alternative designs based on different incidence rates and the projected end of the outbreak.
Based on the evolution of the epidemic and discussions with the FDA, EMA, WHO and regulatory authorities in Sierra Leone, the trial design changed from a staged efficacy approach to that of a safety and immunogenicity study. And as an effectiveness study is currently no longer feasible, alternative licensure pathways are being explored to ensure the vaccine can be made available in case another outbreak occurs. As such it is critical that teams remain flexible to adapt as an outbreak evolves and to maintain ongoing discussions with regulatory authorities.
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By GlobalDataOperational
Many key operational challenges were borne from the epidemic having affected some of the least developed countries in the world. Sierra Leone is perhaps not a natural choice to host a vaccine trial as it has very limited clinical trials experience and continues to suffer from poor infrastructure. Kambia District in northern Sierra Leone was selected as the location for the EBOVAC-Salone trial in part to avoid other districts already hosting trials of another candidate vaccine. Kambia was also chosen because there were still Ebola cases being recorded in the area when early iterations of the study design were being developed. This increased the possibility of studying the efficacy of the vaccine regimen.
However, Kambia brought additional operational challenges and delays to the project because of the limitations of its infrastructure. Notably, Kambia District is not on the national power grid, so generators had to be purchased to service all study sites and a fuel supply chain established in order to provide the 24-hour power required by the crucial vaccine storage facility.
Due to the lack of clinical trials infrastructure in Kambia, all facilities to be used by the trial – such as the vaccine storage depot and the trial clinics – had to be built from scratch or significantly refurbished. The trial initially collaborated with Public Health England to make use of the laboratory at the Ebola Treatment Centre in nearby Port Loko. However, as the epidemic waned this facility was decommissioned, it was necessary to establish a dedicated clinical trials laboratory in Kambia because the local hospital laboratory did not have the space or equipment to process trial samples.
Emergency restrictions implemented to contain the spread of Ebola had some impact during the set-up phase of the trial. For example, curfews limited working hours and restricted movement; and occasional "lock downs" of up to four days caused missed meetings and suspended activities such as construction for their duration. These emergency measures – while crucial in the fight against Ebola -contributed to the unpredictability and delays in an already time-sensitive project. However the emergency context also brought some operational benefits to the project, including a blanket exemption to import goods for the trial which expired when the state of emergency was lifted.
Finally, recruiting staff was made more difficult by the context of the epidemic. International staff, needed for their clinical trials experience, were discouraged by the prospect of working and living in an outbreak situation. The already limited pool of clinicians in Sierra Leone was committed to Ebola control activities and this pool was further impacted by the toll that the outbreak took on the country's health workers. The EBOVAC-Salone team therefore committed to the Sierra Leone authorities not to recruit workers already in post so as not to weaken the Ebola response or the wider health system.
Community Mobilisation
Engaging with communities around a clinical trial in the context of the Ebola epidemic created some unique challenges. Formative research led by the trial's anthropologist and her Sierra Leonean team suggested that a historical lack of trust in international organisations, national governments and local authority figures had been heightened by the devastation that Ebola had wrought across Sierra Leone. In this context, the team had to carefully consider which mobilisation activities would be appropriate and which stakeholders should be approached to lend their support.
While the EBOVAC-Salone team had to operate within the operational context of an emergency, they had to simultaneously separate themselves from the mainstream Ebola response in terms of community mobilisation. In an environment already saturated with Ebola messaging and where both stakeholders and communities were desperate for potential solutions, research teams had to be very clear that the investigational products being trialled were not proven interventions, but those whose safety and efficacy were not yet known. Even so, initial exit interviews carried out with participants suggested that many believed they would be receiving medicines that would cure various illnesses – not just Ebola – by volunteering for the trial.
However, operating within an emergency context also brought some benefits for community mobilisation. The structures put in place for the Ebola response often facilitated stakeholder engagement, bringing together multiple stakeholders in one group or location and serving as a platform for providing regular briefings on the trial's progress. The nature of the epidemic itself also meant that individuals at a national, local and community level were often very receptive to research teams, providing public support for the trial and even personally assisting with engagement.
Conclusion
The additional challenges faced by the trial team in setting up a clinical trial amidst an epidemic were greatly exacerbated by the geographical location of this particular outbreak, the poor health services, and the relative infancy of clinical research in the country. Nonetheless some of these hurdles – such as emergency restrictions and staff recruitment -would likely be encountered by teams establishing trials in the context of an epidemic no matter where in the world they occurred.
Flare ups of Ebola have recently continued in the three worst-affected countries, reinforcing the urgent need for both licensed vaccines against Ebola and better preparedness for conducting research in outbreak settings.
*Dr Deborah Watson-Jones is a Clinical Epidemiologist at the London School of Hygiene & Tropical Medicine and Macaya Douoguih is the Senior Director, Clinical Development at The Janssen Pharmaceutical Companies of Johnson & Johnson
Photo Credit: CDC Global via Flickr Creative Commons
