What if Clinical Trials Deliver Results Too Late for an Emergency?

The debates that have flared over clinical trial adequacy and authorization delays for COVID-19 vaccines acquire a different perspective in light of discussions currently underway over Ebola vaccines in Uganda.

With the emergence of the coronavirus, sharp divisions emerged from 2020 as health authorities in the developing world met, in differing ways, the challenges of countering the impact. The creation, testing, and delivery of effective vaccines provoked criticisms as well as congratulations, criticisms that continue to be mirrored in persistent allegations of insufficient safety or bitterness over inequalities in access. Within Europe, relations between the European Union and the UK are still under a shadow of resentment over the disputed allocation of AstraZeneca's production, and hardly a month goes by without suggestions that adverse effects are being underplayed or ignored.

But in Uganda, where an outbreak of the Sudan Ebola virus is affecting rural and urban environments, the evaluation of candidate vaccines is presenting a very specific challenge: can clinical trials deliver results in time to have a beneficial impact? Unlike the Zaire Ebola virus which sparked most recent outbreaks, there are no approved vaccines or therapeutics for the Sudan Ebola virus, leaving care workers operating in a void. Since this variety of Ebola occurs only rarely there has until now been little possibility to test vaccines against it. Experts working for the World Health Organization (WHO) agreed in November that three candidate vaccines should be deployed to Uganda for a clinical trial. Trial protocols are being prepared, and WHO is working with the national ministry of health and the university of Makerere, as well as with developers and regulatory authorities. A plan to accelerate research to ensure access to investigational doses, and to help in scaling up and access to any subsequent licensed vaccine, is already in place, under the lead of WHO, the Coalition for Epidemic Preparedness Innovations (CEPI)—the public-private partnership on vaccine development—and Gavi, the Vaccine Alliance focused on vaccinating children.

At the same time, there is evidence of a slowing down of transmission in many of the affected districts as the outbreak is controlled without vaccines. As Dr. Matshidiso Moeti, WHO regional director for Africa, acknowledged in late November, "It will take time to get trial results"—and they may come through so late as to provide no assistance in this outbreak. However, WHO favours continuing the trial. “What I don’t want to be doing in six weeks or eight weeks’ time, is looking back if there’s a deterioration of the situation and saying ‘God, we should have. We could have. And if only we had,’” Mike Ryan, head of WHO’s Health Emergencies Program, told a press conference. His view was backed by his colleague, Dr. Ana Maria Henao-Restrepo, co-lead, research and development blueprint for epidemics. The unpredictability of outbreaks means "it’s better for us to work toward generating the evidence,” she said.

As always, there is a resources aspect to the discussions. A WHO appeal for funds to combat the Uganda outbreak is still massively under-subscribed. Right at the end of November the European Union has chipped in with $6 million to support clinical trials. The money is coming from a multiannual EU health program, EU4Health. Stella Kyriakides, the European health commissioner, said it was important to invest in R&D to find vaccines and treatments for the Sudan Ebola Virus as part of the EU's action beyond its borders. Most of the money is earmarked for the trial, and is expected to cover much of the costs. The clinical evidence generated for safety and efficacy will support marketing authorization applications, and to prevent and address future outbreaks. To improve the resilience of the supply chains, the EU's new Health Emergency Preparedness and Response Authority is exploring with EU member countries the possibilities to support production once these medicines are authorized.

Meanwhile, disturbing reports of resurgent COVID in China are demonstrating that even where vaccines are available, management of epidemics is as crucial as immunization. The reports also suggest that confident predictions of having mastered the pandemic could yet prove premature and over-optimistic. There is likely to be still plenty for clinical trials to do on COVID, too.