The expansion of the Randomised Evaluation of COVID-19 Therapy Trial, or RECOVERY — a blockbuster U.K.-based clinical trial of potential COVID-19 treatments — to Indonesia and Nepal last month has called attention to the persistent dearth of similar efforts to find therapeutics that work within the resource constraints of the global south.
“It is a continuing gap,” said Borna Nyaoke, senior clinical project manager at the Drugs for Neglected Diseases initiative’s East Africa office. DNDi is coordinating ANTICOV, a clinical trial consortium that will test COVID-19 treatments in 19 trial sites across 13 African countries, and that, alongside RECOVERY, is one of the few existing efforts to shore up this gap. “We need to ensure that whatever innovations we’re coming up with are applicable to where they’re going to be used,” Nyaoke said.
It is a need that remains pressing despite the acceleration of the global vaccine rollout. With better-resourced countries claiming the vast majority of available vaccines, some countries in the global south are predicting it could take years before their populations achieve herd immunity.
“We need to ensure that we have vaccines and therapeutics working together,” Nyaoke said, “because both are going to be needed for a while.”
RECOVERY’s expansion to Indonesia and Nepal — and eventually, according to current plans, to at least one African country — could be an important boost, both in terms of the research it produces and in signaling the necessity for others to join in the effort. It comes as the only truly global trial of COVID-19 treatments, the World Health Organization’s Solidarity Therapeutics Trial, was recently paused after its first four candidate treatments were found to offer no benefit.
“Things that might have a moderate benefit, which might not have interest in rich countries, could have interest to low-resource settings.”— Nick White, founding member, COVID-19 Clinical Research Coalition
RECOVERY, which launched in the United Kingdom in March 2020, has been instrumental in establishing whether existing or new drugs are effective in treating COVID-19. Researchers have shown that the steroid dexamethasone and anti-inflammatory treatment tocilizumab can both reduce the risk of death among hospitalized patients.
There was a recognition among RECOVERY researchers, though, that “some of the treatments that are being trialled in the U.K. wouldn’t be possible in the global south because of cost or accessibility,” said Emmanuelle Denis, one of the key coordinators for the international expansion of RECOVERY. This prompted the decision to introduce trials that take into account the specific factors at play in a low-income setting, such as treatment availability, safety, feasibility, and price.
It also comes amid mounting pushback against the idea that research done in Europe or the United States should automatically guide policy in other parts of the world.
ANTICOV was partly motivated by a recognition that “Africa tends to get left behind in terms of R&D [research and development], and then we tend to accept results or data from other countries,” Nyaoke said. “But Africa displays the greatest genetic diversity among all the continents, and treatments developed elsewhere may not be as efficacious when applied here.”
Alongside the primary benefit of finding functional treatments that can be effectively deployed in low-income settings, doing the clinical research in those countries can help facilitate the eventual uptake of any recommendations, Nyaoke said. “If you conduct clinical trials within a region, it is easier for the ministry of health to accept it.”
RECOVERY will begin by testing the effects of aspirin on COVID-19 patients in Indonesia and Nepal, though a committee is still considering trials of other possible treatments.
ANTICOV paused the first arm of its inaugural clinical trial, launched in the Democratic Republic of Congo late last year, after a change in WHO guidance on the two treatments being studied. But Nyaoke said the coalition is now back on track with plans to restart trials focused on other treatments within the next three weeks. The researchers hope to have results by October or November.
Nick White was one of founding members of the COVID-19 Clinical Research Coalition, which issued a call near the outset of the pandemic for research into affordable, available, and adaptable interventions in resource-poor settings. Though he still does not “see facilitation and support strongly at a high level” for these efforts, he said the ANTICOV and RECOVERY developments “do signal an important change.”
He said there is still a need, though, for a broader reconceptualization of the purpose of clinical therapeutic trials in the global south.
In better-resourced settings where intensive care capacity is more readily available, it makes sense to think about treatments that can reduce the risk of death among patients who are hospitalized with severe COVID-19 infection, White said. But in countries without those resources, the focus should be on early antiviral interventions that will reduce serious infections.
That shift in priorities may lead researchers back to some of the therapeutics they have dismissed following trials in Europe and the U.S.
“Things that might have a moderate benefit, which might not have interest in rich countries, could have interest to low-resource settings,” White said. While there is no guarantee they will work, he said they are worth investigating. And that will require clinical trials across the global south on a scale that has not yet emerged during the pandemic.
RECOVERY’s difficulties in expanding internationally, though, underscore some of the more systemic challenges to conducting the kind of research White and others are calling for.
Denis said it took about four months to stand up the international arms after RECOVERY decided to go global. There was the immediate — and ongoing — challenge of identifying treatments that would be widely available if they were found to be effective.
There is also the issue of speed. Denis said the team aimed to identify sites that had established clinical research units to quickly navigate national ethics regulations. And it wanted to be able to work in contexts where it could introduce some of the streamlining implemented in the U.K., which proved critical to accelerating the trials — including curtailing the reporting of every adverse event or reaction for treatments with known safety profiles.
RECOVERY’s researchers, who are drawn from two departments within the University of Oxford, ended up expanding to institutions with which they already had working relationships.
“In this case, there was a real desire to try to implement things as quickly as possible to catch cases and get numbers to produce results,” Denis said.
White said it is imperative that other researchers and funders adopt a similar urgency.
“Being realistic about COVID, all we’ve got right now are things that we could do possibly to buy time until people get vaccinated one or two years from now,” he said. “During which time, if something that’s available on the shelves now could be deployed, we need to find out if it will work. And that’s going to require big, well-conducted trials.”
Update, March 23, 2021: This article has been updated to clarify that DNDi is coordinating ANTICOV, rather than funding it.