Researchers have quickly developed an outstanding arsenal of vaccines, treatments and diagnostics to counter COVID-19. But closer global coordination of diverse clinical trials testing the same or similar treatments, extending even to a global platform to pool anonymized patient data, could strengthen and accelerate research findings – especially as emerging variants threaten to unwind gains.

These were among the key points made during a two-day COVID-19 Global Research and Innovation Forum hosted by the World Health Organization (WHO), which brought together two dozen leading figures across academia, civil society, and ministries of health.

There was also growing recognition that equity needs to be built into global health funding –  mainly by redirecting resources to the global south and embedding access provisions into funding agreements.

“The lesson is clear. A collaborative approach to research and innovation is essential to responding to COVID-19 and to the epidemics and pandemics of the future,” said WHO Director-General Dr Tedros Adhanom Ghebreyusus on Thursday. 

“There is a need for us to look at how we organise not just individual pieces of research, but how each individual research initiative or innovation is linked to each other, and how we can drive a coherent strategy for the world,” stressed WHO’s Executive Director of Emergencies Mike Ryan.  

“The issue has not been that science has not delivered,” added WHO’s Chief Scientist Soumya Swaminathan. “We haven’t been able to [work together] as a global community to really achieve the equity that we would have liked to have seen in the availability and access to these absolutely life-saving interventions.”

COVID-19 Research Has Boomed – But More Collaboration Needed

Despite astonishing progress in R&D since the novel coronavirus first emerged – from the development of mRNA vaccines to the use of lifesaving steroids for severe COVID-19 – the findings of many studies remain limited, warned panelists on Thursday. The most common flaws were methodological weaknesses and a lack of comparability, they added.

“There is so much diversity in studies with a lack of standardization across the board that it’s really difficult to reach conclusive evidence for many of the questions that are still outstanding,” said Marion Koopmans from Rotterdam’s Erasmus University Medical Centre Rotterdam, who is a member of the WHO-convened group to investigate the origins of SARS-CoV-2.  

Sylvie Briand, WHO’s Director of Infectious Diseases, explained that coronavirus variants have been particularly difficult to study because a wide range of data from diverse world regions is needed, including genetic sequencing data, epidemiological data, and clinical data. 

All of these data streams are crucial to investigate whether variants are becoming more contagious, virulent, and resistant to existing vaccines, she said. Yet in many regions comprehensive data is scarce and mechanisms to pool all of those streams together are still lacking.

“We need some more new research but particularly we may need different coordination mechanisms because the key challenges that are outstanding really require a multidisciplinary endeavor,” added Briand.

And if existing vaccines turn out to require an update as a result of new variants, that will also require active involvement from the pharmaceutical industry, added Philip Krause from the US FDA’s Office of Vaccines Research and Review. 

“Because vaccination is an international enterprise, you can’t modify vaccines in just a few countries as developers and manufacturers are making vaccines for the world,” he added.

“Some of the companies that hold the critical supplies, reagents and groups, like Illumina, need to contribute and participate,” added Trevor Mundel, President of Global Health at the Bill and Melinda Gates Foundation. 

“We need to be sure that our ability to sequence the virus as it spreads is much better distributed according to where we may anticipate problems [but] so far we haven’t seen at a certain level,” said Mundel.

The Future? A Portfolio of Coordinated Clinical Trials

Going forward, a portfolio of coordinated clinical trials could represent a fruitful strategy that would yield more robust data faster, while also avoiding duplication of research efforts, the panelists suggested.

While such a portfolio has not yet been developed, there are signs that large-scale clinical trials are being increasingly harmonized. Examples including the WHO’s Solidarity Trials to test possible therapeutics, the UK’s Recovery Trials, as well as three large-scale clinical trials investigating antithrombotic treatments  – ATTACC, ACTIV, and REMAP-CAP.

“Something quite remarkable that happened was that three of the large-scale platform trials [anti-thrombotics] were able to collaborate and to agree on common protocols in order to address some of the key questions in the fastest way possible,” emphasized Professor Michael Jacobs, the Clinical Director of Infection at London’s Royal Free Hospital.

“This is an incredibly important achievement for three trials that evolved independently to be able to come together to use common approaches to address key questions as quickly as possible for the benefit of patients.”

Antithrombotics have the potential to broaden the COVID-19 treatment menu, which remains limited to treating severe cases with dexamethasone or through expensive monoclonal antibodies, thus leaving few effective options to treat mild cases, said Jacobs.

Randomisation of Vaccine Distribution

There is also an increasing appetite for a global platform to pool anonymized patient data from large-scale trials. This could shed light on a range of questions about vaccine effectiveness, safety, and dosage regimens in populations after they are approved.

Ideally, those large-scale trials of vaccines following their approval would be randomized to yield more robust results, emphasized Krause, adding that randomization would be ethical in contexts where vaccine supplies are scarce – which seems to be the case across many low- and middle-income countries worldwide.

“You can address important questions by embedding randomised studies within normal vaccine deployment,” said Krause.

“Instead of usual procedures for allocating vaccines, researchers use randomisation to define who and how to vaccinate. And randomization is considered a fair means of allocation, especially when vaccine supplies are limited.”

Importantly, a randomised vaccine distribution strategy would not affect participants nor healthcare personnel as the logistics would be managed by researchers, who would inform vaccinators which participants are eligible for their doses.

“The person who gets vaccinated sees nothing different from what they would otherwise see in registering for a vaccine, and the vaccination personnel doesn’t do anything different from what they would otherwise do if they were administering a vaccine.

“And that’s [randomization of vaccine distribution] a simple thing to do where vaccine supplies are limited. It doesn’t mean that you will get vaccinated while other people don’t get vaccinated.”

Those studies would be particularly useful to understand the impacts of delayed second doses, the efficacy of single doses, and mixing doses, he emphasized. 

“We can use that randomisation to answer very important questions about these vaccines,” explained Krause. Studies could understand the impact of a delayed second dose, the efficacy of a single dose, especially when vaccine supplies are limited.”

But in the long run, a stronger incentive system will need to be developed to encourage such collaborative research efforts, as coordination is easy to recommend, but difficult to implement, warned Jacobs.

Building Access Into Funding Agreements 

Meanwhile, a proposal to integrate explicit access-to-medicines provisions into funding agreements drew widespread support, including from CEPI CEO Richard Hatchett,  Executive Director of Drugs for Neglected Diseases Initiative (DNDi) Bernard Pecoul, the Gates Foundation’s Mundel and the  WHO’s Swaminathan. 

“The great missed opportunity of 2020 is that the funders of vaccine development did not include access provisions in their funding agreements,” said Hatchett. “The major funders could develop and adopt common approaches to achieving equitable access including in their grant and contract provisions.”

“Innovation and access should be combined and should be linked from the start. We do not have to wait until we have innovation to start thinking about access,” added Pecoul.

“Why not have in place clear and transparent terms and conditions in contractual agreements so from the start you include those criteria or incentives to be sure that all knowledge will be shared.”

For that to happen, however, global health funders will have to work together, as most global health initiatives are funded by multiple bodies rather than having one funder from end-to-end.

Tipping Global Health Funding To Global South 

There is also growing recognition that, for equity to be achieved, global health funding will have to be redirected to the global south to leverage untapped research capacity and reduce dependency on rich countries for vaccines, treatments, and diagnostics. 

“There is research capacity available around the globe that has not yet been sufficiently utilized in the pandemic response, particularly in the Global South,” said Dr Tedros.

“Today, the opportunity to carry out research at the highest level is not equally distributed around the world,” said Australian philosopher Peter Singer, who is a professor of bioethics at the University of Princeton. “Talent, without the opportunity to use it, is a shocking waste.”

Of the 9,500 coronavirus-related research projects that are funded to the tune of more than $4 billion, less than 1,000 were funded in the global south, including Asia, Africa, and South America, stressed Charu Kaushic, Chair of the Global Research Collaboration for Infectious Disease Preparedness (GLOPID-R).

“When we track that funding to see where exactly that funding has gone and where most of the dollars are invested, it is unfortunately primarily in the global north. And if you look at the global south, there’s not a lot of investment that has gone in there,” she added.

Image Credits: National Institutes of Health (NIH) , Twitter: @WHO.