NEWS & ANALYSIS an audience With… John-Arne Røttingen Over 180 clinical trials of proposed COVID-19 drugs are already recruiting patients, and another 150 are registered to start recruiting patients soon. But many of these trials are small and not designed to identify the best treatment strategies for the COVID-19 pandemic. For Chief Executive of the Research Council of Norway John-Arne Røttingen, a more collaborative approach is now needed. And as Chair of the Executive Group and the International Steering Committee of the WHO’s recently launched Solidarity trial, he hopes this mega-trial can provide a blueprint, he told Asher Mullard. Council of Norway The Research Credit:
Already 70 countries have said they will What we’ve coined is this novel sort of a can really speed up recruitment — and join the Solidarity trial, paving the way to mother–daughter relationship between trials, that’s why we want to do this at scale in test the efficacy of the most promising agents where a core protocol can be implemented many countries — there will definitely be at scale. For now, it is set up to test Gilead’s at global scale, while countries with more opportunities to increase the number of RNA-polymerase inhibitor remdesivir, capacity can collect much more detailed arms in the trial. the antimalarials hydroxychloroquine and clinical trial data. And everyone will be Another option could be that once we chloroquine, the HIV protease inhibitors using the same randomization rules, have enough data, we will conclude this first lopinavir plus ritonavir, and lopinavir clinical end points, standard of care and Solidarity trial and then restart another with and ritonavir in combination with the inclusion–exclusion criteria. a new set of arms, including potentially any immunomodulatory agent IFNβ1a. Results drugs that have demonstrated an effect as from the adaptive trial could be available How big will the trial be, and what effect standard of care. But this decision will be within 12–16 weeks. size is it powered to detect? driven by the data. But vaccines are needed too. Røttingen We have deliberately not done power Smaller trials can still be hypothesis- has first-hand insight into the pain points calculations, and are rather relying on the generating, in that they will give us ahead here, from his time overseeing an adaptive design and the interim analysis. indications as to promising drugs to look at. umbrella trial of Ebola vaccines and as So, the size will depend on the clinical effect But then these drugs will still need to be founding CEO of the Coalition for Epidemic of the drugs we are testing. The bigger the tested in larger trials, and Solidarity could Preparedness Innovations (CEPI), a global effects, the fewer patients we will need and be a mechanism to do that. alliance set up in 2016 to coordinate the the faster we can stop. development of new vaccines in times of crisis. This first trial is looking at hospitalized Nature Reviews Drug Discovery spoke patients with COVID-19. Why start there? with Røttingen about the Solidarity trial, the That decision was made based on what is challenges ahead for vaccines and the global The scale of these trials is easiest to do currently, and we know that the response to COVID-19. too small, and the variation testing capacity available in many countries right now means that only patients with What do you make of the more than in terms of how they are severe symptoms are tested fully. And so it’s 180 trials of potential COVID-19 drugs being run is too large easiest to have the inclusion at the hospital that are already ongoing? level. Of course, our trial is designed so It’s encouraging in the sense that it is really that we will collect data on disease severity important to do trials in this situation, The WHO has disclosed the first four arms so that we can do subgroup analyses in so that we can actually get solid evidence for this adaptive trial, but has said it might the future. instead of just operating blind. Randomized add more arms. How will this work? trials are really important. The challenge We have appointed an independent data Antiviral agents may provide the most though is the scale of these trials is too small, and safety monitoring committee, and they benefit when they are used earlier in the and the variation in terms of how they are will be the only ones who can do interim course of disease. Is there scope for a future being run is too large. They aren’t really analyses, look at the data and advise in master protocol trial looking at earlier designed to answer the questions that need terms of stopping arms as well as stopping intervention? to be answered. the trial overall. Then, of course, there is the I believe that we might need that as well. question of adding new arms as we go. In terms of prevention, there is already How will the Solidarity trial address this? The challenge is that if we add more arms, a planned large prevention trial with Solidarity provides us with a great way it will take longer to collect solid data on the chloroquine or hydroxychloroquine. of achieving fast-track data generation for therapeutic options that are in the existing So that’s one option. The other option is to promising candidates, on the most important arms. So that will be an issue that the data start a trial in patients with mild symptoms. clinical outcomes, in a very simple, large-scale committee needs to look into. And this will But the ability to get that running depends mega-trial. depend in part on recruitment rates: if we on better testing.
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high-speed vaccine development. I would It’s interesting that we’ve seen that the IMF, like to see — after we have solid phase I trials World Bank and sovereign banks really can I’m not saying these will on vaccine candidates — a parallel clinical mobilize resources for COVID-19. But these be a cure for COVID-19. development track for these. mechanisms provide funding to sovereign states, and we haven’t established clear But even if we can reduce What are the key considerations on mechanisms for global pooled funding for the proportion of patients vaccines, beyond efficacy? technology development. This is something that need a ventilator by, One of the big challenges for vaccines we need to think about, both for COVID-19 say, 20%, that could have a is safety, given how widely these would be and for future situations. used. This is especially true for completely huge impact on our national new vaccine platforms, such as mRNA You and your colleagues proposed the need healthcare systems and DNA vaccines that have yet to make it for the WHO’s R&D Blueprint, following the to market. 2014 Ebola outbreak, recognizing that we For clinical trials, there will need to should start preparing for future infectious Do you hope that Solidarity will provide be key decisions around which patient disease crises. Presumably, you hoped baseline standards of care, end points, inclusion– populations we would do the trials in. then that we’d have more time to prepare. exclusion criteria and case report forms for We will need a population with sufficiently What does the response to COVID-19 say others who are running standalone trials? high risks of actually getting COVID-19, about how well prepared we were? I hope this will happen. Solidarity sets so that there are enough events in the trials, We were not prepared sufficiently. We have out clinical outcomes, inclusion–exclusion but at the same time we do not want to do been talking about a pandemic forever. criteria, and a baseline standard of care. it in communities where there are already Of course, first and foremost we expected a flu The daughter trials also establish even more high levels of immunity. Similarly, we will pandemic, and I think we would have been detailed case report forms, which would be want to see whether these vaccines work better prepared if we had the flu pandemic. particularly useful for some of the newer in elderly individuals and people with But we were not prepared for this. Not even drugs in development. comorbidities, but the challenge with these the scientists that were closest to this sort of elderly populations is that they typically have prediction were prepared. What are realistic expectations for the weaker immune responses. So there needs efficacy of these first-round drugs? to be some consideration of the trade-offs in I don’t have specific numbers in mind. And terms of the types of people you would want I’ve tried to be very clear on why we’re doing to test the vaccines in. We were not prepared this. I don’t want to set expectations too high, Another big challenge for vaccines sufficiently but I do want to communicate that these are compared with therapeutics would be scale. potentially promising therapeutics. The way So volume of manufacturing will be a key I see it is that instead of just using drugs through challenge. That said, I think we are now in a good sort of experimental use or compassionate use, Then we have the access issues. What position of international collaboration. we need to have evidence on whether or not mechanisms could ensure fair distribution And I think we are in a better position now they work. This is a way to give patients the best of vaccines? These vaccines are now being than we were with Ebola. available treatments, but under a mechanism developed with public or philanthropic Of course, Ebola is very different from where we can actually learn from it. funding. So we really need to establish clear a pandemic infectious disease. And to be I’m not saying these will be a cure for systems of fair access, where purchasing honest, the R&D Blueprint was focused on COVID-19. But even if we can reduce the power and geographic production should outbreak-prone viral diseases that could have proportion of patients that need a ventilator not be the limiting factors. big public health impacts at local levels, but by, say, 20%, that could have a huge impact that are not at the highest risk of turning on our national healthcare systems, and Is there enough funding in place for into pandemics. A pandemic situation is really improve the situation a lot. But it will all this? very different. do nothing to overall transmission rates and It’s still too limited. The calculations that have The landscape here is much more complex. infection numbers. been done indicate that we ideally should But I still believe that we have to have the have collectively US$2 billion for vaccine WHO as a convening platform to discuss Which brings us to the need for vaccines. development and testing. We have not the issues, the key priorities, to define model Yes. I believe that a vaccine is a key long-term been able to mobilize all that yet. But some protocols and also to discuss the current solution. I think it’s really important to have countries have really contributed. evidence for treatments.
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