New placebo-controlled Covid-19 vaccine trials are ethically questionable; it's now about comparative effectiveness and availability of registered vaccines.

Now that a number of vaccines against Covid-19 are approved by internationally authoritative regulators for use in a variety of target groups, an important ethical issue is whether investigators of new candidate vaccines should still assign participants to placebo groups, thereby withholding them the protection that already available vaccines can offer [1]. It could be argued that continuation of this research practice is warranted as long as there are insufficient vaccines for most people, including potential trial participants. However, that is neither a strong nor an ethically appropriate argument as increasing the production of already available vaccines is the fastest way to vaccinate everyone.

A methodological comment in favor of continuing placebo-controlled studies could be that published trial results until now [2,3] were generally focused on reduction of laboratory confirmed Covid-19 rather than severe clinical Covid-19 complications and mortality, and interruption of transmission [4]. But given the urgent pandemic circumstances it is arguable that the efficacy and safety of these vaccines have been sufficiently demonstrated for starting their use. Not only because of the plausibility that reduction of primary infections is likely to imply reduction of its complications, but also because delaying decision making on vaccination until definitively conclusive evidence on severe outcomes is collected may allow much additional mortality, severe morbidity, and potentially even more harmful virus variants to occur worldwide. Policy makers and practitioners have the responsibility to make transparent decisions in a context of some uncertainty, followed by post-marketing evaluation based on further follow-up [5].

One could also argue that it is unwise and unethical to discontinue ongoing studies that may provide knowledge and in which many participants have already been enrolled. However, that does not take away the serious ethical objections to placebo administration when approved vaccines are available. But it seems reasonable that studies in which participants have already received a placebo complete their follow-up until sufficient quantities of authorized vaccines are available. At the same time, that implies that companies that have nót yet started phase-3 studies must discontinue initiatives for placebo-controlled trials. That would apply to many dozens of candidate vaccine projects [6]. The only (albeit not easy) ethically responsible and clinically useful route for new vaccine trials is now to compare candidate vaccines directly, head-to-head, with – preferably the most effective and safe - registered vaccines, with effectiveness against both classic and new virus variants as outcome. This requires constructive cooperation between companies [7].

The broader socio-ethical and global health question is: why should a lot of time and resources still be spent on research with yet uncertain outcomes, aimed at gaining a market share, while the world urgently needs a much larger production of vaccines already shown to work? The latter can be achieved by also using production facilities of companies that are currently still working on candidate vaccines that may not be successful, come too late, or are unlikely to be more effective than the best available vaccines for the original or new variants of the virus [8]. This requires transparent access to scientific and technical knowledge about registered vaccines for other manufacturers, whether or not enforced by the international community [9]. This is obviously justified given the billions of dollars and euros spent by governments and the European Union to support the development of Covid-19 vaccines. In addition, industry has profited from vast public investments in scientific, clinical and public health infrastructures for the development and evaluation of the vaccines, as well as for their deployment and monitoring.

Does this put investment in innovation at risk, as is often heard from industry? I do not think so. Many company employees want to serve public health, and science and society will be willing to invest in new vaccines more than before. Nor has it ever been convincingly demonstrated that innovation is only possible in a system of protected knowledge monopolies in a shareholder-driven economy. Furthermore, in line with the significant public investments already made, an international public fund could be set up to provide development opportunities for all vaccine initiatives, including non-profit ones, which are considered promising by independent experts.

A further counter-argument sometimes heard is that new trials could yield cheaper vaccines. But even if that would be true, should pricing considerations - in addition to the ethical issue of giving placebo instead of an available effective vaccine - lead to (too) late availability of possibly less effective vaccines that will most likely be distributed to low-income countries? Instead, the international community should provide resources to deploy highly effective vaccines worldwide as quickly as possible to combat the pandemic successfully and minimize the time for potentially more dangerous virus mutants to occur. Moreover, with more concerted action on a global scale and extensive procurement, significant price reductions, as justified given the enormous amount of public money invested, can be better achieved.

In conclusion, the international medical research community must make clear that the time has come to no longer allow new placebo-controlled Covid-19 vaccine trials, and that the research focus should shift towards investigating comparative effectiveness of new candidate vaccines versus already registered ones. At the same time, WHO, the European Union, governments and industry should now collaborate to maximize the production of already registered vaccines as soon as possible. This would also substantially simplify and strengthen worldwide long-term monitoring of rare and late adverse effects.