key: cord-0690288-u6xztjv6
authors: Dal-Ré, Rafael
title: Placebo control group in COVID-19 vaccine trials: context and timing matters
date: 2021-11-27
journal: Eur J Clin Pharmacol
DOI: 10.1007/s00228-021-03259-x
sha: 92cf7a76298938ce709e3297ef256ae23c8c43ca
doc_id: 690288
cord_uid: u6xztjv6

nan

with fully informed consent and the best possible standard of COVID-19 care must be available to all participants. As soon as the safety and efficacy of the vaccine candidate is demonstrated, participants should have the chance to be unblinded immediately and placebo recipients immunized with the vaccine candidate. Participants should be allowed to unblind and access a known effective vaccine should one become available to them. In addition, and in particular, the research should respond to local needs (placebo-controlled trials should be done in regions impacted with high burden of COVID- 19) , both participants and communities should benefit from the trial, and the vaccine candidate to be tested, if proved to be efficacious and safe, should be made available in the country where the trial is conducted [8] . To this end and from the very beginning, transparency should be the fundamental guiding principle in the cooperation between the sponsor and local stakeholders with full community partnership and engagement throughout. The commitment of local investigators, research ethics committees, and health authorities as well as of local community leaders is a must to ensure a fruitful community engagement and participation.

A review of the WHO databases [11, 12] showed that a number of phase 3 placebo-controlled RCTs in naïve healthy adults are currently being conducted (or should be started soon) in low-and middle-income countries with limited access to temporarily authorized COVID-19 vaccines. The main features of this type of trial and the percentage of the population that have been, at least, partially vaccinated in participating countries, as a proxy of availability of temporarily authorized COVID-19 vaccines, are shown in Table 1 . Only placebo-controlled RCTs that started after 1 April 2021 are described. These are trials that were likely started after, at least, some participating countries had the opportunity to access to a certain number of authorized COVID-19 vaccine doses. These trials are sponsored by local or foreign companies or organizations and are placed in four continents. Of these RCTs, two of them deserve a reflection. First, the one to be conducted in eight Sub-Saharan countries is aimed to assess SARS-CoV-2 variants of concern (PACTR202105817814362). The trial has been approved by 12 local research committees in five participating countries and by the UCSF Human Research Protection Program institutional review board since the trial is sponsored by the US NIAID. The approved protocol states that, at the first set of vaccinations, 7,000 participants will be allocated to receive the two vaccine doses, whereas the other 7,000 will receive two placebo injections; some 2 to 4 months later, in a doubleblind fashion, participants will be crossed over to receive two placebo injections or two vaccine doses. The protocol states that if an authorized vaccine becomes available, participants will have the option of being unblinded and receive the authorized vaccine. Unblinding is not reported in the information posted on the registries for the other trials mentioned in Table 1 , except for the one to be discussed below.

Second, the trial sponsored by Sanofi Pasteur (NCT04904549) was started in the USA in June 2021. This trial should have not been approved neither by American institutional review boards nor by Japanese research ethics committees (RECs), since clinical equipoise was not present at the time the trial protocol was reviewed in these countries [18] . All US sites have stopped recruitment eight weeks after the trial was started, as did the Japanese centers shortly after. As happened in the Sub-Saharan trial mentioned above, participants can request unblinding. This trial has a number of recruiting sites in Africa, Asia, and Latin America. The conduct of this trial in Colombia raises ethical concerns, since with 64% of the population being at least partially vaccinated [15] and with an adult population of 69% of the total [19] , it might have enough doses to vaccinate all adults.

All trials that are being sponsored by Chinese companies are being (or will be) conducted outside China. Having 82% of all Chinese population at least partially vaccinated [15] , and being adults about 77% of the population [19] , it is almost certain that any Chinese adult could have access to any available COVID-19 vaccine. So, no new placebocontrolled RCTs should be conducted in healthy naïve adults in China. All participating countries of these trials have a limited percentage of their populations partially vaccinated against SARS-CoV-2, so the conduct of these placebocontrolled RCTs is ethically sound. However, there are two exceptions. Thus, sites from Malaysia and Mexico should not participate since, with 78% and 58% of their populations partially or fully vaccinated [15] , so no adult should have difficulty getting vaccinated with a temporarily authorized COVID-19 vaccine. Recruitment to these trials should be stopped and participants should have the option of being unblinded and receiving a vaccine out of study something that is uncertain since there is no information available about it.

The same approach should be applied to local companies from Iran and Vietnam that are conducting placebocontrolled RCTs in their countries where 65% and 66% of their populations have been partially or fully vaccinated.

Finally, WHO-sponsored Solidarity Vaccine Trial (ISRCTN15779782) is an adaptive RCT [20] that was started in September 2021 with three COVID-19 vaccine candidates to be assessed vs placebo. These are Codagenix and Serum Institute of India live-attenuated virus vaccine (Covi-Vac); Medigen, Dynamax, and NIAID protein subunit vaccine (MVC-COV1901); and Arcturus mRNA vaccine (ARCT-154) [11] .

Currently, there is a window of opportunity to conduct placebo-controlled RCTs in settings with limited access to authorized COVID-19 vaccines before immunogenicity trials are widely implemented. And this will happen once correlates of protection are accepted by the scientific community and regulatory agencies, something that has not happened yet although several preliminary reports on correlates of protection to a few vaccines have been published [21] [22] [23] [24] [25] . An important concern that has been recently flagged is that immunogenicity RCTs comparing a novel vaccine candidate with an authorized vaccine might find the issue of not having these latter available for the conduct of comparative RCTs, since the use of available temporarily authorized COVID-19 vaccines are restricted to fulfill public health needs [26] . Yet currently, there are three phase 3 immunogenicity RCTs assessing vaccine candidates vs the AstraZeneca vaccine in healthy adults: Valneva's inactivated virus vaccine (France, NCT04864561, n = 4,019, started in April); SK Bioscience's protein subunit vaccine (South Korea, NCT05007951, n = 3,990, started in August); and Medigen's protein subunit vaccine (Taiwan, NCT05011526, n = 1,020, not yet recruiting). In addition, in September, one immunogenicity RCT (CTRI/2021/08/036074; n = 2,140) started in India assessing Biological E's protein subunit vaccine (Corbevax) vs Covishield (the AstraZeneca vaccine manufactured by Serum Institute of India), whereas one month later, a RCT (NCT05077176; n = 7,300) was started to assess Health Institutes of Turkey inactivated virus vaccine (Turkovac) vs Coronavac (Sinopharm inactivated vaccine).

The lack of enough available temporarily authorized COVID-19 vaccines to immunize all their naïve healthy adult populations is the main problem of many low-and middle-income countries regarding the COVID-19 pandemic. Until this huge public health issue is solved and unto the scientific and regulatory acceptance of correlates of protection for temporarily authorized COVID-19 vaccines, denying the conduct of ethically and scientifically sound placebo-controlled RCTs with novel vaccine candidates in countries with limited access to authorized COVID-19 vaccines prevents both having these countries involved in a type of research that is of high social value for their communities and building capabilities in vaccine development that could be critical in future pandemics.

The author declares no competing interests.

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