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Ethics of COVID-19 vaccine trials in rapidly changing contexts

  • J. André Knottnerus
    Correspondence
    Corresponding author.
    Affiliations
    Department of General Practice, Care and Public Health Research Institute, Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Tel/Fax +31433540844
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      In my recent commentary on the ethics of Coronavirus disease 2019 (COVID-19) vaccine trials I argued that the time has come to no longer allow new placebo-controlled vaccine trials [
      • Knottnerus JA.
      New placebo-controlled COVID-19 vaccine trials are ethically questionable; it's now about comparative effectiveness and availability of registered vaccines.
      ]. I am happy that Dal-Ré agrees with this point of view. However, his interpretation of my text “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” is problematic. First, Dal-Ré writes that the meaning of this statement is unclear. He then continues: “If it means that participants should stay in the trial until all citizens of a community (including healthy 18–25-years-olds) have access to a TUA [temporary use authorization] vaccine, many placebo recipients (including healthy middle-aged adults) will stay in the trial for many months after they could be vaccinated according to the prioritization scheme that local health authorities have put in place to address the current limited availability of TUA vaccines” [
      • Dal-Ré R.
      Placebo-controlled trials with COVID-19 vaccines: participants first.
      ]. While I neither said nor meant this, he goes on to say that “this way of thinking was previously supported by other commentators” and links me to a variety of ideas from other authors that I have not mentioned nor endorse. He then says that he believes that ‘the viewpoints described above are mistaken since they require many trial participants not to take advantage of the opportunity to be vaccinated when it is their turn”, thereby rejecting viewpoints that he mistakenly also attributes to me. At the same time, I can understand that a sentence on an issue which I did not further elaborate in my brief commentary was not fully clear to readers. I therefore welcome the opportunity Dal-Ré provided to emphasize that the restriction “until sufficient quantities of authorized vaccines are available” implies that in my view vaccination should be offered to trial participants as soon as they become eligible for vaccination under their national program.
      I also appreciate that Dal-Ré took the time to put forward a number of interesting thoughts in response to my comments. With some of these I agree more than with others. I fully agree that “availability of a TUA vaccine for the prioritization group to which the participant belongs, is likely the most relevant (positive) information that could be communicated to trial subjects.” I do not fully agree that that these latter should “decide whether to be vaccinated with a TUA vaccine as soon as they are eligible for vaccination outside the trial”, as they should be protected from any risk of not receiving the then available new standard prevention. In may sometimes be preferable to discontinue a trial in a country as soon as authorized vaccines in that country become available to the extent that trial participants become eligible for vaccination under the national program.
      Let me add that also the situation that vaccines that many people would like to have are not yet available outside trials poses ethical challenges, because people then only have a chance of getting a vaccine through trial participation. This is an important - additional - reason to properly inform (potential) trial participants in advance about the expectations regarding the availability of already authorized vaccines in their country.
      Dal-Ré writes about elements to consider in developed countries and about placebo-controlled RCTs conducted for the assessment of COVID-19 vaccine candidates in any developed country. It is unclear to me why he is specifically focusing on what he calls developed countries. I believe that essential requirements for trials should be the same for all countries.
      Finally, I would like to reiterate that for COVID-19 vaccine trials the research focus must now shift from placebo-controlled trials to comparing new candidate vaccines with already authorized vaccines (i.e., comparative effectiveness research). At the same time, the WHO, governments and industry must work together to maximize the production of authorized vaccines as quickly as possible [
      • Knottnerus JA.
      New placebo-controlled COVID-19 vaccine trials are ethically questionable; it's now about comparative effectiveness and availability of registered vaccines.
      ], in order to provide all countries with the numbers of vaccines needed to vaccinate their people and to minimize the risk of emerging virus variants that are less sensitive to the vaccines.

      References

        • Knottnerus JA.
        New placebo-controlled COVID-19 vaccine trials are ethically questionable; it's now about comparative effectiveness and availability of registered vaccines.
        J Clin Epidemiol. 2021; 133 (Epub 2021 Mar 16): 175-176https://doi.org/10.1016/j.jclinepi.2021.03.006
        • Dal-Ré R.
        Placebo-controlled trials with COVID-19 vaccines: participants first.
        J Clin Epidemiol. 2021; (In press)