On November 20, Pfizer tweeted saying that it would, along with BioNTech, be submitting a request the same day to the U.S. FDA for Emergency Use Authorisation (EUA) of the mRNA COVID-19 vaccine candidate. The FDA is likely to grant the authorisation by the end of the month, based on which the company says the vaccine will “potentially” be enabled for use in high-risk populations in the U.S. by middle-to-end of December.
The announcement comes two days after Pfizer said in a press release that in the primary efficacy analysis, the vaccine was 95% effective against COVID-19 disease beginning 28 days after the first dose. The analysis was carried out on 170 confirmed cases of COVID-19 disease, of which 162 were in the placebo group and just eight were in the vaccine arm.
Now that the vaccine has been found to be highly efficacious, including in older adults, and can prevent severe disease, a tricky question is whether it would be ethical to deny the vaccine to those participants who have received the placebo when FDA grants an EUA and vaccination of high-risk groups begins in December.
But offering the vaccine right away to those in the placebo group will first require unblinding the study. Unblinding the study and offering the vaccine to the placebo group will make it almost impossible to gather further information on vaccine efficacy, thus making full licensure challenging.
Giving a choice
“My understanding is that participants are offered the vaccine at the end of the designated follow up period, but participants are also given updated information on what is happening with vaccine development as soon as it is available (treating informed consent as a process instead of just at the entry into the study). Which means that when an EUA is granted, the information should be conveyed to all participants and they should be asked what they would like to do,” Dr. Gagandeep Kang, Professor of Microbiology at CMC Vellore says in an email to The Hindu.
Standard of care
“We are dealing with a novel virus and a new vaccine platform. We need longer term data on safety, efficacy and durable immunity. An interim short-term analysis does not provide us with this information. So, the trials should go on and complete their full pre-established planned duration,” Dr. Anant Bhan, a researcher in global health and bioethics, says in an email to The Hindu. “Those in the placebo group cannot be ‘denied’ the vaccine if they want to get it based on an EUA, but since an EUA does not equate to a changed standard of care in my opinion, it would not be ethically required to offer the vaccine candidate to them.”
Virologist Dr. Jacob John too agrees that those in the placebo group cannot be given the vaccine before the completion of the Phase-3 trial. “I don’t think that vaccine will be or should be offered to placebo recipients right away, but only after regulatory agency approves the product’s safety and efficacy,” he says in an email.
Though vaccination of high-risk groups may begin in December, majority of trial participants, including those in the placebo group, will not belong to a priority group that would get the vaccine for at least one year. Hence, delay until vaccine registration may be justified, says Dr. John.
Unblinding the trial
Under these circumstances, should the trial be unblinded and participants in the placebo group be vaccinated? “This could mean that we might delay getting data for a full licensure,” Dr. Kang says.
The independent Data Safety and Monitoring Boards (DSMB) makes sure that trial participants are protected and the integrity of the study is maintained. “So, deliberation is important with all of the stakeholders. This is a complex discussion and cannot have a simple answer for every participant in a trial,” she says.
But it is important that all trial participants are informed of the interim efficacy results and about the EUA for the vaccine, if the FDA grants one. The vaccine should be offered to participants in the placebo group under two scenarios. In the first case, any trial participants belonging to the high-risk group who would otherwise have got the vaccine on priority should be informed of their eligibility and offered the vaccine. This will decrease the power of the study to define accurately how well the vaccine works in them. But we will have find ways of designing effectiveness studies to address how we get this information, Dr. Kang says. Since participants should get only two and nots four doses of the vaccine, it will require unblinding of the status of the participants.
Second scenario
The second scenario would be when the trial is stopped on DSMB’s recommendation based on an interim analysis of vaccine efficacy or when the trial reaches term and the vaccine candidate is found to be efficacious and the vaccine achieves full licensure from a regulatory agency.
