A healthcare worker prepares specimen collection tubes at a coronavirus disease (COVID-19) drive-thru testing location in Houston, Texas, US, November 20, 2020. Reuters/Adrees Latif/File Photo.
New Delhi: Pfizer’s COVID-19 vaccine trial analysis that found the drug was 95% successful against the novel coronavirus was conducted with 170 people confirmed to have the disease. Of them, however, 162 people were in the placebo group and only eight were in the vaccine arm.
These successful results have raised one tricky question, R. Prasad wrote in The Hindu. On November 20, Pfizer said it was asking the US Food and Drug Administration (FDA) for an emergency use authorisation (EUA) for its vaccine candidate. Once an EUA is granted, would it be ethical to deprive the vaccine to those who participated in the trial but received the placebo instead of the real thing?
An FDA advisory committee tentatively plans to meet on December 8-10 to discuss the vaccine. If the EUA is granted, high-risk groups will be vaccinated starting December.
It will be a problem for the vaccine trial, however, if those who were in the placebo group are administered the vaccine immediately. For them to get the vaccine, the trial will have to be ‘unblinded’: the allocation code must be broken and participants must be made aware of whether they got the vaccine or the placebo. Once this is done, and the placebo-group participants are offered the vaccine, it will be “almost impossible to gather further information on vaccine efficacy, thus making full-licensure challenging,” Prasad noted.
A similar problem had arisen as early as April this year, when the drug hydroxychloroquine received an EUA in the US, on flimsy evidence of its efficacy but with the backing of President Donald Trump. Undark had reported at the time that “researchers … worry that if the public comes to believe that the evidence on hydroxychloroquine is settled, few patients will want to participate in clinical trials at all. They’ll just want the hydroxychloroquine — and there is already evidence that this is happening.”
Gagandeep Kang, a top vaccine scientist in India and a professor of microbiology at the Christian Medical College, Vellore, told the newspaper that she believes all participants are usually offered the vaccine at the end of a designated follow-up period. At the same time, they are also kept informed of updates in the vaccine development process. “[This] means when an EUA is granted, the information should be conveyed to all participants and they should be asked what they would like to do,” she said.
The EUA, however, is not the same as a full license. Some of the placebo-group’s members, like healthcare workers, will at this point be legally eligible to receive the vaccine even outside the trial.
And once members of the placebo group know that the vaccine works, but they weren’t administered it, they may ask to be given the vaccine. However, “doing so would prevent a long-term comparison between the placebo group and those who were initially vaccinated,” according to Medical Xpress. It may delay the complete licensing process – and thus push back the public release of the vaccine. Because of this, some scientists believe despite the ethical considerations, companies must keep the studies blind until the phase 3 trials are complete.
“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,” Anant Bhan, a researcher of global health and bioethics, told 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.”
There’s another danger too, as Medical Xpress pointed out: With good news emerging from one vaccine trial, fewer people may agree to join the trials of other vaccines, especially those at earlier stages of development.
Moderna, another company that has come pretty far in its vaccine development, had already seen the placebo-group problem coming in October, and asked authorities how it should be handled. Pfizer and its German partner, BioNTech, had also written to the FDA then, saying they had “an ethical responsibility” to tell members of the placebo group that they hadn’t received the vaccine.
Neither Moderna or Pfizer, however, had mentioned whether or when the placebo group would get access to the vaccine, according to STAT. “Participants are told that if a vaccine becomes available, they are allowed to take it,” the report said.
The FDA is aware that this problem exists, but has not yet come up with an alternative way to evaluate vaccine efficacy. So far, the organisation seems to be suggesting that companies should keep trials involving placebo groups going for as long as possible.
Donald Fink, of the FDA’s vaccine division, had seen this ethical dilemma coming a month ago. “We do acknowledge that situations will likely arise where it is no longer ethically permissible and therefore no longer feasible to continue placebo controlled follow-up in an ongoing trial or to initiate a placebo controlled trial,” he said then.
“I don’t have any specific remedies to offer. At this time, we have asked the vaccine manufacturers and the other government agencies who are involved in conducting these trials to think carefully about how they would ensure clinical trial retention,” Fink continued.
Since the FDA hasn’t yet issued any regulations regarding placebo members, Pfizer appears to be coming up with its own short-term solution.
In a memo to researchers who worked on the Pfizer vaccine, the company said members of the placebo group would eventually be administered the vaccine. The question of when that will happen, though, remains tricky. “If our potential vaccine receives an EUA, we would propose amending the study protocol to create a process so that interested, eligible participants who received the placebo could ‘cross-over’ to the vaccine arm of the study,” the memo reads, according to STAT. “Such a change would require input and approval from regulatory bodies, and we are actively exploring this now.”
William Gruber, a senior vice president of vaccine clinical research and development at Pfizer, also said the same thing in an interview earlier this month. Those in the study who will be eligible to receive the vaccine outside after the EUA certification – such as healthcare workers – will be encouraged to stay in the trial, and receive the vaccine within it.
“Apart from the ethical obligation to make sure they can get the vaccine to which they would otherwise be entitled, I don’t want to lose that data,” Gruber said. “So we’re going to encourage them to stay on the trial and get the vaccine as part of the trial proceedings, but only those that would qualify.”