While randomized double-blind tests have become the gold standard for testing of various hypotheses, they also raise some ethical questions for which there are no easy answers. In the case of the covid-19 vaccine trials, there were discussions as to when the study should be unblinded so that those in the placebo group could also be vaccinated. Commenter Bethany said that a co-worker was in the Pfizer study and told her that it has been unblinded.
But before that happened, a group of scientists who are members of the WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation urged that the double-blind study continue.
While vaccine supplies are limited, available vaccines are still investigational, or public health recommendations to use those vaccines have not been made, we believe it is ethically appropriate to continue blinded follow-up of placebo recipients in existing trials and to randomly assign new participants to vaccine or placebo. Moreover, under these conditions, we believe that trial sponsors are not ethically obligated to unblind treatment assignments for participants who desire to obtain a different investigational vaccine. People who enroll in clinical trials for altruistic reasons would probably understand the value of gathering data that will further elucidate the safety and efficacy of these vaccines and their appropriate use.
Large, placebo-controlled, phase 3 efficacy trials could provide much of the needed information if they have appropriately prolonged follow-up while random assignments are still blinded. Such continuation would yield unbiased evidence on the duration of protection and on longer-term safety, including assessment of any evidence of the vaccine eventually enhancing the risk of severe disease (as was recently detected by continued follow-up of placebo recipients in dengue vaccine studies).
This opportunity to obtain reliable evidence about longer-term effects would be destroyed by early unblinding and immediate vaccination of participants assigned to placebo. Although each participant has the option to pursue any available intervention, if substantial numbers of participants choose not to do so, continuation of blinded follow-up in a population in which no licensed vaccine is being deployed could yield important and unexpected findings that would be difficult to obtain reliably any other way.
There is a price to be paid when using this method to determine the effectiveness of life-or-death treatments. Vaccine inventor Paul Offit is concerned about the ethics of double blind tests where someone will live because they got the vaccine, or die because they got the placebo. He says that with the covid vaccine trials, one person died during the trial and they all held their breath and then everyone gave a huge sigh of relief when it was found that they were in the placebo group. But what about that person who died?
PAUL OFFIT: Because there has never been a medical breakthrough in history that has not been associated with a price. When Thomas Francis did the polio field trial in the mid-1950s, Jonas Salk had made his vaccine, but he didn’t know whether it worked or not. So they chose to do a big field trial. Four hundred and twenty thousand children were given his vaccine over a year period funded by the March of Dimes. Two hundred thousand were given placebo – first- and second-graders throughout the country. And then after it was over, Thomas Francis stood up on the podium at Rackham Hall at the University of Michigan and said, safe, potent and effective. That’s what he said. Those three words were the headline of every major newspaper in this country. I mean, church bells rang. Synagogues and churches held special prayer meetings. Department stores stopped. Trials stopped, you know, so the judges could hear that announcement. It was announced over the Voice of America.
Well, the question is, how do we know that it worked? We knew that it worked because 16 children in that study died from polio, all in the placebo group. Thirty-six children were permanently paralyzed, 34 in the placebo group. But for the flip of a coin, those children could have been alive and well today. Those were first- and second-graders in the 1950s. I was a first- and second-grader in the 1950s. I mean, those people suffered or died because they just happened to be in the control group. That’s what knowledge takes. And that was – that statistic never really rang. I mean, we were so busy celebrating that that I think we didn’t really stop and take a look at just how one comes to acquire knowledge.
Jonas Salk, inventor of the vaccine for polio, said “I would feel that every child who is injected with a placebo and becomes paralyzed will do so at my hands” and that those who demanded a placebo controlled trial to achieve a statistical end point placed their “values in which the worship of science involves the sacrifice of humanitarian principles on the altar of rigid methodology,”
This article has more on Salk’s objections.
Placebos have been essential to clinical trials for decades. It’s vital that neither the volunteers nor the staff running the trial know who is randomly assigned to get the vaccine or the placebo. This “blinding,” as it’s called, eliminates the chance that people will behave differently depending on which treatment they get, potentially skewing the trial’s results.
Yet the prospect of giving people something useless in the face of a life-threatening disease has always been fraught. Even Jonas Salk balked at the idea of giving people placebos when researchers designed a trial to test his new polio vaccine in 1953.
“I would feel that every child who is injected with a placebo and becomes paralyzed will do so at my hands,” he complained. The study, Dr. Salk declared, “would make Hippocrates turn over in his grave.”
But Dr. Salk lost that fight, and the placebo-controlled trial went forward. It clearly demonstrated that the polio vaccine was safe and effective. Only when the trial was over did the children who received the placebo get the vaccine — along with millions of other children.
When it comes to trials for things that are not life or death, there is no question that the double-blind tests are the best. For example, if one is developing a drug for (say) migraines, the people given the placebo may suffer terrible headaches during the trial, but they will not die in the interim. Perhaps someone will come up with a better and more ingenious method than the double-blind test to measure the effectiveness of treatments when the issues are life and death.
As long time readers of this blog know, I got polio as a child. I am trying to think what my feelings might have been if I had been part of the placebo group when I got the disease. Would I (and my parents) have been accepting and philosophical about it, feeling that my misfortune was for the greater good, that it was this study that gave people the confidence to give the vaccine to everyone, preventing a huge amount of suffering? Or would I have been resentful about not having been given something that might have spared me having to deal with the disease? I do not know. It is the essential problem of utilitarian calculations, that things that sound very reasonable in the aggregate can be problematic when viewed on the individual level.