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The debate about ending the placebo in Covid-19 vaccine trials, explained

Thousands of people in clinical trials got the placebo instead of the vaccine. When should they get the vaccine for real?

A sign is seen at the Research Centers of America, on August 18, 2020 during the phase 3 Covid-19 trial of the Moderna vaccine in Hollywood, Florida.
With two Covid-19 vaccines being distributed, researchers are debating when and how to vaccinate clinical trial participants who received a placebo.
Leila Macor/AFP via Getty Images
Umair Irfan is a correspondent at Vox writing about climate change, Covid-19, and energy policy. Irfan is also a regular contributor to the radio program Science Friday. Prior to Vox, he was a reporter for ClimateWire at E&E News.

With supply of the two authorized vaccines for Covid-19 still limited, there’s been a lot of chatter around how exactly to distribute the initial doses in the US. But the prospect of vaccinating one group in particular has proven to be especially vexing for scientists and health officials: people participating in phase 3 clinical trials for these vaccines.

The ongoing phase 3 trial for the Pfizer/BioNTech vaccine includes 44,000 people, and 22,000 received the placebo. For the Moderna vaccine trial, half of the 30,000 participants got it.

These trials demonstrated that both of these vaccines are highly effective at preventing Covid-19. But to get those results, hundreds of people had to get sick, some of them severely ill, and the vast majority of those people received a placebo. And that reality is especially tricky as the trials continue while the vaccines are being distributed to high-priority groups of the general public.

That’s why some vaccine researchers have called for all people in the Moderna and Pfizer/BioNTech trials not just to eventually receive a Covid-19 inoculation but to move to the front of the line right away.

“I think the most important [reason] is that these men and women volunteered and have been instrumental and critical in helping us develop these vaccines,” said Moncef Slaoui, the scientific lead for Operation Warp Speed, during a press conference in December. “They should be rewarded for it rather than, in a way, punished for it by, for instance, being delayed in receiving the vaccine.”

The trial participants themselves have also been agitating to receive the vaccines.

In December, Moderna announced that it would offer placebo recipients the option of getting the vaccine. Earlier this month, Pfizer and BioNTech announced that they would offer their vaccine to any trial participant who wanted it on March 1. In both cases, the decision is left to the individual participant.

Other scientists, however, are concerned that losing the placebo group in these trials squanders a critical opportunity to learn about things such as the rate of long-term complications, how long protection against the disease lasts, and how well the vaccines keep people from spreading it even if they don’t get sick themselves.

At the same time, participants in the trials can drop out at any point. Presented with the threat of a raging pandemic and multiple vaccines being administered, some may choose to do so, leaving researchers with an even smaller pool of subjects.

That’s why regulators, scientists, and vaccine companies spent so much energy debating ways to learn as much as they can from clinical trials before they potentially crumble.

There’s a lot left to learn about Covid-19 vaccines, and placebo-controlled trials are a great way to get answers

To figure out if a vaccine works in the real world, researchers have to test it in tens of thousands of volunteers in trials that can last for years. Roughly half of the volunteers get the actual vaccine while the other half get a placebo, and neither group knows what they received.

Scientists then observe the two groups to see how many people get sick. A substantially larger number of Covid-19 cases in the placebo group indicates that the vaccine is highly effective at preventing disease.

In preliminary results, the Moderna vaccine and the Pfizer/BioNTech vaccine both showed that they can prevent about 95 percent of recipients from getting Covid-19. It took fewer than 200 Covid-19 cases in either trial to determine this.

This rapid discovery was enabled by having so many people in the trials. “[W]e need large numbers of participants to observe relatively few events, and this is exactly why trials number in the thousands,” said Natalie Dean, a professor of biostatistics at the University of Florida, in an email last year.

But these initial numbers only reveal overall efficacy for the whole trial. Within the trial, it’s likely that vaccines offer varying levels of protection and risk within different demographics, like in older adults or in people with preexisting health conditions.

When split into these groups, the differences between the placebo group and the vaccine group isn’t as stark. In the Pfizer/BioNTech trial, there were just 15 Covid-19 cases detected in people between the ages of 65 and 74, with 14 cases in the placebo group. For people 75 and older, just five cases were reported, all in the placebo group. These results are promising, but not as robust as the efficacy results for the trial as a whole.

Letting the trial run longer and allowing more cases to accumulate would clarify the level of protection offered by the vaccine in different groups. That information can then be used to better target doses where they’ll be more effective or compare vaccines against one another to select the most effective one for particular populations. This information would be especially useful as more vaccines gain approval.

Having a large number of participants in clinical trials helps answer some other critical questions about the vaccines, like the chances of rare complications.

There’s also a time element to consider. The emergency use authorizations were granted based on two months of safety results. While complications relating to vaccines often arise shortly after the shots are administered, there could be other issues that arise months or years later.

Another crucial factor is how long immunity from the vaccine lasts, which can only be determined by monitoring recipients of the vaccine — and ideally also of the placebo — over a much longer period.

There are also some important vaccine questions that are beyond the scope of these studies. For instance: Can you spread Covid-19 even if you get the vaccine? Many SARS-CoV-2 infections are asymptomatic, and finding those asymptomatic spreaders would require testing participants on a regular basis, a tedious and time-consuming endeavor, but one that would reveal a critical variable for the pandemic. If it turns out that a vaccine can block transmission about as well as it blocks disease, that would make it easier to achieve herd immunity. It would also help families and communities resume close contact more quickly.

Answers to these questions are all the more urgent now that there are new variants of SARS-CoV-2 circulating that are seemingly more transmissible and that contain mutations that may weaken the protection offered by the Covid-19 vaccines that are currently available.

The structure of a double-blind clinical trial, where neither the participants nor the experimenters know right away who received the vaccine, is also important for gathering good data. It helps ensure that participants don’t change their behavior based on what they received.

“If we unblinded today, vaccine recipients probably would engage in riskier activity immediately,” said Steven Goodman, a professor of epidemiology and population health at the Stanford University School of Medicine. “I mean, why not?”

Someone who knew they were vaccinated might end up engaging in riskier behavior, or someone who knows they received a placebo may take additional precautions. Both types of behavior skew the results and make it harder to draw a direct comparison between the arms of a trial.

Taken together, these factors mean that the longer a placebo-controlled trial remains intact, the more information we will be able to gather on how best to deploy the vaccines and ultimately illuminate a path to the end of the pandemic.

How Moderna and Pfizer/BioNTech are proposing to get Covid-19 vaccines to the placebo groups in their clinical trials

Pfizer, BioNTech, and Moderna have all agreed to monitor their remaining pool of phase 3 clinical trial participants for at least two years. Both companies also say they are ethically obligated to let participants know that they may be eligible to get vaccinated outside of the trial.

But they have very different ideas for how to handle their placebo groups from here on out. During a meeting of the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee, officials at Moderna proposed offering everyone in the placebo group the vaccine. This would unblind the trial and effectively end the placebo control, although the company plans to continue monitoring participants. Moderna did not respond to requests for comment.

Pfizer, meanwhile, proposed what it calls a Vaccine Transition Option that would only unblind participants who would be eligible to receive the vaccine outside of the trial if they weren’t enrolled. Right now, that would mean mainly older participants and front-line health workers in the placebo group would have the option of getting vaccinated. As more vaccines become available to the general public, more people in the placebo group would have the option of getting their shots. And then by March, they would offer the vaccine to anyone in the placebo group.

“Participants should not have to choose between remaining in the study or receiving the investigational vaccine if it is available to them in their community,” wrote a spokesperson for Pfizer in an email. “Please note that this move from the placebo group to the vaccine group is completely optional, and participants are encouraged to remain blinded throughout the full study duration.”

But some are skeptical the company could pull it off. “The Pfizer approach, which I think is intellectually a very elegant and appropriate one, practically is a very difficult one,” said Operation Warp Speed’s Slaoui. He noted that every state has its own eligibility guidelines for vaccines, so it would be hard to keep tabs on 22,000 people in the company’s placebo group in sites across the country and determine who gets what and when. He noted that there are vaccine doses allocated for clinical trial participants independently of the shots meant for the general public, so vaccinating the placebo group would not come at the expense of anyone else.

All the while, more participants will continue dropping out of the trials as they try to get vaccines on their own. Already, 95 participants have dropped out of the placebo group in the Pfizer/BioNTech phase 2 trial. And once someone leaves the trial, researchers will no longer be able to gather data about their experiences.

There is another approach that could help maintain the placebo group for longer

Stanford’s Goodman suggested another strategy known as a blinded crossover. The idea is to get everyone in the trial vaccinated without revealing who is in which group.

To do this, trial administrators would essentially have to administer a second set of shots to anyone in the trial who wants to become unblinded. The people who received the vaccine at the outset would get a placebo, and the people who received a placebo would get the actual vaccine.

Though every participant would then be assured that they are immunized, none could be sure when they were actually immune until two weeks after the second shot, so any subsequent changes in behavior would likely be similar across both the placebo group and the vaccine group.

The challenge for that approach is going to be getting all 30,000 to 44,000 participants back into the clinic to receive another round of injections. “That would require more infrastructure, for sure, but it would expand that period of valid comparison in the clinical trial,” Goodman said. There’s also a chance that some participants might leave the trial anyway once they know for sure they’ve been immunized.

The window for effective clinical trials for Covid-19 vaccines is closing

There is an even bigger problem looming for other placebo-controlled trials for Covid-19 vaccines: It’s going to get much harder to recruit participants from here on out. Why would you enroll in a trial where you have a 50-50 shot of being protected from the disease if you can now get in line for an actual vaccine?

The companies like Johnson & Johnson and Novavax running trials on other Covid-19 vaccines may be faced with the prospect of losing participants or having to vaccinate everyone in the trial — some immediately and some deferred — to have at least a brief placebo comparison group. They may also have to consider conducting trials in places or with populations where no Covid-19 vaccine is available yet.

“These two [Moderna and Pfizer/BioNTech] trials may be among the last placebo-controlled trials we’re going to see,” Goodman said.

The question of how to handle the placebo group is emblematic of the tension recurring throughout the Covid-19 pandemic. With hospitals filling up and thousands dying every day, when is “good enough” good enough?

The scientific questions are indeed important, but balanced against a rising human toll, there is immense pressure to move ahead with incomplete results. This has led to situations like the FDA’s EUAs for questionable Covid-19 treatments like hydroxychloroquine, which it subsequently revoked. At the same time, the longer regulators wait to approve a drug or vaccine, the more people will die.

There is no clear right answer here for placebo groups in clinical trials, but every trial has to make a deliberate decision about how to vaccinate them. Otherwise, researchers will resign themselves to the worst possible outcome, with trial participants haphazardly dropping out and those who stay remaining defenseless against a deadly disease, all while the trials yield less robust data.

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