On Dec. 2, the New England Journal of Medicine published an article coauthored by many prominent medical scientists, including physicians, who advocated for extending the time in which volunteers in the placebo group enrolled in the Pfizer and Moderna COVID-19 clinical trials should be followed.
Essentially, they are arguing that the study volunteers – people who sacrificed for the greater good to join the trials in the first place – should be prohibited from getting the actual vaccines, even after the vaccines become widely available under an EUA (Emergency Use Authorization), because there is “additional scientific information that can be learned.”
Of course, there are always new things we can learn from a clinical trial. But at some point, we know enough that the risk to persons not being given these markedly effective vaccines is greater than benefit that can be learned from withholding vaccination to these persons.
As a physician and a scientist, I recognize no one clinical trial ever solves all the issues needing to be addressed for public health. However, in making decisions when to offer vaccine to placebo participants in a trial in which high efficacy has been demonstrated, one needs to carefully balance scientific interests with withholding the benefits of vaccination to clinical trial participants themselves.
We must consider the real issue of fairness, and perceptions of fairness, at both the individual and community level.
So, let’s discuss these issues.
First, let’s look at what’s to be learned from keeping people on placebo while the EUA is being evaluated and the early days of market authorization, when supplies will be scarce.
Both the Moderna and Pfizer studies, which enrolled 30,000 and 43,000 volunteers, respectively, have reached their goal. Enough information on the number of pre-defined cases of COVID-19 required to define the vaccines’ effectiveness has been reached. More than 150 cases of COVID-19 were found among participants in each trial, and the vast majority of those cases were in people who were on placebo.
The analysis which compared the vaccine to the placebo occurred nearly two months earlier than projected. We got the answer quickly because people at high risk of infection enrolled swiftly in trials, and the widespread epidemic of COVID-19 across our country meant we didn’t have to wait long for cases to appear among volunteers.
The endpoints were well defined. Scientists asked, first and foremost, whether the vaccine reduced the chance of people getting symptomatic disease. The most important secondary endpoint looked at whether the vaccine reduced severe disease (hospitalization).
The results were simply spectacular—approximately 95% efficacy in the primary endpoint; 100% in the secondary for the Moderna vaccine. Even more compelling is that the results were remarkably similar between both the Pfizer and Moderna clinical trials, which both are testing messenger RNA based vaccines.
That’s a key validation for this emerging type of vaccine technology.
To date, the only reported death related to COVID-19 in the trials was in the Moderna trial and that was in the placebo group.
These data are clear and compelling. It’s hard to believe any more data are needed to show that the vaccines reduce the likelihood of developing moderate-to-severe COVID-19. By keeping people on placebo, we are only subjecting them to a higher risk of contracting severe COVID-19 disease. Are we trying to show that hospitalization and/or mortality is only 90% rather than 100%? I doubt that.
Everyone wants to know how long the vaccine can protect people. More time is required to answer that question. But by the time January rolls around and more vaccine doses become available, we will have close to six months of data from the start of the clinical trials in late July.
As I’ll explain below, there is a very good way to assess vaccine durability. One way to assess continued vaccine effectiveness against COVID-19 would be by vaccinating the placebo recipients in a crossover design.
This literally allows people who were on the placebo to “cross over” to get the real vaccine in a second phase of an ongoing study. The participants, and researchers, would still remain blinded as to what they are getting.
By continuing in this way, we could ensure that everyone in the study is getting vaccinated, while we’ll also get the chance to learn something new what the difference is between early versus late effects of vaccination. These data can be obtained by vaccinating the placebo recipients in early 2021, rather than simply waiting and watching them as more and more of them acquire COVID-19 disease in the trial.
Understandably, people want more safety data, and longer-term follow-up.
However, to assess the infrequent side effects of vaccination, it is not the vaccine cohort in the Phase III trials (about 21,500 for Pfizer and 15,000 for Moderna) that will discern this. Instead, this information will be gathered from the cohort of millions of people who receive the vaccine under the EUA and are then closely followed post-vaccination.
Respecting the thoughtfulness of the guidance documents from the FDA, regulators still want to know whether vaccination can result in enhanced disease. They also want to compare the background rate of severe pulmonary infection in placebo recipients. So far, there is no evidence in either trial of severe pulmonary disease from vaccination. In fact, it is quite the converse.
Between the two trials, there are between 40 to 50 cases of severe disease, and while the details of these cases are not known to me or the public (and such data are critical to unpack), it all says these pneumonias and hypoxemias are in placebo recipients.
Should we be more worried about a chance of enhanced disease from the vaccine – even though there’s no evidence to say that’s a real concern – or should we be more worried about exposing unvaccinated placebo recipients who self-identified as at-risk of COVID-19 infection?
In the Moderna trial, 30 (16%) of the 187 reported cases of COVID-19 were classified as severe over the four-month review period. Do we really want to see another 30 people get severe disease by watching them for four more months?
The question in my mind is what scientific justification is there to not vaccinate placebo recipients who had participated in the trial in which there was 95% efficacy and 100% effectiveness from hospitalization?
One can mitigate these numbers by saying only the healthy, so to speak, should be left alone. The tactic of differential handling of placebo recipients is, however, problematic. To take placebo recipients who fall under the category of EUA eligibility—in other words, medical care or first-line workers, nursing home personnel, those who are elderly or essential workers—and provide the vaccine because they are in group 1 of the EUA in their state, or nationally, is logical. But to deny their companions who joined them in being a clinical trial participant is quite problematic both from a social justice, fairness, and public perception point of view.
First, trial participants are essentially a community bonded together in a clinical trial. Thirty to forty thousand people were grouped together and placed under common scrutiny and rules.
We in clinical trials authenticate this bonding by calling them a study cohort. In this medical vernacular all are equal and each benefits from the other. The goal of the cohort is to achieve the study goal, which is not asking participants to get sick, but recognizing that in the course of human life some people will develop this disease.
Within the common community of trial participants, did the endpoints on the trial come from the medical workers or the non-medical workers? Was severe disease only in the elderly or in one group or the other? Does it matter? Does a medical worker who participated in the trial deserve vaccination more than the group of essential workers or someone who lived in the household of an essential worker who developed COVID-19 on the trial? Does either group feel good that the other is excluded when they entered the trial as equals in their own community? Differential access inserts nonequity among this “Band of Brothers and Sisters.” Are they being asked what they want? If so, would they say that they deserve the vaccine more than someone else in the trial? Did the medical worker who did not get infected sacrifice more than the bus driver who did or his friend who did not get infected?
Need I say more?
There are many dispassionate people who say we need and have a societal obligation to learn about the durability of the vaccine’s effectiveness. My colleagues at the CoVPN (COVID-19 Prevention Network) have, in fact, developed a proposal that would answer this quite effectively by vaccinating the placebo recipients, keeping the trial blinded, and following participants for signs of COVID-19 disease for the subsequent 18 months.
In this scenario, the people who got vaccine in the first place would get their blood drawn and be randomized to placebo injection. And those who initially got placebo would get their blood drawn and be injected with vaccine.
Let’s say we start in early January with the first dose, by the end of January after the second dose has been administered, everyone on the trial(s) would be vaccinated. Some could have been vaccinated last July 2020 at the start of the trials; some in January 2021.
By running the trial this way, we will be able to see the changes in durability in that six-month time difference, but everyone in the trials would then be vaccinated and therefore protected.
My colleagues and I feel this is best done blinded, but that is perhaps a lesser issue. The key point is that receipt of the vaccine is intended for all who originally signed up for the trials. Hopefully, most participants will want to continue with the study, and help answer this longer-term issue and continue to go to the clinic for COVID-19 testing and follow-up when they are ill.
With this proposed way forward, we can continue to learn about the efficacy and durability of the vaccine with the placebo group being vaccinated. It is medically difficult to justify keeping people on placebo when we don’t have absolute markers of risk — when we see that even some people ages 15 to 55 have been shown to experience severe disease, when we see increased hospitalization and death but have no clear marker of risk that can guide us as to who is at risk and who is not.
Keeping the vaccine from the very people who got us this far by participating in the trial, and who could benefit from it, is in my view, untenable. I, and almost all of my colleagues I surveyed who conducted these trials, honestly feel it is just not right.
Lastly, some people might argue that by vaccinating those in the placebo group, we would be taking vaccine away from others who are more deserving or who might have a higher risk. This is not the case. Vaccine vials labeled for research purposes are permanently labeled as such and are not those allocated to the general population.
If we’re going to adhere to the determinants of social justice; if we’re going to advocate for the underserved; if we’re going to declare the importance of altruism and act with principles of fairness, then we must treat all of the placebo recipients equally.
They themselves have become their own Band of Brothers…and Sisters, and we must honor their service to us all.
Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, past President and Director of Fred Hutch, and a Professor of Medicine and Virology at University of Washington.