A Band of Brothers…and Sisters

A Band of Brothers…and Sisters:

A commentary on providing study vaccine to placebo recipients in the Pfizer and Moderna COVID-19 vaccine trials

Key points:

• Some have argued that COVID-19 vaccine trial participants who received the placebo should not be vaccinated after the vaccine becomes available, in order to learn more about vaccine safety and the duration of protection.
• But these questions can be answered through a different approach: a cross-over study design that includes vaccination of all study participants, even those who originally received the placebo.
• With this proposed way forward, we can continue to learn about the efficacy and durability of the vaccine with the placebo group being vaccinated, and thus honor their service to us all.

On December 2, the New England Journal of Medicine published an article coauthored by many prominent medical scientists, including physicians, who advocated for keeping volunteers enrolled in the Pfizer and Moderna COVID-19 clinical trials on placebo, even after the vaccine becomes available under an Emergency Use Authorization (EUA), because there is “additional scientific information that can be learned.” As a physician and a scientist, I recognize no single clinical trial ever solves all the issues that need to be addressed for public health. However, in making decisions about when to offer a vaccine to placebo participants in a trial in which high efficacy has been demonstrated, one needs to carefully balance scientific interests with the benefits of vaccination to clinical trial participants themselves. We must consider the perception of fairness from both the individual and community levels.

So, let’s discuss these issues. First, let’s look at what’s to be learned from keeping people on placebo while the impending EUA and coming vaccine scarcity unfold. Both the Moderna and Pfizer studies have reached their goal. Enough information on the number of pre-defined cases of COVID-19 required to define the vaccines’ efficacy has been reached, with the more than 150 cases of COVID-19 that were collected among trial participants. This occurred nearly two months earlier than projected, due to efficiently enrolling persons at high risk of infection, as well as the widespread epidemic of COVID-19 in essentially all regions of the U.S. The primary endpoints of asking whether the vaccine reduced symptomatic disease as well as the most important secondary endpoint of whether it reduced severe disease (hospitalization) were well defined – approximately 95% efficacy in the primary endpoint; 100% in the secondary – and remarkably similar between the Pfizer and Moderna clinical trials. The lower statistical bound of the Moderna trial was about 85% and similar data were obtained for the Pfizer vaccine. 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.

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, and by keeping people on placebo we are only subjecting them to a higher risk of contracting severe COVID-19 disease. Are we now trying to show that hospitalization and/or mortality is only 90% rather than 100%? I doubt that.

Everyone wants to know whether the vaccine’s protective effect is long-lasting and durable, and more time is required to understand that. 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 durability of protection, including continued vaccine effectiveness against COVID-19, by vaccinating the placebo recipients in a crossover design that explores early versus late effects of vaccination. Thus, durability data can be obtained by vaccinating the placebo recipients rather than watching them acquire more COVID-19 disease during the trial.

Understandably, people want greater safety data. However, to assess the infrequent side effects of vaccination, it is not the cohort in the phase three trials (Pfizer 20,000 and Moderna 15,000) that will discern this; it will be 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 U.S. Food and Drug Administration (FDA), regulators still want to know whether vaccination can result in enhanced COVID-19 disease and to compare this with 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 fifty and sixty 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 cases of pneumonias with hypoxemia occurred in placebo recipients. Are we to be more worried about a body of data on enhanced disease from yet-to-be-seen vaccination as compared to exposing unvaccinated placebo recipients who self-identified as at-risk of COVID-19 infection to severe pulmonary disease? In the Moderna trial, 30 (16%) of the 187 reported cases 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 exists to not vaccinate placebo recipients who participated in a COVID-19 vaccine trial in which there was 95% efficacy and 100% effectiveness from hospitalization? One can reduce these numbers by saying only those at lowest risk – the healthy, so to speak – should be left alone and not vaccinated. The strategy of differential handling of placebo recipients is, however, problematic. To take placebo recipients who fall under the top priority categories – 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 the vaccine to their peers who joined as clinical trial participants 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 grouped together and 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 of the trial come from the medical workers or the nonmedical 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 for trial participants inserts nonequity among this “Band of Brothers and Sisters.” Are they being asked what they want? If so, would participants 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 messenger RNA (mRNA) 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 received vaccine in the first place would get their blood drawn and be randomized to placebo injection. And those who initially received 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 in the trial(s) would be vaccinated. Some could have been vaccinated last July at the start of the trials, some not until January. We will be able to see the changes in the durability of protection in that six-month time difference, and 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 and hopefully most will want to 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 the 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 because vaccine doses 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.