By Brandi Greenberg, Vice President, Life Sciences and Ecosystem Research
Three months ago, I wrote an article called, "A vaccine approval is coming. Get ready to ask these 8 questions."
At the time, I was struggling with a storm of emotions that I suspect you've also experienced this year. I wanted desperately to believe that a safe, effective vaccine was on its way—but I also felt confused by the blizzard of vaccine news, and worried the approval process might be rushed, botched, or politicized.
So I sat down to create a sort of "cognitive toolkit": a list of concrete, yes-or-no questions that would help me cut through the noise when a vaccine was approved and evaluate whether FDA had made the right call.
That time is now.
FDA has just authorized a coronavirus vaccine created by Pfizer and BioNTech, and tens of millions of doses will begin rolling out within days. We now know enough to answer the questions I posed three months ago—and to draw conclusions about the effectiveness both of FDA's review process and of the vaccine itself.
My 8 biggest questions, answered
1) Did the vaccine follow the traditional approval pathway, rather than being approved under an emergency use authorization (EUA) or other nontraditional path?
Technically not. FDA authorized the vaccine under an EUA based on two months of safety data. According to Dorian Fink of FDA's clinical division of vaccines and related products applications, Pfizer must collect six months of safety data to apply for full approval.
So should we worry that the vaccine hasn't been formally, fully approved? I'd say no. The EUA process has been deliberative, and despite some experts' fears, the authorization wasn't rushed to meet the artificial deadline of Election Day.
Plus, because the new coronavirus has surged so severely in recent weeks, we've seen a mounting number of Covid-19 cases among placebo recipients—even as those who received the vaccine enjoyed robust protection. In that sense, the worsening of the pandemic has actually increased our confidence that Pfizer's vaccine is effective.
2) Was clinical trial data on the vaccine released to the public?
Mostly yes. Although Pfizer released only topline numbers on the vaccine's effectiveness in its initial announcement of its trial's results, FDA has since published an extensive staff report from its deep dive into the data.
The takeaways were tremendously encouraging. According to FDA, the double-blinded, placebo-controlled study of about 44,000 people revealed that the vaccine is 95% effective at preventing Covid-19, with no serious side effects—although many vaccine recipients reported moderate, flu-like symptoms after their second dose.
Independent experts who reviewed FDA's findings offered effusive praise for the vaccine. Akiko Iwasaki, an immunologist at Yale University, said, "This is what an A+ report card looks like for a vaccine," while Gregory Poland, a vaccine researcher at the Mayo Clinic called it "a grand slam by any measure."
3) Does the available study data clearly show that the vaccine offers meaningful, measurable protection from Covid-19—such as fewer people getting sick, fewer people getting severely ill from Covid-19, or fewer people transmitting the virus after exposure?
In terms of preventing illness, the answer is a resounding "yes."
For the other endpoints I mentioned—that is, reductions in severe illnesses and virus transmission—the picture is fuzzier. According to FDA's staff report, only four trial participants suffered severe Covid-19 cases after receiving their second injection, three of whom had received the placebo. That's just not enough data to make any strong statistical claims.
And FDA didn't even attempt to determine whether the vaccine prevents virus transmission, saying only that "[a]dditional evaluations … will be needed to assess the effect of the vaccine in preventing virus shedding and transmission, in particular in individuals with asymptomatic infection."
Still, let's not be unduly bearish. When I posed these questions in September, I would have been elated to know that, just three months later, we'd have a vaccine that is 95% effective at preventing Covid-19.
4) Did the vaccine clear the 50% threshold for effectiveness that FDA previously announced as its approval requirement?
Yes—with flying colors.
5) Did the vaccine meet that effectiveness threshold for members of all major U.S. demographic groups (by age, gender, race, etc.)?
Yes. FDA's staff report broke down the trial data by age, gender, race, ethnicity, and more, and its conclusions were extremely encouraging: "[Vaccine efficacy] point estimates were uniformly high across the subgroups examined."
There are two small caveats. The study enrolled only limited numbers of people from certain minority groups, making it impossible to draw statistically significant conclusions. For instance, FDA found the vaccine was 74% effective among Asian study participants—which at a glance might look a lot lower than its 95% effectiveness in the broader population. But only five Asian patients fell ill during the trial, four of whom had received the placebo.
Second, the vaccine was not tested in children under the age of 16 or pregnant women, so we simply don't have data on its safety and effectiveness in these populations.
In a perfect world, would we have better data for every subgroup of the U.S. population? Of course. But based on what we know, this vaccine works well across a wide range of populations.
6) Is there a robust plan to follow up with participants to determine how long protection will last? Do early signs indicate that immunity will be durable over time?
Yes. So far, there's no sign that immunity is fading, but because some patients received their last injection only a few months ago, it's too soon to say for sure.
Pfizer plans to monitor trial participants for two years after their final dose. And let's bear in mind that FDA has issued only an emergency authorization for the vaccine, not a full approval, and it intends to continue monitoring safety and efficacy data over time.
This won't be an easy task, however. Clinical trial participants still don't know whether they received a vaccine or a placebo—so once a vaccine becomes publicly available, some might seek it out. Over time, this means more and more "placebo" patients will actually have received the vaccine, making it harder and harder to meaningfully compare the placebo and vaccine groups.
7) Does trial data clearly show that the vaccine's benefits outweigh any safety concerns? Is there a plan to monitor safety once the vaccine is given to a much broader group of people?
Yes. The vaccine protects against a potentially fatal illness, and its only proven side effects are short-term and mild.
Pfizer and FDA will monitor for any more serious risks that may emerge. One thing to keep an eye on, for instance, is that eight trial participants who received the vaccine developed appendicitis during the follow-up period, compared to four who received a placebo. For now, FDA says there's "no clear basis upon which to suspect that this imbalance represents a vaccine-related risk," but it's worth monitoring. Further, regulators in Britain have advised people with a history of allergic reactions not to get the vaccine, based on two reports of anaphylaxis in early vaccine recipients.
Here's where I want to choose my words carefully. Some people may read the paragraph above and decide that, if there is any possible risk associated with this vaccine, they shouldn't get it. That is, I think, the wrong reaction, for two reasons.
First, it is impossible for any drug trial to prove absolute safety. That's just how the math works: There is almost always some rare condition that occurs more frequently in vaccine recipients than in placebo recipients, often only by random chance. (For context, in the Pfizer vaccine study, more people who received the placebo suffered from pneumonia, atrial fibrillation, and syncope—but nobody thinks the placebo caused those conditions! It was likely just a statistical fluke.)
Scientists must do the best work they can within the constraints of this fundamental mathematical limitation. In this case, FDA's judgment—for now—is that the vaccine doesn't pose serious risks. This strikes me as both normal and appropriate, as long as it's accompanied by a plan for continued monitoring.
Second, whenever you or I choose to take any drug, we're balancing risks and benefits. Even a medicine as commonplace as aspirin has potentially serious side effects such as liver damage, anemia, hives, and seizures. But the risks are small, and they're not going to stop me from treating my next headache.
The right question isn't, "Does this treatment carry any risks at all?" Rather, we should ask, "Do the benefits of this vaccine outweigh any potential risks?" That is, are we better off taking the vaccine and accepting a tiny risk of unforeseen side effects—or rejecting the vaccine and bearing a much larger risk of contracting Covid-19, which already has killed nearly 300,000 Americans?
The answer is clear. For most people, the vaccine's benefits appear to dramatically outweigh its risks.
8) Have any participants in the approval process criticized the decision or the process itself? Have outside public health experts, especially those who previously served as senior-level officials at CDC, NIH, or FDA, criticized the approval?
No. So far, public health experts both inside and outside of government have offered enthusiastic takes on the vaccine. I'm also encouraged that regulators in Britain, Canada, and four other countries have authorized the vaccine based on their own analyses of trial data.
To take a step back, however, one of my goals in including this question was to surface any signs of political influence on FDA's decision-making. On that front, a troubling news story broke on Friday afternoon: According to the Washington Post, the White House chief of staff, Mark Meadows, told FDA commissioner Stephen Hahn that he should resign if FDA did not authorize the Pfizer vaccine by the end of the day.
If true, this creates at least the appearance of political influence on what should be an evidence-driven process. That said, Meadows' reported actions came very late in the game, after FDA's advisory committee had already recommended authorization—and it's worth noting that Hahn himself has pushed back on the Post's report. Unless further reporting reveals there's more to this story, it does not fundamentally change my views on FDA's authorization process.
A few conclusions, and one final question
I'll be honest. When I wrote this list of questions in September, I worried a vaccine's authorization would be a close call: a decision that some experts would praise and others would excoriate, with seemingly persuasive arguments on both sides. I wanted to prepare a well-defined list of questions to help me make up my own mind.
But in reality, this wasn't a close call. Based on everything we know so far, this vaccine is clearly safe and effective. Yes, we'll need to monitor closely for any rare, serious side effects—but we always need to do that when a newly approved drug that hits the market. It's not a reason to delay authorization.
There is, however, one final question that I for some reason didn't include on my earlier list. Perhaps I didn't think to include it because it's so inherently subjective, or perhaps I figured it was too personal to be of interest to anyone else.
But in some ways, it's the most important question of all: "Will I take this vaccine myself?"
To that, my answer is yes—as soon as I possibly can.