By Brandi Greenberg, Vice President, Life Sciences and Ecosystem Research
The moment is coming. Really, it is.
Maybe you'll be watching TV with your family when the network interrupts with a breaking news alert. Or maybe your phone will buzz with messages from friends who want to celebrate the news. Or perhaps you'll pick up a print newspaper—any newspaper, since they'll all lead with same story—and you'll read the long-awaited headline: "FDA approves a vaccine to prevent Covid-19."
It will be a joyous, world-changing moment.
But if you're like me, your joy may be tempered by a certain amount of trepidation.
You may worry whether, amid the intense pressures of the epidemic, regulators have had time to fully vet a vaccine. You might question whether political pressures inappropriately sped the process along—especially if, as CDC has recently suggested, an approval arrives in the days before a presidential election. You might wonder whether the vaccine is as safe and effective as we'd hoped.
Or, on the flip side, you might worry that commentators are being too skeptical of a vaccine, potentially limiting its uptake and delaying the day when we gain herd immunity to Covid-19.
Amid these powerful emotions, it will be hard for any of us to weigh the evidence objectively. So I wanted to take time now, before a vaccine is approved, to think through the right way to react. Consider these eight questions to be a "cognitive toolkit" I'll use to evaluate whether the approval process has truly ensured a vaccine's safety and efficacy.
This isn't intended to be a box-checking exercise; it's not as though I'll fully trust a vaccine that clears, say, five of the hurdles below, but distrust a vaccine that clears only four. Rather, it's intended to lay out a structured way of thinking when "Approval Day" arrives.
And when that day comes, I'll publish my responses to these questions to help you think through the approval, too.
8 questions to ask
1) Did the vaccine follow the traditional approval pathway, rather than being approved under an emergency use authorization (EUA) or other nontraditional path?
Why this matters: There are two main pathways for a Covid-19 vaccine to reach the market. One is unexceptional; the other would be nearly unprecedented.
The ordinary path would be for FDA to formally approve the vaccine after full evidence of its safety, efficacy, and side effects has been presented in a public meeting of the Vaccine and Related Biological Products Advisory Committee, or VRBPAC. (It's worth noting that VRBPAC has scheduled a meeting for October 22, just weeks before the 2020 elections.)
But FDA's guidance for the vaccine leaves open another possibility: that the agency could issue an EUA. This would allow a vaccine to bypass the VRBPAC process and be temporarily administered outside of clinical trials, perhaps to limited subpopulations such as the elderly, without being formally approved.
FDA has frequently, and controversially, relied on EUAs to speed up access to other potential Covid-19 treatments, including hydroxychloroquine, remdesivir, and convalescent plasma. But an EUA would be especially unusual for a vaccine candidate, and it would at least raise questions about whether FDA had acted with undue haste. It also could complicate current and future trials of other vaccine candidates--some of which could prove safer, more effective, or easier to distribute—since many potential trial participants will already have received a vaccine under the EUA.
2) Was clinical trial data on the vaccine released to the public?
Why this matters: In the rush to fight Covid-19, many major discoveries have been announced without full data to back up the findings. This practice can speed up adoption of new treatments—but it increases the risk that the study authors are misinterpreting their own data or overlooking red flags.
For instance, when scientists at the University of Oxford announced that the low-cost steroid dexamethasone can reduce deaths among some Covid-19 patients, the research had not yet been peer-reviewed. At the time, Kathryn Hibbert, director of the medical ICU at Massachusetts General Hospital, cautioned, "We have been burned before, not just during the coronavirus pandemic but even pre-Covid, with exciting results that when we have access to the data are not as convincing."
Those fears were partly borne out. When the full data was published, it revealed that dexamethasone may actually be harmful if it's given to patients before they go on ventilators.
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?
Why this matters: Since the pandemic's start, scientists have sought to measure coronavirus antibodies in recovered Covid-19 patients as a marker of potential immunity. Early results from vaccine trials similarly have focused on the production of antibodies.
But researchers still don't know how many antibodies you need to be protected against the virus—or how long that protection lasts. And it's theoretically possible for a vaccine to produce a spectacular antibody response but fail to prevent disease.
At the end of the day, our goal isn't just to create antibodies to the new coronavirus. We want to prevent infections and deaths. I'll feel much more confident in a vaccine approval if the clinical trial data reflects success on those endpoints.
4) Did the vaccine clear the 50% threshold for effectiveness that FDA previously announced as its approval requirement?
Why this matters: FDA has said that an approved vaccine would need to prevent people from developing Covid-19 or decrease Covid-19 symptoms in at least 50% of vaccine recipients. That's comparable to the effectiveness of seasonal flu vaccines.
A higher efficacy rate would, of course, be better; Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, has suggested that 75% could be within reach. But I'll have concerns that FDA is unduly prioritizing haste over effectiveness if it lowers its prior standards to approve a vaccine at, say, 30% efficacy.
5) Did the vaccine meet that effectiveness threshold for members of all major U.S. demographic groups (by age, gender, race, etc.)?
Why this matters: The coronavirus has disproportionately impacted people with pre-existing medical conditions such obesity, diabetes, and kidney disease; people over age 65; Black and Hispanic people; and people with certain genetic makeups.
To determine whether a vaccine is safe and effective among these high-risk groups, researchers ideally should include these populations in Phase 3 trials. But historically, these groups are among the least likely to be included in late-stage trials. Similarly, people with obesity often are excluded from trials due to their higher rates of high blood pressure and other medical conditions.
For its part, FDA "strongly encourages" including diverse populations in coronavirus vaccine trials but doesn't require it. And The Guardian reports that some coronavirus vaccine trials have been "strikingly white," noting that 88% of the participants in one Moderna trial were white.
Other trials are making active efforts to recruit diverse participants. Researchers at Harbor-UCLA Medical Center, for example, are seeking to ensure that, of the 500 participants they're recruiting for a larger trial of an AstraZeneca vaccine, "most, if not all … are people over 65, those with chronic illnesses, and members of underserved racial and ethnic groups," the Los Angeles Times reports.
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?
Why this matters: When the first vaccine against Covid-19 is approved, we won't really know how long its protection will endure. After all, it will only have been tested in humans for a matter of months. No one will really be able to guess how protective it will still be in a year or a decade.
And that's OK! No one believes we should wait an extra five years to approve a vaccine just to gather data on how long its protection lasts. But we should expect that FDA and the vaccine manufacturer will have a plan in place to measure the durability of immunity, and perhaps some early data on how antibody responses are changing over time. If a vaccine's protection is exceptionally short-lived, it may not be valuable in the real world.
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?
Why this matters: While safety is important for any drug that FDA approves, it's especially critical for a vaccine. That's because a vaccine is intended to be administered to practically everyone—and if you administer 300 million doses of a vaccine, even rare side effects could lead to many thousands of complications.
As vaccine candidates undergo Phase 3 trials, researchers will track acute symptoms that arise shortly after an injection. But it also will be important to track safety concerns over the longer term—especially whether the vaccine causes "disease enhancement," which occurs when patients who contract a disease after vaccination end up suffering more severe symptoms.
To be clear, FDA might reasonably approve a vaccine that carries some rare, dangerous side effects, if its net effect is to bring the Covid-19 epidemic to an end. But I'll want to see evidence that FDA has thoroughly investigated any short-term hazards and has a plan in place to monitor for dangers that could emerge later.
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?
Why this matters: The first seven questions identify hurdles a vaccine ideally should clear. This question, by contrast, describes a red flag I hope the approval process will avoid.
Recent months have seen storms of criticism from public health experts—including current government officials—around decisions related to Covid-19 testing and treatments. Just last week, Anthony Fauci criticized CDC's decision to narrow its recommendations on who should be tested for Covid-19, and FDA commissioner Stephen Hahn publicly apologized after overstating the evidence supporting convalescent plasma as a Covid-19 treatment.
So it will be revealing, when a vaccine is approved, whether public health experts—especially those inside the administration—unanimously support the approval, or whether some express hesitancy or outright disagreement.
Most notably, Peter Marks, director of FDA's Center for Biologics Evaluation and Research, has pledged to resign if FDA approves a vaccine that isn't supported by research. If Marks, or someone of similar stature, actually resigns when a vaccine is approved, I'll be deeply concerned about the vaccine's safety and efficacy.
Even after a vaccine is approved, the hard work won't be over
Of course, even if FDA's approval of a coronavirus vaccine clears all the bars above, an approval alone won't end the epidemic. We'll still have manufacture some 300 million doses (or potentially twice that many, if the vaccine requires multiple injections), distribute them to every city and town in the country, overcome vaccine hesitancy among Americans who've voiced skepticism of the approval process, and much more.
To learn more about the next steps, check out our recent interview with Ezekiel Emanuel, the prominent University of Pennsylvania bioethicist and former Obama administration official. Emanuel has put extraordinary thought into the logistics of vaccine manufacturing and distribution—and he shared important insights on how industry stakeholders can prepare now to roll out a vaccine.