Nine companies leading the charge to develop a Covid-19 vaccine released a pledge Tuesday to stick to the science in the development and licensing of a vaccine in what appears to be an attempt to preempt pressure from the White House to rush vaccine approval before the November election.
The vaccine makers said they are committed “to developing and testing potential vaccines for COVID-19 in accordance with high ethical standards and sound scientific principles.”
The statement comes as the Trump administration is expecting significant movement on a Covid-19 vaccine before the presidential election on November 3. The Centers for Disease Control and Prevention (CDC) told hospitals across the country to prepare for the potential delivery of a Covid-19 vaccine within two months, alarming researchers and health workers who fear it is yielding to political pressure. President Trump has also accused the Food and Drug Administration (FDA) without evidence of deliberately delaying vaccine approval.
“How can you not worry that the FDA has been influenced?” said Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.
The new pledge from the nine companies — AstraZeneca, BioNTech, GlaxoSmithKline, Janssen Pharmaceutical Companies of Johnson & Johnson, Merck, Moderna, Novavax, Pfizer, and Sanofi — shows that these manufacturers are concerned that political influence could undermine the successful delivery of the vaccine as well. If there’s a perception that safety was sacrificed for political expediency, manufacturers, pharmacies, and public health agencies could have a harder time getting people to take the vaccine.
“If there is any suspicion that there are political machinations in this process, that is going to make vaccinations much more difficult,” said Jonathan Zenilman, a professor at the Johns Hopkins University School of Medicine.
Recent polling data suggests vaccine hesitancy is rising in the United States. Adding to the confusion are mixed signals from the FDA, which is chalking out all the ways that it could potentially authorize a vaccine by November while insisting it will only be swayed by scientific evidence.
As Covid-19 fatalities mount, as the presidential election draws nearer, and as the prospect of a winter spike in cases looms, these tensions will likely only grow. Let’s walk through how a vaccine can gain approval and how political influence, or even the appearances thereof, can undermine the process.
Federal agencies are already signaling that a vaccine could begin distribution by October, but phase 3 clinical trials have barely begun
Even with all the tensions of the moment, vaccine development for Covid-19 is happening at an unprecedented speed and scale. There are more than 200 vaccine candidates around the world in development and nine are in phase 3 clinical trials, the large-scale human testing needed before the FDA can give a vaccine the go-ahead for distribution.
Nonetheless, agencies are already getting the ball rolling. The New York Times obtained documents sent to state and city officials on August 27 showing that the CDC is instructing hospitals to begin preparing personnel, ultra-cold freezers, and distribution sites to administer a vaccine by as soon as the end of October.
“Jurisdictions must be prepared to immediately vaccinate identified critical populations when the earliest COVID-19 vaccine doses are available and approved by the U.S. Food and Drug Administration (FDA),” according to one of the CDC documents (emphasis in the original document).
But some of the phase 3 trials are just getting started, and they cannot be easily sped up. Such trials are crucial because they show how effective a vaccine is against the actual virus spreading in the wild. They also identify rarer potential complications with a vaccine that may not have emerged in earlier phases of a trial. Since vaccines are distributed to vastly more people than drugs, including those that are healthy and those with preexisting conditions, vaccines must meet a higher safety threshold than other therapies prior to approval.
For phase 3 trials, researchers are recruiting 30,000 volunteers per candidate vaccine. “The reason why they’re having such enormous numbers is if you have a larger trial, you get to the endpoint faster,” said Johns Hopkins’s Zenilman, who has supervised clinical trials for vaccines.
Simply recruiting enough volunteers is a time-consuming task. To date, no trial has finished filling out its trial pool in the United States. Some groups, like the University of Oxford’s Jenner Institute, are conducting trials across multiple countries. Vaccine developer Moderna says it may have enough participants in the US later this month.
Those volunteers will then be divided into two groups, where roughly half will get a vaccine and the other half will receive a placebo. Neither the recipients nor the administrators know which group is which.
Many of these vaccine candidates require two doses, spaced between 14 days and 28 days apart. That means October is the earliest a trial can have a pool of participants with the full dose.
At that point, researchers have to wait and see how many people get infected in their pool of volunteers. After about 150 or so confirmed infections within the group, trial observers can break down the blinds and see how those infections were split between the group that received the vaccine and the group that didn’t to get an estimate of the efficacy of the vaccine.
How quickly infections accumulate in the volunteer group depends on how much Covid-19 is circulating in the community where the trial is occurring. More community spread would mean the number of infections in the pool adds up faster. Some of the phase 3 trials underway have already recruited thousands of volunteers, given many participants the full dose of the vaccine, and are starting to detect infections within the group.
Pfizer, one of the vaccine companies in phase 3 trials, says it has added 23,000 participants to its volunteer roll so far. “A significant number of them have already started getting the second dose of the vaccine,” Albert Bourla, the CEO of Pfizer, told Reuters on September 3.
Covid-19 is a mercurial disease — many people with infections don’t show signs at all, while for others, it can take days or weeks before they experience symptoms like fever, coughing, or shortness of breath. For a phase 3 vaccine trial, suspected infections have to be confirmed with testing, which adds even more delays to getting all the requisite data.
Taken together, these factors mean that it can take weeks or months before a phase 3 trial generates enough data to make a safety and efficacy determination for a Covid-19 vaccine. That’s why some researchers think it’s highly unlikely that such a trial will wrap up in time for the November election.
“All of those pieces are very time consuming and we just haven’t seen enough time go by to allow for” the needed data to come in before the election, said Saskia Popescu, an assistant professor at George Mason University who studies epidemiology.
However, Bourla, Pfizer’s CEO, said the company could make a determination about its vaccine candidate before November. “We expect, by the end of October, normally, we should be able to have enough events to say if the product works or not,” he said. “If we have enough events, we may be able to say the product is safe and efficacious in the October timeframe and submit immediately for approval.”
Researchers are concerned the FDA may abuse its emergency use authorization process to boost an unready Covid-19 vaccine
The current pace of phase 3 clinical trials means that the FDA might not have enough evidence of safety and efficacy to grant full approval to a Covid-19 vaccine before November.
Instead, the agency may invoke an emergency use authorization, or EUA, for a vaccine. This provision gives the FDA wide latitude to allow health providers to use approaches during a public health emergency that have a likely benefit. That’s a much lower bar than is needed for conventional approval, which requires a demonstrated health benefit with completed clinical trials.
FDA Commissioner Stephen Hahn said that his agency is open to the idea of issuing an EUA for a vaccine, bypassing phase 3 trials, but companies would have to take the lead. “It is up to the sponsor [vaccine developer] to apply for authorisation or approval, and we make an adjudication of their application,” Hahn told the Financial Times on August 30. “If they do that before the end of phase 3, we may find that appropriate. We may find that inappropriate, we will make a determination.”
In their statement on Tuesday, nine vaccine developers vowed to “[o]nly submit for approval or emergency use authorization after demonstrating safety and efficacy through a Phase 3 clinical study that is designed and conducted to meet requirements of expert regulatory authorities such as FDA.” So they did not entirely rule it out.
The FDA has received a torrent of criticism in issuing EUAs during the Covid-19 pandemic, apparently bending to political influence.
For instance, the agency granted one to hydroxychloroquine after Trump called it “one of the biggest game changers in the history of medicine,” despite flimsy evidence for its effectiveness. The FDA then revoked this authorization as the benefits failed to materialize and cases of serious side effects mounted.
More recently, the FDA’s EUA for convalescent plasma for Covid-19 treatment has come under scrutiny. The National Institutes of Health reviewed the research justifying the approval of the therapy and called it “insufficient.”
“I think, in isolation, the notion that one could stop a phase 3 [vaccine] trial early is not necessarily upsetting,” Offit, the children’s hospital vaccine center director, said. “The problem is the context of that statement.”
Researchers warn that the FDA could further erode its credibility when trust is most critical.
An EUA still needs to be backed by evidence from clinical trials, and that takes time as well
The standard of evidence for an EUA from the FDA is lower than in granting a full license for manufacturing, but it’s not zero.
“If you’re licensing a vaccine, you have to prove that it’s safe, you have to prove that it’s effective,” Offit said. “If you’re not licensing it, but rather you’re trying to get it authorized through the emergency use authorization, it doesn’t necessarily have to be proven to be effective. The quote in the FDA guidelines is ‘may be effective,’ which is much lesser, and open to interpretation.”
The FDA’s guidance for a Covid-19 vaccine sets a minimum benchmark of 50 percent efficacy for approval, meaning at least half the people who get the vaccine must gain protection from the disease. The same standard holds for an EUA for a vaccine, but officials said that the evidence has to be robust.
“If a vaccine is efficacious, an EUA will require that the documentation and demonstration of efficacy be flawless,” Moncef Slaoui, the lead scientific adviser to the US government’s Operation Warp Speed, said in a September 3 interview in Science magazine. Operation Warp Speed is a $10 billion effort aimed at delivering 300 million doses of a Covid-19 vaccine by January 2021. The program is funding research and development as well as manufacturing so that once a vaccine is approved, doses will be available right away.
The data needed to grant an EUA will still have to come from a phase 3 trial, but it could be gleaned before the trial is completed. The main gatekeepers of this information are data and safety monitoring boards for the various vaccine trials. These are groups of nongovernmental scientists and researchers who independently evaluate the evidence presented in clinical trials.
During a trial, the safety boards periodically review the evidence gathered at predetermined intervals. If a phase 3 trial needs 150 confirmed infections in its 30,000-person testing pool to yield a statistically significant result, boards could conduct a review when 70 infections are confirmed. The board could then examine how the infections are split among the vaccine treatment group and the placebo control group.
“If at that point you see an absolutely even split, then you may want to call the study to an end due to futility. ‘Let’s just call it a day,’” Zenilman said. “On the other hand, if there is a 70 percent split [between the placebo group and the vaccine group], the advice to the study team would be to keep on going.”
But to justify an EUA at this point, the evidence for efficacy would have to be overwhelming, with close to every detected infection in the control group and almost none in the group that received a vaccine. Even so, there will be much less data about the safety of the vaccine at this early point.
“The long-term evidence of safety is going to be limited because these vaccines are going to have only six months or five months of data,” Slaoui said. Establishing safety is especially critical for some of the Covid-19 vaccines in phase 3 trials because they are using vaccine technologies that have never been approved for widespread human use before, like Moderna’s mRNA vaccine and the University of Oxford’s adenovirus vector vaccine.
That could lead to a situation by late October where there is strong evidence that a Covid-19 vaccine is effective but weak evidence that it’s safe for large segments of the population. If a vaccine developer decides to seek an EUA at that point, it could force the FDA to make some difficult decisions.
The question now is what is the lowest standard of evidence the FDA will use to justify an EUA for a vaccine and how soon clinical trials will clear that bar.
Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, the group that would approve a Covid-19 vaccine, insisted that his determination one way or the other would be solely guided by the science. He confirmed to Reuters that he would resign if a vaccine were authorized without adequate data to support it.
“I could not stand by and see something that was unsafe or ineffective that was being put through,” Marks told Reuters. “You have to decide where your red line is, and that’s my red line.”
The FDA and CDC need to go out of their way to show the public their decisions are based on science, not politics
Getting a Covid-19 vaccine approved, whether through a full license or with an EUA, is only the first step in an immunization campaign to thwart the pandemic.
Next steps would require manufacturing capacity to produce the millions of doses needed, thousands of workers trained to administer the vaccine, robust monitoring systems to keep track of recipients, and hardware like freezers to store the vaccine. These things will take months to set up and little if any of this infrastructure will be in place prior to the November election. The earliest doses of a vaccine would also be earmarked for people like doctors and essential workers who face the greatest risk of exposure.
But perhaps the biggest factor affecting a vaccination effort — public faith in a vaccine — may also be the most fragile element. Appearances that political pressure influenced the release of a vaccine or the emergence of complications that weren’t detected in a curtailed clinical trial would make it harder to convince people to get inoculated against Covid-19.
“From a public health standpoint, I think what worries me especially is not just that we’re rushing this ... but also really that if there are negative outcomes, that is really going to impact trust that the public has in the vaccine, the CDC, and our ability to respond,” said Popescu. “It’s kinda hard not to see a November 1 push with a November 3 election date as anything but politically motivated.”
As a healthcare worker, I would be one of the first groups eligible for a vaccine in November. Despite the horror of what I've seen from #coronavirus firsthand, I would not take a vaccine that had not undergone Phase 3 clinical trials. Period.— uché blackstock, md (@uche_blackstock) September 3, 2020
However, Herschel Nachlis, a research assistant professor of government at Dartmouth College, noted that political pressure is almost impossible to decouple from the process.
“Even under the best circumstances, regulatory decision-makings are always a partial combination of law and policy, and political context,” Nachlis said.
Nachlis co-authored a recent article in the journal JAMA examining the FDA’s missteps with its previous EUAs like that for hydroxychloroquine, and how lessons from those mistakes should be applied to a Covid-19 vaccine to increase transparency.
“The FDA conveying to the public that it knows what it’s doing and that it’s doing things consistent with its expertise and high reputation is really important,” Nachlis said.
To this end, the FDA will hold a public meeting of its Vaccines and Related Biological Products Advisory Committee on October 22, less than two weeks before the presidential election. The meeting will go over some of the evidence collected from phase 3 trials by then and discuss any potential vaccine approvals and license applications.
“I want to assure the American people that the process and review for vaccine development will be as open and transparent as possible,” FDA Commissioner Hahn said in a statement announcing the meeting. “It is critical for people to see FDA’s expectations for data to support safety and effectiveness.”
But as the election nears, the political pressure to approve a Covid-19 vaccine will only mount. So the CDC and the FDA will have to go out of their way to demonstrate that their decisions are guided by data and not politics. And with past missteps, the groups have some ground to make up.
“There’s two components here: There’s the science and the public’s trust,” Nachlis said. “Even the best science can’t cure a distrustful public.”