A Real Vaccine Before the Election? It'd Take a Miracle.

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There is a small chance that Pfizer's vaccine trial will yield results by Nov. 3. Here's everything that has to happen and how to tell a political stunt from a real vaccine.
Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

A lab technician sorts blood samples for a COVID-19 vaccine study in Hollywood, Florida, on Aug. 13.

Despite President Donald Trump's promises of a vaccine next month and pundits' speculation about how an "October surprise" could upend the presidential campaign, any potential vaccine would have to clear a slew of scientific and bureaucratic hurdles in record time.

In short, it would take a miracle.

We talked to companies, regulators, scientific advisers and analysts and reviewed hundreds of pages of transcripts and study protocols to understand all the steps needed for a coronavirus vaccine to be scientifically validated and cleared for public use. As you'll see, it's a long shot in 38 days.

There are three key milestones that must be met:

A clinical trial would need to observe enough infections to demonstrate that the vaccine is better than a placebo. Right now, Pfizer's trial is the furthest along. Pfizer has said it expects results by the end of October, but analysts who follow the company aren't so sure it'll be that soon or whether the results will be conclusive. Pfizer would have to turn its trial data into an application to the Food and Drug Administration. The company could either apply for full approval — a very high bar for proving the vaccine is safe, effective and able to be reliably manufactured by the millions of doses — or for an emergency use authorization, which is more flexible. Pfizer has said it could submit its application almost immediately. The FDA has to review the data and decide whether the vaccine is ready to go to market. That could take several weeks to a month, said Dr. Mark McClellan, who led the FDA from 2002 to 2004.

"All of this put together makes it more likely that it'll be a late 2020 availability," McClellan said.

None of this is to say that Trump couldn't suddenly call a White House press conference to try to grab headlines and declare victory. But knowing all the steps that would have to come first can help the public discern between a true, scientifically validated vaccine and a mere political stunt.

Yes, Pfizer Could Have Trial Results by the End of October

Results from ongoing trials are closely guarded so that researchers (and investors) have no opportunity to mess with them. Under strict trial rules that vaccine makers and the FDA set up in advance, there are only a few predetermined times when a data monitoring board is scheduled to look at the data. The purpose of those check-ins (known as "interim analyses") is to see if there's already enough evidence to conclude that the vaccine either works or doesn't.

According to the trial rules that Pfizer released last week, it has four of these check-ins before the final analysis. The first one occurs when 32 people in the trial get sick with COVID-19.

Yes, that is a tiny number in a study designed to enroll 30,000 participants. But it could be enough to show that the vaccine works if far more of the infections occur in people who took the placebo than in those who got the vaccine, so much so that it's probably not random.

The vaccine "would have to be way, way better to meet an interim stopping boundary," said Frank Harrell Jr., professor of biostatistics at Vanderbilt University.

If six or fewer of the first 32 cases are people who got the vaccine, that suggests the vaccine reduced COVID-19 cases by 76%. Under Pfizer's trial rules, the company can then conclude that its vaccine is effective enough to submit its application to the FDA. If, on the other hand, 15 or more of the first 32 infections are people who got the vaccine, it would mean the vaccine doesn't work and the study ends.

The better the vaccine works, the longer it would take to reach 32 cases, because fewer vaccinated people would get sick and more of the infections would have to occur in the placebo group.

So when exactly will Pfizer get to 32 cases?

Analysts at JPMorgan estimate that this first readout would occur on Oct. 31 if the vaccine is 70% effective, or on Nov. 2 if the vaccine is 80%. Their model also estimates that Pfizer is more than twice as likely to be able to file for approval at 80% effectiveness vs 70% effectiveness.

The JPMorgan analysts' prediction is roughly in line with official public statements from Pfizer, though the company has projected even more confidence. "We have a good chance that we will know if the product works by the end of October," CEO Albert Bourla said Sept. 13 on CBS' "Face the Nation."

The key thing we don't know is how fast people in Pfizer's trial are getting sick. The trial doesn't intentionally expose people to the virus; it waits to see who catches it on their own. Even though the pandemic is far from under control, the coronavirus is not spreading as fast as it was a few months ago. The study started with a baseline assumption that just 1.3% of participants would be infected over the course of a year.

It's possible that the thousands of people who signed up for Pfizer's study could be getting sick faster or slower than that, depending on how bad the outbreak is where they are. If Pfizer's trial infection rate is 1.5 to 2 times faster than publicly reported case counts, then Pfizer's first readout could be Oct. 12-19 with a 70% effective vaccine, or Oct. 14-22 with 80% efficacy, according to JPMorgan's model.

"When the trials started there were a lot more cases in the U.S. at that time," said Dr. Vamil Divan, an analyst at the bank Mizuho. "That's a key unknown. How many of these participants are enrolled in hotter areas versus New York or Boston?"

To protect the integrity of trials like this, the drugmakers running them aren't supposed to know what the data is showing as it comes in. And yet, company executives have led some observers to believe they know how many people have tested positive for COVID-19.

"They're making projections based on how rapidly they're accruing data, and they probably know the total number of events," said Susan Ellenberg, professor of biostatistics at the University of Pennsylvania.

"When they say things like that, first of all, it does some wonders for their stock prices," she added.

In a statement, Pfizer said that it expects results "as early as the end of October" based on current infection rates. The trial, the company said, "was designed to evaluate the safety and efficacy of the vaccine candidate as fast as possible."

"Having said that," the company added, "neither Pfizer nor the FDA can move faster than the data we are generating through our clinical trial."

It's highly unlikely that the next front-runner, Moderna, could have results before the election. The JPMorgan analysts' model suggests that infection rates would have to be four times the publicly reported rate for Moderna to be able to report results before Nov. 3.

Dr. Tal Zaks, Moderna's chief medical officer, told investors on Sept. 17 that "some time in November is sort of a reasonable base case" for the first look at Moderna's results. (ProPublica's board chairman, Paul Sagan, is a member of Moderna's board and a company stockholder.)

Other developers are further behind. AstraZeneca's trial is paused in the U.S. while the company investigates what happened with a participant who had a bad reaction. Johnson & Johnson is just beginning its large-scale, end-stage trial, months behind the other three.

So Pfizer is the only company with a shot at results before the election. And if the company has results to share, it's unlikely to let political implications get in the way. The company has an ethical obligation not to delay a product that is ready to save lives, despite the risk that a vaccine announced on the eve of a contentious election could stoke partisan perceptions.

"Once you have signs of a vaccine's effectiveness, it's very difficult to argue anything is ethical other than making it available to those most at risk," Dr. Mani Foroohar, an analyst with the investment bank SVB Leerink, said. "But it's also very difficult to make the argument that you should do anything that undermines public trust. That's one of the problems when you introduce powerful political pressures into what is meant to be a boring, dry, unemotional process."

Once Pfizer Gets Results, It's Poised to Seek the FDA's Go-Ahead Swiftly

As soon as Pfizer has conclusive data, it will submit an application to the FDA. The application will include data from all previous trials as well as proof that the company can consistently manufacture millions of vaccine doses.

Pfizer's CEO has indicated that the company is ready to turn around its application in a flash, if not on the same day it has results. "We will try to be able to be ready to submit with the speed of light, once we have the results ready," Bourla said at an investor presentation on Sept. 16.

Pfizer has two options when submitting its FDA application. It can apply for an EUA or a full approval, known as a biologics license application, or BLA. An EUA would only allow Pfizer to market its vaccine for the pandemic's duration — during the declared "emergency" period that we are currently in. If the company receives full licensure, on the other hand, its product can remain on the market forever. In its statement, Pfizer said it plans to continue its study after a possible EUA to collect more long-term data.

The bar for an EUA is lower than for full approval. By law, an EUA can be issued so long as "the product may be effective in diagnosing, treating, or preventing" the disease and "the known and potential benefits of the product … outweigh the known and potential risks." In contrast, the standard for a full approval requires a drugmaker to prove not only that the product is safe and effective, but also that the product is pure and can be consistently made, because vaccines are biological products made from living materials.

For the COVID-19 vaccine, the FDA has said that it is going to raise the bar for an EUA, going beyond the usual requirements. Previously, the FDA has said a vaccine should be at least 50% effective. The FDA is reportedly close to announcing new standards to include at least two months of monitoring the health of trial participants after they receive their second shot. That could end up being the biggest hurdle to authorizing a vaccine before the election. Trump said on Wednesday that he might reject the new guidelines, but companies and FDA officials…
Caroline Chen, Isaac Arnsdorf, Ryan Gabrielson
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