Contribute Try STAT+ Today

In a U.S. pandemic response dominated by missteps, the effort to develop vaccines to prevent Covid-19 has so far been a triumph. Vaccines against the coronavirus that causes the disease are now racing through giant clinical trials as a result.

It’s a terrible irony, then, that the Trump administration’s statements have resulted in an erosion of public trust, with the percent of Americans who tell pollsters they would take a Covid-19 vaccine dropping and experts worrying the president could compel the Food and Drug Administration to approve a vaccine before one is ready. (Spoiler: No vaccine will likely be ready by Election Day.) 

“When the the president comes out and says, ‘by a very special day, we might have a vaccine,’ the whole thing blows up,” Ashish Jha, the dean of the Brown School of Public Health, said at a session focused on Covid-19 at the STAT Health Tech Summit. “In some ways, we’ve got to get the politicians to shut up and let the scientists talk about this and drive this process.”

advertisement

The process of deciding when a vaccine appears to be safe and effective isn’t as straightforward as the general public might believe. But it’s important to understand it if we are to have confidence in these critical tools for helping to curb the pandemic.

Here, then, is a rundown of the science that goes into the decision-making process, what it tells us about when results could realistically be available, and when vaccines could start to be administered. This story is based on interviews as well as on documents the drug makers have released detailing their clinical trial plans. 

advertisement

When will vaccine makers have enough data?

A clinical trial is typically sponsored by a company making a vaccine candidate or an academic institution, or a partnership of both. But it is actually monitored by what is known as a data and safety monitoring board, or DSMB, a group of independent experts hired to make sure volunteers in the study are safe. In many studies, the DSMB has the ability to recommend stopping a study not only if a treatment is unsafe, but also if it is so clearly effective that continuing just wouldn’t be ethical.

In the case of the vaccine trials, the studies being run by Moderna, AstraZeneca, and Johnson & Johnson with the National Institutes of Health share a common DSMB. The study being run by Pfizer and its partner BioNTech has its own.

The DSMBs will conduct what’s called an interim analysis after a certain number of people have been infected with Covid-19 and shown symptoms. Each of these cases is considered an “event,” and each vaccine maker has set a different number of events as a threshold to conduct an interim analysis as part of their trial protocols.

The study being run by Pfizer and its partner BioNTech, frontrunners in the race for a vaccine, is conducting its first interim analysis after 32 events, and would consider the vaccine effective if 26 people in the placebo group and six in its vaccine group had Covid. A study of Moderna’s vaccine, another frontrunner, is waiting until there are 53 cases of Covid.

In the case of Pfizer and BioNTech, an interim analysis could happen in October. 

Should a vaccine be approved, potentially for millions of people, after its efficacy has been shown based on 32 cases of Covid-19? 

Some experts say no. Eric Topol, the director of the Scripps Research Translational Institute, has been fervently saying that all the trials should continue beyond even their designed ends — when there are about 150 cases of Covid — saying that even the 150 number “may make statistical sense, but it defies common sense.” This could be particularly true if efficacy is limited, given that all the vaccines frequently cause side effects like fever.

Others say that while making a decision based on an interim analysis is fine, the first Pfizer analysis, in particular, seems to set a relatively low bar for efficacy given the small number of events.

The numbers are in line with past vaccine studies. Prevnar 13 was approved to prevent pneumonia in adults based on a study of 84,000 people that detected 139 cases of pneumonia, 90 of them in the placebo group. 

But there’s also a precedent for keeping such studies going to collect more safety data. Researchers studying RotaTeq, a vaccine to prevent a virus that causes childhood diarrhea, collected data from 70,000 patients to rule out a potential side effect which had been seen with a previous vaccine. 

The rules of approval

If and when a company believes its vaccine is safe and effective, it will then submit its data to the Food and Drug Administration.

No Covid-19 vaccine is likely to be fully approved by the FDA in the near term, because of requirements for manufacturing and follow-up that could take years. The FDA is expected instead to use a different authority by granting what is known as an emergency use authorization, or EUA.

The bar for an EUA is low, and past EUAs have seemed unwise in hindsight. A drug, peramivir, was authorized on an emergency basis to treat hospitalized patients during the H1N1 swine flu in 2009; the drug later failed to be shown effective in a clinical trial of such patients. Hydroxychloroquine was given an EUA to treat Covid-19 in hospitalized patients; that authorization was later rescinded once further study showed the drug did not benefit them. The EUA for convalescent plasma involved data that would never pass muster for an approval. These later examples are precisely why many experts are so worried that the FDA’s decision-making is politicized.

The challenge for the FDA will be to make sure that it brings its usual standards for a vaccine to the much more flexible emergency use authorization process.

Reviewing data on a drug candidate normally takes a year, six months if it is fast, and three months at the fastest. Even a truncated review should take weeks. So even if data on Pfizer’s vaccine are available in mid-October, an emergency authorization by Election Day is difficult to imagine. The same is true if data emerge from one of the studies of AstraZeneca’s vaccine being conducted outside the U.S.

That assumes, of course, that politics are not at play.

Vaccine
A Covid-19 vaccine is shown at a clinical trials site in Hollywood, Fla. CHANDAN KHANNA/AFP via Getty Images

Will the trials march on?

In the interim analyses that most people who follow medicine are used to, as soon as there is a clear result, the trial stops. But the plan for Covid-19 vaccines is different: Data from an interim analysis may be released if a vaccine is deemed inarguably effective — but volunteers may not be immediately told whether they are receiving vaccine or placebo. In other words, the study will remain “blinded.” Participants receiving a placebo will not be switched immediately to the vaccine. 

“The protocol is designed in a way that even if we would be able to file after an interim analysis, the protocol is designed to move on, at least for a certain amount of time,” said Kathrin Jansen, Pfizer’s head of vaccine research, on a recent call with reporters. The reason is that there is a need to assess efficacy in smaller groups, such as teenagers, the elderly, and people with HIV, she said. Jansen said that Pfizer and BioNTech hope to gather information about severe infection, too. 

Keeping a trial going after an interim analysis can be difficult, so much so that Thomas Fleming, one of the top minds in clinical trial statistics, co-authored a 2008 paper on why it should be avoided.

In a conference call with reporters to discuss the start of the study for Johnson & Johnson’s vaccine, Anthony Fauci, who heads research on infectious disease at the NIH, said that the other trials will continue in a blinded fashion until half the volunteers in the study have been followed for at least two months, in order to collect more data on efficacy and safety.

The J&J study requires only 20 cases of Covid-19 before an interim analysis is conducted. But Paul Stoffels, Johnson & Johnson’s chief scientific officer, told STAT that his company will wait to even conduct an interim analysis until after half the participants in its 60,000-volunteer study, started this month, have been followed for two months. Such an analysis will also require enough data in other populations, including the elderly. After the data are interpreted, the DSMB might recommend stopping the study.

“Generating enough data is also where we take our responsibility, because in the end we will be liable for the product getting into the market,” Stoffels said.

“You know, we go from a thousand people, to 60,000, to probably 100 million to 500 million people,” Stoffels said. “The information we generate has to be very solid.”

That’s the point that regulators and, especially, politicians need to remember no matter how eager they are to have a vaccine in hand.

  • No mention of (the importance of) phases 1, 2, 3, and scary low phase 3 numbers to “prove” efficacy …. This article aiming to calm a worried general public might just cause the opposite : with this meagre info, more people might want to wait untill well into 2021 before getting vaccinated …………

  • As a layperson I still don’t understand. How do the trials work? When they inject a trial member with the vaccine do they just tell them to go about their lives and walk around without a mask on, don’t wash hands, etc. in order to see if they catch the virus?

    Also, out of the 30,000 people in the trial group, the trial will stop when 6 vaccines trial members catch covid? Can you please explain this in more detail for us lay people like your title says?

    Thanks

    • One third to one half of the volunteers do not even get the trial vaccine. They get a placebo, and no one knows who gets which. So yes, life goes on, but participants would be expected, and advised to follow normal public safety recommendations. Masks, hands, distance, crowds, etc. And then they do what whatever they do…and the eventual outcomes of the two groups are compared to see if the vaccine was worth while.

    • The second part of your question involves statistics. At a preplanned number of infections…say for example 50, an independent secretive group is given access to the preliminary results. They check to see if the vaccine group is seeing say 75% effectiveness. Don’t know the actual numbers, but say out of 50 infections, 43 of them are placebo and 7 are vaccinated. These either meet, exceed or fail expectations and they will report that out for others to make subsequent decisions as to the future of the trial.

  • It is essential to separate determination of safety and determination of efficacy. Safety will be determined fairly quickly because of very large study size and the fact that adverse reactions occur in close proximity to injection. Efficacy is much more difficult because of the small numbers of people in the studies who become infected.

    Many in the public are being led to believe the vaccines are dangerous. This will lead to unnecessary deaths. Safety has already been pretty well determined. Exact efficacy may never be known.

  • It is disappointing that this article does not expkain why Astra-Zeneca’s vsviinecclinucal trial is allowed to resume in the UK but not in the UK with the FDA totally and strangely silent labout it. Can Matt Herper find out!?

  • When we conducting medicine and vaccine, 1st were saving life’s, we should not let someone else make a decision; Doctors and Nurses are saving lives that is the way we live. Each of us have our own choice turn our life to someone else. There will become a time when were dying and can’t speak and someone else is responsible, and I dam hope it not a newsman or writers who put words together to inform the public in there words; not mine.

  • What kind of guide is this? The only thing the article tells you is that Trump is bad which is false. He did a great job handling the COVID-19 pandemic. You accuse him of pressuring the FDA with zero evidence. This is just anti-Trump fake news garbage and you call it “A layperson’s guide to how — and when — a Covid-19 vaccine could be authorized.” Absolutely Disgusting!!! You should be ashamed of yourself!!!

    • Did you even read the article?
      Do you even listen to Trump? You listen to him tell California to “sweep their floors” of the forest to prevent fires. You hear him say Covid is just a “China virus”. You hear him literally tell people not to worry about it, that it’s not a big deal, and America is still leading in number of Covid cases. Covid isnt Trump’a fault. But he sure as hell don’t know how to encourage a country to stay healthy, mask-up, and listen to science instead of ill-informed opinion. He keeps saying we’ll have a vaccine by election: no, we most certainly won’t. It’s like you don’t even actually LISTEN to trump, you just read the news about him and call it “fake news.” Try listening to him talk. He’s dumber than a doorknob.

    • The article doesn’t say anything bad about Trump per se –
      I thought it was kind to Trump as compared to all the lies printed about him in the last four years.
      But it is slanted as usual:
      Only 19 percent of polled said they would get the vaccine; that sounds bad right? But only about 30-40% of people get the flu shot. So that only a 10%-20% drop from what we would typically expect. Could that drop be due to asking only young people if they would get the vaccine? or Dems? We don’t know.
      We do know 19% is plenty enough to achieve heard immunity anyway.
      And who are these ‘experts’ that think any president could ‘compel the fda to approve a vaccine before one is ready‘, no less Trump. He couldn’t even get them to approve HCQ. Big Pharma is way more powerful than the president. If anything they will probably compel the fda to delay the vaccine so that new expensive drugs will be the only option this season.

    • The country is polarized into Trump groupies and Trump haters. Neither group can see past their own ideologic noses. Fact is Trump is prettymuch worthless as a pandemic leader. But his people are great. Which is enough.

      Despite baseless fears to the contrary, Trump has no impact on this fight — his people, like Dr Fauci and the others, do. Just smarten up and ignore Trump’s nonsense. He’s not actually in the loop — just don’t tell him that. 🙂

  • Any chance you could provide some data for a freaking change instead of bashing Trump????????? Is that possible with you left wing idiots? Guess not.

  • problem is how to inoculate the huge population of homeless and all then uninsured retail workers with no health care? Many don’t have the luxury of a car, so there’s no place for them to sit and wait for a test or a shot.

    Prvilefed Ameicans ca’t imagine how anyone would choose t walk everywhere.

    • We don’t need to inoculate every last vagrant and uninsured person; we only need a minority percentage to get the vaccine in order to achieve herd immunity.
      I’m not sure a person is privileged just because they own a car; ask anyone that lives in their car if they feel privileged.

Comments are closed.

Your daily dose of news in health and medicine

Privacy Policy