IIn a response to the pandemic in the United States dominated by missteps, the effort to develop vaccines to prevent Covid-19 has so far been a triumph. As a result, vaccines against the coronavirus that causes the disease are now racing through gigantic clinical trials.
It is a terrible irony, then, that the Trump administration’s statements have resulted in an erosion of public confidence, with the percentage of Americans telling pollsters they would take a Covid-19 vaccine and experts fearing the president could force the Food and Drug Administration approve a vaccine before one is ready. (Spoiler: No vaccines are likely to be ready by election day.)
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The process of deciding when a vaccine appears to be safe and effective is not as simple as the general public might believe. But it’s important to understand if we are to have faith in these critical tools to help curb the pandemic.
So here’s a rundown of the science going into decision making, what tells us when results could realistically be available, and when vaccines could start being administered. This story is based on interviews and documents that drug manufacturers have released detailing their clinical trial plans.
When will vaccine manufacturers have enough data?
A clinical trial is typically sponsored by a company that makes a candidate vaccine or by an academic institution or a partnership of both. But it’s actually monitored by what’s known as a Data and Safety Monitoring Committee, or DSMB, a group of independent experts hired to make sure the 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 would simply be unethical.
In the case of vaccine trials, the studies conducted by Moderna, AstraZeneca and Johnson & Johnson with the National Institutes of Health share a common DSMB. The study conducted by Pfizer and its partner BioNTech has its own.
DSMBs will conduct what is termed an interim analysis after a number of people are infected with Covid-19 and have shown symptoms. Each of these cases is considered an “event” and each vaccine manufacturer has set a different number of events as a threshold for conducting an interim analysis as part of their testing protocols.
The study led by Pfizer and its pioneer partner BioNTech 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 vaccine study by Moderna, another forerunner, awaits until there are 53 cases of Covid.
In the case of Pfizer and BioNTech, an interim analysis could take place in October.
Should a vaccine be approved, potentially for millions of people, after its effectiveness has been proven based on 32 cases of Covid-19?
Some experts say no. Eric Topol, the director of the Scripps Research Translational Institute, fervently said that all evidence should continue beyond its intended purpose – when there are about 150 cases of Covid – stating that even the 150 numbers “it may make statistical sense, but it defies common sense.This may be especially true if efficacy is limited, as all vaccines often cause side effects such as fever.
Others say that while making a decision based on an interim analysis is fine, Pfizer’s first analysis, in particular, appears to set a relatively low limit for effectiveness given the limited number of events.
The numbers are in line with previous vaccine studies. Prevnar 13 was approved to prevent pneumonia in adults based on a study of 84,000 people that found 139 cases of pneumonia, 90 of them in the placebo group.
But there is also precedent for maintaining such studies 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 that had been seen with a previous vaccine.
The approval rules
If and when a company believes its vaccine is safe and effective, it will submit its data to the Food and Drug Administration.
No Covid-19 vaccine is likely to be fully approved by the FDA in the short term, due to requirements for production and follow-up which could take years. The FDA should instead use a different authority by granting what is known as an Emergency Use Authorization, or EUA.
The bar for an EUA is low and previous EUAs have seemed imprudent in hindsight. One drug, peramivir, was cleared in emergency for the treatment of patients hospitalized during H1N1 swine flu in 2009; the drug subsequently did not prove effective in a clinical trial on these patients. Hydroxychloroquine was given an EUA for the treatment of Covid-19 in hospitalized patients; that authorization was later withdrawn once further studies showed that the drug did not benefit them. The UAE for convalescent plasma included data that would never be approved. These latter examples are precisely why many experts are so concerned that FDA decision making is politicized.
The challenge for the FDA will be to ensure 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 one year, six months if fast, and three months at the most. Even a truncated revision should take weeks. So even if Pfizer’s vaccine data were available in mid-October, it’s hard to imagine an emergency clearance by election day. The same is true if the data comes from one of AstraZeneca’s vaccine studies conducted outside the United States.
This obviously presupposes that politics is not at stake.
Will the trials continue?
In the intermediate analyzes that most people following medicine are used to, as soon as there is a clear result, the experimentation stops. But the plan for Covid-19 vaccines is different: data from an interim analysis can be released if a vaccine is deemed unquestionably effective, but volunteers may not be immediately told whether they are receiving the vaccine or the placebo. In other words, the studio will remain “blinded”. Participants receiving a placebo will not immediately switch to the vaccine.
“The protocol is designed in such a way that even if we were able to archive after an interim analysis, the protocol is designed to go on, at least for a certain period of time,” said Kathrin Jansen, head of vaccine research. Pfizer, in a recent phone call with reporters. The reason is that efficacy needs to be evaluated in smaller groups, such as teenagers, the elderly and people with HIV, he said. Jansen said Pfizer and BioNTech hope to gather information on serious infections as well.
Continuing a trial after an interim analysis can be difficult, so much so that Thomas Fleming, one of the leading minds in clinical trial statistics, is co-author a 2008 paper on why it should be avoided.
In a conference call with reporters to discuss the start of the Johnson & Johnson vaccine study, Anthony Fauci, who heads infectious disease research at the NIH, said the other trials would continue blinded until half of the volunteers involved in the study were followed for at least two months, in order to collect more data on efficacy and safety.
The J&J study only requires 20 cases of Covid-19 before an interim analysis is conducted. But Paul Stoffels, chief scientific officer of Johnson & Johnson, told STAT his company will even wait to conduct an interim analysis until half of the participants in its study of 60,000 volunteers, which began this month, have been followed up for two months. Such an analysis will also require sufficient data in other populations, including the elderly. After the data have been interpreted, the DSMB may recommend stopping the study.
“Generating sufficient data is also where we take our responsibility, because ultimately we will be accountable for the product entering the market,” Stoffels said.
“You know, we go from a thousand people to 60,000, to probably 100 to 500 million people,” Stoffels said. “The information we generate must be very solid.”
This is the point that regulators and, in particular, politicians must remember, no matter how eager they are to have a vaccine in hand.