Two major studies of vaccines against Covid-19, both paused because of potential safety concerns, are set to restart, the companies running them said Friday.
“The restart of clinical trials across the world is great news as it allows us to continue our efforts to develop this vaccine to help defeat this terrible pandemic,” Pascal Soriot, AstraZeneca’s CEO, said in a statement. “We should be reassured by the care taken by independent regulators to protect the public and ensure the vaccine is safe before it is approved for use.”
“We as a company have found no evidence the vaccine candidate caused the event, and we have agreed to restart the study,” Paul Stoffels, the chief scientific officer at Johnson & Johnson, said in an interview.
In both cases, new documents describing potential risks for both researchers and volunteers have been prepared, and must be approved by a centralized institutional review board, one of several groups charged with protecting patients in the trial.
AstraZeneca’s restart was first reported by the Wall Street Journal; the impending restart of the J&J study was first reported by the Washington Post.
AstraZeneca stopped administering new doses of its vaccine on Sept. 6, a step first reported by STAT, after a participant in the trial developed neurological symptoms. These symptoms were reportedly caused by transverse myelitis, a serious spinal cord condition.
AstraZeneca said in its statement that the voluntary pause was part of its standard review process for safety events, and that such pauses are not unusual. It said reviews from the trial’s independent monitoring committees indicated it was safe for the trials to resume, and that this conclusion was supported by international regulators.
A study of the vaccine in the U.K. restarted on Sept. 12, and shortly thereafter studies in Brazil and South Africa resumed. A study in Japan restarted earlier this month. But the Food and Drug Administration decided to further investigate the case, and the U.S. trial has remained on hold for more than a month.
A trial of another vaccine, being developed by Johnson & Johnson, was paused on Oct. 11. According to a person familiar with the matter, a male volunteer in his twenties had a cerebral hemorrhage and transverse sinus venous thrombosis. The Washington Post, citing two sources, said this case was a stroke.
Stoffels said that the case was reviewed by external experts, with reports made continuously both by the study’s data and safety monitoring board, an outside panel overseeing the studies, and the FDA. A final report was sent to the agency late this week. Circumstances with the patient made the process slower than it might have been.
“We worked as hard as we could,” Stoffels said. “We would not put more people at risk until we knew what the cause or relationship would be.”
The J&J study could begin enrolling patients again early next week, Stoffels said. He noted that the study already includes a large number of sites, and that the company will be making sure the participants are diverse in their ethnic background, their age, and any disorders they have that could make them higher risk.
The J&J effort is important because it is the only one of the major vaccine efforts to be testing a single dose, and the company has made the main goal of its study to test whether the vaccine prevents severe or moderate Covid-19, not just symptomatic cases of the disease.
Helen Branswell contributed reporting.
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I sure would like to have a chance to take this vaccine. Please hurry
You really should at least try to understand how much of a leap it is to assume these cases have anything to do with the vaccine. You need to understand the numbers of participants in the trials as well as the normal incidence of different kinds of morbidities (and even death), to have even a vague sense of how expected or unexpected these kinds of events are. It is totally irresponsible to assume the vaccines are causing these cases, without having done any calculations, review of the scientific literature, or other due diligence before you go posting your assumptions and scaring people away from the only real tool we have to one day return to normal.
So how unexpected are the results so far? As I said, you need to know the numbers regarding trial size and normal incidence of morbidities. Each trial is enrolling > 30k participants. There’s 4 trials (at least from US/UK companies and subject to independent review in the US), 2 of which have already surpassed 30k, and the other 2 we can assume are well on their way. There’s 2.8 million deaths annually in the US, or .86% of the population; 785 strokes annually, or .24%; there’s 80 different autoimmune diseases (transverse myelitis is only one of them), and the incidence of autoimmune disease in general has been estimated in 2015 by Marrie et al. to be about 1.44%.
What does that tell us about what we should reasonably expect to see in these studies, and what does it say would be truly unexpected? We can do some simple back of the envelope calculations to get a rough sense. Let’s assume a ‘case’ that is cause for concern is one of the above conditions (death, stroke, or onset of autoimmune dysfunction). Note that we shouldn’t really restrict our consideration to those specific medical conditions. There are probably other serious conditions that might warrant pauses in a vaccine trial (e.g. heart attacks), though it’s difficult to know for sure since the exact criteria don’t seem to be published. But by being a bit more exclusive here, we can at least get a sense of the lower bound of what to expect.
And let’s even assume that a condition has to occur within a week of receiving the vaccine or placebo shot for it to be considered for further review. Again, this might also be too restrictive since every participant’s data is presumably being monitored for the entire duration of the study, but I’ll just repeat that the goal is tp get a lower bound of what incidents could even possibly merit a study pause (and, once again, there doesn’t seem to be published criteria).
Then it’s a simple extrapolation from the numbers above. For example, in any given trial, we should expect to see 4.96 deaths, on average, happen within a week of their shot (0.86% annual mortality divided by 52 weeks for 30k participants). We should expect 1.38 strokes within a week of their shot, and 8.3 autoimmune incidents. Of course, I should stress that these are averages, which means that 1 trial may have no strokes and another trial could have 2 or 3, and that’s still not evidence of anything unusual. And I should stress that the time after the shot really matters a lot. But even if we only consider events if that have occurred within a day of the shot, we still have 0.71 deaths, 0.2 strokes, and 1.19 autoimmune incidents.
Per trial. So multiply by 4.
The other main assumption to note at is that the studies are getting a truly representative sample of the US population. While that’s probably not totally true, it’s probably true enough to get a reasonable approximation for these estimates. For example, all the studies, AFAIK, have prioritized getting adults in the studies, to the exclusion of children and infants, which should increase the mortality rate; on the other hand, they may also have opted to recruit less from the very elderly population out of an abundance of caution, which should obviously decrease the mortality rate.
So, in conclusion, is the number of morbidities or deaths in these trials unexpectedly high? Not in any sense. The calculations I gave you are pretty conservative, in terms of what conditions are considered, when they would be considered, and their likely incidence within those time windows. The true expectation for serious events that might warrant review is almost definitely higher.
So, insofar as the data tells us right now, the number of serious events reported is well within the range, and possibly even lower, than what should normally occur to a random sample of 30k people. Therefore there’s absolutely nothing within what’s been reported to imply that the vaccines have contributed to these events. More importantly, I hope the above exercise demonstrates the utility of doing some due diligence, and the importance of doing so before confidently spouting your best guess about what to take away from the headlines you’ve read in the news.
Bunk! Your numbers make no sense. In particular: “For example, in any given trial, we should expect to see 4.96 deaths, on average, happen within a week of their shot (0.86% annual mortality divided by 52 weeks for 30k participants). We should expect 1.38 strokes within a week of their shot, and 8.3 autoimmune incidents” All people are not at equal risk for stroke. A odds of a person in their 20’s having a stroke vs someone in their 60’s are vastly different. Your simplistic rationale results in erroneous conclusions.
I’ll take a cold over transverse myelitis, multiple sclerosis, stroke, or death like has happened in these trials.
It seems obvious that the safer COVID-19 vaccines are the mRNA vaccines being developed by Moderna and Pfizer. KimRN/BSN
It is far too early to say that. mRNA vaccines are in their infancy whilst other methods such as adenovirus have been around for a long time. Statistically, there is nothing unusual so far in the number of reported side effects. Let’s wait and see.
Weeks of delay from a false alarm to investigate two cases, meanwhile thousands dying every day from COVID-19.
you have no credibility. Novavax has best results. Answer this why did they skip ph2 and straight to ph3 ? While novavax is sitting on sidelines, what a disgrace, Fauci should be jailed and your reporter when reported people were hospitilized…
Transparency. Transparency. Transparency.
Everyone keeps talking about it, yet no one is doing it.
Why hasn’t anyone other than AZN published their Participant Information Sheet? Even AZN’s October 21st PIS update does not include the detailed adverse event information that the FDA appears to be asking for.