AstraZeneca Plc is likely to conduct an additional global trial of its coronavirus vaccine to assess the drug's efficacy, after the company acknowledged that a dosage error occurred during its initial trial.
The company's chief executive said a lower dosage was given than had been planned, raising questions over the medication's level of protection.
The lower dosage performed better than a full dose in AstraZeneca's studies, and the new trial would be used to confirm whether that efficacy rate stands.
The United States has preordered at least 300 million doses of AstraZeneca's vaccine.
The announcement this week that the cheap, easy-to-make vaccine appeared to be up to 90% effective was greeted with jubilation. "Get yourself a vaccaccino," a British tabloid celebrated, noting that the vaccine, developed by AstraZeneca and the University of Oxford, costs less than a cup of coffee.
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AstraZeneca and Oxford reported Monday that a lower initial dose of the vaccine, followed by a full dose -- the lower dose by error -- produced a 90% efficacy rate in a smaller set of participants, compared with 62% for two full doses.
And since unveiling the preliminary results, AstraZeneca has acknowledged the mistake in the dosage received by some study participants, adding to questions about whether the apparently spectacular efficacy figure will hold up.
Scientists and industry experts said the error and a series of other irregularities and omissions in the way AstraZeneca initially disclosed the data have eroded their confidence in the reliability of the results.
Officials in the United States have noted that the results were not clear. It was the head of the flagship U.S. vaccine initiative -- not the company -- who first disclosed that the vaccine's most promising results did not reflect data from older people.
The upshot, the experts said, is that the odds of regulators in the United States and elsewhere quickly authorizing the emergency use of the AstraZeneca vaccine are declining, an unexpected setback in the global campaign to corral the devastating pandemic.
"I think that they have really damaged confidence in their whole development program," said Geoffrey Porges, an analyst for the investment bank SVB Leerink.
AstraZeneca's vaccine is one of three that could be approved before the end of the year.
A vaccine from Pfizer and BioNTech SE, and another from Moderna Inc. were both about 95% effective in preliminary analyses of trials of tens of thousands of volunteers, according to data published this month. Both use a technology known as "messenger RNA."
Pfizer has applied to U.S. regulators for emergency approval, and both vaccine offerings seem nearly certain to win emergency authorization from the Food and Drug Administration in coming weeks.
The AstraZeneca vaccine, which uses a different approach involving a chimpanzee virus to provoke an immune response to the coronavirus, had all the hallmarks of a blockbuster.
It was inexpensive -- only a few dollars per dose -- and easy to mass-produce. Unlike the two other vaccines, AstraZeneca's could be stored for months in normal refrigerators. The company has estimated it will be able to produce some 3 billion doses next year, enough to vaccinate nearly one-fifth of the global population. Many low- and middle-income countries are relying on it.
'ADDITIONAL STUDY'
"We have to validate this, so we need to do an additional study," CEO Pascal Soriot said in his first interview since the data was released. It will probably be another international study, "but this one could be faster because we know the efficacy is high, so we need a smaller number of patients."
Soriot said he didn't expect the additional trial to hold up regulatory approvals in the United Kingdom and European Union. Clearance from the FDA may take longer because the agency is unlikely to approve the vaccine on the basis of studies conducted elsewhere, especially given the questions over the results, he said. Authorization in some countries is still expected before the end of the year, he said.
"The question for us was, will we need the U.S. data to get approval in the U.S. or can we get approval in the U.S. with international data, and it was never clear," said Soriot, who is in quarantine after arriving in Australia. "Now with those results it's more likely that we will need the U.S. data."
Stephanie Caccomo, a spokeswoman for the FDA, declined to comment on whether the dosing error would hurt the vaccine's chances of being authorized. The FDA has said it expects vaccines to be at least 50% effective in preventing or reducing the severity of the disease, a bar that the vaccine appears to have cleared even in the group that got the two full doses.
But AstraZeneca and its CEO are facing scrutiny as the drugmaker responds to growing confusion over the vaccine. The company's late-stage data initially increased confidence that the world would soon have multiple shots to combat the pathogen. But scant disclosures and the manufacturing discrepancy have sparked doubts among scientists and investors.
A day after the data was unveiled, the head of the U.S. vaccine program known as Operation Warp Speed said the regimen showing the higher level of effectiveness was tested in a younger population. He also said the half-dose was given to some people because of an error in the quantity of vaccine put into some vials. None of those details were disclosed in AstraZeneca's or Oxford's original statements.
Soriot disputed the idea that the half-dose regimen was an error, saying that after researchers realized the dosing error they formally changed the trial protocol with the blessing of regulators.
"I won't tell you we expected the efficacy to be higher," Soriot said. "People call it a mistake -- it's not a mistake."
AstraZeneca's shares have declined about 7% this week in London trading amid questions about the trial results. Investors seem to be disappointed with the murky results, especially compared with the much clearer data released by two of AstraZeneca's chief rivals in the race for a vaccine.
Sam Fazeli, a Bloomberg Intelligence analyst, said: "we remain most convinced by the Moderna and Pfizer data for now."
AstraZeneca and researchers have declined to provide more data ahead of a peer-reviewed analysis that is expected to be published in coming weeks. Results have been submitted to an undisclosed journal, AstraZeneca said.
DOUBTS RAISED
Almost immediately, there were doubts about the data.
AstraZeneca disclosed in its initial announcement that fewer than 2,800 participants received the smaller dosing regimen, compared with nearly 8,900 participants who received two full doses.
The biggest questions were, why was there such a large variation in the effectiveness of the vaccine at different doses, and why did a smaller dose appear to produce much better results? AstraZeneca and Oxford researchers said they did not know.
Crucial information was also missing. The company said the early analysis was based on 131 symptomatic covid-19 cases that had turned up in study participants. But it did not break down how many cases were found in each group of participants -- those who received the half-strength initial dose, the regular-strength initial dose and the placebo.
"The press release raised more questions than it answered," said John Moore, a professor of microbiology and immunology at Weill Cornell Medical College in New York.
Adding to the confusion, AstraZeneca pooled the results from two differently designed clinical trials in Britain and Brazil, a break from standard practice in reporting the results of drug and vaccine trials.
"I just can't figure out where all the information is coming from and how it's combining together," said Natalie Dean, a biostatistician and an expert in vaccine trial design at the University of Florida. She wrote on Twitter that AstraZeneca and Oxford "get a poor grade for transparency and rigor when it comes to the vaccine trial results they have reported."
And the scant details released by the U.K. partners have sparked worries about whether regulators would clear the vaccine.
The findings had fueled optimism that an end to the pandemic is in sight and that multiple vaccines to combat covid-19 could be ready soon following the positive results from Pfizer and Moderna. AstraZeneca and Oxford remain near the front of the pack, although the way they have handled the large trial could slow them down.
"Any time you have confusion in trials, it's not a good thing, because it effectively removes any kind of credibility you had," said Ketan Patel, a fund manager at EdenTree Investment Management. "I think there will be a lot more scrutiny of Astra's product due to the manufacturing issue."
Oxford said that when it was apparent that a lower dose was used, it was discussed with regulators, and an agreement was reached to push ahead with the two regimens. "The methods for measuring the concentration are now established, and we can ensure that all batches of vaccine are now equivalent," according to the university.
A spokesman for AstraZeneca said the trials were conducted "to the highest standards" and more analysis is being done to refine the efficacy reading.
EFFICACY UNKNOWN
"The most likely explanation for the divergent efficacy in its interim analysis is either chance or patient demographics," Fazeli of Bloomberg wrote in a note. "Either way, approval based on current data means people will be inoculated with a vaccine the true efficacy of which is unknown."
Compared with most of the other leading covid-19 vaccine developers, AstraZeneca is inexperienced when it comes to vaccines. And even before the chaotic release of results, the company was under scrutiny for its handling of the testing process.
In September, AstraZeneca paused clinical trials worldwide after a participant fell ill, but the company didn't promptly announce the decision publicly. AstraZeneca also came under fire for providing details about the nature of the illness on a private conference call with investors hosted by the investment bank J.P. Morgan, rather than disseminating the information to the public. Both of those developments were first reported by STAT, which covers health and science news.
Ever since the AstraZeneca-Oxford team emerged as front-runners in the race to develop a vaccine this spring, Prime Minister Boris Johnson of Britain has embraced the effort. The government preordered 100 million doses and cast the research as one of the country's most important contributions to fighting the pandemic.
Basking in the results Monday, Johnson said the vaccine "has the makings of a wonderful British scientific achievement."
Information for this article was contributed by Suzi Ring and James Paton of Bloomberg News; and by Rebecca Robbins and Benjamin Mueller of The New York Times.