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This week’s announcement that a low-cost, easy-to-produce coronavirus vaccine appeared to be up to 90% effective was greeted with great joy. “Have a vacation,” celebrated a British tabloid, noting that the vaccine in question, developed by AstraZeneca and the University of Oxford, costs less than a cappuccino.
But since announcing the preliminary results, AstraZeneca has admitted that a crucial mistake was made in the dose of vaccine received by some participants in its studies. This raises questions about whether the seemingly spectacular efficacy of the vaccine will be confirmed after further trials.
Scientists and industry experts said the error and a host of other irregularities and omissions in the way AstraZeneca published the data initially weakened their confidence in the reliability of the results.
US officials stressed that the results are unclear. It was the director of the large federal coronavirus vaccine initiative, not the company, that first revealed that the most promising vaccine results did not reflect data for older people.
The consequence, experts said, is that the chances are diminishing that regulators in the United States and other countries will rapidly authorize the emergency use of the AstraZeneca vaccine, an unexpected setback in the global campaign to contain the devastating pandemic.
“I think they [a AstraZeneca] they have really damaged confidence in their entire development program, ”said Geoffrey Porges, analyst at investment bank SVB Leerink.
Michele Meixell, a spokesperson for AstraZeneca, said the tests “were conducted to the highest standards.”
In an interview on Wednesday (25), Menelas Pangalos, the AstraZeneca executive in charge of much of the company’s research and development, defended the way the company handled the lawsuits and its public announcements. He said the dosage error was made by a contracted company and that, once detected, regulators were immediately notified and authorized the plan to continue testing the vaccine at different doses.
When asked why AstraZeneca shared information with Wall Street analysts and some other experts and authorities, but not with the public, Pangalos responded: “I think the best way to reflect the results is in a peer-reviewed scientific journal, not in a newspaper”.
AstraZeneca was the third company this month to announce encouraging initial results for a coronavirus vaccine candidate. At first glance, on Monday morning (23), the results looked promising. Depending on the intensity at which the doses were administered, the vaccine appeared to be 90% or 62% effective. The average effectiveness, the creators said, was 70%.
But the data was questioned almost immediately.
The program that appeared to be 90% effective involved participants receiving a half dose of the vaccine, followed by a full dose a month later. The least effective program involved two full doses. In its initial announcement, AstraZeneca revealed that fewer than 2,800 participants followed the program with a lower starting dose, while nearly 8,900 participants received two full doses.
The most important questions were: why was there such a wide variation in the effectiveness of the vaccine at different doses, and why did a smaller dose seem to have produced much better results? Researchers from AstraZeneca and the University of Oxford said they did not know.
Other crucial information was missing. The company said that the first analysis was based on 131 symptomatic cases of Covid-19 that emerged in study participants. But it did not say how many cases were found in each group of participants: those who received the 50% lower starting dose, those who received the normal starting dose, and those who received a placebo.
“The press release raised more questions than answers,” said John Moore, professor of microbiology and immunology at Weill Cornell Medical College.
To add to the confusion, AstraZeneca combined the results of two differently designed clinical trials conducted in the UK and Brazil. It was a break from the usual practice of reporting the results of drug and vaccine trials.
“I can’t understand where all the information is coming from and how it comes together,” said Natalie Dean of the University of Florida, an expert in biostatistics and vaccine trial creation. He wrote on Twitter that AstraZeneca and Oxford University “receive low marks for transparency and rigor in relation to the results of the vaccine trials they have announced.”
With AstraZeneca shares losing value on Monday, company executives held several private conference calls with analysts from the pharmaceutical industry in which they revealed details that did not appear in the public announcement, including the involvement of Covid-19 cases in the different groups. Disclosure of information to analysts, as in this case, is not uncommon in the industry, but it often raises questions about why the information was not shared with the public.
The main concerns did not take long to emerge.
Pangalos told Reuters on Monday that the company did not intend for any participant to receive half a dose. The British researchers who ran the trial in the UK initially intended to give the volunteers the full dose, but due to a miscalculation, the participants received only half the dose. Pangalos described the mistake as “a happy fluke” that allowed the researchers to find a more promising dosing schedule.
For many outside experts, this has weakened the credibility of the results, because carefully calibrated clinical trials have not been designed to test the efficacy of a 50% lower starting dose.
The company’s initial announcement did not mention that the discovery was accidental.
“The truth is that the error can end up being useful,” Pangalos said Wednesday in an interview with the New York Times. “He did not put anyone at risk. It was a dosing error. Everything was happening very fast. We corrected the error and continued with the study, without changing anything, and agreed with the regulator to include patients who took the initial half dose in the study analysis.
“What is there to reveal? It doesn’t really matter whether it was done intentionally or not. “
In the statement attributed to the University of Oxford, Meixell, a spokesman for AstraZeneca, said the error was due to a problem – which has since been corrected – in the way some of the vaccine doses are manufactured.
On Tuesday, however, Moncef Slaoui, director of Operation Warp Speed, the US initiative to accelerate the creation of coronavirus vaccines, drew attention to another limitation in the AstraZeneca data. In a call with reporters, he suggested that the participants who received the lowest starting dose were at most 55 years old.
Pangalos confirmed the information Wednesday, saying that the participants received the lowest dose for weeks before the error was discovered.
The fact that the lower starting dose has not been tested with older participants, who are especially vulnerable to the virus, may weaken the arguments made by AstraZeneca to regulators that the vaccine should be licensed for emergency use.
Stephanie Caccomo, a spokeswoman for the Food and Drug Administration, declined to comment on whether the dosing error would hurt the chances of the vaccine being licensed. The FDA said it expects the vaccines to be at least 50% effective in preventing the disease or reducing its severity. The AstraZeneca vaccine appears to have crossed that threshold, even among the group of volunteers who received both full doses.
Pfizer and Moderna said this month that their vaccines, which employ a technology known as “messenger RNA,” appear to be 95% effective. It seems almost certain that the two will receive emergency clearance from the FDA in the coming weeks.
The AstraZeneca vaccine, which uses a different approach involving a chimpanzee virus to elicit an immune response to the coronavirus, had everything to be sure of being a success.
It was inexpensive, only a few dollars a dose, and easy to mass-produce. Unlike the Pfizer and Moderna vaccines, AstraZeneca can be stored for months in normal refrigerators. The company estimated that it will be able to produce 3 billion doses in 2021, enough to vaccinate almost a fifth of the world’s population.
In the United States, which has already ordered at least 300 million doses of the AstraZeneca vaccine, the vaccine’s future regulatory pathway is unclear. AstraZeneca said little Monday about its plans to seek approval from regulators. The company said it would seek guidance from the FDA on whether it should formally submit the results of its trials for emergency clearance.
AstraZeneca has not been testing the promising half starting dose in its current trial in the United States. The company said it will work with the FDA to add half the starting dose to this trial as soon as possible.
Pangalos said the company plans to conduct a global test to compare the two dosing schedules. The number of participants to be called has not yet been determined, but it will be thousands.
“The only way they’re going to find out is with trials that specifically test this lucky and chance observation,” Moore said. “It is up to AstraZeneca to prove what is speculated.”
