For a man presenting landmark results from trials of a vaccine that it is hoped will save the world from a devastating pandemic, Sir Menelas Pangalos did not look cheerful on Wednesday.
Pangalos, executive vice-president of biopharmaceuticals R&D at AstraZeneca, and his colleagues are undoubtedly exhausted, having been working round the clock on the coronavirus vaccine with Oxford University since April. But they are now dealing with a sizeable new headache – the doubts of the US regulator.
It is clear that in spite of the critical need for coronavirus vaccines, the Food and Drug Administration is not going to rush to approve the vaccine developed by Oxford University and AstraZeneca, even though the US, through its “Operation Warp Speed”, has put in substantial funding and ordered 300m doses.
Unlike Pfizer/BioNTech and Moderna’s mRNA products, the AstraZeneca vaccine is cheap, can be stored at ordinary fridge temperatures, is easy to manufacture and presents the best hope at the moment for a vaccine for the billions rather than the few.
But while the UK, the rest of Europe, and Canada and India could approve it in the coming weeks, the US, which currently has the world’s biggest epidemic, will have to wait.
The Oxford/AstraZeneca vaccine has been the subject of withering criticism in the US media. It has suffered by comparison with Pfizer and Moderna, whose vaccines, manufactured with a different and novel technology, have effectively scored straight As. Their vaccines have shown 95% efficacy in very large and straightforward trials involving respectively more than 40,000 and 30,000 people.
Criticism of the AstraZeneca vaccine focuses on three main issues. AstraZeneca’s efficacy data relates to fewer people than the other vaccines; so far 11,636 in the UK and Brazil trials, although there are more to come, including a 30,000-strong trial in the US partly funded by Operation Warp Speed.
A woman in the UK given the AstraZeneca jab developed transverse myelitis, a neurological disorder causing inflammation of the spinal cord, leading to the trials being paused worldwide in September. And the efficacy results were 62% overall, but 90% covering a sub-group of fewer than 3,000 people who were inadvertently given a lower starting dose.
Researchers said that pooling the results, which they had agreed to do with regulators before they knew the outcome, gave them 70% efficacy overall.
But it looked messy. One investment analyst opined at that point: “We believe that this product will never be licensed in the US.”
On Wednesday the researchers did what no other vaccine developers had yet done: they published the full data on their trials in the Lancet medical journal. This was not, said Pangalos at a briefing, for the sake of the FDA, EMA or MHRA.
He said: “It’s not to influence the regulator in any way, shape, or form. The regulator will make their own decision based on all of the data we provide them. I think there’s obviously a lot of comments in the media and in the press around the need for transparency and sharing data.
“And of course, the best way of doing that, from a scientific perspective, is publishing your data in high-quality, peer-reviewed journals, which is exactly what we’ve done now, so that all the data is available for public review and scrutiny, not just by the media, but also by the scientific community, which I think is is very important.
“The results for me are very compelling. They clearly show that we have an effective vaccine that meets the regulatory standard for approval around the world. We have no severe infections and no hospitalisations on people that are treated with a vaccine, which is tremendously important. And we can show now that the vaccine is safe and well tolerated.”
Prof Sarah Gilbert of Oxford University, who led the research, said her team had talked to the regulators about what they planned to do at every stage. “So as the trial developed, the regulators were aware of what was happening in the trial and approved every change at every point.”
The US trial was being run by AstraZeneca, not Oxford. The latest allegation to surface, in the New York Times, was that the FDA was not told, during a meeting involving officials and others on 8 September, about the pausing of the UK trial two days earlier after a participant became ill. STAT News broke the story, with a quote from the company confirming the pause.
The FDA appeared more concerned than other regulators about the event. Within four days, the trial resumed in the UK, but it took the FDA until 23 October to give authorisation. That meant the trial is running seven weeks late. It has now recruited only 18,000 participants, a little over half the intended number.
US experts have pointed out that the elderly, who are most at risk from Covid-19, and people of all ethnicities, are not well represented in the data so far. The subgroup in the UK that produced the 90% efficacy result was aged under 55.
There is another question mark over the dosing regime in the UK, which only came to light with the Lancet publication. Some of the volunteers waited longer than four weeks for a second dose of vaccine; the vaccine originally was going to be just one shot. That forms another complication in the data analysis.
Penny Ward, visiting professor in pharmaceutical medicine at King’s College London, said: “These features are going to lead to a need to carefully scrutinise the information and break down the data into like-for-like groups to enable an appropriate assessment of dose response effects.
“This seems likely to need more time to complete than a review of the tightly controlled, very consistent information from clinical trials conducted with the BNT162b2 vaccine [Pfizer/BioNTech].”
It may be because Pfizer is more experienced. Unlike AstraZeneca, it has an “existing, large vaccine business and considerable experience in the clinical development of vaccines”, Ward said.
AstraZeneca is still deciding whether to do another study on dosage, having concluded it was not a good idea to alter the US trial. That was probably a wise decision, given the doubt in the US over the vaccine for now. Not just the company, but those trying to fight the pandemic in the US will be glad of a bit of calm.
The other big fight ahead is to persuade people to receive any vaccine once the regulators have decided that they are safe.
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