Updated: November 27, 2020 7:10:08 am
Half dose followed by a full dose was not the intended regimen. (University of Oxford via AP)
An error in the AstraZeneca-University of Oxford vaccine trials, AZD1222, has questioned the way vaccine clinical trials have been handled during the pandemic. That is why it is important and what needs to be done now.
What was the mistake?
On Monday, Oxford and AstraZeneca said AZD1222 could be as effective as 90%, when given as a half dose followed by a full dose a month later. What they did not initially reveal was that these findings were the result of a mistake. The nearly 3,000 participants in the UK on whom this result was based were never supposed to receive a lower dose in the first place.
The revelation has raised doubts about the way AstraZeneca and Oxford have been conducting these trials, with some scientists pointing to a lack of transparency throughout the process.
“With the exception of the trial conducted in the US, I don’t know details about how these trials are being monitored. Is there a centralized DSMB (Data Security and Monitoring Board)? Are they combining the accumulated data? They seem to have combined events in Brazil and the UK. Why not the other countries? “Natalie E Dean, biostatistician at the University of Florida, tweeted Wednesday.
“And it is undesirable to report a secondary analysis that was not pre-specified (as it appears to be based on a dosing error). If they are looking to get the half dose approved, they must wait until they get a convincing result. Otherwise, we may fall into ‘evidence limbo,’ ”he tweeted.
The development makes it uncertain whether regulators like the US Food and Drug Administration would authorize emergency use, in the confidence that the development program has been “corrupted,” according to a report in The New York Times.
“We have to see how much of this data (from the low-dose group) is potentially usable for regulatory submissions in the strictest sense, because as I understand it, you cannot use data that is not specified in the protocol. Regulators have likely been notified, but this is not exactly a ‘per protocol’ or ‘intention to treat’ analysis, which is the way clinical trial analyzes are usually done, ”said the vaccine scientist, Professor Gagandeep Kang. The Indian Express Thursday.
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Why did the error occur?
Oxford says that due to a “difference in the manufacturing process” of the vaccine batches used for the Phase 3 trials in the UK initially, the doses given to 2741 UK participants were overestimated, resulting in the administration of half dose as the first dose. .
“We have different ways of measuring the concentration of the vaccine and when it became apparent that a lower dose was used, we discussed it with the regulator and agreed on a plan to test both the lower dose / higher dose and the higher dose / dose. higher, allowing us to include both approaches in the phase III trial, ”the university said. “The methods for measuring concentration are already established and we can ensure that all vaccine lots are now equivalent.”
“There are two reasons these errors could have crept in,” said Dr. Amar Jesani, independent consultant, researcher and professor in bioethics and public health, co-founder of the Forum for the Society for Medical Ethics and editor of the Indian Journal of Medical. Ethics.
“One is the rush with which vaccine trials are being conducted during the pandemic… they are trying to compress various stages of vaccine development. The second is that companies are competing with each other to capture the market as soon as possible, ”he said.
Trial results in India no
The efficacy results for AstraZeneca were based on ongoing trials in the UK and Brazil. It does not include trials of the same vaccine that the Serum Institute in India is conducting. The results of the Indian trials are expected to be published in December.
What checks and balances exist for such errors?
In this case, the bug led to a potentially positive finding that AstraZeneca intends to study further in the US arm of the trials, but could have ended badly if the dosing was the other way around.
“In this case, the direction the mistake went was not a tragedy. Overdose has the potential to cause harm. Underdosing is rarely like this, ”said Dr. Kang.
“In clinical trials, everything is precisely protocolized and has to be consistent across all trial participants. You don’t normally see this level of error, ”said Dr. Jesani.
But deviations from the protocol are still common in clinical trials, Dr. Kang said.
“Incorrect sample labeling, data quality issues, your freezer breakdown – all of this is bound to happen. Although errors or deviations may or may not make a difference, it is convenient to stop the study, investigate what is happening and then continue, “he said.
“Mistakes happen. The point is that the study protocol is a guidance document that sets out what to do and how, and follow-up is an approach to avoid as many errors as possible. In any type of clinical trial, despite best efforts, you are likely to have protocol deviations. You have to record that, ”he added.
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Should these participants have withdrawn from the trial?
Since the mistake was to give a lower first dose of the vaccine, it could be considered unethical to remove these participants from the ongoing trial, according to Dr. Kang. “He has recruited these people by telling them that their volunteering, in a spirit of altruism, will benefit the general public. Can you then afford to say, ‘I’m sorry, but all your effort is wasted because we made a mistake, so now we’re going to stop?’ “, Said. “Actually, the correct dose is not known (for this vaccine yet) and this could become an opportunity to understand more about the vaccine,” he said.
However, he said: “I wish there was a lot more transparency; It may be too much to ask of Big Pharma, but in this emergency situation, with misinformation and containment everywhere, to be absolutely open when publishing protocols and articles and sharing information. in detail, it would be much more useful. ” 📣 Express Explained is now on Telegram
Does this raise questions for Covishield of India, which is based on AZD1222?
You shouldn’t completely question the vaccine’s ability, according to some experts.
“The fact that the arms in the UK and Brazil are more than 60% effective means this vaccine is working … and we were targeting 50% in the guidance from the WHO, FDA and DCGI,” he said Dr. Kang.
“But we will have to wait until the regulators review the data and are convinced that this vaccine is worth having, because it is important to understand that regulators will get much more detail than scientists can read in a scientific journal,” he said.
What is required now is that the Serum Institute of India (SII), which is testing Covishield in India, “quickly” present a protocol for further studies that can test this vaccine using half a dose to start with.
“The serum needs to request all the AstraZeneca study data to share with the DCGI and run very fast immunogenicity studies in Covishield to decide the right dose that it can go ahead with – a low dose would mean we could have double the dose.” Said Dr. Kang.
At the same time, this incident should also be a wake-up call for more transparency in the way even Indian companies conduct lawsuits.
“We don’t even know what dose the Serum Institute is testing Covishield here… I can read the full AstraZeneca clinical trial protocol and make an error judgment. Can you do that for the Serum Institute of India protocol? “said Dr. Jesani.
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