Explained: Here are the main takeaways from the Oxford Covid-19 vaccine mistake

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Écrit par Prabha Raghavan | New Delhi |

Updated: Dec 3, 2020 2:15:39 PM

A half dose followed by a full dose was not the intended treatment regimen. (Oxford University via AP)An error in the AstraZeneca-University of Oxford vaccine trials, AZD1222, questioned how clinical trials of vaccines during the pandemic were handled. This is why this is important and what needs to be done now.

What was the mistake?

On Monday, Oxford and AstraZeneca said AZD1222 could be up to 90% effective – when given in half a dose followed by a full dose a month later. What they did not initially disclose was that these conclusions were the result of a mistake. The roughly 3,000 participants in the UK on which this result was based were never supposed to receive a lower dose in the first place.

The revelation added to doubts about how AstraZeneca and Oxford conducted these trials, with some scientists pointing to the lack of transparency throughout the process.
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“With the exception of the US-based trial, I’m not aware of the details of how these trials are monitored. Is there a centralized DSMB (Data Safety and Monitoring Board)? Do they combine the accumulated data? They appear to have combined events across Brazil and the UK. Why not the other countries? Natalie E Dean, a biostatistician at the University of Florida, tweeted Wednesday.

“And reporting a secondary analysis that has not been pre-specified (since it appears to be based on an assay error) is undesirable. If they are seeking approval for the half dose, they must wait until they have a convincing result. Otherwise, we can land in ‘evidence limbo’, ”she tweeted.

Explain

The results of the trial in India

AstraZeneca’s efficacy results were based on trials conducted in the UK and Brazil. It does not include trials of the same vaccine conducted by the Serum Institute in India. The results of the Indian trials are due out in December.

This development makes it uncertain whether regulators such as the United States Food and Drug Administration would allow emergency use, with confidence that the development program has been “damaged,” according to a report released by Le 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 strict sense, because my understanding is that you cannot use data that is not specified in the protocol. They likely informed regulators about this, but it’s not exactly a “by protocol” or “intent to treat” analysis, which is how clinical trial reviews are. generally done, ”said vaccine specialist Professor Gagandeep Kang. L’Indian Express Thursday.

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Why did the error occur?

Oxford says that due to a “difference in the manufacturing process” for the vaccine lots initially used for Phase 3 trials in the UK, the doses given to 2,741 UK participants were overestimated, resulting in administration of a half dose as the first dose. .

“We have different ways of measuring the concentration of the vaccine and when it was evident that a lower dose was being used, we discussed this with the regulator and agreed on a plan to test both the lower dose. / the highest dose and the highest dose / the highest dose. , allowing us to include both approaches in the Phase III trial, ”the university said. “The methods for measuring the concentration are now established and we can ensure that all batches of vaccine are now equivalent.”

“There are two reasons why these errors might have crept in,” said Dr Amar Jesani, independent consultant, researcher and teacher in bioethics and public health, co-founder of the Forum for Medical Ethics Society and editor of the Indian Journal of Medical Ethics.

“One is the haste with which vaccine trials are conducted during the pandemic… they are trying to compress the various stages of vaccine development. The second is for companies to compete as soon as possible to conquer the market, ”he said.
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What checks and balances are in place for such mistakes?

In this case, the error led to a potentially positive conclusion that AstraZeneca intends to study further in the US arm of the trials, but it could have ended badly if the dosage was the reverse.

“In this case, the direction in which the error went was not a tragedy. Overdose can cause damage. Underdosing usually doesn’t do it, ”Dr. Kang said.

“In clinical trials, everything is precisely protocolized and must be uniform for all trial participants. Normally you don’t see this level of error happening, ”said Dr Jesani.

But protocol deviations are still common in clinical trials, Dr. Kang said.
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“Poor sample labeling, data quality issues, your freezer failure – all of this is inevitable. Even though errors or deviations may or may not make a difference, you would want to stop the study, investigate what is going on, and continue, ”she said.

“Mistakes happen. The point is, the study protocol is a guidance document that indicates what to do and how and follow-up is one approach to avoid as many mistakes as possible. In any type of clinical trial, no matter how hard you try, you are likely to have protocol deviations. You have to record this, ”she added.

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Should these participants have been removed from the trial?

Since the error was that of administering a lower first dose of the vaccine, it might be considered unethical to remove these participants from the current trial, according to Dr. Kang. “You recruited these people telling them that your volunteering, in a spirit of altruism, will benefit the general public. Can you afford to say then, “Sorry, but all your efforts are wasted because we made a mistake, so now we’re going to stop?” She said. “You actually don’t know what the right dose is (for this vaccine at the moment), and it could be turned into an opportunity to learn more about the vaccine,” she said.

Still, she said: “I wish there was a lot more transparency – maybe that’s asking too much of Big Pharma, but, in this emergency, with misinformation and conflict everywhere, being absolutely open in posting protocols and articles and sharing information in detail would be much more helpful. 📣 Express Explained is now on Telegram
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Does this raise any questions for Covishield in India which is based on AZD1222?

That shouldn’t completely call into question the vaccine’s ability, some experts say.

“The fact that the guns in the UK and Brazil are over 60% effective means this vaccine is working… and we were aiming for 50% as per WHO, FDA and DCGI guidelines,” said the Dr Kang.

“But we’ll have to wait until regulators look at the data and are convinced that this is a vaccine worth keeping, as it’s important to understand that regulators will receive far more details than scientists.” can’t read in a scientific journal, ”she said.

What is needed now is for the Serum Institute of India (SII), which is testing Covishield in India, to submit a protocol “quickly” for further studies to test this vaccine using initially a half dose.

“The serum would have to request that all data from the AstraZeneca study be shared with the DCGI and do very rapid immunogenicity studies on Covishield to decide on the appropriate dose it can continue with – a low dose would mean we might have double the doses. Said Dr Kang.

At the same time, this incident should also be a wake-up call for more transparency in how even Indian companies are conducting the trials.

“We don’t even know at what dose Serum Institute is testing Covishield here… I can read the full AstraZeneca clinical trial protocol and pass judgment on an error. Can you do this for the protocol of the Serum Institute of India? Says Dr Jesani.

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