rustykettel

TTT, if it's ok with you, I think it would beneficial for the mods to carve out your experience posts and replies directly dealing with it into their own thread. It would be good for a first hand perspective to get more visibility and not buried in this one.

Thank you again, both for volunteering and sharing your "trip report". This is what makes FT a great community.

TTT

Sure, I'm fine with it being in a new thread if the mods are able to do it.

TTT

About 24 hours after the initial injection and I was pretty much back to normal. I was able to go for a run yesterday afternoon but ended up taking a couple of Tylenol before bed.

I would probably put these in the "moderate" category simply because they interfered with my usual routine. Certainly more of a response than I've had with other vaccines.

I've got a few weeks before my next injection. I'll be curious to see how I feel with that one. After all, yesterday's reactions could have all been in my head.

M60_to_LGA

Looks like AstraZeneca made some mistakes with their vaccine program:

https://www.nytimes.com/2020/11/25/b...ca-oxford.html

I hope this doesn't delay vaccine approval or mean effectiveness is lower than first reported.

TTT

I hope it doesn't slow things down for them either. Unfortunate result of the "science by press release" nature of COVID is that we really don't know enough until the full data is released.

But there are some encouraging things for the AZ trial. No severe cases in either treatment arm and an indication that the vaccine prevents infection in addition to preventing disease; that's a metric that the other manufactures haven't measured.

That said, the rapid nature of the other vaccines in the landscape might make trial recruitment difficult, especially in the older demographics.

radonc1

As always, when reading newspaper reports on science, one needs to be especially vigilant for conjecture and hyperbole.

I will quote a few specific portions of the article and my take on them. (Quotes from the article will be in italics)

Let's start with the title of the article

"After Admitting Mistake, AstraZeneca Faces Difficult Questions About Its Vaccine"
Some trial participants only got a partial dose of AstraZeneca’s vaccine. Experts said the company’s spotty disclosures have eroded confidence.

The purpose of data monitoring committees is to .......monitor the data (shocking, I know). If one believes that running a large phase III trial with 30,000 participants is going to be errorless, then candyland is the country best suited for you. The real question is whether the error puts the results into jeopardy? One can certainly run a sub-analysis of the data with the half-dose group excluded, but in trials, you are not permitted to axe participant even if they are protocol violations. All data has to be analyzed and reported.

"But since unveiling the preliminary results, AstraZeneca has acknowledged a key mistake in the vaccine dosage received by some study participants, adding to questions about whether the vaccine’s apparently spectacular efficacy will hold up under additional testing"

By making a calculation error and delivering 1/2 the intended dose, the results were opposite of what one would have expected. They were better. The insinuation of the above is that this was a bad thing. What was bad was that the error was made but as in all well designed and monitored trials, it was caught, and the results followed.

I don't know about you, but if a trial that is designed for 50% efficacy reported a 70% rate, we would consider it fabulous. 90% is a moon launch. So let's say that 2 full doses only produces 70% efficacy. Is that a failure???? According to Rebecca Robbins and Benjamin Mueller it apparently is

"Officials in the United States have noted that the results were not clear. It was the head of the flagship federal vaccine initiative — not the company — who first disclosed that the vaccine’s most promising results did not reflect data from older people."

I also suspect that the results don't reflect diabetics, children under 18 and other subgroups. Subgroup analysis is not the principal aim of this study, although it will be done (many are going to buff their academic careers with the papers from this study). This study is designed to look at vaccine efficacy in a general population.

"“I think that they have really damaged confidence in their whole development program,” said Geoffrey Porges, an analyst for the investment bank SVB Leerink."

Maybe the whole purpose of this article

"Crucial information was also missing. The company said that 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 above shows me how easy it is to make journalistic mistakes. Trials enroll and monitor all participants including the ones that are found to be protocol violations. A mistake AZ was that they reported a sub-group analysis which showed that initial lower dose injection followed by a higher booster dose produced better (not worse) results. However, for this study the entire cohort of patients, (half dose +booster vs full dose and booster), will be analyzed together and eventually reported in a peer reviewed journal.

Unless giving 2 full doses of vaccine produces a worse outcome than placebo, the most likely outcome is that this vaccine works, and if further study confirms that half dose followed by full dose works even better, then that will be a fortuitous mistake and that will really be outstanding.

"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.”

I believe we do meta analysis all the time in science. It has it's know limitations and advantages. There is nothing unusual about it. But it is always good to do your science on Twitter

I could continue but why bother. The NYT's has their agenda. One has to realize that it is to sell newspapers. Articles like this help them achieve their goal. I don't think that this will make it to the Pulitzer stage, however.

doctoravios

I have to say I share the journalists' concerns. Before reading reports in further detail I was under the impression that the half dose/full dose regimen had been a planned, a priori, part of the trial. It now turns out that it was unplanned due to an error (bad for public trust as this was not communicated in the original press release) with no obvious scientific rationale, and that the population was not the same as the full dose trials - there were no older adults involved. So the 70% average efficacy figure could well be inflated and they have performed an unplanned comparison which is statistically unsound, regardless of the result.

The real fault here partly lies with the regulators. Why on earth did they allow the analysis to proceed in this way? The group receiving the "error" half dose should have been analysed separately and not included in the final result. Very disappointing and I hope it doesn't fuel mistrust in the vaccines more generally - that would be a catastrophe.

radonc1

That is not how one does the statistics for randomized trials. You don't exclude groups because they were not treated according to the protocol design. If they were randomized and met the protocol design for inclusion, then they get analyzed even if their treatment was not per protocol. They still get lumped into the final stats.

You can bet your bottom dollar that the half dose group will be analyzed separately (and reported) and I am certain that a new randomized trial of half dose vs full dose is already at the IRB awaiting approval.

I do agree that AZ should have cooled their jets, but these results are pretty amazing from a scientific standpoint, so I can understand the desire to publish them.

It just shouldn't be done by press release.

doctoravios

You have described exactly what you are not supposed to do in an RCT. You can't pick and choose your results. If their planned analysis was intention to treat then why did the press release lead on a 90% efficacy figure of an underpowered sub group which didn't include elderly participants and was effectively an entirely separate clinical trial? This is very poor practice and I am afraid to say I have now lost faith in AZ's processes with respect to the present trial.

You are absolutely right - they will have to redo the trial if they want to have any hope of getting FDA/MHRA approval using the half dose protocol.

Edit: I just want to add, for clarity, I am not at all questioning or suggesting that the running of the trial itself has been poor practice or that there could have been any safety concern to the participants - there is no question of this. I am referring to the analysis and presentation of results to the public/policy makers.

radonc1

Just to clarify as well
I fully concur with your above statement. Subgroup analysis should not have been presented as an endpoint. Certainly it should not have been presented as as a press release.

The study results should have been released as a positive phase III study that met the protocol design of >50% efficacy. If they had wanted to, the subgroup should have been presented as an interesting anomaly that needed further analysis.

I think that a new phase III study would not need as many participants since the efficacy difference between 2 standard doses (68%) and half standard first dose and standard second dose (>90%) is so large. (I suspect that we will hear about this study opening in the next month or so).


If those results are indeed true, the answer to the study would be available before major vaccinations would be underway, and modification of the treatment only requires cutting the first dose in half. This would truly be a serendipitous finding.

MSPeconomist

The big problem is that the subgroup getting the half dose wasn't a randomized representative sample of the study participants.

GUWonder

AstraZ has sort of shot itself in the foot and will have to (at the very least) expand its trial (in some way or another) to get back its footing for general use approval in at least some parts of the world.

The trial shots are on the outside of the upper arm?

corporate-wage-slave

It's intra-muscular, so in the intermediate zone of the deltoid muscle. In most people this would be middle of the dome shape on the upper arm about 10cm down from the top of the shoulder. Theoretically it could be some other muscle area but that won't normally happen.

Dan1113

So will this likely delay its approval or will they approve it in Europe anyway at this dosage?

It's concerning especially in the UK given how much we have banked on this vaccine compared to the others.

radonc1

So untrue
The trial itself with the subgroup included in the analysis was positive (62% vs a required 50%), therefore the vaccine works.

The subgroup is the fascinating issue, since giving half the dose up front produced a dramatic improvement in the response (up to 90%). One would expect that underdosing with a medication would yield poorer, not better results.

Suffice it to say that AZ has an effective vaccine that is actually easier for poorer countries to administer since it does not require super freezers for storage (refrigerators will do), making it easier to distribute and store in parts of the world where ancillary storage equipment is not available.