Covid Vaccine Phase 3 significance

In summary: If I were offered a COVID-19 vaccine that had passed phase 2 trials, I'd accept it. Is that foolhardy of me?If it's only a 80% chance of catching an adverse event, is it worth it to skip phase III trials?
  • #1
Grinkle
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TL;DR Summary
How much risk is one taking if one is a phase 3 participant?
Russia's vaccine news has me pondering.

How often after a successful phase 2 study do phase 3 studies show that the vaccine causes harm?

If I were offered a COVID-19 vaccine that had passed phase 2 trials, I'd accept it. Is that foolhardy of me?

Is it possible to use existing data to model the expected deaths of waiting for phase 3 completion vs skipping phase 3? I am thinking there is risk of ineffectiveness and over-confidence causing more infection, risk of overt harm from the vaccine on the one hand. On the other hand there are the deaths that will occur that wouldn't if the vaccine is effective and introduced early.
 
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  • #2
Grinkle said:
Summary:: How much risk is one taking if one is a phase 3 participant?

Russia's vaccine news has me pondering.

How often after a successful phase 2 study do phase 3 studies show that the vaccine causes harm?

If I were offered a COVID-19 vaccine that had passed phase 2 trials, I'd accept it. Is that foolhardy of me?

Is it possible to use existing data to model the expected deaths of waiting for phase 3 completion vs skipping phase 3? I am thinking there is risk of ineffectiveness and over-confidence causing more infection, risk of overt harm from the vaccine on the one hand. On the other hand there are the deaths that will occur that wouldn't if the vaccine is effective and introduced early.

Overall (for all pharmaceutical drug development), around 50% of drugs that enter phase III trials eventually go on to be approved by the FDA. Reasons for failing to reach approval, however, are not just safety related, and the failure could reflect a lack of efficacy or a level of efficacy below existing standards of care. This figure covers drugs for all conditions, which may not reflect the risks for vaccine development.

For a back of the envelope calculation on safety risks for skipping phase III trials, assume a phase II trial with 100 individuals receiving the vaccine (this seems to be the numbers for Moderna's phase II trials). Even if you observe no serious adverse events in the 100 individuals who were doesed, there is a >80% chance that you would miss any serious adverse events that occur in <0.2% of people. Now, for individual risk this seems small, a two in a thousand chance of a serious event. However, at a population level, this is quite significant. If you dose all 300 million people in the US with a vaccine that causes serious adverse events at a rate of 0.2%, you have just caused 600 thousand adverse events (~4x the number of current Coronavirus deaths in the US). Even if the vaccine is effective (not a guarantee if you have skipped phase III trials), you may have caused a larger problem than you have solved.

Note that the 1976 Swine Flu vaccine is widely seen to be a huge failure because it caused Guillain-Barré syndrome (a serious neurological condition) at a rate of about 1 per 100,000 vaccinated.
 
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  • #3
Ygggdrasil said:
Even if you observe no serious adverse events in the 100 individuals who were doesed, there is a >80% chance that you would miss any serious adverse events that occur in <0.2% of people.

Where does that come from? If I ask what Poisson mean I need so I get zero 20% of the time, it's 1.61. That is, given an observation of zero, I am 80% confident that the true mean is less than 1.61%. Are we calculating the same thing?

That means the 600K adverse effects becomes almost 5M.
 
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  • #4
Vanadium 50 said:
Where does that come from? If I ask what Poisson mean I need so I get zero 20% of the time, it's 1.61. That is, given an observation of zero, I am 80% confident that the true mean is less than 1.61%. Are we calculating the same thing?

That means the 600K adverse effects becomes almost 5M.

Given an adverse event probability p with N individuals, the probability of observing no adverse events is ##(1-p)^N##, so for my calculation, I found the value of p for N=100 where you would have an 80% chance of observing no adverse events. This may not be the best way of calculating the statistical power of the trial (it was only meant to give a back of the envelope estimate), so it may be better to defer to someone like @StatGuy2000 with training in biostatistics.

However, I agree with your calculations that dosing 100 individuals would give a >80% chance of catching at least one instance of any adverse reaction that occurs with a probability of >1.6%, and that's probably a better bound to consider here.
 
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  • #5
Is the difference due to binomial and Poisson models?
 
  • #6
Grinkle said:
Summary:: How much risk is one taking if one is a phase 3 participant?

Is that foolhardy of me?
I read the forum rules and believe answering this question directly violates the rules. I think that should give you the answer.
 
  • #7
atyy said:
Is the difference due to binomial and Poisson models?
The difference is that we're calculating two different things. He's calculating the rate of adverse events that a 100 person trial that would be found with 80% confidence. I calculated the rate of adverse events that a 100 person trial that would be missed with 80% confidence.
 
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  • #8
Grinkle said:
If I were offered a COVID-19 vaccine that had passed phase 2 trials, I'd accept it. Is that foolhardy of me?

Regardless of any other considerations there is simple basic concern for your fellow human beings, what we call mateship here in Australia. I would put my hand up in an instant. Here in Aus they had thousands of volunteers for the 120 needed in stage 1 trials of the UQ vaccine, and thousands have already put up their hands for the 1000 they want in stage 2 trials. Some people still hold to the old values my parents had, and instilled in me, of mateship that led even an ex-prime minister to put his life at risk as a firefighter during our recent bushfires. That of course is not a recommendation, merely a comment on the sociological culture that may also come into play.

Thanks
Bill
 
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  • #9
Grinkle said:
Russia's vaccine news has me pondering.

From BBC News:

https://www.bbc.com/news/world-europe-53751017

Russia has dismissed mounting international concern over the safety of its locally developed Covid-19 vaccine as "absolutely groundless".

On Tuesday, it said a vaccine had been given regulatory approval after less than two months of testing on humans.

But experts were quick to raise concerns about the speed of Russia's work, and a growing list of countries have expressed scepticism.

Scientists in Germany, France, Spain and the US have all urged caution.

and
And in the US, the country's top virus expert, Dr Anthony Fauci, said he doubted Russia's claims.

"I hope that the Russians have actually definitively proven that the vaccine is safe and effective," he told National Geographic. "I seriously doubt that they've done that.
 
  • #10
Mr Green T said:
I read the forum rules and believe answering this question directly violates the rules. I think that should give you the answer.

With my mentors hat on I think the question is fine. We just do not discuss philosophy here, but elucidating queries with a probabilistic analysis so you can make up you own mind is fine. We just can't make a recommendation - simply give the facts. We can also, as I did, point to sociological factors that may come into it because of the culture of where you live.

Thanks
Bill
 
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  • #11
atyy said:
Is the difference due to binomial and Poisson models?

I personally just used the Binomial model in my analysis and didn't even think a Poisson model could be used. Here is an interesting paper I found on the issue:
https://www.tandfonline.com/doi/pdf/10.1080/21645515.2018.1433972

That takes me back a while to when I took statistical modelling at uni.

Thanks
Bill
 
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  • #12
bhobba said:
I personally just used the Binomial model in my analysis and didn't even think a Poisson model could be used. Here is an interesting paper I found on the issue:
https://www.tandfonline.com/doi/pdf/10.1080/21645515.2018.1433972

Interesting paper, but for the difference between the estimates by @Ygggdrasil and @Vanadium 50 it is as Ygggdrasil said, that they were calculating different things, and just for estimation, it is good enough to use the Poisson approximation to the binomial.

Using Ygggdrasil's formula ##\text{Pr(no adverse events)} = (1-p)^{N}##

if ##p=2/1000##, we get ##\text{Pr(no adverse events)} = 0.82## (same as Ygggdrasil's calculation)

if ##p=16/1000##, we get ##\text{Pr(no adverse events)} = 0.20## (same as Vanadium 50's calculation)
 
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  • #13
Ygggdrasil said:
Given an adverse event probability p with N individuals, the probability of observing no adverse events is ##(1-p)^N##, so for my calculation, I found the value of p for N=100 where you would have an 80% chance of observing no adverse events. This may not be the best way of calculating the statistical power of the trial (it was only meant to give a back of the envelope estimate), so it may be better to defer to someone like @StatGuy2000 with training in biostatistics.

However, I agree with your calculations that dosing 100 individuals would give a >80% chance of catching at least one instance of any adverse reaction that occurs with a probability of >1.6%, and that's probably a better bound to consider here.

Since my name has been mentioned, I should note that in general, the statistical power of the trial is almost always calculated based on the test of the null hypothesis based on efficacy. So in the context of a trial for a brand-new vaccine, one would, for example, look at the geometric mean titres of antibody levels in comparison to a placebo, and determine whether, say, the antibody levels persist after a given period of time by a certain percentage. The null hypothesis could be, say, that the mean titres may be no different than the placebo (I'm generalizing here, as I'm not currently involved in COVID-19 vaccine trials, and my past vaccine experience had involved a different design).

The probability of rejecting the null hypothesis would be the power, so one would calculate the null hypothesis by setting the power for efficacy to be, say, 90% (which we could calculate through simulations).

The main reason we don't compute statistical power through safety is that it is difficult to model what potential safety issues may arise and by what proportion or severity. And in all clinical trials, the default is to report all adverse events (whether serious or not, or whether it may be linked to treatment or not).
 
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  • #14
I feel as if I'm going to commit an act of heresy with this one when I say that the maths doesn't really help in answering the question. We go into vaccine trials with a great deal of information about what is the likely response, there are really only small parts that can be considered new and even then not totally new. We also have some limited information from animal trials and from the phase 1 & 2 human trials. We can't really compare drug trials as vaccines tend to be held to a higher standard, they have a different function. Phase 3 trials are still conducted in many thousands of humans before vaccines are made more widely available but Grinkle's concern is a valid one. There may be some risk to early release, but this is most likely a risk to public confidence, this has to be put against the risk of the uncontrolled pandemic.

Russia has decided that they will vaccinate medics and teachers early, they say this will be voluntary and then make the vaccine more widely available. If these people are carefully monitored they would be using this group as the subjects of the phase 3 trials. If the vaccine proved to be ineffective it would be withdrawn, if serious side effects occurred, these should be very quickly identified, but the same thing would happen during the normal phase 3 trials. China has apparently taken a similar decision using the army as subjects and the issue of vaccine challenge trials is also still on the agenda in the west.

The fact is that even with the results of the phase 3 trials, the vaccines will still be introduced to particular groups first and we will still be waiting to find out which of the vaccines are most effective.
I think what we are seeing are decisions being made based on a risk / benefit analysis, perhaps contaminated with some competitive national pride. Maybe the issue of reassuring the public and countering the antivax propaganda is so important in the west that the cost of the delay is worth it, I don't know, but there appears to be 100's of 1000's of people worldwide, who have volunteered to take that risk.
 
  • #15
have a queston...

if you get the two dose vaccince for covid... no one knows how long the vaccine lasts... How many times will you need to be vaccinated after the first round?

I believe this virus will mutate/become smarter as we see different strains. what if the virus mutates to make the vaccine obselete?? lol... what if you get the first two doses of the vaccine, virus mutates, then find out if you had first round vaccine you cannot get any updated vaccines in the future?

If they have found in France mutated strain that is pretty much undetected, and possible more variations of this virus come out in the future will the current vaccines be of any help?

it seems like, with current vaccine the hope is that everyone receives vaccine so the tide turns and Covid no longer a threat. seems like a gamble as we see new or mutated strains lol... seems like only plan A is there which is get vaccinated fast to stop the virus but chances are this will mutate become immune to the vaccine lol then what? No plan B very scary!
 
  • #16
OK - first have a look at the real world data from the UK about effectivines up until now:

Note - the Dr doing it is interestingly not a MD but has a PhD in Medicine - which you can do in the UK without becoming a MD eg
https://www.manchester.ac.uk/study/...l-medicine/entry-requirements/#course-profile.

He had no need to be a MD because he only taught medicine at nursing schools. I suspect his primary degree was in nursing because he had practiced as a nurse according to his history.

How long it will last nobody knows at this stage. The above data is for the UK variant, which is the main variant circulating in the UK, and likely to soon be the main variant circulating in the US. Australia may be able to keep it out if our quarantine measures work - we will see - but what is happening in PNG is very worrying. But I do not think it really matters how long protection lasts because the way this virus is mutating we will need vaccinations against the mutations as they emerge. Oxford and other vaccine developers are working on them right now, and expect to have them out quicker than the less than a year it took for the original vaccine because it is more a 'tweak' than a new vaccine:
https://www.bbc.com/news/health-56274293

Some people think we will not have Covid fully under control until something like 2025 - but nobody really knows. Some even think we may need yearly vaccines like the Flu vaccine - they may even be combined so you get vaccinated against the flu and main Covid variants circulating that year.

Thanks
Bill
 
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  • #17
tonyd11 said:
what if the virus mutates to make the vaccine obselete?? lol... what if you get the first two doses of the vaccine, virus mutates, then find out if you had first round vaccine you cannot get any updated vaccines in the future?
That makes no sense. I get a flu shot every year and every year it is a different vaccine.
 
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  • #18
phinds said:
I get a flu shot every year and every year it is a different vaccine.
This is quite possibly where COVID-19 is going.

But for now we attack the problem immediately in front of us, vaxinating against the strains active now. After the current pandemic ends and the dust settles (perhaps in 4-6 months) we'll see what strains are still active, how effective the vaccines are against them and how long, then figure out what to do. Perhaps everyone in the west will be getting a booster shot in Oct-Dec.
 
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  • #19
russ_watters said:
This is quite possibly where COVID-19 is going.

Quite possibly yes. Just a personal opinion - I think it likely - but nobody really knows. As I said it may eventually be combined with the flu vaccine either in one shot or two shots separated by a couple of weeks.

Thanks
Bill
 
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  • #20
tonyd11 said:
have a queston...

if you get the two dose vaccince for covid... no one knows how long the vaccine lasts... How many times will you need to be vaccinated after the first round?

I believe this virus will mutate/become smarter as we see different strains. what if the virus mutates to make the vaccine obselete?? lol... what if you get the first two doses of the vaccine, virus mutates, then find out if you had first round vaccine you cannot get any updated vaccines in the future?

If they have found in France mutated strain that is pretty much undetected, and possible more variations of this virus come out in the future will the current vaccines be of any help?

it seems like, with current vaccine the hope is that everyone receives vaccine so the tide turns and Covid no longer a threat. seems like a gamble as we see new or mutated strains lol... seems like only plan A is there which is get vaccinated fast to stop the virus but chances are this will mutate become immune to the vaccine lol then what? No plan B very scary!

Researchers have been testing the current vaccines against different variants of the Coronavirus that have emerged recently (see this PF thread for more discussion). For many variants, such as the B.1.1.7 variant originally found in the UK, the vaccines seem to work just fine. There are some variants, however, where the vaccine seems to be less effective (e.g. the B.1.351 variant originally found in South Africa).

This is not the whole story, luckily. Most of the research showing lower efficacy of the vaccines against some new variants focus on the virus' susceptibility to antibodies. Antibodies form an important arm of the body's adaptive immune response (the humoral immune response) that can help prevent our bodies from becomming infected by neutralizing incomming viruses with antibodies. However, there is another arm of the adaptive immune response, the cellular immune response, that also plays a role in controlling infections through the action of a subset of immune cells called T-cells. Recent research suggests that the vaccines elicit T-cell immunity that is equally effective against the original SARS-CoV-2 virus as it is against the new variants (including those that seem to evade antibody-based immunity).

These results suggest that the new variants could still infect and sicken vaccinated individuals (because the virus can evade humoral immunity), but the body would then be able to fight off the infection (via pre-existing cellular immunity) so that the infections will result only in mild disease. If this turns out to be true, this could still allow for society to return to normal without risking overflowing hospitals and huge numbers of deaths.

Note that scientists are currently working on vaccines against the new variants, so if these turn out to be necessary, they should be available soon. If it turns out that vaccines need to be updated yearly due to either waning immunity or the emergence of new variants, we should have the capability to do so. For the mRNA vaccines, it is likely that booster shots against new variants could be administered without any problem. For adenoviral vectored vaccines (such as those from Johnson & Johnson or AstraZeneca/Oxford), there is concern that administration of the vaccine could induce an immune response against the adenovirus used to deliver the vaccine, which would make booster shots less effective.
 
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  • #21
Ygggdrasil , Thank you so very much for your time and explination! Importantly your knowledge, i was afraid of being laughed at and put down for my post. (not saying on a site like this would happen i believe this is a professional informative place to share knowledge and better ourselves). Going to be reading a lot here now.

i learned so much from your response i am inspired i want to learn more. I wish I had the confidence years ago to be involved in this type of work :eek:( sadly no.

Please let me know if there is any reading materials ect.. ect.. to help a beginner.

thanks again tony
 
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  • #22
tonyd11 said:
have a queston...

if you get the two dose vaccince for covid... no one knows how long the vaccine lasts... How many times will you need to be vaccinated after the first round?

I believe this virus will mutate/become smarter as we see different strains. what if the virus mutates to make the vaccine obselete?? lol... what if you get the first two doses of the vaccine, virus mutates, then find out if you had first round vaccine you cannot get any updated vaccines in the future?

If they have found in France mutated strain that is pretty much undetected, and possible more variations of this virus come out in the future will the current vaccines be of any help?

it seems like, with current vaccine the hope is that everyone receives vaccine so the tide turns and Covid no longer a threat. seems like a gamble as we see new or mutated strains lol... seems like only plan A is there which is get vaccinated fast to stop the virus but chances are this will mutate become immune to the vaccine lol then what? No plan B very scary!
Really we can't know how long the protection from a vaccine will last because we have only being using them for a short while. We know its greater than 6 months and its beginning to look as if some level of protection will be present for quite some time.
Virus mutate all the time but its not because they are smart, it follows the same basic evolutionary principles as every other organism. Most mutations occur by chance at the point of reproduction and the effects are either deletrious to the virus or irrelevant, we are only really interested in changes that might affect transmission or disease severity. This is why they focus on what they call variants of concern, the rate and accumulation of changes depends very much on the reproduction rate, the virus population in the community and the internal checks that the virus uses to remove "mistakes" in its genetic material. This means that reducing the level of infection in the community should help reduce the opportunity for mutation.
The vaccines all produce antibodies to a number of epitomes on the virus so changes to the virus sensitivity to the antibodies involves multiple changes, so far none of the variants are totally resistant to the antibody response. Then as Ygggdrasil suggests there are other parts of the immune response that still confer some protection, this should give our immune system a head start in adapting its response to new variants. Its still not very clear that updated vaccines will be needed.
The other important consideration is that the survival of new variants depends on "fitness" the virus wants to survive and reproduce. Generally this means that mutations that increase transmissability would be more likely to be selected, however mutations which increase disease severity actually reduce the organisms ability to spread and killing the host also kills the virus, these would be selected against.
Its suggested that over time evolution would work in our favour and some people believe that the other Corona viruses that cause cold like symptoms may have had a similar life history to Covid 19 and evolved to become a milder disease.
Its safest to ignore the mass media, new variants will arise, its inevitable, most simply don't matter. Rapid control of the disease in the short term will reduce the rate of mutations and prevent deaths and disability while allowing the virus to properly adapt to its new host (us). This is on the optimistic side of the predictions, not something I'm usually associated with and there are lots of things that could change the outcomes. At the same time the vaccine technology is improving and more treatments are becoming available, I really don't think that this will be a long term problem, pandemics rarely are.
 
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  • #23
tonyd11 said:
it seems like, with current vaccine the hope is that everyone receives vaccine so the tide turns
That hope is so far from any remotely possible outcome in American today that it is just a pipe dream and not even worth considering.
 
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  • #24
Laroxe said:
The other important consideration is that the survival of new variants depends on "fitness" the virus wants to survive and reproduce. Generally this means that mutations that increase transmissability would be more likely to be selected, however mutations which increase disease severity actually reduce the organisms ability to spread and killing the host also kills the virus, these would be selected against.
Its suggested that over time evolution would work in our favour and some people believe that the other Corona viruses that cause cold like symptoms may have had a similar life history to Covid 19 and evolved to become a milder disease.
While this is generally true, there is data to suggest that the B.1.1.7 variant is more deadly that the original SARS-CoV-2 virus:

Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study
BMJ 372:n579 (2021)
https://www.bmj.com/content/372/bmj.n579

Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7
Nature (2021)
https://www.nature.com/articles/s41586-021-03426-1

The B.1.1.7 variant seem better adapted to humans as a host than the original virus (e.g. by exhibiting stronger binding to the ACE2 receptor) which seems to result both in better person-to-person transmission as well as more severe disease.
 
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  • #25
I think there is still some debate about this, it took ages to get some general agreement on transmissability but I think that's settled now. Its still early days really and even if this does turn out to be true it may not change the longer term outcome. Unfortunatly when you say that this is generally true, when biological organisms are told how they should behave, they have a nasty habit of doing whatever they want. Predicting the future can be very difficult at times, but I was told there was some money in it, just not for me apparently. :)
 

1. What is the significance of Phase 3 trials for the Covid vaccine?

The Phase 3 trial is the final stage of testing for a potential vaccine. It involves a large number of participants (usually thousands) and is designed to assess the safety, efficacy, and potential side effects of the vaccine. The results of Phase 3 trials are crucial in determining whether a vaccine is safe and effective enough to be approved for public use.

2. How long do Phase 3 trials typically last?

Phase 3 trials can last anywhere from several months to over a year, depending on the number of participants and the rate of infection in the population being studied. The duration of the trial is also affected by the time it takes to collect and analyze data, as well as any unexpected delays or setbacks.

3. What is the role of the control group in Phase 3 trials?

The control group in a Phase 3 trial is a group of participants who receive a placebo or a standard treatment instead of the experimental vaccine. This group serves as a comparison for the group that receives the vaccine, allowing researchers to determine the effectiveness of the vaccine by comparing the outcomes between the two groups.

4. How are participants selected for Phase 3 trials?

Participants for Phase 3 trials are typically selected through a rigorous screening process to ensure they meet specific criteria, such as age, health status, and risk factors for the disease being studied. This helps to ensure that the results of the trial are representative of the general population and can be applied to a wider group of people.

5. What happens after Phase 3 trials are completed?

After Phase 3 trials are completed, the data is carefully analyzed by researchers and regulatory agencies to determine the safety and efficacy of the vaccine. If the results are positive, the vaccine may be approved for public use. However, even after approval, ongoing monitoring and surveillance of the vaccine's effectiveness and potential side effects continue to ensure its safety and efficacy.

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