top | item 24411540

Covid vaccine makers commit to not seek approval until complete Phase III trials

190 points| sethbannon | 5 years ago |statnews.com

321 comments

order
[+] Animats|5 years ago|reply
The New York Times has a chart, updated daily, of all the vaccines in development.[1] This is worldwide, not US.

Phase I: 24

Phase 2: 14

Phase 3: 9

Limited approval: 3 (CanSinoBio, Gamaleya Research Institute (Russia), Sinovac)

Full approval: 0

That's not even including the hundred or so still in lab or animal testing. It's encouraging; something is likely to work.

The real question is, how effective are the ones that make through the safety tests? Nobody really knows yet. The FDA (pre-Trump push) announced that their minimal effectiveness for approval was 50%, which is low for a vaccine. Moderna is aiming for 60%. Effectiveness times fraction of population getting it has to be > 70% or so to stop the epidemic with a vaccine alone. That's the "herd immunity" fraction for a disease with a growth rate of 3.

Useful questions:

- If a vaccine is only partially effective, will an antibody test tell if it worked?

- Will taking one vaccine limit the effectiveness of another vaccine taken later? That's happened for a few vaccines.[2] It's usually more of a timing thing; some vaccines should not be given within a few weeks of other vaccines.[3]

- Could widespread use of a moderately effective vaccine cause people to abandon mask-type precautions and cause an epidemic spike in the unprotected part of the population?

Is someone working those issues effectively?

[1] https://www.nytimes.com/interactive/2020/science/coronavirus...

[2] https://www.tandfonline.com/doi/pdf/10.1080/21645515.2015.10...

[3] https://www.ok.gov/health2/documents/IMM_PRG_5-20_Intervals_...

[+] umanwizard|5 years ago|reply
> That's the "herd immunity" fraction for a disease with a growth rate of 3.

Only if you assume (1) perfectly homogeneous mixing and (2) nobody is naturally immune (either due to cross-reactivity with immune responses to other coronaviruses or for any other reason).

[+] 2bitencryption|5 years ago|reply
Of all the different vaccine "types" mentioned in the article (proteins, whole virus, mRNA, etc), which of those general types of vaccines are the most traditional, the most widely used, the most experimental, the most novel, etc?

I'm genuinely curious if "tried and true old vaccine tech" will come out on top in this case, or if "fancy new vaccine tech" will lead the way.

[+] cpeterso|5 years ago|reply
If multiple vaccines are ready at the same time, who will decide which vaccine is distributed to which people? Would it be regional? Random?
[+] mchusma|5 years ago|reply
I hope that the benchmark for approval is "for a given group, the risk of the vaccine is lower than the risk of COVID".

This has some good commentary: https://marginalrevolution.com/marginalrevolution/2020/09/on... some thoughtful commentary.

I believe that for at risk populations it is very likely that taking a phase III vaccine candidate is the safer option right now, let alone after another month of data.

I think let anyone who wants to volunteer to take it make their own risk assessment but be required to send data back. The only real arguments I have seen against this are political or paternalistic. But I also think people should be allowed to run human challenge studies on volunteers, which is also an ethical no brainier. But that doesn't seem to be happening either.

It basically feel like the world in 2020 decided the answer to the "trolley car problem" https://en.wikipedia.org/wiki/Trolley_problem. 2020 society's action seems to be: "inaction causing 5 deaths is better than action causing 1 death".

[+] outside1234|5 years ago|reply
If the vaccine confers only limited immunity - but the users run off and act like they are immune for life - we could pretty quickly end up in a situation where giving a vaccine could result in 5 deaths where 1 only would have happened without it because people would have been more careful.

This is why it is important to understand not only that it doesn't kill people, but how much immunity it provides.

[+] jmull|5 years ago|reply
The phase 3 trial is where the safety and efficacy of a vaccine is determined for various groups. The risk/benefit decision you suggest can’t be made until it has been done.

It’s like the trolley problem but you don’t know whether more people will be killed if you throw the switch or not.

Also, if people are encouraged to take a vaccine that later turns out to have significant, previously unknown negative side effects, they will be less likely to take vaccines in the future. Squandered trust is very, very costly to regain so needs to be accounted for in a risk analysis.

[+] crx07|5 years ago|reply
Absolutely this.

I'm in an at-risk population, as are the two others in my household, and this pattern of perpetually delaying is driving me insane.

I'll gladly take a 0.1% chance of an unspecified SAE over a 50% chance of death. I'm about to the point where I'd consider outright bribing someone at a research lab to slip me a dose of any of them, even if I had to administer it myself.

[+] jwieczorek|5 years ago|reply
Meanwhile, Russia just today announced it is starting the release of the first batch of its own vaccine to the public.

https://www.aljazeera.com/news/2020/08/sputnik-russia-corona...

[+] avaika|5 years ago|reply
Well. As of now the Russian vaccine doesn't look like a trustworthy solution. Recently Russians published article in The lancet [1], but scientists who read this have a lot of questions. Especially on data consistency. They even published open letter to head of vaccine research Denis Logunov with open questions [2].

According to first reaction by Denis Logunov (don't have a link on this) the open letter doesn't worth to answer. Unless The lancet asks to react.

imho: It actually shouldn't be a surprise that if the government is corrupted, the other governmental institutions most likely do not function well either. This research center is a governmental institution. And might be interested and involved in some political games as well.

[1]: https://www.thelancet.com/journals/lancet/article/PIIS0140-6...

[2]: https://cattiviscienziati.com/2020/09/07/note-of-concern/

upd: formatting

[+] ConsiderCrying|5 years ago|reply
Not sure why this got downvoted, it's not like the person is endorsing Russia's decision. I'm highly skeptical a country that refused to go on lockdown and underreported cases would make a safe vaccine faster than the rest of the world.
[+] samatman|5 years ago|reply
Correct, and this announcement is, among other things, a response to that.
[+] warent|5 years ago|reply
I've recently heard an argument that the probability of being injured/killed by a vaccine (e.g. due to complications, allergies, etc.) is on average greater than the probability of covid causing damage/fatality to an individual, therefore if people are administered these vaccines then we'll actually see an increase in mortality/illness.

Can anyone speak to this? I'm not sure how legitimate this is, but it sounds somewhat convincing enough to be concerning.

EDIT: Downvoting someone for asking questions, even if based on a false premise, is completely shameful, especially when there's no claim to fact and it's clearly not made to be inflammatory. This community should encourage asking questions. Think carefully before throwing around a downvote as a marker of disagreement.

[+] evilsnoopi3|5 years ago|reply
This is simply not the case except when talking about a totally untested vaccine. The whole point of phase III trials is to confirm "safety and efficacy" in a wide population. Moderna, for instance, aims to enroll 30k people in it's (currently ongoing) phase III trial. After that, it's just a matter of data analysis. The FDA would certainly not approve a vaccine that had comorbidity higher than the disease it is trying to treat.
[+] airza|5 years ago|reply
I think ruling that out is the point of a phase 3 trial.
[+] hedgew|5 years ago|reply
Try finding out how many people have died from vaccines that have passed phase 1 & 2 in the past few decades.

The number seems to be closer to zero than anything else.

Even one of the worst vaccine disasters, the Cutter incident in 1955, seems to have resulted in only some 10 deaths, of which 5 were indirectly caused.

[+] rodonn|5 years ago|reply
Somewhere around 0.5-1% of people who are infected with COVID die and a larger share experience very serious symptoms, some of which can be long lasting/permanent. The risks for the elderly are even higher, something like 15% death rate for people older than 80.

In comparison the risks of a vaccine are much much much smaller, as long as the risks are similar to existing approved vaccines. The testing process is explicitly designed to make sure that no vaccine gets released that causes more harm than good.

For comparison here is the symptom sheet for the flu vaccine https://www.who.int/vaccine_safety/initiative/tools/vaccinfo... Or an easier to read summary https://immunizebc.ca/side-effects The risks of serious complications for flu vaccine are closer to 1 in 100,000 or 1 in 1 million, and even then the effects are usually much less serious than death.

[+] gamblor956|5 years ago|reply
EDIT: Downvoting someone for asking questions, even if based on a false premise, is completely shameful, especially when there's no claim to fact and it's clearly not made to be inflammatory.

A lot of inflammatory topics are raised by asking questions based on false premises.

If you assert that a vaccine is more likely to kill/injury you than the disease it prevents, it is more than reasonable for others to assume you that are trolling rather than satisfying your curiosity, especially since you could have asked it in a different manner: what is the risk of being injured/killed by the vaccine compared to the risk of being injured/killed by the disease itself?

And nobody knows the answer to that question, yet. That's why they're doing the Phase III trials right now.

[+] remy_0|5 years ago|reply
What are your sources?
[+] wearhere|5 years ago|reply
What’s the timeline for Phase III trials? The article doesn’t seem to say. I don’t feel reassured that those won’t be rushed.
[+] woke_neolib|5 years ago|reply
They did not actually commit to finishing the clinical trials.

> The companies did not rule out seeking an emergency authorization of their vaccines, but promised that any potential coronavirus vaccine would be decided based on “large, high quality clinical trials” and that the companies would follow guidance from regulatory agencies like the Food and Drug Administration.

https://www.nytimes.com/2020/09/08/world/covid-19-coronaviru...

[+] nfw2|5 years ago|reply
The question of whether the virus or vaccine poses a greater risk seems like a controversial one.

I (28, no health conditions) personally would be willing to take the vaccines that have gone through stage 2 trials. I registered myself as a willing volunteer but have not been selected.

It seems to me that there is a middle ground between approving and recommending a vaccine to all Americans and completely blocking access to vaccines that have been through some baseline safety testing.

What seems like a good solution to me is to have open phase 3 trials that accept anyone willing to waive the risks. This would also accelerate us towards to a point where we are ready to approve a vaccine for everyone.

[+] credit_guy|5 years ago|reply
The actual pledge is here [1].

There are 4 bullet points, 3 of them are quite generic; the one that made all the waves is:

"[we pledge to] Only submit for approval or emergency use authorization after demonstrating safety and efficacy through a Phase 3 clinical study that is designed and conducted to meet requirements of expert regulatory authorities such as FDA."

I feel there's some weasel wording going on here. They don't pledge to ask for approval after the completion of Phase 3. Instead they use a very convoluted phrasing, that's designed to make people think it's after Phase 3 is completed, but if you read more closely says something quite different.

When is the Phase 3 for Moderna expected to be completed anyway? This is readily available information at clinicaltrials.gov [2]. The estimated study completion date is October 27, 2022. Is the CEO of Moderna saying he will not seek approval prior to that date?

Pfizer's estimated study completion date is November 14, 2022 [3].

Two years from now doesn't sound quite "warp speed" to me. Did they take billions of dollars of public money to deliver a vaccine in 2 years?

[1] https://www.businesswire.com/news/home/20200908005282/en/Bio...

[2] https://clinicaltrials.gov/ct2/show/NCT04470427

[3] https://clinicaltrials.gov/ct2/show/NCT04368728

[+] maxerickson|5 years ago|reply
'after demonstrating safety and efficacy' is not weasel wording though, it's just a different benchmark than 'completing the study'.

The headline is inaccurate, but that's on Statnews.

When studies go really well, doctors consider themselves ethically obligated to end them early, so that the placebo group can receive the treatment. That these studies have planned end dates well into the future doesn't mean that they must run that long (or that it will take that long to collect sufficient safety data).

[+] darkerside|5 years ago|reply
I agree. They are only saying they will demonstrate safety and efficacy through the trials, not that the trials will be technically completed.

And, I think that's fine. I'm not taking a politician's word for whether that has been achieved, but I agree with it in concept.

[+] ars|5 years ago|reply
"82% of Democrats and 72% of Republicans expressed concern that the Covid-19 vaccine approval process would be driven more by politics than by science.

More than 80% of independents, Republicans, and Democrats said they would worry about the safety of a vaccine that was approved quickly."

Wow.

And lest you think this is a Trump thing, the figures are similar in European countries.

A bad COVID vaccine (one that doesn't work), or heaven help us, one that causes harm, could set public healthcare back decades.

[+] treeman79|5 years ago|reply
It is a political decision. The kind leaders are supposed to make, the kind they don’t like making.

A leader has to decide on either pushing early and either saving/condemning hundreds of thousand of lives.

Or playing it safe and condemning/saving hundreds of thousands to death while we complete years worth of trials.

Oh because that’s not enough pressure the economy is burning, which will cost many lives as well.

It’s a horrible decision to make anyway you slice it.

Politician is going to be hated no matter what.

If it works, they are bad for taking so long, taking risk. If it goes south...

[+] sugarpile|5 years ago|reply
“A bad COVID vaccine (one that doesn't work), or heaven help us, one that causes harm, could set public healthcare back decades.”

I see this a lot (and am not jumping on you), do you mind explaining why you feel this way? To me one of the few things that could restore my faith in public health after how this pandemic has been handled is allowing widespread early access to the vaccine with full access to whatever data has been gathered. In flight is fine.

This “hur dur the masses can’t be trusted to make their own decisions” shit has got to stop. It has become clear public health in the US is more politics than health so any sort of management on an individual level gets zero trust from me.

[+] gizmo686|5 years ago|reply
It doesn't even have to be a "bad" vaccine. The FDA has already said that 50% effectiveness would be sufficient, which would put it about on par with the seasonal flu vaccine.

Combined with a high baseline infection rate, and an aggressive testing regime (at least compared to flu/other non-pandemic diseases), there will be a lot of people who get vaccinated and proceed to get sick and test positive.

The real evidence of the vaccine working would be by the herd immunity it creates. But that is a population level effect, and people are terrible at understanding population level effects.

[+] polote|5 years ago|reply
> the figures are similar in European countries.

Do you have a source ?

[+] blackflame7000|5 years ago|reply
Do you really believe polls like this are accurate?
[+] eanzenberg|5 years ago|reply
Not sure how this is an ‘only’ Trump thing. Republicans believe D-politics will delay the vaccine so it doesn’t come out before Nov 3rd, and Democrats believe R-politics will prematurely release a vaccine before Nov 3rd.

This country has become so politically cancerous that I wonder if a WW2 style event were to happen (as if Covid isn’t one already) if the country could unite around it, today.

And before you question the thesis, I’ve had the pleasure of listening to a few doctors lament the possibility of having life-saving therapies or vaccines if it helped Trump get re-elected.

[+] nfw2|5 years ago|reply
After hearing Fauci's recent comments on the matter, my understanding is that the phase III trials can be considered for approval once there are enough infections in the control group to do a comparative analysis.

Since the events now needed to confirm the vaccine are in the control group, not the experimental group, it seems that the blocker for approval now isn't SAFETY, as it has been continually suggested, but EFFICACY.

If that is indeed the case, what makes the most sense to me would be to allow an early approval of any vaccine that meets reasonable safety requirement (some x months in stage 3 trial), but the patient must sign a waiver saying that they understand there may be rare side effects and there is no guaranteed immunity.

[+] bglusman|5 years ago|reply
So, correct me if I'm wrong, but

a) current hypothesis is people with prior exposure to common-cold non-COVID-19 coronaviruses are by and large either asymptomatic or have milder symptoms than those without such exposure

b) presumably it should be possible to test people for these antibodies much as we can test people for COVID antibodies

If people would volunteer for the b) anti-body test in reasonable numbers, and a subset of them who have them would volunteer for a modified trial, we could possibly do a double-blind intentional-exposure test on people to confirm that the vaccine confers BETTER immunity than the existing similar antibodies do, right? Would it be possible to ethically and realistically use that strategy to accelerate effectiveness testing (if not safety testing) of any vaccine candidates? or would the smaller scale of that have only made sense for something more like Phase 2 trials?

Arguably, as long as safety is near perfect, we should be willing to tolerate only moderate (say, 90%) effectiveness (and I'd read one of the vaccines took two doses to get 100% effectiveness but was 90% after a single dose), but I don't know how safety is evaluated and obviously long-term safety and short-term safety are pretty different/I imagine a lot of people will be more concerned about long term safety and I don't know how you can reassure them on that on any kind of accelerated schedule.

[+] Invictus0|5 years ago|reply
Without fast track approval, in the best case scenario, approximately how long would it take for any of these vaccine candidates to go through phase 3 trials?
[+] GavinB|5 years ago|reply
Given that a vaccine may not provide total protection, they should consider how to sell a potential early, safe but only moderately effective vaccination. For instance, calling it a "COVID-19 Immune Booster Shot," and be very transparent that it reduces your protection against the virus but is not total immunity. Then the world won't lose faith in science and medicine when folks who had the shot are testing positive and even dying.

Hopefully either way the amount of news coverage will be enough that most people will get informed about it, in a way that they don't for most issues.

[+] mola|5 years ago|reply
What exactly is this news source doing here? Just repackaging a press release? There are very important questions being asked here about the wording. Journalists should be the one thinking up these questions and asking them. They shouldn't publish these kinds of statements without doing this. Otherwise they are no more than propaganda machines.

Fake news is not only out-right lying, it's journalists not doing their jobs of asking the hard questions.

[+] jrochkind1|5 years ago|reply
Sure, who even needs a regulator if pharmaceutical companies will just promise not to bring products to market unless they are "safe and effective".
[+] ISL|5 years ago|reply
Looming in the background are torts. If vaccine makers are forced to race ahead of safety in order to get to market and one turns out to be insufficiently safe, the manufacturer may get sued into the ground.

By agreeing not to jump the safety protocol, they are continuing to both limit their liability directly (by ensuring a safer product) and adhere to best-practices (which might help in a future court case).

[+] blumomo|5 years ago|reply
Here in Europe they are freed from legal consequences should the vaccine harm someone. Instead our countries are to pay any occurring damaging. So I don’t quiet get what motivated the vaccine makers to await the approval given that they are practically free from prosecution anyway.
[+] snowwrestler|5 years ago|reply
The U.S. has a similar regulatory regime to manage vaccine liability. But it's not a free-for-all; vaccines need to meet certain criteria before they qualify for this program.

This is a huge reason that these companies are concerned. If they are pushed to release a vaccine too early, and it harms a bunch of people, any evidence they bent the rules at all will be used to try to break their immunity from civil liability. It would be a field day for personal injury lawyers.

[+] eCa|5 years ago|reply
It should be in everyone's (and certainly the manufacturers') interest that the vaccines actually are safe.