On trial
Commenter and blogger, Professor Joel Eissenberg, Department of Biochemistry and Molecular Biology, Saint Louis University.
Introduction: “A group of clinicians and researchers is petitioning the FDA to delay fully approval of any COVID-19 vaccines before clinical trials have been completed, calling the notion of approval to stimulate vaccination rates ‘backward logic.’
The group, led by Linda Wastila, BSPharm, MSPH, PhD, professor of pharmaceutical health services research at the University of Maryland School of Pharmacy, includes 27 petitioners, including 16 experts outside the U.S., primarily based in Europe.
The message of our petition is ‘slow down and get the science right. There is no legitimate reason to hurry to grant a license to a coronavirus vaccine.’ We believe the existing evidence base, both pre- and post-authorization, is simply not mature enough at this point.”
Taken from a blog post published in The BMJ.
If the FDA listens to us, they won’t give serious consideration to approving a COVID-19 vaccine until 2022.”
_____________
I enrolled in the Moderna phase III COVID-19 vaccine trial last August. The trial lasts two years. Initially, it was a double-blind trial, although I knew I was in the vaccine arm 12 h after the booster and unblinded myself with the spike antibody test a month later. In January, all subjects were offered unblinding and the placebos were offered the vaccine.
Meanwhile, the Moderna vaccine has emergency use approval for everyone over age 12, so the number of people vaccinated outside the trial dwarfs the number in the trial.
So the issue is whether the FDA should relent and give full approval to this (and the Pfizer, J&J and AstraZenica) vaccine before the phase III trial is done. Trial participants like me are subject to a much higher degree of surveillance than the rest of the vaccinated public (weekly phone log, monthly wellness calls, six month clinical visits and blood samples) for research purposes. I can understand why the FDA would want the trials to be completed, but what if granting full FDA approval would convince more folks to get vaccinated?
A bunch of physicians just weighed in on the side of withholding full approval pending completion of the trial. As a scientist, I get the importance of data-driven decision making, but the horse is already out of the barn and way down the road on COVID-19 spike protein vaccines. Here’s an article. You decide.
Docs, Scientists Call on FDA to Delay Approval of COVID Vaccines, MedPage Today, June 10, 2021
Wait for the process to be completed. If the idea is to grant approval specifically as part of a plan to influence the unvaccinated why risk that taking a shortcut will become a big story and harden opposition at a final level higher than just following the process? Also I imagine there will be lawsuits coming out of it if formal approval is involved in mandated vaccination, as I think probably would be the case with the military. But the idea behind this is at least comic genius of a sort: ‘let’s not complete the full process to push beyond emergency authorization because these current vaccination rates are an emergency!’
hmmm. let’s see. the trials are not complete. but the vaccine-hesitant are free loaders? oh-kay, i get it.
on the other hand…my completely unscientific guess would be that with the very large numbers of already vaccinated, with apparent reduction in cases of the disease, and no scary increase in dangerous side-effects… i would count that as a ‘trial.’ maybe not quite a horse is out of the barn trial…as there may be things the “continure the trial” scientists know or want to know that i don’t know…before they put their stamp on it.
but if “grant approval now” is intended to “influence the unvaccinated” then “approval” is a political decision and not a scientific one. no wonder weaker minds than mine are confused.
spoiler alert: i am not a trumpist, or even a Fox-ist. just always hated lynch mobs, right or left.
@Eric,
As I said, you decide. I posted my opinion but I also provided a link.
Joel
Thanks for the link. It does appear the question is more political than scientific. On the other hand “political” is not necessarily a bad word. If preliminary evidence suggests important reasons to hasten the vaccination rate at the risk of late appearing bad side effects, it might be the wisest choice to go ahead with a program of vaccination. On the other hand, if those late appearing adverse effects are significant, it might turn out to have been a bad idea to sully the science by pinning the “approved” decision on the scientists. [i did note that one of the scientists is of the hydroxychloroquine school.]
a personal side note: it has seemed to me that politicians are usually more interested in “high abstraction” or fantasies than in reality or even “science.” Economists will adhere to a “deficits are bad” idea while millions of people suffer the effects of an economic downturn. You here seem more interested in the “fantasy” of “maybe”an increase in free-loaders taking the vaccine (i call it a fantasy because it is at this moment still in “not real land”, not even “scientifically” evaluated.)…than you are in an arguably “scientific” trial which needs a few more steps before it can issue a “scientific” approval. Note that I am not arguing that your preference is “wrong” or that my (unstated) preference is “right.” Merely musing about the power of “things unseen.”
oh, well. more on fantasies:
i recently read a short statement of Hoover’s rationale for rejection of Roosevelt’s “deficits and inflation” plan. I was surprised to find myself thinking “that makes sense.” Then I read a short statement of Roosevel’ts rationale…. and found myself thinking “that makes sense”. but Roosevelt’s plan struck me as depending on unknowns and taking more mental energy to understand. As it turned out [I think…contrary to current prevailing opinion among public economists] Roosevelt was right, and Hoover was wrong…or so ordinary people thought for at least the next fifty years. Moral to this story is that sometimes it is braver and smarter to step into “fantasy land” than to stick to those known knowns,,,that turn out to have always been fantasies themselves. But don’t expect everyone to agree with you…even after fifty years of real world evidence.
Simple fantasies have more power than complex facts. In fact…
The word “freeloaders” was used in comments on the post https://angrybearblog.com/2021/06/coronavirus-dashboard-for-june-7-a-tale-of-two-pandemics-the-vaccinated-states-vs-the-idiotic-states
It should be okay to discuss whether some people are “free-riders” as that does appear to be a term of art in economics, but discussing whether people are “freeloaders” is not the same thing. (I echoed the latter and wish I had not.)
The examples I know of people trading off the unknowns in their own compromised health with the advantage of opening up the economy as the death rate decreases are probably not properly considered free-riders as they continue to maintain social distancing.
@Arne,
I don’t endorse the term “freeloaders” myself.
Most people in the US don’t have “compromised health.”
I doubt full approval would make much difference, except to the military and maybe a few school districts. The “vaccine hesitant” who are waiting for a full rundown of the data evaluations of a clinical trial before taking a vaccine are probably the smallest portion of the unvaccinated.
I was very hesitant because of the apparent rush and lack of full evaluation back in January, but by April enough people had been vaccinated to make the hesitancy go away.
Has anyone suggested dropping the rest of the planned or in progress trials if full authorization is granted? We have already paused distribution because of side-effect concerns, would that not happen regardless of full or emergency authorization? I know at least two medications I took for years got pulled after they had millions of people to sieve data on. Would a vaccine be any different?
@Jane,
I agree the most “vaccine hesitant” neither understand nor care about the data.
By the time I joined the Moderna phase III trial last August, thousands of people had been vaccinated in the phase I (safety) and phase II (efficacy) trials already. By January, tens of thousands had been vaccinated in both the Moderna and Pfizer trials. I don’t understand how “apparent rush” applies. There is no rush, just an abundance of caution and adherence to tradition.
Yes, vaccines are very different from drugs.
Terminating trials for benefit has always been a bit controversial. The usual reasons for early termination are for harm or futility. But, now and then a treatment works so well that “it’s considered unethical to deny a study participant an effective treatment” (*), so patients in the control group are allowed to crossover.
The usual problem is that truncated trials, especially smaller trials, might overestimate effectiveness. Combine statistical flukes with optimism, desperation and the profit motive and early termination for benefit can lead to serious problems. We haven’t seen that with the COVID vaccines. Smaller usually means N in the hundreds, not tens of thousands as in the COVID vaccine trials
They’re also problematic when they are not done as part of a planned interim assessment. The COVID vaccine trials were designed with an early assessment step that led to the application for EUAs. The original FDA statement was that an efficacy of 50% or over would be sufficient for approval. The actual numbers were much, much better. No one played games with the protocol. Since then, they’ve demonstrated efficacy with N in the hundreds of millions, so the early results was not a statistical fluke.
It is really hard to argue that termination for benefit would be a mistake for the COVID vaccines. Vaccinated people don’t get serious cases of COVID. Unvaccinated people do. The trials were never formally terminated. Many people want to learn as much as possible about a novel disease and a novel set of vaccines, particularly how long they remain effective. Still, it may be time for termination.
P.S. Look at the brouhaha over the FDA approving an Alzheimer’s drug where the last trial was terminated for futility. Maybe the critics should raise more of a stink over that.
(*) https://link.springer.com/article/10.1007/s11739-012-0871-0
Kalesberg:
Emergency approval does not result in a shortened Clinical Trial III to my knowledge. The trial will be completed to my knowledge. Joel may have a better answer than I. I am pretty cofident it will be completed. I believe Joel is still a part of the trials for Moderna. I just had a site up that showed ongoing trials for Moderna with younger people (<18).
@Run,
Correct. I’m still in the Moderna Phase III trial. Had my monthly update call last week while on vacation. Posted my weekly wellness check on my cell this past Sunday. Next scheduled bleed in September.
I see no reason why the FDA couldn’t grant regular approval while at the same time continuing the Phase III trials for all the vaccines. One of the important outstanding questions is the durability of protection and I’m among the earliest vaccinated subjects.
Joel:
I think the EA is a half step to a regular approval. The 21st Century Cures Act, I believe gave the FDA the ability to do such as they did now.
Arne
if free-rider is a term of art it should be fine, as long as it remains a term of art. it could easily become a term of contempt if used as a synonym for free-loader.
that said, i may have gotten lost here. i thought there was a controversy about “approval.” as far as i know no one has suggested stopping the current vaccination program. or stopping the formal trials. perhaps i am mistaking “approval” for a term of art.
meanwhile, it seemed to me that some people here were dancing around the idea of forced vaccination, or maybe just justified contempt.
I choose the justified contempt thing.
The forced vaccination thing may require some definition of terms.
If I say it is OK to require everyone on a cruise ship to be vaccinated, is that forced vaccination?
If I say you can keep unvaccinated people (including nurses) out of the ICU, is that forced vaccination?
If I say a beautician must provide vaccination status to any customer who asks, is that forced vaccination?
At this point, full approval is mostly marketing as production and use are fully authorized. Don’t undercut the marketing by not completing everything as per standards. In my mind, if 2 years of phase 3 data is a part of the approval, how does even 1000 times the amount of <1 year experience substitute for that if you need to assess phenomena that might happen at the 2 year point? The Atlanta Falcons were Super Bowl champs a few seasons ago on that basis.
Arne
contempt is dangerous for your soul, even if you believe you don’t have one.
as for your questions..the answer to all of them is “no.” a person may choose not to be vaccinated. that does not give him the right not to be excluded from certain social interactions. the difference is “force” vs “choice.” I can’t force you to quit smoking. I can tell you “not in my house.”
by the way
if i understand, those vaccinated have nothing to fear from the un-vaccinated. which is a good thing, since 8 billion people are going to be unvaccinated even after we force every american to be vaccinated.
the rationale behind forced vaccination is to reach “herd immunity.” but herd immunity is a result of the virus running out of hosts. this can also be achieved by social distancing and mask wearing.
i think you need to visualize yourself bursting into someones home and tying them down while you inject an unknown substance into them and thier children. it helps to threaten them with death if they resist.
but its okay if you wear your uniform. feldgrau is fashionable i hear.
please note “science” may tell you the vaccine is effective and safe, and even necessary. but “science” does not tell you what’s in the substance you are injecting. that’s “faith”. faith in the “higher ups.” very popular in the thirties and among people who don’t believe in a “higher power.”
why is spell check okay with “thier”?
@Eric,
I’m staying in the Moderna trial for the full two years. I could have dropped out when I unblinded myself last October, or when I was officially unblinded in the trial in January, but since I have a vaccine card, I’m good with staying in.
The choice isn’t between the “risk” of the vaccine and no risk, it is between the unknown risk of the vaccine and the known risk of contracting COVID-19 without the vaccine. The latter includes not only significant risk of death but also risk of long haul syndrome.
My browser is not happy with thier. Not Chrome and not Edge. It does not auto-correct.
contempt: the feeling that a person or a thing is beneath consideration, worthless, or deserving scorn.
I think that the idea that if you get a vaccine you will be chipped is worthy of scorn. I do not believe a person who believes the idea is worthless, but I think someone who pushes such an idea for political purposes is contemptible.
I have heard politicians express the view that they only represent people who actually voted for them. That is holding me to be beneath consideration. It is very hard for me not to reciprocate, but I think my soul will live though it.
Arne
i tend to agree with you, but if you pay attention i think you will notice people who make a habit of holding others in contempt, and they are not always so careful about whom they choose. also, i think if you spend a lot of time holding even bad guys in contempt you will miss out on just that much happiness. i don’t know if it’s a habit that gets worse with time, but i am told it can be dangerous.
it was AB’s spell checker (or my apple’s?) that accepted t h i e r. oops, this time it corrected it. one of us has a loose connection.