Sadly, this is the case. The German regulator's FAQ explicitly called this out; they are not interested in determining the path that saves the most lives, they are simply following the process that checks all of the boxes that the regulations require. In the EU this regulatory pause of AZ has likely killed thousands of people.
> The valid argument would be, those that issue the emergence order for use to should amend the order to acknowledge the issue but not block use immediately.
Or, more generally, in the emergency-order regime, all decisions that can demonstrate a clear 10:1 improvement in expected deaths should be taken, regardless of regulatory red tape.
The FDA and other regulators have over-fitted their process for "minimize likelihood of another Thalidomide, for drugs which have a small chance of saving a life, and a very small chance of causing harm". This is defensible for testing a new statin, where we have existing safe drugs to choose from, and we're looking for incremental improvements. But it's shockingly harmful in an emergency.
One thing that has become very clear is that the FDA and other regulators are structurally incapable of making even rudimentary risk-based tradeoffs in emergency situations, and we need to fix this.
A drug regulator should do its job, which is following established rules for approving and recommending new medicines. Not invent new rules, not push experimental drugs when new problems are being discovered on the go. Advocating for "greater-good" trade-offs and risks is a political effort, the regulator should be immune from political pressures.
I'm glad people there prefer to err on the side of going with established rules and caution.
If what you want is experimental drug being accessible to as many people as possible as soon as possible, you should advocate for the option to bypass the regulator and letting the people decide for themselves.
Do not advocate for corrupting the regulator.
> In the EU this regulatory pause of AZ has likely killed thousands of people.
I don't know how you came to that conclusion, but even if so, how many thousands of people would be eventually harmed or killed if the pause wasn't introduced? We don't know, because we are discovering properties and effects of the vaccines on the go. The data and estimates we have are based on short-term experience with the vaccines. They will change.
In treating people for illness it is a long established rule that "first, do no harm". And vaccine does not even help the patient with any illness - it is rather to help in case the patient would get one in the future. For many people, getting vaccinated has zero to negative benefit.
Nobody is entitled to get a fast-tracked rubber stamp to push vaccines on people. If you want to take experimental drugs, I support your right to do so, however I expect you let other people decide for themselves, including the regulators.
Otherwise you could delay your updating your side-effects listing because you know FDA will take your druf off-market (and this delay will/could cause harm to people).
In this case, the new side effect kills people. Very rarely, but if you belong to some unlucky group, you're screwed. It is better to figure out which people are endangered. The recommendations and documents have to be good for everybody, not just for the good statistics.
I wish the health agencies were a bit more open about their thought processes. OTOH, the rate of incidence doesn't seem higher than baseline AFAIK, which seems absurd. It also seems absurd that the various health authorities around the world would all make such a big deal of if if there wasn't some elevated risk. So I don't really know what to make of it, but privately, I'm leaning towards the interpretation that the idea is to avoid backlash against the vaccines by being irrationally strict about any potential hazards.
Yes, causation is hard to show with certainty.
However, regulator have to follow rules, and those rules probably err on the side of caution. Similarly to "first, do no harm".
I agree that the matter of public trust is also relevant here. In some countries large part of the population already does not want to get vaccinated. So the vaccinator is naturally motivated to prevent any PR screw-ups even at the cost of slowing down.
The rules are not some holy writ handed down from above, they are our way of trying to properly manage risk. When the situation changes, the rules can also change.
I don’t think jerking our knees over an ethics safeguard that led to a pause in administration of a vaccine that soon won’t be widely available anyway is a great habit to get into.
Imposing political pressure on experts and forcing them to approve against their judgment would be a horrible corruption of these regulator institutions.
Maybe the expert regulator think that the bar should be lowered. But then they should come forward. This should not be ordered by politicians or their handlers.
I get the need to make sure medicine is safe and effective, and we absolutely should follow those to a T when it comes to new medicines on the market in non-emergency situations.
However, that's not the case here. vaccines are well studied in general and J&J is one of the more "normally developed" vaccines on the market. After generally ensuring that it's safe (Phase I/II tests), there should have been a damn good reason to pull it even temporarily. The "we are seeing a small increase in blood clots" really doesn't seem like a valid reason to pull a vaccine.
Personally, I lay the blame primarily on anti-vaxxers. They've made us far too cautious around vaccinations. It has screwed up our risk management rules. I've no doubt that this pull back will result in anti-vaxxers publishing BS about the safety of J&J vaccinations to try and scare people away from it.
This has nothing to do with "anti-vaxxers". Vaccines usually take years to develop precisely because we give them to everyone, and rare, long-tail risks matter. This was the case well before the MMR autism scare defined "anti-vax" as it has come to be known today.
In this case, we bypassed that standard development process. It was the right choice, in my opinion, but it's not the right attitude to start claiming that our standard level of risk mitigation for vaccines is excessively cautious because "anti-vaxxers" exist. That's simply reactionary.
If anything, we've tossed out all of our usual standards of evidence in 2020, and did a bunch of stuff willy nilly, with no supporting evidence or rational consideration of trade-offs. We tore off all the safety belts. We don't need lower bars for evidence, we need less reactionary hysteria.
The vaccine trials were limited in their power to detect rare events. The Pfizer trial [1], for example, explicitly said that events rarer than 0.01% are less likely to be detected:
> This trial and its preliminary report have several limitations. With approximately 19,000 participants per group in the subset of participants with a median follow-up time of 2 months after the second dose, the study has more than 83% probability of detecting at least one adverse event, if the true incidence is 0.01%, but it is not large enough to detect less common adverse events reliably. This report includes 2 months of follow-up after the second dose of vaccine for half the trial participants and up to 14 weeks’ maximum follow-up for a smaller subset. Therefore, both the occurrence of adverse events more than 2 to 3.5 months after the second dose and more comprehensive information on the duration of protection remain to be determined. Although the study was designed to follow participants for safety and efficacy for 2 years after the second dose, given the high vaccine efficacy, ethical and practical barriers prevent following placebo recipients for 2 years without offering active immunization, once the vaccine is approved by regulators and recommended by public health authorities. Assessment of long-term safety and efficacy for this vaccine will occur, but it cannot be in the context of maintaining a placebo group for the planned follow-up period of 2 years after the second dose.
Even a 0.001% risk is not small, when you're talking about giving the vaccines to billions of people.
(I don't mean to single out Pfizer here. It's just the one I've read most recently.)
Anti-vax hysteria has been around for longer than MMR and autism.
> rare long-tail risks matter
I agree, but at the same time I also think that it's an overblown problem with vaccinations. We aren't talking about medication that screws around with the metabolism in unusual ways. Vaccines (other than the newer mRNA stuff) are by and large large enough chunks of whatever we are vaccinating against to trigger an immune response when the real thing comes along + preservation/delivery medium.
At the end of the day, the worst case for vaccination is that you might be infected with the disease you are vaccinated against (when live viruses are used).
That's not the case for J&Js vaccine.
So the next question is, if the worst case scenario is you get a disease you were attempting to prevent, then what is the next real biggest threat from a traditionally developed vaccination?
> If anything, we've tossed out all of our usual standards of evidence in 2020, and did a bunch of stuff willy nilly, with no supporting evidence or rational consideration of trade-offs. We tore off all the safety belts. We don't need lower bars for evidence, we need less reactionary hysteria.
I'd argue that pulling a vaccine over a very minor number of reports of increased blood clots is overly reactionary.
Edit: And... reading this it makes it sound like I'm skeptical of mRNA vaxxes. Just to be clear, I'm not and I've gotten the pfizer vaccine myself. I do think they'd have more justifiable scrutiny to make sure they are safe as it's a new technique for mass vaccinations (even though it's been used in immunotherapy for a while now).
The worst case for vaccination isn't that you get the illness. It is that you are one of the unlucky ones that gets some severe reaction and gets killed.
The type of severe reactions you'd expect are allergic reactions. They would show up right away, not as an event 2 weeks later. Given that J&J has already done 6 million dosages it seems pretty safe to say that those allergic reactions are pretty much non-existent.
I see a lot of maybe and mights, yet never any actual evidence or example of the fear around vaccine safety or a cogent explanation of HOW these things could happen. That's because you'd have to explain how proteins from the vaccination are somehow more dangerous than the same proteins present in the diseases.
The linked explanation would have been a reason for a longer and wider phase II/III study. However, now that the cat is out of the bag and we've got millions of people who've been dosed for multiple months, that's the study. Until we start seeing severe negative side effects in the 100s or 1000s of individuals, it doesn't make sense to pull a vaccine.
I think some people would choose the J&J vaccine if it meant getting vaccinated faster. Some people would choose Moderna / Pfizer, later.
It really depends on things like whether or not you can work from home, how depressing it is not interacting with people, or how concerned you are about the risk of long COVID19. That's not something we can answer for anyone centrally.
From a public health perspective, vaccinating people now with Johnson is an obvious win.
I think this is unrealistic for medical application, not only for vaccinations but in general for anything related to side effects of drugs.
First of all, most people don't have the data and in this case part of the risk management is to get more data or consolidate and evaluate existing data more thoroughly. Second, while you might be an exception, the vast majority of people do not have the knowledge and skills to properly assess risks or perform multiattribute cost-benefit analyses. Layman cannot even compare small probabilities correctly and frequently mix up risks that differ from each other by multiple orders of magnitude. Even people with fairly good knowledge of probability theory will have a hard time judging small risks without extensive comparison data and maybe some didactic tools like "micromort" comparisons.
So do public health professionals. The passive death and disability from COVID19 is weighed far less than the active death of side-effects. Providing J&J to everyone in the US would obviously reduce spread and reduce the thousand-or-so deaths we're continuing to see in the US every day by far more than blood clots.
In general, doctors leave medical decision making to patients, is central to medical ethics. This even applies to patients with incomplete capacity.
However, keep in mind we are continuing the vaccinate people are a really high rate, we just are not using the JJ vaccine. No one is stopping all of vaccinations. A brief pause in JJ while they relabel is just a minor hiccup in our overall vaccination plans
And the damn good reason was that there's a bunch of people out there who don't want to take the vaccine for political reasons. And there's a smaller amount of people who don't want to take the vaccine because they're uninteresting in taking a new vaccine. They're looking for reasons to validate their fears.
If you just keep pushing the vaccine even though a bad thing happened to a small number of people, then there will be people who use this as an excuse to avoid all of the vaccines completely.
Take down the vaccine and make a bunch of lab coats spend a hectic two weeks double checking some figures and people will feel listened to and they'll have less arguments to not get the vaccine. The vaccine that you're taking is as safe as it can be. After all when we saw a problem we did something about it.
This is 100% about optics and PR AND that's 100% necessary right now in order to get the job done.
> I lay the blame primarily on anti-vaxxers
Don't even talk about anti-vaxxers right now. The only thing bringing up anti-vaxxers will do is grow that movement. The people who don't want the covid vaccine are not anti-vaxxers. They get the flu vaccine and they get their children vaccines. They're only afraid of the new covid vaccine. They don't like anti-vaxxers any more than you do, BUT if you call them that then some of them are going to decide they might as well join the anti-vaxxer movement.
These are two groups of people who I do not want to join forces. Covid hasn't exactly been a fun time, but I'm really not interested in seeing polio and friends come back.
Have rational debates, quit the name calling, go the extra mile to convince people who don't like your position to do something for the greater good. Otherwise, we're not going to see enough vaccinations to make a difference.
If thousands are dying for lack of a drug or not has, at best, very little impact on the decisions.
The job of the FDA is to enforce regulations, not to save lives.
I'm sorry, but when dealing with healthcare organizations and policy-makers, it's more like the "holy writ" than the idealized system you describe later.
Serious question, how many of those people would have died in the past 12 months if they didn't get COVID? The number is most likely not 500,000, but it also probably isn't 0.
Is it most likely something insignificant like 5,000?
[1] https://www.medrxiv.org/content/10.1101/2021.01.27.21250604v...
This can be answered using “excess mortality” data.
Studies have shown during that time period, about 600,000 more people died than would have been expected compared to deaths in the previous year.
The official covid death count is likely an undercount of deaths caused by covid, because a number of people died from covid related complications and got recorded as pneumonia, Alzheimer’s, or heart disease/attack/stroke related deaths.
https://www.nytimes.com/interactive/2021/01/14/us/covid-19-d...
Also offset by excess deaths over the next few years due to long term effects of a sedentary lifestyle, stress, and all the overcompensating we are likely to see next year with people trying to “make up for lost time”.
I'm not sure how outdoors-y fatalities will be impacted by all of this, but people are definitely not "doing fewer outdoor actives" right now.
That's a theory. Meanwhile, we know that many places are classifying anyone who dies within N days of a positive test (N is typically 30) as a "covid death", regardless of actual cause.
I can guarantee that not all of those people died from Covid-19. Point being: there's likely to be overcount and undercount, for different reasons.
In 2020, approximately 3,358,814 deaths occurred in the United States (Table). The age-adjusted rate was 828.7 deaths per 100,000 population, an increase of 15.9% from 715.2 in 2019.
Assuming the rates stayed the same or roughly so from year to year, it appears that not many of them would have died sans COVID19. Certainly well over 5000. If there is a trend, none of the data I looked at on the CDC site supported this, raw deaths have been rising in the last 5 years but death's per 100,000 have held. So if it's a small increase per 100,000 is "normal" given those trends 16% is still well outside the normal, so it's likely something like 300,000 or there about. I sure someone here could do the math to verify that but I don't feel like it. :)
ref: https://www.cdc.gov/nchs/products/databriefs/db395.htm https://www.cdc.gov/mmwr/volumes/70/wr/mm7014e1.htm
Are those side effects lists just a catch it all sort of exception where they throw anything there just in case? Honest question.
How many people will point to this or feel a bit hesitant about getting J&J vaccine now?
Also: the side effect profile for the moderna and pfizer vaccines in the clinical trials was far WORSE than the jnj vaccine.
Edit: gene-based not gene-therapy
A potential danger of DNA-based vaccines is the integration of plasmid DNA into the cell genome (1). Insertional mutagenesis occurs rarely but can become a realistic danger when the number of events is very large, i.e. as in mass vaccination of a population.
First of all, plasmid != viral vector. That's why the Nature paper you cited had to use electroporation to introduce the payload. As J&J is a viral vector vaccine, I would not be confident in using this paper to make the argument that an adenovirus-based vaccine could modify a host's DNA.
Second, your article does not make the claim you think it does. Specifically, the discussion says:
> Using simple intramuscular injection, the vast majority of plasmid DNA that persists is extrachromosomal, and the frequency of integration, if it occurs at all, is negligible.
> However, even if the residual plasmid in the gel-purified genomic DNA did represent integrated plasmid, one copy... would be at least three orders of magnitude below the frequency of spontaneous gene-inactivating mutations...
That is, the delivered gene does not integrate directly into the genome itself, but rather stays in the cell. To detect whether the gene stays in the host cell, the article compares molecular weight and uses a PCR test. Both methods do not tell us whether the gene inserts itself into the host DNA; one way to detect that would be to sequence the subsequent DNA, which would be monstrously expensive (because the modification incidence is extremely low).
The only way that a gene might integrate itself into the chromosome is if during DNA transcription, an error occurs and the foreign DNA is merged onto the host DNA. But this would be incredibly rare because it would require most base pairs to match up between the host & foreign DNA; otherwise, the cell would attempt to repair itself or induce apoptosis.
And even if the resulting base pairs match up, the resulting DNA might not have any behavioral differences because it's (approximately) the same sequence of characters. (And you would need another transcription error later on that happens to reduce the non-modified strand by approximately the same length. That's also extremely unlikely.)
Fourth, the Pfizer and Moderna vaccines use a mRNA-based vector, which (in my limited knowledge) is very difficult to integrate into the genome. The most plausible mechanism I could imagine would be:
1. (Optional) an enzyme which converts a modified nucleoside mRNA strand into one that mimics the mRNA chemical structure that is compatible with a reverse transcription enzyme [1].
2. A reverse transcriptase to convert the mRNA strand into a (foreign) DNA strand.
3. A restriction enzyme that cleaves the host DNA suitably so that the foreign DNA can be inserted.
4. A matching ligation enzyme which actually inserts the foreign DNA into the the host DNA.
All these above enzymes do not naturally occur in humans, so DNA modification through this mechanism would be incredibly rare.
[1] https://link.springer.com/protocol/10.1007/978-1-4939-6481-9...
Additional dangers of DNA vaccines include production of anti-DNA antibodies and autoimmune reactions(2). I think we should be communicating these dangers to the public so that healthy individuals at no risk can make a proper benefit-risk decision, instead of just saying "vaccines good" and brushing over concerns.
(1) https://coronavirus.medium.com/decoding-johnson-johnsons-cov...
(2) https://link.springer.com/protocol/10.1007/978-1-62703-110-3...
The article you linked estimates the risk of DNA integration is three orders of magnitude times lower than gene deactivation through regular mutations. I think we're safe.
> Additional dangers of DNA vaccines include production of anti-DNA antibodies and autoimmune reactions
Any documented cases in clinical trials?
To date, there is no licensed DNA vaccine for use in humans, which is my whole point we aren't testing for this and instead just using the whole US population as test subjects without informing them of the risk.
There's no plasmids in the Covid vaccines, a virus has been modified to include instructions for the target proteins.
Edit: plasmids are used to encode the virus for production, they aren't part of the delivery mechanism: https://www.addgene.org/viral-vectors/
> and the present coronavirus vaccines have not undergone preclinical testing as normally required by international regulations.
Citation needed.
The risks could be higher, but maybe our data is not yet there.
Just as a side note, the risks (and gains) are different, maybe I really don't want a child accidentally, but I don't consider the coronavirus too dangerous to me (it's just a hypothetical, this hypothetical person could be wrong, but in the end we all operate on incomplete data)
The type of blood clots (low platelet) the J&J causes gets worse with the standard treatment of blood thinners. This was on the CDC call this morning.
In this pandemic, inaction costs lives. The logical and ethical thing to do is evaluate the cost/benefit and choose the path that kills fewer people. You wouldn't say "we should exit the burning house one at a time in case we get hit by a meteor outside, caution here is the logical and ethical thing"; you're making the same kind of logical error, just with a less-absurd difference between the risk of the two options we need to choose between.
I always appreciate an apt analogy.