But it highlights how badly broken our regulatory system is. We need real reform. There's too many rules, many of which are stupid, and often administered by bureaucrats that don't care.
Well explained. As a strategy it might even work in the near term. It definitely makes sense to try to eliminate as many of the evolutionary labs (that's us) in which Covid is conducting experiments. You certainly can tune vaccines to use those currently invariant epitopes to make a generalized vaccine. It is a mistake however to assume that no mutation can take place that will change that. It might take awhile since the odds are much lower of it happening. And evolution will always keep trying in its random way.
This is a reasonable project but it probably would not make a huge difference in populations outside of the very old, nursing home patients and the immunocompromised
Unless you are part of one of those groups, your first infection will probably be your worst becaue your immune system is naive. After the first infection, you have anti pant T cells that recognize parts of all the virus’s proteins and you’ve developed a mucosal immune response. A pan-SARD-Cov2 vaccine may not provide much benefit to most people. A dangerous new variant would have to somehow evade the prior immunity to severe disease and that’s not particularly likely because that’s not something we see with other human coronaviruses
It actually may be a good idea for those groups i mentioned above. And renew variants probably emerge in people whose immune systems are compromised enough that it leads to a chronic infection with enough immune pressure to select for immune evasion. A vaccine that would prevent this would be great for that reason In addition to protecting immunocompromised people from chronic infections
I would also double check the vaccine efficacy studies to see whether they are comparing vaccinate people to unvaccinated and never infected or all unvaccinated because prior infection does protect against death and that can lead to an underestimation of VE.
And while we’re at it, it would be very nice to get vaccines for other human coronaviruses. One of them, I think OC43 has a case fatality rate of a round 30% in nursing home patients. It would be nice to have a pan-OC43 vaccine.
A proper universal vaccine would likely need to deliver sterilizing immunity. If it does not the nexus of diffusion rate and selective pressure may drive a dangerous mutation.
A few bigger themes remain:
1) COVID is a vascular disease. Just as HIV research in the 80s gave us Immunotherapy for cancer, so will COVID vaccines unlock tools that curtail inflammation. COVIDs vascular behavior will help expose the tricks we need. CVD, T2D and Alzheimers are mostly inflammatory diseases. T2D is a pandemic much larger than COVID.
2) We should figure out how to do challenge studies. The issue is ethics. Medical community sees them as unethical. Losing 24k people a day waiting for RCT trial seems unethical to me. Especially since the RCT of 40k is just a stochastic way to find the 2000 people you would use in a challenge study.
3) Unlocking Biobank data: we have 100 years of biobank data. Biological samples locked up in universities. Data from failed trials. We learn more from failure than success, but access to this biobank data is limited. A breakthrough in HIV came when a WashU doctor recalled a 14 year old boy who presented with AIDS like symptoms in 1962. They found his blood sample and confirmed HIV.
4) We should be able to build MRNA platform technology, or nanoparticle, as a foundation for annual vaccine derivatives. Validate the platform, with broader longitudinal RCT. Then insert annualized active entity tested with challenge study. This is basically how we build annual flu vaccine.
5) Allow people to "Donate their data to science" while alive. Build a database of longitudinal (Phenotypical, meta, and specific assays). Use as foundation for digital twin/synthetic control arms.
What are the political action items? Is there a bill to ask my representatives to support? Are we calling for new leadership in the FDA? If so, who is the scapegoat? Compared to what happened to banks in 2009, the response on institutional COVID failures has been pathetic.
I realize the author is an interested party and take his optimistic estimate with a grain of salt. That said, it sounds totally bonkers to me that there isn’t a more serious effort on better pharmaceutical solutions to COVID, both vaccines (and prophylactics generally) and therapeutics. The summary at he beginning is particularly commendable as a sober account reminding us why, despite what we would all like, COVID actually still matters, certainly from a policy stand point.
The majority of my career was in the biopharma industry doing drug regulatory affairs and safety. Mr. Collinson's column while interesting needs to be put into perspective. One major hurdle for vaccines is doing the necessary safety studies to demonstrate that the benefits outweigh risks. Lots of the side effects seen with vaccines are small, if present at all, and on the order of 1 in 10,000 or less. You cannot pick up these in a normal clinical trial of 3000 patients. This necessitates that vaccine trials be done on a far larger cohort and is one reason the FDA is more conservative than looking at a new cancer drug.
Vaccine manufacturing is not trivial. Vaccines are sterile products made under exacting conditions. However, one the process is validated, it is possible to make changes in the vaccine to adopt to new variants. This is why we are able to get new seasonal influenza vaccines each year. Public health authorities and the vaccine industry agree upon the circulating flu viruses and change the production strain. Major regulatory filings and review are not required. We are seeing this approach being applied by both manufacturers of mRNA vaccines right now. A similar approach can be taken by companies who are close to approval of adjuvant/protein vaccines.
During the first year of the pandemic, I put out a daily newsletter for former industry colleagues and friends surveying the research that was being done. I stopped once the first vaccines became available. I looked closely at vaccine development and saw a lot of interesting work going on. Some of the projects are still going on. Canada has licensed a tobacco produced protein vaccine and the ferritin nano particle vaccine developed by Walter Reed is in clinical trials right now:. Volunteers are still being sought to finish up the Phase 1 trial: https://www.wrair.army.mil/node/645
Nasal vaccines have been used in the past with varying degrees of success. A commercial influenza vaccine has been around since 2003 but is not recommended for those > 50 years of age. There is also a bacterial delivery system that will get Covid antigen to the gastric mucosal system.
A number of vaccine approaches were under development several years ago when Zika virus was thought to pose a major public health problem When the virus disappeared these projects were shelved and a major opportunity to test vaccine platforms for the development of neutralizing antibodies was lost. Had such work continued it might have provided valuable information that could have helped out Covid vaccine developers.
There are a number of other issues that can be discussed but I'll stop with these. Intrepid uses of google can find the archive of my Covid-19 newsletter fairly easily.
"Lots of the side effects seen with vaccines are small, if present at all, and on the order of 1 in 10,000 or less"
Ok, so? Tell people there might be a 1 in 10k chance of something going wrong, pay out compensation if it does happen, and then release it on the market.
Right?! Of course the only way to measure a side effect like that would be to more quickly run larger trials. So highlighting this risk is not really a counterargument to speeding up the process. And this is to say nothing of the probability of death from COVID for the elderly without a vaccine. It's basic cost-benefit analysis that the FDA fails terribly at: death > rare possible side effects. The haunting reality is that Moderna had already developed and manufactured the vaccine for testing before the first American died from COVID.
It's interesting that there's basically no constituency for this. People on the right largely never thought covid was a big deal, so them taking action now all of a sudden won't happen, and people on the left seem very hesitant to criticize the FDA or the public health establishment, so they're not going to support reform if they won't admit reform is even needed.
So we're just left with bad policy. It's unfortunate.
We need smart people who believe in science to stand up and say the quiet part out loud: the FDA, NIH and CDC have all been proven incompetent. Reform and urgency are both very much needed. But the opposition from the right seems to make everyone reluctant to do that for fear of looking like a Trump supporter or anti-vaxxer or some such nonsense. This post is a great step in the right direction. I hope to see this type of column in the NYT and be mainstreamed.
I would rather put it that there is no apparent political feasibility. It seems like one of many many no-brainer centrist position that in fact would have a very healthy constituency in terms of percentage of the electorate supporting some of the suggested moves (and certainly the goal of government doing more to facilitate the speedy development of safe and effective next generation of covid vaccines and therapeutics) but it's rather the polarized political landscape that makes it difficult to get the popular will to actually matter.
Yes, assuming it's accurate, the most persuasive point in the article that this is a $1 trillion bill just laying on the sidewalk, whatever you think about it's overall significance in the scheme of things. But there're probably a lot of $1 trillion bills, or at least large ones, laying around that we don't pick up, because they're not important enough to anybody in particular.
The right would respond by saying that if we stopped caring about covid and sucked it up and got on with our lives, we can pick up a bill greater than $1 trillion. The left would respond by saying that why are you caring about money when it's clearly less important than people's lives.
(But yeah I agree that that's the most persuasive point.)
Exactly, this is pretty how a collective organism like a human society makes decisions about where the cutoff is between a collective problem that everyone needs to stop and focus on, and one that that can be muddled through.
Call it hive/swarm decisionmaking vs centralized decision-making. The difference is illustrated by the contrast between how the US and China have responded to covid.
Great post. One thought about getting things done faster is that it doesn’t quite make sense to drive this research exclusively through academic labs. As with OWS, it would likely be faster to work with biotech/pharma companies or to arrange partnerships between academic and industry groups where it makes sense. I’ve worked in both worlds, and academics just really aren’t set up to do translational research in the same way that companies are (e.g. navigating the red-tape that the author provides several examples of). For a grant-making institution, it of course makes sense to work with academics, but to drive things across the finish line, I think it’s reasonable to bring in industry as well. Again this is a role government can/should be playing.
CEPI in particular has done a good job in my opinion of identifying groups in academia and industry with novel approaches. They have a running list of their awardees and are cutting checks for exactly this purpose.
Correcting a lot of the federal administrative and bureaucractic dysfunction (and general gov't competence) really needs to be an electoral issue.
Perception of inefficiency/incompetence is probably to blame with a decent amount of the default/knee-jerk resistance to more and bigger government. (The dedicated small government types won't care, but the vast squishy middle could be persuaded)
Because bureaucracy is super resistant to change and risk, executive action alone can only do so much, and making a real impact is probably going to require a fight and the expenditure of political capital.
But long-term I think it will be a clear net positive for the party that actually wants the government to...you know...do stuff.
We need to get a new age version of Jon Stossel (maybe John Oliver? Jon Stewart?) who gets a weekly show that highlights cases of government incompetence like this in easy to understand terms. Ideally in a manner that nudges toward *better government* not *no government*.
It's probably not terribly important to the main thrust of the article, but where is the 380 deaths per day figure coming from? I'm seeing under 300, currently, and that number being below 400 since April.
Matt, would you be open to having someone who takes the other side of this debate, or is at least more concerned about the risks of rushing a vaccine that doesn’t work or hurts people, give their side of the story? I’m not able to evaluate this argument, and I bet most of your readers are in the same boat. I can identify concerns - I mean, this is a developer saying he knows about this *amazing* technology, and why isn’t everyone getting out of the way to let it come to market. That take has earned at least as much suspicion as government regulators, especially in the health area (Theranos, anyone?)
What would be especially helpful is to get beyond directional arguments (faster! slower!) to get a better sense of the specific requirements that take a lot of time and what’s the risk of not running them. E.g., he complains about having to run animal trials. How much time is involved, and what’s the risk in running them concurrently instead of in series? Can we focus on some big-ticket items to evaluate the debate? If it really is about death by 1000 cuts, ok, let’s still engage on that: where is the obstacle?
One perspective taking measure: for all the complaints about FDA, didn’t the US have the vaccine broadly available earlier than any other country? It’s not as though there is another paragon country out there we are lagging, is there? Or if there is it would be good to know.
The argument against accelerating approval for pandemic vaccines needs to be distinguished from the more general libertarian position that drug approval barriers should be lowered. I've spent my career in pharma and medical devices, in commercial roles but continually working on clinical studies and interpreting their data.
Those advocating against faster pandemic vaccine rely on straw man arguments. It's difficult to find somebody to competently take this position. A protest "review," (https://tinyurl.com/3bzn6ph4) which included two authors who quit the FDA in protest of booster approvals, is representative. This and others tend to rely on three arguments: 1) vaccines are not riskless, 2) the positive data for [insert new vaccine or application] is not yet definitive, and 3) moving quickly will undermine confidence in vaccines. Instead of reckoning with the cost-benefit tradeoffs of the decision, the logic is one-sided : highlighting risks of approval but not of delay. And, not only does the "if you disagree with me, people will be more skeptical of vaccines" have no data to support it--note people who critique a lack of data while simultaneously making unsupported claims--but I've anecdotally found that most such claims in the pandemic ended up being completely wrong.
The more general libertarian view has two flavors. One, call it the "strong acceleration" view, wants to shift decision making from regulators to consumers and their physicians. One mechanism is making the FDA approve any drug approved by selected other countries (a lowest-common denominator approach to regulation). Another is expanding compassionate use programs where people can access unapproved drugs for extreme cases, but making the bar for this much lower. In my personal view, this is batshit crazy. Anybody who has seen how drug approvals flow to drug promotion and then to consumer choice would recognize the risks here. This is an area where having somebody write a post would be very valuable.
There is a much better argument, call it the "weak acceleration" view, that calls for streamlining the approval process in many ways. I'm very sympathetic to this. Arguments against it often have the straw man quality of those against pandemic vaccine acceleration.
I basically agree with you, but would like to steel man the argument for robust efficacy endpoints prior to vaccine booster rollout (I agree that safety concerns and the armchair social psychology are weak objections at this point, at least with the mRNA platform):
The original vaccine series had a huge and relatively durable effect size on major outcomes like hospitalization and death. The first booster had a much smaller absolute effect size, but did improve hospitalization and death in higher risk populations and people > 50. The second booster has shown minimal effect on any clinically significant outcomes, even in high risk populations.
It's not clear to me, in a landscape where we have relative equipoise on the efficacy of future vaccine boosting, and in a patient population (vaccinated and boosted) where the risk of serious adverse outcomes approximates that of seasonal influenza, that we owe Pfizer and Moderna the right to extract billions of dollars in perpetuity on the basis of expedited, poorly correlated surrogate markers like antibody titers.
That's an excellent point. Thank you for making it. it underscores the need to balance the risks of approval with the risks of delay. The combination of the significant benefit of the vaccines, extremely safe side effect profile, and impact of the pandemic all argued for speed and lowering bars to appeal.
But, a future vaccine with a worse safety profile or lower efficacy could change that calculus.
And I agree that the push to only use antibody titers is not clear cut. I view that as more of a "break glass in case of emergency" option. Healthcare is replete with times when surrogate markers did not correlate with health outcomes.
I'd argue that the commercial rewards for vaccine development are still too low. Covid has been the exception to the rule. But you're right that initial approval should not be able to be gamed into a perpetuity.
Yes the original covid vaccines were ready extremely quickly. But the problem is that now it's business as usual. And business as usual is a horrible regulatory state
Obvi it’s Matt’s prerogative to set the editorial agenda of his own blog, but I do want to second Theodore’s initial comment about how useful it would be to know what these types of posts are arguing against.
“…lack of basic institutional seriousness” and “self-imposed straightjackets” seem like harsh characterizations of differing values and principle stacks. The author makes it clear that his #1 goal is speed, so any barrier to that is a straight jacket, but speed is not the #1 goal of the FDA, so those straight jackets are in service of something else. I wish speed were more of a priority, maybe it should be the top priority, but I fail to see how it not being so makes them institutionally unserious.
I don't have the background to comment on the nature, scope, and appropriateness of the regulatory burden faced by biopharma with regards to vaccine development, but some of his statements about the fundamental science raise eyebrows.
(e.g., he proposes using antibody titers as a surrogate endpoint in clinical trials, when we know that short-term elevations in antibodies do not have robust correlation with long-term protection against infection or long-term protection against severe illness).
But net of the entire performance of the govt, did any other country make the vaccine available more quickly? I’m asking for a big-picture benchmark. Takes descend very quickly into charged language (“wasn’t in any hurry”) and I’m skeptical that these are well informed. I’m open to believing things can be done faster - and I want them to, if the risk-benefit makes sense - but it would help to see the homework. It’s relevant to know how fast other regulators acted. And maybe, even if other regulators took the same amount of time, roughly, it only means that all the regulators are too slow. But if you want to make that argument, ’d like to know how you arrived at it: what risks were they too cautious about, and what is the improvement?
When pharma wants to justify high drug prices, they go on and on about the difficulty of drug development: they have to try tens of thousands of molecules to find a successful drug, and candidates fail at every step along the way. Succeed at phase 1? You might fail phase 2. Make it through phase 2? The results at phase 3 might uncover a very serious adverse even that affects 1 patient in 300. And so on. But now come the people who want things done very differently and it’s all impatience: why are we doing all these stupid tests? What a waste! We know these drugs work and are safe! I am not an expert, and I can’t really adjudicate these disputes. I would like to see experts, who are well informed, pick out what they see as the key risk-benefit pivots - where we would save a lot of time - and ask: do we need to do this? Why or why not?
Israel absolutely smoked everyone else at getting vaccines into arms. In the UK we didn't make the vaccine generally available until long after the US did, but that's because we did a much stricter rollout by age cohort, aimed at maximizing lives saved - in terms of jabs administered per capita, we've been ahead of you for most of the time.
The US paid a lot early on to get ensured early access to several hundred million doses each from several manufacturers (including some whose products were never approved but still got the money). The EU made the big different decision of negotiating a bit on price, and saving several billion dollars on drug costs, but getting them a few months after the US.
I think the regulatory process was similarly slow in all countries (though as others mentioned, the UK did grant approval a week or so earlier).
To answer your first question, the UK administered the first Pfizer jab outside of clinical trials on Dec 8, and for the US it was Dec 14 (Sputnik doesn't count, sorry Russia). Not sure this is praise for the NHS, but the US and UK were more or less tied for first. Roll out, distribution, voluntary uptake, etc., are different questions of course.
I'm interested, but is the median American? What do we understand about reinfection? Seems like bundling with yearly flu shot is best hope. I also think we could pay people to take it. I do not understand why so many incentives were left on the table the last time.
"Virtually everyone knows plenty of people who contracted COVID after being vaccinated and were out of commission for a week or more." Having just had COVID after being vaccinated and boosted, while getting sick wasn't super fun, easily the worst part was being essentially unable to work and being trapped in the house for *weeks* as COVID moved through our family and we desperately waited daycare's required quarantine to end, even though the kids are fully vaccinated and were symptom free shortly after testing positive. I think encouraging liberalizing daycare COVID restrictions will be very popular in a couple of months after all the little kids have had an opportunity to be vaccinated.
My experience is similar. I know plenty of people who have had Covid who were vaccinated and it was just annoying. Even in people who weren’t boosted. I would prefer Covid to a regular old rhinovirus because it was milder and I recovered fully after 3-4 days.
Yeah, the author chose to, ah... operate at a credibility deficit... with language like that (see also post-vax long-covid doomscrolling). I have no idea why. It seems fairly common, like you need to establish bona fides by being Still Rather Concerned. I think it plays the opposite.
*The worst* post-vax covid case I personally know apologized when he called into the next week's meeting, because he hadn't gotten as much done on the project as planned on account of "covid kicked my butt". He wasn't "out of commission"--he was working throughout the dang thing!
Did you test your kid(s) for covid every time they got sick this fall? Mine got sick from daycare so many times it just made no sense to me to try to schedule an appointment, wake up really early, drive down to the testing place, wait in line for an hour or more, etc..
She was probably sick more than a dozen separate times from Oct-March, and we had the same symptoms around half those times. I assume that one of those illnesses was covid but I guess I'll never know.
All this is to say: I'm curious if your experience with testing is similar or not. I suppose now it would be easier to do the tests than it was in the winter, so maybe I will get one for her next time she has a cold. But sometimes I wonder why so many people are still testing for covid if they're already vaccinated and boosted. For young, healthy, vaccinated people, what difference does it make if the test comes back positive or negative?
Ah but you were a victim of FDA not approving dirt cheap tests in early 2020. Asymptomatic testing could have avoided a lot of the cost of restrictions on (and fear of) social interactions
I wish we had multi-virus tests. It seems that it should be not too much harder for Abbott to make a little card with four potential stripes - one control stripe, one that turns red if you have COVID antigens, one that turns red if you have flu antigens, and one that turns red if you have RSV antigens. I don’t exactly know how much good would be achieved by being able to know which of these you have, but I do think this is one of those things where having the ability to have widespread knowledge would enable better responses.
As someone who will shortly have two children under two, I would love to be able to test visitors for RSV on their arrival to my home. That would be quite valuable to me.
I hear where you're coming from, but I think my conclusions are most like Belisarius below. They just get sick so often, for my kid she'd get a cold or fever every other week from about November to March. Maybe if I knew first exposure was less risky at age 4 than age 3 then delaying the inevitable makes some sense. But my sense is its worse for younger kids mostly because it's their first exposure, not because of their age.
We tested a lot, mostly because both kids are in the Moderna trial. We also mostly did rapids, even though those aren't technically approved for kids under two.
The test that started our quarantine was we were headed to a party with grandparents who have risk factors and my wife was symptomatic.
Agree overall that we should stop testing because it's not like we're trying to stop transmission anymore in the US
If you're a rule follower and you test positive for the virus, close contacts are supposed to test. Kids would be close contacts. We have a very similar story to OP and the reason we tested the kids is we were supposed to as they are close contacts; and of course, camp / childcare does not want your positive kid attending even if they are asymptomatic.
I very much support this.
But it highlights how badly broken our regulatory system is. We need real reform. There's too many rules, many of which are stupid, and often administered by bureaucrats that don't care.
This needs to change
We lament the change in federal government focus from Warp Speed to complacency, but we don’t endeavor to explain why the change. Hmmm, what changed?
Well explained. As a strategy it might even work in the near term. It definitely makes sense to try to eliminate as many of the evolutionary labs (that's us) in which Covid is conducting experiments. You certainly can tune vaccines to use those currently invariant epitopes to make a generalized vaccine. It is a mistake however to assume that no mutation can take place that will change that. It might take awhile since the odds are much lower of it happening. And evolution will always keep trying in its random way.
This is a reasonable project but it probably would not make a huge difference in populations outside of the very old, nursing home patients and the immunocompromised
Unless you are part of one of those groups, your first infection will probably be your worst becaue your immune system is naive. After the first infection, you have anti pant T cells that recognize parts of all the virus’s proteins and you’ve developed a mucosal immune response. A pan-SARD-Cov2 vaccine may not provide much benefit to most people. A dangerous new variant would have to somehow evade the prior immunity to severe disease and that’s not particularly likely because that’s not something we see with other human coronaviruses
It actually may be a good idea for those groups i mentioned above. And renew variants probably emerge in people whose immune systems are compromised enough that it leads to a chronic infection with enough immune pressure to select for immune evasion. A vaccine that would prevent this would be great for that reason In addition to protecting immunocompromised people from chronic infections
I would also double check the vaccine efficacy studies to see whether they are comparing vaccinate people to unvaccinated and never infected or all unvaccinated because prior infection does protect against death and that can lead to an underestimation of VE.
And while we’re at it, it would be very nice to get vaccines for other human coronaviruses. One of them, I think OC43 has a case fatality rate of a round 30% in nursing home patients. It would be nice to have a pan-OC43 vaccine.
A proper universal vaccine would likely need to deliver sterilizing immunity. If it does not the nexus of diffusion rate and selective pressure may drive a dangerous mutation.
A few bigger themes remain:
1) COVID is a vascular disease. Just as HIV research in the 80s gave us Immunotherapy for cancer, so will COVID vaccines unlock tools that curtail inflammation. COVIDs vascular behavior will help expose the tricks we need. CVD, T2D and Alzheimers are mostly inflammatory diseases. T2D is a pandemic much larger than COVID.
2) We should figure out how to do challenge studies. The issue is ethics. Medical community sees them as unethical. Losing 24k people a day waiting for RCT trial seems unethical to me. Especially since the RCT of 40k is just a stochastic way to find the 2000 people you would use in a challenge study.
3) Unlocking Biobank data: we have 100 years of biobank data. Biological samples locked up in universities. Data from failed trials. We learn more from failure than success, but access to this biobank data is limited. A breakthrough in HIV came when a WashU doctor recalled a 14 year old boy who presented with AIDS like symptoms in 1962. They found his blood sample and confirmed HIV.
4) We should be able to build MRNA platform technology, or nanoparticle, as a foundation for annual vaccine derivatives. Validate the platform, with broader longitudinal RCT. Then insert annualized active entity tested with challenge study. This is basically how we build annual flu vaccine.
5) Allow people to "Donate their data to science" while alive. Build a database of longitudinal (Phenotypical, meta, and specific assays). Use as foundation for digital twin/synthetic control arms.
"Network Medicine" is the future. Need more data https://amzn.to/3nHbidX
If anyone wants to help on this feel free to email me cwilliams@iselectfund.com @jcarterwil
What are the political action items? Is there a bill to ask my representatives to support? Are we calling for new leadership in the FDA? If so, who is the scapegoat? Compared to what happened to banks in 2009, the response on institutional COVID failures has been pathetic.
HOW DO WE HELP MAKE THIS HAPPEN-SOONER THAN LATER? Thx for all this.
I realize the author is an interested party and take his optimistic estimate with a grain of salt. That said, it sounds totally bonkers to me that there isn’t a more serious effort on better pharmaceutical solutions to COVID, both vaccines (and prophylactics generally) and therapeutics. The summary at he beginning is particularly commendable as a sober account reminding us why, despite what we would all like, COVID actually still matters, certainly from a policy stand point.
The majority of my career was in the biopharma industry doing drug regulatory affairs and safety. Mr. Collinson's column while interesting needs to be put into perspective. One major hurdle for vaccines is doing the necessary safety studies to demonstrate that the benefits outweigh risks. Lots of the side effects seen with vaccines are small, if present at all, and on the order of 1 in 10,000 or less. You cannot pick up these in a normal clinical trial of 3000 patients. This necessitates that vaccine trials be done on a far larger cohort and is one reason the FDA is more conservative than looking at a new cancer drug.
Vaccine manufacturing is not trivial. Vaccines are sterile products made under exacting conditions. However, one the process is validated, it is possible to make changes in the vaccine to adopt to new variants. This is why we are able to get new seasonal influenza vaccines each year. Public health authorities and the vaccine industry agree upon the circulating flu viruses and change the production strain. Major regulatory filings and review are not required. We are seeing this approach being applied by both manufacturers of mRNA vaccines right now. A similar approach can be taken by companies who are close to approval of adjuvant/protein vaccines.
During the first year of the pandemic, I put out a daily newsletter for former industry colleagues and friends surveying the research that was being done. I stopped once the first vaccines became available. I looked closely at vaccine development and saw a lot of interesting work going on. Some of the projects are still going on. Canada has licensed a tobacco produced protein vaccine and the ferritin nano particle vaccine developed by Walter Reed is in clinical trials right now:. Volunteers are still being sought to finish up the Phase 1 trial: https://www.wrair.army.mil/node/645
Nasal vaccines have been used in the past with varying degrees of success. A commercial influenza vaccine has been around since 2003 but is not recommended for those > 50 years of age. There is also a bacterial delivery system that will get Covid antigen to the gastric mucosal system.
A number of vaccine approaches were under development several years ago when Zika virus was thought to pose a major public health problem When the virus disappeared these projects were shelved and a major opportunity to test vaccine platforms for the development of neutralizing antibodies was lost. Had such work continued it might have provided valuable information that could have helped out Covid vaccine developers.
There are a number of other issues that can be discussed but I'll stop with these. Intrepid uses of google can find the archive of my Covid-19 newsletter fairly easily.
"Lots of the side effects seen with vaccines are small, if present at all, and on the order of 1 in 10,000 or less"
Ok, so? Tell people there might be a 1 in 10k chance of something going wrong, pay out compensation if it does happen, and then release it on the market.
Right?! Of course the only way to measure a side effect like that would be to more quickly run larger trials. So highlighting this risk is not really a counterargument to speeding up the process. And this is to say nothing of the probability of death from COVID for the elderly without a vaccine. It's basic cost-benefit analysis that the FDA fails terribly at: death > rare possible side effects. The haunting reality is that Moderna had already developed and manufactured the vaccine for testing before the first American died from COVID.
https://johnhcochrane.blogspot.com/2020/12/free-market-vaccines.html
It's interesting that there's basically no constituency for this. People on the right largely never thought covid was a big deal, so them taking action now all of a sudden won't happen, and people on the left seem very hesitant to criticize the FDA or the public health establishment, so they're not going to support reform if they won't admit reform is even needed.
So we're just left with bad policy. It's unfortunate.
We need smart people who believe in science to stand up and say the quiet part out loud: the FDA, NIH and CDC have all been proven incompetent. Reform and urgency are both very much needed. But the opposition from the right seems to make everyone reluctant to do that for fear of looking like a Trump supporter or anti-vaxxer or some such nonsense. This post is a great step in the right direction. I hope to see this type of column in the NYT and be mainstreamed.
Well you can be nicer and just say they fail to use the best methodology in making their decisions, something like rule utilitarianism.
The point of this Substack is to reform the Left on this as on many other things.
I would rather put it that there is no apparent political feasibility. It seems like one of many many no-brainer centrist position that in fact would have a very healthy constituency in terms of percentage of the electorate supporting some of the suggested moves (and certainly the goal of government doing more to facilitate the speedy development of safe and effective next generation of covid vaccines and therapeutics) but it's rather the polarized political landscape that makes it difficult to get the popular will to actually matter.
Id volunteer
Yes, assuming it's accurate, the most persuasive point in the article that this is a $1 trillion bill just laying on the sidewalk, whatever you think about it's overall significance in the scheme of things. But there're probably a lot of $1 trillion bills, or at least large ones, laying around that we don't pick up, because they're not important enough to anybody in particular.
The right would respond by saying that if we stopped caring about covid and sucked it up and got on with our lives, we can pick up a bill greater than $1 trillion. The left would respond by saying that why are you caring about money when it's clearly less important than people's lives.
(But yeah I agree that that's the most persuasive point.)
The point is to care optimally about COVID; neither refuse to get vaccinated nor to close outdoor playgrounds.
But on the margin are we pushing as hard as we used to in order to overcome the obstacles to progress?
A major premise of this blog is that, in relation to bureaucratic efficiency, the past really *was* vastly different.
Yes, but I would argue we are no longer so good at it
Exactly, this is pretty how a collective organism like a human society makes decisions about where the cutoff is between a collective problem that everyone needs to stop and focus on, and one that that can be muddled through.
Call it hive/swarm decisionmaking vs centralized decision-making. The difference is illustrated by the contrast between how the US and China have responded to covid.
Great post. One thought about getting things done faster is that it doesn’t quite make sense to drive this research exclusively through academic labs. As with OWS, it would likely be faster to work with biotech/pharma companies or to arrange partnerships between academic and industry groups where it makes sense. I’ve worked in both worlds, and academics just really aren’t set up to do translational research in the same way that companies are (e.g. navigating the red-tape that the author provides several examples of). For a grant-making institution, it of course makes sense to work with academics, but to drive things across the finish line, I think it’s reasonable to bring in industry as well. Again this is a role government can/should be playing.
CEPI in particular has done a good job in my opinion of identifying groups in academia and industry with novel approaches. They have a running list of their awardees and are cutting checks for exactly this purpose.
Correcting a lot of the federal administrative and bureaucractic dysfunction (and general gov't competence) really needs to be an electoral issue.
Perception of inefficiency/incompetence is probably to blame with a decent amount of the default/knee-jerk resistance to more and bigger government. (The dedicated small government types won't care, but the vast squishy middle could be persuaded)
Because bureaucracy is super resistant to change and risk, executive action alone can only do so much, and making a real impact is probably going to require a fight and the expenditure of political capital.
But long-term I think it will be a clear net positive for the party that actually wants the government to...you know...do stuff.
We need to get a new age version of Jon Stossel (maybe John Oliver? Jon Stewart?) who gets a weekly show that highlights cases of government incompetence like this in easy to understand terms. Ideally in a manner that nudges toward *better government* not *no government*.
If that's the definition of "Left" then it's miniscule.
1 nanoFox
It's probably not terribly important to the main thrust of the article, but where is the 380 deaths per day figure coming from? I'm seeing under 300, currently, and that number being below 400 since April.
https://www.worldometers.info/coronavirus/country/us/
Matt, would you be open to having someone who takes the other side of this debate, or is at least more concerned about the risks of rushing a vaccine that doesn’t work or hurts people, give their side of the story? I’m not able to evaluate this argument, and I bet most of your readers are in the same boat. I can identify concerns - I mean, this is a developer saying he knows about this *amazing* technology, and why isn’t everyone getting out of the way to let it come to market. That take has earned at least as much suspicion as government regulators, especially in the health area (Theranos, anyone?)
What would be especially helpful is to get beyond directional arguments (faster! slower!) to get a better sense of the specific requirements that take a lot of time and what’s the risk of not running them. E.g., he complains about having to run animal trials. How much time is involved, and what’s the risk in running them concurrently instead of in series? Can we focus on some big-ticket items to evaluate the debate? If it really is about death by 1000 cuts, ok, let’s still engage on that: where is the obstacle?
One perspective taking measure: for all the complaints about FDA, didn’t the US have the vaccine broadly available earlier than any other country? It’s not as though there is another paragon country out there we are lagging, is there? Or if there is it would be good to know.
The argument against accelerating approval for pandemic vaccines needs to be distinguished from the more general libertarian position that drug approval barriers should be lowered. I've spent my career in pharma and medical devices, in commercial roles but continually working on clinical studies and interpreting their data.
Those advocating against faster pandemic vaccine rely on straw man arguments. It's difficult to find somebody to competently take this position. A protest "review," (https://tinyurl.com/3bzn6ph4) which included two authors who quit the FDA in protest of booster approvals, is representative. This and others tend to rely on three arguments: 1) vaccines are not riskless, 2) the positive data for [insert new vaccine or application] is not yet definitive, and 3) moving quickly will undermine confidence in vaccines. Instead of reckoning with the cost-benefit tradeoffs of the decision, the logic is one-sided : highlighting risks of approval but not of delay. And, not only does the "if you disagree with me, people will be more skeptical of vaccines" have no data to support it--note people who critique a lack of data while simultaneously making unsupported claims--but I've anecdotally found that most such claims in the pandemic ended up being completely wrong.
The more general libertarian view has two flavors. One, call it the "strong acceleration" view, wants to shift decision making from regulators to consumers and their physicians. One mechanism is making the FDA approve any drug approved by selected other countries (a lowest-common denominator approach to regulation). Another is expanding compassionate use programs where people can access unapproved drugs for extreme cases, but making the bar for this much lower. In my personal view, this is batshit crazy. Anybody who has seen how drug approvals flow to drug promotion and then to consumer choice would recognize the risks here. This is an area where having somebody write a post would be very valuable.
There is a much better argument, call it the "weak acceleration" view, that calls for streamlining the approval process in many ways. I'm very sympathetic to this. Arguments against it often have the straw man quality of those against pandemic vaccine acceleration.
I basically agree with you, but would like to steel man the argument for robust efficacy endpoints prior to vaccine booster rollout (I agree that safety concerns and the armchair social psychology are weak objections at this point, at least with the mRNA platform):
The original vaccine series had a huge and relatively durable effect size on major outcomes like hospitalization and death. The first booster had a much smaller absolute effect size, but did improve hospitalization and death in higher risk populations and people > 50. The second booster has shown minimal effect on any clinically significant outcomes, even in high risk populations.
It's not clear to me, in a landscape where we have relative equipoise on the efficacy of future vaccine boosting, and in a patient population (vaccinated and boosted) where the risk of serious adverse outcomes approximates that of seasonal influenza, that we owe Pfizer and Moderna the right to extract billions of dollars in perpetuity on the basis of expedited, poorly correlated surrogate markers like antibody titers.
That's an excellent point. Thank you for making it. it underscores the need to balance the risks of approval with the risks of delay. The combination of the significant benefit of the vaccines, extremely safe side effect profile, and impact of the pandemic all argued for speed and lowering bars to appeal.
But, a future vaccine with a worse safety profile or lower efficacy could change that calculus.
And I agree that the push to only use antibody titers is not clear cut. I view that as more of a "break glass in case of emergency" option. Healthcare is replete with times when surrogate markers did not correlate with health outcomes.
I'd argue that the commercial rewards for vaccine development are still too low. Covid has been the exception to the rule. But you're right that initial approval should not be able to be gamed into a perpetuity.
Yes the original covid vaccines were ready extremely quickly. But the problem is that now it's business as usual. And business as usual is a horrible regulatory state
Obvi it’s Matt’s prerogative to set the editorial agenda of his own blog, but I do want to second Theodore’s initial comment about how useful it would be to know what these types of posts are arguing against.
“…lack of basic institutional seriousness” and “self-imposed straightjackets” seem like harsh characterizations of differing values and principle stacks. The author makes it clear that his #1 goal is speed, so any barrier to that is a straight jacket, but speed is not the #1 goal of the FDA, so those straight jackets are in service of something else. I wish speed were more of a priority, maybe it should be the top priority, but I fail to see how it not being so makes them institutionally unserious.
I'd say that the problem is that FDA does not seem to consider delayed benefits (and costs) in the way it designs its cost benefit analyses.
I don't have the background to comment on the nature, scope, and appropriateness of the regulatory burden faced by biopharma with regards to vaccine development, but some of his statements about the fundamental science raise eyebrows.
(e.g., he proposes using antibody titers as a surrogate endpoint in clinical trials, when we know that short-term elevations in antibodies do not have robust correlation with long-term protection against infection or long-term protection against severe illness).
But net of the entire performance of the govt, did any other country make the vaccine available more quickly? I’m asking for a big-picture benchmark. Takes descend very quickly into charged language (“wasn’t in any hurry”) and I’m skeptical that these are well informed. I’m open to believing things can be done faster - and I want them to, if the risk-benefit makes sense - but it would help to see the homework. It’s relevant to know how fast other regulators acted. And maybe, even if other regulators took the same amount of time, roughly, it only means that all the regulators are too slow. But if you want to make that argument, ’d like to know how you arrived at it: what risks were they too cautious about, and what is the improvement?
When pharma wants to justify high drug prices, they go on and on about the difficulty of drug development: they have to try tens of thousands of molecules to find a successful drug, and candidates fail at every step along the way. Succeed at phase 1? You might fail phase 2. Make it through phase 2? The results at phase 3 might uncover a very serious adverse even that affects 1 patient in 300. And so on. But now come the people who want things done very differently and it’s all impatience: why are we doing all these stupid tests? What a waste! We know these drugs work and are safe! I am not an expert, and I can’t really adjudicate these disputes. I would like to see experts, who are well informed, pick out what they see as the key risk-benefit pivots - where we would save a lot of time - and ask: do we need to do this? Why or why not?
Israel absolutely smoked everyone else at getting vaccines into arms. In the UK we didn't make the vaccine generally available until long after the US did, but that's because we did a much stricter rollout by age cohort, aimed at maximizing lives saved - in terms of jabs administered per capita, we've been ahead of you for most of the time.
The US paid a lot early on to get ensured early access to several hundred million doses each from several manufacturers (including some whose products were never approved but still got the money). The EU made the big different decision of negotiating a bit on price, and saving several billion dollars on drug costs, but getting them a few months after the US.
I think the regulatory process was similarly slow in all countries (though as others mentioned, the UK did grant approval a week or so earlier).
And all things that the UK regulators did.
To answer your first question, the UK administered the first Pfizer jab outside of clinical trials on Dec 8, and for the US it was Dec 14 (Sputnik doesn't count, sorry Russia). Not sure this is praise for the NHS, but the US and UK were more or less tied for first. Roll out, distribution, voluntary uptake, etc., are different questions of course.
I'm interested, but is the median American? What do we understand about reinfection? Seems like bundling with yearly flu shot is best hope. I also think we could pay people to take it. I do not understand why so many incentives were left on the table the last time.
"Virtually everyone knows plenty of people who contracted COVID after being vaccinated and were out of commission for a week or more." Having just had COVID after being vaccinated and boosted, while getting sick wasn't super fun, easily the worst part was being essentially unable to work and being trapped in the house for *weeks* as COVID moved through our family and we desperately waited daycare's required quarantine to end, even though the kids are fully vaccinated and were symptom free shortly after testing positive. I think encouraging liberalizing daycare COVID restrictions will be very popular in a couple of months after all the little kids have had an opportunity to be vaccinated.
FWIW I was vaxxed and Omicron put me out of commission for 3-4 days
My experience is similar. I know plenty of people who have had Covid who were vaccinated and it was just annoying. Even in people who weren’t boosted. I would prefer Covid to a regular old rhinovirus because it was milder and I recovered fully after 3-4 days.
Yeah, the author chose to, ah... operate at a credibility deficit... with language like that (see also post-vax long-covid doomscrolling). I have no idea why. It seems fairly common, like you need to establish bona fides by being Still Rather Concerned. I think it plays the opposite.
*The worst* post-vax covid case I personally know apologized when he called into the next week's meeting, because he hadn't gotten as much done on the project as planned on account of "covid kicked my butt". He wasn't "out of commission"--he was working throughout the dang thing!
Did you test your kid(s) for covid every time they got sick this fall? Mine got sick from daycare so many times it just made no sense to me to try to schedule an appointment, wake up really early, drive down to the testing place, wait in line for an hour or more, etc..
She was probably sick more than a dozen separate times from Oct-March, and we had the same symptoms around half those times. I assume that one of those illnesses was covid but I guess I'll never know.
All this is to say: I'm curious if your experience with testing is similar or not. I suppose now it would be easier to do the tests than it was in the winter, so maybe I will get one for her next time she has a cold. But sometimes I wonder why so many people are still testing for covid if they're already vaccinated and boosted. For young, healthy, vaccinated people, what difference does it make if the test comes back positive or negative?
Ah but you were a victim of FDA not approving dirt cheap tests in early 2020. Asymptomatic testing could have avoided a lot of the cost of restrictions on (and fear of) social interactions
I wish we had multi-virus tests. It seems that it should be not too much harder for Abbott to make a little card with four potential stripes - one control stripe, one that turns red if you have COVID antigens, one that turns red if you have flu antigens, and one that turns red if you have RSV antigens. I don’t exactly know how much good would be achieved by being able to know which of these you have, but I do think this is one of those things where having the ability to have widespread knowledge would enable better responses.
As someone who will shortly have two children under two, I would love to be able to test visitors for RSV on their arrival to my home. That would be quite valuable to me.
I hear where you're coming from, but I think my conclusions are most like Belisarius below. They just get sick so often, for my kid she'd get a cold or fever every other week from about November to March. Maybe if I knew first exposure was less risky at age 4 than age 3 then delaying the inevitable makes some sense. But my sense is its worse for younger kids mostly because it's their first exposure, not because of their age.
Seems good to do what you can to avoid newborn exposure to RSV. I’m far less concerned about my robust toddler.
That's a fair point. When you said two children under two, I didnt think that one might be a newborn.
It's probably worth some effort to delay, even though success is...unlikely.
Especially if toddler is in preschool/daycare.
As someone with 4 kids under 11, and one still under 2...you are never going to avoid RSV unless you live in a bubble.
Same for many of the other childhood illness.
And RSV in particular sucked for my kids. 3 of them had 104+ fevers from it at some point ~2-3.
We tested a lot, mostly because both kids are in the Moderna trial. We also mostly did rapids, even though those aren't technically approved for kids under two.
The test that started our quarantine was we were headed to a party with grandparents who have risk factors and my wife was symptomatic.
Makes sense
Agree overall that we should stop testing because it's not like we're trying to stop transmission anymore in the US
If you're a rule follower and you test positive for the virus, close contacts are supposed to test. Kids would be close contacts. We have a very similar story to OP and the reason we tested the kids is we were supposed to as they are close contacts; and of course, camp / childcare does not want your positive kid attending even if they are asymptomatic.