After the FDA advisory committee voted in favor of Pfizer’s EUA last Thursday–as almost everyone thought they would–the FDA had difficulty finishing the paperwork. The NYTimes reported:
People familiar with the F.D.A.’s situation say that regulators are now racing to complete a fact sheet, information for physicians and other required documents that go with the authorization.
The paperwork delay meant that the FDA was going to wait to issue the EUA until Monday. That’s when Trump called the FDA “a big, old, slow turtle” and yelled at Hahn to “Stop playing games and start saving lives!!!.” The FDA then sped up and issued the EUA on Friday. As a result, the first tranche of vaccines are being delivered today.
The advisory committee for the Moderna vaccine meets this coming Thursday. Here’s a polite request of the FDA–please have the fact sheet, information for physicians and other required documents ready to go. Thanks.
P.S. We would also be really grateful and, you know, it might save some lives if you allowed Moderna to start shipping now so the vaccine is on-site and ready to go on Friday. Please give it some thought and thanks again for your kind consideration. It’s been very stressful seeing thousands of people dying every day.
If indeed it did, they are asking a similar question at The Economist. In recent times you might cite the onset of Apple’s M1, GPT-3, DeepMind’s application of AI to protein folding, phase III for a credible malaria vaccine, a CRISPR/sickle cell cure, the possibility of a universal flu vaccine, mRNA vaccines, ongoing solar power progress, wonderful new batteries for electric vehicles, a possibly new method for Chinese fusion (?), Chinese photon quantum computing, and ongoing advances in space exploration, most of all from SpaceX. Tesla has a very high market valuation, and Elon is the world’s second richest man.
Distanced work is very important, and here is a separate post on that.
I would say that almost certainly the great stagnation is over in the biomedical sciences. It is less obvious that the great stagnation is over more generally, as we might simply retreat into our former sloth and complacency once we are mostly vaccinated. Applied Divinity Studies has posed some pointed questions about why we might think that stagnation is over.
If you are looking for a quick metric to indicate the great stagnation might be over, consider total factor productivity. It is entirely possible that tfp in 2021 will be 5 or more, its highest level ever. (To be sure, this will show up as a measured increase in inputs more than as tfp, but we all know why those inputs will be increasing and that is because of science…yes this is a problem with tfp measures!) Over the two years to follow after that, we should be seeing very high tfps around the world. So that will be very high tfp for a few years.
Again, that is not proof of a permanent or even an ongoing end to the great stagnation. But it is something.
Two more general points seem relevant. First, many of the biomedical advances seem connected to new platforms, new modes of computation, new uses of AI, and so on, and they should be leading to yet further advances. Second, there are (finally!) some very real advances in energy use, and those tend to bring yet other advances in their wake, and not just advances in bit space.
But not all is rosy. If you recall my paper with Ben Southwood, the obstacles standing in the way of faster scientific progress, such as specialization and bureaucratization, mostly remain and some of them will be getting worse.
My The Great Stagnation, published in 2011, offered some pointed predictions. It argued that the “next big thing” was already with us, namely the internet, but we simply hadn’t learned to use it effectively yet. Once we put the internet at the center of many more of our institutions, rather than treating it as an add-on, the great stagnation would end. Numerous times (using roughly a 2011 start date) I predicted that the great stagnation would be over within twenty years time, though not in the next few years. The Great Stagnation in fact was an optimistic book, at least if you read it to the end and do not just mood affiliate over the title.
By no means would I say that specific scenario has been validated, but as a prediction it is looking not so crazy.
The gains from truly mobilizing the internet may in fact right now be swamping all of the accumulated obstacles we have put in the way of progress.
I also wrote, in 2011, that as the great stagnation approaches its end, we will all be deeply upset, and long for the earlier times. That too is by no means obviously wrong.
Gotta love the logic of bioethicists…
>> Hey guys, can we maybe run a vaccine challenge trial to help accelerate research? We’ve got 30k volunteers signed up already
Aw jeez, that would be horrible! Humans are unable to consent to taking a deadly risk! (though lets ignore doctors volunteering to work despite PPE shortages or soldiers volunteering to fight in remote countries) We might harm a few hundred people with this challenge trial so its best if we just run a Phase 3 trial and wait for months and months to get the results. Who cares if lives could be saved by accelerating the research?
>> Hey guys, we’ve got this vaccine candidate that’s only effective on young people. Can we just launch a Phase 3 trial for young people while we run a separate Phase 1/2 trial for older people?
Aw jeez, that would be bad! Old people are people too and we might hurt someone’s feelings if we declare that there’s a vaccine that’s only available for young folks. Lets just delay it by many months instead to the point where it becomes irrelevant, even if it could’ve saved tens of thousands of people in the meantime.
>> Folks, I’ve got this Oxford vaccine that’s 62% effective and has no major side effects. Can we start using it?
Aw jeez, absolutely not! Some people might get offended because they could’ve received the 90% effective vaccine instead, even if that 90% vaccine is in short supply and wouldn’t actually be available to them for many months to come. Rather than offending people, we should just let them die from COVID – that way we’re not to blame for anything. So lock that vaccine up until you run many more trials and ignore the fact that this causes tens of thousands of extra deaths. Bio ethics above all!
Here is the post link. From myst_05.
I will be doing a Conversation with him, here is a partial bio:
Noubar was born in Beirut to Armenian parents in 1962, did his undergraduate work at McGill University in Montreal, and completed his Ph.D. in biochemical engineering at MIT in 1987.
He founded Flagship Pioneering:
Flagship has fostered the development of more than 100 scientific ventures resulting in $30 billion in aggregate value, thousands of patents and patent applications, and more than 50 drugs in clinical development.
During his career as inventor, entrepreneur, and CEO, Noubar has cofounded and helped build over 50 life science and technology startups.
Here is that link, and he is by the way co-founder and chairman of Moderna. And on the board of the Boston Symphony Orchestra.
So what should I ask him?
Two to three thousand people a day are dying from COVID. Thus anything that delays rolling out a vaccine has a very high cost in human lives. People want to deny this, perhaps because it is so horrifying. I get a lot of pushback when I say that FDA delay is deadly. Let’s dispense with a few objections. It is true, of course, that the people who are dying today can’t literally be saved by a vaccine today but they could have been saved had they been vaccinated four or five weeks ago and similarly projecting forward.
Another response that many smart people tell me is that a vaccine can’t be rolled out immediately so even under the best scenarios you couldn’t save that many people immediately. That’s true but irrelevant. Since a lot of people are getting this wrong, I want to show this in a simple model using pictures. Red is for deaths. Green is for life. Suppose two thousand people are dying from COVID a day as in panel 1. Let’s for the sake of the simple model assume that you could deliver a vaccine to everyone on Day 1. You would then save 2000 lives a day going forward for however long the pandemic would have lasted as shown in panel 2. If you delay by one day then two thousand people die who would have lived without the delay, as shown in panel 3. Pretty obvious so far.
Now assume that the vaccine can’t roll out to everyone immediately. For the sake of this simple model let’s assume that on day one you can only vaccinate half the population. By doing so you save 1000 lives on day 1 and 2000 lives every day thereafter for the length of the pandemic. That’s the fourth panel. Now suppose we delay the vaccine rollout by one day. 2000 people die on Day 1 but you save 1000 on Day 2 and 2000 on Day 3 and every day thereafter for the length of the pandemic. How many people were killed by the delay? Compare the 4th and 5th panels. 2000 exactly as before! The slow ramp up doesn’t change the number of deaths caused by delay it just spreads them out over different days. You can adjust the ramp so that it occurs over 10 days or 30 days. Doesn’t change much on the delay margin unless you delay for so long that the pandemic is close to being over.
What could matter is if delay increases the speed at which you can ramp up. I doubt that this is true. We were ready to go with millions of doses in late October (guess why?). (In fact we had a vaccine in January and millions of doses around March-April.) We won’t really be better prepared tomorrow than we are today. It’s learning by doing that matters. See the point Tyler made earlier about economic time versus calendar time.
As Tyler noted, this is hardly the final analysis but many people are not even conceptualizing the problem correctly and this is a good place to begin.
A number of scientists (including, but not only, those funded by Fast Grants) have reported some interesting findings related to fluvoxamine, SSRIs and sigma-1 receptor (S1R) agonists more broadly.
- A small RCT at Washington University (n=152) published in JAMA found that patients receiving fluvoxamine had a 0% hospitalization rate (vs. 8.3% for placebo). https://jamanetwork.com/journals/jama/fullarticle/2773108
- Another group reported (data not yet published but reported here with permission) a 0% hospitalization rate in a fluvoxamine-treated cohort compared to 11% in the non-treated group. (n=146)
- A large observational analysis (n=7345) of hospitalized French patients found that those on SSRIs (of which fluvoxamine is one) had a very substantially reduced risk of death. (n=257, HR = 0.56.). SSRIs with the highest Sigma1 activation showed the greatest protection. https://www.medrxiv.org/content/10.1101/2020.07.09.20143339v2
- Fluvoxamine is a potent sigma-1 receptor agonist. Following their initial report on the role of S1R in SARS-CoV2 – host interaction, Nevan Krogan’s group found that patients receiving another sigma-1 agonist (indomethacin) had a materially reduced likelihood of requiring hospitalization compared to those receiving celecoxib, which doesn’t activate sigma-1. This work was supported by Fast Grants. https://science.sciencemag.org/content/370/6521/eabe9403.full
- Lastly, a genetic screen by a Fast Grants-funded lab (not yet published but reported here with permission) has found that genes upregulated by fluvoxamine significantly inhibit SARS-CoV2 mediated cell death.
On the off chance there is something here, fluvoxamine is relatively safe, cheap, and widely available. We are very open to both positive and negative data in this area, and have funded a further effort. Do let us know if you hear anything on this topic!
Some assorted thoughts:
In the big picture, the efficacious of a vaccine doesn’t matter per se what matters is getting to herd immunity. If you have a less efficacious vaccine you need to vaccinate more people but herd immunity is herd immunity, i.e. vaccines mostly protect people not because they are efficacious but because we reach herd immunity. I’ve never had measles mostly because I have probably never been challenged with measles not because I have been challenged but due to a vaccine I fought it off. The AZ vaccine at 70% efficacious will work just fine. (One potential issue, as Josh Gans notes, we don’t yet have data on transmission reduction which could vary by vaccine.)
As I mentioned in The Vaccine Works Fast, the first shot of the Pfizer vaccine seems to work well enough so that one *might* consider delaying the second dose a few weeks to get the first dose out more widely. In fact, the accidental low-dose, standard-dose regime for the AZ vaccine had people getting the second dose 7 to 8 weeks after the first dose and that was the 90% efficacious regime. We don’t have full-information but the exact timing of the second-dose does not seem critical, although everyone should get a second dose.
A related point is that we could mix and match vaccines. The UK will run a trial on this question. Mix and matching has two potentially good properties. First, mix and matching could make the immune system response stronger than either vaccine alone because different vaccines stimulate the immune system in different ways. Second, it could help with distribution. It’s going to be easier to scale up the AZ vaccine than the mRNA vaccines, so if we can use both widely we can get more bang for our shot. (As Tyler has noted the British have really stepped up on rational trial design.)
The mRNA vaccines are getting the press but for the world as a whole the AZ, Chinese, Russian and similar more traditional vaccines are going to be the big players because facilities exist for scaling them up around the world.
Addendum: Countries in the world that now have a vaccine: the UK, Canada, Bahrain, China, Russia. One country without a vaccine: the United States. The US FDA advisory committee is meeting today. You can watch here.
- We believe COVID-19 herd immunity (>60% of population immune) will be reached in the US by late summer/early fall 2021 (Sep-Nov 2021).
- At the time herd immunity is reached, roughly half of the immunity will be achieved via natural infection, and the other half will be achieved via vaccination.
- New COVID-19 infections may become negligible before herd immunity is reached. Our current best estimate of when daily community transmissions will drop below 1,000 per day is summer 2021 (Jul-Sep 2021).
- Summarizing the above findings, our best estimate of a complete “return to normal” in the US is late summer 2021 (Aug-Oct 2021).
- We estimate around 30% of the US population (~100 million) will have been infected by the SARS-CoV-2 virus by the end of 2021. This translates to a final US COVID-19 death toll of roughly 500,000 (+/-100k) reported deaths.
From mathematician Gary Cornell:
For people 65 to 74, while the average number (92.9%) looks great, the confidence interval is not. It says that what we can say is that there is a 19/20 chance that the efficacy is between 53.2 to 99.8. This kind of confidence interval says that didn’t have enough cases in this group to really say much at all and so the confidence range is too large to be really useful.
And when we get to people over 75, what they describe isn’t a confidence interval, it’s a joke. A confidence interval of -12.1 to 100 is a lot like saying they threw a bunch of darts at a dart board at random and did everything from hit bystanders (i.e. the vaccine made things worse) to perfect protection. They simply didn’t have enough cases to say anything meaningful and so what they say is just totally useless.
But I don’t want to end on a depressing note! My friends who think about these questions feel pretty strongly that while the vaccine will likely be less effective in people over 65 than it is in younger people, the dropoff won’t be great enough to make a big difference. For example, if it is 20-25% less effective in these age groups (which they think is the worst case scenario), you still get a vaccine that is roughly between 70% and 75% effective – which is still pretty darn good.
Still I wish they had enrolled enough people >65 to have a better signal!
There is much more useful information at the link.
The drop-off [in expected vaccine deliveries] is a product of manufacturing problems, bottlenecks in the supply of raw materials and other hurdles in ramping up clinical-trial production of 5 liters of protein-based vaccine at a time to commercial-scale fermentation of 2,000-liter batches, the companies and the Trump administration said.
Note that Operation Warp Speed, for all its wonders, creates some bad incentives. A pre-purchase, whatever other advantages it may bring, is also a kind of indirect price control. And when price controls are present, quality declines ex post, as in many other procurement problems. But the companies do not wish to lower the quality of their vaccines, so instead they have “slack” incentives to boost quality along other parts of the supply chain.
Here is a simple analogy. Let’s say the government did a pre-purchase of left shoes, at the price of a left shoe/right shoe combination. But to get the upfront money the company only had to produce a left shoe. There might be a relative shortage of right shoes.
So there is pre-purchase for “the vaccine,” but not for “all of the complements to the vaccines.” (Listen to Alex!) The companies are getting paid for the vaccines no matter what. So their incentive to be speedy with the complementary infrastructure — whether producing it themselves or contracting for it in Coasean fashion — just isn’t as strong as it would be for a social optimum.
The more you rely on pre-purchase, the more you have to worry about what is happening on the fringes of that activity. And you can expand pre-purchase to the initial complements, and probably should, but of course in doing so new fringes arise as well.
From the FDA report:
Two doses is great but one dose already looks good even though sample is small. “Efficacy against severe COVID-19 occurring after the first dose was 88.9%.” (Added. n.b this is over the entire sample.)
Based on the number of cases accumulated after Dose 1 and before Dose 2, there does seem to be some protection against COVID-19 disease following one
dose; however, these data do not provide information about longer term protection beyond 21 days after a single dose.
This is potentially important as we could vaccinate more people in a hot-spot and potentially delay the second dose. Noting, however, that this is a post-hoc analyses and the second dose came within 3 weeks.
As expected, a bit of pain, swelling and fatigue in a minority of participants are the biggest issues. No major safety concerns. Of course, we still need to monitor long-term.
Serious adverse events, while uncommon (<1.0%), represented medical events that occur in the general population at similar frequency as observed in the study…. No specific safety concerns were identified in subgroup analyses by age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection.
Hat tip: Biostatistician LucyStats.
Since back in April, Michael Kremer, myself, and the AHT team have been advising governments to go big on investing in vaccines. The US, to its credit, made early purchases but they made two mistakes. First, they didn’t buy enough as the Washington Post indicates:
Last summer, Pfizer officials had urged Operation Warp Speed to purchase 200 million doses, or enough of the two-shot regimen for 100 million people, according to people knowledgeable about the issue who spoke on the condition of anonymity because they weren’t authorized to discuss the situation. But the Warp Speed officials declined, opting instead for 100 million doses, they said.
“Anyone who wanted to sell us … without an [FDA] approval, hundreds of millions of doses back in July and August, was just not going to get the government’s money,” said a senior administration official.
But last weekend, with an FDA clearance expected any day, federal officials reached back out to the company asking to buy another 100 million doses. By then, Pfizer said it had committed the supply elsewhere and suggested elevating the conversation to “a high level discussion,” said a person familiar with the talks who spoke on the condition of anonymity because they were not authorized to share the conversation.
In our discussions, we were talking about at least a $70 billion dollar program and optimally double that and we continually faced the sticker shock problem. Investing in unapproved vaccines seemed risky to many people despite the fact that the government was spending trillions on relief and our model showed that spending on vaccines easily paid for itself (the mother of multipliers!). I argued that this was the world’s easiest cost benefit calculation since Trillions>>Billions. But it was hard to motivate more spending—not just in the United States but anywhere in the world. For reasons I still don’t understand anything out of the ordinary–big spending on at-risk vaccines, spending on testing and tracing, challenge trials–was met with a kind of apathy and defeatism. As I said in July:
Multiple people [in Congress] have told me that things move slowly, no one is stepping up to the plate, leadership is absent. “Who is John Galt?,” they sigh. Ok, they don’t literally say that, but that sigh of resignation is what it feels like in the United States today at the highest levels of government.
OWS was actually the one area where there was some action. But there was a second mistake. We argued that governments shouldn’t buy doses but capacity, i.e. they should cover the cost of building a factory or production line in return for an option on doses from that line. The problem with buying doses is that if you buy without a timeline then the company takes all orders and pushes the low-priced orders to the back of the queue. If you demand a timeline, however, that puts a lot of risk on the firms, since not everything is under their control, and that’s expensive and difficult to contract for and monitor. Thus, we advocated for push funding to de-risk capacity construction for the firms. Capacity construction is well understood–double this line–and thus much easier to contract for and monitor. (Contracting on capacity is also cheaper than a traditional AMC for reasons explained here and also in my discussion with Tyler here.) The nice thing about buying capacity is that it changes the dynamic from one where countries are scrambling to buy before others do to one where early purchases increase capacity that is later available for everyone. OWS, to its credit, did fund capacity construction for Moderna but we wanted more and other governments didn’t step up to the plate.
OWS has been a success. In combination with investments from other governments and organizations like CEPI it will save trillions of dollars and many lives. It could have been better but the main takeaway is that the case for going big is still strong. We have solved the scientific problem of making the vaccine but step two is getting billions of doses in arms. If we can increase capacity enough to vaccinate millions more people next year than currently planned that would still pay for itself many times over. Increasing capacity is not impossible. China is increasing capacity for its vaccines. It will be harder to increase capacity for mRNA vaccines since the technology is new and bespoke but it can be done. We need a second Operation Warp Speed, OWS: Delivery and Distribution.
As Tyler said yesterday, Williams wants a cow! We want billions of vaccine doses quickly. It can be done, it should be done.
I am reading many people claim something like “production and distribution of the vaccine is the constraint, not FDA approval.”
There are multiple mistakes in such a view, and here I wish to focus on the logic of constraints rather than debate the FDA issue.
First, there are vaccines available right now, and it helps some people (and their contacts) to have those distributed sooner rather than later.
Second, easing the FDA constraint encourages the suppliers and distributors to hurry to a greater degree. Just imagine if the FDA were to take a few months longer to approve. The more general point is that citing “x is right now the main constraint right now” does not mean “the elasticity of x is zero.”
“Sure” wrote in the comments:
On the economics side, I am not convinced that production has ramped up as full and as fast as possible. After all there is some risk premium for expanding plants, running constant shifts, etc. and the danger of delayed approval, particularly if you are in some (mostly negligible) way to the other vaccines may not warrant the investment.
After all, approvals appear to move stocks. Do we really think the market is that dumb? If approval has an impact on market value, why exactly would it not also have an impact on the cost of borrowing, expanding, etc.? Surely somebody believes that approval will result in something different will happen than was happening the day before.
Third, “FDA vaccine approval” is a complementary good for the final vaccine service, strongly complementary in fact. If the other complementary infrastructure goods have price/quality combinations that are “too disadvantageous,” the theory of the second best implies that approval processes should be speedier and more lax than you otherwise might have thought. This is just the converse of the classic result that multiple medieval princes imposing multiple tolls on a river create negative externalities for both river users and each other. Lower those tolls wherever you can.
Fourth, let’s say there were three constraints, each absolutely binding at the current margin. Speeding FDA approval, taken alone, would have absolutely no effect. We then ought to be obsessed with identifying and remedying the other two constraints (along with approval)!
But we are not. Instead we keep on citing those (supposed) constraints in defeatist fashion. This absence of obsession with easing constraints is in fact one of the biggest reasons for thinking we can do better. We need to throw more money and talent at these problems, and we are not working hard enough on how to do that. We are just citing the constraints back and forth to each other and pleading helplessness.
As a final note, I recall that my recently deceased colleague Walter E. Williams was especially good on these issues. I recall him once saying he wanted to hire a helicopter to drop a cow into the campus central quad, just to show people that supply has positive elasticity. “I’m going to call them up and say “Williams wants a cow!””
Many people are asking me this question. I don’t mean to relitigate the question of whether the FDA should be moving faster, rather consider this an exercise in how to think about the trade-offs. I thus am going to hold the safety and quality of the vaccine constant.
To proceed, consider the distinction between processes defined by economic time and processes defined by calendar time. In Virginia it may snow in February but not in October, and that is defined by calendar time, not caused by local gdp. But for many inventory processes, they do not restock until the shelf is emptied by buying customers, and that is economic time. They don’t check to see if it is June or July.
Let us say that only economic time matters, though I will drop that assumption shortly.
Now, given how late we are in “the season,” it is easier to think about pushing the approval date back rather than moving it forward. Let’s say that the FDA postponed the December 10 meeting to January 10. Some number of people would die of Covid during that month — the current clip being around 2600 a day but changing — and then around Jan.10 some kind of vaccine-related health and economic recovery would move into fuller gear.
If only economic time matters, it seems the Dec.10 recovery and the Jan.10 recovery run about the same. The net difference between the two scenarios is the lives lost in the meantime, to oversimplify say 2000 x 30 days, or 60,000 lives plus accompanying lost jobs and gdp.
I do not think that losing those lives would somehow speed the later, Jan.10-starting recovery process, and it may in some ways render it more fractious.
On top of that, the postponed recovery period likely will imply some kind of grinding uncertainty in the meantime, and possibly intertemporal substitution from some agents (like me!) who are waiting for the change to come before going to the barber. The true net costs are thus higher than what I listed two paragraphs above.
Now, how might the introduction of calendar time alter those estimates?
First, the production of complementary goods for vaccines (say freezers, but the point is more general) may be on a clock of its own, more or less on automatic pilot and requiring time. When approval comes later, more of those complementary goods are in place, and thus the later recovery is a more powerful one. That factor tends to lower the cost of delaying approval.
(Of course to the extent those same complementary inputs depend upon economic time, that is reason not to delay approval! The sooner you approve, the sooner they will get working on getting those freezers in place, which of course boosts recovery power. Supply is elastic with respect to approval, as suggested for instance by stock market reactions to approval decisions.)
Second, the seasonal effects will differ. Ideally you want the spread of vaccines to be covering some of the more infectious and thus more difficult winter months. February is worse than March, and so on. Given the current clock, this is a big reason to be hurrying.
You might think of other ways calendar time could matter. You also might think of various non-linear effects and interactions, though I am not sure whether they would make delay more or less costly.
Overall it seems to me that the costs of approval delay are likely very high. They are not obviously overturned or minimized by citing the relevance of complementary inputs. The import of complementary inputs might be more ruled by “economic time,” or the seasonal effects may be a stronger quantitative magnitude, again favoring faster speed of approval.
I do understand this is far from a final analysis, rather it is a starting point for conceptualizing the problem.
Doses of the coronavirus vaccine developed by AstraZeneca and the University of Oxford could be available for purchase in India as soon as March, according to one manufacturer, in the first sign that the sought-after jab will make its way on to the private market.
Serum Institute of India, the world’s largest vaccine manufacturer, has a licence to produce the shot and has already manufactured 40m doses. Once the job is approved for use, Serum will initially supply the Indian government but then expects to sell 20m-30m doses to private facilities, according to Adar Poonawalla, chief executive.
“Everybody’s asking ‘When can I access the vaccine?’ I’ve told those guys it’s probably going to be March or April,” Mr Poonawalla told the Financial Times.
…the future availability of vaccines for sale privately in other countries, such as India, increases the likelihood of a secondary market developing for vaccines where locals or foreign visitors could pay for a vaccination if not eligible to be inoculated under their own government’s scheme.
Here is the full FT article, via J., the price is expected to be around eight dollars.