Category: Medicine

My Conversation with the excellent Noubar Afeyan

Among his other achievements, he is the Chairman and co-founder of Moderna.  Here is the audio and video and transcript.  Here is part of the summary:

He joined Tyler to discuss which aspect of entrepreneurship is hardest to teach, his predictions on the future of gene editing and CRISPR technology, why the pharmaceutical field can’t be winner takes all, why “basic research” is a poor term, the secret to Boston’s culture of innovation, the potential of plant biotech, why Montreal is (still) a special place to him, how his classical pianist mother influenced his musical tastes, his discussion-based approach to ethical dilemmas, how thinking future-backward shapes his approach to business and philanthropy, the blessing and curse of Lebanese optimism, the importance of creating a culture where people can say things that are wrong, what we can all learn by being an American by choice, and more.

Here is one excerpt:

AFEYAN:

I should point out, Tyler, what these people don’t yet realize is that mRNA, in addition to being unique in that it’s really the first broadly applied code molecule, information molecule that is used as a medicine and with all the advantages that come with information — digital versus analog — or where you actually have to do everything bespoke, the way drugs usually work.

The other major advantage that it has is that it is something that is actually taking advantage of nature. There was a lot of know-how we had going into this around how the process could be done. In fact, let me tell you the parallel that we used.

We have a program in cancer vaccines. You might say, “What does a cancer vaccine have to do with coronavirus?” The answer is the way we work with cancer vaccines is that we take a patient’s tumor, sequence it, obtain the information around all the different mutations in that tumor, then design de novo — completely nonexistent before — a set of peptides that contain those mutations, make the mRNA for them, and stick them into a lipid nanoparticle, and give it back to that patient in a matter of weeks.

That has been an ongoing — for a couple of years — clinical trial that we’re doing. Well, guess what? For every one of those patients, we’re doing what we did for the virus, over and over and over again. We get DNA sequence. We convert it into the antigenic part. We make it into an RNA. We put it in a particle. In an interesting way, we had interesting precedents that allowed us to move pretty quickly.

And at the close:

Imagine if all of us were also born imagining a better future for ourselves. Well, we should be, but we’ve got to work to get that. An immigrant who comes here understands that they’ve got to work to get that. They have to adapt. The problem is, if you’re born here, you may not actually think that you’ve got to work to get that. You might think you’re born into it.

This will be a funny thing to say, and I apologize to anybody that I offend. If we were all Americans by choice, we’d have a better America because Americans by choice, of which I’m one, actually have a stronger commitment to whatever it takes to make America be the place I chose to be, versus not thinking about that as a core responsibility.

Definitely recommended, he is working to save many many lives, and with great success.

Ireland fact of the day, coming soon to a state near you

Some experts estimate this could mean, if we do not accelerate the pace of vaccination, one million deaths for the United States.

N95 and KN95 Masks

Mask use is near 100% here in Northern Virginia. I am surprised, however, how many people continue to use simple cloth masks when much better N95s and KN95s (Chinese equivalent to N95s) are widely available. Gold standard appears to be the Respokare N95s which are NIOSH approved (under Innonix) but are quite expensive. I also like these cheaper KN95s from Kingfa which are not NIOSH approved. Some of the Chinese masks are garbage but limited testing by the CDC suggests the Kingfa are pretty good. No guarantees. Use your own judgment.

No Learning Without Risk

Here’s something from a paper that I am working on. The context is why first doses first makes more sense the greater the uncertainty but the point made is larger. No indent.

An important feature of First Doses First (FDF) and other policies such as fractional dosing is that they are reversible. In other words, FDF contains an option to switch back to Second Doses First (SDF). Options increase in value with uncertainty (Dixit and Pindyck 1994). Thus, contrary to many people’s intuitions, the greater the uncertainty the greater the value of moving to First Doses First. Indeed, the value of the option can be so high that one might want to move to First Doses First even if it were worse in expectation. For example, if the expected efficacy of the first dose were just 45% then in expectation it would be worse than Second Doses First (95% efficacy) but if there were lots uncertainty around the 45% expected efficacy it might still be better to switch to First Doses First. If there was a 75% chance that the efficacy of the first dose was 30%, for example, and a 25% chance that it was 90% (.75*.3+.25*.90=45%) then under reversibility one would still want to switch to First Doses First to learn whether the true efficacy was 30% or 90%.*

Put differently shifting away from the default strategy to an alternative such as FDF or fractional dosing might be considered to be “risky”. But in this context, learning requires risk. When learning is desirable, it is also desirable to take on risk. Risk aversion can prevent learning and thus can be dangerous.

If FDF is worse in expectation than SDF then it would be optimal to switch to the most minimal form of FDF necessary to learn about the true efficacy rate. In other words, to run an experiment. If FDF is superior in expectation to SDF then it might also be better to run an experiment before switching but not necessarily. If FDF is superior in expectation to SDF then the cost of running the experiment is keeping the policy with lower expected value while the experiment is running. If these costs are high then switching immediately is better.

It would take at least 16 weeks, for example, to run an experiment on extending dosing from 3 weeks to 12 weeks (including, optimistically, just 1 week to setup the experiment). As of early January 2021, confirmed cases in the United States are increasing at the rate of 200,000 per day or 1,400,000 per week. Thus there could be 22,400,000 new confirmed cases in the time it takes to run the experiment. At a case fatality rate of 1.7% that means 380,800 new deaths. If First Doses First reduces the infection rate in expectation by 10% that would imply that running the experiment has an expected cost of 38,080 lives.

At these rates, more lives could be saved in expectation by switching to the policy with higher expected value and simultaneously running experiments. Randomized trials that explicitly test the impact of dosing timing, fractional dosing and different timings of additional doses on severe, symptomatic and asymptomatic infections, and also on transmission should be incorporated as part of roll-out plans (Kominers and Tabarrok 2020, Bach 2021). However, roll-out of modified plans should not wait until these trial results are known; instead, plans should be adjusted as new information emerges. Most notably the British moved to First Doses First and they approved the AstaZeneca vaccine on December 30, 2020 and the consequences of both of these decisions should be monitored very closely to help improve decisions in other countries.

*This assumes that one could learn the true efficacy rate quickly enough relative to the ongoing pandemic to benefit from the new information. One might respond that in principle SDF also contains an option to switch to FDF but this option is valueless since Second Doses First provides no opportunity to learn. Only under First Doses First do we learn valuable new information.

Approve the AstraZeneca Vaccine Now!

Here’s Marty Makary, M.D., a professor of surgery and health policy at the Johns Hopkins University School of Medicine:

Finally, the FDA needs to stop playing games and authorize the Oxford-AstraZeneca vaccine.  It’s safe, cheap ($2-$3 a dose), and is the easiest vaccine to distribute. It does not require freezing and is already approved and being administered in the United Kingdom.

Sadly, the FDA is months away from authorizing this vaccine because FDA career staff members insisted on another clinical trial to be completed and are punishing the company for inadvertently giving a half-dose of the vaccine to some people in the trial.

It’s like the FDA is holding out, pontificating existing excellent data and being vindictive against a company for making a mistake while thousands of Americans die each day.

Ironically, those in the Oxford-AstraZeneca trial who inadvertently received half the initial vaccine dose had lower infection rates. And this week Dr. Moncef Slaoui, the chief adviser to Operation Warp Speed, acknowledged that using half a dose might be a good broader strategy for the U.S. to double our supply as long our supply is severely constrained. That’s a good strategy that makes sense.

See also my post The AstraZeneca Factory in Baltimore. Thousands of people are dying every day. We have a vaccine factory ready to go. The FDA should lifts its ban on the AstraZeneca vaccine.

The end of the Swedish model

The government this week proposed an emergency law that would allow it to lock down large parts of society; the first recommended use of face masks came into force; and the authorities gave schools the option to close for pupils older than 13 — all changes to its strategy to combat the pandemic.

“I don’t think Sweden stands out [from the rest of the world] very much right now,” said Jonas Ludvigsson, professor of clinical epidemiology at Karolinska Institutet in Stockholm. “Most of the things that made Sweden different have changed — either in Sweden or elsewhere.”

…Sweden has reported more than 2,000 Covid-19 deaths in a month and 535 in the past eight days alone. This compares with 465 for the pandemic as a whole in neighbouring Norway, which has half the population. As Sweden’s King Carl XVI Gustaf said just before Christmas: “We have failed.”

Here is more from the FT.  U.S. Covid deaths per day have now exceeded 4,000 for some days, and they are running at about 50% of the normal number for total daily deaths.  And no, it is not that the payments to classify these as Covid deaths have increased, rather the virus and the deaths have increased.  So the “no big deal” question we now can consider settled?  The new and more contagious strains haven’t even started playing a major role yet in the United States.

“Second Doses” post-mortem

The most striking thing about the Biden administration shift to a version of “First Doses First” is how little protest there has been.  Given how many public health experts were upset about the idea only a few days ago, you might expect them to organize a Wall Street Journal petition from hundreds of their colleagues: “Biden administration proposal endangers the lives of millions of Americans.”

But of course they won’t do that.  Some of that is pro-Democrat partisanship, but that is not even the main factor.  One reason is that public health experts, with their medical and quasi-medical backgrounds, typically have very little sense of how to respond in the public arena if challenged.  For instance, not a single one stepped forward with a calculation to defend “Second Doses.”  They are not especially good at “the internet rules of the game,” which of course are now supreme (not always for the best, to be clear).

The second and probably most important reason is that, as I had explained, sins of omission are treated as far less significant than sins of commission.  Now that a version of “First Doses First” is on the verge of becoming policy, to do nothing about that is only a sin of omission, and thus not so bad.  Remarkable!  Status quo bias really matters here.

I haven’t seen a single peep on Twitter opposing the new policy.

Just keep all this in mind the next time you see a debate over public health policy.  There is often less behind the curtain than you might think.

First Doses First, coming soon to a state near you…

Of course on this particular issue, Alex was the one who started the intellectual campaign…

Be Prepared! Sars-COV-3

The federal government was unprepared for the pandemic, despite multiple, loud and clear warnings. State and local governments were unprepared for vaccines, despite multiple, loud and clear warnings. The Capitol Police were unprepared for rioters, despite multiple, loud and clear warnings.

The record isn’t good but as a Queen’s Scout I persist. We now have multiple, loud and clear warnings that new variants of the SARS-COV II virus are more transmissible and thus much more dangerous. But we can do something. As wrote in The New Strain and the Need for Speed

One of the big virtues of mRNA vaccines is that much like switching a bottling plant from Sprite to 7-Up we could tweak the formula and produce a new vaccine using exactly the same manufacturing plants. Moreover, Marks and Hahn at the FDA have said that the FDA would not require new clinical trials for safety and efficacy just smaller, shorter trials for immune response (similarly we don’t do new large-scale clinical trials for every iteration of the flu vaccine.) Thus, if we needed it, we could modify mRNA vaccines (not other types) for a new variant in say 8-12 weeks.

Thus, let’s start doing much more sequencing to discover new strains–and also think about potential new strains–and start phase I and phase II trials of new vaccines. Florian Krammer suggested an even more ambitious plan to do the same thing for all potential pandemic viruses:

From each of the identified virus families, which should certainly include the Paramyxoviridae, Orthomyxoviridae, and Coronaviridae families, a handful of representative strains with the highest pandemic potential should be selected for vaccine production. Up to 50–100 different viruses could be selected and this would broadly cover all phylogenies that may give rise to pandemic strains….It should be possible to choose candidates that are close to viruses that might emerge in the human population. The idea is that once viruses are selected, vaccines can be produced in different platforms and tested in phase 1 and phase 2 trials with some of the produced vaccine being stockpiled. This would likely cost 20–30 million US dollars per vaccine candidate resulting in a cost of 1–3 billion US dollars.

What I am suggesting is less ambitious–just do this for Sars-COV-3, 4, 5 and 6. But do it now!

Hat tip: Daniel Bier.

Broken Record Addendum: We should make better use of our limited vaccine supply by moving to First Doses First and/or fractional dosing and approve the AstraZeneca vaccine immediately and spend billions to increase the rate of vaccinations and to speed new vaccines (such as those from J&J and Novavax) to market.

A legal and regulatory question about First Doses First

It isn’t clear to me who in the United States is legally entitled to make this decision.  An FDA EUA is required before a vaccine can be used in the U.S.  But once an EUA has been issued, is “off-label use” permitted?  The CDC’s Advisory Committee on Immunization Practices recommends how scarce vaccine doses should be prioritized, but “states” (governors?) are free to make contrary prioritization decisions.  Can states also decide to give half-doses or lengthen the interval between first and second doses?  Can a hospital, a nursing home, or an individual doctor make such a decision?  (If so, can it also deviate from its state prioritizations?)  Can HHS or the President specify how these decisions must be made, or alternatively can they explicitly free lower-level decision-makers to use their own judgment?

You’re not a specialist in pharmaceutical law, I realize.  But I doubt you’ll let that stop you!  When you recommend a less risk-averse approach to COVID-19 vaccination, to whom are you addressing the recommendation?  Who has a right to implement it?

That is from MR reader Peter Sandman.  Can any MR reader inform us on this?

Mass vaccination for Virginia (from my email)

A vaccination center with 4 vaccination stations requiring 58 staff (only 16 of which seem to need medical training to prepare and administer vaccines and 1 EMT on hand for adverse reactions (I imagine med students and military/other governmental personnel could also be used in this endeavor)) working a total of 16 hours/day (i.e. 2 shifts) is estimated to be able to vaccinate 1900 people per day.

If there were 50 of these across Virginia, the entire population could be given one dose in 90 days. Given that 2 doses are required, you could get the vaccination done by summer (if there were no supply constraints). With 30 vaccination centers, Virginia could be done distributing its 317,000 remaining unadministered doses in 5 days. Instead, Virginia reported 828 vaccinations yesterday. (I’m hoping Virginia is already finished with nursing facilities since Kaiser estimates that Virginia only had 19,900 residents in skilled nursing facilities in 2019).

And staffing is easily solved. 30 vaccination centers require 480 medical personnel to prepare and administer the vaccine and 30 EMTs. There are about 120,000 nurses in Virginia. Chances are, more than 480 nurses were on vacation for longer than 5 days at some point this past year so it won’t cripple the healthcare system. Getting 1 percent of the nursing workforce for this should not be that hard (and that’s not including med students and military/other governmental personnel who could also aid in this endeavor).

What boggles my mind is the number of staff they have allocated for paperwork.

If the US had been prepared, it could’ve set up a system of vaccination tickets with QR codes (much like tickets for air travel or going to a sporting event) that could be handed out by primary care physicians, hospitals, etc. (or just based on administrative records of age). Those would transfer the relevant data that would have been collected by the paperwork people. People would schedule a slot via some app (even doctors’ offices have online scheduling now), show up, provide ID verification, and get the shot. So you could open up a vaccination center with less staff. I get that not everyone has a smartphone, but seriously, this is not that hard.

The more you think about how many times large logistics problems are solved every single day by 100s and 1000s of organizations, the performance of the US just looks worse and worse.

From a loyal (and anonymous) MR reader.

First Doses First and Herd Immunity

The simplest argument for First Doses First (FDF) is that 2*0.8>.95, i.e. two vaccinated people confers more immunity than one double vaccinated person. But there is more to it than that. Perhaps more important is that with FDF we will lower R more quickly and reach herd immunity sooner. Here’s an extreme but telling example.

Suppose you have a pop of 300 million, need 2/3 to get to herd immunity and you have 100m doses and can vaccinate 100m a month. Then with FDF you vaccinate 100m in first month and a new 100m in the second month and then you are “done.” i.e. you can then do 2nd doses more or less at leisure since you are at herd immunity (yes, I know about overshooting, this is a simple example). If instead you do second doses you vaccinate 100m in first month and the same 100m in the second month which leaves 100 million at risk for another month. Under second doses you don’t reach herd immunity until the third month. Thus, under FDF you save a 100m infection-month which is a big deal.

Now when you put this into a more sophisticated SEIR model you won’t get as strong a result but the result will be in the same direction. Note also that getting to herd immunity sooner is probably the best thing we can do to prevent further mutations.

See also Youyang Go’s thread where he discusses his modeling of similar ideas. He notes:

Reaching herd immunity two or three months sooner will have profound benefits throughout society, ranging from fewer cases & deaths to faster economic recovery.

Addendum: Please read Tyler’s post, FDF?-Show Your Work! before you comment.

“New York’s mass-vaccination plans are shelved as Cuomo takes different path”

County officials who have for years been planning for a mass vaccination said they are seeing that training and preparation — much of it funded by millions of dollars in federal grants — pushed aside as the administration of Gov. Andrew M. Cuomo has retained control of the state’s coronavirus vaccination program, including having hospitals rather than local health departments administer the doses.

Interviews with multiple county officials over the past week confirm that many are unclear why the governor’s administration has not activated the county-by-county system, a plan that included recent practice sessions in which members of the public received regular flu vaccines at drive-thru sites.

…In Albany County, officials have privately said they could vaccinate the population of the southern half of the county in a few days if they were given the coronavirus vaccines and allowed to mobilize their plan.

Here is the full, gory story.  It is clear they have just begun thinking about this.  I really do not understand why Paul Krugman has been praising the New York State response for so many months, they have gone from one disgrace to another.  Ross Barkan offers further commentary.  And here is de Blasio on Cuomo.

As a side note this is interesting: “The Times Union is not disclosing the [vaccination] location because county officials contend the vaccination sites should not be publicly disclosed for security purposes.”

To be clear, other states are messing up too, some of them worse than NY.

The politics of Covid just got even more hellish

That is the title of my latest Bloomberg column, here is one excerpt:

Preliminary data indicate that the new strain in the U.K. allows the virus to spread from one person to another more easily. The practical upshot is that even the strict lockdowns of early 2020, such as the one just ordered in the U.K. by Prime Minister Boris Johnson, may not be enough to reverse the spread of the virus.

It is far from obvious that politicians will be able to sell voters on strict lockdowns if they still allow the virus to spread. Furthermore, vaccine distribution has been sufficiently slow that a full lockdown would have to last for many months, and that probably isn’t feasible or desirable. Yet not having lockdowns would lead to a much more rapid spread of the virus, overloading hospitals and public health facilities.

And:

The biggest moral dilemmas might come in those countries that to date have been fairly successful at containing the spread of the virus. Apart from restrictions on foreign travel, life in Taiwan has been normal for some time now, and Covid-related casualties have been miniscule. Other successful examples of virus containment can be found throughout Asia and the Pacific.

But how will those countries deal with the new strain? It has already appeared in both Taiwan and China. So far it has not taken over, but the previous tactics of quarantine and tracing may no longer suffice, should the new strain become more active. It is already spreading in Denmark, which did a good job against Covid-19 early on.

Imagine being a leader of a country that has successfully contained Covid, and now realizing that a single mistake could undo almost a year of very hard work. You also know that, precisely because your country has been so effective at fighting the virus, it is not on the verge of vaccinating your entire population. What if you let a single returning citizen pass through customs taking one Covid test rather than three? What if you then cannot control the subsequent spread of the strain that person is carrying?

When was the last time that stakes for such apparently minor decisions were so high? How will leaders deal with the extreme moral anxiety that their decisions will likely induce?

It is like we are living in a horror movie, and just when we think it’s over, the monster comes back, stronger than ever.

Important throughout.