Category: Current Affairs

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.

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 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.