Category: Medicine

Single-Shot and First Doses First

The FDA panel voted unanimously to authorize the J&J vaccine. Good. Note, however, that the single-shot J&J vaccine is quite comparable to the first dose of the Pfizer and Moderna vaccines. Yet, few people are demanding that J&J be required to offer a second shot at all, let alone in 3-4 weeks (What about vaccine escape! How long does immunity with a single-shot last! What about the children!). It really is scandalous how these objections to a single-shot have disappeared. This is evidence of what I call magical thinking–an undue focus on the clinical trial design as having incantatory power.

Why did J&J focus on a single-shot? Was this because of “the science”, i.e. something unique about their vaccine? No. J&J focused on a single-shot vaccine for the same pragmatic reasons that I favor First Doses First.

J&J representatives said they chose to begin with the single shot because the World Health Organization and other experts agreed it would be a faster, more effective tool in an emergency. (emphasis added).

My view is that it would be good if the J&J vaccine was followed by a booster–perhaps of some other vaccine–but that it’s individually fine and in fact socially beneficial to get more people protected quickly by delaying the booster for at least 12 weeks to when vaccines are less scarce. I don’t currently see a reason for thinking differently about the Pfizer and Moderna vaccines.

UK to fast track drug trials

Drugmakers will be offered fast-tracked approvals for innovative medicines in the UK as ministers seek to build on the country’s world-leading approval of a Covid vaccine and attract life sciences companies to invest post-Brexit.

The UK’s medicines regulator will become independent of EU pharmaceutical rulemaking when Britain quits the European Medicines Agency at the end of the year, which means companies will need to apply separately to register drugs.

With ministers eager to try to refashion the UK as a post-Brexit hub for global life sciences, companies with drugs that promise to treat unmet medical needs will be offered help through the development process, including manufacturing, according to three people familiar with the situation.

Under the so-called Innovative Licensing and Access Pathway, companies are set to be offered the same rolling review of data that speeded approval of the Pfizer/BioNTech Covid-19 vaccine ahead of the rest of the world.

Here is more from Sarah Neville at the FT, via J.

Potential yet still thwarted Filipino nurse vaccine barter markets in everything?

The Philippines will let thousands of its health care workers, mostly nurses, take up jobs in Britain and Germany if the two countries agree to donate coronavirus vaccines, a senior official said on Tuesday.

Britain’s health ministry said it was not interested in such a deal and its priority was to use shots domestically, but added it would share surplus vaccine internationally in the future.

The Philippines, which has among Asia’s highest number of coronavirus cases, has relaxed a ban on deploying its health care workers overseas, but still limits the number of medical professionals leaving the country to 5,000 a year.

Alice Visperas, director of the labor ministry’s international affairs bureau, said the Philippines was open to lifting the cap in exchange for vaccines from Britain and Germany, which it would use to inoculate outbound workers and hundreds of thousands of Filipino repatriates.

Here is the full story, via Marvin Vista.

A Majority of Doses are Now Second Doses

As of Feb. 18 (last day of full data) we gave out 817,708 second doses and just 702,426 first doses. In other words, a majority of doses are now second doses. As Daniel Bier writes this means that we are boosting some people from ~85% to ~95% protected when we could be vaccinating more first timers and getting them from 0% protected to ~85% protected.

If we followed the British rule and delayed the booster to 12 weeks, we could immediately more than *double* the number of people going from 0% protected to to ~85% protected. More first-doses would be great for the newly protected and more people at ~85% protection would also reduce transmission so there would be fewer new infections and less threat to the non-vaccinated.

The opportunity cost of not delaying the booster is measured in lives lost.

The AstraZeneca Vaccine Works Well

A new study looking at essentially the entirety of the Scottish population finds that both the Pfizer and AstraZeneca vaccine work very well at preventing hospitalizations from the first dose.

UK policy for use of vaccines against COVID-19 involves an offer of a first dose followed by a second dose 12 weeks later. To our knowledge, this is the first study of COVID-19 vaccine effect against hospitalisation for an entire nation after a single dose of vaccine. We found that a single dose of BNT162b2 COVID-19 vaccine was associated with a vaccine effect (VE) of 85% (95% CI 76 to 91) for COVID-19 hospitalisation 28-34 days post-vaccination. A single dose of ChAdOx1 vaccine was associated with a vaccine effect 94% (95% CI 73 to 99) at 28-34 days post-vaccination. VEs increased over time with a peak at 28-34 days post-vaccination for both vaccines. Comparable VEs were seen in those aged ≥80 years for prevention of COVID-19 hospitalisation with a high combined VE of 81% (95% CI 65 to 90) at 28-34 days post-vaccination.

Arne Akbar, president of the British Society for Immunology, noted “…overall these new findings should provide reassurance around the UK’s decision to offer the two doses of the vaccine 12 weeks apart.”

Another important point is that the AstraZeneca vaccine actually shows a higher effectiveness than the Pfizer vaccine. The study wasn’t designed to compare the vaccines and the populations getting the vaccines aren’t random samples. Nevertheless, the AstraZeneca vaccine appears to work well and it was actually given to a greater proportion of elderly patients.

The new results from Scotland support the UK, EU, and WHO decisions to authorize the AstraZeneca vaccine. If the US had authorized the AstraZeneca vaccine in late December at the same time as did the UK, millions more Americans could have been vaccinated saving many lives.

Where is the FDA’s cost-benefit calculation?

Hungary’s Vaccine Approval Rule

AP: Hungarian health authorities were the first in the EU to approve the Sinopharm jab for emergency use on Jan. 29. That came after a government decree streamlined Hungary’s vaccine approval process by allowing any vaccine administered to at least 1 million people worldwide to be used without undergoing review by the country’s medicines regulator.

The country expects to receive 5 million total doses of the Sinopharm vaccine over the next four months, enough to treat 2.5 million people in the country of nearly 10 million.

Authorize any vaccine already used by at least 1 million people is a type of reciprocity or peer-review rule in which you speed up approval in your country based on data from another country. As with all such rules, it’s imperfect–new and extensive use will reveal common, serious side effects and many uncommon ones as well but extensive use is not a guarantee of safety or efficacy. Nevertheless, when time is of the essence the 1 million+ rule is a smart rule.

Hat tip: Bart Madden.

From the Comments, On FDF

Sure and Tom Meadowcroft have been hitting it out of the ballpark in the comments sections. Two examples.

Sure:

Protocol was made to serve man, not man to serve the protocol.

The reason we have protocols is because we need to weight the harms of waiting without a treatment against the harms that happen if the treatment is counterproductive in some unforeseen manner.

We can, normally, pretty easily measure the benefit side: count up the mortality and morbidity for the illness in question. The risk side is harder so we developed tests and processes to elucidate those: RCTs, literature reviews, regulatory oversight, mandatory waiting periods. At the end of the day though, the whole process is just one giant test to measure the likely harm of a new entity.

So when is a test worth doing? After all I do not order an MRI for every patient even though I could find a lot of early stage cancers that way.

..GSW to the abdomen with crashing bp with minimal response to volume? Straight to the OR. No matter the results of the CT scan they are still getting opened to stop the bleeding.

…So now we look at the vaccine approval process and methods to stretch doses. Pre-test probability that vaccines work? Inordinately high after passing Phase II. Odds that we hit on the precise optimal timing regimen on the first go? Nil.

The likelihood ratios for RCTs and approval mechanisms are powerful. But we are talking thousands of deaths per day. The odds that these tests will remotely alter management decisions is nil. It is malpractice to delay life saving treatment on tests exceedingly unlikely to change management decisions.

And remember the UK is not seeing horrid outcomes for doing this for a while now. A lot of theoretical failure mechanisms are now off the table.

Science is wholly about building a reliable model that accurately predicts future outcomes of current actions. While doing the actual experiment is the gold standard for knowledge acquisition, it is not the only option and in cases like this pandemic is not sufficiently better than past data to merit waiting.

As far as the regulators. I work with some of them directly. They are not overburdened to anywhere near the degree that the frontline clinicians have been hit. When I ask them to explain their cost benefit calculations, they have none. Not I cannot follow them. Not I disagree with them. They have done not an iota of math to justify their course of action.

Sorry, but I believe in evidence based medicine, not eminence based medicine. If you as a regulator cannot explain to me in technical terms the math behind your decision process, even if only back of the envelope, you are not worth putting in charge.

Approve all the vaccines, FDF, fractional dosing trials, and first dose followed by variolation trials should all be done now. It is was [what] the math demands.

Also this from Tom Meadowcroft:

Scientific researchers search for the truth. Medical clinicians use limited data balance cost and benefits in the face of uncertainty to save the most lives.

When searching for the truth, it is important to have high standards of statistical significance, integrity, and patience, because credibility and a reputation for integrity is everything. Every academic knows that a retracted paper or an accusation of playing fast and loose with statistics can be the death knell for a career. As a result it is prudent to be very certain before publishing. Public health officials, particularly those in charge of approving vaccines, dread the possibility that a vaccine that will be given to millions of healthy people, often children, to prevent diseases where death is rare, which could harbor some flaw that causes a hundred avoidable deaths; they seek the highest standards of proof of safety and efficacy before approving such a vaccine.

But a pandemic is not a search for truth, and a COVID vaccine administered in the midst of a pandemic is very different than a measles vaccine administered to 2-year-olds. The pandemic makes these decisions for FDF or for vaccine approvals into clinical decisions, where health professionals should be balancing the certain benefit of reducing the thousands of daily deaths against the uncertain cost of the possibilities of harmful side-effects and uncertain details of efficacy (when does immunity kick in, how long does it last, how valuable is a booster) that additional months of testing and trials would reveal more clearly.

Public health researchers, academics for the most part, lack the ability (and courage) to make the sort of cost/benefit analysis with necessarily limited data that clinical physicians make every day in examination rooms. Any good clinician, faced with the citizenry of a country as their patient, would have opted for FDF, the AZ vaccine, and quite likely reduced doses by the start of the year. Because we are stuck with academics and administrators as our decision makes, unable to see beyond their usual routine of searching for the truth and protecting their reputations, thousands more will die.

The First Dose is Good

WSJ: The Covid-19 vaccine developed by Pfizer Inc. and BioNTech SE generates robust immunity after one dose and can be stored in ordinary freezers instead of at ultracold temperatures, according to new research and data released by the companies.

The findings provide strong arguments in favor of delaying the second dose of the two-shot vaccine, as the U.K. has done . They could also have substantial implications on vaccine policy and distribution around the world, simplifying the logistics of distributing the vaccine.

A single shot of the vaccine is 85% effective in preventing symptomatic disease 15 to 28 days after being administered, according to a peer-reviewed study conducted by the Israeli government-owned Sheba Medical Center and published in the Lancet medical journal. Pfizer and BioNTech recommend that a second dose is administered 21 days after the first.

The finding is a vindication of the approach taken by the U.K. government to delay a second dose by up to 12 weeks so it could use limited supplies to deliver a single dose to more people, and could encourage others to follow suit. Almost one-third of the U.K.’s adult population has now received at least one vaccine shot. Other authorities in parts of Canada and Europe have prioritized an initial shot, hoping they will have enough doses for a booster when needed.

Preliminary data also suggest that the other widely used vaccine in the U.K. developed by AstraZeneca PLC and the University of Oxford could have a substantial effect after a first dose .

The Israeli findings came from the first real-world data about the effect of the vaccine gathered outside of clinical trials in one of the leading nations in immunization against the coronavirus. Israel has given the first shot to 4.2 million people—more than two-thirds of eligible citizens over 16 years old—and a second shot to 2.8 million, according to its health ministry. The country has around 9.3 million citizens.

…”This groundbreaking research supports the British government’s decision to begin inoculating its citizens with a single dose of the vaccine,” said Arnon Afek, Sheba’s deputy director general.

The Israeli study is here. Data from Quebec also show that a single dose is highly effective, 80% or higher (Figure 3) in real world settings.

It’s becoming clearer that delaying the second dose is the right strategy but it was the right strategy back in December when I first started advocating for First Doses First. Waiting for more data isn’t “science,” it’s sometimes an excuse for an unscientific status-quo bias.

Approximately 16 million second doses have been administered in the US. If those doses had been first doses an additional 16 million people would have been protected from dying. Corey White estimates that every 4000 flu vaccinations saves a life which implies 4000 lives would have been saved by going to FDF. COVID, of course, is much deadlier than the flu–ten times as deadly or more going by national death figures (so including transmission and case fatality rate)– so 40,000 deaths is back of the envelope. Let’s do some more back-of-the-envelope calculations. Since Dec. 14, there have been approximately 10 million confirmed cases in the United States and 200,000 deaths. There are 200 million adults in the US so 1/1000 adults has died from COVID, just since Dec. 14. If we use 1/1000 as the risks of a random adult dying from COVID, then an additional 16 million vaccinations would have saved 16,000 lives. But that too is likely to be an underestimate since the people being vaccinated are not a random sample of adults but rather adults with a much higher risk of dying from COVID. Two to four times that number would not be unreasonable so an additional 16 million vaccinations might have avoided 32,000-64,000 deaths. Moreover, an additional 16 million first doses would have reduced transmission. None of these calculations is very good but they give a ballpark.

It is excellent news that the vaccine is stable for some time using ordinary refrigeration. Scott Duke Kominers and I argue that there is lot of unused vaccination capacity at the pharmacies and reducing the cold storage requirement will help to bring that unused capacity online. The announcement is also important for a less well understood reason. If Pfizer is only now learning that ultra-cold storage isn’t necessary then we should be looking much more closely at fractional dosing.

When I said that we should delay the second dose, people would respond with “but the companies say 21 days and 28 days! Listen to the science!”. That’s not scientific thinking but magical thinking. Listening to the science was understanding that the clinical trial regimen was designed at speed with the sole purpose of getting the vaccines approved. The clinical trial was not designed to discover the optimal regimen for public health. Don’t get me wrong. Pfizer and Moderna did the right thing! But it was wrong to think that the public health authorities could simply rely on “the science” as if it were written on stone. Even cold-storage wasn’t written on stone!  Now that the public health authorities know that the clinical trial regimen isn’t written in stone they should be more willing to consider policies such as delaying the second dose and fractional dosing.

We are nearing the end in the US but delaying the second dose and other dose-stretching policies are going to be important in other countries.

Profile of Youyang Gu, data scientist

In mid-April, while he was living with his parents in Santa Clara, Calif., Gu spent a week building his own Covid death predictor and a website to display the morbid information. Before long, his model started producing more accurate results than those cooked up by institutions with hundreds of millions of dollars in funding and decades of experience.

“His model was the only one that seemed sane,” says Jeremy Howard, a renowned data expert and research scientist at the University of San Francisco. “The other models were shown to be nonsense time and again, and yet there was no introspection from the people publishing the forecasts or the journalists reporting on them. Peoples’ lives were depending on these things, and Youyang was the one person actually looking at the data and doing it properly.”

The forecasting model that Gu built was, in some ways, simple. He had first considered examining the relationship among Covid tests, hospitalizations, and other factors but found that such data was being reported inconsistently by states and the federal government. The most reliable figures appeared to be the daily death counts. “Other models used more data sources, but I decided to rely on past deaths to predict future deaths,” Gu says. “Having that as the only input helped filter the signal from the noise.”

The novel, sophisticated twist of Gu’s model came from his use of machine learning algorithms to hone his figures.

Here is the full Bloomberg piece by Ashlee Vance, I am especially pleased because Youyang was an Emergent Ventures winner.  Here is Youyang Gu on Twitter.

Canada and First Doses First

…With such a highly protective first dose, the benefits derived from a scarce supply of vaccine could be maximized by deferring second doses until all priority group members are offered at least one dose. There may be uncertainty about the duration of protection with a single dose, but the administration of a second dose within 1 month after the first, as recommended, provides little added benefit in the short term, while high-risk persons who could have received a first dose with that vaccine supply are left completely unprotected. Given the current vaccine shortage, postponement of the second dose is a matter of national security that, if ignored, will certainly result in thousands of Covid-19–related hospitalizations and deaths this winter in the United States — hospitalizations and deaths that would have been prevented with a first dose of vaccine.

Danuta M. Skowronski, M.D.
British Columbia Centre for Disease Control, Vancouver, BC, Canada

Gaston De Serres, M.D., Ph.D.
Institut National de Santé Publique du Québec, Quebec City, QC, Canada

That’s from a letter to the NEJM which also includes a debate on delaying the second dose and a poll (vote for delaying the second dose!). What I want to point out today is that the authors are experts from Canada. I believe that first doses first will save lives in the US but delaying the second dose and other dose-stretching policies are even more vital in countries where vaccines supplies are more limited than in the United States.

Political economy matters

Schools in Oregon, Washington, and much of the west coast are slow to reopen, even with teachers getting vaccinated:

Marguerite Roza, a Georgetown University school finance expert based in Seattle, points out that Washington, Oregon and California “all have more left-leaning leadership that is cozier with the unions.” But Boston, Chicago and New York also have strong public employee unions.

Those Eastern cities also have mayoral control of the school systems. Elected school boards govern the districts on the West Coast, and in most, teachers’ unions are strong political players, particularly in major cities such as Portland, Seattle, Los Angeles and San Francisco.

I guess you could say that the mayors have more “inclusive” constituencies?  Here is the full NYT article, depressing throughout.

The problem with rapid testing was always on the demand side

The U.S. government distributed millions of fast-acting tests for diagnosing coronavirus infections at the end of last year to help tamp down outbreaks in nursing homes and prisons and allow schools to reopen.

But some states haven’t used many of the tests, due to logistical hurdles and accuracy concerns, squandering a valuable tool for managing the pandemic. The first batches, shipped to states in September, are approaching their six-month expiration dates.

At least 32 million of the 142 million BinaxNOW rapid Covid-19 tests distributed by the U.S. government to states starting last year weren’t used as of early February, according to a Wall Street Journal review of their inventories…

“The demand has just not been there,” said Myra Kunas, Minnesota’s interim public health lab director.

…the tests are piling up in many states, the Journal found.

Here is more from Brianna Abbott and Sarah Krouse at the WSJ.  You may recall the discussions of demand-side issues from my CWTs with Paul Romer and Glen Weyl.  The envelope theorem remains underrated.

The regulatory state and the passage of time

The mere passage of time as an explanatory factor is underrated in public choice and regulatory economics, though Mancur Olson understood it well.  Here is an update on the new CDC guidelines for school reopening:

For months, President Biden has been urging schools to reopen, and promised that guidelines from the Centers for Disease Control and Prevention would help them do so safely.

At the same time, public health experts including some at the CDC said available evidence suggested schools could safely open as long as precautions were in place. That raised expectations that the nation’s K-12 education system might accelerate its return to in-person learning.

But the much-anticipated guidelines released Friday were, in fact, more measured than some expected, with full in-person schooling recommended only when levels of community transmission are quite low, a standard that almost no place in the U.S. meets today.

Here is the full article.  The American Federation of Teachers is happy, but six feet between all students for virtually all districts is a non-starter.  No matter what you think of the substance of the school reopening issue, it takes only a modicum of sense to realize if you tell people that six feet of distance is needed, in essence you are saying that a safe reopening is impossible altogether.  Here is the rant of a “progressive” parent.

You will notice that these regulatory factors are another reason why the speed premium during a pandemic is so high — if you wait too long to fix the core problem, the regulators, slow though they may be, will encumber just about everything.

Against Regulatory Nationalism

I’ve long argued that if a drug or medical device is approved in another country with a Stringent Regulatory Authority it ought to be approved in the United States. But, of course, the argument is even stronger in the other direction. Drugs and devices approved in the United States ought to be approved elsewhere. Indeed, this is how much of the world actually works because most countries do not have capability to evaluate drugs and devices the way the FDA or say the EMA does. Although it’s the way the world works, few will admit it because that would violate pretensions of regulatory nationalism. Moreover, keeping up with pretenses means transaction costs and unnecessary delays.

The price of such regulatory nationalism can be very high as indicated in this interview with Adar Poonawalla, chief executive of the Serum Institute of India (SII), the world’s largest producer of vaccines.

Some people think the reason that rollout has been slow in many countries is because the developers who hold the patents on the vaccines have licensed too few manufacturers to make them. Do you agree?

No. There are enough manufacturers, it just takes time to scale up. And by the way, I have been blown away by the cooperation between the public and private sectors in the last year, in developing these vaccines. What I find really disappointing, what has added a few months to vaccine delivery – not just ours – is the lack of global regulatory harmonisation. Over the last seven months, while I’ve been busy making vaccines, what have the US, UK and European regulators been doing? How hard would it have been to get together with the World Health Organization and agree that if a vaccine is approved in the half-dozen or so major manufacturing countries, it is approved to send anywhere on the planet?

Instead we have a patchwork of approvals and I have 70m doses that I can’t ship because they have been purchased but not approved. They have a shelf life of six months; these expire in April.

Did you get that? Regulatory nationalism has added months to vaccine delivery and now threatens to put to waste millions of stockpiled doses.

Addendum: See also Scott Sumner on the costs of regulatory nationalism.