Results for “first doses”
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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.

Medical ethics? (model this)

Steven Joffe, MD, MPH, a medical ethicist at the University of Pennsylvania, said he doesn’t believe clinicians “should be lowering our standards of evidence because we’re in a pandemic.”

Link here.  That sentence is a good litmus test for whether you think clearly about trade-offs, statistical and speed trade-offs included, procedures vs. final ends of value (e.g., human lives), and how obsessed you are with mood affiliation (can you see through his question-begging invocation of “lowering our standards”?).  It is stunning to me that a top researcher at an Ivy League school literally cannot think properly about his subject area at all, and furthermore has no compunction admitting this publicly.  As Alex wrote just earlier today: “Waiting for more data isn’t “science,” it’s sometimes an excuse for an unscientific status-quo bias.”

To be clear, we should run more and better RCT trials of Ivermectin, the topic at hand for Joffe (and in fact Fast Grants is helping to fund exactly that).  But of course the “let’s go ahead and actually do this” decision should be different in a pandemic, just as the “just how much of a hurry are we in here anyway?” calculus should differ as well.  I do not know enough to judge whether Ivermectin should be in hospital treatment protocols, as it is in many countries, but I do not condemn this simply on the grounds of it representing a “lower standard.”  It might instead reflect a “higher standard” of concern for human lives, and you will note the drug is not considered harmful as it is being administered.

If you apply the standards of Joffe’s earlier work, we should not be proceeding with these RCTs, including presumably vaccine RCTs, until we have assured that all of the participants truly understand the difference between “research” and “treatment” as part of the informed consent protocols.  No “therapeutic misconception” should be allowed.  Really?

If the pandemic has changed my mind about anything, it is the nature of expertise.

Canada and Novavax

Canada has made some smart moves with the Novavax vaccine. First, they initiated a rolling review of the Novavax vaccine in late January which suggests that they might authorize the vaccine based on the British trial before the US trial is concluded. The FDA will probably wait until the US trial is concluded. Second, Canada also signed a production agreement to bring some capacity online in Canada, although that will take time. That agreement, however, is on top of an advance purchase of 52 million doses with an option on another 24 million doses.

In short, if they act quickly, Canada could approve the Novavax vaccine before the United States and get a jump on its own vaccination efforts.

Vaccine politics in Europe and America

The contentiousness is much worse in Europe, where zero- and negative-sum thinking is the order of the day.  That is the theme of my latest Bloomberg column, here is one bit:

In most of Europe, it’s hard to see much good news. It’s one thing not to have a vaccine. It’s far worse to turn on television or go on the internet and see people in other countries being vaccinated as their pandemics recede. Most of Europe will not be making significant vaccination progress until April, and even then shortages may remain.

At stake is the very legitimacy of the EU. Most of the vaccination contracts were handled at the EU level, although Germany sidestepped the agreed-upon procedures and cut some deals. If the EU fails at the most significant crisis in a generation, it may not maintain much legitimacy.

And:

When people judge how painful an experience was, they often place a high value on first and last impressions. The last impressions of the U.S. and U.K. will be pretty positive. Most of the U.S. pandemic will be over by July, even under a subpar vaccination schedule. And it may turn out that mRNA vaccines are more protective against the new strains of Covid than any alternatives….

Many European countries may end up with fewer deaths per capita than the U.S. But at the end of the pandemic many Europeans may feel like their leaders failed them, that they suffered lockdowns for many months but received little in return. Right now vaccine politics is all about momentum, and so far only a few countries have it.

Here is a related piece by Bruno M.  And a good piece (slow to start) on what went wrong in the EU.

Vaccines Are Not Like Emergency Rations!

According to the Guardian the First Minister of Wales explained their policy of doling out the Pfizer vaccine evenly over the next six weeks:

the Pfizer vaccine has to last us until into the first week of February.

…We won’t get another delivery of the Pfizer vaccine until the very end of January or maybe the beginning of February, so that 250,000 doses has got to last us six weeks.

That’s why you haven’t seen it all used in week one, because we’ve got to space it out over the weeks that it’s got to cover.

Bonkers! A vaccine isn’t like a limited supply of water that needs to be rationed until you arrive at the next oasis. The sooner you get the vaccine out the better! Start lowering R now! If you run out of vaccine, well scarcity is bad but running out means that at least one part of your system is working well! It’s a bad idea to kill people to make it look like you are following some sort of numerically neat plan.

One year into the pandemic and people still don’t understand vaccines or viral growth.

Hat tip: Arthur Baker.

Fact of the day, get to those rooftops!

Pepvar’s first goal should be supporting the production of enough doses to vaccinate the entire world within a year. It is estimated that building such capacity for an mRNA vaccine like Moderna’s would cost less than $4 billion — that’s significantly less than the U.S. government already spends each day on Covid-19 relief — with the cost about $2 per dose. Of course, making the vaccines is just the first step: Pepvar must

People, even if that estimate is off by a factor of ten or more…etc.  Here is the NYT link, bJames KrellensteinPeter Staley and .

The Tony Blair “one dose” idea

Here is the source, of course Alex Tabarrok was there first.  For now give everyone one dose rather than two, and enjoy the partial but more broadly spread protection.  Here are the reactions from two epidemiologists:

Professor Wendy Barclay, from the department of infectious disease at Imperial College London, said Mr Blair’s idea was interesting but agreed it was “too risky” to try without further evidence.

And Professor Neil Ferguson, also from Imperial, added that the UK regulator had authorised the vaccine on the basis that people would receive two doses.

Administering one dose only would require “an entirely different regulatory submission”, he told a Commons committee.

A Department of Health and Social Care spokesperson said: “Over the coming weeks and months, the rate of vaccinations will increase as more doses become available and the programme continues to expand.”

Where are their cost-benefit analyses?  Letting people get infected at current and indeed accelerating rates is also “too risky,” yes?  Is there an epidemiologist or public health expert out there willing to show his or her work, either for or against this idea?  A genuine query, and of course comments are open.  How about one dose for Moderna only?  If we are to defer to their expertise, they do actually have to step up and be the experts, right?

The Vaccine Works Fast

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.

The case for going big is still strong

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.

India vaccine markets in everything

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.

The political economy of Swine flu vaccine allocation

Previous research has isolated the effect of “congressional dominance” in explaining bureaucracy-related outcomes. This analysis extends the concept of congressional dominance to the allocation of H1N1, or swine flu, vaccine doses. States with Democratic United States Representatives on the relevant House oversight committee received roughly 60,000 additional doses per legislator during the initial allocation period, though this political advantage dissipated after the first 3 weeks of vaccine distribution. As a result political factors played a role in determining vaccine allocation only when the vaccine was in particularly short supply. At-risk groups identified by the Centers for Disease Control (CDC), such as younger age groups and first responders, do not receive more vaccine doses, and in fact receive slightly fewer units of vaccine.

That is from an Economic Inquiry paper by Matt E. Ryan.  Via Henry Thompson.

Graduating in a Recession Can Be Rough

Graduating in a recession can be rough. Wages start lower and advance more slowly. It’s hard to get hired at a top firm which means it takes longer to get on a rapid ascent career path. As Till von Wachter notes in a review of the long-term consequences of initial labor market conditions, failure to takeoff leads to choices which often makes things worse.

…initial labor market conditions persistently increases excessive alcohol consumption (Maclean 2015) and leads to higher obesity and more smoking and drinking in middle age (Cutler, Huang, and Lleras-Muney 2015)…College graduates entering during the 1980s recession experience higher incidence of heart attacks in middle age (Maclean 2013). Following all labor market entrants from these cohorts, Schwandt and von Wachter (2020) find that starting in their late 30s, unlucky entrants begin experiencing a gap in mortality compared to luckier peers that keeps increasing in their 40s, driven by higher rates of heart disease, liver disease, lung cancer, and drug overdoses.

…Marital patterns of unlucky cohorts are affected from the time they enter the labor market up into middle age, when these cohorts have fewer children (Currie and Schwandt 2014), are more likely to have experienced a divorce, and are more likely to live on their own (Schwandt and von Wachter 2020). Initial labor market conditions also have been found to have effects on attitudes towards economic success and the role of the government (Giuliano and Spilimbergo 2014) and to lead to increasingly lowering individuals’ self esteem (Maclean and Hill 2015).

Don Peck had a good popular survey of these effects in The Atlantic in 2010 that remains vital:

Andrew Oswald, an economist at the University of Warwick, in the U.K., and a pioneer in the field of happiness studies, says no other circumstance produces a larger decline in mental health and well-being than being involuntarily out of work for six months or more. It is the worst thing that can happen, he says, equivalent to the death of a spouse, and “a kind of bereavement” in its own right. Only a small fraction of the decline can be tied directly to losing a paycheck, Oswald says; most of it appears to be the result of a tarnished identity and a loss of self-worth. Unemployment leaves psychological scars that remain even after work is found again, and, because the happiness of husbands and the happiness of wives are usually closely related, the misery spreads throughout the home.

Especially in middle-aged men, long accustomed to the routine of the office or factory, unemployment seems to produce a crippling disorientation. At a series of workshops for the unemployed that I attended around Philadelphia last fall, the participants were overwhelmingly male, and the men in particular described the erosion of their identities, the isolation of being jobless, and the indignities of downward mobility.

Of course, most people who graduate during a recession do just fine in the grand scheme of things.You could have graduated in Sierra Leone. But if you want to be on a rapid ascent career path remember that your first job is not your last job, look for opportunity, and be prepared to take a risk and switch jobs early. Stay off drugs and alcohol.

From the comments, on HCTs

The box most bioethicists are in is so small their thinking can’t extend beyond a few target people. In this case, the control group in a vaccine trial.

The subjects could be paid for the risk, which is what we do for jobs all the time. Those risk/reward amounts for risky jobs are used to make estimates for the value of human life. Life insurance would allow high-risk people (us geezers) to join the trials.

Their box doesn’t even consider human challenge trials (HCT) that give you very rapid and accurate data on efficacy even with pay and insurance to cover the risk. The lives saved by a month faster approval is in the 10’s of thousands more than offsetting and risk to a few people. Tracking the first million doses for side effects would provide the side effect data that is usually within days of injection.

Outside their mental box, 1000 people per day are dying for each day they study the issue and delay a decision, but those lives are not included in their thinking and analysis.

That is from Dallas.  I would stress there are higher costs yet from delay, noting the hundreds of millions of people in developing nations who are falling back into poverty while the pandemic continues to rage.  Some of them are dying too.

New results on the Chinese vaccine

Importantly, this was the first study of an inactivated SARS-CoV-2 vaccine to include participants older than 60 years—the most vulnerable age group for this infection. In the phase 1 dose-escalating trial, the vaccine was given at a two-dose schedule at three different concentrations (2 μg, 4 μg, and 8 μg per dose) and was well tolerated in both age groups (18–59 years and ≥60 years). The older age group had lower rates of solicited adverse events than the younger adults: the overall rates of adverse events within 28 days after vaccination were 34 (47%) of 72 participants in the group aged 18–59 years, compared with 14 (19%) of 72 participants in the group aged 60 years and older. At the same time, in both age groups the vaccine was similarly immunogenic: the geometric mean anti-SARS-CoV-2 neutralising antibody titres measured by a 50% virus neutralisation assay 14 days after the booster dose were 88, 211, and 229 in the group aged 18–59 years and 81, 132, and 171 in the group aged 60 years and older for 2 μg, 4 μg, and 8 μg vaccine doses, respectively. Moreover, the authors tested cross-reactivity of the neutralising antibodies against several drifted SARS-CoV-2 isolates and showed the potential of their vaccine to protect against evolutionary diverged viruses, should they appear in circulation.

And:

The current study is the second to report the interim results of safety and immunogenicity of inactivated SARS-CoV-2 vaccine, with the first being the another β-propiolactone inactivated aluminium-adjuvanted whole-virion SARS-CoV-2 vaccine developed by Wuhan Institute of Biological Products.

Both studies showed very similar levels of adverse events and neutralising antibody titres post vaccination, which indicates the reproducibility of clinical results of similar vaccine modes produced by different manufacturers.

All good news of course, and this vaccine exists right now.  Just not for you!  Here is the piece from The Lancet, and here is associated commentary, also seeming to confirm the positive results.  A phase III trial is underway in the UAE to measure efficacy.  I cannot speak to data reliability issues, but presumably the referees at The Lancet find this credible enough to recommend publication.

Via Alan Goldhammer.