(2021-08-20) Goldhaber First Do No Harm How The Fda Crippled Americas Response To Covid19

Ben Goldhaber: First, do no harm - how the FDA crippled America's response to COVID-19. This is a partial account of how the FDA and the medical establishment failed America in fighting COVID-19, and how the inherent structure of the FDA made the pandemic worse. They prevented individuals and companies from creating and providing timely drugs and tests to combat COVID-19, contributing to the deaths of hundreds of thousands of Americans and trillions of dollars of lost economic output.

This was not a one-off failure of the FDA. Since the modern FDA was created in the 1960s it has exacerbated epidemics and slowed life saving medical progress.

We should break up the functions of the FDA and create a more robust, decentralized process with competing government and non-government licensing bodies.

Setting the Stage

Its significantly larger than international peers - for instance the FDA's 2018 requested budget is 20x greater than its Japanese counterpart.
The biggest pharmaceutical companies in the world are headquartered in the US.
Many governments modeled their own drug approval practices on those of the FDA.

Daniel Carpenter quoted from one Pharma CEO in the introduction to his excellent book on regulation and the FDA: The FDA is standing there with a machine gun against the pharmaceutical industry, so you better be their friend rather than their enemy

the FDA is the sole gatekeeper for the entire, $500 billion+ US pharmaceutical market.

No other regulatory agency in the US has this level of power

From this power, the FDA shapes the culture of medicine and medical science in the United States.

In essence the FDA sets the rules for public health policy and process.

By the 1950s the FDA was responsible for certifying drugs were safe before they could be used in the United States.

However, there was a 'discontinuity event' with the FDA's powers; while before they were but an actor in the pharmaceutical ecosystem, afterwards they would fully control it.

In the early 1960's a new drug, Thalomide, was developed and used in Europe to treat pregnant mothers' morning sickness

While Thalomide had not been approved for use in the United States - and in fact was still being assessed by FDA officials for safety - the public outcry in response to the horrifying reports coming from overseas demanded immediate action.

after Thalomide, Kefauver's amendment quickly gained political support. Even though it was not targeted at preventing Thalomide like events, and even though Thalomide had not been officially approved in the US, the urge to 'do something' was compelling, and the amendment sailed through

Carpenter disagrees with the view that the amendment represents a radical break in FDA power; his book has a wealth of details on the 'continuous' growth in the FDA's regulatory power in the 20th century

It's wrong to view the question of whether a drug is effective as having a single, stand alone yes-or-no answer

The graph below, from the FDA Review, details how the number of new drugs approved fell dramatically after the expansion of FDA powers with the 1962 amendment.

Initial Response

In late 2019, reports started to emerge of a potentially dangerous virus in Wuhan, China

While local Chinese officials tried to suppress the news, information leaked out as brave individuals warned of the threat. (Li Wenliang)

In January 2020 the CDC created a test for what was now known as COVID-19, and submitted it to the FDA, who approved it. However, troubling reports started coming in of bad results and bad data

Faced with the failure of the CDC's test, hundreds of universities, commercial labs, and individual researchers sprang into action and began working on creating their own tests and ways to scale up testing. It was the civic sector stepping up to help combat a country wide crisis.

But, instead of being greeted as heroes trying to fill the testing gap left by the failure of the CDC, they were greeted by a blizzard of paperwork and an icy bureaucracy that made it illegal to test for COVID-19.

So groups like the Seattle Flu Study, a group staffed by world-class researchers and physicians, with funding from the Bill & Melinda Gates foundation, had to hunt and beg for someone to grant them an approval to move forward, to use their functioning tests and labs to learn whether people were unknowingly spreading a deadly virus. They were repeatedly denied, because their lab was not certified as a clinical laboratory under existing CMMS regulations

Let's pause for a second and ask the obvious question - should they have been allowed to test? On the one hand, we can look back and see that yes god yes wtf how is this even a question

But on the other, when judging policy, we're evaluating a decision rule - the general process that we follow when making a decision

Given this, it becomes a question of 'what's the meta decision rule' - how do we know to throw out our existing process and do something different because the circumstances have changed

The ability to deviate from the script is the mark of a live player.

Reasonable people can disagree about when this call can be made, but it's a call that at the very least needs to be actually evaluated by someone.

The actions of the FDA revealed they couldn't do that, that in the end all they had were their existing scripts.

The emergency authorizations would take months.

he had e-mailed the material, and the F.D.A. insisted that he print it out and mail a hard copy, along with the digital file in physical form, such as a thumb drive or a CD, to a separate ‘documentation’ office

Contrast the behavior of FDA officials with the South Korea government.

“We promise a fast approval,” said one South Korean health official at the time, saying the government would buy unused supply if the outbreak never reached a significant size

One firm, Kogene Biotech Co., demonstrated a successful test and got the regulatory green light within four days.

In the US, on the other hand, creative solutions from the public and private sector to expand access to testing were either never implemented or put into action too late to be useful

Consider pooled testing

was delayed until the point of uselessness - emergency authorization for pooled testing from the FDA was only given in mid July

Bottlenecks

The failure to test would continue throughout 2020

For the default, PCR COVID tests, it was a multi-stage process with many potential bottlenecks: You needed a nurse or doctor to swab your nose and collect the sample

There were a limited number of processing centers

Reagents were in short supply for the reactions. So were PCR machines

These are all artificial bottlenecks.

There's no more striking example of this artificial constraint than the failure of the US to leverage rapid testing.

Rapid tests provide quick, immediate feedback on whether someone is contagious

While they are less accurate than PCR tests, they are more effective at the public health goal of detecting if someone can spread the virus.

Not only are rapid tests faster, they're much cheaper, cheap enough to be mass produced for everyone in the country.

And we didn't use this tool, despite it being invented in April, because the FDA had a single pathway for approving testing, and it didn't account for the value of speed or cost. Instead they insisted on treating them like PCR tests.

it was only in December that they were approved, and in a crippled form that required a doctor's supervision, decreasing their usefulness as a population level tool.

Vaccines

The fastest vaccine development ever carried out has turned the tide

But, they were only a triumph in that external actors overrode the default instincts and approach of the FDA.

The FDA repeatedly added stumbling blocks to the vaccine development and deployment

Clinical Delays

The AstraZeneca vaccine candidate was paused twice,

the actual incidence was two out of 18,000 people. Of those, one already had a chronic illness that caused an increase risk of TM

For other vaccines, the FDA altered the analysis requirements, adding more time to the approval process.

With Pfizer's vaccine...The FDA career staff also delayed the vaccine by adding an unprecedented requirement to slow down Phase III trials

when Pfizer submitted their clinical data for final review and approval, it took the FDA weeks to schedule and hold the approval meeting.

First Doses First

a hidden assumption went unchecked for far too long - for vaccines that 'require' two doses, should we instead give out first doses to as many people as possible before the second dose?

However, it was a question that the FDA was, at first, uninterested in. Because the clinical trials had been carried out with two doses, that was, as far as the FDA was concerned, the only proper way to administer them.

Johnson and Johnson

*Unlike the Pfizer and Moderna vaccines, which used the novel, mRNA technique, up until March 2021 if you were - rightly or not - concerned about this approach, you could use the more traditional J&J vaccine.

I said up until March 2021, because at that point the FDA decided to be extra cautious and destroy the reputation of this vaccine.*

Eight million people got the J&J vaccine - 28 cases of blood clots in total were identified in people who received that vaccine, with three deaths. There was no clear causal link, but the FDA played it safe

Even if the J&J vaccine was the trigger, thats a micromort of 0.375.

just existing in America in 2020 exposed you to 0.5 micromorts from the risk of COVID-19!

and the delay ended up destroying public confidence in the vaccines, which shows up in the sudden drop in vaccination rate.

It's crucial to keep in mind that during all of these delays and concerns about safety, we were actually administering another drug called 'lockdown'. For an organization that was monomaniacally focused on proper safety testing, this other intervention wasn't tested by the FDA and the side effects weren't evaluated

Human Challenge Trials

What if we could've engaged in a highly risky process, in which 10,000 volunteers risked their lives to save millions of people, perhaps in exchange for a handsome paycheck and hero status. Imagine in this scenario that their chance of death is 10%.

Oh, and it wouldn't have taken ten thousand people. Maybe a thousand - with a chance of mortality of ~2%.

After a few weeks to months, needing only a few hundred volunteers, the world would have had strong evidence on whether a vaccine worked

the FDA declared that they wouldn't accept human challenge trials as evidence for vaccine development

Monopolies

If the right person had been at the helm of the FDA, would everything have turned out differently?

It's a tough counterfactual to evaluate - I think its fair to say that a better leadership team, one attuned to the crisis and willing to fight to implement an effective bureaucracy, would have done on the margin better.

The structure and culture of the FDA is shaped by the fact that they're a monopoly provider of approvals for medicine.

The lesson from the failures of the FDA is not that we shouldn't have certifying organizations or good controls on medical practices, it's that we need more than one.

Conspiracy

In a world of over 7.5 billion people, living in 195 countries, why is there is a near uniformity of approach in medical regulation?

Defenders of the FDA will say this is evidence of its superiority.

So, what does the convergence indicate?

A few hypotheses:

Convergent Evolution: The similar systems have evolved in this way because it's an efficient way to maximize health, safety, and public trust.

External Pressure: The similarity of the medical systems is because the FDA, and other western governments, implicity and explicitly force other governments to follow their system

Cultural Mimicry

I suspect all three are at play

A Better Way

Repeal the Kefauver-Harris Amendment

The FDA went sideways when they were tasked with evaluating and approving drugs for efficacy instead of just safety

Removing their legal mandate to test for effectiveness, and returning more of that power to other organizations - like groups of doctors, universities, and companies, would increase avenues for drug approvals.

The costs of this change seem minor, as the effectiveness testing by the FDA is not all that effective!

Good Housekeeping Seal of Approval

having an FDA seal certifying that a drug is effective at the FDA's level would be a major selling point for pharma. The FDA would not legally be able to deny access to the US market except for safety reasons, but would instead certify certain drugs as having proven their effectiveness

Peer regulatory approval

When the UK approved the J&J vaccine and the US didn't, why did I as an American need to solely rely on the wisdom of the US FDA?

Increased progressive approval

In a progressive approval regime drugs would be approved after they pass Phase I and Phase II testing for safety, but would continue through later Phase III and Phase IV testing, and market surveillance for side effects and efficacy.