FDA issues first emergency use authorization for point-of-care diagnostic | Hacker News Reader

FDA issues first emergency use authorization for point-of-care diagnostic

fda.gov

159 pointsdoener109 comments

This is the device - http://www.cepheid.com/en_US/systems/GeneXpert-Family-of-Sys...

Brochure (pdf) - https://p.widencdn.net/jdgicj/Cepheid-GeneXpert-Xpress-Syste...

Promo video - https://www.youtube.com/watch?v=lPTHRqDyWC4

About the size of a small laser printer.

I'm not clear how it returns results so quickly. I thought that the RT-PCR process required numerous heating and cooling cycles which is what makes it take as long as it does.

I looked at their one of their patents and it looks like they might be using something like rolling circle amplification instead of traditional amplification techniques for faster speed (I don't know off sure but it's one of the options in their claims). Kind of like LAMP pcr where you can amplify really quickly to get a signal really rapidly (although the dna at the end isn't really useable for further synthetic biology - it just provides a strong signal). They also mention a couple other types in this patent like strand displacement etc, so there's a lot of options they could be using.

Edit: the keyword to look for might be "isothermal" amplification, which means same - temperature amplification. Again, no clue if that's what they're using, I just see that they have patents on using isothermal techniques. These allow for amplifying DNA without cycling the temperature, usually letting the reaction accelerate quickly until a signal is detected, and it can accelerate really quickly sometimes. You know those videos of supercooled liquid water where you bump the bottle and the whole thing freezes? Imagine that you have a situation like that where adding non-coronavirus dna bumps the bottle incorrectly and nothing happens, while adding coronavirus dna makes the whole thing freezes. It's a rapid signal that just gets generated, but often (like with lamp) you just end up with a polymerizated mess that you can't use for DNA engineering in synthetic biology which is why you might use your temp. cycling methods for those uses. Also, they're good for telling you if something is or isn't there, but not so good at telling you how much dna you started with. To figure that out you again use a cycling reaction with the amount of dna doubling each step until it levels out so you know how many doublings happened and can calculate backwards (quantitative rt-pcr, or qPCR).

https://patents.google.com/patent/US8900828

https://en.m.wikipedia.org/wiki/Rolling_circle_replication

https://en.m.wikipedia.org/wiki/Loop-mediated_isothermal_amp...

Thank you for the informative comment! Your example of the water bottle is perfect

Thanks! I was trying to find a universally known example or party trick of something just polymerizing quickly,which I couldn't think of, so went freezing instead (since it looks line if like polymerizing? And I think lots of people have seen those videos showing off that trick). If you want clear, beautiful ice, you've gotta freeze it the right way. But if you want to know if water is cold enough to freeze and don't care about using the ice, bump the supercooled bottle. Trying to convey the differences in constraints between a) detecting dna, where it's a destructive test for all intents and purposes since the end product is just tossed into biohazard - you just wants signal and b) making more usable dna for further research, where you want that end product for further manipulation and so has to high quality, usable dna, not just a polymerized mess. Lots of rapid PCR diagnostics take advantage of this to use gunk-creating rapid tests while scientists working on engineering the same DNA will use temperature cycling processes to clone the DNA and do work on it - each has its use.

chemistry video: https://www.youtube.com/watch?v=j-y3xi1K7JE

The fast turnaround time is from integrated sample prep and reagent cartridge. It just uses standard thermocycling PCR. PCR doesn't take long when volume is small and heating surface is large.

It's worth nothing that this machine is very low throughput - the larger one only takes 4 samples and you have to use their proprietary disposable cartridges.

edit: as pointed out below - the largest of the machines has 80 slots and could probably do 2000/day taking around 45min-1hr/test all in

Contrast that with a modern real-time PCR machine which typically has capacity for 96 samples, with some machines able to test 384 or even 1536 at a time. The tradeoff is that those machines take 2-3 hours and the lab needs to do nucleic acid extraction separately.

The main advantage of this machine is that it does the nucleic acid extraction and PCR in one cartridge and in ~20 minutes. It's great for clinics and field hospitals but for an established laboratory running hundreds or thousands of tests per day, I'd wager that the standard methods are much cheaper and a bit faster overall.

They have bigger systems--- https://www.cepheid.com/en_US/systems/GeneXpert-Family-of-Sy...

It's pretty neat-- they have 1, 2, 4, or 16 slot things that you can slot samples into as you're ready, and they process in the background... or the big robot. It's also neat in that they have combined cartridges to do a couple of influenza detections + RSV in one rapid test (with a different color of fluorescence for each).

But you're spot on in that this has a costly consumable (the cartridge)

What is the false positive rates of this, if 10k people are tested everyday, can we expect 100 false positive everyday?

PCR tends to have great specificity and great in vitro sensitivity. The sensitivity drops off with pre-analytic errors that accumulate in real world testing (wrong collection method, wrong media, wrong swab, etc). So false negatives are the problem.

The nice thing is that it catches acute infections even earlier than IgM.

PCR tends to have pretty low false positive rates if used properly - so from a technology perspective the contribution to that would be low. Although, if they're using more innovative PCR methods, maybe there's a risk.

Where I think there's room for them to introduce false positive rates (that we would not know without having access to proprietary information) is in how they design something called a primer sequence. this is a little bit of DNA that will go and find to a different little bit of DNA that's part of a larger bit of DNA. Basically it lets you target it a little bit of DNA within a larger bit of DNA. you want to make this primer so that it only will bind to coronavirus DNA but will not bind to any other DNA. It's important to design it that way because in PCR the DNA that amplifies to give you the signal is whatever that primer was able to bind it to.

If you accidentally make a primer that can bind to some non coronavirus DNA (something we call off Target binding) then you would end up with false positives. There are bioinformatics tools to evaluate this and presumably the FDA and the company did some work into making sure they didn't make any mistakes when designing that, but that's what I think of first when it comes to false positives.

If this works, it should be open-sourced so it can be manufactured and distributed at multiple locations, in many countries at once.

I don't think that's going to work because this is a fairly complicated machine, and the company itself which has experience building molecular testing equipment and has a manufacturing supply chain in place is one of the only few that can build this.

Also asking them to open-source their technology seems unfair, they're entitled to their share of pay for their hard work. The average engineer at this company probably makes much less than the average engineer at your FAANG company.

I wouldn't ask. This is what eminent domain is literally for.

If you seize someone's company every time they have a worthwhile breakthrough, that's really going to put a damper on working on problems like this. Not only would you be toiling for uncertain/small reward, you might be flushing your entire business down the toilet.

Also, you seize the company-- then what? Are you going to be able to ramp up production, etc, as well as the original product group could? Are you going to make them work on it at gunpoint?

I agree there's a good point to this. At the same time I dislike and disbelieve the capitalist narrative that the deepest motivation is the profit one.

It's not that the deepest motivation is the profit one. It's that it's the best at bringing together large scale consistent cooperative teams. When you have a profit motive, you don't need to convince every single necessary person or resource provider to believe in your mission, you just have to pay them. And that makes a lot of things possible that wouldn't otherwise be.

Eminent domain in the US still requires fair compensation.

Indeed, a 20% return would be more than fair, wouldn’t it? So, pay off their development costs + 20%.

Oh yah, that makes a lot of sense. /s IF you succeed, you get upside bounded at +20%, but you still have full downside risk. And of course, most things in bio R&D don't work.

Also, re: your other hyperbole point-- this test system is neat and fills a small gap in testing capabilities. It does not have the ability to "save millions of lives" but could be a nice tool among many to help slow things down. It doesn't scale well, so it's not how you'll do most tests, but there are scenarios where having a close-to-immediate result noticeably helps.

> Show me another breakthrough in the past 100 years that could save millions of lives ...

The past century is littered with thousands of examples of technologies that have contributed in this or bigger ways. The Rosch and Abbott machines are going to be the workhorses here, not the Cepheid ones.

No, you make 20% and save millions of lives. Identifying and quarantining the infected is literally the only tool we have now to slow this pandemic.

It seems you missed both points:

* "Making" 20% if you happen to be successful, when most efforts fail, is not much of a prize-- especially if you lose your company in the process. Not even the most diehard gambler would play slots with those rules. ;)

* It's not going to save millions of lives. There's lots of tests available meeting different needs. It may save some lives, and will likely improve quality of life of those suspected of having COVID-19 quite a bit.

Identifying and quarantining is a complicated strategy and this test is not going to be the "workhorse" of it and is certainly not going to save millions of lives. Look to Rosch, Abbott, and others that have made pieces of already-deployed infrastructure to fill that need.

20% for a few months worth of effort is more than fair. They would not lose the entire company, simply the rights to the specific technology. And, even if it is "the whole company," then they can go start another one, or go cry me a fucking river. You seem to think I care; I don't.

Mass testing literally will save lives. It worked in South Korea. If we could run 700M tests (slightly more than 2 per US resident, because you have to run at least 2 as an accuracy check) right now, I guarantee you we could get this under control.

Don't believe me? Believe this guy. He's a doctor:

> Testing, Testing, Testing: We must widely test our population, diagnose mild and even asymptomatic cases. Requires point of care diagnostics in doctor's office. We must advance these immediately to market. It means serology to know who was exposed and developed immunity. 9/n

(From https://twitter.com/ScottGottliebMD/status/12414195930144849... )

But, every incremental step helps here. Information is literally our only weapon against this disease right now, and testing is how you get that. Getting something like this into the hands of doctors on the front line right now is what is needed.

TL;DR: You are wrong on both counts.

> 20% for a few months worth of effort is more than fair. They would not lose the entire company, simply the rights to the specific technology. And, even if it is "the whole company," then they can go start another one, or go cry me a fucking river. You seem to think I care; I don't.

The rapid test technology is something that Cepheid has been developing since before 2010. Now they have gotten approval to load reagents into the disposable cartridges their machine uses to test for COVID-19. There is no way to parcel off "just this test".

> Mass testing literally will save lives. It worked in South Korea. If we could run 700M tests

The Cepheid technology, as I've been patiently explaining to you, is about the dumbest way to run millions of tests.

The Cepheid test costs about $40 in raw materials, when a similar test from Roche has an underlying cost of $0.75, but it requires a much lower degree of operator skill and capital equipment. But because it requires less operator skill and less capital equipment, it can be closer to patients, especially in remote areas.

But you're too much into "rah rah let's nationalize the technology" before you even realize what it's useful for. Neat.

Okay, it's been in development for 10 years? 20% per year, then. Done. A 200% return over 10 years is a CAGR of 11.61%, just a hair lower than what you'd get dumping it all into an S&P 500 index fund on 2010-01-01 and cashing out 2019-12-31, plus you get to put "saved millions of lives" on your resume. Totally fair.

You don't think the US government can afford $80 ($40x2, because you should run 2 tests for confirmation) to test every resident of the country? Google tells me there are 327.2M people in the US. $80/person is only $26 billion. How much are we spending again on useless foreign wars that nobody questions? How much did the Fed spend in a failed effort to stabilize the market a couple weeks ago?

You also forgot, this test returns results in 45 minutes, whereas the other version takes hours. Reducing the time to result by an order of magnitude means you can test an order of magnitude more people. You said it right here: "... it requires a much lower degree of operator skill and capital equipment. But because it requires less operator skill and less capital equipment, it can be closer to patients, especially in remote areas."

So, what do you want, $26 billion in the US treasury, or every single human inside the US borders to be tested for coronavirus? Granted, that testing will not happen instantaneously, but it will happen far, far faster with this technology deployed at scale than not. And, I don't see Cephid moving to put 10 of these in every hospital in the country yet. Do you?

Let me put it to you another way: do you want to go the way South Korea has, or the way Italy has?

I want to use the machines that are built for high volume testing, and not try to ramp up production of a cost-inefficient cartridge thing for the bulk of testing that we could never get enough tests from in a reasonable time. (Takes a week+ to make tooling for injection molding even on an expedited basis and I guarantee you they cannot produce enough of these fancy plastic cartridges to test everyone with present tooling).

Of course, I also want to take advantage of the unique capabilities of the cartridge based system where they're most useful.

This is mostly because I'm not stupid. Neither is South Korea; they're getting fine just by with traditional, cost-efficient RT-PCR practices.

Save lives first, think about compensation after the pandemic is dealt with.

Sure, but I am sure the government can compensate them if the government want.

What - are they couriering the money from a secure vault in Germany by barge, horse and carriage? I think not. It'd take a day or so to negotiate and then a few hours of banking transfers. Governments around the world are currently engaging in multi-billion to potentially multi-trillion dollar emergency spending programs. There is room for negotiation and cash up front while the company holds all the cards.

It isn't a good idea to fight economics in this crisis; beyond cushioning people in the very short term against quarantines. It will leave everyone in a very uncomfortable place if the incentives push individuals to avoid helping in the next crisis. Or worse; avoiding the entire field. The problem with all these 'experts should give away this lifesaving X for free' ideas is that then only an idiot would try to become a medical expert - anyone smart would try to go to Wall Street where they are allowed to make crazy profits.

The people working on this stuff are doing an insane amount of good. If there aren't a few billionaires minted in the medical community out of this something has gone terribly wrong - the incentives aren't there to guide resources towards preparedness.

Why open-source? It is enough to license it so that they reap the reward for their work.

The next crisis will come. People need to know that it is rewarding to be prepared.

This, a thousand times this.

Instead of open-sourcing, shouldn't we just give them as much funding as possible to manufacture as quickly as possible? This isn't software. You can't just `git clone` their repo, and random indie hackers 3D printing things that seem to work might do more harm than good.

"Hey guys, thanks for working on this thing that's really useful during this unexpected pandemic, great you were working on that while nobody else was paying any attention. We're just going to steal it now and give it away for free, kthxbye."

Maybe they should use your house to do the testing?

[Since you have no problem taking other people's property].

Open Source is probably not the right model - because this gear is very complicated, only a few entities can possibly be involved.

The 'best software in the world' is often written by some dude, at home, working when he wants, possibly in his pajamas, possibly collaborating interactively with other people.

Software often does not need experience or teams, just intelligence, creativity, assertion. Although experience helps.

This kind of gear, or anything physical really, 100% requires the experience of various kinds.

If we had a really competent industrial board that understood medical technology, we could feasibly put together a kind of 'shared IP' contract very quickly.

Bidders could be quickly approved, sign up, get the plans, and start making according to specific terms.

Just because we're in a panic doesn't mean there can't be standards & controls - they just have to be rapid and risk-adjusted.

It could be a win-win-win even in a time of the pandemic.

I have little faith in our governmental leaders for the most part. It's not that they're not smart, it's that I don't think they generally have operational wherewithal to make decisions, push stuff through in such a crude and cold manner. Surely they are some, but you need a critical mass of them, and political backing as well.

A number of reasons thats wouldn’t help anything:

1) there’s going to be a ton of point of care tests, in fact there already are. The bottleneck is FDA approval.

2) scaling up manufacturing of a device like this is HARD. It’s not some raspberry pi hobby kit.

This company is owned by Danaher, a fortune 200 or so which has many engineers and manufacturing sites. They’ll figure out a way to make as many as are needed.

Is this a different test than the 20-minute antibody test discussed here a couple days ago?

Yes, it's completely different. That one is a blood test that only detects infections that are pretty far along.

Would it detect resolved infections?

Yes, with an outer bound of however long antibodies against the disease persist. That's the big value in that test.

This is PCR test. Antibody test generally has lower sensitivity i.e. higher false negative rate because PCR amplifies target molecules.

FDA is remarkably quick to authorize things like this test that will make the epidemic look worse, and yet are somehow utterly unwilling to consider authorizing the treatments that have been shown to be effective.

I wonder why that is

How accurate is it?

Is this what Theranos was trying to do? (sorry, I'm a n00b!)

If you mean a machine to automate medical tests, yes. But there are plenty of companies that already make such machines. If you mean a machine to run every possible test using only a few drops of blood, no.

Ah, thanks! I didn't realize Theranos was trying to do 240 tests on one device.

Where are the 5000/day (hour?) machines doing it for $1 a test?

This was promised weeks ago. It was a matter of automated diagnostic reprogramming?

So this is promised in 10 days. How many units, 15000?

> Where are the 5000/day (hour?) machines doing it for $1 a test?

This fills a different need. Rosch has their tests to market and test quantity is ramping up at designated centers. $1/test is just what Rosch gets, so it's gonna cost more than that.

> It was a matter of automated diagnostic reprogramming?

Nah, you still need reagents.

> So this is promised in 10 days. How many units, 15000?

The Cepheid machines are neat. They make bigger machines, but mostly you buy a machine with 1-8 slots and disposable testing cartridges. When a patient needs a test, you put their sample in the cartridge, stick it in a slot, and that slot yields an answer in 45 minutes.

This will be a very nice tool for individual, smaller hospitals (and even large clinics) to have in the next 10 days when it rolls out, and for situations where we want to get immediate feedback. Probably not a massive number of units at first. And not nearly as cost-effective as the Rosch.

I dream that in post-crisis clarity, some news sources will reverse the traditional "FDA as protagonist" wording of such headlines, and instead prefer formulations like:

"FDA removes threats of fines & imprisonment for one company's point-of-care COVID-19 diagnostic"

How would that help improve people’s understanding of this issue?

It’s the same reason certain folks insist automatic income tax payment schemes would cause people to forget about tax policy.

The FDA has no role in creating this test – or any other. They've just dangled a threat of prosecution over companies, hospitals, research labs, and universities who wanted to develop & use a variety of tests – including tests that have proven very useful elsewhere.

When they "authorize" something, all they've really done is removed the prior threat of fines & imprisonment. This threat exists even if the thing they're holding up had little to no risk of harm or confusing anyone. (People, especially those in research labs and the medical profession, are not idiots! Even all sorts of long-approved diagnostic tests have significant errors associated that doctors & patients need to discuss & account for!

This administrative-law threat exists even if traditional product liability – as applies for all sorts of other product/service/info-product category – would be more than sufficient to ensure quality, & punish recklessness.

The FDA's delays have held back US testing capacity for months. The current economic disaster, & many deaths, are a direct outgrowth of both the legislation which gives them this veto-power, and their incompetent exercise of the various discretionary powers they have. They could have offered the same arbitrary waiver that they finally did, on February 29, back in last December!

Even now, urgently needed medical supplies are held up, waiting for FDA inspection/certification backlogs to clear:

A news story: https://www.washingtonexaminer.com/opinion/fda-inspections-c...

Testimony from a Google employee & philanthropic investor: https://twitter.com/mekkaokereke/status/1241151194812186624

The FDA shouldn't get to tout themselves as doing a good thing with this "authorization" – when the risk of harm of such vitally-necessary new testing options is so small that a delay of days, much less months, is unwarranted. Let scientists, doctors, & patients experiment!

Hacker news is extremely pro FDA. I never understood why.

People fear that without some oversight, dangerous things would be sold

Yet they go to the local restaurant who's preparing dishes with no special oversight ex ante, just good logic and the fear of being closed if there's an hygiene investigation ex post.

For some reason, reviews can filter out bad restaurants but not drugs? Even if food can also kill? Evidence of the opposite, from darknet markets where people review drugs and sellers, is routinely ignored.

But when the CDC delivers a non working test, people want more money for the CDC- so that next time, they don't deliver one non working test, but maybe 2 or 3 instead?

My personal conclusion is that the "modern hacker" trust centralization and likes social control - whether it comes from government organizations, or private companies like google or facebook. Based on comments, working there would be a dream from most people here - and not just for the money. People seem to find some kind of prestige in that, for... reasons?

There's a generational disconnect I think. I stopped trying to understand. When I see a movement pushing away Eric Raymond and Richard Stallman, I think it's time to stop associating with this movement, let these people make their own mistakes and hopefully learn from their failures.

People have a choice in which restaurants they patronize.

They do not have a choice in which medical devices their ER doctor uses.

Their doctor has a choice - or should, & could with fewer barriers to competition, especially barriers against things which work just fine throughout the world.

>Yet they go to the local restaurant who's preparing dishes with no special oversight ex ante, just good logic and the fear of being closed if there's an hygiene investigation ex post.

Yes, because there are health and safety regulations in place!

> Yes, because there are health and safety regulations in place!

Exactly my point: ex post.

The restaurants do not have to declare the recipes they will use or the list of ingredients. They are free to buy from any supplier.

Yet for some mysterious reasons, healthcare needs ex-ante regulations. Read https://thedispatch.com/p/timeline-the-regulationsand-regula... ; do you honestly believe the regulations/FDA/CDC are not at fault here?

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