“—and so biomedical companies are bleeding 500,000 every year.”
April 13, 2017 3:53 PM Subscribe
The Blood Of The Crab [Popular Mechanics] “Their distinctive blue blood is used to detect dangerous Gram-negative bacteria such as E. coli in injectable drugs such as insulin, implantable medical devices such as knee replacements, and hospital instruments such as scalpels and IVs. Components of this crab blood have a unique and invaluable talent for finding infection, and that has driven up an insatiable demand. Every year the medical testing industry catches a half-million horseshoe crabs to sample their blood. But that demand cannot climb forever. There's a growing concern among scientists that the biomedical industry's bleeding of these crabs may be endangering a creature that's been around since dinosaur days.”
Totally fascinating. The New Yorker had a piece about this a few years ago.
posted by gwint at 4:09 PM on April 13, 2017 [1 favorite]
posted by gwint at 4:09 PM on April 13, 2017 [1 favorite]
I'm frankly stunned that nobody has tried building an artificial system in which to grow these amoebocytes in culture. Why hasn't the synthetic LAL caught on?
posted by actionpotential at 4:22 PM on April 13, 2017 [3 favorites]
posted by actionpotential at 4:22 PM on April 13, 2017 [3 favorites]
Horseshoe crabs are awesome! I hope an alternative is found.
posted by grumpybear69 at 5:19 PM on April 13, 2017
posted by grumpybear69 at 5:19 PM on April 13, 2017
Heck, we do the same thing to humans too. If we gave orange juice and a cookie to the crabs would it be okay then?
posted by Splunge at 5:37 PM on April 13, 2017 [3 favorites]
posted by Splunge at 5:37 PM on April 13, 2017 [3 favorites]
I'm frankly stunned that nobody has tried building an artificial system in which to grow these amoebocytes in culture.
I am not a horseshoe crab expert, but consider saying "Why do the humans donate bone marrow? Why don't they just grow it in culture?". Some cells are easy to grow, others will require several Nobel prizes worth of effort.
posted by benzenedream at 7:21 PM on April 13, 2017 [2 favorites]
I am not a horseshoe crab expert, but consider saying "Why do the humans donate bone marrow? Why don't they just grow it in culture?". Some cells are easy to grow, others will require several Nobel prizes worth of effort.
posted by benzenedream at 7:21 PM on April 13, 2017 [2 favorites]
The big fail in this article: While several companies have come up with synthetic alternatives for detecting the presence of endotoxins in vaccines, medicine, and medical instruments, LAL is still the only test that has received FDA approval.
There are alternatives already. There are even alternatives that have been approved for use in place of the LAL by governments across the globe. But companies don't use it, because regulatory agencies (especially in the U.S.) are not rushing to accept it in practice.
The best replacement is the monocyte activation test (MAT), which uses tiny volumes of human blood (lab jockey note: human blood is a really common reagent, and easy to buy at low cost as a byproduct of hospitals, plasma centers, etc.). It's been around for almost two decades, and has been formally approved for use in place of LAL and the even worse rabbit pyrogen test (RPT, which is also still performed routinely). Lab companies have even developed kits for it, or offer the service for a fee, and it's cheaper than that LAL and RPT. Companies use it all the time during product development, but still worry that FDA won't accept results from MAT.
The LAL/RPT industry in the US is huge, so companies offering it aren't in a rush to make themselves obsolete, so they keep telling companies they need to use LAL/RPT to get FDA approval. FDA doesn't say a peep because they don't like change. In the absence of a mandate to stop using an archaic animal test when a new method is developed and approved for use that doesn't use animals (which is the law of the land in the EU), it's a self-reinforcing loop: companies and labs keep using what they've always used. The result is huge frustration in the toxicology community--we've had this ideal method for years and nothing but inertia keeps it from wiping out LAL/RPT.
If people, en masse, wrote or tweeted or social media'd drug companies and regulators like the FDA about their distaste over this, things would change.
posted by late afternoon dreaming hotel at 7:24 PM on April 13, 2017 [28 favorites]
There are alternatives already. There are even alternatives that have been approved for use in place of the LAL by governments across the globe. But companies don't use it, because regulatory agencies (especially in the U.S.) are not rushing to accept it in practice.
The best replacement is the monocyte activation test (MAT), which uses tiny volumes of human blood (lab jockey note: human blood is a really common reagent, and easy to buy at low cost as a byproduct of hospitals, plasma centers, etc.). It's been around for almost two decades, and has been formally approved for use in place of LAL and the even worse rabbit pyrogen test (RPT, which is also still performed routinely). Lab companies have even developed kits for it, or offer the service for a fee, and it's cheaper than that LAL and RPT. Companies use it all the time during product development, but still worry that FDA won't accept results from MAT.
The LAL/RPT industry in the US is huge, so companies offering it aren't in a rush to make themselves obsolete, so they keep telling companies they need to use LAL/RPT to get FDA approval. FDA doesn't say a peep because they don't like change. In the absence of a mandate to stop using an archaic animal test when a new method is developed and approved for use that doesn't use animals (which is the law of the land in the EU), it's a self-reinforcing loop: companies and labs keep using what they've always used. The result is huge frustration in the toxicology community--we've had this ideal method for years and nothing but inertia keeps it from wiping out LAL/RPT.
If people, en masse, wrote or tweeted or social media'd drug companies and regulators like the FDA about their distaste over this, things would change.
posted by late afternoon dreaming hotel at 7:24 PM on April 13, 2017 [28 favorites]
Horseshoe crabs have been around almost twice as long as dinosaurs.
Dinosaurs emerged between 230 and 240 million years ago. At that point horseshoe crabs had already existed for over 200 million years. These organisms have survived ALL FIVE of the 'Big Five' mass extinctions, including the Permian-Triassic and the K-Pg asteroid that killed the dinosaurs. The span of time over which these animals have existed, largely unchanged, simply overwhelms the human imagination.
posted by Vic Morrow's Personal Vietnam at 8:32 PM on April 13, 2017 [26 favorites]
Dinosaurs emerged between 230 and 240 million years ago. At that point horseshoe crabs had already existed for over 200 million years. These organisms have survived ALL FIVE of the 'Big Five' mass extinctions, including the Permian-Triassic and the K-Pg asteroid that killed the dinosaurs. The span of time over which these animals have existed, largely unchanged, simply overwhelms the human imagination.
posted by Vic Morrow's Personal Vietnam at 8:32 PM on April 13, 2017 [26 favorites]
late afternoon dreaming hotel how does that work in this case?
If I develop a test kit is it on me to get FDA approval for use by my customers when releasing a medical product? (Like developing a diagnostic kit to sell to consumers, my job to prove it works.)
Or is it that my customers can use whichever test they are able to validate in their release specs as fit for purpose? (Like selling someone an HPLC or other analytical equipment.)
posted by mark k at 10:53 PM on April 13, 2017 [1 favorite]
If I develop a test kit is it on me to get FDA approval for use by my customers when releasing a medical product? (Like developing a diagnostic kit to sell to consumers, my job to prove it works.)
Or is it that my customers can use whichever test they are able to validate in their release specs as fit for purpose? (Like selling someone an HPLC or other analytical equipment.)
posted by mark k at 10:53 PM on April 13, 2017 [1 favorite]
(Or is it even harder, ie, convince FDA to change very specific guidelines that talk about crab blood?)
posted by mark k at 10:55 PM on April 13, 2017 [1 favorite]
posted by mark k at 10:55 PM on April 13, 2017 [1 favorite]
mark k
A primer:
Federal laws like the Food Drug and Cosmetic Act (FFDCA) lay down broad responsibilities of agencies like FDA. They'll say something like, 'the FDA should make sure drugs are safe enough to sell to people before they can be marketed, and the FDA is in charge of deciding how that should be done.' Then the FDA writes more specific regulations that say, 'to meet the terms of the FFDCA, you need to show that the process you use to make your drug/device includes controls that you can prove keep those products from becoming contaminated with pyrogens, and we won't let you sell those products until you prove that to us. You can prove that to us however you like, but we require you to use specific approved methods unless you come up with a better one. We have guidance documents on what those required tests are.' Then the FDA publishes guidance documents that get down to the nitty gritty and say, 'Right now, we require the LAL, but you can develop new methods if you want." They do it this way because guidance documents are easier to revise than regulations, and regulations are easier to change than laws. In theory, that's supposed to mean that innovation is welcomed because guidances can be kept up to date with much less effort than rewriting laws and regulations.
Short answer:
In very general terms, yes, if you're the developer of a new method that replaces an existing one then you're responsible for doing the work to prove to the FDA that it works at least as well as the existing one. This is a pretty well defined process called validation, and it's written into federal regulations and regulatory agency guidance (here's an example). One a more modern method is developed and validated, it can be used widely. You can think of validation as a process of running both methods side by side and comparing the results. Validation is considered stronger when those side by side comparisons are run with a lot of different kinds of substances (drugs, chemicals, medical device extracts, etc.). If you want your kit approved for use with X, you have to show that you tested X during the validation.
The issue with LAL is that it only detects a single kind of pyrogen--bacterial endotoxin--because that's the only pyrogen that the FDA specifically requires companies to look for when proving that a product isn't contaminated with pyrogens. Tests like MAT detect all pyrogens that humans can react to, even undefined pyrogens. So, how to proceed? We can't rely on companies to use the approved MAT if it increases the odds that the test they're using will show that their product is contaminated with non-endotoxin pyrogens. They just want to get a product on the market, and if the FDA only needs proof that there's no endotoxin present... well, LAL it is. So who's responsible for the next step here? Is it change-averse FDA, who needs to revise its guidance to say as much? Like, 'hey companies, you know we approved this better test that detects more pyrogens, so now we're going to require you use it,"--or is it companies' jobs to say, "hey FDA, we've validated MAT for our product and it detects more pyrogens than the LAL so please accept our results'? It's both, most likely, but there's no clear requirement for either to take action.
Really responsible companies can do the good thing here and take the lead. For now, that's the ideal solution.
posted by late afternoon dreaming hotel at 11:34 AM on April 14, 2017 [2 favorites]
A primer:
Federal laws like the Food Drug and Cosmetic Act (FFDCA) lay down broad responsibilities of agencies like FDA. They'll say something like, 'the FDA should make sure drugs are safe enough to sell to people before they can be marketed, and the FDA is in charge of deciding how that should be done.' Then the FDA writes more specific regulations that say, 'to meet the terms of the FFDCA, you need to show that the process you use to make your drug/device includes controls that you can prove keep those products from becoming contaminated with pyrogens, and we won't let you sell those products until you prove that to us. You can prove that to us however you like, but we require you to use specific approved methods unless you come up with a better one. We have guidance documents on what those required tests are.' Then the FDA publishes guidance documents that get down to the nitty gritty and say, 'Right now, we require the LAL, but you can develop new methods if you want." They do it this way because guidance documents are easier to revise than regulations, and regulations are easier to change than laws. In theory, that's supposed to mean that innovation is welcomed because guidances can be kept up to date with much less effort than rewriting laws and regulations.
Short answer:
In very general terms, yes, if you're the developer of a new method that replaces an existing one then you're responsible for doing the work to prove to the FDA that it works at least as well as the existing one. This is a pretty well defined process called validation, and it's written into federal regulations and regulatory agency guidance (here's an example). One a more modern method is developed and validated, it can be used widely. You can think of validation as a process of running both methods side by side and comparing the results. Validation is considered stronger when those side by side comparisons are run with a lot of different kinds of substances (drugs, chemicals, medical device extracts, etc.). If you want your kit approved for use with X, you have to show that you tested X during the validation.
The issue with LAL is that it only detects a single kind of pyrogen--bacterial endotoxin--because that's the only pyrogen that the FDA specifically requires companies to look for when proving that a product isn't contaminated with pyrogens. Tests like MAT detect all pyrogens that humans can react to, even undefined pyrogens. So, how to proceed? We can't rely on companies to use the approved MAT if it increases the odds that the test they're using will show that their product is contaminated with non-endotoxin pyrogens. They just want to get a product on the market, and if the FDA only needs proof that there's no endotoxin present... well, LAL it is. So who's responsible for the next step here? Is it change-averse FDA, who needs to revise its guidance to say as much? Like, 'hey companies, you know we approved this better test that detects more pyrogens, so now we're going to require you use it,"--or is it companies' jobs to say, "hey FDA, we've validated MAT for our product and it detects more pyrogens than the LAL so please accept our results'? It's both, most likely, but there's no clear requirement for either to take action.
Really responsible companies can do the good thing here and take the lead. For now, that's the ideal solution.
posted by late afternoon dreaming hotel at 11:34 AM on April 14, 2017 [2 favorites]
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posted by Burn_IT at 4:00 PM on April 13, 2017