Bottle of Lies(nytimes.com)
nytimes.com
Bottle of Lies
https://www.nytimes.com/2019/05/13/books/review/bottle-of-lies-katherine-eban.html
47 comments
There was a Chinese hit movie last year (Dying to Survive) about a patient's illicit business smuggling cheap generic drugs from India, the movie is one-sided sympathetic toward the protagonist so did the audience.
Yet a prior investigative report of the guy depicted in the movie, showed the whole thing was all kinds of fishy, including misleading marketing, entangled business interest, fake company addresses in India, untrue claims and poor quality.
But people refused to believe the report and was cursing the reporter and the evil price-gauging foreign drug companies.
Yet a prior investigative report of the guy depicted in the movie, showed the whole thing was all kinds of fishy, including misleading marketing, entangled business interest, fake company addresses in India, untrue claims and poor quality.
But people refused to believe the report and was cursing the reporter and the evil price-gauging foreign drug companies.
Well, I haven’t seen the movie, but if I couldn’t afford pills that would save my life I’d probably take some risks to at least have some hope.
A relative of mine used to work on automation for a large pharmaceutical manufacturer in the US. He used to talk about how unrelenting the FDA was in their inspections. The better your processes were, the harder the FDA would try to find new and seemingly arbitrary faults, almost to the point that it would be better to have some glaring but easily fixable issue to distract from all the minor things they would find.
One example he said was that the FDA decided that they couldn't share tools (hammers, wrenches, etc) across manufacturing lines used for different drugs. This was supposedly to prevent cross contamination of the drugs. Generics made in India and China don't have to compete with such high standards.
One example he said was that the FDA decided that they couldn't share tools (hammers, wrenches, etc) across manufacturing lines used for different drugs. This was supposedly to prevent cross contamination of the drugs. Generics made in India and China don't have to compete with such high standards.
> share tools (hammers, wrenches, etc) across manufacturing lines used for different drugs
I never would’ve guessed that they use hammers and wrenches to manufacture drugs.
I never would’ve guessed that they use hammers and wrenches to manufacture drugs.
My reading of the above is that the hammers and wrenches are used indirectly, i.e., to maintain the equipment on the lines.
I once attended a talk by a Formulations guy at I think Vertex. They had an incident where one of their production facilities made the wrong crystalline isoform and nobody could figure out why. It eventually ended up being related to the interior paint of the facility.
Meh. Not educated enough to tell if this is FUD but sure seems like it. As if the US pharma industry has not been caught countless times hiding data and making patients sick.
"They just don't make it in that India or China or whatever like they can here" comes off as incredibly racist imo.
"They just don't make it in that India or China or whatever like they can here" comes off as incredibly racist imo.
If all countries had the same level of regulations and quality control, maybe. But look to the issue like tilapia farming, and there are very valid reasons to be weary of tilapia that is sourced from China.[0][1][2] The farmers feed those fish with manure rather than fish feed in order to cut costs:
>At Chen Qiang’s tilapia farm in Yangjiang city in China’s Guangdong province, which borders Hong Kong, Chen feeds fish partly with feces from hundreds of pigs and geese. That practice is dangerous for American consumers, says Michael Doyle, director of the University of Georgia’s Center for Food Safety.
>“The manure the Chinese use to feed fish is frequently contaminated with microbes like salmonella,” says Doyle, who has studied foodborne diseases in China.
So no, I don't instinctively think it's "racist" to be concerned that drugs and other materials imported from previously third-world countries might not be exactly what they say they are. We're not importing them because of their quality, we're importing them because they're cheaper. It's a race to the bottom, and anyone trying to reach the bottom is likely to take shortcuts.
---
https://www.bloomberg.com/news/articles/2012-10-11/asian-sea...
https://www.snopes.com/fact-check/tilapia-consumption/
http://web.archive.org/web/20130308100945/http://@ers.usda.g...
>At Chen Qiang’s tilapia farm in Yangjiang city in China’s Guangdong province, which borders Hong Kong, Chen feeds fish partly with feces from hundreds of pigs and geese. That practice is dangerous for American consumers, says Michael Doyle, director of the University of Georgia’s Center for Food Safety.
>“The manure the Chinese use to feed fish is frequently contaminated with microbes like salmonella,” says Doyle, who has studied foodborne diseases in China.
So no, I don't instinctively think it's "racist" to be concerned that drugs and other materials imported from previously third-world countries might not be exactly what they say they are. We're not importing them because of their quality, we're importing them because they're cheaper. It's a race to the bottom, and anyone trying to reach the bottom is likely to take shortcuts.
---
https://www.bloomberg.com/news/articles/2012-10-11/asian-sea...
https://www.snopes.com/fact-check/tilapia-consumption/
http://web.archive.org/web/20130308100945/http://@ers.usda.g...
If inferior drugs are being imported into your country, that raises big questions about your regulator.
I think it's inarguable that generics have offered live-saving medication to millions, if not billions, around the world, much to the disgust of the pharmaceutical companies who would prefer a captive market like they've stitched up in the US.
I think it's inarguable that generics have offered live-saving medication to millions, if not billions, around the world, much to the disgust of the pharmaceutical companies who would prefer a captive market like they've stitched up in the US.
It's significantly harder to test than it is to control the process used to create the drugs.
The idea that the FDA can test every batch of every drug imported is ridiculous, they can however implement strict controls for the production of the drug.... but not abroad.
The idea that the FDA can test every batch of every drug imported is ridiculous, they can however implement strict controls for the production of the drug.... but not abroad.
> The idea that the FDA can test every batch of every drug imported is ridiculous,
Why? I'm pretty sure that large scale manufacturers of electronic devices test every batch of components that they receive. Why should drugs be different?
It's not as if they have to test them for effectiveness, they just have to check that they contain certain compounds and don't contain others.
Also they could put that duty on the distributor.
Why? I'm pretty sure that large scale manufacturers of electronic devices test every batch of components that they receive. Why should drugs be different?
It's not as if they have to test them for effectiveness, they just have to check that they contain certain compounds and don't contain others.
Also they could put that duty on the distributor.
Agreed, compounding pharmacies[1] in the U.S. operate with the same regulatory oversight described in the article - almost none. That lack of over oversight was at last partially responsible for the NECC meningitis outbreak[2] a few years ago.
[1] https://en.wikipedia.org/wiki/Compounding
[2] https://en.wikipedia.org/wiki/New_England_Compounding_Center...
[1] https://en.wikipedia.org/wiki/Compounding
[2] https://en.wikipedia.org/wiki/New_England_Compounding_Center...
China has a long and very bad history of adulterated food and drugs.
https://en.wikipedia.org/wiki/Food_safety_incidents_in_China
https://en.wikipedia.org/wiki/Food_safety_incidents_in_China
I’ve taken and still take quite a few psychoactive drugs and have clearly noticed a lack of quality control and potency in generic drugs.
I wouldn’t say they are poison, but in my experience they often don’t work as well.
One of the best examples is amphetamines. Name brand Adderall and Dexedrine are significantly more potent than the generic alternatives I’ve tried. Maybe this has to do with the binders, or maybe there is less amphetamines in it, I don’t know.
As an anecdote, my dad works as a pharma regulator for the FDA and never takes generic medication. He’s told me that generics are inadequately regulated to ensure equivalency to the original.
I wouldn’t say they are poison, but in my experience they often don’t work as well.
One of the best examples is amphetamines. Name brand Adderall and Dexedrine are significantly more potent than the generic alternatives I’ve tried. Maybe this has to do with the binders, or maybe there is less amphetamines in it, I don’t know.
As an anecdote, my dad works as a pharma regulator for the FDA and never takes generic medication. He’s told me that generics are inadequately regulated to ensure equivalency to the original.
Just another anecdote for the pile but I’ve had the same experience with generic Adderall being significantly less potent. After a decade+ on the generic my insurance company switched me to brand name and it was utterly shocking how different it was. I had previously belived that generics were literally identical and figured I was experiencing a placebo effect.
To try to understand what was going on I recapped 7 generics and 7 brand name pills so that I couldn’t identify which was which and had my wife give me one at random each day for 14 days with her keeping track of which was given when.
After 14 days I had 100% accuracy identifying the generic vs brand name. Not good.
To try to understand what was going on I recapped 7 generics and 7 brand name pills so that I couldn’t identify which was which and had my wife give me one at random each day for 14 days with her keeping track of which was given when.
After 14 days I had 100% accuracy identifying the generic vs brand name. Not good.
Apologies if I don't take your drug taking anecdotes as any kind of fact.
If you knew that they were generics beforehand, and had preconceived beliefs about generics, your subjective experience of their recreational aspects is severely flawed.
If you knew that they were generics beforehand, and had preconceived beliefs about generics, your subjective experience of their recreational aspects is severely flawed.
The book provides details with FDA reports, court and patient cases why these are not anecdotes...
[deleted]
In America, yeah? As in, your regulators might be shit, but other countries might be better. The FDA have hardly been covering themselves in glory.
Anecdotes in general are useless but the Adderall example is not just a single person's anecdote. It's an extremely common experience that almost everyone who takes the medication deals with.
Many of the patients are kids who don't really understand what the difference between generic or name brand pills even is, so its hard to attribute the difference to their beliefs. Many pediatric doctors try to start treatment with generics and then move to the name brand as an alternative to increasing dosage.
Many of the patients are kids who don't really understand what the difference between generic or name brand pills even is, so its hard to attribute the difference to their beliefs. Many pediatric doctors try to start treatment with generics and then move to the name brand as an alternative to increasing dosage.
I’m prescribed them and have been taking some form of anphetamine for over 10 years.
If it matters, I remember discovering this because I ended up taking a lot more because I wasn’t feeling them. Only afterwards did I notice they weren’t namebrand.
If it matters, I remember discovering this because I ended up taking a lot more because I wasn’t feeling them. Only afterwards did I notice they weren’t namebrand.
Your thoughts mirror my thoughts perfectly - it may not be FUD but it sure comes off like FUD. I scrolled down to find the author's credentials and...
> David Dobbs is the author of “My Mother’s Lover,” a memoir of his mother’s long-secret wartime affair.
Oh, okay, clearly well versed on pharmaceuticals.
> David Dobbs is the author of “My Mother’s Lover,” a memoir of his mother’s long-secret wartime affair.
Oh, okay, clearly well versed on pharmaceuticals.
I think it is valid skepticism to at least wonder if the publication forgot to include a more relevant credential.
If the issue is the quality of manufacture, why would there be an expectation that brand name drugs be manufactured with higher quality controls, or be made in the US (just following in the article's implication of a very US-centric view of big pharma). Couldn't big-pharma-company contract out manufacturing to whomever does it cheapest internationally?
Manufacturing costs are roughly similar between generics and brand name drugs (say ~$1/pill as an example). A large portion of costs for brand name drugs are in the development and qualification. Generics avoid these costs.
For a brand name drugs, manufacturing costs are a relatively low portion of the price and margins are high (example: $20/pill, 95% gross margin). For generics, manufacturing costs are a larger portion of the price and margins are lower (example: $2/pill, 50% gross margin).
For generics, because a substantial portion of the price is driven by manufactured costs, margins can be increased substantially by a reduction of the manufactured cost (example: cost $1->0.50, price: $2, margin ->75%, a 50% increase in profitability!). For the brand name drug, the same reduction (example: cost $1->0.50, price: $20, margin ->97%) yields less increase in margin. As a result, there is less incentive for the brand name drug to push for the manufacturing cost reduction (whether or not quality is affected.) And if there is a risk of reduced quality, then the brand name has much more to lose, both in terms of profitability and in the value of it's brand name.
For a brand name drugs, manufacturing costs are a relatively low portion of the price and margins are high (example: $20/pill, 95% gross margin). For generics, manufacturing costs are a larger portion of the price and margins are lower (example: $2/pill, 50% gross margin).
For generics, because a substantial portion of the price is driven by manufactured costs, margins can be increased substantially by a reduction of the manufactured cost (example: cost $1->0.50, price: $2, margin ->75%, a 50% increase in profitability!). For the brand name drug, the same reduction (example: cost $1->0.50, price: $20, margin ->97%) yields less increase in margin. As a result, there is less incentive for the brand name drug to push for the manufacturing cost reduction (whether or not quality is affected.) And if there is a risk of reduced quality, then the brand name has much more to lose, both in terms of profitability and in the value of it's brand name.
Big pharma already does a lot of contracting out to varying degrees.
Probably nobody makes their own excipients/binders or capsules. Others contract out API manufacture, and others the whole product.
Shareholders want lowered costs while maintaining revenues, and contracting out manufacturing is one way to do it.
Especially when you revealed all your secrets in your patents anyway.
Probably nobody makes their own excipients/binders or capsules. Others contract out API manufacture, and others the whole product.
Shareholders want lowered costs while maintaining revenues, and contracting out manufacturing is one way to do it.
Especially when you revealed all your secrets in your patents anyway.
>"Unlike American plants, which matured in an environment where constant oversight made shortcuts risky, the Indian industry evolved in a culture in which outwitting inefficient bureaucracies was an essential skill."
There is an interesting parallel here with the deterioration of regulatory oversight at Boeing that seems likely to have contributed to recent issues with the 737 Max. Similar to how the FDA was only visiting these foreign drug manufacturing operations once ever 11 years on average, the FAA was also resource constrained, to the point that Boeing was responsible for most of it's own oversight.
Maybe the story is just that at a certain point every company becomes rotten in the pursuit of profits (although that seems a contrived conclusion). A better analysis would maybe be what made these companies act in similar ways, skirting regulation at the cost of safety.
There is an interesting parallel here with the deterioration of regulatory oversight at Boeing that seems likely to have contributed to recent issues with the 737 Max. Similar to how the FDA was only visiting these foreign drug manufacturing operations once ever 11 years on average, the FAA was also resource constrained, to the point that Boeing was responsible for most of it's own oversight.
Maybe the story is just that at a certain point every company becomes rotten in the pursuit of profits (although that seems a contrived conclusion). A better analysis would maybe be what made these companies act in similar ways, skirting regulation at the cost of safety.
These problems will solve themselves, but at the cost of human life. I remember someone telling me that governments only move when a lot of people die.
The Indian government will eventually learn to regulate their pharma industry, it will just take the deaths of thousands of Indians before it will happen. We fucked up a lot of people in the Western world before we learned that regulations matter. Thalidomide anyone? That whole period in the early 1900s when we didn't have much of a medical profession and scientists were doing whatever the hell they wanted?
The Indian government will eventually learn to regulate their pharma industry, it will just take the deaths of thousands of Indians before it will happen. We fucked up a lot of people in the Western world before we learned that regulations matter. Thalidomide anyone? That whole period in the early 1900s when we didn't have much of a medical profession and scientists were doing whatever the hell they wanted?
I wonder if this becomes a cycle - otherwise I'm not sure how it explains the problems at Boeing.
I assume there was a point where the FAA was reasonably thorough (although if anyone knows the contrary to be true correct me), but then a general lack of perceived risk led to a leaner FAA with lower regulatory resources, which then contributed to the problems at Boeing. Maybe this will lead to an increase of regulatory oversight, and then the cycle continues.
I assume there was a point where the FAA was reasonably thorough (although if anyone knows the contrary to be true correct me), but then a general lack of perceived risk led to a leaner FAA with lower regulatory resources, which then contributed to the problems at Boeing. Maybe this will lead to an increase of regulatory oversight, and then the cycle continues.
It’s not just complacency, there’s been a significant push for deregulation and gutting of oversight by business interests since the economic problems of the 70s. It’s been one of the top issues for the followers of Milton Friedman, of which there are many in government.
I think the natural engineer intuition is that if a drug is just a chemical, and generic and name-brand drugs are the same chemical, how could there possibly be any difference? Don't be duped by advertising, save the money, be rational, etc.
One interesting case where there was a real problem was with generic extended-release bupropion (an antidepressant). The time-release mechanism on one of the generics didn't work correctly, although the manufacturer managed to get it past the FDA (they actually tested only a 150mg dose, and extrapolated the results to approve the 300mg dose).
https://blogs.sciencemag.org/pipeline/archives/2012/10/18/th...
One interesting case where there was a real problem was with generic extended-release bupropion (an antidepressant). The time-release mechanism on one of the generics didn't work correctly, although the manufacturer managed to get it past the FDA (they actually tested only a 150mg dose, and extrapolated the results to approve the 300mg dose).
https://blogs.sciencemag.org/pipeline/archives/2012/10/18/th...
It gets complicated fast.
Sometimes small differences in formulations will be mostly irrelevant (oh no, your ibuprofen takes a few extra minutes to absorb, but will 99% absorb under almost all circumstances).
But other times, a new crystalline form exists that you weren’t aware of and destroys your entire ongoing production. Same molecule, but different structure that’s too stable and doesn’t dissolve effectively. See: ritonavir.
Sometimes small differences in formulations will be mostly irrelevant (oh no, your ibuprofen takes a few extra minutes to absorb, but will 99% absorb under almost all circumstances).
But other times, a new crystalline form exists that you weren’t aware of and destroys your entire ongoing production. Same molecule, but different structure that’s too stable and doesn’t dissolve effectively. See: ritonavir.
This was one of the cases discussed in the book.
The book said the manufacturer didn't test the 300mg because it might cause seizure.
The book said the manufacturer didn't test the 300mg because it might cause seizure.
Is there any evidence that substandard generic drugs are causing real harm to patients? I'm sure that there are all sorts of dodgy pills ending up in unregistered pharmacies in the developing world, but do people in countries with functioning regulatory systems really need to worry about foreign-manufactured generics?
I'm going to be vague so don't ask for more, but I recently had a minor medical problem, nothing life threatening at all.
I was prescribed a long course of X for it. My complaint responded well to that, but near the end of the course I got a new batch from an Indian generics company. They tasted far less bitter (all the pills from all sources were uncoated so it was very noticeable), and the complaint I had flared up again rapidly even while I was taking them.
I reported this to the body was responsible, giving them the batch number I'd saved. They re-analysed a sample from that batch (they keep back a sample of each) and said it was OK, but I'm pretty sure it wasn't. Stupidly I'd taken all the suspicious tablets when should have kept one back for them.
My story. Not solid but all I've got. If it had been something serious, I dunno...
(BTW this line "I'm sure that there are all sorts of dodgy pills ending up in unregistered pharmacies in the developing world" isn't kind. Their lives still matter, distance and poverty don't change that. I appreciate that may not have been the way you intended it though)
I was prescribed a long course of X for it. My complaint responded well to that, but near the end of the course I got a new batch from an Indian generics company. They tasted far less bitter (all the pills from all sources were uncoated so it was very noticeable), and the complaint I had flared up again rapidly even while I was taking them.
I reported this to the body was responsible, giving them the batch number I'd saved. They re-analysed a sample from that batch (they keep back a sample of each) and said it was OK, but I'm pretty sure it wasn't. Stupidly I'd taken all the suspicious tablets when should have kept one back for them.
My story. Not solid but all I've got. If it had been something serious, I dunno...
(BTW this line "I'm sure that there are all sorts of dodgy pills ending up in unregistered pharmacies in the developing world" isn't kind. Their lives still matter, distance and poverty don't change that. I appreciate that may not have been the way you intended it though)
> I'm sure that there are all sorts of dodgy pills ending up in unregistered pharmacies in the developing world, but do people in countries with functioning regulatory systems really need to worry about foreign-manufactured generics?
From Wikipedia[0]:
> According to Outsourcing Pharma in 2012, 75% of counterfeit drugs supplied worldwide had some origins in India, followed by 7% from Egypt and 6% from China.[12]
> ...
> Around 25% of India's drugs are fake, counterfeit or substandard.[16] If the fake drugs market grows at the current rate of 25%, it will cross US$10 billion mark by 2017.
There have been a number of proposals in the US, usually around election time, to import drugs from overseas in one way or another. It always boils down to this: drugs are cheaper if no one is checking quality control. That would be a disastrous public health mistake.
___
0. https://en.wikipedia.org/wiki/Counterfeit_medications
From Wikipedia[0]:
> According to Outsourcing Pharma in 2012, 75% of counterfeit drugs supplied worldwide had some origins in India, followed by 7% from Egypt and 6% from China.[12]
> ...
> Around 25% of India's drugs are fake, counterfeit or substandard.[16] If the fake drugs market grows at the current rate of 25%, it will cross US$10 billion mark by 2017.
There have been a number of proposals in the US, usually around election time, to import drugs from overseas in one way or another. It always boils down to this: drugs are cheaper if no one is checking quality control. That would be a disastrous public health mistake.
___
0. https://en.wikipedia.org/wiki/Counterfeit_medications
Is this why there's shortages and plants being suspended? And all the cholesterol generics having contaminants causing cancer?
Yup, the book talks in detail about those.
...which carcinogenic contaminants?
Probably referring to the ARB (angiotensin receptor blocker) shortages.
Basically, an API manufacturer changed up its process, but it turned out to generate very small quantities of a very small molecule side-product that’s carcinogenic.
NDMA and NDEA.
https://www.google.com/search?q=arb+ndma
Basically, an API manufacturer changed up its process, but it turned out to generate very small quantities of a very small molecule side-product that’s carcinogenic.
NDMA and NDEA.
https://www.google.com/search?q=arb+ndma
[deleted]
Archive.is link for paywall bypass:
http://archive.is/AyJ5g
http://archive.is/AyJ5g
Painting western companies as victims and to simply blame it on overseas companies would be a gross oversimplification. Whenever you order material from any supplier or vendor it is YOUR responsibility to conduct a vendor audit, its YOUR responsibility to perform incoming materials testing, etc, etc. You don't just simply take what a supplier gives you and inject it into a live human. As you go towards filing an IND, you have to do tox studies, stability studies, pre-clinical, clinical studies, and on and on.
I know of several cases where big name US pharma companies banned their employees from conducting certain tests because if the results came out less than flattering they might have to show those to the FDA, and they might end up having to delay or cancel the product.