I don't know why this is allowed to go on. It's been going on for years with almost no consequences. At one point relatively recently they threatened to cut off one generic manufacturer from the US market but then backed off, as far as I remember.
They know this is a trend, it's been documented in many articles over the last decade at least.
They could make unannounced spot checks, they could do more quality control sampling, they could increase accountability by mandating manufacturing information and links to safety violation records be printed on drug labels. And so forth and so on.
Sometimes I feel as if the entire medical industry in the US, and especially the drug regulation culture, has its head in the clouds with either some form of regulatory capture and/or narcissistic feeling of impunity or disregard.
Several years ago there was an article in a major news outlet about generics, and how lower income individuals were more likely to to choose brand name drugs over generics. The entire article, with interviews with physicians and medical experts, was framed around this idea that lower income individuals were less educated and didn't understand that generics were "chemically exactly the same" as brand names. This was going on at the same time as all this adulteration and dangerous manufacturing of generics. Not once did they mention that the possibility that maybe lower income individuals had a realistic, healthy fear of being screwed over by inferior products and lack of real oversight from authorities who are supposed to protect them.
The entire article was like a snapshot of problems with healthcare in the US: impoverished individuals getting screwed over by credentialed, overprivileged individuals in authority positions who are more concerned about maintaining a fiction of superiority and regulatory capture benefits than actually thinking of protecting the individuals who actually need help.
It's like cargo cult medical regulation, but with motivated ignorance.
The FDA needs to focus more on safety and quality control and less on the murkier and more questionable topics around efficacy and gatekeeping access.
> The FDA needs to focus more on safety and quality control
yes
> less on the murkier and more questionable topics around efficacy and gatekeeping access.
no
By all means, let's work out a way to use the FDA to better ensure quality control of generics (and other stuff), but reducing their focus on the efficacy of drugs is a terrible idea. You can't meaningfully talk about the safety of drugs without understanding their efficacy. Every medication comes with a cost benefit tradeoff, and the only way to make a reasoned decision is to have good data about the efficacy and side effects.
Defense-in-depth, especially at both the beginning and ends of the supply chain. All US pharmacies (retail and otherwise) should be required to capture a random sample of 0.1% of stock to the FDA for comprehensive mass spec characterization processed at federal labs with data released to the public openly. This data must be correlated with complementary point-of-production batch sampling. The data should agree, and would annihilate cheating, scamming, negligent, and incompetent manufacturers from harming patients.
Pharmacies in the US are the last place to do it unless the FDA is going to compensate them in full. The shitshow that is the pharmacy supply chain actually puts pharmacies in shitty positions when it comes to drug pricing. Many independent pharmacies actually have to pay the distributor if someone uses one of those discount PBMs like GoodRX. Not to mention some drugs are just obscene at book value for the pharmacy.
Instead, pretty much all pharmacies get their drugs from centralized regional distributors. Those distributors should be mandated to take part.
Sampling tests will accept a base rate of failure, and governments have a bad habit of mixing up what sampling results mean. For example take a look at NZ’s corngate where they ignored the test results…
The FDA is just pharma execs looking out for themselves. There is nobody at all looking out for us guinea pigs but ourselves. If the opiate thing hasn't made this clear enough for us to do something different, I'm not sure it's possible to change. I worked at a pharma company for a few years - what I saw and learned has led me to trust none of them or the FDA.
But how "random" are they, because the government knows you're coming and can tip someone off if they value their export manufacturing industry enough.
"...Sometimes I feel as if the entire medical industry in the US, and especially the drug regulation culture, has its head in the clouds with either some form of regulatory capture and/or narcissistic feeling of impunity or disregard...."
Why is it ok to say this about anything not covid related?
Not sure why any of this would be surprising. This is what happens when you allow for-profit corporations to basically run the health care system in this country.
Of course they will do absolutely everything in their power to increase profit margins, with no regard for customer safety. And that includes regulatory capture, as well as cutting corners with regards to safety, and quality control.
If you're interested in the safety of generic drugs you should read "Bottle of Lies" by Katherine Eban. She presents a convincing argument that FDA regulators were/are unprepared for ensuring the safety of drugs from overseas manufacturers.
For example, in the US, drug makers are subject to surprise inspections but in India and China, manufacturers have weeks or MONTHS of warning. There was a program to station inspector in India and perform random inspections but it was cancelled. She argues because it was too effective, every plant inspected was found to have serious issues.
And it's not just ignorance of good manufacturing practices or a few bad actors. She shares the story of whistleblower Dinesh Thakur who revealed Ranbaxy executives committing safety-compromising fraud.
I did an IT consulting gig at a western pharma company that specialises in generics. They develop the chemistry and the manufacturing process at the head office, and then pack up the factory and ship it to India or China for low-cost operation.
I overheard an emergency conference meeting about a batch that had gone bad. I can't remember the details, it overheated or something like that, certainly ruining some horrifically complicated organic chemistry process step.
The Indian chemical engineers were arguing for hours about how they could "save" the batch or "use it somehow" while the westerners were repeatedly telling them that there is no safe way to do that, and the only option was the throw it out and start from the beginning.
"Sir, we can fix it!"
"No, no, no! Throw it out!"
... for hours.
Their culture is just not compatible with certain modes of thinking, like "safety first". Saving face takes priority in their culture, even if that means kids might die because the drug batch was bad.
That is not how the FDA operates. For more than 2 decades, the FDA has basically given these overseas generic factories months of advanced notice of inspections. There are even former inspector who tried to whistleblower over how many times theyve caught those factories fabricating data and other circumstnaces and the FDA just buried the issue.
The real question, what in the world changed that made the FDA decide to suddenly cause the effective discontinuation of chemo as a treatment option for the US LOL
If I'm a European, Israeli, or Japanese conglomerate that wants to make a clone of Pfizer or Abbott compounds, I can't do that in the EU or US+Canada because I'd be sued for patent infringement.
On the other hand, India, Israel, and Japan don't recognize or enforce American patents for pharmacuticals.
After Israel and Japan became developed countries in the 80s-90s, it became expensive to manufacture within both, so the Pharma companies like Teva and Takeda began investing heavily in the Indian Pharma manufacturing base in the Himachal Pradesh-Chandigarh-Haryana-Uttarakhand corridor and the Hyderabad-Pune corridor.
If what you said was true, The Serum Institute of India wouldn't have licensed the Oxford-AZ vaccine. Same applies for drugs like Molnupiravir where local manufacturers licenced the drug from Merck.
Even if these manufacturers were able to get away with patent violations, they still wouldn't be able to export them to the biggest and richest markets.
The COVID vaccine was a bad example as it was manufacted on license from AstraZeneca, but the larger Indian market absolutely does this due to how the Indian Patent Act is structured.
"Section 3(d) of the Patents Act, 1970, explains that a new form of a known substance, new property / new use for a known substance and the mere use of a known process are not patentable and is not considered distinct from the known substance. Based on this principle, inventions using known substances are not patentable unless, for example, the alleged invention displays a significant increase in efficacy." [0]
Ranbaxy, Reddy Labs, and Sun Pharma all started thanks to this loophole, and it has been a massive blocker in any US-India Free Trade Agreement.
This is all open knowledge to all
players in the India market [1]. It's not necessarily a bad thing btw - it's a major reason India's Pharma and Agrochemical R&D pipeline punches above its weight, but it has an impact on US-India relations, but for other regions such as the EU, Japan, or Developing countries it doesn't have much of an impact.
You need to trade that off with 'kids might die because the drug batch was thrown out.'
In any supply and demand market, any supplier chucking out product means some buyer somewhere is priced out of the goods they would have bought.
If the faulty drugs were even 50% as effective as good drugs, then more lives were probably saved by shipping them. The problem is that there is no way to find those people who would have been priced out and offer them the maybe-50%-effective-maybe-deadly drugs.
> If the faulty drugs were even 50% as effective as good drugs, then more lives were probably saved by shipping them. The problem is that there is no way to find those people who would have been priced out and offer them the maybe-50%-effective-maybe-deadly drugs.
Huh? You are assuming that they are effective at all and, even worse, let’s assume that it is 50% effective intended drug dose what the hell is in the other 50%?! Does it cause cancer or lead to other disease? Is it innocuous? Frequently contaminants are really not. Look up Chanticleer, Metformin, ranitidine just in the last couple of years.
These aren’t expired medications. They are ineffective at an overly generous best and likely dangerous.
These also aren’t street dealers where you are okay if 50% is coke and 50% is flour.
No pharma company is your friend. They can be useful, sure.
Is your argument really "we should let people take dangerous and potentially deadly pharmaceuticals to reduce costs." Because I agree that would reduce cost by dropping demand.... Because the people taking them would be dead.
A bad batch of a drug or precursor does not conform to standards is no good in a safety-critical industry. We are looking at generic drugs, it's not like you have a batch of polyethylene from the pilot plant which does not conform to any standard, and you send it off to SE Asia for use in cheap plastic toys.
The FDA's regulatory scheme is absolutely backwards.
Investigating foreign facilities and forcing manufacturers to comply with onerous paperwork and recordkeeping details does little or nothing to ensure the availability, quality, and low cost of generic drugs. (In fact, you could argue that it does just the opposite, in reducing availability and increasing cost, with at best indifferent results where drug quality is concerned.)
Instead, the FDA should test a statistically valid random sample of any given drug _upon its import and introduction to the US pharmaceutical supply chain._
This would be considerably less expensive for all involved, less demanding and even demeaning for all involved, and of far greater relevance to the quality and safety of the drugs available on the US market.
Quality control has limits, if you only test some samples you are likely to miss issues. Especially as there is a wide variety of potential problems, and you can't easily test for all of them. That is why the processes themselves are regulated, and not just the products.
And the issues here are not just onerous paperwork. This is the company shredding documentation that would otherwise show that they had data that indicated potential issues, but which they ignored.
I think what you’re missing here is that generics are already approved with pretty large deviations in e.g. serum response from the underlying approved drug, but without re-testing.
So the current system is already producing bad-for-consumer outcomes at a rapid pace.
Can confirm, the generic for the adhd med a couple of my kids take is super obviously not even close to as good as the real thing. Took us a little bit to put 2 and 2 together the first time we got that instead of the "real thing", but that was definitely the problem. Of course we still end up with the generic a lot, what with the shortage, and just have to deal with it barely-working instead of being wonderfully effective, until we get to roll the dice again 30 days later and hope we luck into name-brand pills being available.
Makes one wonder about, you know, all the other generics.
Yeah. The generics use a different ER mechanism, which is surely part of the problem, but others report issues with non-ER versions, too, presumably due either to purity/consistency issues or different filler material, so I doubt the ER difference is the only problem—we did use name brand non-ER at first before switching to extended release, and that wasn't even close to as ineffective as generics of the ER. I've read (but not confirmed) that some adhd generics are also allowed to use cheaper-to-manufacture almost-but-not-quite-identical isomers that haven't been tested and may have significantly worse efficacy, though, no clue if that affects ours (or if that's even true, really).
I wouldn’t be surprised. Concerta (osmotic time release) is so much more effective than normal generics (non-osmotic time release) that they shouldn’t even be considered the same drug.
unmedicated << generic <<<<<<<<<<<<<<<<<<<<<<<<<<<<< name brand
in terms of perceived effect. They're sure as hell not close enough to be considered equivalent under any reasonable classification scheme (but I assume insurers really, really, really want the generic to count as equivalent and work to ensure it is so-regarded—and, anyway, availability's so spotty that we just have to take what we can get regardless).
Absolutely not. Historically, time and time again the pharmaceutical industry has proven it cannot be trusted and that regulatory oversight is required.
You don’t mention quality controls. What should FDA do if upon said random testing there are concerns? How can they and/or the manufacturer trace the causes without documentation?
> What should FDA do if upon said random testing there are concerns?
Destroy or return the entire batch, depending on the level of concern.
> How can they and/or the manufacturer trace the causes without documentation?
That shouldn't be the FDA's concern. The FDA's concern should begin and end with the quality of the actual drugs that are entering the US supply chain. The drugs are things in themselves and can be tested as such -- without regard to where they came from or exactly how they were made.
A random sample by definition isn’t the entire batch, so how would you define ‘batch’ without documentation? The FDA would force recall on the entire product entering the country? Until how many samples are cleared?
Most cheap generic drugs are imported by the containerload, so simply create an arbitrary "batch" from each instance of importation. If the manufacturer is decent and has its own batch number, then the label could read
"Manufacturer batch: XXXX
FDA Import of Record batch: YYYY."
Drugs that are imported in more specialized ways -- e.g. by small-volume refrigerated air freight -- are, as a general rule, far more expensive and batches are correspondingly smaller. The above paradigm would still work, where each importation instance is, for the FDA's purposes, a batch.
Testing fees, which shouldn't amount to more than a few thousand bucks per import, can be the responsibility of the importer -- so as to dissuade importers from receiving small batch after small batch.
So you treat each subsequent container load as a new batch without a potential common cause, like manufacturing defects? Testing every single batch for any possible harmful defects?
Every import, which could be multiple container loads.
If there's a manufacturing defect, the manufacturer -- after losing a couple of batches or having them returned to sender, and having paid for multiple transit and testing costs -- should wise up.
In any case, this would absolutely protect the US pharmaceutical supply chain without pushing unnecessary and excessively onerous requirements onto manufacturers. How foreign facilities manufacture drugs should not be the FDA's concern; drugs are chemical systems and chemicals are easily amenable to testing as things in themselves.
So instead of manufacturers bearing the cost of quality control during manufacturing you expect every single import to be tested for all potential contamination? How would that work exactly? And without documentation of quality assurance, how would any contamination be traced by the manufacturer?
It's not difficult. There are known quantitative and qualitative testing methods for finished drug products, and these usually cost anywhere from a couple hundred to a few thousand dollars. In other words: It's typically very cheap.
So say a company imports 1M doses, and say you're an FDA inspector. At the port of entry, you take a statistically valid sample from that batch of doses, and you subject them to those tests. (This could be at an FDA/Customs lab or a third party lab -- in any case, the importer pays.) If there's a problem, you either test additional samples, or dispose of the batch summarily with a note to the importer as to what you've found.
Testing every import shipment, instead of stationing FDA inspectors overseas, would do more to improve the quality and availability of drugs, and more to reduce costs.
As things stand right now, a lot of drug companies don't want anything to do with the USA simply because they don't want the FDA getting into their business, inspecting their facilities, etc. It is a great, and wholly unwarranted and unnecessary, burden.
> how would any contamination be traced by the manufacturer?
That's not the FDA's problem. A batch of drugs is a thing in itself. A metformin capsule is a metformin capsule regardless of who made it and how.
But of course there would be import records and any halfway competent manufacturer would be able to tie a shipment to a production run.
There's a lot of details in there related to manufacturing of pharmaceuticals, it's not clear how egregious these irregularities actually are to people that don't know this stuff.
So... what does Intas make? What is "an irregularity", what does it mean in plain language? How bad was it there?
Is this going to end up as just needing corrective action, or is Intas now barred from selling in the US?
This is pretty indicative of how bad things are: [A] quality control officer ... alleg[ed to investigators] another employee -- upon learning investigators were on the way -- "immediately rushed and tore apart balance printouts along with Auto Titrator spectrums and threw the torn pieces into the small trash container,” which the employee then doused with an acid solution in a bid to “destroy the evidence of tests" with potentially damning results. (https://www.fiercepharma.com/manufacturing/burn-after-readin...)
Intas is under an import alert for most of their drugs, but FDA is allowing twenty-five short-supply drugs (including a lot of chemo drugs) to be imported, which should also tell you how stressed the pharma supply chain is right now.
For perspective, the document indicates their manufacturing area which was supposed to be sterile had bacteria and/or fungus growing on sentinel culture plates.
I think most people can understand that re-runninf quality checks to fudge the results and destroying records as soon as you realize inspectors have arrived is pretty bad.
I really wonder what triggered this inspection. Generics in the US have been a shitshow for a long time and plenty of whistleblowers from the FDA have come out over how much the FDA heads have buried the issue completely.
Personally, this goes back a few years. In high school, we had a quantitative analysis class where we decomposed various brands of acetaminophen pills to measure the % of active ingredient (acetaminophen) and compare to the labeled totals. Pretty every generic brand tested by multiple groups in this lab resulted in contents below 80% of the label. I think the Rite-Aid generic was 60% of the label content. The only one even close was Tylenol coming in at 95%. (With potentially the last 5% being experiment error in recovery since we are talking milligrams and not the most extremely careful lab setup). And that's why I avoid generic acetaminophen if I want it to work LOL
This is like the third incident in the last year. Indian government seems to be sleeping at the wheel. ITT the surprise inspection is absolutely a must. The government should step up, the negative consequences for people and industry are very bad.
"on 22-Nov-2022, when he came to know that the
Investigators are on the walkthrough inspection ofBlock~t> QC laborat01y and are coming in the
direction ofbalance room, he immediately rushed and tore apart balanceprintouts along with
Auto Titrator spectrums and threw the torn pieces into the small trash container located next to
the balance. Later, he threw1<b) <
4) -7 acid solution inside the same trash in an attempt
to destroy the evidence ofthe tests that he was working on that had issues with high % RSD and weighing ofmaterial was not in line with the expectation.
This trash was removed from the area
immediately by your area housekeeper and moved to the QC scrap area. This trash bag was later
found hidden under the staircase leading to the fb) <
4>7 floor of your QC laborato1y by another
Investigator. No justification was provided upon asking by your QC management for hiding the
trash bag."
Why is this redacted. FDA observations should be published in real time so that end users can make judgements and watchdog groups can evaluate and grade companies, batches, and products.
That would be a better role for most federal agencies. If states want to make mandates that require adherence to some standard, that is more in line with the original constitutional role of states.
I cannot say for certain, but I "feel" that these types of issues crop up quite often and are only publicized when certain corporations do not make the proper lobbying donations to certain people. Limiting the lobbying potential to a state level may prevent my "feeling".
They know this is a trend, it's been documented in many articles over the last decade at least.
They could make unannounced spot checks, they could do more quality control sampling, they could increase accountability by mandating manufacturing information and links to safety violation records be printed on drug labels. And so forth and so on.
Sometimes I feel as if the entire medical industry in the US, and especially the drug regulation culture, has its head in the clouds with either some form of regulatory capture and/or narcissistic feeling of impunity or disregard.
Several years ago there was an article in a major news outlet about generics, and how lower income individuals were more likely to to choose brand name drugs over generics. The entire article, with interviews with physicians and medical experts, was framed around this idea that lower income individuals were less educated and didn't understand that generics were "chemically exactly the same" as brand names. This was going on at the same time as all this adulteration and dangerous manufacturing of generics. Not once did they mention that the possibility that maybe lower income individuals had a realistic, healthy fear of being screwed over by inferior products and lack of real oversight from authorities who are supposed to protect them.
The entire article was like a snapshot of problems with healthcare in the US: impoverished individuals getting screwed over by credentialed, overprivileged individuals in authority positions who are more concerned about maintaining a fiction of superiority and regulatory capture benefits than actually thinking of protecting the individuals who actually need help.
It's like cargo cult medical regulation, but with motivated ignorance.
The FDA needs to focus more on safety and quality control and less on the murkier and more questionable topics around efficacy and gatekeeping access.