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Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

bloomberg.com

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Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#81

Post by Scoundreller »

fucking_tragedy wrote: post #5
knolax wrote: post #3

> Some of the contaminated valsartan contains as much as 17 micrograms of NDMA in a single pill. That’s equivalent to eating 48 pounds of bacon. The FDA estimates that for every 8,000 people who took the highest dose of contaminated valsartan daily for four years, there would be one additional occurrence of cancer. Given the relatively small significance and the fact that this article was published in an issue with t…

For a blood pressure medication, 1 in 8,000 is not a small risk. Serzone, an antidepressant, has a similar risk rate for inducing liver failure, and was taken off the market.

For nefazodone, we had other antidepressants (so why take the risk?), and it was only taken off the market when it went generic (lol).

For BP medication, hopefully at least 1 in 100 recipients are benefitting from it. Probably more like 1 in 10. Overall, don't stop taking it. Reducing the cancer risk is possible and feasible in this case without changing therapy.

We'll probably see further testing of APIs and validation of synthetic route changes in the future because of it.

Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#82

Post by Scoundreller »

kevingadd wrote: post #41
KingMachiavelli wrote: post #2

> By 2014, the FDA had closed its offices in Shanghai and Guangzhou, leaving only the Beijing office with inspectors who could visit Chinese factories on short notice. > The FDA checks less than 1% of drugs for impurities or potency before letting them into the country. For a regulator body who's job it is to make sure medical products are safe and available. These comments, if true, lend credability that the FDA is…

Considering the fine American tradition (dramatically amplified in the last decade) of underfunding every important regulatory agency and then hollowing it out through other methods, it doesn't seem very surprising that the FDA is bad at checking products. Hard to imagine closing offices because of "regulatory capture", if anything the big US companies would want more enforcement on foreign generic drug manufacturers…

Dunno how much the US FDA is to blame here: these API plants pretty much supply the world with generics.

If anything, it's the FDA that's doing foreign plant inspections and every other country's regulator just does what the FDA does.

My real question is: Why is each country doing its own inspections? Why not one global inspection?

Everyone else is getting a free ride from the FDA's work.

Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#83

Post by perl4ever »

Most of the gardening implements, and most of the cheap shower heads in my local home improvement store say they cause cancer. I assume people buy them anyway, or the store would stock something else.

So are these drugs with carcinogens of more concern than the other stuff? Should we be more concerned about the other stuff?

Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#84

Post by Scoundreller »

refurb wrote: post #77
cooljacob204 wrote: post #56

Earlier quoted context omitted.

And I would have never learned about this unless I was surfing hacker news. Bleh. From the NDMA wiki: [NDMA] is also used to create cancer in rats for cancer research. That is super alarming.

It's a different issue than the valsarten issue. Valisure is suggesting that ranitidine breaks down itself into NDMA, which, as an organic chemist, I guess could happen to a small degree based on the structure[1], but it would be hard to mimic the conditions inside the body in a lab. The Valisure petition speculated that the source of the NDMA was the result of the “inherent instability” of the ranitidine molecule, w…

> I guess could happen to a small degree based on the structure

There's no N-N bond in ranitidine. And nitration/amination isn't a metabolic pathway for good reason.

Must be a funky re-arrangement reaction if it is from breakdown.

My money is still on side-reaction from synthesis.

Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#85

Post by perl4ever »

JMTQp8lwXL wrote: post #34
MegaButts wrote: post #25

Earlier quoted context omitted.

I understand that. OP said: > There is no sensible reason to pay a premium for brand name if the generic is chemically equivalent. If they're not chemically equivalent and have different medicinal effects as a result, then it's much easier to justify a price difference. I understand chemistry is more than just a list of ingredients. It's how those ingredients are combined that gives them their unique interactions.

For sake of the discussion here, bio-equivalence is the more helpful way for meaningfully comparing generic to brand names. The filler might be different, but if the biological effect is identical at half the cost, one would be prudent to chose the generic option.

Yet we see drugs that are, say, 100 times the cost of the generic. So how can that happen; how is that sustainable? Presumably nearly everyone starts on the generic, and then switches to the brand name if they have problems with the generic. So there is actually not competition so much as price discrimination! You can't tell someone who the generic has failed that they are equivalent, because their only hope is that they are not! Not only is the generic no longer an alternative, but psychologically, it's easier to put your hope in a super-expensive option because of the cliche "you get what you pay for".

So I think telling people continually that generics are identical is not helpful, because it's not information. It's an assumption, which might be true or it might not be, but is essentially never helpful to any individual in making a decision.

Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#86

Post by perl4ever »

refurb wrote: post #27
thereisnospork wrote: post #23

Earlier quoted context omitted.

Chemically equivalent but formulated differently. Think hot dog vs. corn dog: the meat is the same but the packaging is slightly different. The packaging can have a surprisingly large effect on drug absorption, and therefore efficacy. Notably with difficult to dissolve drugs a lot of work typically goes into formulating them to be more efficiently processed by the intestinal tract.

The FDA approves generics based on bioequivalence, not just chemical composition. In order to be an "AB" rated generic (and used as a substitute for the branded product), the generic has to fall between 80-125% bioequivalence of the brand, which measure dissolution and absorption. The fillers in the generic don't have to be the same as the branded product, but the drug does have to behave the same as the branded prod…

There was an issue I read about with a drug where they did not test all the different dosages of a generic, and I think the behavior of one of the doses was not as expected because it didn't dissolve well or something.

This was a psychiatric drug, and so of course, reports of problems went unheeded for years because patients were assumed to be imagining things.

Saying "the drug does have to behave the same as the branded product" is like saying "the product as delivered does have to match the spec".

Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#88

Post by wil421 »

perl4ever wrote: post #83

Most of the gardening implements, and most of the cheap shower heads in my local home improvement store say they cause cancer. I assume people buy them anyway, or the store would stock something else. So are these drugs with carcinogens of more concern than the other stuff? Should we be more concerned about the other stuff?

All of my fishing weights and some lures have these warnings. It’s because of lead. I certainly don’t put them in my mouth and neither should you.

Shower heads are very concerning. Never seen those warnings.

Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#89

Post by refurb »

Scoundreller wrote: post #84
refurb wrote: post #77

Earlier quoted context omitted.

It's a different issue than the valsarten issue. Valisure is suggesting that ranitidine breaks down itself into NDMA, which, as an organic chemist, I guess could happen to a small degree based on the structure[1], but it would be hard to mimic the conditions inside the body in a lab. The Valisure petition speculated that the source of the NDMA was the result of the “inherent instability” of the ranitidine molecule, w…

> I guess could happen to a small degree based on the structure There's no N-N bond in ranitidine. And nitration/amination isn't a metabolic pathway for good reason. Must be a funky re-arrangement reaction if it is from breakdown. My money is still on side-reaction from synthesis.

Ranitidine has a nitro group which can be cleaved and reduced to nitrous acid and combine with the dimethylamino group to give NMDA.

Whether that’s a reasonable metabolic pathway I have no idea.

Re: Carcinogens Have Infiltrated the Generic Drug Supply in the U.S.

#90

Post by refurb »

dahfizz wrote: post #24
lostmsu wrote: post #19

Earlier quoted context omitted.

>> The FDA checks less than 1% of drugs for impurities or potency before letting them into the country. > For a regulator body who's job it is to make sure medical products are safe and available. These comments, if true, lend credability that the FDA is more regulatory capture than actual useful regulation. I wonder though if this statement misrepresents the facts. If they check only 1% of the entire import volume a…

I agree, I think the statement is ambiguous. 1% of all products (e.g. one pill from every bottle of 100 pills) being tested seems like plenty. 1% of shipments (1 out of 100 shipments is sampled) seems insufficient.

Very ambiguous.

Generally how it works is you submit a proposed purity level to the FDA, with rationale and backup by your own validated analyses.

The FDA dives into it and says “this is reasonable” or “this won’t work” or “based on the chemistry, you need to test for X also”.

Then they require you to “release” any product you make, showing that it conforms to the agreed upon purity. If it fails, they expect you to follow up and figure out why.

Note, most of this is done in good faith - the FDA isn’t repeating the science in a lab, but they pay enough attention that if you’re making things up, it’ll be apparent in the data. The CMC (chemistry manufacturing controls) section of the NDA can be hundreds of pages long.

When it comes to inspections, they are typically random (but if you have a bad track record they happen more often). They can happen any time and they’ll look at all your processes, not just for a specific drug. Don’t have a record that you cleaned your equipment between runs? That’s a paddlin’.

Repeatedly run tests until you get a “pass” result? Yeah, your product will get banned from importation.

But yes, much of the regulation is based on good faith simply because the manpower required to verify everything made would be massive.

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