12 ms·

The big secret is that bio-equivalent and generic drugs sometimes aren't effective! http://cmlnetwork.ca/generic-imatinib-is-it-really-the-same/ http://cmlnetw

by AdamN 9y ago

The big secret is that bio-equivalent and generic drugs sometimes aren't effective! http://cmlnetwork.ca/generic-imatinib-is-it-really-the-same/ http://cmlnetwork.ca/generic-imatinib-is-it-really-the-same/ http://cml-iq.com/generic-gleevec-is-the-same-the-same/ http://cml-iq.com/generic-gleevec-is-the-same-the-same/ Frustrating that the article doesn't point that out. These new formulas do not need to prove they work, they just have to prove that their active ingredient is the same after the patent expires.

stuartaxelowen 9y ago
Has there been a study that established that the drugs with the same active ingredient don't perform as well?
- ihodes 9y ago
  There are studies showing that some generics don't perform as well as the brand name. Different formulations of the same drug (e.g. extended release medications, different sized particles in inhalers, etc) can have vastly different effects.
- brians 9y ago
  Yes, in the specific case of Valproic Acid, a powerful mood stabilizer used for schizophrenia. The generics are different salts, metabolize differently, and different patients typically end up preferring one. If you like one of the two generics, great! If your body best tolerates the name brand... oops.
- gumby 9y ago
  Yes, there's more to a treatment than the API (Active Pharmaceutical Ingredient) which is used to prove bioequivalence. The excipients aren't typically considered relevant, especially when they're on the GRAS list. One of my former colleagues once made a "drug" where the excipient actually was therapeutically valuable while the listed API was barely better than placebo. Luckily we didn't submit it for approval.
  - icelancer 9y ago
    >One of my former colleagues once made a "drug" where the excipient actually was therapeutically valuable while the listed API was barely better than placebo. Luckily we didn't submit it for approval. That seems... ridiculously illegal.
    - gumby 9y ago
      Why should it be illegal? The submission process would be the same. The reason I sail "luckily" was just that it would be complicated. I believe there are some topical OTC drugs that work this way :-( Or did you think making unlicensed drugs is illegal? Of course it isn't -- that's what drug development IS. It's not legal to give such a drug to humans without a valid IND that hasn't been rejected by the FDA but formulating, doing in vitro testing and animal in vivo testing is all perfectly legit.
- atmosx 9y ago
  I am not aware of any studies on the subject, but from experience I can say that most generics don't perform as well.
  - kagamine 9y ago
    What sorts of drugs treating what sorts of illness? My employer (Europe based) does work for pharmacies and they actively push customers to choose generics[1] because it's cheaper for the customer and the markup is higher (in price -> sales price = greater margin on generics even with a lower sales price than the non-generic). These are long established companies with vertical integration throughout the manufacturing and supply chain. This is a strictly regulated industry in Europe and I don't see them getting-away-with-it if there were health issues for the patient. I'm surprised to see so many comments here agreeing with the notion that generics are of lesser effect. [1] prescription drugs, not over the counter paracetamol.
    - beagle3 9y ago
      It's likely a placebo effect. I'm not saying they are exactly equivalent -- things like particle sizes, buffers, release speed, etc (which are often different in different formulations) are known to make a difference. It is, however, extremely unlikely (to the point of impossibility) that every single brand name is better than every single equivalent generic. I have anecdotal evidence about a specific generic working significantly better than a related name brand for a specific person. There are specific studies showing a specific brand name is better than a specific [set of] generics. In the few cases I looked into it, that study was financed by the brand. They wouldn't publish a result saying the generic is better if that was the conclusion (and it's usually possible to p-hack a favorable result). I am not aware of generic manufacturers commissioning a study either way. I can accept a "75% of brands are better than generic" if it came from a well defined study. It's statistically impossible that "100% of brands are equal or better to generics".
      - compuguy 9y ago
        Agreed. In the case of the drugs mentioned in the article (ADHD), the generic equivalents of the extended release aren't as good and/or potent as the brand name. This sucks because the generic drugs are so much cheaper, even with insurance.
- belorn 9y ago
  Regulative approval of a generic drug is given by the FDA on the therapeutic effect of the drug, which must be within a 90% confidence interval of 80–125% based on the original. The FDA evaluated 2,070 studies conducted between 1996 and 2007 that compared the absorption rate, and found that average difference between generic and brand was 3.5%, comparable to the difference between two batches of a brand-name drug. Some comments in here talk about Active Pharmaceutical Ingredient or excipients, but a generic isn't given approval based on their active ingredients. This is one of the common objection given to the patent model for drugs, in that generics still need to show that their version with their unique combination of active and excipients have the same therapeutic effect, which normally means that they need to conduct new studies. The only way you can "copy" a drug is if you make a identical copy in every aspect, including the excipients, and the patent don't include enough information to do that.
  - kgwgk 9y ago
    That's not correct. To get a generic approved you don't have to show a therapeutic effect. You only have to show bioequivalence: a similar blood concentration time curve for the active ingredient.
    - belorn 9y ago
      http://journals.sagepub.com/doi/10.1345/aph.1M141 http://journals.sagepub.com/doi/10.1345/aph.1M141 If the therapeutically value of an excipient is that they change the absorption rate of the active ingredient, then that effects the bioequivalence of the drug. For example, comments in this thread refereed to different sized particles in inhalers which can have a direct effect on absorption rates. If we disregard the therapeutic effect from the rate and extent that the "active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives" reaches the site of drug action, what is left to change the therapeutic effect?
      - kgwgk 9y ago
        The point is that you don't need to show that the therapeutic effect is the same, you need to show that you expect the therapeutic effect to be the same. The trials required to prove the latter are orders of magnitude simpler, faster and less expensive.
- briandear 9y ago
  Yes. Here’s one: https://www.ncbi.nlm.nih.gov/m/pubmed/12860486/ https://www.ncbi.nlm.nih.gov/m/pubmed/12860486/
- asmithmd1 9y ago
  Yes, the coating on extended release drugs can be very sophisticated: https://www.nytimes.com/2015/06/17/business/generic-ritalin-drug-not-equivalent-to-the-brand-is-in-use-anyway.html https://www.nytimes.com/2015/06/17/business/generic-ritalin-...
  - belorn 9y ago
    It should be noted that inn that article, the FDA concluded that this meant that the two drugs were no longer bioequivalence. At that point, you don't have a brand and a generic drug but rather two different drugs that just happen to have similar ingredients. The article do bring up a major issue when the FDA changed their decision in regard to a generic. The market and even the FDA itself is having a problem to address the problem. The doctor is quoted: “If the F.D.A. rules it’s not the same, how can it be sold? I don’t understand the rationale for that happening.”. It is indeed odd and a major complaint about how the FDA managed this case.
blackguardx 9y ago
The difference in effectiveness comes from differences in manufacturing. Drug manufacturers typically don't test the effects of drug manufacturing on performance. Because of this, generics can sometimes perform worse. But, it seems likely that this effect could lead them to sometimes perform better as well.
tomohawk 9y ago
It's very frustrating. I know people who cannot tolerate some of the fillers and other additives put into some medicines. They end up trying various generic and non-generic brands until they find one they can use. In most cases, the name brands seem to use better quality ingredients because those are the most likely to be tolerated. It's amazing that the FDA requires an ingredients list on food but not on drugs. Additionally, the manufacturing standards can really vary. If the active ingredient is measured in micrograms and the FDA allows 10% variance, then you can be really screwed if the generic manufacturer is sloppy, while the name brand is manufacturing to tighter than FDA specs. A 10% difference could be the difference between one dose and the next higher dose. Seen this too.
- slackingoff2017 9y ago
  Almost everything in this comment chain is incorrect. Manufacturers do list all ingredients including fillers and inactive ones. Ask for the "package insert" and the pharmacy will give you the sheet with that info. Also, brand name and generics are tested to the same tolerances. If the generic is allowed 10% margin the brand is too. In fact, sometimes they're made on the same production line. A few years back when generic Protonix came out it was a huge issue, as it was extremely easy to mix up the "brand" and "generic" because they looked identical and came in similar packaging. I remember hearing about pharmacies getting fined for supposedly mixing them up. If there is any chance of a mixup between brand and generic (missing DAW is a common typo) you had to throw them away because there was no way to tell them apart. Something else you overlooked, related to the above, is that "Brand name" companies typically own as least one subsidiary that produces generics. For example, GreenStone is 100% owned by Pfizer, so i have doubts their generic products could be any different. I'm not normally a dick on HN but I don't appreciate people blowing facts out their ass when it relates to common misconceptions. The drug companies want you to believe generics are inferior, and they spend more on marketing than drug research. You should speak to some pharmacists if you want honest opinion on the matter. They're easy enough to talk to and I think you'll find that the vast majority share my opinion.
  - briandear 9y ago
    I am going to strongly disagree with you, it seems as if you are guilty of blowing facts “out of your ass,” we the the implication that bioequivalence is the same as therapeutic efficacy. Because that isn’t always true, especially in psychiatric drugs. It could be true in many cases, but it isn’t always true – which means there is sometimes a clinical justification for non-generics. Here’s one study addressing that specific issue: https://www.ncbi.nlm.nih.gov/m/pubmed/12860486/ https://www.ncbi.nlm.nih.gov/m/pubmed/12860486/
compuguy 9y ago
This is especially true with generic versions drugs like Adderall xr (and SSRI's), is that the potency can be up to 20% less than the brand name.
dm319 9y ago
Haematologist here - your references don't support your argument. Here is the referenced ASH abstract from 2015 [1]. It doesn't show any statistically significant finding. Even if it did, it is simply an observational study with few patients - there may be other confounding factors at play - you would need a randomised control trial to find out. I doubt that is going to happen. Also it should be noted that all authors disclose receiving payment from Novartis, and there isn't a follow-up paper by the same authors, from my brief googling. Actually, the figure looks very strange - they have an n=11 according to the number at risk along the bottom. A published paper from Turkey compared 36 on brand versus 26 on generics. They didn't find any differences, but noted this[3]: Among our patient cohort, the generics were at least non-inferior to the original molecule regarding efficacy and tolerability when used in the upfront setting, as well as when used subsequently (Eskazan et al, 2014). Prospective randomized trials with larger number of patients are needed to address the efficacy of generics of IM in patients with CML. The chemical structure of imatinib, C29H31N7O isn't that complicated[2]. If a medicine can be proven to contain the same amount of the active drug, particularly when the structure is relatively straight forward, I'm inclined to believe that. The story is a bit different for more complex treatments (i.e. antibody treatments like rituximab - C6416H9874N1688O1987S44) and for drugs with various preparations (especially inhaled or slow-release versions). In those cases you have to check the active ingredient and formulation - in which case the Brand usually does matter. [1]http://www.bloodjournal.org/content/126/23/2778?sso-checked=true http://www.bloodjournal.org/content/126/23/2778?sso-checked=... [2]https://en.wikipedia.org/wiki/Imatinib https://en.wikipedia.org/wiki/Imatinib [3]http://onlinelibrary.wiley.com/doi/10.1111/bjh.12937/full#bjh12937-bib-0001 http://onlinelibrary.wiley.com/doi/10.1111/bjh.12937/full#bj...

by AdamN 9y ago

stuartaxelowen 9y ago

Has there been a study that established that the drugs with the same active ingredient don't perform as well?

ihodes 9y ago
There are studies showing that some generics don't perform as well as the brand name. Different formulations of the same drug (e.g. extended release medications, different sized particles in inhalers, etc) can have vastly different effects.
brians 9y ago
Yes, in the specific case of Valproic Acid, a powerful mood stabilizer used for schizophrenia. The generics are different salts, metabolize differently, and different patients typically end up preferring one. If you like one of the two generics, great! If your body best tolerates the name brand... oops.
gumby 9y ago
Yes, there's more to a treatment than the API (Active Pharmaceutical Ingredient) which is used to prove bioequivalence. The excipients aren't typically considered relevant, especially when they're on the GRAS list. One of my former colleagues once made a "drug" where the excipient actually was therapeutically valuable while the listed API was barely better than placebo. Luckily we didn't submit it for approval.
- icelancer 9y ago
  >One of my former colleagues once made a "drug" where the excipient actually was therapeutically valuable while the listed API was barely better than placebo. Luckily we didn't submit it for approval. That seems... ridiculously illegal.
  - gumby 9y ago
    Why should it be illegal? The submission process would be the same. The reason I sail "luckily" was just that it would be complicated. I believe there are some topical OTC drugs that work this way :-( Or did you think making unlicensed drugs is illegal? Of course it isn't -- that's what drug development IS. It's not legal to give such a drug to humans without a valid IND that hasn't been rejected by the FDA but formulating, doing in vitro testing and animal in vivo testing is all perfectly legit.
atmosx 9y ago
I am not aware of any studies on the subject, but from experience I can say that most generics don't perform as well.
- kagamine 9y ago
  What sorts of drugs treating what sorts of illness? My employer (Europe based) does work for pharmacies and they actively push customers to choose generics[1] because it's cheaper for the customer and the markup is higher (in price -> sales price = greater margin on generics even with a lower sales price than the non-generic). These are long established companies with vertical integration throughout the manufacturing and supply chain. This is a strictly regulated industry in Europe and I don't see them getting-away-with-it if there were health issues for the patient. I'm surprised to see so many comments here agreeing with the notion that generics are of lesser effect. [1] prescription drugs, not over the counter paracetamol.
  - beagle3 9y ago
    It's likely a placebo effect. I'm not saying they are exactly equivalent -- things like particle sizes, buffers, release speed, etc (which are often different in different formulations) are known to make a difference. It is, however, extremely unlikely (to the point of impossibility) that every single brand name is better than every single equivalent generic. I have anecdotal evidence about a specific generic working significantly better than a related name brand for a specific person. There are specific studies showing a specific brand name is better than a specific [set of] generics. In the few cases I looked into it, that study was financed by the brand. They wouldn't publish a result saying the generic is better if that was the conclusion (and it's usually possible to p-hack a favorable result). I am not aware of generic manufacturers commissioning a study either way. I can accept a "75% of brands are better than generic" if it came from a well defined study. It's statistically impossible that "100% of brands are equal or better to generics".
    - compuguy 9y ago
      Agreed. In the case of the drugs mentioned in the article (ADHD), the generic equivalents of the extended release aren't as good and/or potent as the brand name. This sucks because the generic drugs are so much cheaper, even with insurance.
belorn 9y ago
Regulative approval of a generic drug is given by the FDA on the therapeutic effect of the drug, which must be within a 90% confidence interval of 80–125% based on the original. The FDA evaluated 2,070 studies conducted between 1996 and 2007 that compared the absorption rate, and found that average difference between generic and brand was 3.5%, comparable to the difference between two batches of a brand-name drug. Some comments in here talk about Active Pharmaceutical Ingredient or excipients, but a generic isn't given approval based on their active ingredients. This is one of the common objection given to the patent model for drugs, in that generics still need to show that their version with their unique combination of active and excipients have the same therapeutic effect, which normally means that they need to conduct new studies. The only way you can "copy" a drug is if you make a identical copy in every aspect, including the excipients, and the patent don't include enough information to do that.
- kgwgk 9y ago
  That's not correct. To get a generic approved you don't have to show a therapeutic effect. You only have to show bioequivalence: a similar blood concentration time curve for the active ingredient.
  - belorn 9y ago
    http://journals.sagepub.com/doi/10.1345/aph.1M141 http://journals.sagepub.com/doi/10.1345/aph.1M141 If the therapeutically value of an excipient is that they change the absorption rate of the active ingredient, then that effects the bioequivalence of the drug. For example, comments in this thread refereed to different sized particles in inhalers which can have a direct effect on absorption rates. If we disregard the therapeutic effect from the rate and extent that the "active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives" reaches the site of drug action, what is left to change the therapeutic effect?
    - kgwgk 9y ago
      The point is that you don't need to show that the therapeutic effect is the same, you need to show that you expect the therapeutic effect to be the same. The trials required to prove the latter are orders of magnitude simpler, faster and less expensive.
briandear 9y ago
Yes. Here’s one: https://www.ncbi.nlm.nih.gov/m/pubmed/12860486/ https://www.ncbi.nlm.nih.gov/m/pubmed/12860486/
asmithmd1 9y ago
Yes, the coating on extended release drugs can be very sophisticated: https://www.nytimes.com/2015/06/17/business/generic-ritalin-drug-not-equivalent-to-the-brand-is-in-use-anyway.html https://www.nytimes.com/2015/06/17/business/generic-ritalin-...
- belorn 9y ago
  It should be noted that inn that article, the FDA concluded that this meant that the two drugs were no longer bioequivalence. At that point, you don't have a brand and a generic drug but rather two different drugs that just happen to have similar ingredients. The article do bring up a major issue when the FDA changed their decision in regard to a generic. The market and even the FDA itself is having a problem to address the problem. The doctor is quoted: “If the F.D.A. rules it’s not the same, how can it be sold? I don’t understand the rationale for that happening.”. It is indeed odd and a major complaint about how the FDA managed this case.

blackguardx 9y ago

The difference in effectiveness comes from differences in manufacturing. Drug manufacturers typically don't test the effects of drug manufacturing on performance. Because of this, generics can sometimes perform worse. But, it seems likely that this effect could lead them to sometimes perform better as well.

tomohawk 9y ago

It's very frustrating. I know people who cannot tolerate some of the fillers and other additives put into some medicines. They end up trying various generic and non-generic brands until they find one they can use. In most cases, the name brands seem to use better quality ingredients because those are the most likely to be tolerated. It's amazing that the FDA requires an ingredients list on food but not on drugs. Additionally, the manufacturing standards can really vary. If the active ingredient is measured in micrograms and the FDA allows 10% variance, then you can be really screwed if the generic manufacturer is sloppy, while the name brand is manufacturing to tighter than FDA specs. A 10% difference could be the difference between one dose and the next higher dose. Seen this too.

slackingoff2017 9y ago
Almost everything in this comment chain is incorrect. Manufacturers do list all ingredients including fillers and inactive ones. Ask for the "package insert" and the pharmacy will give you the sheet with that info. Also, brand name and generics are tested to the same tolerances. If the generic is allowed 10% margin the brand is too. In fact, sometimes they're made on the same production line. A few years back when generic Protonix came out it was a huge issue, as it was extremely easy to mix up the "brand" and "generic" because they looked identical and came in similar packaging. I remember hearing about pharmacies getting fined for supposedly mixing them up. If there is any chance of a mixup between brand and generic (missing DAW is a common typo) you had to throw them away because there was no way to tell them apart. Something else you overlooked, related to the above, is that "Brand name" companies typically own as least one subsidiary that produces generics. For example, GreenStone is 100% owned by Pfizer, so i have doubts their generic products could be any different. I'm not normally a dick on HN but I don't appreciate people blowing facts out their ass when it relates to common misconceptions. The drug companies want you to believe generics are inferior, and they spend more on marketing than drug research. You should speak to some pharmacists if you want honest opinion on the matter. They're easy enough to talk to and I think you'll find that the vast majority share my opinion.
- briandear 9y ago
  I am going to strongly disagree with you, it seems as if you are guilty of blowing facts “out of your ass,” we the the implication that bioequivalence is the same as therapeutic efficacy. Because that isn’t always true, especially in psychiatric drugs. It could be true in many cases, but it isn’t always true – which means there is sometimes a clinical justification for non-generics. Here’s one study addressing that specific issue: https://www.ncbi.nlm.nih.gov/m/pubmed/12860486/ https://www.ncbi.nlm.nih.gov/m/pubmed/12860486/

compuguy 9y ago

This is especially true with generic versions drugs like Adderall xr (and SSRI's), is that the potency can be up to 20% less than the brand name.

dm319 9y ago

Haematologist here - your references don't support your argument. Here is the referenced ASH abstract from 2015 [1]. It doesn't show any statistically significant finding. Even if it did, it is simply an observational study with few patients - there may be other confounding factors at play - you would need a randomised control trial to find out. I doubt that is going to happen. Also it should be noted that all authors disclose receiving payment from Novartis, and there isn't a follow-up paper by the same authors, from my brief googling. Actually, the figure looks very strange - they have an n=11 according to the number at risk along the bottom. A published paper from Turkey compared 36 on brand versus 26 on generics. They didn't find any differences, but noted this[3]: Among our patient cohort, the generics were at least non-inferior to the original molecule regarding efficacy and tolerability when used in the upfront setting, as well as when used subsequently (Eskazan et al, 2014). Prospective randomized trials with larger number of patients are needed to address the efficacy of generics of IM in patients with CML. The chemical structure of imatinib, C29H31N7O isn't that complicated[2]. If a medicine can be proven to contain the same amount of the active drug, particularly when the structure is relatively straight forward, I'm inclined to believe that. The story is a bit different for more complex treatments (i.e. antibody treatments like rituximab - C6416H9874N1688O1987S44) and for drugs with various preparations (especially inhaled or slow-release versions). In those cases you have to check the active ingredient and formulation - in which case the Brand usually does matter. [1]http://www.bloodjournal.org/content/126/23/2778?sso-checked=true http://www.bloodjournal.org/content/126/23/2778?sso-checked=... [2]https://en.wikipedia.org/wiki/Imatinib https://en.wikipedia.org/wiki/Imatinib [3]http://onlinelibrary.wiley.com/doi/10.1111/bjh.12937/full#bjh12937-bib-0001 http://onlinelibrary.wiley.com/doi/10.1111/bjh.12937/full#bj...