11 ms·

> The findings surprised both researchers: A dozen of the 14 compounds were still as potent as they were when they were manufactured, some at almost 100 percent

> The findings surprised both researchers: A dozen of the 14 compounds were still as potent as they were when they were manufactured, some at almost 100 percent of their labeled concentrations. What kind of reporting is this? Anything less than 100% is not "as potent as when manufactured", and the sentence implies some of those dozen weren't close to 100%. > The idea that drugs expire on specified dates goes back at least a half-century, when the FDA began requiring manufacturers to add this information to the label. The time limits allow the agency to ensure medications work safely and effectively for patients. To determine a new drug’s shelf life, its maker zaps it with intense heat and soaks it with moisture to see how it degrades under stress. It also checks how it breaks down over time. The drug company then proposes an expiration date to the FDA, which reviews the data to ensure it supports the date and approves it. Despite the difference in drugs’ makeup, most “expire” after two or three years. That seems to be the problem. There was a procedure in place to set expiration dates scientifically, and it was ignored for some reason, limiting the legal shelf life of even the most stable compounds to a few years.

thaumasiotes 9y ago
> That seems to be the problem. There was a procedure in place to set expiration dates scientifically, and it was ignored for some reason, limiting the legal shelf life of even the most stable compounds to a few years. To investigate how a drug breaks down over a ten-year timespan, you'd need to do at least one ten-year study of the drug. That seems difficult to justify.
- funkymike 9y ago
  I was thinking about this today after hearing a report on the radio this morning on this topic. Hospitals end up throwing away large amounts of drugs each year due to expiration, potentially hundreds of millions of dollars - although there is no real data currently. It seems like it would be a good long term investment for a group of hospitals to partner together and begin a systematic study of the actual lifetimes of drugs. Instead of destroying all expired drugs they could send off samples to a lab for testing. They could even intentionally keep expired drugs in an off-limits area for 1, 2, 3 years past their expiration dates to gather more information. With enough hospitals participating they could gather a significant amount of data without any one hospital shouldering all of the burden. Once there is enough evidence that a particular drug is still potent the FDA could extend the allowed shelf life. This would save the hospitals money over time since they could stop paying to dispose of and replace as many expired drugs. It would also provide a general benefit to the public since people would have solid scientific evidence for the actual effective lifetime for particular drugs. This would include poison control centers, the hospitals themselves, etc. that would be able to better handle cases where someone has already taken an expired drug. Of course an alternate way would be to require the drug companies to accept returns from hospitals of small amounts of expired drugs that they would then be responsible for testing and providing the data to the FDA. Limiting the returns to large institutions would keep the costs down (reducing push-back from the pharma companies).
burkaman 9y ago
From the study: > Twelve of the 14 drug compounds tested (86%) were present in concentrations at least 90% of the labeled amounts, the generally recognized minimum acceptable potency. Three of these compounds were present at greater than 110% of the labeled content. Two compounds (aspirin and amphetamine) were present in amounts of less than 90% of labeled content. One compound (phenacetin) was present at greater than 90% of labeled amounts from 1 medication tested, but less than 90% in another medication that contained that drug. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1377417 http://jamanetwork.com/journals/jamainternalmedicine/fullart... Sounds like maybe concentrations are allowed to vary a bit from the label at manufacturing time? Not sure, maybe someone who knows more can comment.
- bb611 9y ago
  My brother-in-law works in pharma manufacturing, this stuff is really hard and it's basically impossible to create exactly identical pills, apparently in large part because the active ingredient is frequently <1% of the volume of the pill. The best they can do is control the range of dosage in pills, and there's variance in what that range is across drugs (i.e. some compounds can't be spray dried, can't be heated hot enough to make binders liquid, etc). Depending on necessity and value they can typically engineer more precision, but it gets very expensive very fast.
dopamean 9y ago
I wonder for certain drugs how much of a difference 98% potency is vs 100%. Surely that 2% must matter. Also, what does it mean to be less potent? It's still the same drug right? So does that just mean the pill contains less of it somehow?
- phinnaeus 9y ago
  Chemical reactions between air, mostly, and to a lesser extend between the drug and the pill substrate itself, I would imagine. I'm sure on such small size and long time scales the pill does simply ablate some of it's material. Disclaimer: this is conjecture.
- Zigurd 9y ago
  You can get a rough idea of the required precision by checking if the dose is weight dependent. If it isn't, 2% won't matter.
  - mikeash 9y ago
    And if 2% does matter, you'd better make sure you can measure both the dose and your weight to better than that accuracy.
- klipt 9y ago
  IANAD but it probably means some of the drug molecules have been rendered chemically inactive. For many drugs a 2% difference is probably unnoticeable. Why are Ibuprofen pills 200mg? Because it's a nice round number that happens to work for many people. If I have a headache I often break the 200mg pill and only take half of it. It still does the job fine for me with fewer side effects.
- qq66 9y ago
  No drug where a 2% difference matters can be administered outside of a monitored hospital setting. There are too many variables that affect the drug uptake far more than 2%, such as body weight (100 pound person will have 3x the drug dosage of a 300 pound person), drug absorption (based on body chemistry, other food eaten, etc.) and the actual intake dosage itself (Eye drops, for example, can have a 500-fold variance in how much actually gets administered). That's why over-the-counter drugs have to have very high therapeutic index. https://en.wikipedia.org/wiki/Therapeutic_index https://en.wikipedia.org/wiki/Therapeutic_index
theandrewbailey 9y ago
It appears that potent is properly used in this article: producing powerful physical or chemical effects. ( http://www.dictionary.com/browse/potent http://www.dictionary.com/browse/potent ) chemically or medicinally effective ( https://www.merriam-webster.com/dictionary/potent https://www.merriam-webster.com/dictionary/potent ) exerting or capable of exerting strong physiological or chemical effects ( http://www.thefreedictionary.com/Potent http://www.thefreedictionary.com/Potent )
civilitty 9y ago
When working with biological systems, most of the time your acceptable error margin is between 10-25%. There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical. The ones where it does matter are tightly controlled and clinically applied by a professional with active monitoring. The only drugs that weren't within 10% of their original concentrations, according to the study, were amphetamines and aspirin. I can't think of any uses off the top of my head for those two where even 25% would make much of a difference to outcomes - amphetamines are mostly used as general purpose stimulants or to treat ADD and aspirin is not the blood thinner of choice for life and death situations. With amphetamines especially, what you eat and small factors like blood pH can have a massive impact on their effectiveness so we're already talking 10-20% differences day by day, let alone person to person.
- JohnJamesRambo 9y ago
  And to add into that, dosage studies are rarely adequately done for most drugs. The dose we take is often a best guess and may be twice or more than we need, so 10% is even more inconsequential.
  - criley2 9y ago
    This is completely wrong. Dosage studies happens between Phase 2 and Phase 3 trials (and Phase 4 "post marketing" too) and are the most expensive, longest and most scientific process that arguably any business engages in in the entire world. Phase 1 is a safety test in healthy ~men. These seek to find the maximum dose before adverse effects appear in the healthiest humans. Phase 2 is a safety/dosage test in a much larger and varied sample. We know dose ranges and begin testing them for efficacy in a varied population. Phase 3 is the big one. It's a randomized, controlled, double blind test of SPECIFIC dosages in SPECIFIC target populations to scientifically prove efficacy over placebo. The dose we take is not a "BEST GUESS" It is the result of a billion dollars of scientific study and that PRECISE NME (new molecular entity) has been studied, at that PRECISE dose, in a target population, for it's effectiveness, and it must be better than existing-treatments and better than placebo. It should be highlighted that this process takes on average 10 years, costs $1 billion dollars, and has a success rate (success meaning FDA approval) of about 1 in 10,000 attempts (hence the price tag). Source: Drugs: From Discovery to Approval, Second Edition http://onlinelibrary.wiley.com/book/10.1002/9780470403587 http://onlinelibrary.wiley.com/book/10.1002/9780470403587
Greed 9y ago
I work for a company that has some periphery exposure to FDA-regulation, and as a result we have to do a lot of very similar scientific calculations to satisfy their archival records. A big part of why most medicines still expire (at least for medicines available over the counter) much earlier than they should is that a majority of the testing is done to determine the expiration date at a controlled temperature, pressure, and humidity. They test how it degrades under stress to determine a maximum viability under perfectly stable conditions. They are not accounting for the typical medicine storage places: a bathroom cabinet where the temperature and humidity will vary wildly within a matter of minutes, a cool, damp fridge, or even the reading table next to your bed-- constantly exposed to UV light from the windows. I'm relaying this secondhand from a former FDA contractor, but I can only surmise that for a company with the litagative risk level that any pharmaceutical entity incurs, the old adage of "Better Safe Than Sorry" is a major part of the story that's missing here.
- beebmam 9y ago
  Great comment, and I couldn't agree more.
- lostcolony 9y ago
  Beyond that, what is the incentive on the part of the company? No one is evaluating medications based on shelf life. Longer expiration dates -at best- do nothing favorable for the company, and at worst both reduce the purchase of more of the drug, -and- open the company up to litigation in the even it's dangerous. Why take that risk? There is simply no economic pressure to.
  - Spooky23 9y ago
    I don't think there's an economic pressure to have a longer shelf life either. It's not any more efficient to stockpile drugs, and it doesn't make sense to do so, as your need for prescription drugs is likely not going to be multiple years.
  - sliverstorm 9y ago
    Well, although supposedly the Army specifically liked Cipro because of the shelf life, so that's one case counter.
bpodgursky 9y ago
I think it would introduce a huge amount of legal liability to guess that a drug would survive on a shelf for 10 years based on 6 months of testing. Especially if it's something critical like an EpiPen or cancer med. At the end of the day, there's no really reliable way to speed up time, and it would be a waste of time to add 10 years to a drug development timeline just so you can leave it on a shelf for 10 years to test if it still works. And yeah, we could probably go through and retroactively test some Ibuprofin, but also remember that these drugs are repackaged / reformulated slightly every couple years for various reasons, and without a lot of legal protections, no company will consider it worth it to guess about drug lifetime.
deleted 9y ago
[deleted]
barrkel 9y ago
I think you're confusing percentage of concentration with the threshold of potency.
pizzetta 9y ago
Don't Drug MFGs know this and are allowed to "donate" to weak economies.
Florin_Andrei 9y ago
> What kind of reporting is this? Anything less than 100% is not "as potent as when manufactured" Relax, this is the real world, not a computer based series of 0s and 1s. Any such compound begins drifting off from the original specs as soon as it leaves the factory - and in a very real sense it's not exactly at 100% at any time post the moment of manufacture. The question is what kind of deviation can be tolerated.
- TuringNYC 9y ago
  Well said. Another aspect: Having the option of a 90% effective drug vs a 100% effective drug you DONT have because you cannot afford. There was a time in my life where our family lived dollar to dollar and skipped medical care due to cost. We would easily settle for 90% efficacy.
  - AstralStorm 9y ago
    It is not even 90% effective. You could adjust the dosage in many cases.
- r00fus 9y ago
  Offtopic, but even the world of 1's and 0's is subject to real-world constraints - learned in my 90s computer hardware class as I spent weeks in summer after semester debugging why my "basic 8-bit processor" kept crashing after only a few hours of uptime: faulty silicon that periodically read median-voltage differentials cascaded eventually into bad instructions. The world of logic is built on the shifting ground of reality. Only redundancy and checksums keep it from crashing down in compounded errors.
vilhelm_s 9y ago
The paper discusses this, they say that 90%-110% is the usual range which is allowed when the drug is sold new. The FDA can set limits on a per-drug basis, and there are some where they require 95-105%, but 90-110% is the most common. (C.f. https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4228B1-04-FDA-PotencyStabilityredacted.pdf https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4228B1...) Several of the drugs they tested were > 100%, so it seems reasonable to assume that a lot of this is due to variation in manufacturing rather than to the drug degrading.
dragonwriter 9y ago
> Anything less than 100% is not "as potent as when manufactured", Since the % is of labelled strength, it might still be “as potent as when manufactured” if the drug was at less than labelled strength when manufactured, though that, too, would be a serious issue.

thaumasiotes 9y ago

> That seems to be the problem. There was a procedure in place to set expiration dates scientifically, and it was ignored for some reason, limiting the legal shelf life of even the most stable compounds to a few years. To investigate how a drug breaks down over a ten-year timespan, you'd need to do at least one ten-year study of the drug. That seems difficult to justify.

funkymike 9y ago
I was thinking about this today after hearing a report on the radio this morning on this topic. Hospitals end up throwing away large amounts of drugs each year due to expiration, potentially hundreds of millions of dollars - although there is no real data currently. It seems like it would be a good long term investment for a group of hospitals to partner together and begin a systematic study of the actual lifetimes of drugs. Instead of destroying all expired drugs they could send off samples to a lab for testing. They could even intentionally keep expired drugs in an off-limits area for 1, 2, 3 years past their expiration dates to gather more information. With enough hospitals participating they could gather a significant amount of data without any one hospital shouldering all of the burden. Once there is enough evidence that a particular drug is still potent the FDA could extend the allowed shelf life. This would save the hospitals money over time since they could stop paying to dispose of and replace as many expired drugs. It would also provide a general benefit to the public since people would have solid scientific evidence for the actual effective lifetime for particular drugs. This would include poison control centers, the hospitals themselves, etc. that would be able to better handle cases where someone has already taken an expired drug. Of course an alternate way would be to require the drug companies to accept returns from hospitals of small amounts of expired drugs that they would then be responsible for testing and providing the data to the FDA. Limiting the returns to large institutions would keep the costs down (reducing push-back from the pharma companies).

burkaman 9y ago

From the study: > Twelve of the 14 drug compounds tested (86%) were present in concentrations at least 90% of the labeled amounts, the generally recognized minimum acceptable potency. Three of these compounds were present at greater than 110% of the labeled content. Two compounds (aspirin and amphetamine) were present in amounts of less than 90% of labeled content. One compound (phenacetin) was present at greater than 90% of labeled amounts from 1 medication tested, but less than 90% in another medication that contained that drug. http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1377417 http://jamanetwork.com/journals/jamainternalmedicine/fullart... Sounds like maybe concentrations are allowed to vary a bit from the label at manufacturing time? Not sure, maybe someone who knows more can comment.

bb611 9y ago
My brother-in-law works in pharma manufacturing, this stuff is really hard and it's basically impossible to create exactly identical pills, apparently in large part because the active ingredient is frequently <1% of the volume of the pill. The best they can do is control the range of dosage in pills, and there's variance in what that range is across drugs (i.e. some compounds can't be spray dried, can't be heated hot enough to make binders liquid, etc). Depending on necessity and value they can typically engineer more precision, but it gets very expensive very fast.

dopamean 9y ago

I wonder for certain drugs how much of a difference 98% potency is vs 100%. Surely that 2% must matter. Also, what does it mean to be less potent? It's still the same drug right? So does that just mean the pill contains less of it somehow?

phinnaeus 9y ago
Chemical reactions between air, mostly, and to a lesser extend between the drug and the pill substrate itself, I would imagine. I'm sure on such small size and long time scales the pill does simply ablate some of it's material. Disclaimer: this is conjecture.
Zigurd 9y ago
You can get a rough idea of the required precision by checking if the dose is weight dependent. If it isn't, 2% won't matter.
- mikeash 9y ago
  And if 2% does matter, you'd better make sure you can measure both the dose and your weight to better than that accuracy.
klipt 9y ago
IANAD but it probably means some of the drug molecules have been rendered chemically inactive. For many drugs a 2% difference is probably unnoticeable. Why are Ibuprofen pills 200mg? Because it's a nice round number that happens to work for many people. If I have a headache I often break the 200mg pill and only take half of it. It still does the job fine for me with fewer side effects.
qq66 9y ago
No drug where a 2% difference matters can be administered outside of a monitored hospital setting. There are too many variables that affect the drug uptake far more than 2%, such as body weight (100 pound person will have 3x the drug dosage of a 300 pound person), drug absorption (based on body chemistry, other food eaten, etc.) and the actual intake dosage itself (Eye drops, for example, can have a 500-fold variance in how much actually gets administered). That's why over-the-counter drugs have to have very high therapeutic index. https://en.wikipedia.org/wiki/Therapeutic_index https://en.wikipedia.org/wiki/Therapeutic_index

theandrewbailey 9y ago

It appears that potent is properly used in this article: producing powerful physical or chemical effects. ( http://www.dictionary.com/browse/potent http://www.dictionary.com/browse/potent ) chemically or medicinally effective ( https://www.merriam-webster.com/dictionary/potent https://www.merriam-webster.com/dictionary/potent ) exerting or capable of exerting strong physiological or chemical effects ( http://www.thefreedictionary.com/Potent http://www.thefreedictionary.com/Potent )

civilitty 9y ago

When working with biological systems, most of the time your acceptable error margin is between 10-25%. There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical. The ones where it does matter are tightly controlled and clinically applied by a professional with active monitoring. The only drugs that weren't within 10% of their original concentrations, according to the study, were amphetamines and aspirin. I can't think of any uses off the top of my head for those two where even 25% would make much of a difference to outcomes - amphetamines are mostly used as general purpose stimulants or to treat ADD and aspirin is not the blood thinner of choice for life and death situations. With amphetamines especially, what you eat and small factors like blood pH can have a massive impact on their effectiveness so we're already talking 10-20% differences day by day, let alone person to person.

JohnJamesRambo 9y ago
And to add into that, dosage studies are rarely adequately done for most drugs. The dose we take is often a best guess and may be twice or more than we need, so 10% is even more inconsequential.
- criley2 9y ago
  This is completely wrong. Dosage studies happens between Phase 2 and Phase 3 trials (and Phase 4 "post marketing" too) and are the most expensive, longest and most scientific process that arguably any business engages in in the entire world. Phase 1 is a safety test in healthy ~men. These seek to find the maximum dose before adverse effects appear in the healthiest humans. Phase 2 is a safety/dosage test in a much larger and varied sample. We know dose ranges and begin testing them for efficacy in a varied population. Phase 3 is the big one. It's a randomized, controlled, double blind test of SPECIFIC dosages in SPECIFIC target populations to scientifically prove efficacy over placebo. The dose we take is not a "BEST GUESS" It is the result of a billion dollars of scientific study and that PRECISE NME (new molecular entity) has been studied, at that PRECISE dose, in a target population, for it's effectiveness, and it must be better than existing-treatments and better than placebo. It should be highlighted that this process takes on average 10 years, costs $1 billion dollars, and has a success rate (success meaning FDA approval) of about 1 in 10,000 attempts (hence the price tag). Source: Drugs: From Discovery to Approval, Second Edition http://onlinelibrary.wiley.com/book/10.1002/9780470403587 http://onlinelibrary.wiley.com/book/10.1002/9780470403587

Greed 9y ago

I work for a company that has some periphery exposure to FDA-regulation, and as a result we have to do a lot of very similar scientific calculations to satisfy their archival records. A big part of why most medicines still expire (at least for medicines available over the counter) much earlier than they should is that a majority of the testing is done to determine the expiration date at a controlled temperature, pressure, and humidity. They test how it degrades under stress to determine a maximum viability under perfectly stable conditions. They are not accounting for the typical medicine storage places: a bathroom cabinet where the temperature and humidity will vary wildly within a matter of minutes, a cool, damp fridge, or even the reading table next to your bed-- constantly exposed to UV light from the windows. I'm relaying this secondhand from a former FDA contractor, but I can only surmise that for a company with the litagative risk level that any pharmaceutical entity incurs, the old adage of "Better Safe Than Sorry" is a major part of the story that's missing here.

beebmam 9y ago
Great comment, and I couldn't agree more.
lostcolony 9y ago
Beyond that, what is the incentive on the part of the company? No one is evaluating medications based on shelf life. Longer expiration dates -at best- do nothing favorable for the company, and at worst both reduce the purchase of more of the drug, -and- open the company up to litigation in the even it's dangerous. Why take that risk? There is simply no economic pressure to.
- Spooky23 9y ago
  I don't think there's an economic pressure to have a longer shelf life either. It's not any more efficient to stockpile drugs, and it doesn't make sense to do so, as your need for prescription drugs is likely not going to be multiple years.
- sliverstorm 9y ago
  Well, although supposedly the Army specifically liked Cipro because of the shelf life, so that's one case counter.

bpodgursky 9y ago

I think it would introduce a huge amount of legal liability to guess that a drug would survive on a shelf for 10 years based on 6 months of testing. Especially if it's something critical like an EpiPen or cancer med. At the end of the day, there's no really reliable way to speed up time, and it would be a waste of time to add 10 years to a drug development timeline just so you can leave it on a shelf for 10 years to test if it still works. And yeah, we could probably go through and retroactively test some Ibuprofin, but also remember that these drugs are repackaged / reformulated slightly every couple years for various reasons, and without a lot of legal protections, no company will consider it worth it to guess about drug lifetime.

deleted 9y ago

[deleted]

barrkel 9y ago

I think you're confusing percentage of concentration with the threshold of potency.

pizzetta 9y ago

Don't Drug MFGs know this and are allowed to "donate" to weak economies.

Florin_Andrei 9y ago

> What kind of reporting is this? Anything less than 100% is not "as potent as when manufactured" Relax, this is the real world, not a computer based series of 0s and 1s. Any such compound begins drifting off from the original specs as soon as it leaves the factory - and in a very real sense it's not exactly at 100% at any time post the moment of manufacture. The question is what kind of deviation can be tolerated.

TuringNYC 9y ago
Well said. Another aspect: Having the option of a 90% effective drug vs a 100% effective drug you DONT have because you cannot afford. There was a time in my life where our family lived dollar to dollar and skipped medical care due to cost. We would easily settle for 90% efficacy.
- AstralStorm 9y ago
  It is not even 90% effective. You could adjust the dosage in many cases.
r00fus 9y ago
Offtopic, but even the world of 1's and 0's is subject to real-world constraints - learned in my 90s computer hardware class as I spent weeks in summer after semester debugging why my "basic 8-bit processor" kept crashing after only a few hours of uptime: faulty silicon that periodically read median-voltage differentials cascaded eventually into bad instructions. The world of logic is built on the shifting ground of reality. Only redundancy and checksums keep it from crashing down in compounded errors.

vilhelm_s 9y ago

The paper discusses this, they say that 90%-110% is the usual range which is allowed when the drug is sold new. The FDA can set limits on a per-drug basis, and there are some where they require 95-105%, but 90-110% is the most common. (C.f. https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4228B1-04-FDA-PotencyStabilityredacted.pdf https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4228B1...) Several of the drugs they tested were > 100%, so it seems reasonable to assume that a lot of this is due to variation in manufacturing rather than to the drug degrading.

dragonwriter 9y ago

> Anything less than 100% is not "as potent as when manufactured", Since the % is of labelled strength, it might still be “as potent as when manufactured” if the drug was at less than labelled strength when manufactured, though that, too, would be a serious issue.