4 ms·

A couple of things really surprised me about this article. First, I'm sure that there is other evidence the FDA is using to determine whether or not to grant t

A couple of things really surprised me about this article. First, I'm sure that there is other evidence the FDA is using to determine whether or not to grant this drug FDA approval but a 63 person drug trial seems like an exceedingly small sample size to work with. Perhaps because this disease is so rare they could not put together a larger trial? Also, it seemed a little bizarre for an FDA panel to receive comments about a decision it is trying to reach from the families of those involved in the drug trial. I suppose there is nothing wrong with that, per se, but shouldn't these types of decisions be reach on the basis of scientific evidence and strive to be devoid of any kind of sentimentality? Either way, it's always excellent to see new cancer treatments on the market, particularly when they are as groundbreaking as this one.

gumby 9y ago
It's an orphan indication which has special rules to promote development. Otherwise, the thinkingngoes, nobody would develop treatments for uncommon diseases.
- bluGill 9y ago
  The downside of this is a treatment that you can get approved for something rare, but now it is on the market and they can tell doctors it has promise for some common X. Getting approval for treating X would be more expensive because you have to do a larger trial. (you should do a large trial for the rare thing, but since there are not enough people with the rare thing you cannot)
  - gumby 9y ago
    That's almost true, and is a well known part of pharma strategy. For example Botox was initially approved for hyperhydrosis (excessively sweaty palms and armpits) and was used off label for its most well-known application, wrinkles. It was finally approved for wrinkles only recently having been approved for other things along the way. Any MD can prescribe any (non-opiate) drug for any indication. But the drug companies are prohibited from doing what you say: telling docs about usages they haven't proven in trials. Sometimes the sales rep will drop off a scientific paper (often funded by the drug company) about some other use of the drug -- enforcement in this area is uneven. If they do want to advertise new uses they need to do new trials. And though existing trial data can also be used, if the dosage regime is different or, say the patient pool tox risks are different (perhaps the new indication is less serious than the orphan one) whole new tox studies may be needed. Which seems fair.
    - refurb 9y ago
      Since the US v. Caronia decision, off-label promotion is more complicated. The judge said restricting off-label promotion violates the 1st amendment, as long as the speech is "truthful"
    - doormatt 9y ago
      I'm pretty sure Botox was originally used for Strabismus.
  - ekianjo 9y ago
    > they can tell doctors it has promise for some common X That's not authorized, that's called "off label promotion" and it is severly punished when discovered. Also, doctors who use a non-approved drug for another indication can be tracked and investigated as well if needed (conflict of interests). Reimbursment also works only in certain conditions and may not apply if you use the drug outside of its allowed/approved indications.
    - gumby 9y ago
      Slight correction: as noted by others above, off label use while extremely illegal enforcement has been eroded and is patchy. And US law allows any MD (but not other prescribers such as podiatrists or NPs) to prescribe any approved drug for any medical purpose (opioids have recently been somewhat of an exception here). However, as you point out, insurance companies in practice have a say. Also if the usage is implausible and there's an adverse event I think there could be a malpractice issues so those insurance companies also have an impact. This is US law I'm talking about BTw.
- honestoHeminway 9y ago
  I wonder though, assuming a population has a inherited disease in 0.3 % of every generation. That might not be enough to fund research into it. Now if those 0.3 % could get all future generations, to donate into a kickstarter for research. Now taking on this a loan, and taxing every future generation the same amount- research could happen. Of course there would be a tax-revolt, demanding a right to sickness, but thats just america.
epmaybe 9y ago
It's not that small, if the statistics look good. And they really do look better than most everything else on the market. Also, the approval isn't for patients newly diagnosed yet, it's only for patients that have relapsed or resistant to current therapies. You'll see a larger phase IV trial later, most likely. Now, off topic from your comment, I'm worried about cost. I know that the R&D for this kind of therapy is exceedingly high, but these therapies need to get cheaper for us to be able to justify using them in a larger population.
- sjg007 9y ago
  If it works then it's certainly worth the cost. Also it is likely that you can do donor car-T which will also reduce costs in the future.
- jlg23 9y ago
  > I know that the R&D for this kind of therapy is exceedingly high Do you have a source for that? I happen to be involved (genetically only - my family) into medical research and everyone I know agrees that costs are vastly inflated: * Marketing for a new drug is not "research". * Reformulation of trial-targets is not "research", it's re-shaping of the test settings so you can get $drug to market ASAP. * When the government/"the people" pay for research (through co-operations with universities), it's not your "R&D cost". * When you do basic research, it's incredibly easy to claim "10k hours". Ok, but can we please claim those 10k hours only once? Not for every variation of the substance you research again and again?
  - doctoring 9y ago
    (I'm a physician who used to work with large pharma companies on trial design and trial innovation.) I think the cost of R&D in pharma that we hear about is sometimes vastly inflated and sometimes pretty accurate, but definitely oftentimes misapplied (especially by pharma). On the whole, trials are expensive. Sure, there's the pre-clinical stuff -- basic research that you're alluding to. There's the stuff that is R&D but fails in the pipeline at some point. There's animal studies. But in most cases, most of the cost comes from human trials (Phase I-III, and mostly Phase III), which can sometimes span dozens of countries and tens of thousands of participants. For some drugs, the Phase III trial(s) account for over 80% of the total R&D cost. Even when they are relatively small trials (as in this CAR-T therapy trial), the administrative and logistical effort to implement something like this is immense. The whole point of these trials is to collect data, and so that data is subject to the highest amount of scrutiny of any data in any medical enterprise. If you come into my clinic for a pre-op before surgery and I measure your blood pressure to be 140/85, give or take a few (oh wait maybe I used the wrong cuff size, lemme try again, oh it's pretty close), that's fine. But if you come into my clinic because you're a participant on a trial for drug X, and I measure it to be 140/85... I better be damn sure that's right (and the study coordinator at my clinic, and the pharma company, and the FDA), even if drug X isn't a blood pressure drug. We've seen cases where certain innocuous data discrepancies trigger central study monitors (study employees) being flown out to remote clinics to manually verify paper records or equipment logs to confirm/reconcile errors. Inaccuracies can cause you to miss things, or patients to be harmed, or can cause a study or a clinic or a hospital to be shut out from performing research again. And of course it can make the difference between a drug approval and failure. It's a lot of resources around the idea of data integrity. So even small versions of these types of trials can be very expensive. Now, is it TOO expensive? We often hear about the cost of bringing a drug to market to be around $1B. (Some studies have put it over $2B when you account for failed drugs, etc.) This may or may not be right, but let's not forget, the pharma industry makes more profit than just about any other industry. And the way CMS and insurers agree to pay for medicines... well, pharma has a lot of freedom in pricing (upwards). You've hit on a lot of things that make the release of some new drugs/devices/therapies less expensive than we are commonly led to believe: reusing previous data, getting new approval for a specific enantiomer of a previously approved racemic drug, making cosmetic updates to existing devices, the tricks go on and on and on. And pharma keeps saying "R&D is so expensive! This drug should definitely be 2X more expensive than the one we're replacing." Planned obsolescence is a pain with your smartphone; it's a lot worse with your insulin pump or even the insulin itself! And one outcome of the high cost of large trials is that pharma does more of these types of un-innovation in some cases, which (due to the patent and regulatory and reimbursement systems) simply give pharma a free pass at making easy money off of our backs. The high cost of trials also leads to really high prices of "true" innovation, such as in CAR-T trials. This type of therapy (like a lot of new oncology therapy) is highly customized, and no longer simply some chemical compound you make in a factory and then ship all over the world. You have to take a patient's own cells/fluid/materials/etc, process them, and then make modifications (in some cases unique to the patient), and then return the processed product (to the same patient). This is indeed highly costly on top of the cost of performing a lengthy trial, where for certain rare and/or terminal diseases your study endpoints are pretty tough to capture (um, did the patient die? uh, how long do we wait?).
ekianjo 9y ago
> a 63 person drug trial seems like an exceedingly small sample size Sampling is basically decided on 1) recruitability and 2) effect size. If your effect is extremely large, even with a relatively small base size you can demonstrate the benefits of your drug. Basically very, very large trials are mostly useful to demonstrate benefits that are not that large to begin with.
kurthr 9y ago
Apparently, it's not uncommon for pharma to coach the families that comment to the committee either... And in another orphan drug case with small sample size, that of Sarepta/eteplirsen, in which several evaluating scientists seem confused and the majority were overridden (for approval) by the FDA director in charge. Comments included, “serious irresponsibility” (by selectively publishing data during the whole process) and saying that the drug was a “scientifically elegant placebo”. http://blogs.sciencemag.org/pipeline/archives/2016/09/20/sarepta-gets-an-approval-unfortunately http://blogs.sciencemag.org/pipeline/archives/2016/09/20/sar... This new leukemia treatment is a really interesting, and perhaps the effect size is large enough for the small trial size, but we seem to have some problems in the review process (ignoring data) and incentive structure (coaching parents) for these "orphan drugs". http://blogs.sciencemag.org/pipeline/archives/2017/05/19/im-surprised-that-theyre-surprised http://blogs.sciencemag.org/pipeline/archives/2017/05/19/im-...

gumby 9y ago

It's an orphan indication which has special rules to promote development. Otherwise, the thinkingngoes, nobody would develop treatments for uncommon diseases.

bluGill 9y ago
The downside of this is a treatment that you can get approved for something rare, but now it is on the market and they can tell doctors it has promise for some common X. Getting approval for treating X would be more expensive because you have to do a larger trial. (you should do a large trial for the rare thing, but since there are not enough people with the rare thing you cannot)
- gumby 9y ago
  That's almost true, and is a well known part of pharma strategy. For example Botox was initially approved for hyperhydrosis (excessively sweaty palms and armpits) and was used off label for its most well-known application, wrinkles. It was finally approved for wrinkles only recently having been approved for other things along the way. Any MD can prescribe any (non-opiate) drug for any indication. But the drug companies are prohibited from doing what you say: telling docs about usages they haven't proven in trials. Sometimes the sales rep will drop off a scientific paper (often funded by the drug company) about some other use of the drug -- enforcement in this area is uneven. If they do want to advertise new uses they need to do new trials. And though existing trial data can also be used, if the dosage regime is different or, say the patient pool tox risks are different (perhaps the new indication is less serious than the orphan one) whole new tox studies may be needed. Which seems fair.
  - refurb 9y ago
    Since the US v. Caronia decision, off-label promotion is more complicated. The judge said restricting off-label promotion violates the 1st amendment, as long as the speech is "truthful"
  - doormatt 9y ago
    I'm pretty sure Botox was originally used for Strabismus.
- ekianjo 9y ago
  > they can tell doctors it has promise for some common X That's not authorized, that's called "off label promotion" and it is severly punished when discovered. Also, doctors who use a non-approved drug for another indication can be tracked and investigated as well if needed (conflict of interests). Reimbursment also works only in certain conditions and may not apply if you use the drug outside of its allowed/approved indications.
  - gumby 9y ago
    Slight correction: as noted by others above, off label use while extremely illegal enforcement has been eroded and is patchy. And US law allows any MD (but not other prescribers such as podiatrists or NPs) to prescribe any approved drug for any medical purpose (opioids have recently been somewhat of an exception here). However, as you point out, insurance companies in practice have a say. Also if the usage is implausible and there's an adverse event I think there could be a malpractice issues so those insurance companies also have an impact. This is US law I'm talking about BTw.
honestoHeminway 9y ago
I wonder though, assuming a population has a inherited disease in 0.3 % of every generation. That might not be enough to fund research into it. Now if those 0.3 % could get all future generations, to donate into a kickstarter for research. Now taking on this a loan, and taxing every future generation the same amount- research could happen. Of course there would be a tax-revolt, demanding a right to sickness, but thats just america.

epmaybe 9y ago

It's not that small, if the statistics look good. And they really do look better than most everything else on the market. Also, the approval isn't for patients newly diagnosed yet, it's only for patients that have relapsed or resistant to current therapies. You'll see a larger phase IV trial later, most likely. Now, off topic from your comment, I'm worried about cost. I know that the R&D for this kind of therapy is exceedingly high, but these therapies need to get cheaper for us to be able to justify using them in a larger population.

sjg007 9y ago
If it works then it's certainly worth the cost. Also it is likely that you can do donor car-T which will also reduce costs in the future.
jlg23 9y ago
> I know that the R&D for this kind of therapy is exceedingly high Do you have a source for that? I happen to be involved (genetically only - my family) into medical research and everyone I know agrees that costs are vastly inflated: * Marketing for a new drug is not "research". * Reformulation of trial-targets is not "research", it's re-shaping of the test settings so you can get $drug to market ASAP. * When the government/"the people" pay for research (through co-operations with universities), it's not your "R&D cost". * When you do basic research, it's incredibly easy to claim "10k hours". Ok, but can we please claim those 10k hours only once? Not for every variation of the substance you research again and again?
- doctoring 9y ago
  (I'm a physician who used to work with large pharma companies on trial design and trial innovation.) I think the cost of R&D in pharma that we hear about is sometimes vastly inflated and sometimes pretty accurate, but definitely oftentimes misapplied (especially by pharma). On the whole, trials are expensive. Sure, there's the pre-clinical stuff -- basic research that you're alluding to. There's the stuff that is R&D but fails in the pipeline at some point. There's animal studies. But in most cases, most of the cost comes from human trials (Phase I-III, and mostly Phase III), which can sometimes span dozens of countries and tens of thousands of participants. For some drugs, the Phase III trial(s) account for over 80% of the total R&D cost. Even when they are relatively small trials (as in this CAR-T therapy trial), the administrative and logistical effort to implement something like this is immense. The whole point of these trials is to collect data, and so that data is subject to the highest amount of scrutiny of any data in any medical enterprise. If you come into my clinic for a pre-op before surgery and I measure your blood pressure to be 140/85, give or take a few (oh wait maybe I used the wrong cuff size, lemme try again, oh it's pretty close), that's fine. But if you come into my clinic because you're a participant on a trial for drug X, and I measure it to be 140/85... I better be damn sure that's right (and the study coordinator at my clinic, and the pharma company, and the FDA), even if drug X isn't a blood pressure drug. We've seen cases where certain innocuous data discrepancies trigger central study monitors (study employees) being flown out to remote clinics to manually verify paper records or equipment logs to confirm/reconcile errors. Inaccuracies can cause you to miss things, or patients to be harmed, or can cause a study or a clinic or a hospital to be shut out from performing research again. And of course it can make the difference between a drug approval and failure. It's a lot of resources around the idea of data integrity. So even small versions of these types of trials can be very expensive. Now, is it TOO expensive? We often hear about the cost of bringing a drug to market to be around $1B. (Some studies have put it over $2B when you account for failed drugs, etc.) This may or may not be right, but let's not forget, the pharma industry makes more profit than just about any other industry. And the way CMS and insurers agree to pay for medicines... well, pharma has a lot of freedom in pricing (upwards). You've hit on a lot of things that make the release of some new drugs/devices/therapies less expensive than we are commonly led to believe: reusing previous data, getting new approval for a specific enantiomer of a previously approved racemic drug, making cosmetic updates to existing devices, the tricks go on and on and on. And pharma keeps saying "R&D is so expensive! This drug should definitely be 2X more expensive than the one we're replacing." Planned obsolescence is a pain with your smartphone; it's a lot worse with your insulin pump or even the insulin itself! And one outcome of the high cost of large trials is that pharma does more of these types of un-innovation in some cases, which (due to the patent and regulatory and reimbursement systems) simply give pharma a free pass at making easy money off of our backs. The high cost of trials also leads to really high prices of "true" innovation, such as in CAR-T trials. This type of therapy (like a lot of new oncology therapy) is highly customized, and no longer simply some chemical compound you make in a factory and then ship all over the world. You have to take a patient's own cells/fluid/materials/etc, process them, and then make modifications (in some cases unique to the patient), and then return the processed product (to the same patient). This is indeed highly costly on top of the cost of performing a lengthy trial, where for certain rare and/or terminal diseases your study endpoints are pretty tough to capture (um, did the patient die? uh, how long do we wait?).

ekianjo 9y ago

> a 63 person drug trial seems like an exceedingly small sample size Sampling is basically decided on 1) recruitability and 2) effect size. If your effect is extremely large, even with a relatively small base size you can demonstrate the benefits of your drug. Basically very, very large trials are mostly useful to demonstrate benefits that are not that large to begin with.

kurthr 9y ago

Apparently, it's not uncommon for pharma to coach the families that comment to the committee either... And in another orphan drug case with small sample size, that of Sarepta/eteplirsen, in which several evaluating scientists seem confused and the majority were overridden (for approval) by the FDA director in charge. Comments included, “serious irresponsibility” (by selectively publishing data during the whole process) and saying that the drug was a “scientifically elegant placebo”. http://blogs.sciencemag.org/pipeline/archives/2016/09/20/sarepta-gets-an-approval-unfortunately http://blogs.sciencemag.org/pipeline/archives/2016/09/20/sar... This new leukemia treatment is a really interesting, and perhaps the effect size is large enough for the small trial size, but we seem to have some problems in the review process (ignoring data) and incentive structure (coaching parents) for these "orphan drugs". http://blogs.sciencemag.org/pipeline/archives/2017/05/19/im-surprised-that-theyre-surprised http://blogs.sciencemag.org/pipeline/archives/2017/05/19/im-...