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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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November 19, 2009

Plavix vs. Effient

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Posted by Derek

The InVivo Blog has a good article on a controversy in the blood-thinning market. Plavix (clopidogrel) has a very strong share of that, of course, but since Effient (prasugrel) was finally approved, Lilly and Dai-Ichii are looking to take as much of that market as they can. And one opening might be that not everyone responds similarly to Plavix.

In some cases, that's because there are some drug-drug interactions, a problem the FDA has recently addressed. The proton pump inhibitors, especially, are metabolized through the CYP2C19 pathway. That's a problem, since that enzyme is needed to convert clopidogrel into its active form (Plavix, as it comes out of the pill, is a prodrug - its thiophene ring needs to get torn open). This sort of thing has been seen many times before - it's one of the many headaches that you can endure in drug development as you profile the metabolizing pathways for your drug candidate and compare them to the other compounds your patient population might be taking. There are some combinations that just will not work (several involving CYP3A4, which is often the first one you test for), and it looks like we can add Plavix/2C19 to the list.

But the population genetics of the 2C19 enzyme are rather heterogeneous. About a third of the patients taking Plavix have a less-active form of the enzyme to start with, and they might not respond as robustly to the drug. The FDA has emphasized this effect in its latest public health warning. That's an opportunity for Effient, since it doesn't go through that metabolic route.

The In Vivo people point out, though, that this story isn't being driven by the usual players. It's not the FDA that's pushed to find this out, and it's not even Eli Lilly. It's Medco and Aetna. They studied their insurance claims data to see if the numbers supported the proton pump inhibitor/Plavix interaction, found that they did, and publicized their findings - and that led to an actual observational trial from BMS and Sanofi, which confirmed the problem. Now Medco is going further, and is actually running its own observational study comparing Plavix and Effient. Their theory is that the efficacy that Lilly showed compared to Plavix was driven by the (deliberate, one assumes) inclusion of a high number of poor metabolizers.

Medco is getting ready for generic Plavix, and trying to keep its costs down by making the case that the drug will do the job just fine for most patients. They could, on the other hand, end up making the case for Effient in that poor-metabolizing third of the patients, which would also be interesting. Lilly would presumably settle for that, although they'd like even more of the market if they can get it, naturally.

And I have to say: I like this sort of thing. I like it a lot. This, to me, is how the system should work. Companies are pursuing their own competing interests, but in the end, we get a higher standard of care by finding out which drug really works for which patients. The motivation to do all this? Money, of course, earning it and saving it. This may sound crass, but I think that's a reliable, proven method to motivate people and companies, one that works even better than depending on their best impulses. You could even build an economic system around such effects, with some attention to channeling these impulses in ways that benefit the greatest number of people. Worth a try.

Comments (22) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Regulatory Affairs


COMMENTS

1. Chemjobber on November 19, 2009 9:31 AM writes...

You could even build an economic system around such effects, with some attention to channeling these impulses in ways that benefit the greatest number of people.

No way, dude. I like "From each according to his ability, to each according to his need" better.

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2. Derek Lowe on November 19, 2009 9:38 AM writes...

How do you feel about "From each according to his ability, to each according to his political connections?"

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3. Chemjobber on November 19, 2009 9:47 AM writes...

Perish the thought -- that would never happen!

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4. Hap on November 19, 2009 9:54 AM writes...

Problem with Marx is that people are people and have individual desires that don't correlate at all with what might be best for groups or people as a whole, and we are generally willing to try to fulfill those desires with whatever means we have, and with little regard for consequences. I don't know if it's inevitable, but attempts to implement Marx end up instead with the bastard child of Marx and Smith, and (almost of all of) the people usually end up as the single mother forced to carry the child to term.

I think another relevant aphorism, though, is "When elephants fight, the grass gets trampled." Most people, the environment, and anything that can't be counted (externalities) tend to end up in the grass category. Everyone wants to be the elephants.

Unless there isn't any government, I think the political connection thing tends to happen no matter what - the consequences of the injustice depend on how much power the government has. Perhaps it's just a fortunate irony, though, but many of the places with lots of government power don't tend to be so corrupt - the interaction of powerful government, self-interest with few internal constraints, and the lack of societal constraint seems to make corruption likely.

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5. HappyDog on November 19, 2009 11:16 AM writes...

There's a bigger problem with Marx. If:

my ability > my needs

(as defined by, let's face it, someone besides me), then I just reign in my ability so that:

my ability = my needs

If everyone does this, then society as a whole goes from:

total ability = total needs

to:

total ability

oops.

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6. HappyDog on November 19, 2009 11:19 AM writes...

(Sorry about the duplication. Part of my post got cut off for some reason while posting . . .)

There's a bigger problem with Marx. If:

my ability > my needs

(as defined by, let's face it, someone besides me), then I just reign in my ability so that:

my ability = my needs

If everyone does this, then society as a whole goes from:

total ability = total needs

to:

total ability

oops.

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7. Chemjobber on November 19, 2009 11:40 AM writes...

I owe the thread a substantive comment, so here goes:

Why shouldn't the FDA (or CMS or NIH) do the same thing, i.e. open an Institute of Comparative Pharmaceutical Effectiveness? My guess is that it would be quite easy for that Institute to be seized by one interest group or the other.

Presumably, the insurance companies can't be bought off by any providers (or can they?!?) - and yet, they're the ones who are taking it in the back of the neck in this round of health care reform.

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8. boolean-yah!! on November 19, 2009 11:45 AM writes...

But imagine if there are two individuals each striving to meet thier own needs and as you say:

A) my ability= my needs

but the second individual is the wrench where

B) my ability (less than) my needs

then A NAND B=good outcome.
(though I forget how to add in if only B=true then outcome=false)

The problem lies in who picks up the slack for individual B. This is where the problem has always been - not everyone is equally capable so how does society compensate for that while still functioning. Who decides who takes extra work - especially in a system where each individul is trying to get out of it as much as they can.

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9. Hap on November 19, 2009 11:45 AM writes...

If people were selfless, then the gap from the first stage to the second wouldn't occur (people would be willing to product more output than their needs mandate for others), and people who need more than they can produce would try harder to produce to minimize their deficit (such as they are able to - in some cases, they can't do anything to alter the gap). The problem, though, is that people aren't selfless - we are willing to act for the betterment of all, but usually for our own reasons and our own fulfillment.

Sometimes individual desires work out for the best (for people as a whole), but not always. Hoping that they will always do so seems almost as vain as hoping that people will magically forget themselves, for the sake of the state.

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10. Hap on November 19, 2009 11:58 AM writes...

Health insurance companies are an easy and at least somewhat valid target - at least some of their profit comes from denying legitimate claims and hoping that someone else will pay for it. (They are also the blunt edge of the knife - they tell people they can't have medical care for what they can afford, driving the strong connection between work and health care, because people can not often get medical care in other ways). Their decisions on what care to cover aren't generally transparent, and often may not be in the interests of their customers.

The problem comes when someone (the government, insurers, etc.) has to make the decisions on what care to cover. The current system doesn't seem to do that well (because it costs a lot more than other systems that provide care to a larger fraction of people and have similar or better patient outcomes), but any system that does it better will make lots of people unhappy, and any system that doesn't do it well will not exist for long. Efficiency improvements (better checks on care, more access to information, consistent data standards, etc.) will help, but not enough to avoid someone(s,thing) having to make difficult and unpopular decisions on what care to provide.

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11. Yonemoto on November 19, 2009 12:12 PM writes...

"The problem comes when someone (the government, insurers, etc.) has to make the decisions on what care to cover."

Isn't there a more general problem here? Sometimes it's not a coverage but a science issue. Say, I have an absolutely terminal disease which will kill me in 4 years but keeps me productive. Why the heck am I paying for other people's coverage against my will, by "paying for things I might get (but really won't) like diabetes, alzheimer's etc). It's one thing if I decide to be altruistic and pay for other people's healthcare out of my own good will, it's another thing if someone reaches into my pocket and does it for me.

Sure it's reductio ad absurdum, but the whole thing becomes more pernicious when you realize that diseases of minorities are less researched than diseases of the majority, and for statistical reasons, sampling of minority populations for drug safety and efficacy is likewise poorer. "Universal coverage" can never be "Equal coverage". Thank you Derek for alluding to this problem which has completely eluded the healthcare debate.

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12. Sili on November 19, 2009 1:53 PM writes...

"From each according to his ability, to each according to his need"

As a needy one, I like that one, too. Oddly enough now that I've had my share, I really wanna pay it back, if only someone'd employ me. I wonder what's wrong with me.

You could even build an economic system around such effects, with some attention to channeling these impulses in ways that benefit the greatest number of people. Worth a try.
This is exactly the problem with the current system. Much much too little attention to the Tragedy of the Commons (externalities?).

It's all well and good for some company to make money for themselves, but they should not do it at the cost of the the wholesale exploitation of my share of the Earth, Wind and Water.

Hence laws governing pollution and carbon taxes are a Good Thing™.

That is not to say that those things can't also be twisted for personal gain, but that is a flaw with the execution, not one inherent to the concept.

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13. qetzal on November 19, 2009 2:02 PM writes...

Yonemoto,

You could make a similar argument about a lot of things that we're all expected to contribute towards. If you expect to be dead in four years, why would you pay for new highway construction or defense initiatives or NIH research? You won't be here to benefit from any of them? Yet the government will continue to reach into your pocket to help pay for all of that, up until you die (and possibly beyond).

I disagree that this issue is being ignored in the healthcare debate. Haven't you heard people arguing about whether healthcare is or is not a "right" (or perhaps more accurately, that it should/shouldn't be an entitlement)? They are addressing exactly that question.

P.S. I hope Derek will excuse my contribution to the threadjacking, since everyone seems to be in the mood for it today. ;-)

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14. milkshake on November 19, 2009 3:39 PM writes...

Marx and Lenin were quack-cure hucksters - if they were real scientists they would have tested their socialism on dogs first

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15. Inverse Agonist on November 19, 2009 4:05 PM writes...

Marx and Lenin lived in a time prior to the establishment of formal Game Theory. End of discussion.

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16. metaphysician on November 19, 2009 6:18 PM writes...

Both Marx and Smith suffer for the Tragedy of the Commons ( albeit different commons ). However, its a hell of a lot easier to patch the flaws in capitalism ( via business regulation ), than to patch the flaws in communism.

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17. ex-Pfizerite on November 19, 2009 8:54 PM writes...

The real lesson in this story might be that diagnostics become more valuable to determine the optimum dose and/or drug for a given patient

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18. Yonemoto on November 20, 2009 12:45 AM writes...

qetzal: We're expected to contribute towards the 18 things in article I section 8 that congress is authorized to do. I see highways in there*. I don't see healthcare there (or education, DOE, NIH, for that matter)

You could say, that the constitution isn't restrictive on government - but that is both historically inaccurate, and also incorrect because of Amendment X (anything not listed in the constitution is reserved to the states or to the people). The constitution is a take it or leave it proposition - if you're not going to follow the constitution to the letter, what gives you the authority to be president, or a congresscritter? Isn't it convenient then that they pick the parts that confer power upon them and ignore the parts that restrict what they should do?

And if you're going to argue that it's a "living document", wait until someone "lives" away the freedom of speech, or right to a fair trial. Oh wait, that already happened. during Bush II.

*post roads, technically. While driving across country, I spotted a USPS truck on the interstate. so, it counts.

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19. yonemoto on November 20, 2009 12:51 AM writes...

metaphysician:

come again? How does smith suffer from the 'tragedy of the commons'? In a true capitalism, the price of diminishing resources is built into the cost. However, we live in an inflationary-spiral capitalism. This is a kleptocratic move decided by government edict (not market forces) and utterly takes the axe to any notion of sustainability by punishing savers and rewarding spenders.

so, yeah. In a real capitalism, where governments protect individual assets by preserving the value of currency, instead of engaging in outright thievery by fiat inflation - capitalism takes care of the tragedy of the commons. Unfortunately, we have been living in a regime of secular inflation for the last 80 years.

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20. alig on November 20, 2009 7:49 AM writes...

yonemoto,

You need a refresher course on economics. The "tragedy of the commons" covers all resources that do not have a price to be used. Originally this came from a common field that everyone could graze their sheep at, quickly the field was over-grazed to the point that no grass was left. Later this problem was associated with water and air (it was free to dump waste so everyone did it and the air and water became polluted). There is a real cost to society for these activities but they are not paid (and therefore not factored into the cost of the good) by producers so the market makes the wrong decisions. These costs that producers do not pay are called extranalities. I believe one of the roles of government in a capitalist country should be to force the cost of extranalities into the price of goods.

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21. Petros on November 20, 2009 8:05 AM writes...

A couple of comments

The insurers may well go for generic clopidogrel. low at how well it sold during its short lived availability in the US.

And this week AZ announced the results of the PLATO study in which Brilinta trounced Plavix (Brilinta isn't filed yet and has a different mechanism of action)

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22. xanguin8 on November 21, 2009 4:05 PM writes...

agree with #21.
watch the AZ cmpd...will take over the 8 billion currently enjoyed by plavix...
you heard it here first!

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