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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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June 5, 2008

Merck, Vioxx: Seventeen and Three

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Posted by Derek

You may or may not have noticed, but slowly and quietly, Merck has been getting many of the large Vioxx judgments against it overturned on appeal. These cases made huge headlines when they were first tried, but the articles that tell the end of the story have not, for the most part, made the front page.

This is one reason that the company was finally able to settle a huge number of pending lawsuits for much less than many people thought likely. Merck seemed to like its chances, considering the cases they’d won and the way things looked in the appeals courts, and the amount of money they were able to settle for finally became a better deal for them than the alternative of fighting out every case. Of course, now people are starting to wonder if the company settled too soon - opinions differ.

It's important to note, though, that some of these reversals have been less than total victories for Merck. The first Texas case falls into that category, but the New Jersey punitive damages were thrown out based on the idea of pre-emption. A state jury, the appeals court ruled, can't decide if Merck defrauded the federal government when it got Vioxx approved. (We'll be revisiting that part of the argument when Wyeth v. Levine and Warner-Lamber v. Kent get decided).

But in the end, what looked for a while like an avalanche that might sweep the company away has come down to . . .what? Twenty cases went to juries, and Merck has now prevailed, to a large degree, in 17 of them, including all the largest awards. The Vioxx affair has still been a big financial hit, and it’s definitely had effects on Merck, but it hasn’t been quite the disaster it looked like being. Well, not financially - the company's reputation has taken a fearsome beating, and the drug industry as a whole hasn't come out of the business looking any better, either.

I can’t claim to have kept a cool head through the thing. There really was a period where the entire Vioxx affair could have taken a different turn – if Merck had lost a string of jury trials at the start, a settlement would have been much harder to arrange, and would have cost (naturally) a huge amount more. But fighting the first wave of cases to an expensive draw and appealing every verdict that went against them turned out to be the right strategy. Of course, any rational observer would have wished for a world where the whole business never would have taken place, but that's not where we find ourselves.

But, as you’ll have noticed, the preceding paragraphs are written from a point of view that’s pretty sympathetic to Merck. Zooming out to a more neutral view, what do we have? Vioxx certainly did some people a great deal of harm. The clinical data that led to its withdrawal make it extremely likely that some people experienced heart attacks, fatal in some cases, because they took the drug. Where the arguing starts is when you start pinning numbers to that last sentence. Vioxx’s bad effects, though real, were also small compared to the number of people who took it. (And the arguing continues when you try to balance its bad effects with the good that it did for the patients who really needed it, who were surely, though, a small subset of the people who actually were on the drug).

Those last two sentences point to some of the problem. If Merck had not tried to make Vioxx the pain drug for everyone in the world with any kind of inflammation pain, it’s quite possible that its cardiovascular effects would never have been noticed. And it’s worth remembering that they were noticed during a trial for a completely different indication, the possibility that COX-2 inhibitors might have a protective effect against colon cancer. Only after that trial flashed an unmistakable statistical warning did everyone go back to Merck’s earlier data and start arguing about what could or should have been noticed before.

The problem is that many other drugs have data that, in retrospect, look like trouble. It’s just that in many cases, the trouble never appears, either because it never rises to the level of being noticed, or it never was really there to begin with. There are drug candidates that cause bad effects in one out of every ten people who take them, and those never make it out of the clinic. (Most of the ones causing trouble at that level don’t even make it into the clinic in the first place). The ones that cause trouble at one in a hundred get weeded out, too, if that trouble is bad enough. The one in a thousand, one in ten thousand, one in a hundred thousand levels are where the difficulty is, because clinical trials have an increasingly difficult time picking up those problems. They’ll show up, if they do, after a drug comes to market.

But why stop there? There’s no reason not to believe that there are drugs that also cause direct harm, but only to one out of every million patients. Or ten million, or hundred million. Some unlikely combination of genetic and environmental factors comes up – we really don’t know enough to rule that sort of thing at all. We call those drugs “safe”, but “safe” means “causing harm at too low a level to see”. Every single drug in the world has bad side effects, from the bottom of the scale (hideous old last-ditch chemotherapy drugs that are one step away from World War One battlefield agents), all the way up to the top. It's just a question of how often they turn up.

Comments (9) + TrackBacks (0) | Category: Cardiovascular Disease | Toxicology


COMMENTS

1. bill.trayner on June 5, 2008 4:59 PM writes...

Now the jury decisions are being overturned by appeal court judges, I presume 3 judges, it would be interesting to find out how many of the judges involved received financial backing, directly or otherwise from Merck. Is it fair that the decision of 3 men can overule the decision of 15? If it was merely the amount of damages then that would be fair enough but to overthrow the entire findings of the earlier trial seems to say juries are a waste of time.

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2. sroy on June 5, 2008 5:05 PM writes...

The problem with Vioxx was very simple. It killed more people than older drugs in it's class (naproxen, ibuprofen etc). It did not however offer any therapeutic benefit (was it any better than say meloxicam for not causing GI ulcers?).

It would have been acceptable if the major adverse effect of Vioxx was unexpected, but it was not. Instead Merck conducted a fairly elaborate coverup.

Merck,like many pharma companies, was consumed by hubris and thought they get away with anything. Well they did not. I do not realize why so many still want to defend the indefensible, even if the defense is now tangential as opposed to a head on defense.

No sane person expects that drugs will have no adverse effects, but deliberate fraud and misrepresentation of the safety or efficacy of a drug is criminal (and not worth spinning unless one is on Mercks payroll).

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3. anon on June 6, 2008 9:02 AM writes...

It did not however offer any therapeutic benefit

That's not true - I know a number of physicians and patients who lament the fact that Vioxx is off the market. For some people with chronic pain, reducing their pain was worth the risk...

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4. hamilton on June 6, 2008 11:49 AM writes...

i took vioxx then had the almost inevitable myocardial infarction. The company (Merk) did wrong in marketing this drug with the knowledge they had about its side effects. Why then are American courts so lenient on this company. Surely a jury of 15 can make an informed judgement. There can be no need for appeal courts to rule so ruthlessly in favour of Merk unless of course it benefits them directly. Why allow a jury trial if the JUDGE always knows better. Crazy.

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5. hamilton on June 6, 2008 11:49 AM writes...

i took vioxx then had the almost inevitable myocardial infarction. The company (Merk) did wrong in marketing this drug with the knowledge they had about its side effects. Why then are American courts so lenient on this company. Surely a jury of 15 can make an informed judgement. There can be no need for appeal courts to rule so ruthlessly in favour of Merk unless of course it benefits them directly. Why allow a jury trial if the JUDGE always knows better. Crazy.

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6. trrll on June 6, 2008 4:16 PM writes...

I don't think that it is at all clear that vioxx killed more people than other drugs in its class. I haven't seen any analysis that takes into account the mortality associated with the substantial bleeding risk of the nonselective COX inhibitors. And there is some evidence that even the nonselective agents may carry some degree of cardiovascular risk, which is only partially balanced by their protective effect.

On the other hand, for some people, vioxx seems to have been very nearly a miracle drug. I've had quite a few people tell me that vioxx stopped their pain when nothing else worked, and that they would gladly take it again, cardiovascular risk and all, if they could get it. I've even heard that some people at Merck squirreled away a stash for personal use after it was discontinued.

It seems very likely that the liability issues killed a drug that was extremely valuable for at least some people, and that may even have saved lives.

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7. sroy on June 6, 2008 4:58 PM writes...

Drugs that increase the rate of death by more than 300% in patients with early Alzheimer's (taking Vioxx vs not taking Vioxx) cannot be considered be be safe.

It increases the risk of death by 4-5 times beyond what early Alzheimer's does to old people! That is simply not acceptable for a widely used medication.

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8. Bill Aldrich on June 12, 2008 4:06 PM writes...

Hello,
I had been on Indocin and other NSAIDs for 27 years before I took Celebrex (just because my PCP thought it would be easier on my GI: WRONG...WRONG). Then, she asked me to "try" Vioxx. It seemed no better than Indocin. But within a few weeks I started to trip, fall down stairs, get dizzy, and then get aural migraines. I thought I was hypoglycemic. Six months after starting Vioxx, I momentarily passed out on my right side while biking downhill. I thought I was tired (I was in the middle of a 165 mile bike trip). A few days after 9/11 I started to fall over at work (while having an aural migraine). I told the PCP and she scheduled me for an MRI in November! A month later I had a TIA in the middle of the night while sleeping a friend's place on the Cape. I thought maybe I had pinched a nerve in my back. The next day I reported it to the HMO's on-call nurse. I had no idea what a TIA was.
I since have had one "atypical hemoplagic migraine" that put me in a hospital's risk floor for 36 hours when I went off Aggrenox for 7 days (before having a hemorrhoidectomy due to the after-effects of the migraine medicine).
I could add more detail. The FDA commissioner at the time said Vioxx would cause 100,000 or more deaths and injuries. I think Vioxx and Merck are the tip of an iceberg of corruption, deceit, and prevarication.

Permalink to Comment

9. ken on June 21, 2008 5:26 AM writes...

took vioxx for several months for back problem--9 months later--bingo---triple bypass,Hey! back problem gone,wooptedo....

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