Merck better settle . . . and settle fast

[BaliBabyDoc]

CNN Money

NEW YORK (CNNMoney.com) - New data from drug maker Merck suggests that heart risks associated with painkiller Vioxx begin much earlier than it had previously suggested, said a report published Thursday.

The data suggest that cardiovascular risks increase for Vioxx users after four months of use, rather than 18 months as the company had previously said, according to the Wall Street Journal.

Hmm, looks like the "long-term use" defense may take it on the chin. Although I would like to see this in a more reputable source than the WSJ.

In a statement, Merck said that the data "do not establish that the risk for Vioxx starts earlier than had previously been reported," said the report.

That's basically true . . . others have been reporting increased risk well before 18 months. But it's a nice piece of truthiness.

 

[Meuge]

It's interesting, because I have a feeling that concealing the results of that study was not a board decision at Merck. I suspect a project manager for Vioxx decided that they were going to conceal it because quick approval would get him a promotion or a pay raise... or even someone lower. Nobody in their right mind would have ever thought that this would remain secret forever.

At least maybe this will serve as a lesson that they have to disclose the results of the clinical trials and get drugs approved based on ALL available information. Vioxx would have been approved anyway, just with the appropriate red label, and a year or two more of studies. But no - someone wanted it out NOW... so that's how they'll lose 10X as much as a 2-year delay and a warning would have cost them.

 

[Jadow]

it's really too bad. My dad was on Vioxx for a couple years, while he was on it, it was tremendously helpful with his hip and knee pain. Now he's off it of course, also off all the Cox 2's, and he takes some crappy drug that doesn't work very well, and about 8-10 tylenol a day. Before he could take ONE Vioxx for the whole day.

It really was a miracle drug, too bad it was too good to be true.

Fortunately, he didn't have a heart attack.

 

[BaliBabyDoc]

Originally posted by: Meuge
It's interesting, because I have a feeling that concealing the results of that study was not a board decision at Merck. I suspect a project manager for Vioxx decided that they were going to conceal it because quick approval would get him a promotion or a pay raise... or even someone lower. Nobody in their right mind would have ever thought that this would remain secret forever.

At least maybe this will serve as a lesson that they have to disclose the results of the clinical trials and get drugs approved based on ALL available information. Vioxx would have been approved anyway, just with the appropriate red label, and a year or two more of studies. But no - someone wanted it out NOW... so that's how they'll lose 10X as much as a 2-year delay and a warning would have cost them.

It's kind of complicated. Merck CLEARLY had reasons to suspect Vioxx could cause excess cardiovascular events. That information went ALL the way to the top . . . chief medical officer, exec VPs, CEO.

The NEJM study was actually two errors. The first was NEJM failing to actually look at the data ON THE DISK or to demand info from the authors after others raised questions. The second was Merck's failure to acknowledge the additional events that occured after the predetermined cutoff for primary data analysis.

I'm not sure Vioxx could have avoided a black box. But even at that level it was going to pull down at least $500mil a year for a decade. Unfortunately, the desire for that 10th digit got the best of them.

I still expect Merck to petition FDA for a return to market. The damage is done. Plus, it's not a bad drug . . . if appropriately used. Merck needs the money to pay off their own bloodsucking lawyers.

 

[IHateMyJob2004]

I dumped my MRK stock at $34.50 or so. It's going no where for a while.

Best to sit back and watch than worry about it.

MRK will not go under though. They have that much money.

EDIT: Oh, and mght as well link an artcile ... MRK has a cancer vaccine that just got approved by the FDA.

Yes, I said a vaccine. Only for certain cancers thoguh if I understand.

 

[rickn]

Originally posted by: Jadow
it's really too bad. My dad was on Vioxx for a couple years, while he was on it, it was tremendously helpful with his hip and knee pain. Now he's off it of course, also off all the Cox 2's, and he takes some crappy drug that doesn't work very well, and about 8-10 tylenol a day. Before he could take ONE Vioxx for the whole day.

It really was a miracle drug, too bad it was too good to be true.

Fortunately, he didn't have a heart attack.

has your dad tried pot?

 

[EagleKeeper]

I have noticed more Merck commercials on the tube lately.

Attempt to alter public perception?

 

[bozack]

Originally posted by: BaliBabyDoc

I still expect Merck to petition FDA for a return to market. The damage is done. Plus, it's not a bad drug . . . if appropriately used. Merck needs the money to pay off their own bloodsucking lawyers.

I wouldn't count on the return to market petition...

 

[bozack]

Originally posted by: EagleKeeper
I have noticed more Merck commercials on the tube lately.

Attempt to alter public perception?

not just Merck, all big pharma...I remember sitting in meetings at my last big pharma company, when they talked of how they would change their marketing strategy away from hospitals and doctors and more towards the consumer...the whole industry is trying to "educate" consumers so their product is requested instead of merely being prescribed.

I currently work for another pharma, and the strategy is the same.

 

[TheBeast]

Yes, I said a vaccine. Only for certain cancers thoguh if I understand.

Its a vaccine for HPV (human papilloma virus, or in common terms genital warts). HPV is the leading cause of cervical cancer. So technically its not a cancer vaccine per se, its a vaccine against the virus that is the leading cause of cervical cancer.

 

[TheBeast]

The NEJM study was actually two errors. The first was NEJM failing to actually look at the data ON THE DISK or to demand info from the authors after others raised questions. The second was Merck's failure to acknowledge the additional events that occured after the predetermined cutoff for primary data analysis.

I'm not defending Merck in any way shape or form ... but who reports data after predetermined cutoff points in any trial?

Also, to me, after reading VIGOR I immediately stopped recommending Vioxx. The investigators suggestion that Naproxen was somehow cardio protective or that more people in the trial should have been on ASA didn't cut it for me. Couple that with the countless small studies showing increased BP's in patients on Vioxx and it wasn't too difficult to see that this wasn't going to be pretty. Physicians should have been able to deduce from the information that was available in plain sight to everyone that this was not some miracle drug.

 

[Meuge]

Originally posted by: TheBeast

Yes, I said a vaccine. Only for certain cancers thoguh if I understand.

Its a vaccine for HPV (human papilloma virus, or in common terms genital warts). HPV is the leading cause of cervical cancer. So technically its not a cancer vaccine per se, its a vaccine against the virus that is the leading cause of cervical cancer.

I've seen good evidence that while this vaccine is damn near 100% effective for the virus isotypes it targets (16, 18 and I think one more), it may actually lead to more cases of cervical cancer, because women who receive the vaccine are less likely to keep to a yearly schedule of pap smears, and the vaccine only covers viruses that are involved in 2/3 of the cervical cancer cases.

The statistics I saw said that if 50% of women receive the vaccine, it would only take 10% of the to stop visiting the gynecologist for the statistical impact of the vaccine to vanish. Anything beyond 10% would actually raise the number of cancer cases.

 

[BaliBabyDoc]

Originally posted by: TheBeast

The NEJM study was actually two errors. The first was NEJM failing to actually look at the data ON THE DISK or to demand info from the authors after others raised questions. The second was Merck's failure to acknowledge the additional events that occured after the predetermined cutoff for primary data analysis.

I'm not defending Merck in any way shape or form ... but who reports data after predetermined cutoff points in any trial?

Also, to me, after reading VIGOR I immediately stopped recommending Vioxx. The investigators suggestion that Naproxen was somehow cardio protective or that more people in the trial should have been on ASA didn't cut it for me. Couple that with the countless small studies showing increased BP's in patients on Vioxx and it wasn't too difficult to see that this wasn't going to be pretty. Physicians should have been able to deduce from the information that was available in plain sight to everyone that this was not some miracle drug.

It is the responsibility of ANY author that publishes in a scholarly journal to "update" findings. If it's an oversight or "mistake" it's called an erratum. I don't know the nuts/bolts of the NEJM-Vioxx trial but if I had to guess they decided they were going to submit efficacy data soon after closing enrollment while realizing that long-term safety data would lag by up to two years after closing enrollment.

As Merck was finishing up the manuscript revisions (I doubt it was accepted without revisions), the rest of the safety data became available. IMO, it appears that SOMEONE put the more complete safety data in the manuscript and then SOMEONE took the more complete data out.

Believe it or not some physicians actually make treatment decisions based on well-designed trials . . . instead of pablum from the drug reps. NEJM isn't exactly in the clear. Not long after publication, a pharmacist called into some show where the NEJM editor was appearing. This pharmacist noted cardiac and stroke events . . . and explicitly called out NEJM to publish something to get the word out. The editor took the "establishment" position. He said there was absolutely NO reason to question the Vioxx results and even if there was an issue . . . the NEJM cannot check everything or followup on what it publishes.

 

[TheBeast]

"Believe it or not some physicians actually make treatment decisions based on well-designed trials . . . instead of pablum from the drug reps."

And what did the results of VIGOR show? Increased risk of cardiac morbidity in the Vioxx group (whether you include the other events or not). The trial wasn't designed with this endpoint in mind and the difference was statistically significant, but not highly significant. Further exploration was warranted and prescribing it to everyone in the name of GI safety was completely irresponsible with the information that was right there in plain sight!

I haven't seen the statistics on how the addition of the 2 events in the vioxx group vs. the 1 event in the naproxen group (that were reported after the prespecified cutoff) would have affected the results. My guess is it would have had little effect on the p value and wouldn't have had any effect on physicians prescribing of the drug. It would have saved Merck some headaches at this point, though, for all of the conspiracy theorists out there.

 

[BaliBabyDoc]

I think you are a little off in understanding the difference between "statistically significant" and "clinically significant." Granted, that's probably not what you meant.

25% 50% 100% increased RISK of a cardiac event in non-aspirin middle-aged people is clinically significant even if a trial result didn't reach statistical significance.

From my personal stash . . .

To P or Not to P: Why Use a P Value, Anyway?

Andrew J. Vickers, PhD
Medscape Business of Medicine. 2006;7(1) ©2006 Medscape
Posted 03/02/2006

My nonstatistical colleagues seem to imagine that I spend my off-hours calculating the mean time it takes to grill a piece of fish, or an exact binomial confidence interval for the proportion of Saturdays that I get to lie in. In truth, of course, I spend my off-hours trying not to think of statistics at all. But let's indulge the fantasy of the 24/7 statistician.
Going home each night, I have a choice between cycling down a busy road or winding through the beautiful backstreets of Brooklyn. Being statistically obsessed, I have recorded how long each route takes me on a number of occasions and have calculated means and standard deviations. Imagine that, one day, I had to get home as soon as possible for an appointment. To choose a route, I conduct a statistical analysis of my travel time data: it turns out that the travel time for the busy road is shorter, but the difference between routes is not statistically significant (P = .4). Nonetheless, it would still seem sensible to take what is likely to be the quicker route home, even though I haven't proved that it will get me there fastest.
Now let's imagine that this incident got me fired up, and I spend 2 years randomly selecting a route home and recording times. When I finally analyze the data, I find strong evidence that going home via the busy road is faster (P = .0001), but not by much (it saves me 57.3 seconds on average). So I decide that, unless I am in a real rush, I'll wind along the backstreets, simply because it is a more pleasant journey and well worth the extra minute.
We tend to think that P values should determine our actions; in the case of a drug clinical trial, for example, we say: "P < .05: use the drug; P = .05: don't use the drug." Yet, the bicycle example shows the opposite: I chose the busy road when P was .4 but not when P was .0001. This suggests we need to think a little harder about what P values are and how we should use them.
The most important thing to remember about P values is that they are used to test hypotheses. This sounds obvious, but it is all too easily forgotten. A good example is the widespread practice of citing P values for baseline differences between groups in a randomized trial. The hypothesis being tested here is whether there are real differences between groups. Yet we know that groups were randomly selected, so any differences in characteristics such as age or sex must be due to chance alone.
Science is often said to be about testing hypotheses, but in many cases this is not what we want to do at all. When I had to get home in a rush, I wasn't interested in proving which was the quickest way home, I just needed to work out what route was likely to get me to my appointment on time. Moreover, even when we do want to test hypotheses, our conclusion is a necessary but not sufficient guide to action. I eventually proved that using the busy road was quickest but decided to choose a different route on the basis of considerations -- pleasure and quality of life -- that formed no part of the hypothesis test.
An even more difficult problem is when our P value is > .05, that is, when we have failed to prove our hypothesis. This is often interpreted as proof that our hypothesis is false. Such an interpretation is not only incorrect, but it can also be dangerous; I'll discuss this in a future column.

Andrew J. Vickers, PhD, Assistant Attending Research Methodologist, Memorial Sloan-Kettering Cancer Center, New York, NY

Disclosure: Andrew J. Vickers, PhD, has disclosed no relevant financial relationships.

 

[TheBeast]

I think you are a little off in understanding the difference between "statistically significant" and "clinically significant." Granted, that's probably not what you meant.

You're right, thats not what I meant. I'm also very confident in knowing the difference between statistically and clinically significant (pretty much every overactive bladder treatment and sleep med come to mind). In VIGOR, the difference in CV morbidity WAS statistically significant (with or without the extra cases). If true, it was also very clinically significant. Something can be "statistically significant" and still be incorrect (ie a type 1 error .... rejecting the null hypothesis when the null hypothesis is correct). The trial was designed to detect reduction in GI events (bleeds, perforations), it was not designed to detect increased CV morbidity (nor was this endpoint prespecified). It did demonstrate an increase in CV morbidity, but alone, in this trial, that was not enough to say for sure that Vioxx increased CV morbidity. Had the p value been <.001, (ie highly significant) the likelihood of the statistically significant CV morbidity increase being due to chance would be small. That was my point.

As I am sure you know, if you look at enough endpoints, you are going to find things that are "statistically significant" in your data even though in reality there is no difference. In otherwords, they were statistically significant by chance. That is the whole reason trials are designed with prespecified enpoints to have alpha's of .05 and with enough patients to assure adequate power to detect differences in treatment. When non prespecified endpoints show up statistically significant, new trials are designed to test the newly generated hypothesis.

My point is this: The data in VIGOR, published exactly like they were, should have been a giant red flag to physicians. If enough physicians had refused to prescribe the drug due to CV safety concerns, Merck would have been forced to "prove" that Vioxx was not increasing CV morbidity. The only way to do that would have been through a clinical trial. If Merck had added the 3 other CV morbidity cases (2 in Vioxx, 1 in Naproxen) to VIGOR in violation of the trial protocol, it would not have changed anything fundamentally about the prescribing of the drug (IMO).

 

[OS]

Originally posted by: Meuge

Originally posted by: TheBeast

Yes, I said a vaccine. Only for certain cancers thoguh if I understand.

Its a vaccine for HPV (human papilloma virus, or in common terms genital warts). HPV is the leading cause of cervical cancer. So technically its not a cancer vaccine per se, its a vaccine against the virus that is the leading cause of cervical cancer.

I've seen good evidence that while this vaccine is damn near 100% effective for the virus isotypes it targets (16, 18 and I think one more), it may actually lead to more cases of cervical cancer, because women who receive the vaccine are less likely to keep to a yearly schedule of pap smears, and the vaccine only covers viruses that are involved in 2/3 of the cervical cancer cases.

The statistics I saw said that if 50% of women receive the vaccine, it would only take 10% of the to stop visiting the gynecologist for the statistical impact of the vaccine to vanish. Anything beyond 10% would actually raise the number of cancer cases.

they say later generations of this vaccine will protect against more strains of hpv

 

[3chordcharlie]

Originally posted by: rickn

Originally posted by: Jadow
it's really too bad. My dad was on Vioxx for a couple years, while he was on it, it was tremendously helpful with his hip and knee pain. Now he's off it of course, also off all the Cox 2's, and he takes some crappy drug that doesn't work very well, and about 8-10 tylenol a day. Before he could take ONE Vioxx for the whole day.

It really was a miracle drug, too bad it was too good to be true.

Fortunately, he didn't have a heart attack.

has your dad tried pot?

hahaha...

no... really... has he?