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Tuesday, April 11th 2006

Vioxx with Devil Horns

A 77-year-old diabetic gets another 9 million in a punitive award. This on top of an original 4.5 million dollar verdict.

In order to award punitive damages, the jury of six women and two men in New Jersey Superior Court needed to find that Merck withheld material information on Vioxx from the U.S. Food and Drug Administration, and that the company’s actions were deliberately meant to harm.

What exactly did Merck hide? Well, not much actually. There are really no damning memos, no smokey room meetings. Seeing that this seems a requirement for punitive damages in New Jersey, Merck is looking to appeal.

[T]he $9 million punitive damages award was unsupported by New Jersey law, which allows punitive damages only where there is clear and convincing evidence that (1) Merck knowingly withheld or misrepresented (2) information required to be submitted to the FDA under the FDA regulations (3) which information was material and relevant to the harm in question. The Shapiro analysis on which plaintiffs rely flunks all three requirements; only the slimmest of evidence (a deposition slip by Edward Skolnick) supports the first prong, and the other two prongs are completely naked.

No, the criticism of Merck is based only on a number of studies that people can now look at and say, ‘you should’ve known.’ You can find a Power Point summary of the history of our understanding of the risks of Vioxx here.

What the study data even shows is up for debate, although there is some statistically significant increase in the risk for cardiovascular disease in all of the three major studies which have been done. The VIGOR study, the Lancet study, and the APPROVe study which led to Merck voluntarily pulling Vioxx.

It should be pointed out that these risk factors in and of themself aren’t suprising. These are virtually the same risk factors associated with some other cyclooxygenase inhibitors.

Almost every NSAID holds some life threatening risk factors. Even good ol’ aspirin, which, because of its blood thinning properties, has been touted as a savior during a heart attack (seemingly paradoxical when looking at its COX-2 inhibitor cousins as causes of heart attacks), can be dangerous.

Non-steroidal anti-inflammatory drugs (NSAIDs), including low-dose aspirin, are behind a third of all hospitalizations and deaths associated with GI bleeding, according to two Spanish studies.

Low-dose aspirin alone accounted for between 8.2% and 12.2% of all GI complications and deaths, the research team reported in the August issue of the American Journal of Gastroenterology.

The most damning reports center around the 2000 VIGOR study which looked at gastrointestinal problems associated with Vioxx use, and was published in the New England Journal of Medicine. That the researchers had excluded and even deleted some cardiovascular events from the VIGOR study suddenly became a hot topic once Vioxx was actually pulled,

“I was somewhere between surprised and stunned,” Dr. Gregory Curfman, executive editor of The Journal, says. “They allowed us to publish an article that was just incomplete and inaccurate in some respects and was misleading and may have contributed to the detriment to the public health.”

The Forbes article (link above), like so much media makes it sound like the data was covered up. What a bunch of baloney. Two points must be made:

  1. Everyone knew the figures from the VIGOR data. The NEJM had them by 2001 (it takes them 4 years to get outraged) and the FDA had them, even if they were left out of the publication. Yet now they pretend it was some kind’ve cover up.
  2. The data did not make the statistical conclusions of the study any different.

Here’s Rangel MD at the time of NEJM’s editorial (subscription required) on the VIGOR study and just what is significant and isn’t.

The three cases of heart attack (which have been known since 2001) increase the statistical power of the VIGOR results which showed an increased risk of heart attack in the Vioxx taking patients but they do not at all change the conclusions. Why the VIGOR authors would withhold data on three cases from the Journal when it would not have made a difference is beyond me. This is like accusing the government of trying to cover up the fact that 9/11 even happened by showing that they tried to cover up the evidence of United flight 93 which crashed in Pennsylvania.

That is because they didn’t. The three heart attacks fell outside the time frame of the study, fell outside the specifics of the study, didn’t effect the conclusions, and there is no evidence their lack of appearance was mediated by Merck action or persuasion on the University of Toronto researchers. Yet it is some type of outrage that they were left out and proves Merck was hiding the terrible dangers of Vioxx all along.

[The researchers] say the heart attacks and strokes in question were not included because they were reported in a two-week period after the study termination date.

“Even if that data had been included, they would not have changed the results,” Dr. Bombardier said in an e-mail interview yesterday.

Dr. Bombardier defends the study saying it was not designed to draw findings about the heart or the cardiovascular system.

“It was designed to draw statistically significant data about the effects of Vioxx on the gastro-intestinal system,” she said.

As if anyone would’ve looked at Vioxx differently if the data had been included. Yet, this is the scenario upon which the NEJM basically condemned Merck to failure in the most important court of all, that of public opinion.

Such public misconception and media driven opinion makes 9 million dollar punitive awards, for 77 year olds with other significant risk factors for myocardial infarct, possible.

Here’s a breakdown of Mark Lanier’s favorite piece of evidence, the Lancet published Kaiser Permanente study, by an economist blogging over at Econobrowser:

1.39-fold increase risk of heart attack from taking rofecoxib [Vioxx] compared to no NSAID. Is that statistically significant, in other words, can you rule out that you’d see a difference of that size just by chance? Yes, the study claimed, but just barely.

The obvious question here is whether in fact the authors were able to observe all the relevant risk factors. The study openly acknowledged that it did not, missing such important information as smoking and family history of myocardial infarction.

How is a jury member with a high school diploma suppose to crunch this stuff? You better dumb it down into analogies everyone can understand. Here is an expert at it:

[R]esponding to witness Gilmartin’¬ís argument that the results of a study showing Vioxx users had six episodes of heart attacks or strokes to one for placebo users were not statistically significant, [Mark Lanier] asked:

“Have you got $6 on you? I’m going to give you a dollar and you give me the six. It is not statistically significant in the difference. What do you think, are you in or out?”

But as Econobrowser points out, while that is a folksy way to package the statistics and bring them down to a level, it is misleading.

[H]ere’s how the deal actually works– you give me the dollar, but you don’t know whether I give you $6 or I give you nothing. Or, to be a little more accurate, even if there actually is an elevated risk of the magnitude the studies suggest but can’t prove, the question is whether I might want to accept a 1 in 4,000 risk of dying from a heart attack in order to get the only medication that makes my pain bearable and a mobile life livable.

And saying the public and their physicians weren’t informed enough to make that risk-reward analysis because Merck maliciously withheld three heart attacks from a study is baloney. Saying, even if data had no releavance, that by putting themselves in a situation where subversion could be inferred (say by deleting data), that they brought this upon themselves is baloney. I’m sure every plantiff is suing to make drug research more transparent. *Rolls Eyes*

No, what this is, is the expectations game again. The same game that drives medical malpractice lawsuits (instead of actual negligence).

The truth is there is no such thing as the perfect drug. They all carry risks, and there are things that can be done, from all sides, to lessen those risks and make drugs with both great risks and great benefits available to patients who understand the balance. From the patient/plantiff’s point, stop asking your doctor for everything that shows up in DTC advertising and popping it into your mouth. Just respect these drugs a little more. They’ve become far too common. Realize the very basic truth that you are putting foreign chemicals into your body, and bad things can happen.