Monday, June 12, 2006


A few days ago NPR ran an interesting and remarkable story about Vioxx, a pain reliever that was withdrawn from the marketplace in 2004 by its maker Merck after a study showed that its use increased the risk of a heart attack. The main theme of NPR's story was that in fact there was data from a study already in 1999 that showed an increased risk of heart attacks in Vioxx users, but that information was not made public. The report placed much of the blame for this failure to report the increased risk on the data safety and monitoring board (DSMB) of the study.

A DSMB is a group of scientists who are not investigators in a study, but who are charged with periodically reviewing the data and results of a study, with the responsibility of stopping the study before its planned endpoint if the data shows that one group or another is being harmed or suffering an unusual number of deaths or injuries. In the late 1990's Merck was funding a study comparing Vioxx, an investigational drug at that time, with naproxen, an already approved anti-inflammatory drug. The NPR report charges that the DSMB should have stopped the study early and reported an increased risk of heart attacks in Vioxx users, but they did not because, the report implies, some members of the DSMB, including its chairman, had financial interests in Merck. (Interestingly enough, the report does not come down too hard on Merck itself. The story almost seems to assume that a big drug company will be motivated by corporate greed and cannot be expected to do the correct ethical thing - such as stop a study if need be.) An FDA scientist estimates that between 1999 and 2004, 38,000 people died from heart attacks caused by Vioxx, deaths that could have been prevented if the information about Vioxx causing heart attacks came out in 1999 instead of 2004.

Far be it from me to wish to defend a corporation so motivated by profits that it withholds vital safety information. But I don't really know what went on in the heads of the DSMB members, and it is only fair to point out that a DSMB has a very tough job. When studies are planned, the number of subjects needed to show a certain degree of benefit is carefully calculated. Stopping a study early may mean that a benefit of a drug is not demonstrated because not enough patients were enrolled.

Not too long ago there was a large, multicenter study comparing premature newborns given hydrocortisone, a type of steroid, shortly after birth with those given a placebo, primarily to see if there was less lung disease in the hydrocortisone treated patients. The study was stopped early by its DSMB because the hydrocortisone treated babies had a higher chance of a gastric or intestinal perforation, basically a hole in the stomach or intestine. Some people were critical of the decision to stop the study early, fearing that a greater good of possibly finding a benefit to hydrocortisone treatment was nullified by a perhaps lesser safety concern.

If the study had proceeded to its conclusion, would we have found a benefit to hydrocortisone? Probably not. But there are two sides to everything - even if one of them is a large, hungry corporation.


Blogger Ex Utero said...

OK NeoDoc, with regard to perforations and steroids, are you trying to bait me?

Which reference of mine do you want me to quote?

How about this?

There's no excuse for continuing any randomized study on living people when there is a known risk of death or serious morbidity and an unknown benefit. Period. True for Viox, true for early postnatal steroids. I've built my whole academic career on that priniciple. The people on that ESDM committee should have their licenses revoked and be liable to lawsuits on behalf of the patients as far as I'm concerned.

For the rest of the readers, if you want to know about steroids and spontaneous intestinal perforations, plug in "gordon pv" on Pubmed.

5:56 PM  
Blogger That Girl said...

Perhaps I am not well-informed enough but I would not be upset about a study, however long it lasted - I WOULD be upset about mass distribution while the jury was (maybe) still out on whether a drug kills people (or really, really hurts them).

8:05 AM  
Blogger neonataldoc said...

Thanks for the comments. Ex utero, I wasn't baiting you, but I figured you'd respond if I talked about gastric perforations! I pretty much agree with your comments about the DSMB and studies, but let me raise a hypothetical situation. What if steroids improved the babies' BPD so much that even though the steroid group had more gut perforations, they still ended up better than the placebo group? And what if stopping the study early meant you did not find that difference?


8:38 PM  
Blogger Ex Utero said...

Lex Doyle pretty much makes that same argument in an exchange of editorial letters that we're having in Pediatrics this month. He and his colleagues essentially say that we should complete the studies and then decide if the overall benefits might outweigh the risk of perforations.

The problem with that argument is two fold. First, there is the problem of reporting the incidence of perforations. None of the studies ever start out trying to report perforations, it is something they find as a un-intended observation or at best a poorly defined secondary outcome in most of these studies. So when they find it on an interim analysis, we have to respect that as a "tip of the iceberg" finding.

Second, if you were the parent of child who had a perforation after an interim analysis showed steroids to be a clear and significant risk factor (or after multiple studies showed steroids to be a risk factor), how would you feel if you found out they chose to continue the study anyway and your child ended up with this known complication (especially if they did a shitty job of telling you that your child was at risk for it)?

You'd be mad as hell and rightfully so. Why?

primum non nocere.

You said it yourself in a previous post - DO NO HARM. This is the rule that should guide everything we do in medicine, including our clinical trials. If we can't find a way to do it without causing harm, then we simply haven't done enough basic science. Sacrificing some babies to get a significant improvement in the cohort as a whole should never be an exceptable practice as far as I'm concerned.

Ethically, the only scenerio I can think of where I might change my mind would be a doomsday scenerio (supervirus that is going to kill 90% of us versus a live vaccine which will only kill 1%) and even then I would allow patients personal choice.

Thanks for the chance to vent.

9:13 PM  
Blogger neonataldoc said...

Interesting stuff, ex. I'll be sure to read the letters in Pediatrics this month.

7:52 PM  
Blogger Tassie_gal said...

This comment has been removed by a blog administrator.

12:46 AM  
Anonymous Vioxx Prescription Medication said...

My name is Tony Gomez and i would like to show you my personal experience with Vioxx.

I am 56 years old. Have been on Vioxx for 2 years now. Everybody that works for the fda that oked this drug should be put in jail.

I have experienced some of these side effects -
heart attack hardening of the arteries and nerve damage in my feet

I hope this information will be useful to others,
Tony Gomez

9:44 AM  

Post a Comment

<< Home