Vioxx was BETTER than Celebrex but neither was EVER approved by FDA for long-term (years) treatment. The scope of this problem is difficult to explain to people that lack general knowledge of FDA approval process or cardiovascular/cerebrovascular disease pathophysiology.
1) Most FDA drugs are approved based on short-term (several months) efficacy and safety studies through 3 phases. The few caveats have evolved from disasters. Due to the FenPhen debacle weight loss drugs are required to have 1-2yr safety data. Arguably, our next Wonder Drug (rimonabant) would be melting fat, stopping smoking, and cutting the ganja habit of millions of Americans already if not for questionable postmarket practices by others.
Despite being short-term trials that were NOT powered to PROVE CV safety, Merck aggressively marketed Vioxx to clinicians serving patients with high pre-existing risk of CV events. Yeah, your knees hurt but strokes and MIs kill. The troubling data was evident in at least one pre-approval study. Despite excluding people with significant CV risk, there was clear signal of increases morbidity and mortality.
In fact even the GI bleeds were reduced solely in comparison to high dose ibuprofen. Ibuprofen was indeed a standard therapy but it was also chosen b/c bleed risk is significantly higher than naproxen . . . ie drug companies always want their drug to look as good as possible.
Drug companies brag about safety data but the pre-approval dbase for Vioxx was 5000 patients. After approval Vioxx continued GI bleed trials since the earlier ones really didn't show a clinically significant improvement. It's a substantive distinction often lost on the general public that statistically significant differences often don't mean jack in the real world.
Anyway the VIGOR study was larger than all previous Vioxx trials combined. Naturally, it was for a new indication (rheumatoid) and it was now being compared to naproxen. But due to the fact they were now using more "typical" patients (instead of "ideal" premarket subjects), the real effects of VIOXX became apparent. Both long-term and mod/high dose Vioxx was clearly unsafe for general use.
Unfortunately, FDA/Merck settled for mediocre labelling revisions that few doctors read. Merck even argued (Feb 2001) the 5x increase in MI risk was due to a protective effect of naproxen. Even FDA didn't buy that one. In the FDA's defense, the true scope of Vioxx morbidity/mortality was not apparent . . . primarily b/c we have one of the weakest postmarket surveillance systems amongst developed nations.
Merck (MRK), on the otherhand, informed it's battalion of drug reps to avoid discussing the Advisory panel or results of the VIGOR study with MDs.
2) Once a drug is approved, that's when the real experiment starts. The truth is we really don't know how any particular person will respond to a drug. Sometimes we get lucky (say SSRIs) where even if the drug is overprescribed and overdosed . . . you pretty much have to swallow the bottle (the one it came in) to kill somebody.
Unfortunately, the consumers are barraged with DTC (direct to consumer) ads that scarcely resemble the product being advertised. They certainly fail to inform on practical issues of risk/benefit. That leads us to #3.
3) In a perfect world, knowledgable doctors would correctly diagnose their patients (100% accuracy) and select the most appropriate treatment based on that diagnosis AND individual patient characteristics. I want to believe it happens most of the time, hopefully overwelmingly so. But available evidence implies that isn't necessarily the case. Many clinicians are NOT aware of the basic pharmacology of the drugs they prescribe. Far too many rely on drug rep hype, what's in the sample closet, or a luncheon/dinner given by a peer (hosted by the drug companies). Even our conferences are underwritten by pharmaceutical companies. Admittedly, the food is universally good . . . I mean REAL good.
When you combine #1 (a process that was NEVER intended to test drugs under the "real world" conditions in which it would be used), #2 (ignorant public and bottomline driven companies), and #3 (arguably ignorance and duplicity amongst physicians) . . . you get Vioxx, Celebrex, Bextra, Lotronex, Serzone, Rezulin, and others.
IMO, all of these drugs should STILL be on the market. But FDA and the respective manufacturers mishandled the research, approval process, postmarket surveillance, and marketing of these medications. Yet, they still needed an ignorant public and weak doctors to create these "success" stories.
1) Most FDA drugs are approved based on short-term (several months) efficacy and safety studies through 3 phases. The few caveats have evolved from disasters. Due to the FenPhen debacle weight loss drugs are required to have 1-2yr safety data. Arguably, our next Wonder Drug (rimonabant) would be melting fat, stopping smoking, and cutting the ganja habit of millions of Americans already if not for questionable postmarket practices by others.
Despite being short-term trials that were NOT powered to PROVE CV safety, Merck aggressively marketed Vioxx to clinicians serving patients with high pre-existing risk of CV events. Yeah, your knees hurt but strokes and MIs kill. The troubling data was evident in at least one pre-approval study. Despite excluding people with significant CV risk, there was clear signal of increases morbidity and mortality.
In fact even the GI bleeds were reduced solely in comparison to high dose ibuprofen. Ibuprofen was indeed a standard therapy but it was also chosen b/c bleed risk is significantly higher than naproxen . . . ie drug companies always want their drug to look as good as possible.
Drug companies brag about safety data but the pre-approval dbase for Vioxx was 5000 patients. After approval Vioxx continued GI bleed trials since the earlier ones really didn't show a clinically significant improvement. It's a substantive distinction often lost on the general public that statistically significant differences often don't mean jack in the real world.
Anyway the VIGOR study was larger than all previous Vioxx trials combined. Naturally, it was for a new indication (rheumatoid) and it was now being compared to naproxen. But due to the fact they were now using more "typical" patients (instead of "ideal" premarket subjects), the real effects of VIOXX became apparent. Both long-term and mod/high dose Vioxx was clearly unsafe for general use.
Unfortunately, FDA/Merck settled for mediocre labelling revisions that few doctors read. Merck even argued (Feb 2001) the 5x increase in MI risk was due to a protective effect of naproxen. Even FDA didn't buy that one. In the FDA's defense, the true scope of Vioxx morbidity/mortality was not apparent . . . primarily b/c we have one of the weakest postmarket surveillance systems amongst developed nations.
Merck (MRK), on the otherhand, informed it's battalion of drug reps to avoid discussing the Advisory panel or results of the VIGOR study with MDs.
2) Once a drug is approved, that's when the real experiment starts. The truth is we really don't know how any particular person will respond to a drug. Sometimes we get lucky (say SSRIs) where even if the drug is overprescribed and overdosed . . . you pretty much have to swallow the bottle (the one it came in) to kill somebody.
Unfortunately, the consumers are barraged with DTC (direct to consumer) ads that scarcely resemble the product being advertised. They certainly fail to inform on practical issues of risk/benefit. That leads us to #3.
3) In a perfect world, knowledgable doctors would correctly diagnose their patients (100% accuracy) and select the most appropriate treatment based on that diagnosis AND individual patient characteristics. I want to believe it happens most of the time, hopefully overwelmingly so. But available evidence implies that isn't necessarily the case. Many clinicians are NOT aware of the basic pharmacology of the drugs they prescribe. Far too many rely on drug rep hype, what's in the sample closet, or a luncheon/dinner given by a peer (hosted by the drug companies). Even our conferences are underwritten by pharmaceutical companies. Admittedly, the food is universally good . . . I mean REAL good.
When you combine #1 (a process that was NEVER intended to test drugs under the "real world" conditions in which it would be used), #2 (ignorant public and bottomline driven companies), and #3 (arguably ignorance and duplicity amongst physicians) . . . you get Vioxx, Celebrex, Bextra, Lotronex, Serzone, Rezulin, and others.
IMO, all of these drugs should STILL be on the market. But FDA and the respective manufacturers mishandled the research, approval process, postmarket surveillance, and marketing of these medications. Yet, they still needed an ignorant public and weak doctors to create these "success" stories.
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