美国专家谈默克制药公司的COX-2抑制剂万络（rofecoxib，Vioxx）退出全球市场。
VIOXX WITHDRAWAL: Learning valuable lessons from rofecoxib
Eric J Topol MD Provost and Chief Academic Officer Chair, Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, OH
Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC
VIOXX WITHDRAWAL Merck & Co takes the selective COX-2 inhibitor rofecoxib off worldwide market
Topic
VIOXX: New opportunities
Opportunity to move medical profession in the right direction
System out of kilter for some time
Therapeutic knowledge has advanced beyond the FDA and medical marketing systems currently in place
Califf
VIOXX: Great concept
COX-2 target represented "the ultimate of biomedical science"
COX-2 inhibitors, introduced a few years ago for the treatment of pain and inflammation, had comparable efficacy but improved GI safety and tolerability compared with NSAIDs
Short-term, biomarker-based studies brought drug to market
Califf
Direct-to-consumer advertising
Merck & Co led the way in "direct-to-consumer" advertising with the drug
But issues began to arise early about the increased cardiovascular risk
Outcome studies in patients with arthritis and cardiovascular disease were needed
Califf
VIOXX: Outcome studies needed
Merck & Co refused to conduct the necessary outcome studies
- Topol
Company launched three studies looking at noncardiovascular outcomes, but measuring cardiovascular events
APPROVE trial
One study--Adenomatous Polyp Prevention on VIOXX (APPROVE)--tested rofecoxib 25 mg vs placebo in the prevention of the recurrence of colorectal polyps in 2600 patients with a history of colorectal adenoma
RESULTS
Study showed an increased relative risk for MI and stroke with rofecoxib, which became evident after 18 months of treatment
45 confirmed events in the rofecoxib group (1.48%) vs 25 in the placebo group (0.75%)
VIOXX: Risk and benefit
Rofecoxib withdrawn September 30, 2004
"This is just one of many types of drugs that are given to people for years with absolutely no understanding of what the chronic balance of risk and benefit is because it's never been studied."
- Califf
But also the norm, not an exception
VIOXX: Topol's thoughts
In the VIOXX Gastrointestinal Outcomes Research (VIGOR) study--which indicated an increased risk of cardiovascular events with rofecoxib vs naproxen--curves diverged at 30 days
"You can get an MI or stroke from one Vioxx pill."
Topol
VIOXX: Should have acted earlier
There was the potential for Merck and the FDA to do the right thing much earlier
Merck defended past studies as flawed and the drug as cardioprotective
Direct-to-consumer advertising fueled the induction of MI and stroke
Drug launch most successful in history of pharmaceuticals
Topol
VIOXX: Equal playing fields
Other drugs have been flagged for cardiovascular toxicity and not all of these have outcome studies
- Califf
"Then I would say, Uh-oh, we got a problem. What's the FDA doing about it?"
- Topol
VIOXX: Equal playing fields
"That's a fair question, but how much can the FDA do when this is the norm and not the exception?"
- Califf
TARGET: What about Advil?
In the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), naproxen had a slight cardioprotective effect because ibuprofen "was just the opposite"
What then to do about the risks of over-the-counter Advil?
VIOXX: Increased risks
Systematic overview of the data will reveal that the risk of Vioxx is approximately 1.5 to 2.0 fold higher
- Califf
But if you look at the VIGOR trial--patients with heart disease who took Vioxx--you'll see the cardiovascular risk was 4.9-fold higher
- Topol
VIOXX: Vigorous data
"I'm talking about the largest trial ever done with the drug."
Signal with Advil is considerably less than the signal we saw with Vioxx over three years ago
Topol
VIOXX: Agreement
Agree that a direct cardiovascular outcome trial should have been done with Vioxx
For other drugs where there is a signal, the question must be addressed with a cardiovascular outcomes trial
FDA and Merck failed to address the issue while tens of millions of people knowingly took the drug
Key issues
Direct-to-consumer advertising
"What man can watch television now and not think that he has erectile dysfunction?"
- Topol
"What about the case of statins, where doctors only recommend them to about a quarter of people who should be on them?"
- Califf
DTC Advertising
Direct-to-consumer advertising caveats
Only for drugs that promote survival and prevent life-threatening illnesses
Not for drugs that treat conditions like arthritis and erectile dysfunction
Topol
DTC Advertising
Direct-to-consumer advertising caveats
Only for drugs with outcome studies that demonstrated improved survival or prevent life-threatening complications
Drugs that enhance quality of life only when proven safe
Califf
What about the doctors?
Why are doctors not able to get the data?
Immense impact of the pharmaceutical industry
Need for congressional review to find out what we can learn from the Vioxx withdrawal
Doctors need to see the data before they write a prescription
VIOXX: Mixed results
THUMBS-UP
"I give thumbs-up to Merck for withdrawing the drug last week. That's great."
THUMBS-DOWN
"On the other, I give thumbs-down, and I give multiple thumbs-down to the FDA, for having taken so long to get to this critical juncture."
Topol
Need for long-term studies
Final statement
Drugs should enter the market where they currently are, but with a warning that the complete safety data are not yet known
For drugs given chronically, there is a need for long-term, randomized clinical trials
Califf
What happens next?
Practical applications
For patients with chronic joint pain that meets the criteria for NSAIDs, the best bet would be naproxen, based on the TARGET data
It is also recommended that a generic proton-pump inhibitor be prescribed for patients at significant risk of GI bleeding