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

Topic VIOXX WITHDRAWAL Merck & Co takes the selective COX-2 inhibitor rofecoxib off worldwide market

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VIOXX: Risk and benefit Rofecoxib withdrawn September 30, 2004 "This is just one of many types of drugs that are given to people for years with absolutely no understanding of what the chronic balance of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 Topol 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 Califf 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 THUMBS-DOWN Topol "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