Testimony of Sidney M. Wolfe, M.D.
Director Health Research Group of Public Citizen
Before FDA Arthritis Advisory Committee
Thank you for the opportunity of appearing before this advisory committee. I have no financial conflicts of interest.
The consideration of approval of etoricoxib involves three outcome variables: Relative efficacy for osteoarthritis, relative cardiovascular risk and relative gastrointestinal toxicity (serious complications such as perforation, bleeding and obstruction).
As shown in the first slide, the first consideration, relative efficacy, is easiest to discuss because Merck admits, in its conclusions, that “Once daily treatment with etoricoxib 60 mg shows comparable efficacy to naproxen 1000 mg (500 mg 2 times daily) and to diclofenac 150 mg (50 mg 3 times daily) in patients with OA.”
For the second variable, relative cardiovascular risk, the paper in the New England Journal of Medicine in January of this year by Bruce Psaty and Noel Weiss concerning the choice of comparator drugs is extremely important. They are concerned, as shown in this slide, that “Sponsors need incentives to evaluate drugs in a manner that highlights potential clinical value, not marketing potential.”
They point out that the COX-2 inhibitors are associated with an increased risk of vascular events. But they illustrate the importance of the issue of the choice of comparator by reviewing clinical trials of naproxen and, separately, those of diclofenac. They state that “These data suggest that as compared with naproxen, diclofenac may increase the risk of vascular events by about 70%.”
One source of their information is a classic meta-analysis involving COX-2 drugs published in the British Medical Journal last year. This slide, taken from that paper, shows that the overall statistically significantly increased rate of vascular events for the 121 trials in which various COX-2 drugs were compared with a placebo was 1.86 times higher with the COX-2 drugs.
The next slide shows comparisons between COX-2 drugs and older NSAIDs. As can be seen, when COX-2 drugs are compared with naproxen, the earlier “problem” with Vioxx shows up. The aggregate statistically significant increased risk with the COX-2 drugs for myocardial infarctions is 2.04 times that of naproxen. When the comparison is with diclofenac or other non-naproxen NSAIDs, the COX-2 risk decreases to 1.2 and is no longer statistically significant.
Yet another way of examining the importance of the comparator drug that is chosen is reviewed in last month’s American Heart Association recommendations concerning the use drugs to relieve pain. As shown in the slide, they found that, compared to a placebo, the cardiovascular risk of naproxen was 0.92, not significantly different from 1. But for diclofenac, the increased cardiovascular risk was a significant 1.63 times placebo. These recommendations included naproxen as the drug of choice for anyone with cardiovascular risk factors or cardiovascular disease and recommended, for such people, that COX-2 drugs are a last choice.
The following slide, also from the AHA paper, compares the odds of vascular events in randomized controlled trials of COX-2 drugs in which naproxen is the comparator with those in which another non-naproxen NSAID, primarily diclofenac is the comparator to the COX-2 inhibitor. Whereas the relative risk of naproxen, compared to the COX-2 drug, was 0.64, the relative risk of the non-naproxen NSAIDs was 1.14, not significantly different from the COX-2 drugs.
It is thus clear, from all of these analyses, that the choice of a comparator, especially from the perspective of cardiovascular risk, makes a world of difference.
Although Merck has said that the choice of diclofenac as the comparator for etoricoxib for the MEDAL study was strongly related to the fact that diclofenac is the most prescribed NSAID in the rest of the world, this rings somewhat hollow since it is not nearly the most prescribed NSAID in the US, where approval is being sought.
A look at earlier (pre-MEDAL) studies in which etoricoxib was compared to naproxen suggests another reason why Merck might have chosen diclofenac this time. The following slides are from an FDA presentation at the meeting of this committee in February, 2005.
The first slide shows that for all of the studies submitted as part of the NDA several years ago, etoricoxib had a much more unfavorable comparison with naproxen than with non-naproxen NSAIDs. Thrombotic cardiovascular deaths occurred at a rate of 0.12 with naproxen but 0.22 with etoricoxib.
This is further illustrated on the next slide in which the relative risk of confirmed thrombotic CV serious adverse events with etoricoxib is 1.70 times higher than with naproxen but only 0.83 times as high compared with non-naproxen NSAIDs.
The next slide shows that categories within the thrombotic cardiac events included MI, fatal; MI, sudden death; and unstable angina as well as strokes. It can be seen that the greatest numbers of events were MIs and strokes.
The earlier EDGE study also used a comparison with diclofenac and, as seen in the next slide, found a marked increase (more than two-fold) in significant hypertension in patients using etoricoxib.
The same increased cardiac risk, even in comparison to diclofenac, can be seen in the next slide in which there is more than a two-fold increase in heart failure in patients getting etoricoxib.
The FDA summary of this review several years ago is of particular interest because of the parallel it draws between etoricoxib and rofecoxib (Vioxx).
Confirming the “wisdom” of Merck’s choice of diclofenac as the comparator for the MEDAL study are the results as shown in the FDA presentation for this meeting in the slide below. As predicted from comparisons between diclofenac, with its own increased cardiac risk, and other COX-2 inhibitors, there is no significant difference in the confirmed APTC endpoint between etoricoxib and diclofenac.
Even though the increase in thrombotic events did not show up because diclofenac was chosen as the comparator, there was clearly an increase in patients discontinuing etoricoxib because of hypertension-related adverse events as shown in the following slide. At either the 60 or 90 milligram dose of etoricoxib, significantly more patients had to discontinue the drug.
Finally, in the case of serious gastrointestinal toxicity, there was no benefit to etoricoxib compared with diclofenac as shown in the next slide. The rate of serious confirmed G-I events with etoricoxib was 0.30 per 100 patient years vs. 0.32 with diclofenac, not significantly different.
The next slide, presented at the AAC meeting in February, 2005, shows the range of COX selectivity for various NSAIDs. It is clear that both rofecoxib and etoricoxib are at the far end of the spectrum of increased COX-2 selectivity and that diclofenac shows much more COX-2 selectivity than naproxen. Thus, the similarity in the cardio-toxic properties of rofecoxib and etoricoxib are not surprising. Nor is the fact that diclofenac is much more cardio-toxic than naproxen.
As can be seen in the next slide, the sulfone moiety S02CH3 is common to both rofecoxib and etoricoxib and might be related to the increased cardiac toxicity of both drugs.
In summary, Merck seems to by trying to have it both ways: Looking at naproxen studies, there is some GI advantage but significant cardiovascular disadvantage (as was the case with Vioxx). Looking at diclofenac studies, there is no cardiovascular difference but also no GI advantage as far as confirmed serious gastrointestinal complications.
If Vioxx were coming up for approval vs. naproxen (Vigor study) would it get approved?
If the answer is no, then why should the similarly dangerous offspring of Vioxx, etoricoxib (Arcoxia), get approved just because its cardiovascular risks are no greater than an older NSAID with known cardiovascular risks (diclofenac) as in the MEDAL study when, like its parent Vioxx, it has been previously shown to have increased cardiac risks in randomized controlled trials in which it is compared to naproxen?
For etoricoxib, there is no evidence of a benefit in efficacy compared to older NSAIDs, nor evidence of a benefit in terms of reduced serious G-I complications such as perforations, ulcers or bleeding compared to older NSAIDS. Thus, in the face of seriously increased cardiovascular risk compared to drugs such as naproxen, how can the approval of etoricoxib and the large numbers of preventable, life-threatening cardiovascular adverse reactions be justified?
If you were prescribing etoricoxib to a patient with osteoarthritis, on the basis of what evidence would you inform them that the significantly increased risk of a heart attack or other cardiovascular events with this drug is outweighed by the increased benefits when there is no evidence that there are any such benefits unique to etoricoxib, as far as increased efficacy or reduced serious gastrointestinal adverse reactions? Since there is no basis for informing your patient of such a favorable risk/benefit ratio, there is no basis for recommending the approval of etoricoxib. Thousands, probably tens of thousands of patients have already had needless heart attacks because they took one of the marketed or previously marketed COX-2 drugs instead of clearly safer alternatives such as naproxen.
It is time to shut the door on further additions to this dangerous class of COX-2 inhibitor drugs. The idea that there may be certain patients, however unidentifiable they are, who might benefit from this drug is just not good enough as a basis for its approval. Such anecdotes often sufficed before 1962, when the FDA’s legal authority was finally expanded to include the requirement for evidence of effectiveness from randomized controlled trials. Only with this kind of information can an accurate assessment of benefits and risks be made.
Etoricoxib does not fulfill an “unmet need”, as required by the FDA, for any identifiable group of patients. The Merck discussion about “unmet need” for treating OA in their submission for this meeting merely describes how prevalent OA is, reviews the treatments. The company actually admits that for people with GI problems, the recommendation includes use of a traditional NSAID with a gastro protective agent (PPI or misoprostol) or a COX-2 inhibitor. No explanation is given as to why etoricoxib fills an unmet need.
In addition to strongly urging your committee and the FDA to reject Merck’s effort to approve etoricoxib in the U.S., I urge prompt removal of Arcoxia from the market in the 60+ countries where it is causing unacceptable risks to the hundreds of thousands of people using the drug.