Global Insight Perspective | |
Significance | The studies perforate the notion that the side-effects that resulted in the withdrawal of Vioxx in September 2004 were class-based among COX-2 inhibitors, as Celebrex (celecoxib; Pfizer (U.S.)) has been cleared. Instead, deeper—and more worrying—safety issues are beginning to emerge among general non-steroidal anti-inflammatory drugs (NSAIDs). |
Implications | These are post facto analyses, and will be heavily criticised as such by the industry. However, they will inevitably add fuel to the raging fire over the safety of painkillers. Unlike the "expression of concern" posted ahead of schedule by the New England Journal of Medicine (NEJM) in December 2005, the early timing of these two studies is linked to real public health issues that could result in a regulatory clampdown on diclofenac. |
Outlook | Ultimately, Global Insight does not envisage a product withdrawal for diclofenac, which is marketed by Swiss giant Novartis as Voltaren (10% sales growth in 2005, to US$161 million), although regulatory agencies around the world have already indicated that reviews will be put in place. Merck’s Vioxx defence will be hurt by the studies, but we have not changed our outlook that the litigation risks are manageable. |
The Saga Continues
The Journal of the American Medical Association (JAMA) yesterday published two studies regarding withdrawn COX-2 inhibitor Vioxx (rofecoxib; Merck & Co, U.S.)) and non-steroidal anti-inflammatory drug (NSAID) Voltaren (diclofenac; Novartis (Switzerland)). The results were published several weeks ahead of schedule, due to “the public health implications of the findings.”
The first study was conducted at Harvard Medical School, and analysed 114 clinical trials, involving 116,094 people; it focused the COX-2 inhibitors Vioxx, Celebrex (celecoxib; Pfizer (U.S.)), Bextra (valdecoxib; Pfizer), Dynastat (parecoxib; Pfizer), Arcoxia (etoricoxib; Merck) and Prexige (lumiracoxib; Novartis). Results were pooled via random-effects models and meta-regressions, and there were a total of 6,394 composite renal events (2,670 peripheral oedema, 3,489 hypertension, 235 renal dysfunction) and 286 arrhythmia events. There was no class effect.
- Instead, compared with controls, Vioxx was associated with an increased risk of arrhythmia (relative risk (RR): 2.90) and composite renal events (RR: 1.53); adverse renal effects increased with greater dose and duration. For all individual renal end points, rofecoxib was associated with an increased risk of peripheral oedema (RR: 1.43), hypertension (RR: 1.55) and renal dysfunction (RR: 2.31).
- By contrast, Celebrex was associated with a lower risk of both renal dysfunction (RR: 0.61)and hypertension (RR: 0.83) compared with controls. Other agents were not significantly associated with risk.
Full results of the study are available via the AMA's website.
The second study, conducted at the University of Newcastle (Australia), further confirmed Vioxx’s cardiac risks. Data were combined using a random-effects model, and a dose-related risk was evident with Vioxx, at an RR of 1.33 for 25 mg/d or less, and 2.19 with more than25 mg/d. Notably, the risk was elevated during the first month of treatment. Celebrex was not associated with an elevated risk of vascular occlusion, with a summary RR of 1.06. Among older non-selective drugs, diclofenac had the highest risk, with a summary RR of 1.40. The other drugs had RRs close to 1.0 (naproxen, 0.97; piroxicam, 1.06; ibuprofen, 1.07). The researchers also noted the lack of data on cardiovascular risk from Mobic (meloxicam; Boehringer Ingelheim (Germany)).The summary RR was 1.25, meaning that it may be no different from other relatively COX-2–selective drugs. They also found an elevated risk of cardiovascular events with indomethacin.
The full results of this study are also available through the AMA.
Outlook and Implications
The studies add more fuel to the fire over the safety of painkillers; following the withdrawal of Vioxx, the cardiac side-effect was considered in many quarters to be a class effect. However, what most analysts were not considering was that this effect may not just be confined to the COX-2 type of NSAIDs, but to general NSAIDs themselves. The data since September 2004 point in many different directions, and while Celebrex has been largely cleared by the JAMA studies, it is by no means out of the woods. However, the general conclusion appears to be that it differentiates itself from Vioxx in many important ways, and does not carry the same cardiac risks. Nonetheless, Celebrex has never been proven to have the stomach benefit long touted as the main marketing tool for coxibs.
Diclofenac, meanwhile, has been far less studied than Vioxx and Celebrex, and the JAMA studies point to an uncertain future, which may involve severe regulatory clampdowns. It has been thought to have a similar degree of selectivity to Celebrex, and its cardiac side-effects are now likely to require stringent monitoring—not just by Novartis, but also by generic manufacturers. By extension, the problems with diclofenac will also affect Merck, as the company used this drug in its trials for Arcoxia. Merck is hoping to receive U.S. approval for Arcoxia, but the FDA is unlikely to be impressed by comparisons with diclofenac as an assurance of etoricoxib’s safety. Merck had used naproxen for its early studies of Vioxx, and when the cardiac risk emerged, the drug-maker argued initially that it was due to naproxen’s cardioprotective effects; the JAMA studies pierce a further hole in this argument. The use of NSAIDs in clinical trials clearly needs to be carefully considered (Pfizer is in the midst of a major trial comparing Celebrex and NSAIDs).
However, the most damaging evidence for Merck is that the cardiac risks from Vioxx emerged after one month. This further invalidates the 18-month defence it has used in Vioxx trials to date. However, Merck has won trials without this defence, and we are not changing our outlook on Vioxx litigation. Instead, we see the likelihood of strong positives emerging in the near-term, and there is a chance that the Garza case, which Merck lost, may be thrown out due to the revelation of financial ties between a juror and the plaintiff. The recent award of US$50 million against Merck in a New Orleans court is also an important development, as this could serve as a marker for other federal trials.
Diclofenac, naproxen and Mobic have played a particularly important role in replacing Vioxx—and, to a lesser extent, Celebrex—in many markets. The diclofenac findings are therefore likely to have major repercussions, and Novartis’ Voltaren group of drugs, which grew by 8% to US$689 million last year, will suffer as a result. The two studies also raise the issue of both kidney and arrhythmia side-effects for Vioxx, which were previously less studied; Merck has claimed in the trials so far that Vioxx was not linked to arrhythmia. Its likelihood of returning to the market is clearly diminishing, although we do not foresee that it will significantly add to the case load; we believe most arrhythmia cases have already been filed, despite Merck’s contentions.