"Country Doctor"
JOIN CDA NEWS INDEX POLITICS DISPENSING EDUCATION FEATURES BOOKS SMALL ADS GP FEES LIGHT BITES LINKS FEEDBACK
|
|
DATAMONITOR PRESS RELEASE Will FDA’s axe fall on COX-2s? INDPENDENT ANALYST COMMENT Duncan Emerson, Datamonitor Senior Healthcare analyst The recent news that Merck & Co voluntarily withdrew their blockbuster COX-2 Vioxx (rofecoxib) from the market due to concerns over cardiovascular safety sent shock-waves through the pharmaceutical sector. Merck’s decision stemmed from a large clinical trial that showed patients taking Vioxx had a significantly higher relative risk of suffering heart attacks and stroke compared to patients taking placebo. Celebrex also causing concern In addition to this, Pfizer has revealed that patients in their Adenoma Prevention with Celebrex (APC) trial, (in which patients were taking 400 to 800 mg of Celebrex daily), had a 2.5 times higher risk of experiencing major fatal or non-fatal cardiovascular events compared to patients taking a placebo. However data from another Pfizer-sponsored study, Prevention of Spontaneous Adenomatous Polyps (PreSAP) in which patients were taking 400 mg of Celebrex daily, revealed no increase in relative risk compared to placebo, suggesting a dose effect. In a recent interview with UK newspaper the Financial Times, Dr Lester Crawford, Acting Commissioner of the US Food & Drug Administration (FDA), is quoted as saying “we are looking at all the COX-2s and will make an announcement shortly. All regulatory options are open…including withdrawal...I have serious concerns about the COX-2s as a class.” In response, Dr Hank McKinnell, CEO of Pfizer, has been quoted as saying that Pfizer are “leaving Celebrex on the market because it is an appropriate option for many, many patients”, a move that many are seeing as a serious strategic error by Pfizer, as keeping Celebrex on the market could increase legal, financial and reputational costs for the company in the future. Due to safety concerns, the FDA has decided to collect and analyze all available information from the most recent studies of COX-2 selective and nonselective NSAID products to determine whether additional regulatory action is needed. With a meeting planned in February 2005, an FDA advisory committee will provide a full public discussion of these issues and determine whether or not COX-2s should continue to be marketed. Current COX-2 Market In 2003 the global COX-2 market, including sales of Mobic (meloxicam), was worth approximately $5.6 billion. Vioxx was the market leader, recording sales of $2,533m, closely followed by Celebrex which recorded sales of $1,833m, and Bextra (valdecoxib) which recorded sales of $687m. he area in which the specific COX-2 inhibitors, such as Celebrex, have the biggest advantage over the traditional non-steroidal anti-inflammatory drugs (NSAIDs), such as Voltaren (diclofenac) and naproxen, is gastrointestinal (GI) toxicity. For traditional NSAIDs, this toxicity manifests itself as gastrointestinal symptoms (e.g. bloating, therapeutic approach to treating patients with rheumatoid arthritis (RA) and osteoarthritis (OA). However it is interesting to note that concerns about the cardiovascular safety of the COX-2s were raised back in 2001 when a study showed a potential increase in cardiovascular event rates for the presently available COX-2s, namely Celebrex and Vioxx*. n addition to these cardiovascular issues, the COX-2s also suffer from other weaknesses that garner little media attention due to a combination of clever marketing and the important GI benefits when compared to traditional NSAIDs. Specifically, a study in 1999 showed that in RA patients, celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac**, despite celecoxib having a lower frequency of gastrointestinal adverse events and better tolerability. In essence, diclofenac is as good as celecoxib in controlling the pain associated with RA, which is unsurprising when you consider their mechanism of action. Two scenarios: 1) the FDA review the COX-2s and do not advise on the withdrawal of the class Without exception, this would be good news for all companies who currently market and are developing COX-2 inhibitors, namely Pfizer, Novartis, Merck and GlaxoSmithKline. However Datamonitor predicts that sales of all COX-2s will still be adversely affected as the level of uncertainty regarding the class will still linger on in patient’s and physician’s minds. Quoted on the US-based HealthDay website***, Dr Martin Fendrick, Professor of Medicine at the University of Michigan, said “…even if these drugs do remain on the market, given the availability of other therapies that provide equivalent pain relief and, if needed, equal levels of stomach protection, it would be extremely prudent to avoid these drugs until we know for sure – and I emphasize for sure – about their cardiovascular safety.” However companies that market COX-2s could see this as an opportunity to prove to their customers that they take these issues very seriously and make sure any long-term safety studies requested by the FDA for all future medications are well designed, answer the key questions about cardiovascular safety, and that the data is made available to the general public. In the meantime, Datamonitor predicts that when the European Medicine’s Agency (EMEA) and the FDA meet in January 2005 and February 2005, respectively, to review the safety of COX-2 selective and nonselective NSAID products, they will recommend a “black-box” warning be placed on the labeling of these products to inform patients of the potential cardiovascular risks associated with taking high doses. How this will effect future sales of COX-2s will depend greatly on the severity of the warning. 2) the FDA review the COX-2s and advise on the withdrawal of the class This would be an unprecedented move on the part of the FDA because, as far as Datamonitor is aware, there are no historic examples of when a whole class of medicines has been withdrawn from the market. he beneficiaries of this situation will likely be companies that currently market alternatives to the COX-2s, such as Boehringer-Ingelheim and Abbott, and generic companies that manufacture a range of older NSAIDs such as ibuprofen and naproxen. On the back of increased demand for the more traditional NSAIDs, manufacturers of anti-ulcerants may also see an increase in demand for their products. Despite this confusion, Datamonitor does not predict that the COX-2s will be withdrawn. Upon closer inspection, much of the data that has lead to many of the announcements regarding cardiovascular safety have come from studies in which the dose being taken by the patient is far in excess of the clinically effective dose in RA and OA patients, a major market for the COX-2s. For example, patients in the APC study, who were shown to have an increase risk of experiencing major cardiovascular events were taking between 400 and 800 mgs per day, while the approved dose for Celebrex is between 100 and 400 mgs per day. In addition, Pfizer announced on its website on December 21, 2004, that the National Institutes of Health (NIH) in the US has reported in an Alzheimer’s Disease Prevention Study (ADAPT) that there was no increased cardiovascular risk seen in elderly patients taking Celebrex at doses of 400 mgs daily for up to three years, adding more evidence to a possible dose effect. However, it is interesting to note that the ADAPT trial has been halted by the NIH due to concerns about the cardiovascular safety of naproxen, a more traditional NSAID****, Main threat to patient The main threat in this situation is to the patient. Regardless of what the FDA decides, confidence in the COX-2s has now been dented, possibly irrevocably. Several high-profile physicians have been quoted saying that they can no longer prescribe COX-2s to their patients due to the uncertainty regarding their cardiovascular safety. Despite this, Datamonitor believes that the level of anxiety that has been witnessed regarding the COX-2s and subsequent threats of “class withdrawal” from the FDA are somewhat unwarranted. In patient populations where the products are used according to their labeling they provide safe and effective relief from the symptoms of both RA and OA. However, the use of COX-2s at high doses should not be encouraged. It seems that on the basis of data released by Pfizer regarding Celebrex there is a dose effect, with a higher risk of cardiovascular events associated with high doses of the product. Further, more extensive long-term safety studies on all COX-2s are advised.
(8/1/05) |