Will FDA's axe fall on COX-2s?

The pharmaceutical sector has been on the receiving end of multiple body blows to many of its bestselling drugs that have not only raised questions about patient safety but also issues concerning clinical practice and the interpretation of trial data.

In response to these accusations, pharmaceutical companies worldwide have agreed to reveal the results of clinical trial drug data. Major industry players including Glaxosmithkline, Pfizer and Novartis are to publicise their trial results on a voluntary database, available online from 1 July this year, with some trials included on the register by mid-September.

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.

In a similar vein, Pfizer revealed 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.

The furore that has sent shockwaves throughout the industry has placed the spotlight on the FDA like never before. Concerns about the cardiovascular safety of the COX-2s were raised as early as in 2001 when a study showed a potential increase in cardiovascular event rates for the presently available COX-2s, namely Celebrex and Vioxx.

In a recent interview with UK newspaper the Financial Times, Dr Lester Crawford, Acting Commissioner of the FDA, was 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."​

Due to safety concerns, the FDA has decided to collect and analyse all available information from the most recent studies of COX-2 selective and nonselective non steroidal anti-inflammatory drug (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.

In an act of faith over its product, Pfizer is leaving Celebrex on the market because it thinks it is an appropriate option for many patients, a move that many are seeing as a serious strategic error. In keeping Celebrex on the market it could increase legal, financial and reputational costs for the company in the future.

The FDA's decision is likely to have a significant impact on the future of the COX-2 class as a viable drug treatment in ailments such as arthritis and pain relief. In addition the fallout as a result of these revelations means sales are unlikely to reach the sales seen during the height of their popularity.

Should the FDA review the COX-2s and not advise on the withdrawal of the class would undoubtedly favour companies that are developing new COX-2 inhibitors, namely Pfizer, Novartis, Merck and GlaxoSmithKline. However, according to the report's authors, Datamonitor, the questions raised over their cardiovacular safety will continue to linger on in the minds of patients and doctors.

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.

Datamonitor predicts that when advisors to the European Medicines Agency (EMEA) and the FDA meet in January and February , respectively, to review the safety of COX-2 selective and nonselective NSAID products, they will recommend a black-box warning be placed on the labelling of these products to inform patients of the potential cardiovascular risks associated with taking high doses. How this will affect future sales of COX-2s will depend greatly on the severity of the warning.

In 2003 the global COX-2 inhibitor market, including related product Mobic (meloxicam) sold by Boehringer Ingelheim and Abbott in the US, was worth approximately $5.6 billion (€4.2 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.

COX-2 inhibitors' biggest advantage over non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac and naproxen, is gastrointestinal (GI) toxicity. For NSAIDs, this toxicity manifests itself as gastrointestinal symptoms (e.g. bloating, flatus), ulceration, haemorrhage and even death, and have been partly responsible for the change in therapeutic approach to treating patients with rheumatoid arthritis (RA) and osteoarthritis (OA).

If however, the FDA reviews the COX-2s and advise on the withdrawal of the class, it would be a first because as there have been no historic examples of a whole class of medicines being withdrawn from the market.

The 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. The report expected the FDA not to withdraw the COX-2s as much of the data that 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.

Regardless of what the FDA decides, confidence in the COX-2s has now been dented. Despite this, Datamonitor said it believes the level of anxiety that has been witnessed regarding the COX-2s and subsequent threats of class withdrawal from the FDA are somewhat unwarranted.