Shock and pain after rofecoxib

Risk-benefit profile for a drug and the societal need and desire for new drugs should determine the regulatory approval, as no drug is fully safe, says Dr Krishan Maggon

The withdrawal of rofecoxib (Vioxx) by Merck has cast a dark shadow over the research-based pharmaceutical industry which is driven by unmet medical need and raised questions about the current drug approval system and marketing of drugs in USA and Europe. Drug stocks of research based companies have lost 5-10 per cent of the market value (total loss $45-50 billion) and the intense media coverage has continued with Vioxx related stories making daily headlines. On September 30, 2004, Merck withdrew the drug from 80 countries where it was marketed.

Merck has acted responsibly and in the best interest of patients by withdrawing rofecoxib and its action has been praised by FDA and some industry experts. If there was a way to identify and exclude patients at higher risks to CV with rofecoxib, it could have stayed on the market. There is no advantage in keeping it in the market for short term use due to its high cost. However, its critics have termed the action as too little and too late and its inaction to address the CV risk earlier.

The APPROVE study was to show the beneficial effect of three year treatment with 25 mg of rofecoxib in prevention of potentially cancerous colon polyps. The double blind placebo controlled trial enrolled 2600 patients and after 18 months of treatment, 25 patients in the placebo group and 45 in the rofecoxib group had a serious thromboembolic and vascular events.

The safety monitoring board and Merck terminated the study. Thus 20 patients out of 1300 or 13 out of 1000 had increased CV risk due to chronic rofecoxib treatment for 18 months. Out of the 100 million patients using rofecoxib, assuming that only 5-10 million were regular long term user, then 1300 patients out of every million regular users of rofecoxib were probably exposed to increased risk.

In the VIGOR trial in 8076 patients, 50 mg of rofecoxib reduced the incidence of ulcers in patients by half as compared to 500 mg of naproxen for first year. However the incidence of myocardial infarction increased fivefold in the rofecoxib group. Merck argued that naproxen was cardioprotective and reduced the incidence of MI and FDA/EMEA accepted this rationale.

Merck studied rofecoxib in 28,000 patients in randomised controlled clinical trials that included patients at higher risk for cardiovascular disease. Results of these clinical studies showed no increased risk of cardiovascular events with rofecoxib. Rofecoxib was the only CycloOxygenase (Cox)-2 inhibitor in the market without the standard NSAID warning of increased GI toxicity in the package insert and labelling.

Merck has been the dominant R&D-driven and most admired company during the 1980s and 1990s and had one of the highest market cap in the industry. During the past two years, it has lost 40 per cent of the market value including the loss of 27 per cent of market value after rofecoxib news. Thus a sale loss of $2.5 billion resulted in a loss of $27 billion market value in one day.

Several analysts had downgraded the stock due to late termination of two R&D projects in phase III last year, rofecoxib withdrawal, product injury and litigations costs and the patent expiry of Zocor in 2006. Merck with its current market value at $68 billion has now become a takeover target by a European or Japanese company or corporate raiders due to a weak dollar. Initially impression that rofecoxib patients will switch to celecoxib and benefit Pfizer did not increase its share price due to concerns about the class cardiotoxicity of all Cox-2 inhibitors.

Several class action lawsuits have been filed in courts. Provisions of $15 billion were made by Wyeth, Pfizer and Bayer involved in previous withdrawals like phen-fen (Redux), glitazone (Rezulin) and cerivastatin (Baycol) respectively. Analysts have provided estimates of $5-10 billion for rofecoxib litigation, which may increase if any internal company document shows prior awareness and internal discussion of the problem. As happens with all drug withdrawals, regulatory agencies start review of the Cox-2 inhibitors to rule out a class effect, ask for additional safety data for marketed drugs and add additional regulatory requirements for drugs in development.

This will result in longer time and increased costs to market drugs of this class. FDA and the European Medicines Agency EMEA have announced review of all COX II inhibitors and their role in increasing the risk of heart attack and stroke. In Europe, EMEA after a two year review of data had just cleared celecoxib, valdecoxib and parecoxib of increased CV risk in June 2004.

In the USA, NSAID induced ulcers and GI bleeding is linked to deaths of 16,000 patients every year. Thus there is a medical need to develop new safe and effective analgesic and anti-inflammatory agents. Discovery of the CycloOxygenase-2 (Cox-1 and 2) in 1990 and its role in inflammation, and that of Cox-1 in GI protection, selective Cox-2 inhibitors were developed to provide pain relief without GI toxicity. However, the Cox-2 has cardioprotective role in and prevents clot formation. The Cox-2 inhibitors were labelled as “super aspirin” by the media and their high pricing makes them the Rolls Royce of analgesics.

The first two selective Cox-2 inhibitors celecoxib (Celebrex) by Pfizer and rofecoxib (Vioxx) Merck were approved in USA and Europe in 1999 and the third valdecoxib (Bextra) Pfizer in 2001. Parecoxib (Dynastat) is the prodrug of valdecoxib for injections in Europe marketed by Pfizer in Europe. Two newer Cox-2 inhibitors etoricoxib (Arcoxia) of Merck and lumiracoxib (Prexige) of Novartis are approved in 47 and 16 countries mainly in Europe and awaiting FDA approval. Japan has not yet approved any Cox-2 inhibitor.

Several other Cox-2 inhibitors are in development and in clinical trials. The total global sales of Cox-2 inhibitors were $8 billion in 2003, USA accounted for $6 billion and sales of celecoxib and rofecoxib were $1.9 and $2.5 billion respectively. In the first half of 2004, global sales of Cox-2 inhibitors were celecoxib $1.5 billion, rofecoxib $1.3 billion, valdecoxib $545 million and etoricoxib $92 million.

Worldwide 80-100 million patients each have used celecoxib and rofecoxib respectively and 40 million in USA. When medicines are used on such a large scale in millions of patients for long term, very rare latent delayed serious adverse reactions appear. An increased risk in any type of toxicity even in a fraction of a percentage translates into thousands of affected patients.

To expand and protect the market share and dominance, several Cox-2 inhibitors are in clinical trials for additional indications like prevention of cancer and Alzheimer’s disease. There is a place for Cox-2 inhibitors for patients with increased risk to GI toxicity with NSAIDs. However, a new analgesic limited to only patients with high risk GI toxicity is unlikely to recover its R&D cost. Under the present system, more than half of all drugs introduced have a new side effect discovered during marketing. It will kill the R&D if regulatory requirements take 15-20 years to ensure safety and require clinical data in 100,000 patients and 3-5 years of drug treatment and follow up. Risk-benefit profile for a drug and the societal need and desire for new drugs should determine the regulatory approval, as no drug is fully safe.