In the dark

The best advice available today (as you read this now in March 2005) regarding the safety of COX-2 inhibitors is to take the lowest effective dose for the shortest possible period of time (if you must use them at all) because there are proven dangerous cardiovascular side effects, including stroke and heart attack, linked to the use of any and all of them.

This counsel, which is more accurately a set of imperative safety restrictions, comes direct from the European Medicines Agency (EMEA) and also warns that COX-2s are unsuitable for use in patients with coronary heart disease or a history of stroke. Prescribers are also warned to exercise acute caution when prescribing COX-2s for patients who are at risk of heart disease, plus those with peripheral arterial disease.

In America, the Food and Drug Administration (FDA) has just concluded a three-day hearing regarding the safety of the entire class. Key discussions focused on a potential ban of direct-to-consumer (DTC) advertising for COX-2s, black box warnings on labelling and a MedGuide for consumers, which would make clear the cardiovascular risks.

The FDA heard that heavy dosages pose a greater risk of heart attack than does diabetes, smoking or even high blood pressure. In fact, the risk from low doses is likely to be only marginally lower than these other, high-profile, risk factors, according to outspoken FDA scientist, Dr David Graham, who published his eye-opening study results in the Lancet in January this year. Dr Graham is the man who enlightened the world to the fact that 56,000 people may have died because they took Merck & Co's COX-2 inhibitor, Vioxx (now withdrawn).

To put into context the severity of this safety issue on a global scale, you need only make reference to another shocking blow to human health that occurred in recent months. Based on Dr Graham's extrapolation of his study findings, approximately 10,000 more people have died since 1999 as a direct result of taking Vioxx than were killed by the 2004 Boxing Day Asian tsunami in Sri Lanka, Thailand and on India's south-east coast put together. You could twice fill Cardiff's Millennium Stadium with Vioxx-takers who have not died, yet now suffer from cardiovascular illness because of the side effects of the medicine.

Muck up
It's clearly appallingly serious and unless you've been slumbering in the closed Kingdom of Bhutan, or living in a media-free protection bunker for six months, you will already be well up on the risks now officially attributed to COX-2 inhibitors - touted not that long ago as breakthrough targeted painkillers, don't forget.

However, despite everything that has happened, the general sentiment beginning to surface in most quarters it that COX-2s will probably stay - or, in the case of Vioxx, be brought back - for the plain and simple reason that for some patients the benefits of these drugs outweigh the risks.

Indeed, the EMEA's impositions on the use of COX-2s represent its holding position, with the outcome of a full, conclusive review on the safety of the entire class expected in April. When Pharmaceutical Marketing went to press, the FDA was still working on its final official recommendations, and the results should be made available presently.

Stepping back to behold the full scale of this problem, it is no wonder that 60 seconds after Vioxx' withdrawal back in September 2004 one question started to burn a hole in countless consciences: 'Whose dog's dinner of a job has allowed this to occur?'

Which group of persons is responsible, to whatever n'th degree, of (not) acting to prevent a COX-2 catastrophe that has touched the lives of almost three times the number of people who died in London's 17^th Century bubonic plague scourge?

You could suggest that it's because the regulators were insufficiently rigorous, says Jane Tadman, of the UK's Arthritis Research Campaign. There have been trials going back as far as 2000 that indicated patients on Vioxx were at a higher risk than those who were not. So you have to ask, why did it remain on the market for a further four years? Why did it continue to be sold in vast quantities, making vast amounts of money for Merck? It's shocking.

Speak out 
Was it really a case of slovenly regulators unable to reliably assess drug safety? Unethical pharmaceutical companies knowingly marketing unsafe drugs? Apaternalistic, nanny-state modern-day ethos and the resistance to accept that drugs come with side effects? A combination, or maybe just an accident?

There may well be a clear answer in the end, but right now it's up for debate.

Think back briefly to when the experts first told us that mad cow disease could, in a fashion, jump from four-legged bovines to bipedal Homo sapiens. Plenty of us would have felt shocked for a good minute and a half - at least until the news programme moved on to the next item, or the newspaper page was turned, to reveal how some of us will suffer from obesity in 50 years.

The possibility for vCJD to run rampant through the human population was known. Yet, as there was, in the early days, little sure-fire evidence apparent to the public to highlight our potential encroaching neurological desolation, we worried briefly about it, before ignoring it - or putting it in the same room in our minds that's reserved for the kids in Africa when Comic Relief is off the telly. We do care, but today there's the dinner to cook and the car to insure, so we'll think about it another time.

Yet, suddenly, people were dying from it. vCJD was leaping around like a rabid kangeroo. It was all over the news on television, radio and stole all the front-page headlines in the papers. People were boycotting butchers' shops left, right and centre, and vegetarianism had never enjoyed such popularity. Even the hospitals weren't safe as you might have been infected from contaminated surgical instruments.

Only then were we scared of being struck down by some awful, incurable blow to our health. Why didn't anyone tell us about the risks? [Well, actually they did]. Yes, but, why weren't we properly informed - before it was too late?

That's the $675m question; which is also the figure that's been reported Merck & Co has nestled away to later give to lawyers and generally blow on generating as watertight a case as it can to defend itself against writs from any number of the potential 140,000 patients who could have developed coronary heart disease as a result of taking Vioxx.

Aside from anecdotal quarrelling, no real blame has been apportioned. Yet, the moves to change the regulations, as well as boost the power and involvement of the regulators, surely points to one area where, given recent events, it was no longer satisfactory to continue doing things as before.

The ability of the regulatory authorities to both approve new medicines for marketing and track their safety and efficacy after launch came under fire numerous times over the last 12 months - also for SSRIs, remember. One might allude, then, that the gravity of the whole furore was underlined by the FDA's moves to create an independent Drug Safety Oversight Board, establish Dr Lester Crawford as the new permanent commissioner, as well as announce a budget increase for surveillance.

That said, the pharma companies are not getting off lightly either.

~

COX-2 promotion clampdown 
If you read across the media, it looks somewhat set in stone that the firms that make and market COX-2 inhibitors, including Merck, Pfizer, Boehringer Ingelheim and Novartis among others, are in for an expensive day in court followed by years of distrust from patients.

But this drug class has not been consigned to the rubbish bin yet. Let's not forget that these can be highly effective medicines in treating a painful and debilitating disease.

In spite of the EMEA and FDA's sobering probes into the safety of these popular and widely administered drugs, the latest industry chat suggests that it may be acceptable for firms to continue selling them, albeit in a more controlled and targeted fashion.

No drug is totally safe, but we need to remember that people rely on drugs to treat illnesses and COX-2s are an important option, says Laura Schoen, head of Weber Shandwick's global healthcare division. There are other treatment options, including over-the-counter medications, such as Tylenol, but for some patients living with pain, who have not responded to other drugs or who have gastrointestinal problems, COX-2s are a very valuable alternative.

Pfizer's Celebrex and Bextra products and Merck's Vioxx received the all-clear from a 32-member FDA advisory panel in late February for continued use, despite the fact that all three drugs have been acknowledged to increase the risk of heart attacks and strokes.

DTC ban dismissed 
The prospect of an all-out ban on DTC advertising in the US for these products was considered, and then rejected by 17 votes to 15. The sentiment of the marginal majority is that these drugs can continue to be marketed, provided that pharma adheres to a number of new caveats.

The FDA advisory panel still recommended that some DTC activity be made illegal and called for bespoke black box warnings over the cardiovascular risks. Black box warnings are designed to provide healthcare professionals with a clear understanding of potential serious medical complications, to help them minimise the risks.

It make options very limited with regard to marketing and communications, and restricts promotional activities enormously, notes Schoen. Products with black box warnings [in the US] have to focus mostly on physician communications.

As the UK's Medical Healthcare products Regulatory Agency (MHRA) announces a clampdown on 'poor' and 'misleading' advertising, the debate over the ethicality of DTC in the US rolls on. Pfizer has already voluntarily pulled its COX-2 DTCa.

Healthcare programmes discussing treatment alternatives should always be clear on risk versus benefit. [Yet], I believe that some misconceptions regarding safety may have been communicated through the tone of some DTC advertising. The medium, which requires fast, colourful, attention-grabbing messages, makes it easier for consumers to ignore the warnings, adds Schoen. Healthcare is a serious business and we should not forget it.

MHRA chief executive, Professor Kent Woods, adds that while in the UK most medicines advertising is responsible and of high quality, even a small number of poor adverts can have public health consequences that mean swift action is necessary.

Announcing the UK agency's new tougher stance (after a complete overhaul) on the way in which it regulates medicines advertising, which is outlined in its new Blue Guide publication, he continues: As with regulators worldwide, we cannot pre-vet every piece of advertising material, but by effectively targeting problem areas we can prevent potentially misleading adverts reaching healthcare professionals, or the public. That's why it's important [to] deal not only with compliance with the letter of the law, but with its spirit.

Schoen says: I expect to see [in the US] more direct-to-patient communications, including town hall meetings and other activities that educate patients who have already been prescribed an arthritis drug. In my opinion, you will see less DTC communications and the tone of the information will be more balanced, focusing on a risk versus benefit discussion that requires involvement of the physician.

Vioxx relaunch... 
The terrible beauty of these drugs, according to COX-2 expert and researcher at the University of Pennsylvania Dr Garret FitzGerald, is how predictably they reveal their side effect profiles, leading to the possibility of selecting patients who can take them - rather like personalised medicine can be matched to recipients. Many patients will still be able to experience pain relief, and with a lower GI risk than older non-steroidal anti-inflammatories.

Merck says it has new data to show that while Vioxx may well have something of a unique profile in the class, the cardiovascular malevolence is not the reason for it.

In a statement, it explained: `It is not clear that the cardiovascular risk observed in [the] APPROVe [trial] makes Vioxx unique in the class. We do know that Vioxx offers unique benefits among coxibs marketed in the US' - specifically that it is the only one not contraindicated in patients with sulfonamide allergies, the only one to be proven in reducing GI risks versus naproxen, and the only such drug approved for use in children - potentially a new target focus for Merck.

Of course, there is no guarantee that the FDA will follow the panel's recommendation to allow Vioxx' return, and even if it did there would very likely be heavy labelling changes. The label would almost certainly carry black box warnings and may also restrict its use to the 12.5mg dose and as a `last-resort' treatment option, say market analysts Wood Mackenzie.

Merck may take the initiative, perhaps surrendering all arthritis claims (which requires higher dosage and chronic administration) and repositioning Vioxx for acute pain instead. This narrower indication would limit sales potential, but would expedite its return to the market - which is of far greater significance.

For the time being however, the beleaguered firm remains tight-lipped: `Merck has not altered its position on the voluntary withdrawal of Vioxx. 'Anything further would be speculation.'

The Author
Robin Skelding is assistant editor, Pharmaceutical Marketing magazine