Jeremy Warner's Outlook: Big Pharma at mercy of regulatory backlash

The storm clouds gathered around the world's already besieged pharmaceuticals industry grow ever more threatening. Price and patent issues abound, while the number of class actions from compensation hungry lawyers for allegedly addictive or toxic medications is reaching mountainous proportions. With Senator John Kerry beginning to bounce back in the polls, there's every possibility that the industry could soon face de facto price controls in the world's largest pharmaceuticals market, or if not that a set of measures which would in the round be enormously deflationary for US drug prices.

Yet the biggest threat of all is the industry's own growing inability to produce new, cost effective drugs that don't poison their patients. This has combined with an ever more vigilant "safety first" approach among regulators to produce a sharp fall off in decent levels of drug discovery and approval. The number of approvals for genuinely new drugs has dropped markedly in recent years. The number of potentially promising new products failing at the final hurdle after huge amounts have already been spent on their development has also increased.

Who's to blame? In part, it's the science. Most of the low hanging fruit of drug discovery has already been plucked. Decent cures or medications are becoming more problematic as the industry begins to attack more complex and less well understood disease, in particular the cancers and dementias. Yet a growing aversion to risk is also a large part of the mischief.

Merck's sudden withdrawal of its best selling painkiller, Vioxx, after the discovery that it can increase propensity to heart attacks and stroke in long term users, will further accelerate the trend towards safety first. More evidence of the phenomenon comes from the US Food and Drug Administration's recent challenge to the safety of AstraZeneca's most exciting new compound in years, an anti-blood clotting drug called Exanta. Sir Tom McKillop, Astra's chief executive, is unrepentant about what he regards as a perfectly safe and effective drug. Yet he also concedes that Exanta is now quite unlikely ever to win approval in the US.

The worrying thing about the Vioxx episode is that it seems to be as much symptomatic of a failure in regulation as in Merck's own internal controls and trials. That's going to make the Food and Drug Administration (FDA) more wary and demanding still of new compounds. Doctors on both sides of the Atlantic have accused the industry and its regulators of a failure to protect people in the wake of the Vioxx affair, which is fast developing into one of the worst cases of unsafe drug approval in the industry's history.

THE SENSE of alarm surrounding the debacle has grown steadily over the past week. On Tuesday, the European Medicines Agency announced an urgent review of all similar painkillers in a move which in a matter of weeks could lead to their withdrawal from the European market. And on Thursday, coincidental articles in the The Lancet and the New England Journal of Medicine confirmed the stock market's worst fears by reporting that other painkillers in the same category as Vioxx, known as Cox 2 inhibitors, could pose the same risks.

Vioxx has meanwhile been confirmed as a much more high risk product than Merck was prepared to admit when it withdrew the drug a little over a week ago. Merck's legal position is made more precarious still by the revelation that it has for some years known of the risks but failed to run the necessary trials to assess the danger. An internal assessment by the FDA, leaked to the Wall Street Journal this week, has found that Vioxx may already have caused 27,000 heart attacks, some 7,000 of them fatal. It is that finding, which Merck must have known about, which no doubt led the company to attempt to pre-empt the FDA by withdrawing the product of its own back. Richard Horton, editor of The Lancet, describes the affair as "a public health emergency".

It is also a catastrophe for the pharmaceuticals industry. Public trust in the industry is already at rock bottom. Whether justified or not, there is a growing view that drug companies routinely put the pursuit of profit before the best interests of patients. Danger signals are ignored or suppressed. Even when the drugs are not obviously dangerous, in many instances they seem to be completely useless.

Worse still, regulators are now quite widely perceived as being complicit in the failure adequately to assess risk and protect the public from it. A recent Panorama programme bluntly accused medicine regulators in Britain of being guilty of "extreme negligence or worse dishonesty" in its assessment of Seroxat, an anti-depressant marketed by GlaxoSmithKline. The dangers of counterproductive backlash are now all too apparent.

WHEREVER IT is applied, public interest regulation is all about getting the right balance between risk and reward. Too much suppression of risk, and there won't be any innovation. Too little regulation of risk and potentially catastrophic accident becomes inevitable. With pharmaceuticals the judgement about where to draw the line has to be varied according to the nature of the condition. Patients with life threatening conditions can afford to take very high risks with their medication if it might save their lives. With common, non life threatening complaints, a much more cautious approach necessarily has to be be adopted.

The more savvy drug companies nowadays work with regulators in the approvals process. The effect is to make the process more transparent to outsiders and more importantly from the drug company's point of view to limit the risk of costly failure. By working with the regulator, the drug company can tailor its clinical trials to the regulator's demands, thus helping to limit the costs of development. But it can also lead to the charge of complicity. From the drug company's point of view, this is a very welcome development. If problems emerge subsequent to approval, the regulator becomes as much to blame as the drug company, which limits the risk of litigation.

However, it can also lead to what Americans sometimes call "regulatory capture", where the regulator becomes beholden to the industry, rather than as it should be, the other way round. This, in essence, is what Panorama was accusing British regulators of with Seroxat. It may also have been the case with the FDA and Vioxx.

Interestingly, the opposite may have occurred with AstraZeneca's Exanta. In this case, the FDA's rejection took both the company and the markets were taken completely by surprise. Many in the industry think that's because they hadn't engaged with the FDA at an early enough stage. The FDA panel that examined the evidence didn't like the way the data was presented, or the way the clinical trials had been conducted.

Mix all these cases together, and we are all too likely to end up with more demanding, costly, standoffish and ultimately obstructive regulation. That cannot be in anyone's long term interests. There is a real danger of the baby being thrown out with the bathwater.

To innovate effectively, the pharmaceuticals industry has to be allowed to profit from its successes. The public also has to be protected from the hawkers and the con artists, of which, regrettably, there are a few in this industry. Yet if too high a safety hurdle is set, then it won't be worth the candle.

Sir Tom always likes to quote the example of aspirin, a miracle drug when it was discovered which eased the pains of life for countless millions. Yet because it can ulcerate the stomach, it also causes death in a small number of cases. He wonders whether if it had been discovered today it would ever have got past the regulators. If he's right in concluding that it would not, then we really are in trouble.