DRUG TESTING: Every pharmaceutical company hopes to make a blockbuster drug - one that will net them more than a million dollars and boost their chances of making it into the highest bracket of one of the top earnings leagues in the world. The money to be made is astronomical. Pfizer, the biggest drug company on earth, made a gross profit of $42.7 billion in the year to April 2005.
But, the companies will tell you, they spend a fortune on failed drugs. Thousands of compounds are tested in the labs, but few show promise. Of those that get as far as trials, six out of seven fall by the wayside. That's why the drug industry claims that it costs it $800 million to research and develop each medicine. The price tag includes the failures as well as the marketing of the successes. Yet if it's a lottery, the companies show no signs of wanting to tear up their tickets.
The journey from lab to medicine cupboard used to begin with a gleam in the eye of a researcher, usually at a university - an inkling that a certain molecule might play a part in treating a disease. Now it's more likely to start with the computerised mass screening of potential compounds. Something is identified that looks promising. Work in the lab confirms that it has an effect on, say, tissue samples or a virus. Once the scientists have done all they can to establish what the product does and how, and whether it is helpful or harmful, the animal tests begin.
The point of the animal tests - generally on rats or mice - is to prevent what happened at Northwick Park. If the mice die or exhibit disturbed behaviour, it's time to think again. As of 2004, the Medicines and Healthcare Products Regulatory Authority, which licenses drugs in the UK, has to see the results before it will allow any human trials to begin. In Ireland clinical trials are regulated by the Irish Medicines Board (IMB) and governed by the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations, 2004. Under this directive clinical trials carried out across a number of hospitals need only the approval of one ethical committee. Previously the approval of an ethics committee in each hospital was needed. An IMB subcommittee considers applications for clinical trials. It also monitors compliance and can inspect facilities and documents. Trials can be stopped if problems or non-compliance is determined. Legislation is this area was updated in the 1980s after the death of a young man who took part in a drug trial in Dublin.
The pharmaceutical firms used to run their own clinical trials. Now they tend to hand over the work to professional companies such as the US-based Parexel, which recruits volunteers, gets ethical approval and has its own medical staff to apply the experimental medicine. On their website Parexel advertises for healthy male volunteers (women are not recruited for most trials because of potential risks to any foetus if they get pregnant). Those first trials, involving a small number of volunteers, overwhelmingly students, are known as phase one. For phase two, patients with the disease that the new drug is intended to treat are recruited. There may be a couple of hundred, and the trials may take place in several countries.
If the drug has a beneficial effect on their disease, phase-three trials are launched. Several thousand patients are recruited worldwide. These trials have to be double-blind, randomised and controlled. The subjects are split randomly into two groups, with half given the trial drug and the other half a placebo. Nobody is supposed to know who gets which. When the code is finally broken, after a year or two, scientists will know whether they have a wonder drug or an expensive failure.
The company now applies for a licence, armed with boxes of trial data to prove the drug is safe and "effective". That means it has an effect. It could be a small effect - it is not for the regulator to worry about how good the drug is.
The tight regulatory framework was devised in the post-Thalidomide days, in the horror of babies born with truncated limbs after their mothers took a drug for morning sickness.
Yet now we have Vioxx. Thousands of patients are suing manufacturers Merck after it was forced to withdraw the painkiller, widely used by arthritis sufferers, in 2004. Data from its trials had shown it increased the risks of heart attack. David Graham of the Food and Drug Administration, the US drug regulator, said it could have caused up to 140,000 cases of heart disease in the US since it was licensed in 1999.
How did this happen? Merck said it tested Vioxx not against placebo - since it would be unethical to take people off their painkillers completely - but against another drug that had a protective effect on the heart. But some doctors have accused Merck of trying to cover up the problem for years.
The fact is drug trials demonstrate only what they are designed to demonstrate. Seroxat and other antidepressants of the SSRI (selective serotonin reuptake inhibitors) class have had to be forbidden to children after a number of awful cases. A close analysis of the trial data would have shown children becoming more suicidal than they did on placebo - but no one was looking for that at the time.
It is only in the years after the trials, when not thousands but hundreds of thousands of patients are taking the pills, that we truly find out about them.
Most doctors will say the European regulatory system is as safe as it can be. But the drug companies are heading out of Europe and the US in droves. They can cut their costs and speed up trials if they test their medicines in developing countries. This is the story at the heart of John le Carre's book The Constant Gardener, which is now a film.
Could we see a Constant Gardener scandal in Asia or Africa, as the pharmaceuticals test drugs on people who may not fully understand what could happen, or may say yes under the influence of a father or a chief? The companies insist not. The Declaration of Helsinki, drawn up in the aftermath of Nazi experiments, and other internat- ional ethical codes should prevent it.