Expensive errors - the cost of getting it wrong

Despite increasingly rigorous testing procedures, it may be only when drugs are used by large numbers of people that serious side-effects emerge

The pharmaceutical industry's 'holy grail' of a foolproof formula for safe, effective drugs for common conditions that will underpin their bottom line for a decade or more seems as elusive as ever, despite recent advances in drug discovery techniques. Regulatory bodies like the FDA and EMEA are becoming ever more vigilant about what they will allow onto the market, and demanding increasingly vigorous testing of potential side-effects and interactions of new drugs. Second tier advisory bodies such as NICE in the UK are springing up, providing a further hurdle for many medicines to clear before they can be reimbursed by government.

And yet we still see drugs reaching the market that are hastily withdrawn because of problems that are evident only once they have been in more widespread use. Some drugs that initially looked highly promising in trials may, ultimately, not reach the market at all, or only for limited indications, following a full analysis of trial data. All these factors have been impacting heavily on the share prices of the pharma companies in recent times, with even high profile mergers failing to plug the holes in their pipelines.

The extremely careful consideration of new medicines before they are licensed became essential in the wake of the disastrous side-effects on unborn children after their mothers took thalidomide. This is precisely the problem that should be pinpointed in clinical trials, and a medicine that produces such appalling side-effects is now extremely unlikely to reach the market. However, this does not mean that all potential problems are spotted prior to marketing. By their nature, clinical trials are always going to be limited, and sometimes a rare, but potentially fatal, side-effect may not be picked up until a medicine has reached the market and is used by larger numbers of people. Hence the current system was developed for the monitoring of all available drugs, so that information about any reported adverse effects can be collated and, if necessary, a medicine withdrawn.

However, with the huge amounts of money that the pharma companies spend on developing a drug, a failed product can be disastrous for a company's share price as it suddenly finds a huge hole in its balance sheet. And fewer drugs are making it all the way through trials and onto the market these days. A few short years ago, the US FDA would routinely approve more than 50 new molecular entities every year. By last year, that had fallen to 34. And in the first half of 2002, a mere nine new molecules gained approval. This is partly because a medicine is now less likely to be approved if it shows little or no clinical advantage over existing therapeutic options. But the number of recent high profile failures may well have had some effect too, and increasingly the FDA will ask the company to carry out further studies before it will approve a drug.

This not only adds costs onto the pharma company as it has to pay for the further testing, but it puts back the date by which the drug will start earning money for the company. And by the time it does reach the market, it will have less time on the market with its patent protection intact, so its earnings potential is also reduced.

potential problems

As a spokesman for the Association of the British Pharmaceutical Industry (ABPI) explains, regulators argue that the lower number of approvals is not a case of them getting tougher.

It is more that, as time goes on, the regulations are becoming better developed and the potential problems of medicines are better understood, and this is having an effect on the number of medicines that pass successfully through the whole licensing process.

He adds that the pharma companies themselves are putting more emphasis on removing potentially problematic drugs from the pipeline at an earlier stage. Modern techniques, such as toxicogenetics and informatics, mean it is now easier to predict and identify potential problems with new medicines much earlier in the discovery process, before expensive, extensive clinical trials have been started. This can save the company a great deal of money, as it means it is not having to spend huge amounts of cash developing drugs that, on the balance of probabilities, are unlikely to make it all the way to the market.

However carefully clinical trials are designed and analysed, side-effects will always occur. Therapeutic classes that have experienced problems are likely to have close attention paid to them. For example, regulators seem to have become more nervous about cholesterol-lowering statin medicines following the problems experienced with Bayer's cerivastatin. (Baycol/Lipobay). The statins are 3-hydroxy-3-methylglutaryl coenzyme A, or HMG-CoA inhibitors, and reduce the amount of cholesterol in the system by interrupting the body's biosynthetic route by inhibiting the rate-limiting step.

Statins themselves are a modern medical miracle. That they cut the risk of heart problems is unarguable. A couple of months ago, the results of a long term study of the use of Merck & Co's simvastatin (Zocor) were published.¹ More than 20,000 patients were involved in the trial, which lasted five years. Those given simvastatin were a third less likely to develop stroke, myocardial infarction or revascularisation, even if their blood cholesterol levels were normal or low. Long-term statin use was also shown to be extremely safe, with no significant adverse effects.

Yet there were still problems with cerivastatin in use. That they arose largely from mis-prescribing was irrelevant in the decision to withdraw the drug. Despite warnings to the contrary, some physicians still prescribed it in combination with Pfizer's gemfibrozil (Lopid), an unrelated cholesterol-lowering drug. The combination led to patients developing the muscle weakness rhabdomyolysis. And some doctors also started patients off on the highest licensed dose, rather than the lowest, despite prescribing advice, which led to a number of fatalities. The upshot of all this was the removal of cerivastatin from the market, initially in the US and ultimately elsewhere, and a big hole in Bayer's balance sheet.

The next statin in line for problems is AstraZeneca's rosuvastatin (Crestor). Big things were expected of the as yet unlicensed medicine, with the company hoping it would provide the revenue needed to replace that lost with the expiry of its patents on the proton pump inhibitor omeprazole (Losec/Prilosec). It originally hoped that rosuvastatin would be on sale and earning money by now. But after a series of delays, the company has had to admit that rosuvastatin will probably be delayed by at least another year while AZ compiles further data from clinical trials, despite having received the FDAs' initial 'approvable' letter in June.

delayed launch

This announcement sent an already weak share price tumbling further, amid speculation that the approvable letter, whose contents AZ had declined to disclose, had put severe restrictions on its use. Concerns have been expressed about the side-effects experienced when the drug was taken in the highest dose in the trials, 80mg. Although AZ says it was not seeking approval for the drug at this dose, merely the lower doses of 20 and 40mg, regulators' concerns remained. The company remains confident that the drug will ultimately make it a lot of money, but the delay in reaching the market has certainly hit it hard.

Rosuvastatin is not the only one of AZ's developmental drugs to have hit its share price recently. Another of its novel medicines for which great things had been predicted has hit problems. ZD-1839 (Iressa) is a cancer medicine, designed to treat non-small cell lung cancer, and is the first in class of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. It has been shown to be effective as monotherapy in patients with advanced cases of the cancer, and has already been approved for this indication in Japan.

However, disaster has struck with the results of a trial where it was used to treat lung cancer patients in combination with standard platinum-based chemotherapy regimes. Results of the trial indicated that it does not provide improvement in survival over platinum chemotherapy alone. It is still being pursued as monotherapy, but the strategy of using the medicine in combination with platinum drugs was essential to AZ's plans, and a long delay before its launch is looking increasingly likely.

Although the drug is still undergoing Phase II trials for a range of other solid tumours, including head and neck, colorectal and breast cancers, this knock-back has certainly hit the potential for future success of the drug, and analysts have halved, at best, their sales projections for the medicine.

Another class of drugs that has had its problems is the glitazone class of insulin sensitisers used to treat Type II diabetes. The first in class was troglitazone (Rezulin), licensed by Warner Lambert from Sankyo. Initially hailed as a big step forward in the treatment of this increasingly common condition when it was first approved in January 1997, reports of adverse effects on the liver soon began to roll in. This led in November of the same year to the FDA requiring Warner Lambert to change the prescribing information and add further warning information to the labelling.

In the first nine months on the market, 35 of the half million people who had taken the drug had reported liver problems, ranging from mildly elevated blood levels of the liver transaminase enzymes, to total liver failure, which resulted in one death and one liver transplant. The FDA required patients to have their liver transaminase levels to be checked regularly.

However, this proved insufficient. First, the frequency of required monitoring was increased. July 1998 saw a further tightening of the prescribing advice, and then in June 1999 it was tightened again, with its indication for use as monotherapy withdrawn, leaving it to be used only in combination with insulin or sulphonylurea. Finally in March 2000 the manufacturer voluntarily withdrew it from the market, despite the company saying that it still believed the benefits of the drug outweighed the associated risks, and blaming sensationalist reporting of the drug's side-effects.

The two other drugs in this class, GlaxoSmithKline's rosiglitazone (Avandia) and pioglitazone (Actos) from Takeda, are still widely used, and the liver problems that beset troglitazone have not been seen. However, they have still not been without their problems. Reports of the potential for an increase in the likelihood of developing congestive heart failure led to the FDA requiring label revisions to be made.

second chance

Sometimes, the withdrawal of a drug on precautionary grounds does not spell the end for its presence in the marketplace. Back in early 2000, Glaxo-Wellcome launched the selective 5-HT3 antagonist alosetron (Lotronex) as a treatment for irritable bowel syndrome. IBS is poorly understood and difficult to treat, and the introduction of Lotronex appeared to be a huge leap forward in the treatment of women with diarrhoea-predominant IBS, being the first drug to have been proved in large-scale trials to address the multiple symptoms of the condition.

Yet towards the end of 2000, the product was withdrawn following discussions with the FDA about gastro-intestinal side-effects, such as ischaemic colitis, and serious complications of constipation. These have resulted in hospitalisation, blood transfusion and surgery, and some fatalities have been reported, although no causal relationship with the drug had been established.

At least half a million prescriptions for the drug were written in the nine months it had been available. In April this year, alosetron received a lift - a joint advisory panel to the FDA recommended that the drug should be reintroduced, as long as certain restrictions were in place, so there is hope that GSK may ultimately be able to recoup the investment in its development.

Similarly, Abbott's antiobesity drug sibutramine (Reductil) was temporarily withdrawn from the market in Italy earlier this year, following several reports of severe side-effects. The Italian authorities referred it back to the EMEA, which decided there was no evidence that the medicine was directly responsible for the adverse effects. It confirmed its efficacy and safety, although it added that it would keep the medicine under regular review as a precaution.

Another reason for the falling number of new drugs reaching the market is that many of the 'easy' targets have already been hit. Most of the straightforward disease processes now have medicines that interrupt their progress at some stage, leaving fewer straightforward targets for the pharma companies to aim at. The diseases and conditions that are less well understood are clearly going to be more difficult to create new medicines for in a rational manner, regardless of side-effect problems.

Perhaps the ultimate solution lies in pharmacogenomics. Many side-effects result from interactions with specific metabolic pathways that exist only in some patients. If the precise pathway by which the adverse effect operates can be ascertained, then patients could be screened to establish whether they are likely to be affected.

Of course, this would require clear policing, and a great deal of education of both patients and medical practitioners to ensure that prescribing guidelines are strictly adhered to. After all, many of the difficulties experienced with cerivastatin can be directly attributed to mis-prescribing. But if this could be overcome, then maybe in future we will see larger numbers of new molecular entities reaching the market once again, even if many of them are aimed at only a certain proportion of the patient population. And, as well as being good for the drug companies' bottom lines, this can only be better for patients.