New Drugs: New Profits for Old Product

Most new drugs are simply old drugs with a bit of window dressing to justify double the price tag. Yet, the dangers multiply from these novel twists and aren’t picked up until after the drugs are taken by millions.

When your doctor reaches for his pad, the first question to ask him is how old the drug is that he’s prescribing for you. If it’s less than five years old, chances are, by taking that drug, you’re taking your life in your hands.

Medical critic Dr Joe Collier, editor of Drugs and Therapeutics Bulletin, estimates that only 60 per cent of drugs offer more benefit than harm – so, nearly half of all drugs do us more harm than good.

In the US, figures from the Department of Health & Human Services show that doctors are 9000 times more hazardous to your health than gun owners.

Indeed, the statistics back that up. In the US, 106,000 people die every year because of prescription drugs. In the UK, as many people die every month from prescription drugs as were blown up in the World Trade Center in 2001. This means that 40,000 Britons are killed by drugs every year.

But outright deaths are only the paper-thin edge of the wedge. An astonishing 2.2 million are either hospitalised, and seriously – and usually permanently – incapacitated in Britain alone.

While the older, tried-and-tested drugs send their fair share to the morgue every year, the vast majority of problems are caused by new products that haven’t been adequately studied and, in effect, are being tested out on the population at large.

New money for old rope
The major lifeblood of any industry, and this is especially true for drug companies, is new product. Shareholders and city analysts alike thirst for headlines about new breakthroughs and cures. It’s what drives the share price and keeps investor interest strong.

The problem is that it can cost a pharmaceutical company anything up to £350 million to successfully bring a new drug to market. It’s also very hit-and-miss, with plenty of false trails before the research chemists feel they are finally on to something.

It’s been estimated that it can take from 10 to 15 years from that first ‘eureka’ moment until the drug is finally licensed for use. Only three out of 10 drug companies ever recoup all of their development costs in bringing a new drug to market.

Despite the risks, most drug companies continue to chase after the pharmacy’s equivalent of the Holy Grail – the next magic bullet, the next great new breakthrough pill that’ll revolutionise the treatment of a particular condition.

The importance of new product lines for the pharmaceutical industry cannot be overstressed. In the US in 2000, 33.7 per cent of all drug prescriptions were for new products, closely followed by the Canadian market, where new drugs accounted for 29.8 per cent of all sales. In the UK, new drugs represented 15.7 per cent of the total market.

This market share is mirrored in revenues. For GlaxoSmithKline, new products represented 22 per cent of total pharmaceutical sales in 2001. In all, the conglomerate introduced 10 new products into development that year.

The pharmaceutical companies argue that new product research is essential to combat disease, a view that, to some extent, is true. But the argument is only valid if it can be shown that existing drugs on the market can’t perform equally as well. Unfortunately, this question is rarely asked.

It’s also worth noting that, while drug companies like to see themselves as altruistic champions of mankind, most spend twice as much on marketing and advertising as than on research. In 2001, the pharmaceutical giants’ advertising expenditure outstripped that of major retail manufacturers like Nike while they spent far less than expected on research.

This is particularly true in America, where the pharmaceutical industry has begun highly aggressive advertising directly to patients, largely in the form of print and TV advertising, but also any means that will impact on the largest number of patients. One ingenious drug company went as far as to advertise its latest offering for lowering cholesterol on one airline’s luggage tags.

This is another symptom of the licensing process. A patent, usually running for 20 years, is taken out once the research team has made an initial breakthrough. However, by the time the licensing process has been completed, the patent may only have another five or six years left to run before other drug companies can produce ‘me-too’ copies. This means the drug company has only a small window of time to recoup its £350 million initial investment. Hence, the aggressive marketing campaign from the outset.

Drug companies are also not as innovative as they’d have us believe. The high cost of research tends to prevent highly experimental work. Most new drugs are modifications of existing ones, old products simply given a little tweak or new window dressing to justify a claim of being ‘new’.

Dr John Griffin, then a senior official in the medicines division at the Department of Health, conducted a study in 1981 and found that 204 new chemical entities (NCEs) marketed over the previous decade had been introduced into areas ‘already heavily oversubscribed’. ‘Innovation is directed towards commercial returns rather than therapeutic need,’ he said in his report.

Later research suggests that nothing has changed. A study in the US discovered that, of all the drugs approved during the 1990s, only 15 per cent contained new active ingredients and could be viewed as a significant improvement over existing drugs on the market. This means that 85 per cent of all new drugs are basically copies of older drugs.

The study, by the National Institute for Health Care Management (NIHCM) Foundation, reviewed 1035 prescription drugs approved by the Food and Drug Administration (FDA), the US drug regulator, between 1989 and 2000. Only one-third, or 361 drugs, were new molecular entities that treated diseases in novel ways, and less than half of these were given priority status by the FDA, an indication that the agency believes that these drugs in particular could result in significant clinical improvement over existing medications.

Among the truly innovative drugs were Pfizer’s Lipitor (atorvastatin) for high cholesterol and Viagra (sildenafil) for erectile dysfunction, Merck’s Fosamax (alendronate sodium) for osteoporosis, and GlaxoSmithKline’s Avandia (rosiglitazone) for type II diabetes.

The remaining 674 drugs in the NIHCM study were ‘me-too’ drugs, containing active ingredients already available in drugs previously approved.

The only difference in most cases was a different dosage or an added ingredient. A drug previously only available in oral form might, instead, be available as a transdermal patch, for instance.

So why go to the expense and bother of creating a ‘new’ drug that adds nothing to the wellbeing of mankind?

Apart from the buoyant effect that a new drug can have on the share price, drug companies can also charge more for the new drug. The NIHCM study found that all new drugs were priced considerably higher than the old ones they were replacing. In the US in 2000, the average price per prescription for the most innovative class of drugs was $91.20 vs an average price of $37.20 for older drugs approved before 1995.

Even the me-too drugs commanded a higher price. On average, the more recently approved drug – which was virtually the same as an existing drug – cost 75 per cent more than an older one with an almost identical function.

And herein lies the maths to explain the drug company’s constant spinning out of old drugs with a novel twist. The rule of thumb is that you can charge three times more for a genuinely innovative product than the cost of an older drug for the same condition. But even me-too drugs with just the tiniest of new wrinkles can also command nearly double the price of the old drug and with far less cost to research and licence.

Drug companies may argue that the extra revenues are needed to support research into new drugs – but if the so-called new offerings are identical to older ones, it seems fair to say that much of the R&D in the pharmaceutical industry is carried out mostly to boost share prices and revenues.

The cost of creating a me-too drug is still great, but not as arduous as creating a new drug from scratch. However, the dangers can multiply from those little novel twists. Adding a new ingredient here and increasing the dosage there can have a profound impact on the overall pharmacological effect, causing problems that often aren’t picked up until after the drug is on the market and taken by millions of people.

The public as guinea pigs
Around one in five new drugs will have a serious side-effect ‘discovered’ after all the expensive licensing procedures and trials have been completed. Sometimes, the effect can take up to 25 years to uncover, as revealed by a study from Harvard Medical School (JAMA, 2002; 287: 2215-20).

There, researchers monitored the status of 548 new drugs approved for use in the American market during 1975-1999. They checked to see if they had been withdrawn or had received a ‘black-box warning’ in the US drugs bible, the Physicians’ Desk Reference. The black-box warning appears at the very beginning of the drug description, and alerts the medical professional to a very serious adverse reaction that is usually life-threatening.

It’s important to note that the Harvard team restricted themselves to those adverse reactions resulting in either death or permanent disability. The more usual side-effects revealed after the drug was licensed, and which can also ruin a person’s life, were not even looked at.

Of the 548 drugs tracked, 56 (10.2 per cent) had acquired a new black-box warning – which means a very serious side-effect was discovered only after patients had started taking the drug – or were withdrawn altogether because the potential side-effects were so serious that they were probably a threat to life.

Overall, the likelihood of a new drug acquiring a new black-box warning or being withdrawn was 20 per cent. Half the changes took place within seven years of the drug reaching the market, and half of all withdrawals occurred within the first two years.

However, this means that half of all the deadly drugs were not easily detected, so exposing millions of people to a dangerous compound. The record longest time taken to give a drug a new black-box warning was nearly 23 years. This was for pemoline, a central nervous system stimulant, which was finally discovered to cause liver poisoning.

The time to withdraw a drug from the market was usually much swifter, but then, drug regulators were dealing with reactions that often resulted in death. While some drugs were withdrawn within months of their introduction, others went on for years before finally being removed.

The worst example found by the Harvard group was terfenadine, an antihistamine that had been prescribed for nearly 13 years before it was discovered that it could cause serious heart problems if the patient was taking another drug at the time.

Similarly, astemizole, another antihistamine, reacted badly with other drugs, but this took nearly 11 years to uncover.

The drugs industry is riddled with examples of serious side-effects not discovered until they are prescribed en masse to the general public; in fact, that is exactly how side-effects are identified.

The class of cholesterol-lowering drugs known as statins, for example, was thought to have few side-effects, and were being touted for everything from heart disease to osteoporosis. However, as doctors started prescribing them in numbers, they found that men were complaining of becoming suddenly impotent. This usually appeared within a week of starting treatment.

Doctors at Guy’s Hospital in London discovered the problem when five men reported this side-effect (how many more kept quiet is anybody’s guess) – but how could they be sure the drug was the culprit?

When the doctors turned to the datasheets, the official documents released with the drug and based on the early marketing trials, they could find no mention of impotence as a possible side-effect. It was only when they delved deeper and looked at the findings of the Australian Adverse Drug Reactions Committee that they found the answer. the Australian committee had received 42 reports from men complaining of impotence after taking simvastatin, one of the statins. The problem had often occurred within 48 hours of starting treatment (BMJ, 1997; 315: 31).

This is an object lesson that highlights several of the central problems. It shows the inadequacies of the early trials that determine whether a new drug should be approved and, but for the perseverence of the doctors at Guy’s, impotence may never have been recognised as an adverse reaction to a statin.

How many times has a doctor not recognised a reaction because it was not listed and so, instead, blamed the reaction on some other aspect of the patient’s life rather than on the drug itself?

Even death can sometimes not be enough to get a drug taken off the market. Seven months after Viagra, the impotence drug, became available, the FDA received 230 reports of deaths associated with the drug. But this did not result in withdrawal of the drug; instead, the FDA insisted only that the manufacturer change the warning on the label.

In the case of Prepulsid (or cisapride, its generic name), which was designed to treat heartburn, it was finally withdrawn from the UK market in July 2000, four months after the FDA announced that 80 people in the USA, and a further 10 in Canada, had died as a result of the drug.

This four-month interval is alarming enough, but the Committee on Safety of Medicines, the UK drugs watchdog, said that reports had been coming in of fatalities from the time the drug won its licence in 1988. It took 12 years before it was finally withdrawn.

Nobody knows for sure how many people died while taking Prepulsid, but conservative estimates put it at around 125, plus a further 50 suspicious deaths. In addition, there had been 341 cases of serious heart rhythm abnormalities reported in the USA, 44 in Canada and 60 in the UK.

Had this had been a 747 plane crash – and the number of fatalities is similar – there would have been a public outcry and a major investigation. In the case of the Concorde crash in July 2000, all airplanes were grounded until the reasons for the crash were identified. In the case of drugs, the product continues to be marketed, even without a warning, and it may take years and many more deaths before the drug is finally taken off the market.

Only the drug regulators can explain why they were so slow to react to Prepulsid and the others like it that endanger people’s lives and wellbeing, but as they are not accountable to the public, there is no way of knowing.

The meetings of the UK’s Committee on Safety of Medicines are held in secret, and minutes from those meetings are not available to the public. Indeed, every meeting begins with a reminder that the proceedings cannot be discussed with anyone outside of the room.

Experts from drug companies fill many important, and influential, positions on various advisory groups. More than half the experts sitting on committees of the FDA have financial relationships with the pharmaceutical industry.

The licensing process is such that it’s not in a drug company’s interest to have exhaustive trials before a licence is awarded.

By the premarketing stage, the drug company has already spent a good part of the £350 million average investment on the new product. It hardly wants to uncover nasty side-effects at this late stage and so, as the Harvard team point out, the early trials are ‘often underpowered to detect ADRs (adverse reactions), and have limited follow-up’.

This is adapted from The Secrets of the Drugs Industry (£11.75 plus £2 p&p), available now from What Doctors Don’t Tell You.

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