A further 2.3 million patients in America needed emergency hospital treatment for an adverse reaction during the year, despite following the prescription correctly.
These shocking statistics are linked-but it takes a fourth statistic to understand why that is. The pharmaceutical industry has enjoyed extraordinary growth over the past 20 years. In that time, its revenues have increased sixfold, a remarkable leap for an established industry, and unparalleled outside of the high-tech and Web-based sectors.
To achieve that level of growth, drug companies have unleashed a tsunami of pharmaceuticals, requiring indiscriminate-and sometimes illegal-use that is poorly monitored by doctors and invariably ignored by the regulators.
Astonishingly, this enormous sales growth has been achieved at a time when the introduction of innovative new drugs has almost dried up. Instead, the slack has been more than made up by cheap 'me-too' drugs and off-label use-where doctors prescribe pharmaceuticals for conditions for which they have not been licensed to treat or to groups, such as the very young, for whom safety tests have never been carried out.
Off-label drugs generate 40 per cent of pharmaceutical revenues (Arch Pediatr Adolesc Med, 2007; 161: 282-90), and account for one out of every five prescriptions written; the ratio is even higher for some medications, such as seizure and heart drugs (Arch Intern Med, 2006; 166: 1021-6).
Off-label prescribing takes the patient into uncharted waters, as a study into the wrongful use of coronary stents discovered. Stents are metal tubes inserted into the arteries that slowly release a drug to help prevent restenosis, where artery walls become blocked by plaque. The study, which involved 7752 heart patients, discovered that stents were prescribed off-label in 47 per cent of cases, more than doubling the patient's risk of dying or suffering a serious heart attack compared with someone whose stent had been prescribed properly. These patients faced such a risk for 12 months even after the stent was removed (JAMA, 2007; 297: 1992-2000).
Drugs for fun
Once a patient starts taking a prescription drug-whether off-label or not-he or she runs the risk of becoming an addict. Many hundreds of thousands of middle-aged people are addicted to a prescription drug, such as a mood-enhancing antipsychotic or a painkiller, that can be more powerful than heroin or cocaine, according to America's Centers for Disease Control and Prevention (CDC).
Because of indiscriminate off-label prescribing and addiction, most homes have prescription and over-the-counter drugs in their bathroom cabinets-and this has created a third social problem, which also happens to benefit the drug companies. Teenagers in the family home are popping their parents' prescription pills to get a 'high'.
And because the drugs are either prescribed by a doctor or bought at the local pharmacy, the teenager thinks the drugs are safe to take, even in excess or as part of a cocktail of prescription drugs found in the home.
The latest statistics from the CDC demonstrate how wrong they are. A pharmaceutical is killing one person every 14 minutes in the US, creating an annual death toll of 37,485 victims in 2009, the first time that pharmaceutical-related deaths have outstripped road traffic fatalities, which claimed 36,284 lives. Deaths from pharmaceuticals have doubled in the last 10 years.
Most of the deaths involve teenagers and middle-aged addicts, who are taking drugs, such the painkillers Oxycontin and Vicodin, and anti-anxiety treatments such as Xanax, that are more lethal than heroin and cocaine combined, says the CDC. One new drug, the painkiller Fentanyl, is a hun-dred times more powerful than morphine (Los Angeles Times, 17 September, 2011; http://articles.latimes. com/2011/sep/17/local/la-me-drugs-epidemic-20110918).
More pills, more profits
Industry watcher Linda Rosenstock, dean of the University of California at Los Angeles's school of public health, reckons the drugs tsunami started around 10 years ago, when deaths from pharmaceuticals were still relatively low, according to the CDC.
Around that time, drug companies started to employ a more aggressive sales approach with doctors who, in turn, believed the hype of the drugs salesmen to operate a more liberal and indiscriminate policy of prescribing, especially of the new painkillers coming onto the market. Off-label prescribing started to become the norm, and patients constantly topped-up their pres-criptions without anyone check-ing to see if they really needed to continue with the drug.
Doctors also started to prescribe drugs to adolescents, even though the vast majority of drugs are licensed for use in adults only. The most common drugs prescribed were for gastrointestinal problems and central nervous diseases, one study of 31 children's hospitals discovered. Overall, the researchers reckon that 79 per cent of adolescents under the age of 18 years have been given at least one 'off-label' prescription-a drug that has never been tested for its safety in that age group (Arch Pediatr Adolesc Med, 2007; 161: 282-90).
The problem is exacerbated in the US where drug companies can run 'direct-to-consumer' advertisements in newspapers and magazines, and on television. Although the doctor ultimately determines whether to write the prescription, consumers are encouraged to tell the doctor what drug they want.
The drug company is constrained by law to advertise its drugs only for the condition for which they are licensed: it isn't supposed to advocate off-licence use. It does, of course, even though the act is illegal under US 'false-claims' laws. And, on rare occasions, the company will have its wrists slapped.
In the last few years, Baxter, the pharmaceutical and medi-cal fluids manufacturer, has been fined $1.3 billion for fraud and illegal sales activity, while Pfizer paid out $2.3 billion after it was accused of illegally promoting four of its drugs, including the painkiller Bextra, its antibiotic Zyvox, the anti-epileptic Lyrica and the anti-psychotic Geodon.
Illegal off-label promotion was responsible for most of the 165 financial penalties-totalling $19.8 billion-levied against drug companies in the US in the 20 years up to 2010. However, 121 of the cases, and $14.8 billion of the fines, occurred in the last five years that the study covered, reflecting the more aggressive approach of the industry in recent times.
Other offences included overcharging, colluding with other drug companies to maintain a monopoly on a drug even though its patent had expired, giving hospitals and doctors financial 'kick-backs' for using their products, hiding the results of studies that might throw a poor light on a drug and tax fraud.
Four drug giants-the UK's GlaxoSmithKline (GSK), and Pfizer, Eli Lilly and Schering-Plough-alone accounted for $10.5 billion, or 53 per cent, of the fines.
However, these fines-by far and away the largest in any industry sector, including even defence-have not been the result of positive action by doctors or the vigilance of regulators. Instead, virtually all of the cases have come to light because of 'whistleblowers' within the drugs industry, and usually by a company's own employees.
Whistleblowers have initiated 67 per cent of the cases against drugs firms from 2001 to 2010, a steep rise from the previous decade when they were responsible for just 9 per cent of cases. This reflects a recent change in the law, known as 'qui tam', which now allows a handsome reward to be paid to a whistleblower who reports fraudulent behaviour to a regu-lator, or state or federal agency (see Factfile B).
Sidney Wolfe, of the Public Citizen's Health Research Group, a lobby responsible for a report into drug company fines entitled Rapidly Increasing Criminal and Civil Monetary Penalties against the Pharma-ceutical Industry: 1991 to 2010, said the escalation of fines mirrors the aggression of the drugs industry in marketing their products and maximizing their profit margins.
However, regulators have been taken by surprise, and have failed to match this new aggressive approach with appro-priate enforcement and fines. Even though the drugs industry is now the most fraudulent, and most heavily fined, the penal-ties are insignificant compared with the enormous revenues the companies are generating, says Wolfe. GSK and Pfizer paid out a total of $7.44 billion in financial penalties in the 20 years the report covers and, yet, their typical combined net profits in just one year are around $16.5 billion.
Not many dead
There is a human price to pay for the aggressive, fraudulent and inappropriate prescribing that fuels the drugs industry's growth and burgeoning profits. The CDC's alarming report on pharmaceutical-related deaths is only the tip of the iceberg.
Another US government agency, DAWN (Drug Abuse Warning Network), reveals that, while 32,000 people in the US died after taking pharmaceuti-cals in 2009, another 2.3 million needed emergency hospital treatment for an adverse reaction to a prescribed medication. The figure repre-sents an 83-per-cent increase in the four years from 2005, when 1.25 million people were treated in emergency wards.
Alarmingly, none of the 2.3 million people had done anything wrong. They all had their drug prescribed by a doctor, and were following the correct dosages and frequency, say the DAWN researchers-although the extent of off-label prescribing is not mentioned. Virtually every case involved someone aged 21 years or older, and the largest grouping was in the over-65s.
And that is only half the story. A further 1.2 million needed emergency hospital care after misusing a pharma-ceutical drug, such as for recreational purposes.
Around half of all emergency procedures were related to an adverse reaction to-or misuse of-a painkiller, such as oxy-codone or hydrocodone.
The DAWN researchers say the steep rise in adverse reactions reflects the level of polypharmacy-where more than one drug is prescribed at the same time, which is typical in the over-65s group-and the patient's implicit belief in drug safety and underappreciation of a pharmaceutical's powerful toxic effect (The DAWN Report, December 28, 2010).
Typical drugs users, addicts and teenagers are not the only groups paying the price of the drugs tsunami-the under-fives are in the firing line too. Like their older siblings, small children are also finding the pharmaceuticals in the bath-room cabinet, and more than 68,000 need emergency hospital treatment every year. In all, 544,133 children were rushed to emergency wards between 2001 and 2008, according to the American Association of Poison Control Centers, and 66 died.
Although most cases were the result of accidental use, 6529 children (1.2 per cent) needed emergency care after an adverse reaction to a drug given to treat a health problem, usually a cough or cold.
The number of children harmed by a drug has risen by 22 per cent compared with the previous eight years. The most worrying trend is the amount of painkillers that toddlers are taking by accident. The US Drug Enforcement Adminis-tration's ARCOS (Automation of Reports and Consolidated Orders System) database for 2000-2007 reveals that emer-gency treatment has doubled compared with previous figures, while the rate of injury has increased by 92 per cent.
According to researchers from the University of Cincinnati Children's Hospital Medical Center, the increase is a reflection of the growing levels of all pharmaceuticals present in the typical family home.
In 1998-9, half of all adults in the US had taken one prescription drug during the previous week, and 7 per cent were taking five or more drugs. By 2006, the same researchers discovered that 55 per cent of adults had taken a prescription drug the previous week-an increase of 10 per cent-and 11 per cent were taking five or more drugs (J Pediatr, 2011; in press; published online: 16 September 2011; 10.1016/j.jpeds.2011.07.042).
A thousand gnats
In the 1990s, commentators came up with the expression 'pharmageddon' to describe a time when the risks of drugs finally outweighed their benefits-and it looks as though we are getting very close to that nightmare scenario. If we are, the fault can be laid squarely at the door of the drug companies themselves and their push for growth, irrespective of the cost to human health and life.
They may yet be saved from devouring themselves. Tighter controls, tougher penalties and whistleblowers-a "thousand gnats" as Marcia Angell, former editor of the New England Journal of Medicine, vividly described the backlash-could combine to curb their worst excesses.
In her book The Truth about the Drug Companies (New York, NY: Random House, 2005), Angell points out that consumer groups in the US are starting to band together to form new collectives such as the Prescription Access Litigation Project, which had, at one stage, filed suits against more than 20 drug companies.
The pharmaceutical sector's collective decision to focus on 'me-too' drugs rather than pursue novel treatments is another factor, and one that could eventually affect their stock price, says Angell. By failing to innovate and generate new revenue streams, investors worry that off-label and dubious prescribing is a short-term tactic, and one that is attracting the regulators and whistle-blowers alike.
For much of the past century, the pharmaceutical sector was in the enviable position of being not only a profit-generating monopoly, but was also seen as a benefactor of humanity. In the last 10 years, it has become apparent that it will soon have to decide which of the two it really is.
Factfile A: Vioxx's final bill
US drugs giant Merck has been presented with the final bill after it concealed data showing that its new painkiller, Vioxx, could cause heart problems. Last November, the company agreed to pay lb640 million ($1 billion) to settle criminal and civil charges, which can be added to the $4.85 billion it has already paid out to the relatives of thousands of victims killed by the drug.
The drug, primarily designed to ease arthritis pain, was withdrawn from the market in 2005 after studies showed that it increased the risk of heart disease and stroke. Although no one knows for sure, conservative estimates reckon that the drug was responsible for the deaths of around 60,000 people.
Merck executives may have known about the drug's deadly side-effects as early as 2000. In that year, Vioxx, a COX-2 inhibitor, was tested against naproxen, an over-the-counter painkiller. Although both drugs had similar painkilling qualities, Vioxx patients had only half the risk of serious gastrointestinal problems, such as stomach bleeding-an expected benefit of the drug over other NSAIDs (non-steroidal, anti-inflammatory drugs) such as aspirin. However, the study also discovered that the Vioxx group had a fourfold higher risk of heart attack-a fact that was left out of the final published study (N Engl J Med, 2000; 343: 1520-8).
Factfile B: Who'd be a whistleblower?
Most cases of drug company fraud are brought to light by a whistleblower who invariably turns out to be an employee. Although, in the US, a whistleblower can win a handsome reward, it's a bumpy ride until the cheque arrives-and in the UK, you do it just for the warm glow of doing the right thing.
Dr Ryta Kuzel, who was head of regulatory affairs at Roche UK, was frog-marched out of the building after she reported some wrongdoing over the supply of the company's slimming drug Xenical (orlistat) to a clinic.
The company denied that her very sudden departure had anything to do with whistleblowing, but an industrial tribunal disagreed, and awarded Dr Kuzel lb80,000 for wrongful dismissal.
Even researchers whose studies are 'sponsored' by drug companies can feel the icy draught of penury if they speak out. Professor John Buse at the University of North Carolina inadvertently stumbled upon the fact that the diabetes drug Avandia increased the risk of cardiovascular disease. Unfortunately for Dr Buse, GlaxoSmithKline (GSK), which happened to be sponsoring his study, manufactured the drug.
His comments sparked a revenge attack within GSK. Executives tried to stop all of Dr Buse's research funding, while a senior GSK executive was putting plans in place to sue Dr Buse and launch a damage-limitation campaign.
The plans were leaked, and the executives were asked to explain themselves to a US Senate committee. GSK later admitted that "perhaps we could have handled interactions with Dr Buse better" (BMJ, 2007; 335: 1113).
Factfile C: Who regulates the regulators?
Why is it that our well-paid regulators don't uncover most drug company fraud? The answer is all too simple-most are receiving some payment from drug companies. Many 'experts' who sit on any of the advisory committees of America's drugs regulator, the Food and Drug Administration (FDA), are paid consultants for one of the drug companies whose products they are supposed to monitor.
Four of the six experts on the advisory committee that first approved the controversial Vioxx drug in 1999-which was associated with perhaps 60,000 deaths-had industry connections. Six years later, 10 of the 32 members of a panel that decided that the COX-2 drugs should stay on the market had connections with one of these drugs' manufacturers (New York Times, February 25, 2005).
More recently, whistleblowers within the FDA have shouted 'foul' over the approval of a medical device. They say their managers "corrupted the scientific review process" and approved a device in gross violation of federal law. The scientists first raised their concerns with FDA Commissioner Andrew von Eschenbach, who told them to "move forward". Undeterred, the scientists instead moved on to their Congressmen, who suggested to von Eschenbach that he review the safety approval procedures at the agency (JAMA, 2009; 301: 152; doi: 10.1001/ jama.2008.878).
Factfile D: Drug companies on the naughty step
Drug companies featured strongly in the Top 100 Corporate Criminals of the Decade, a catalogue of wrong-doing during the 1990s in the US.
- Hoffmann-La Roche. The Swiss pharmaceutical paid the largest criminal fine issued against a corporation when it paid out $500 million in 1999 for its part in a worldwide conspiracy to raise and fix prices for vitamins sold globally.
- Genentech. The San Francisco-based company paid a $30 million criminal fine and $20 million in civil penalties for marketing its drug, Protropin, to doctors before it had been approved by the Food and Drug Administration (FDA). It aggressively marketed the drug, a synthetic growth hormone, to doctors and hospitals from 1985 to 1994-without anyone even realizing that it hadn't been approved.
- Pfizer. The corporation paid $20 million for its part in two international price-fixing conspiracies in the food-additives business.
- Copley Pharmaceutical. The company was fined $10.6 million after changing its manufacturing methods for its prescription and over-the-counter drugs without the approval of the FDA.
- Warner-Lambert. A $10 million fine was paid for failing to inform the FDA about problems with some of its prescription drugs. The corporation's second fine-this time $3 million-was levied for discharging pollutants into the water system.
- Ortho Pharmaceutical. The company was fined $5 million after it tried to destroy documents relating to its acne treatment, Retin A. It had also been marketing the drug off-label as an anti-wrinkle treatment.
- Bristol-Myers Squibb. The corporation was fined $3 million for discharging pollutants into New York waters.
- Baxter International. The company was fined $500,000 after it admitted to illegally helping the Arab League to carry out a boycott of Israel. In a separate civil settlement, it paid out $5.9 million for giving the Arabs information about Baxter's business in Israel.
WDDTY VOL 22 NO 11, February 2012