None of the papers presented any graphs that could tell the readers what was gained by using a higher dose. Instead, a significant linear relationship between dose and response was claimed, which gives the readers the clear message that by doubling the dose, they double the effect. This comes close to fraud. I presented nine dose-response curves in my review of NSAIDs and an example is shown in Figure 2.1. There is nothing to be gained by using higher doses. The difference between 250 mg and 1500 mg naproxen is six times in terms of money but only 1.0 cm on a 10 cm pain scale, and the least difference in pain patients can perceive is about 1.3 cm.19 The difference of 1.0 cm therefore makes no difference for the patients. The smallest clinically relevant effect, i.e. an effect that might make it worthwhile to take a drug or increase the dose, is larger than what the patients can barely perceive. In contrast, the harms actually do increase in a linear fashion so that twice the dose means twice the amount of harms.20 As some harms are serious, e.g. bleeding ulcers and death, these drugs should be used at the lowest possible dose.
Figure 2.1 Dose-response curve for naproxen. The effect on pain is shown with black dots (10 is the highest pain possible) and the mean percentage improvement for all the reported outcomes is shown with open circles
Such manipulations with the science have the intended effect, to increase sales. Few doctors are able to read research reports critically and they might have forgotten what they learned in clinical pharmacology. The dose-response curves for drugs virtually always have the shape of a hyperbola and standard doses are quite high, corresponding to the uppermost part of the curve where the effect levels off and approaches a ceiling (see Figure 2.1).
The marketing of naproxen is an unequivocal example that drug companies put profits before patients and don’t care that their actions increase deaths. The worst company was not Astra-Syntex, however, it was Pfizer. There was general agreement in other companies that Pfizer’s marketing was particularly aggressive and ruthless.21 Pfizer’s NSAID, piroxicam (Feldene), was also touted at a very high dose.18 Piroxicam has a long half-life and we therefore felt it was inappropriate to use it in the elderly, as their impaired elimination mechanisms lead to accumulation of the drug and increased toxicity.
Pfizer’s marketing was very successful and completely untruthful, stating that piroxicam was more effective than aspirin and had a lower rate of gastrointestinal side effects than many other NSAIDs.22 The truth was the opposite: piroxicam had more fatal reactions and more fatal gastrointestinal side effects than other drugs. Nonetheless, the US and UK drug regulators protected Pfizer all along instead of protecting the patients, and Pfizer tried to dissuade the editors of the BMJ to publish a paper that concluded about the high incidence of severe ulcer disease with piroxicam.23 Pfizer even denied indisputable facts, e.g. that greater concentrations of an NSAID in the blood increase the risk of harms, and the company tried to get away with a ludicrous statement that the gastrointestinal toxicity to a large part was due to a local effect on the stomach rather than a systemic effect. Even if it had been correct, the harms inflicted on the patients would be the same. It is telling in relation to whether good or bad manners pay off that Pfizer became the largest drug company in the world.
Another company, Eli Lilly, also continued its aggressive marketing of its NSAID, benoxaprofen (Opren or Oraflex), undisturbed by the terrible harms they knew their drug caused.22 The company touted that, based on laboratory experiments, the drug was different from other NSAIDs in having an effect on the disease process, but this wasn’t true. Lilly presented a series of 39 patients that experienced a worsening of their joint damage, but the company concluded exactly the opposite.
Lilly ignored or trivialised the harms and failed to inform the authorities of liver failure and deaths, which a subsequent court case described as ‘standard practice in the industry’.24,25 Lilly published a paper in the BMJ that claimed that no cases of jaundice or deaths had been reported, but this wasn’t true.22 Furthermore, benoxaprofen causes other horrible harms, e.g. photosensitivity in 10% of patients and loosening of the nails from the nailbed in 10%, but it was approved despite this and despite insufficient animal toxicology studies, in violation of the Food and Drug Administration’s (FDA’s) own rules. When independent researchers found that benoxaprofen accumulated in the elderly, Lilly tried to prevent the study from being published and, as always, the UK drug regulator’s action was grossly inadequate and allowed Lilly to trivialise the problem. These omissions proved fatal for some elderly patients, and the drug was withdrawn after only 2 years on the market.
I doubt any drug regulator can convince the patients that it was a good idea to approve a drug that harms at least one in five patients pretty badly when there were many less harmful NSAIDs on the market.
The FDA violated its own rules for several other NSAIDs, which, for example, had shown troubling carcinogenicity in animals and should therefore not have been approved, or drugs for which the animal studies were either insufficient or fraudulent, as many of the rats had never existed. The FDA even downplayed highly statistically significant findings in two rodent species and called them marginal or benign although they were malignant.22
The NSAID area is a horror story filled with extravagant claims, bending of the rules, regulatory inaction, and complacency with what the industry wants even though statements from industry scientists were often logically inconsistent or plainly wrong.22 Several drugs that were so kindly treated by the FDA were later withdrawn from the market because of their toxicity despite claims to the contrary, e.g. ‘Excellent gastrointestinal tolerance’ (benoxaprofen), ‘superior tolerance’ (indoprofen), ‘proven gastrointestinal safety’ (rofecoxib), ‘hurts the pain not the patient’ (ketorolac) and ‘least possible side effect profile’ (tolmetin).24 Sheer nonsense, as a least possible side-effect profile can only occur if you don’t take a drug at all. Other withdrawn drugs are, for example, zomepirac, suprofen and valdecoxib.22,26
The NSAID story illustrates that drug regulators are consistently willing to award the benefit of scientific doubt to manufacturers rather than patients and also that the regulators became even more permissive during the 1980s.22 As I shall show in later chapters, and illustrate with newer NSAIDs and other drugs, this decline in drug safety has continued.
References
1 Bjelakovic G, Nikolova D, Gluud LL, et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2008; 2: CD007176.
2 Knaus H. Corporate profile, Ciba Geigy: pushing pills and pesticides. Multinational Monitor. 1993. Available online at: http://multinationalmonitor.org/hyper/issues/1993/04/mm0493_11.html (accessed 10 July 2012).
3 Dunne M, Flood M, Herxheimer A. Clioquinol: availability and instructions for use. J Antimicrob Chemother. 1976; 2: 21–9.
4 Hansson O. Arzneimittel-Multis und der SMON-Skandal. Berlin: Arzneimittel-Informations-Dienst GmbH; 1979.
5 Hench PS, Kendall EC, Slocumb CH, et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949; 24: 181–97.
6 Pearce N. Adverse Reactions: the fenoterol story. Auckland: Auckland University Press; 2007.
7 Gøtzsche PC. Mammography Screening: truth, lies and controversy. London: Radcliffe Publishing; 2012.
8 Michaels D. Doubt is their Product. Oxford: Oxford University Press; 2008.
9 Smith SM, SchroederK, Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev. 2008; 1: CD001831.
10 Tomerak AAT, Vyas HHV, Lakhanpaul M, et al. Inhaled beta2-agonists for non-specific chronic cough in children. Cochrane Database Syst Rev. 2005; 3: CD005373.
11 Wilkinson EAJ, Hawke CC. Oral zinc for arterial and venous leg ulcers. Cochrane Database Syst Rev. 1998; 4: CD001273 (updated in 2010).
12 H
usain SL. Oral zinc sulphate in leg ulcers. Lancet. 1969; 1: 1069–71.
13 Andersen LA, Gøtzsche PC. Naproxen and aspirin in acute musculoskeletal disorders: a double-blind, parallel study in sportsmen. Pharmatherapeutica. 1984; 3: 535–41.
14 Jørgensen FR, Gøtzsche PC, Hein P, et al. [Naproxen (Naprosyn) and mobilization in the treatment of acute ankle sprains]. Ugeskr Læger. 1986; 148: 1266–8.
15 Allen C, Glasziou P, Del Mar C. Bed rest: a potentially harmful treatment needing more careful evaluation. Lancet. 1999; 354: 1229–33.
16 Gøtzsche PC. Bias in double-blind trials. Dan Med Bull. 1990; 37: 329–36.
17 Gøtzsche PC. Sensitivity of effect variables in rheumatoid arthritis: a meta-analysis of 130 placebo controlled NSAID trials. J Clin Epidemiol. 1990; 43: 1313–18.
18 Gøtzsche PC. Review of dose-response studies of NSAIDs in rheumatoid arthritis. Dan Med Bull. 1989; 36: 395–9.
19 Lopez BL, Flenders P, Davis-Moon L. Clinically significant differences in the visual analog pain scale in acute vasoocclusive sickle cell crisis. Hemoglobin. 2007; 31: 427–32.
20 Gøtzsche PC. Non-steroidal anti-inflammatory drugs. Clinical Evidence. 2004; 12: 1702–10.
21 Rost P. The Whistleblower: confessions of a healthcare hitman. New York: Soft Skull Press; 2006.
22 Abraham J. Science, Politics and the Pharmaceutical Industry. London: UCL Press; 1995.
23 Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ. 1996; 312: 1563–6.
24 Virapen J. Side Effects: death. College Station: Virtualbookworm.com Publishing; 2010.
25 Joyce C, Lesser F. Opren deaths kept secret, admits Lilly. New Sci. 1985; 107: 15–16.
26 Cotter J. New restrictions on celecoxib (Celebrex) use and the withdrawal of valdecoxib (Bextra). CMAJ. 2005; 172: 1299.
3
Organised crime, the business model of big pharma
Drug companies never talk about the benefits and harms of their drugs but about their efficacy and safety. Words create what they describe and the preferred semantics is seductive. It makes you think it can only be good for you to take drugs, as they are both efficacious and safe. Another reason why patients and doctors generally trust their drugs as being both efficacious and safe is that they think they have been carefully tested by the drug industry and carefully scrutinised by the drug regulatory agencies using high standards before they are allowed onto the market.
It’s the other way round. In contrast to food and water, which are not only pretty harmless but something we need to survive, drugs are generally neither efficacious nor safe. Paracelsus stated 500 years ago that all drugs are poisons and that the right dose differentiates a poison from a remedy. Drugs always cause harm. If they didn’t, they would be inert and therefore unable to give any benefit. For all drugs, it is therefore essential to find a dose that causes more good than harm in most patients. Even when we succeed with this, most patients will still not achieve any benefit from the drugs they take (see Chapter 4).
Although it is rather obvious that drugs can kill you, this is often forgotten, both by patients and doctors. People trust their medicines to such a degree that the Canadian physician Sir William Osler (1849–1919) wrote that ‘the desire to take medicine is perhaps the greatest feature which distinguishes man from animals’.1 A particularly amusing example is botulinum toxin, which is a neurotoxin produced by the bacterium Clostridium botulinum. It is one of the strongest poisons in nature, and a dose of only 50 ng killed half of the monkeys in a toxicity study (which means that 1 g can kill 10 million monkeys). I wonder who needed this information so badly that it was worth killing our animal relatives to get it. And yet, what is this amazing killer drug used for? For treating wrinkles between the eyebrows! This comes with age, but you shouldn’t be too old and have too much tremor when you inject the toxin, as it can be absorbed from the mucous membranes in the eye and kill you. The package insert warns that deaths have occurred. Is it really worth running a risk of dying, however small it might be, just because you have wrinkles? Other questions that pop up are: Can the drug be used for suicide or murder? Why was it ever approved?
The fact that drugs are dangerous and should be used with caution means that the ethical standards for those who do research on drugs and market them should be very high. I have talked to many people in the drug industry to find out what the companies think of themselves, and the replies have ranged from very positive ones from people who were proud of the clinical trials they carried out to very negative ones. What is perhaps more interesting is to see which impression the drug companies want to give of themselves to the public and to compare this with what they actually do. The Pharmaceutical Research and Manufacturers of America (PhRMA) claims its members are ‘committed to following the highest ethical standards as well as all legal requirements’.2 Its Code on Interactions with Healthcare Professionals states that:3
Ethical relationships with healthcare professionals are critical to our mission of helping patients … An important part of achieving this mission is ensuring that healthcare professionals have the latest, most accurate information available regarding prescription medicines.
Here is another quotation. Under the heading, FOCUS ENGAGEMENT HONESTY, came this text: ‘Our goal is to be the world’s most successful, respected and socially responsible consumer ware producer.’4 As you’ll see shortly, the drug industry’s actions have very little to do with honesty, respect and social responsibility. How could they then write this about themselves? Well, they didn’t. They could have, but the quotation comes from a newspaper advertisement for Philip Morris that shows a portrait of a smiling young woman who won’t continue to look so good if she smokes.
I tell you this to illustrate that not even the most deadly industry on the planet can resist the temptation of spreading bullshit while they increase the total consumption of tobacco because their marketing is directly targeted towards teenagers in the developing countries who have not yet started smoking. This marketing more than compensates for the decline in smoking in developed countries. How can it be socially responsible to deliberately kill millions of people every year who didn’t need the product in the first place? People who have tried to smoke a cigarette know what I’m talking about. Aged 15, I only succeeded in smoking half a cigarette before I became so intoxicated that I vomited and left school to go directly to bed, as white as my sheets. My mother wondered what terrible disease had hit me so hard and told me later that she’d found half a cigarette in my shirt pocket.
The disconnect between the drug industry’s proclamations of ‘highest ethical standards’, ‘following … all legal requirements’ and ‘most accurate information available regarding prescription medicines’ and the reality of big pharma’s conduct is also vast. The top executives’ views of themselves – or rather the impression they try to convey about their activities – are not even shared by their own employees. An internal 2001 survey of Pfizer employees, which is not available to the public, showed that about 30% didn’t agree with the statement, ‘Senior management demonstrates honest, ethical behavior.’5
In 2012, Pfizer agreed to pay $60 million to settle a US federal investigation into bribery overseas. Pfizer wasn’t only accused of bribing doctors, but also hospital administrators and drug regulators in several countries in Europe and Asia.6 The investigators said Pfizer units sought to hide the bribery by listing the payments in accounting records as legitimate expenses, such as training, freight and entertainment. According to court papers, the company wired monthly payments for what it described as ‘consultancy services’ to a doctor in Croatia who helped decide what drugs the government would register for sale and reimbursement. Pfizer didn’t admit or deny the allegations, which is routine practice when drug companies settle accusations of fraud.
Hoffman-La Roche, the biggest drug pusher
Th
e 10 largest drug companies7 are all signatories to the US PhRMA code, apart from Hoffman-La Roche, Switzerland,3 which was the largest corporate fraudster worldwide in the 1990s according to a 1999 listing of all industries, including banks and oil.8 High-level Roche executives led a cartel that, according to the US Justice Department’s antitrust division, was the most pervasive and harmful criminal antitrust conspiracy ever uncovered.9 Top executives at some of the world’s biggest drug companies, largely from Europe and Asia, met secretly in hotel suites and at conferences. Working together in a coalition they brazenly called ‘Vitamins Inc.’, they carved up world markets and carefully orchestrated price increases, in the process defrauding some of the world’s biggest food companies. Roche alone had revenues of $3.3 billion in the United States while the conspiracy was running, and during that time, the conspirators gradually and artfully raised the prices of raw vitamins, so as not to attract notice; they also rigged the bidding process.9
The Justice Department charged Kuno Sommer, former Director of Worldwide Marketing, Hoffmann-La Roche Vitamins and Fine Chemicals Division, with participating in the vitamin cartel and for lying to Department investigators in 1997 in an attempt to cover up the conspiracy.10 Sommer pleaded guilty and got a 4-month prison term. After the conspiracy collapsed, those involved agreed to pay nearly $1 billion to settle federal antitrust charges, and virtually every big vitamin maker in the world was on the brink of agreeing to pay an additional $1 billion. Roche agreed to pay $500 million, equivalent to about 1 year’s revenue from its vitamin business in the United States, and two executives were sentenced to prison terms of a few months. In Europe, the European Commission fined some of the world’s biggest drug companies, including Roche, a record £523 million in 2001.11 It is surprising that the cartel could exist for so long, as a Roche insider blew the whistle already in 1973, which the European Commission acted on (see Chapter 19).
Deadly Medicines and Organised Crime Page 5