Deadly Medicines and Organised Crime

by Peter Gotzsche

  Figure 9.2 Bias in trials comparing granisetron with placebo for postoperative nausea and vomiting. Results are shown for the use of a rescue antiemetic

  Despite the huge amount of data, the Cochrane review couldn’t conclude anything about the possible differences between the drugs. This must also be some sort of record for research waste; after 737 trials and 100 000 patients no reliable conclusion can be made, although it’s so simple to study postoperative nausea and vomiting!

  I have been a member of the drug committee at our hospital for 20 years and, in 2012, the clinicians wanted to get permission to use some new antinausea drugs as standard. One was palonosetron, which cost 44 times more than ondansetron and 17 times more than granisetron. We were told that in those trials that had been submitted to the drug agency for obtaining marketing approval, palonosetron had a similar effect to the older setrons when heavy chemotherapy was used, but was slightly better when the chemotherapy caused less nausea and vomiting (81% and 69%, respectively, did not develop nausea). I couldn’t participate in the meeting but warned the chairman of the committee against selective publication of the most positive results. I also noted that we needed access to the unpublished trials and their protocols, and that a full Cochrane review was needed if we wanted to know whether the new drugs were any better than the cheap ones.

  The minutes from the meeting said that it was agreed to allow the clinicians to use the expensive drugs when heavy chemotherapy was used (where there was no advantage of palonosetron), including a drug that cost 300 times as much as the cheapest one, and that the clinicians should carefully consider when the drugs should be used. Experience has shown that such recommendations rarely prevent people from using expensive drugs, although it’s impossible that they can be 300 times more valuable than the cheap ones.

  I withdrew my membership of our drug committee after 20 years of uninterrupted disappointment. No matter how shaky or irrational the arguments, or how expensive the new drugs, drug committees almost always please the clinicians. I think it’s about not getting into trouble. Heads of departments are powerful and often on industry payroll, and if too many complaints are being made, top managers might not get their tenure renewed. It also takes time to say no, as protests are likely to ensue, and those at the top have far too little time already. I have discussed this with chairmen of drug committees elsewhere and they have also experienced a lack of management support for unpopular decisions.

  We don’t live up to our values as a profession. Drug salespeople may come to heads of departments and ask whether they will make an application to the drug committee, with the tacit understanding that those who refuse will be out of favour come conference time, and that is also how it works.59

  The interactions between physicians and the industry were until recently chiefly of interest to medical ethicists.60 That is not the case any longer, and two previous editors of the New England Journal of Medicine, Marcia Angell and Jerome Kassirer, and a previous editor of the BMJ, Richard Smith, each wrote a book with a telling title after they had stepped down as editors:

  The Truth about the Drug Companies: how they deceive us and what to do about it.32

  On the Take: how medicine’s complicity with big business can endanger your health.61

  The Trouble with Medical Journals.62

  Highly expensive drugs

  I have tried to find out just how expensive drugs can be compared to the benefit they offer and yet succeed getting used. Treatment of one patient with biologic agents can cost up to €16 000 a year in Denmark, which is 120 times as much as treatment with conventional drugs.63 Biologic agents are widely used for rheumatoid arthritis, but a 2010 meta-analysis showed that they are not any better in retarding joint damage than a combination of two cheap disease-modifying antirheumatic drugs (DMARDs).64 Unfortunately, the meta-analysis came 4 months too late. The European League Against Rheumatism (EULAR) had posted new recommendations stating that biologic agents should be initiated without first trying therapy with a combination of DMARDs in patients whose arthritis was not sufficiently responsive to therapy with a single DMARD.

  The EULAR recommendations were based on a review of only a fraction of the published studies, but once an organisation has issued new guidelines, it is extremely difficult to change them, even though, as in this case, billions of Euros could be saved in the EU every year (in Denmark alone, the cost for biologic agents was €130 million in 2011). The authors of the meta-analysis recently conducted a more sophisticated network meta-analysis that confirmed their results (Graudal, personal communication).

  In 2010, the BMJ reported that a vaccine – not to prevent cancer but to treat metastatic prostate cancer – was approved by the FDA.65 It cost $93 000 for three doses, and who knows whether the doctors would try more doses if they didn’t see signs of the expected effect, which is a life extension of merely 4 months.

  In 2012, Denmark decided to pay for a drug against metastatic melanoma that cost about $100 000 for one patient and which prolongs life by 3.5 months.66 The oncologists sold the idea to the public by claiming that 10% of the patients would be cured,67 although the trials didn’t in any way justify this generous interpretation. A member of the working group that decided to pay for the drug couldn’t see it was a problem that she received money from the company that stood to benefit from her decision.68 In 2006, a new drug for head and neck cancer cost about $110 000 a year.69

  The wooden spoon in futility I have seen so far goes to erlotinib for treatment of pancreatic cancer. Both the FDA and the EMA approved it, although it only prolongs life by 10 days, is toxic and will cost almost $500 000 for 1 year of life gained (10 days for each of 36 patients that aren’t even pleasant).70

  Examples of even more expensive drugs follow in Chapter 20, but here is one about a drug that didn’t work. Intravenous alpha-1 antitrypsin is used in some countries for patients with lung disease caused by inherited alpha-1 antitrypsin deficiency. Some lung specialists had successfully lobbied a political majority in the Danish Parliament to agree to reimburse the drug, which may cost up to €116 000 annually per patient and which is to be used in many years, as the deterioration in lung function is slow, and very slow if the patients don’t smoke. Before the decision was made, I was asked to review the trials and I found out that there is no convincing evidence that the drug is effective. It took me only 4 weeks to produce the report, which we later published.71 It made the politicians decline to reimburse the drug, which saved Danish taxpayers at least €30 million every year.

  Something is terribly wrong in the way we prioritise. The most intensive and expensive therapy is often given in the last few days or weeks of life. It would be much better if we used this precious time constructively with our loved ones, instead of being pestered by the toxic effects of chemotherapy in a fight we cannot win.

  Such simple ideas have powerful enemies in interest groups. After prominent doctors had declared publicly that they would abstain from life-prolonging chemotherapy if they got lethal cancer,72 the chairman of the Danish Cancer Society, Frede Olesen, reprimanded them, saying they harmed the trust between patients and doctors.73 They didn’t; they gave very sound advice to the public. Why should the patients not have the same privileges as health professionals? Few oncologists and nurses are willing to accept the chemotherapy their patients endure for minimal benefit.74 In elderly patients, aggressive treatment is even more misplaced. What is most important to them is to maintain their independence and dignity,75 not a few extra intolerable weeks.

  What is even more remarkable is that the conservative attitude cancer societies don’t like may in some cases not only improve the patients’ quality of life but also make them live longer. A randomised trial in patients with newly diagnosed metastatic non-small-cell lung cancer showed that those assigned to palliative care early on received less aggressive treatment and lived 3 months longer.76 Drugs can kill you also when your life is almost over.

  Excesses in hypertension

/>   What we need more than anything else to put a brake on the exploding expenditures on new drugs and their harms is independent drug trials. One such trial, the 2002 ALLHAT trial, shows how strong the counteracting forces of the medico-industrial complex can be. With 33 357 patients, it was the largest hypertension trial ever conducted.42 It compared four drugs: doxazosin (an alpha-blocker from Pfizer), amlodipine (a calcium channel blocker from Pfizer), lisinopril (an ACE inhibitor) and chlorthalidone (a diuretic). The doxazosin arm was stopped prematurely, as the drug was clearly inferior. However, Pfizer started a damage control campaign, which was very effective, as there was no decline in sales the same year. When the ALLHAT study was presented at a large congress in California, Pfizer invited the doctors on sightseeing to ensure they didn’t learn about the results.77

  In a press release, the American College of Cardiology urged doctors to ‘discontinue use’ of doxazosin, but this was changed within hours after Pfizer had contacted the College which now said that the doctors should ‘reassess’ its use.77 Rather unfortunate advice about a drug that had just been proven inferior, but it might have played a role that donations from Pfizer to the College exceeded $0.5 million annually. ALLHAT demonstrated that the cheapest of the four tested drugs, the diuretic, was also the best. The chair of the ALLHAT steering committee, Curt Furberg, estimated that the use of the expensive calcium channel blockers and ACE inhibitors cost an excess of $8–10 billion without providing any benefit to patients, and in some instances adding more risk. The use of inferior drugs had caused heart failure in 40 000 patients in the United States at the same time as they had to pay 20 times more for the inferior drugs.78

  Unsurprisingly, the results generated a huge ‘controversy,’ with innumerable letters and papers written by seemingly independent whore doctors who were hired guns for the company.

  A paper from 2003 reported that Pfizer’s other ALLHAT drug, amlodipine, was the most sold antihypertensive drug in Norway, although it was 10 times as expensive as a diuretic, and although the evidence for a preventive effect on heart disease didn’t exist.79 If doctors had used a diuretic rather than amlodipine, $750 million could have been saved annually in Germany, the UK and the United States.80 In 1996, amlodipine was the most heavily advertised drug in the New England Journal of Medicine, while there wasn’t a single ad for diuretics.32 The ALLHAT trial wasn’t published in this journal, but in JAMA.

  An article from 2009 reported that the difference between the cost for the cheapest and the most expensive ACE inhibitor was a factor of 30 and that Denmark could save about €40 million a year by using the cheapest drug.81 It looked like a no brainer, but no. The chairman of the Danish Society for Hypertension, Hans Ibsen, declared that we needed to be very cautious about changing drugs in patients with a well-regulated blood pressure, whereas another hypertension specialist, Ib Abildgaard Jacobsen, said that he had changed many patients’ drugs without problems. Which of the two specialists was on industry payroll? That’s a no brainer!

  A year later, Ibsen shared his thoughts with us. He initially supported the use of losartan, the first angiotensin II receptor antagonist, marketed by Merck, which was one of Ibsen’s benefactors.82 When new similar drugs were introduced, Ibsen recommended those instead, although they were 10–20 times more expensive, with the argument that hypertension research would disappear from Denmark if we didn’t use the expensive drugs. In this, Ibsen was supported by the medical director of Novartis, another of his benefactors, who stated that Novartis conducted research to introduce their products on the market so that they would be used and that she saw no great future for trials in Denmark if there wouldn’t be subsequent sales. It was rather bold that Novartis – which sold one of the highly expensive new angiotensin II receptor antagonists – didn’t try to hide the fact that its ‘research’ wasn’t research but marketing. A colleague who, like me, is a member of Doctors Without Sponsors remarked about the astonishing revelations that when the purpose of research was to teach the doctors to use far too expensive drugs, it might be better that the research was performed elsewhere.82 We could have saved €67 million in just 1 year if all doctors had used losartan,83 which is an enormous amount of money for a small country.

  I mention this story because I cannot recall any other where people have been so honest about their shady motives. Ibsen once attacked me in our medical journal saying I should be more positive towards the drug industry and acknowledge the important work sincere researchers did in collaboration with sincere drug companies. In reply, I asked what Ibsen meant by a sincere company and noted that he collaborated with Merck, Pfizer, AstraZeneca and Novartis, all of which had received giant fines for fraud, and that tens of thousands of patients had lost their lives because of the misdeeds committed by Merck and Pfizer.84 Since these patients died from cardiovascular events, which hypertension experts try to avoid, it might have been expected that Ibsen would have refused to collaborate with such companies for the rest of his professional life, rather than calling them sincere. Doctors have a remarkable capacity for denial, whereas the bereaved spouses cannot deny that their loved ones are dead because they took a drug they didn’t need.

  Patient organisations

  A chapter on hard sell wouldn’t be complete without mentioning patient organisations. They are usually funded by – and speak with the same voice as – big pharma. In 2006, a pan-European cancer campaign, Cancer United, was presented as a pioneering effort by a coalition of doctors, nurses and patients to push for equal access to cancer care across the EU.85 It was entirely funded by Roche, the world’s leading drug pusher (see Chapter 3) and maker of cancer drugs, some of which are exceedingly expensive, e.g. Herceptin for breast cancer and Avastin for bowel cancer. Roche’s PR firm was the secretariat and the principal study on which the propaganda was based was funded by Roche. The study report was written by Nils Wilking from the Karolinska Institute in Stockholm and Bengt Jönsson from Stockholm School of Economics. It received a lot of publicity but was seriously flawed, and its conclusions were unsupported by the data.86 It concluded ‘It is clearly in the best interest of cancer patients that new, innovative drug therapies are made available to them as soon as possible. Reduced or delayed access to cancer drugs has a very real impact on patient survival.’

  Traditional company speak it was, and the promotional material said that the campaign aimed to collect one million signatures and would press the European Commission for an EU-wide strategy. The chairman of the European Cancer Patients Coalition found herself listed as a member of the campaign’s executive board without her agreement. She and members of the European Parliament withdrew from the board. The chair of the executive board, Professor John Smyth, who committed editorial misconduct in his role as editor of the European Journal of Cancer in relation to one of our studies on mammography screening,87 wrote the foreword to the Karolinska report, said the campaign was his idea and expressed a wish that people should stop seeing the industry as the enemy.

  NovoSeven for bleeding soldiers

  In 2011, Novo Nordisk agreed to pay $25 million to resolve its civil liability arising from the illegal promotion of its haemophilia drug, NovoSeven.88 Haemophilia is a very rare disease, but Novo promoted the drug, which contains factor VII, unlawfully to healthcare professionals as a coagulatory agent for trauma patients and similar uses, resulting in false claims to be submitted to government healthcare programmes that were not reimbursable by those programmes. The case involved a whistle-blower lawsuit and an expansive Corporate Integrity Agreement with the Department of Health and Human Services.

  The Justice Department suit alleged that Novo improperly paid influential US Army physicians to use and promote NovoSeven and provided illegal incentives also for researchers.89 The company engaged in a ‘fraudulent scheme to use kickbacks and off-label promotion’ to boost sales, which trebled in 5 years to $750 million in 2004 and exceeded $1 billion in 2007. The activities involved speaking engagements, positions on advisory boards and un
restricted research grants for people working at the US Army Institute of Surgical Research.

  In 2005, a heavily manipulated trial in 301 severely bleeding trauma patients was published in a little-known journal that purported to show that NovoSeven worked.90 If true, it would have been sensational and we would have expected to see the trial published in the New England Journal of Medicine or the Lancet, with huge reprint orders. The abstract was highly misleading and described two trials, although it was only one trial. The data analysis was seriously flawed, using a new outcome that wasn’t specified in the protocol and an arbitrary cut-off for number of transfusions, and excluding patients from analysis who died within the first 48 hours. The data massage was so clumsily made that it was fairly easy to see that the trial hadn’t shown any effect.

  The trial was funded by Novo and had a Novo employee and four physicians on Novo payroll among the authors. It was torn into pieces by experts, also in the journal where it was published which spoke of ‘information laundering’,91 but Novo’s research director, Mads Krogsgaard Thomsen, maintained that it was the physicians who stood for the positive conclusions and that the company had had limited input into the paper.92 This is hard to believe, as the statistician was also from Novo. A physician from my hospital had acquired access to the protocol, which made it possible for him to see the manipulations. Some people believed in this mockery of science, and Novo embarked on a new trial, which my hospital declined to participate in. We had seen enough already.