Deadly Medicines and Organised Crime

by Peter Gotzsche

  These drugs were superseded by sibutramine in 2001, which not only increases serotonin in the brain but also norepinephrine and dopamine. It came as no surprise when it was removed from the market in 2010 because of cardiovascular harms. In 2007, we asked for access to the unpublished trials with this drug at the Danish drug agency, which was granted a year later, but the lawyer of the company, Abbott, blocked the permission for another year by lodging a complaint with the Danish Ministry of Health. Using our Freedom of Information Act we found out that a hired gun, cardiologist Christian Torp-Pedersen, had signed the letter from Abbott to the Ministry, which undoubtedly gave it more credibility. We felt that the cardiologist should have worried more about his patients and the cardiovascular harms of sibutramine than about the company’s health.

  Why on earth are such drugs still being approved given their history? And why was benfluorex (Mediator from Servier), which is structurally related to fenfluramine and has similar harms, not taken off the European market until 2009 when Pondimin disappeared in 1997? Well, there is nothing new under the sun. There were conflicts of interest among expert advisers and also ‘institutionalised cooperation’ with the drug industry – the much hyped and lauded public–private partnership.39,40 Unhealthy ties between the regulator and the industry were also uncovered and there were suspicions that Servier, which is a French company, had obtained far too much political influence. The head of the French drug agency resigned because of the scandal.

  Slimming pills are poor drugs that are not liked by the patients. In drug trials, doctors have financial incentives for keeping patients on the drug, but in real life, the situation is very different. A study showed that after just 1 year, less than 10% of the patients still took their drugs (sibutramine or orlistat, a drug that decreases fat absorption) and after 2 years, it was less than 2%.41

  Recent decisions underline that drug agencies refuse to learn from history. FDA staff explained in 2012 why the FDA had approved two new slimming pills, Belviq (lorcaserin, Arena Pharmaceuticals) and Qsymia (phentermine + topiramate, Vivus).42 Lorcaserin increases serotonin, increases the incidence of multiple tumours and valvulopathy in rats, and increases valvulopathy by 16% in patients. Topimarate may increase the risk of orofacial cleft if taken during pregnancy, which is a problem the FDA solved with a fake fix we know won’t work: tell the women to protect themselves against pregnancy. Both drugs may create psychiatric disturbances and other important adverse effects, and the FDA required a rigorous assessment of long-term cardiovascular safety for the drugs, although it doesn’t and cannot enforce such demands, another fake fix. We will surely see new slimming pill scandals.

  Obesity specialists have defended the slimming pills all along by saying that the increased risk of dying caused by the drugs is counteracted by the fact that even a minor weight loss in a large population leads to more lives saved than lost. This is a poor argument. First, it hasn’t been shown to be true. Second, even if it were true, there is a huge difference between being slowly killed by a drug under terrible suffering and a benefit at population level. It’s a fact of life that we may die sooner if we have unhealthy lifestyles. We all know this. If we want to reduce the number of people dying from obesity, we should first and foremost tackle the food industry. Giving people drugs is a fake fix that is very dangerous. A 2008 study of 5743 users of fenfluramines showed that the prevalence of mild aortic regurgitation or moderate mitral regurgitation, or worse, was 20% in women and 12% in men; the risk increased markedly with months of use; and valve surgery was performed in one of 200 patients with drug-induced valvulopathy.43 And yet the FDA has now approved a similar drug.

  References

  1 Vedantam S. Antidepressant makers withhold data on children. Washington Post. 2004 Jan 29.

  2 Melander H, Ahlqvist-Rastad J, Meijer G, et al. Evidence b(i)ased medicine – selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ. 2003; 326: 1171–3.

  3 Melander H. [Selective reporting – greater problem than selective publishing?] Läkartidningen. 2005; 102: 224–5.

  4 Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008; 358: 252–60.

  5 Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Med. 2008; 5: e217.

  6 Lenzer J. Drug secrets: what the FDA isn’t telling. Slate. 2005 Sept 27.

  7 Rennie D. When evidence isn’t: trials, drug companies and the FDA. J Law Policy. 2007 July: 991–1012.

  8 Chalmers I. From optimism to disillusion about commitment to transparency in the medico-industrial complex. J R Soc Med. 2006; 99: 337–41.

  9 Scherer RW, Langenberg P, von Elm E. Full publication of results initially presented in abstracts. Cochrane Database Syst Rev. 2007; 2: MR000005.

  10 MacLean CH, Morton SC, Ofman JJ, et al. How useful are unpublished data from the Food and Drug Administration in meta-analysis? J Clin Epidemiol. 2003; 56: 44–51.

  11 Goldacre B. Bad Pharma. London: Fourth Estate; 2012.

  12 Chalmers I. Underreporting research is scientific misconduct. JAMA. 1990; 263: 1405–8.

  13 Danish Association of the Pharmaceutical Industry. [Revised collaborative agreement between the Medical Association and the Danish Association of the Pharmaceutical Industry about clinical trials and non-intervention studies]. 2010 June 1.

  14 Gøtzsche PC, Jørgensen AW. Opening up data at the European Medicines Agency. BMJ. 2011; 342: d2686.

  15 Wikipedia. Rimonabant. Available online at: http://en.wikipedia.org/wiki/Rimonabant (accessed 17 January 2013).

  16 World Medical Association. Declaration of Helsinki – ethical principles for medical research involving human subjects. 2008.

  17 Gøtzsche PC. Why we need easy access to all data from all clinical trials and how to accomplish it. Trials. 2011; 12: 249.

  18 Topol EJ. Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med. 2004; 351: 1707–9.

  19 Lenzer J. FDA is incapable of protecting US ‘against another Vioxx’. BMJ. 2004; 329: 1253.

  20 Anonymous. Institute of Medicine urges reforms at FDA. Lancet. 2006; 368: 1211.

  21 Relman AS, Angell M. America’s other drug problem: how the drug industry distorts medicine and politics. The New Republic. 2002 Dec 16: 27–41.

  22 Carpenter D. Drug-review deadlines and safety problems (authors’ reply). N Engl J Med. 2008; 359: 96–8.

  23 Moore TJ. Deadly Medicine: why tens of thousands of heart patients died in America’s worst drug disaster. New York: Simon & Schuster; 1995.

  24 Cowley AJ, Skene A, Stainer K, et al. The effect of lorcainide on arrhythmias and survival in patients with acute myocardial infarction: an example of publication bias. Int J Cardiol. 1993; 40: 161–6.

  25 EMA. European Medicines Agency Widens Public Access to Documents. Press release. 2010 Nov 30.

  26 Regulation (EC) No 1049/2001 of the European Parliament and of the Council of 30 May 2001 regarding public access to European Parliament, Council and Commission documents. Official Journal of the European Communities. 2001; L145: 43–8.

  27 Hawkes N. Lobby groups call for closure of ‘revolving door’ between drug regulators and industry. BMJ. 2011; 343: d8335.

  28 European Medicines Agency. Access to clinical-trial data and transparency. Workshop report. 2012. Available online at: www.ema.europa.eu/docs/en_GB/document_library/Report/2012/12/WC500135841.pdf (accessed December 2012).

  29 Editorial. [Straight talk]. Information. 2004 June 30.

  30 Alfter B, Teugels M, Bouma J. Media lift lid on secret reports on drug side-effects. Euobserver. 2008 Oct 22.

  31 Abraham J. Science, Politics and the Pharmaceutical Industry. London: UCL Press; 1995.

  32 Gøtzsche PC. UK drug regulator destroys all evidence after 15 years. BMJ. 2011; 343: d4203.

 
33 Jüni P, Reichenbach S, Egger M. COX 2 inhibitors, traditional NSAIDs, and the heart. BMJ. 2005; 330: 1342–3.

  34 Caldwell B, Aldington S, Weatherall M, et al. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. J R Soc Med. 2006; 99: 132–40.

  35 Mundy A. Dispensing with the Truth. New York: St. Martin’s Press; 2001.

  36 Avorn J. Powerful Medicines: the benefits, risks, and costs of prescription drugs. New York: Vintage Books; 2005.

  37 Jørgensen AW. Robustness of results and conclusions in systematic reviews, trials and abstracts [PhD thesis]. Copenhagen: University of Copenhagen; 2011.

  38 Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997; 337: 581–8.

  39 Mullard A. Mediator scandal rocks French medical community. Lancet. 2011; 377: 890–2.

  40 Mintzes B. New UK guidance on industry-health professional collaboration. BMJ. 2012; 344: e3952.

  41 Padwal R, Kezouh A, Levine M, et al. Long-term persistence with orlistat and sibutramine in a population-based cohort. Int J Obes (Lond). 2007; 31: 1567–70.

  42 Colman E, Golden J, Roberts M, et al. The FDA’s assessment of two drugs for chronic weight management. N Engl J Med. 2012; 367: 1577–9.

  43 Dahl CF, Allen MR, Urie PM, et al. Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals. BMC Med. 2008; 6: 34.

  12

  Neurontin, an epilepsy drug for everything

  Several events in 2004 were a wake-up call for those who still believed the drug industry stands for respectable business. Two of the largest US companies had quite different reputations before the scandals broke lose: Pfizer was considered one of the worst whereas Merck (see Chapter 13) was known as one of the most ethical drug firms. After 2004, it was hard to tell the difference. The heat was also turned on GlaxoSmithKline in 2004 (see Chapter 16).

  In 2004, Pfizer agreed to plead guilty to two felonies and pay $430 million to settle charges that it fraudulently promoted the epilepsy drug Neurontin (gabapentin) for unapproved uses.1 A company whistle-blower would receive $27 million. The fine was small considering that the sales of gabapentin were $2700 million in 2003 alone, and as about 90% of the sales was for off-label use,1,2,3 the fine would not be expected to have any deterrent effect.

  Warner-Lambert, later bought by Pfizer, paid doctors to allow salespeople to sit with them as they saw patients and to suggest using Neurontin for a wide array of ailments, including bipolar disorder, pain, migraine, attention deficit disorder, restless leg syndrome, and drug and alcohol withdrawal,1,2 although the drug was only approved for treatment-resistant epilepsy.2,4,5 A drug index, Drugdex, listed no less than 48 off-label uses for Neurontin, and Medicaid was obliged to pay for the drug if being prescribed for one of these uses.4 Furthermore, the company that owns Drugdex sells ‘medical education’, a truly incestuous enterprise.

  The common practice of planting salespeople in doctors’ offices is euphemistically called ‘preceptorship’,4 as if the doctor trained a medical student, but a more appropriate term would be ‘predatorship’, as it harms patients.5 The patients are not always aware that the salesperson isn’t a medical student, not even when they are examined for breast cancer.6 A company executive told a salesperson:

  ‘Dinner programs, CME programs, consultantships all work great but don’t forget the one-to-one. That’s where we need to be, holding their hand and whispering in their ear, Neurontin for pain, Neurontin for monotherapy, Neurontin for bipolar, Neurontin for everything … I don’t want to hear that safety crap.’7

  Much of the illegal promotion took place at meetings that were supposed to educate doctors. A physician whistle-blower testified that he was trained to distort the scientific evidence,5 and at some Neurontin meetings, the company paid not only the speakers but also the listeners, treating them to luxury trips to Hawaii, Florida or the 1996 Olympics in Atlanta.1

  It was very easy to corrupt doctors. Of 40 influential thought leaders identified as potential speakers in north-eastern United States, including 26 current or future department chairs, vice chairs, and directors of academic clinical programmes or divisions, no fewer than 35 participated in company-sponsored activities, and 14 requested or were allocated $10 250–$158 250 in honoraria or grants.6 One doctor received almost $308 000 to tout Neurontin at conferences.6

  The speakers were updated on the company’s promotional strategies,6 and Warner-Lambert tracked high-volume prescribers and rewarded them as speakers or consultants, or for recruiting patients in studies. Doctors were also paid to lend their names to ghostwritten articles purporting to show that Neurontin worked for unapproved conditions,4,6 and a professor requested and received over $300 000 to write a book on epilepsy.5,8 It was surely true what was stated in an internal document obtained through US court proceedings: ‘Medical education drives this market!’7

  Other internal documents illustrate the extent to which the company was willing to distort the evidence.6,9 In relation to the illegal marketing, the company had a publication strategy:

  ‘The results, if positive, will … be published’, and ‘I think that we can limit the potential downsides of the 224 study by delaying the publication for as long as possible.’

  The manipulations also involved selective statistical analyses, selective reporting of outcomes that happened to show a positive effect, inappropriate exclusion or inclusion of patients in the analyses, multiple publication of desirable results, differential citation of Pfizer results, and spin to make negative results appear positive. The bias was already introduced at the design stage, e.g. high doses were used that led to unblinding and biased reporting of subjective outcomes. Pfizer even recognised that unblinding due to adverse events could result in corruption of the study’s validity.

  The final layer of corruption of the evidence was accomplished by ghostwriters: ‘We would need to have “editorial” control’; ‘We are using a medical agency to put the paper together which we will show to Dr. Reckless. We are not allowing him to write it up himself’ (the doctor’s name was actually Reckless); and ‘We know Alison wants to make sure that we align publication messages with your global marketing efforts.’ A medical writer asked Pfizer: ‘How do we make it sound better than it looks on the graphs?’10

  Kay Dickersin, director of the US Cochrane Center, uncovered all this and summarised what she felt about it: ‘Outright deception of the biomedical community, highly unethical, harmful to science, wasteful of public resources, and potentially dangerous to the public’s health … As with all the trials I reviewed, selective analyses … could explain any positive findings observed.’9

  Pfizer was unsure how it should tackle requests from Cochrane researchers about getting access to unpublished data,9 and a previous case explains Pfizer’s dilemma. As explained in Chapter 6, Pfizer got bad publicity in 1999, when my wife and I described in JAMA how the company had rigged a series of trials of its antifungal drug, fluconazole, and refused to provide us with the data we needed to sort things out.11 Even after JAMA’s deputy editor had urged the company to reply, Pfizer refused to respond to simple and pertinent questions. The story made front-page news in the New York Times. Shortly afterwards, the founder of the Cochrane Collaboration, Iain Chalmers, told me he was visited by a director from Pfizer UK and wanted to show him how easy it is to search in The Cochrane Library. He typed ‘Pfizer’, which brought him to the Discussion section of our Cochrane review of fluconazole where we wrote:12

  We experienced unexpected difficulties in obtaining responses to our requests for additional or clarifying information about the trials … We did not succeed to get any information from the investigators or Pfizer, the manufacturer of fluconazole, on the most pertinent issues: why oral amphotericin B was used, why the results for this drug were lumped together with those of an ineffective drug … and whether there was overlap between different trials reports.

&nb
sp; Our paper and the media attention gave Pfizer something to think about, which was revealed 2 years later when its vice president for research responded to another Cochrane request by providing a list of references, which was entirely unhelpful. The internal deliberations were interesting:9

  ‘I would not send unpublished data to anyone outside Pfizer … The decision is ultimately yours … the risk is that in the Cochrane review there is a statement saying Pfizer declined to provide the information requested! which does not look good for the company.’

  Three years later, the Cochrane group again reminded Pfizer of its request but in vain. The Cochrane protocol was eventually withdrawn and the review was never completed. In relation to another Cochrane review, Pfizer stated: ‘We definitely will not supply any internal data, we all agree on that.’

  It is indisputable that the illegal and fraudulent promotion, which was approved by some of the company’s top executives, led to harm.2,6 An internal memorandum showed that doctors who attended dinners given by the company to discuss unapproved uses of Neurontin wrote 70% more prescriptions for the drug than those who didn’t attend.2 The company even insisted on pressing doctors to use much higher doses of Neurontin than those that had been approved, which means higher income for more harm.

  A seeding trial, the STEPS study, which had no control group, had the marketing objective to increase the dose of Neurontin and its market share, and it involved 772 physicians who only treated four patients each, on average.13 Physicians with little or no experience in trials were recruited and the data were very dirty, which the two published papers said nothing about. Drug salespeople collected data and were directly involved in suggesting to the doctors which patients to enrol while being present in the doctors’ offices. The trial was deeply unethical, as the patients were not informed about the true marketing purpose of the study, and as the doctors were the actual study subjects without knowing this, as the effect of their participation on sales was closely monitored.