Deadly Medicines and Organised Crime

by Peter Gotzsche

  Troglitazone (Rezulin) was withdrawn in the UK in 1997 and in the United States in 2000 because it may be associated with an increased risk of liver failure; sorry, I meant it causes liver failure.3 It was approved despite doubts about both efficacy and safety,36 but the experienced FDA medical officer who had reviewed the drug was removed at the request of the company, Parke-Davis, before the advisory committee vote.37 (I fully understand if you have become angry after having seen so much fraud and abuse of power that harm and kill patients, but that’s exactly why I wrote this book: to wake people up to what is happening. The worst is still to come, in the next two chapters about psychiatric drugs.) Parke-Davis cheated the advisory committee by saying that the risk of liver toxicity was comparable to placebo and that additional data from other studies confirmed that the rate of liver damage was ‘very, very similar’.38 When the company provided these additional data a week after approval, they showed a substantially greater risk with the drug than with placebo. As usual, the FDA responded by a fake fix. It advised monthly liver function tests, but they were rarely performed, e.g. in only 1% of patients after four months.39 What is more serious is that it’s a fatally incorrect assumption that liver tests prevent liver failure.37

  Outright fraud was also an issue. When cases of serious liver damage accumulated, Parke-Davis tightened the criterion for ‘abnormal’ for those treated with its drug but not for those treated with placebo, whereby they obscured the true risk for the FDA.38 When a new advisory committee reviewed the drug again in March 1999, the committee voted 11 to 1 to keep it on the market, but nine of the 10 physicians who reported on safety were paid consultants to the company.37 Is there anything the FDA doesn’t allow?

  In Europe, Glaxo Wellcome took Rezulin off the UK market after only 3 months because of rapidly increasing reports of liver damage, and Glaxo and the Japanese company that had developed the product withdrew applications for marketing in 26 additional countries.38

  At the FDA, however, the story rolled on, as depressing as always: intimidation of scientists that warned about the drug and protection of the drug by higher-ups.39 David Graham reported that the drug increased the risk of liver failure by a factor of 1200, whereas the company, assisted by nine prominent diabetes experts who were later shown to be on company payroll, claimed the incidence was only one in 100 000. I greatly admire people like Graham who against all odds stay at the FDA and do what they can to protect patients, when most people with their heart in the right place would have run screamingly away from an institution like that.

  Parke-Davis continued lying. It wrote to US doctors that Glaxo Wellcome had temporarily suspended marketing and that it only had experience with 5000 patients, although Glaxo’s decision was based on cases of liver failure worldwide including those in the United States.38 The company also reassured the doctors that the new reports had not indicated a greater potential for serious harm than previously estimated.

  At the same time, the NIH conducted a trial to see if troglitazone could prevent healthy people becoming diabetic. The director of its diabetes division, Richard Eastman, wrote to the doctors who had enrolled patients that Glaxo’s decision was apparently a marketing decision and that the NIH was comfortable with continuing with troglitazone. Eastman had received over $78 000 from the company as a consultant to Parke-Davis, but when this was revealed in a newspaper, neither his boss nor the university-based chairman of the study saw any problems with it.38 Six months after Eastman’s reassuring letter, a healthy teacher died of rapidly progressing liver failure and there was no way the regular liver tests could have prevented this from happening. At this point, the NIH discontinued the troglitazone arm in their study, but the drug remained on the US market for almost another 2 years. Why? Why 3 years more in the United States than in the United Kingdom?

  Independent researchers saved the FDA from yet another diabetes scandal. Muraglitazar has a similar mechanism of action to the glitazones, and an FDA advisory committee recommended approval of the drug. However, independent researchers who analysed the trial data submitted to the FDA found that Bristol-Myers Squibb and Merck had produced flawed analyses and that the drug was harmful.40,41 The companies’ presentations to the advisory committee concluded that no significant excess risk of deaths or cardiovascular events occurred with muraglitazar. However, there was a two-fold increased risk in the composite outcome of death, heart attack or stroke and a seven-fold increase in heart failure (albeit with a wide confidence interval). The drug also increased weight and oedema, like the glitazones do. The Freedom of Information Act made the independent analysis possible, and it saved many lives. Although the FDA had already prepared an approval letter, it refused to approve the drug after this analysis.

  I have no doubt about what I would do if I should get type 2 diabetes. I would eat less and exercise more. These are highly effective interventions, the best we have, considering also that they won’t kill us. However, when the non-profit American Diabetes Association on its website announced that diabetes management involves more than blood sugar control, namely blood pressure and cholesterol control, there was nothing about the best interventions, weight loss and exercise.42 Perhaps because the so-called non-profit organisations leading this initiative had many corporate sponsors: AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck/Schering-Plough, Monarch, Novartis, Pfizer and Wyeth.

  If I decided to take a drug, it would be metformin, which is old and very cheap, and which – in contrast to the other drugs – actually reduces cardiovascular morbidity and all-cause mortality, and even reduces body weight slightly. It is clearly the best drug,43 and was introduced to the United Kingdom already in 1958, in Canada in 1972, but not in the United States until 1995.44 Perhaps it tells us something about unrestrained capitalism and US healthcare that the FDA has been so quick to approve expensive and harmful drugs while the best and cheapest drug was introduced so late (see also Chapter 21).

  The extent to which the diabetes area has been corrupted is sickening. The Endocrine Society in the United States is supposed to be an academic society for diabetes doctors, but it invites companies to ‘get complete access to the endocrine marketplace by partnering with the Endocrine Society’, which offers ‘the full range of endocrinologists you want to reach … to fit your needs’.37 I could vomit. The Society’s first practice guideline recommended testosterone to be measured in all men above 50 years of age and also that treatment might be warranted even if the level wasn’t low when the symptoms suggested hormone deficiency.37 I could vomit again. A horrendously dangerous guideline, as testosterone increases the risk of prostate cancer and as no screening trials have ever been performed that might tell us whether this advice does more harm than good. Such a trial is actually not needed. I am pretty sure it would show that screening for ‘low testosterone’ – whatever that is supposed to mean – is harmful. I don’t understand why my colleagues have sold out of their common sense; money isn’t that important, particularly not for people who are already very wealthy. It’s greed.

  Novo Nordisk interferes with an academic publication

  In 2011, academic researchers published a paper in Gastroenterology that reported an increased risk of pancreatitis and pancreatic cancer in patients with diabetes treated with two glucagon-like peptide-1 drugs. They had used the FDA’s database of reported adverse events of drugs and an elegant design. Their results were convincing, and they also agreed with animal experiments and an analysis performed by the Drug Commission of the German Medical Association that found 11 reports of pancreatic cancer with one of the drugs, which was an unusually high number compared with other diabetes drugs.45

  The study was published on the journal’s website in February 2011, which said it was an unedited manuscript that had been accepted for publication, and that the manuscript would undergo copyediting, typesetting and review of the resulting proof before it was published in its final form.

  Novo Nordisk has a glucagon-like peptide
-1 drug on the market, liraglutide (Victoza), and its research director, Mads Krogsgaard Thomsen, wrote a six-page letter to the editor, ‘Potentially damaging controversial analysis to be published in Gastroenterology’. The letter ended by saying: ‘On behalf of Novo Nordisk, in order to ensure the most optimal guidance to patients and public reaction, we would urge Gastroenterology to withhold the publication of Elashoff et al. until it has been confirmed by an independent statistical analysis.’

  There was no threat of litigation, but every editor knows that when a company’s sales are threatened and it shows its muscle, this is always a possibility. The editor retracted the article, which was republished in the print journal in July 2011, after the authors had looked at their data again, with the same findings.46

  It’s appalling that a drug company interferes with academic publication. Publication on a journal’s website is publication and according to the International Committee of Medical Journal Editors, a journal should in no instance remove an article from its website.47 People can have their say in letters to the editor and corrections can be posted if needed. It was wrong of the editor to withdraw the paper, and it’s essential that we oppose gangster methods and do our utmost to protect our academic freedom, without which the progress of science will wither. We shouldn’t be afraid of threats of litigation when we have done honest science; we must stand by it. Elephants often threaten; they rarely attack.

  Novo’s actions become particularly absurd when we consider the facts. When Novo sought approval of the drug, grave concerns about liraglutide were raised at the FDA by two reviewing pharmacologists and a clinical safety reviewer.48 The safety reviewer said in her statement that she didn’t recommend approval because ‘In the United States, there are already 11 classes of drugs approved for glycemic control in type 2 diabetes … The need for new therapies for type 2 diabetes is not so urgent that one must tolerate a significant degree of uncertainty regarding serious risk concerns.’

  Victoza was approved in January 2010 against the advice of the FDA’s own reviewers. The director of the FDA’s Office of Drug Evaluation II, Curtis Rosebraugh, swept aside their criticisms and explained that while ‘many sponsors may responsibly introduce a drug into marketing, theirs is a profit-based business and the pressures to generate revenue are strong. Also, with most classes of drugs, there are similar drugs in development from competitors which places even more pressure to generate profit before there is more competition’. Sydney Wolfe from Public Citizen said about this remark that it was the kind of comment one would expect from the drug’s sponsor or from Wall Street, not from a high-ranking FDA official.

  In June 2011, Novo had warned all US doctors about the adverse effects of Victoza. The FDA had demanded this after a study had shown the doctors had far too little focus on the harms of the drug.49 The FDA warned that the drug may cause thyroid tumours and pancreatitis, which is a risk factor for pancreatic cancer. It also stated that it shouldn’t be used as initial treatment until additional studies had been completed, and required studies of cardiovascular safety and establishment of a cancer registry to study the occurrence of thyroid and other cancers.50

  In April 2012, Public Citizen sent a petition to the FDA asking the agency to ban Victoza.51 Experiments had shown that mice that were genetically predisposed to pancreatic cancer developed pancreatic cancer more quickly than usual in response to one of the glucagon-like peptide-1 drugs.

  I believe the academic researchers were right and that we shall see a withdrawal of Victoza because of its harms. Just like so many other diabetes drugs and those that should have been withdrawn but never were, like tolbutamide (see Chapter 10) and rosiglitazone in the United States.

  References

  1 Strengthening the credibility of clinical research. Lancet. 2010; 375: 1225.

  2 Nissen S. Slides presented at the FDA advisory meeting about rosiglitazone. 2010 July 13.

  3 Cohen D. Rosiglitazone: what went wrong? BMJ. 2010; 341: 530–4.

  4 Harris G. Diabetes drug maker hid test data. New York Times. 2010 July 13.

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

  6 Khan H, Thomas P. Drug giant AstraZeneca to pay $520 million to settle fraud case. ABC News. 2010 April 27.

  7 Bass A. Side Effects – a prosecutor, a whistleblower, and a bestselling antidepressant on trial. Chapel Hill: Algonquin Books; 2008.

  8 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007; 356: 2457–71.

  9 Nissen SE. Setting the RECORD straight. JAMA. 2010; 303: 1194–5.

  10 Mitka M. Critics press FDA to act on evidence of rosiglitazone’s cardiac safety issues. JAMA. 2010; 303: 2341–2.

  11 Moynihan R. Rosiglitazone, marketing, and medical science. BMJ. 2010; 340: c1848.

  12 Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes – an interim analysis. N Engl J Med. 2007; 357: 28–38.

  13 Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009, 373: 2125–35.

  14 Psaty BM, Prentice RL. Minimizing bias in randomized trials: the importance of blinding. JAMA. 2010; 304: 793–4.

  15 Psaty BM, Furberg CD. The record on rosiglitazone and the risk of myocardial infarction. N Engl J Med. 2007; 357: 67–9.

  16 Graham D, Gelperin K. More on advisory committee decision. BMJ. 2010; 341: 519.

  17 Mello MM, Goodman SN, Faden RR. Ethical considerations in studying drug safety – the Institute of Medicine report. N Engl J Med. 2012; 367: 959–64.

  18 Cohen D. FDA puts rosiglitazone post-marketing trial on hold. BMJ. 2010; 341: c4017.

  19 Tanne JH. GSK is accused of trying to suppress editorial on rosiglitazone. BMJ. 2010; 340: c2654.

  20 Slaoui M. The rise and fall of rosiglitazone: reply. Eur Heart J. 2010; 31: 1282–4.

  21 FDA Drug Safety Communication. Avandia (Rosiglitazone) Labels now Contain Updated Information about Cardiovascular Risks and Use in Certain Patients. 2011 Mar 3.

  22 Wang AT, McCoy CP, Murad MH, et al. Association between industry affiliation and position on cardiovascular risk with rosiglitazone: cross sectional systematic review. BMJ. 2010; 340: c1344.

  23 Lehman R, Yudkin JS, Krumholz HM. Licensing drugs for diabetes. BMJ. 2010; 341: 513–14.

  24 Solomon DH, Winkelmayer WC. Cardiovascular risk and the thiazolidinediones: déjà vu all over again? JAMA. 2007; 298: 1216–18.

  25 Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366: 1279–89.

  26 Charbonnel B, Dormandy J, Erdmann E, et al. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care. 2004; 27: 1647–53.

  27 PROactive Study Executive Committee and Data and Safety Monitoring Committee. PROactive study. Lancet. 2006; 367: 982.

  28 Gøtzsche PC, Hróbjartsson A, Johansen HK, et al. Constraints on publication rights in industry-initiated clinical trials. JAMA. 2006; 295: 1645–6.

  29 Chan A-W, Hróbjartsson A, Haahr MT, et al. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA. 2004; 291: 2457–65.

  30 Chan A-W, Hróbjartsson A, Jørgensen KJ, et al. Discrepancies in sample size calculations and data analyses reported in randomised trials: comparison of publications with protocols. BMJ. 2008; 337: a2299.

  31 Jack A. European drugs watchdog to step up scrutiny. Financial Times. 2012 March 6.

  32 Hillaire-Bu
ys D, Faillie JL, Montastruc JL. Pioglitazone and bladder cancer. Lancet. 2011; 378: 1543–4.

  33 European Medicines Agency. Assessment report, Pioglitazone ratio. EMA/391408/2012. 2012 May 24.

  34 Ray WA, Stein CM. Reform of drug regulation – beyond an independent drug-safety board. N Engl J Med. 2006; 354: 194–201.

  35 Hillaire-Buys D, Faillie JL. Pioglitazone and the risk of bladder cancer. BMJ. 2012; 344: e3500.

  36 FDA Drug Safety Communication. Update to Ongoing Safety Review of Actos (pioglitazone) and Increased Risk of Bladder Cancer. 2011 June 6.

  37 Kassirer JP. On the Take: how medicine’s complicity with big business can endanger your health. Oxford: Oxford University Press; 2005.

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

  39 Brody H. Hooked: ethics, the medical profession, and the pharmaceutical industry. Lanham: Rowman & Littlefield; 2008.

  40 Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005; 294: 2581–6.

  41 Brophy JM. Selling safety – lessons from muraglitazar. JAMA. 2005; 294: 2633–5.

  42 Abramson J. Overdo$ed America. New York: HarperCollins; 2004.

  43 Saenz A, Fernandez-Esteban I, Mataix A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005; 3: CD002966.

  44 Wikipedia. Metformin. Available online at: http://en.wikipedia.org/wiki/Metformin (accessed 12 October 2012).

  45 Spranger J, Gundert-Remy U, Stammschulte T. GLP-1-based therapies: the dilemma of uncertainty. Gastroenterology. 2011; 141: 20–3.