Deadly Medicines and Organised Crime

by Peter Gotzsche

  A clinical trial can be different. In that process, it is very much in the interest of the drug’s sponsor, or manufacturer, to make everyone in the process its dependent, fostering as many conflicts of interest as possible. Before the approval process, the sponsor sets up the clinical trial – the drug selected, and the dose and route of administration of the comparison drug (or placebo). Since the trial is designed to have one outcome, is it surprising that the comparison drug may be hobbled – given in the wrong dose, by the wrong method? The sponsor pays those who collect the evidence, doctors, and nurses, so is it surprising that in a dozen ways they influence results? All the results flow in to the sponsor, who analyses the evidence, drops what is inconvenient, and keeps it all secret – even from the trial physicians. The manufacturer deals out to the FDA bits of evidence, and pays the FDA (the judge) to keep it secret. Panels (the jury), usually paid consultant fees by the sponsors, decide on FDA approval, often lobbied for by paid grass-roots patients organizations who pack the court (that trick is called ‘astro-turfing’). If the trial, under these conditions, shows the drug works, the sponsors pay subcontractors to write up the research and impart whatever spin they may; they pay ‘distinguished’ academics to add their names as ‘authors’ to give the enterprise credibility, and often publish in journals dependent on the sponsors for their existence. If the drug seems no good or harmful, the trial is buried and everyone reminded of their confidentiality agreements. Unless the trial is set up in this way, the sponsor will refuse to back the trial, but even if it is set up as they wish, those same sponsors may suddenly walk away from it, leaving patients and their physicians high and dry.

  In short, we have a system where defendant, developers of evidence, police, judge, jury, and even court reporters are all induced to arrive at one conclusion in favour of the new drug.

  Doctors know perfectly well what this means for the trustworthiness of industry trials. When physicians were presented with abstracts of hypothetical trials, they downgraded the perceived rigour of the trial when it was industry funded and were only half as willing to prescribe drugs studied in such trials as they were if they had been studied in National Institutes of Health (NIH) funded trials.34

  The study was published in the New England Journal of Medicine, whose editor, Jeffrey Drazen, downgraded it in an editorial. He questioned whether the lack of trust was justified and argued that this reasoning ‘has been reinforced by substantial press coverage of a few examples of industry misuse of publications, involving misrepresentation of the design or findings of clinical trials’.35 He furthermore noted that investigators in NIH-sponsored studies also have substantial incentives, including academic promotion and recognition, to try to ensure that their studies change practice. Drazen’s way of arguing is very similar to the way the industry and its apologists argue, and it is not tenable. The press is not to blame; we are not seeing a few examples but a research literature that has been systematically distorted by industry; and academic motives are not similarly strong distorting factors as is economic motives.

  What Drazen’s arguments really demonstrate is the pervasive conflict of interest at high-impact medical journals, which I shall discuss in the next chapter. Here is an example. A systematic review found that subgroup analyses in trials were more common in high-impact journals, and in those trials without statistically significant results for the primary outcome, industry-funded trials were twice as likely to report subgroup analyses as non-industry-funded trials and twice as likely not to have prespecified the subgroup hypotheses.36 This is really bad. It’s bad science to embark on subgroup analyses when the main analysis didn’t find a statistically significant result. Such exercises in trawling the data till some of them happen to show something are called data massage or fishing expeditions. If you fish long enough, you may catch something, even an old boot.

  Drazen has a point: Academics can be (but usually aren’t) equally unforthcoming as the drug industry. Despite the Freedom of Information Act and NIH statements that data sharing is essential to improve human health, no one seems to have gotten access to data from NIH-funded trials.37 When a study showed that children with attention deficit hyperactivity disorder (ADHD) had smaller brains than other children and critics suspected it might be a drug effect, access to the data was denied.

  An example of a fishing expedition was a 1990 NIH study of high-dose steroids in 487 patients with spinal cord injury.38 The data published in the abstract of the New England Journal of Medicine were a subset of those randomised and described an effect on neurological outcomes for patients treated within 8 hours after the injury. That was really fishy, as the inclusion criterion was that the patients must get treatment within 12 hours, so why create an arbitrary cut-off in addition to the 12 hours? It turned out that there were no significant effects if all patients were analysed. Researchers who were critical of this were denied access to the data, and a co-investigator told a journalist that he broke with the primary author as he ‘was always trying to find something that I couldn’t find’.37

  Fourteen years later, a gigantic trial of steroids given to 10 000 people with serious brain injuries, the CRASH trial, was published in the Lancet, and it showed that steroids are very harmful. For every 31 patients treated with steroids rather than placebo, there was one additional death.39 Thousands of patients with spinal cord or brain injuries have died because they were given steroids and the fishing expedition in the New England Journal of Medicine is to blame for many of these deaths.40 Scientific dishonesty can kill people and it often does.

  The social contract with patients who volunteer for trials has been broken. It’s a fact that advertising and PR firms are now running clinical trials in Europe and North America,41 and this is perhaps the clearest sign that the companies do not separate marketing from research. Many patient consent forms for industry trials should therefore state something like this:

  I agree to participate in this trial, which I understand has no scientific value but will be helpful for the company in marketing their drug. I also understand that if the results do not please the company, they may be manipulated and distorted until they do, and that if this also fails, the results may be buried for no one to see outside the company. Finally, I understand and accept that should there be too many serious harms of the drug, these will either not be published, or they will be called something else in order not to raise concerns in patients or lower sales of the company’s drug.

  References

  1 Boseley S. Scandal of scientists who take money for papers ghostwritten by drug companies. The Guardian. 2002 Feb 7.

  2 Vandenbroucke JP. Without new rules for industry-sponsored research, science will cease to exist. BMJ. 2005 Dec 14.

  3 McHenry L. Biomedical research and corporate interests: a question of academic freedom. Mens Sana Monographs. 2008 Jan 1.

  4 Brynner R, Stephens T. Dark Remedy: the impact of thalidomide and its revival as a vital medicine. New York: Perseus Publishing; 2001.

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

  6 Medawar C, Hardon A. Medicines out of Control? Antidepressants and the conspiracy of goodwill. Netherlands: Aksant Academic Publishers; 2004.

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

  8 Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007; 357: 2001–15.

  9 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.

  10 Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361: 1045–57.

  11 Serebruany VL, Atar D. Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials – common patterns
in TRITON, RECORD, and PLATO? Thromb Haemost. 2012; 108: 412–14.

  12 Davidoff F, DeAngelis CD, Drazen JM, et al. Sponsorship, authorship, and accountability. JAMA. 2001; 286: 1232–4.

  13 Nordic Medical Research Councils’ HIV Therapy Group. Double-blind dose-response study of zidovudine in AIDS and advanced HIV infection. BMJ. 1992; 304: 13–17.

  14 Gerstoft J, Melander H, Bruun JN, et al. Alternating treatment with didanosine and zidovudine versus either drug alone for the treatment of advanced HIV infection: the ALTER study. Scand J Infect Dis. 1997; 29: 121–8.

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

  16 Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010; 303: 1180–7.

  17 Schulman KA, Seils DM, Timbie JW, et al. A national survey of provisions in clinical-trial agreements between medical schools and industry sponsors. N Engl J Med. 2002; 347: 1335–41.

  18 Mello MM, Clarridge BR, Studdert DM. Academic medical centers standards for clinical-trial agreements with industry. N Engl J Med. 2005; 352: 2202–10.

  19 Meier B. Contracts keep drug research out of reach. New York Times. 2004 Nov 29.

  20 Steinbrook R. Gag clauses in clinical-trial agreements. N Engl J Med. 2005; 352: 2160–2.

  21 Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003; 289: 454–65.

  22 Statistics from the EudraCT database. EMEA/363785/2005.

  23 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.

  24 Department of Health and Human Services, Office of Inspector General. Recruiting Human Subjects: pressures in industry-sponsored clinical research. June 2000, OEI-01-97-00195 (accessed 18 February 2008).

  25 Cuatrecasas P. Drug discovery in jeopardy. J Clin Invest. 2006; 116: 2837–42.

  26 Werkö L. [It is always about the life] [Swedish]. Helsingborg: AB Boktryck; 2000.

  27 Boseley S. Junket time in Munich for the medical profession – and it’s all on the drug firms. The Guardian. 2004 Oct 5.

  28 Gagnon M-A. The Nature of Capital in the Knowledge-Based Economy: the case of the global pharmaceutical industry [dissertation]. Toronto: York University; May 2009.

  29 Angell M. The Truth about the Drug Companies: how they deceive us and what to do about it. New York: Random House; 2004.

  30 Elliott C. The drug pushers. The Atlantic Monthly. 2006 April.

  31 Marcovitch H. Editors, publishers, impact factors, and reprint income. PLoS Med. 2010; 7: e1000355.

  32 Bodenheimer T. Uneasy alliance – clinical investigators and the pharmaceutical industry. N Engl J Med. 2000; 342: 1539–44.

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

  34 Kesselheim AS, Robertson CT, Myers JA, et al. A randomized study of how physicians interpret research funding disclosures. N Engl J Med. 2012; 367: 1119–27.

  35 Drazen JM. Believe the data. N Engl J Med. 2012; 367: 1152–3.

  36 Sun X, Briel M, Busse JW, et al. The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials: systematic review. BMJ. 2011; 342: d1569.

  37 Lenzer J. NIH secrets. The New Republic. 2006 Oct 10.

  38 Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990; 322: 1405–11.

  39 Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet. 2004; 364: 1321–8.

  40 Lenzer J, Brownlee S. An untold story? BMJ. 2008; 336: 532–4.

  41 Mintzberg H. Patent nonsense: evidence tells of an industry out of social control. CMAJ. 2006; 175: 374.

  6

  Conflicts of interest at medical journals

  In what has been called the age of accountability, editors have continued to be as unaccountable as kings.

  The whole business of medical journals is corrupt because owners are making money from restricting access to important research, most of it funded by public money.

  Richard Smith, former editor, BMJ1,2

  A conflict of interest is commonly defined as ‘a set of conditions in which professional judgement concerning a primary interest (such as a patient’s welfare or the validity of research) tends to be unduly influenced by a secondary interest (such as a financial gain)’.3

  The International Committee of Medical Journal Editors has declared that ‘researchers should not enter into agreements that interfere with their access to the data and their ability to analyze it independently, to prepare manuscripts, and to publish them’ and that ‘editors may choose not to consider an article if a sponsor has asserted control over the authors’ right to publish’.4 However, despite this well-intentioned declaration, our journals nonetheless accept the virtually complete lack of academic freedom in industry trials.

  Our most prestigious journals have a serious conflict of interest when they deal with industry trials, as they might lose large incomes from sales of reprints if they are too critical. The BMJ’s former editor, Richard Smith, has written a paper with the informative title, ‘Medical journals are an extension of the marketing arm of pharmaceutical companies’,5 and has explained that sometimes companies will ring when a paper is submitted and say they will purchase reprints if accepted.2 An editor may face a frighteningly stark conflict of interest: Publish a trial that will bring US$100 000 of profit or meet the end-of-year budget by firing an editor.5 Smith has suggested an attractive solution to the journals’ conflict of interest problem: journals should stop publishing trials; instead, the protocols, results and the full dataset should be made available on regulated websites.6 This would stop journals from being beholden to companies, and instead of publishing trials, journals could concentrate on critically describing them.

  Advertising also creates a conflict of interest. When the BMJ in 2004 devoted a whole issue to conflicts of interest and had a cover page showing doctors dressed as pigs gorging at a banquet with drug salespeople as lizards, the drug industry threatened to withdraw £75 000 of advertising.2 Annals of Internal Medicine lost an estimated US$1–1.5 million in advertising revenue after it published a study that was critical of industry advertisements.7,8

  The solution to this problem is simple: drop advertisements for drugs, which is the only respectable thing to do, as they are harmful for patients (see Chapter 9). And let those journals die that cannot survive without advertisements. They don’t deserve to survive anyway, and their death would benefit us, as it would diminish substantially the pollution of the research literature with papers of little or no value. That would make it less laborious to search the literature when we are looking for answers to pertinent questions.

  The drug industry’s preferred journal is the New England Journal of Medicine.9 Previously, this journal had a very reasonable policy related to reviews and editorials:

  ‘Because the essence of reviews and editorials is selection and interpretation of the literature, the Journal expects that authors of such articles will not have any financial interest in a company (or its competitor) that makes a product discussed in the article.’10

  But alas, in 2002, the editors lamented that it was difficult to find non-conflicted authors and changed the rule so that only a significant financial interest was banned, which was defined as one exceeding $10 000.10 There was no dollar limit on incomes from companies whose products were not discussed. Jerome Kassirer, a previous editor with the journal, w
rote that he was disappointed with this decision and added that he had always been able to find good authors without conflicts of interest.11 Kassirer hit the nail. My respect for the journal was gone and never came back.

  The Lancet is the industry’s second most preferred journal.9 Lancet’s editor, Richard Horton, is as equally outspoken as Richard Smith and has stated that ‘Journals have devolved into information laundering operations for the pharmaceutical industry.’12 He has also described how drug companies sometimes offer journals to purchase a large number of reprints and may threaten to pull a paper if the peer review is too critical.13 The income from reprints is very large for top journals; a 2012 study found that the cost for the median and largest reprint order for Lancet were £287 353 and £1 551 794, respectively.14

  In 2001, we published a paper in the New England Journal of Medicine about the effect of placebos and my co-worker wanted to buy some reprints; ‘once in a life-time,’ as he said.15 They carried the front page of the journal where the title of our paper was in normal print whereas everything else was toned down, in a light grey colour. There is nothing as helpful for a drug salesperson as to give a reprint of a trial report from this journal to a doctor. The only thing that is needed is to draw the doctor’s attention to the last sentence in the abstract under Conclusions.

  I have noticed on many occasions that these conclusions – and also often the results – in the abstracts of drug trials in the New England Journal of Medicine have been misleading. When I lecture doctors and tell them about this, I am usually met with hostile reactions. How dare I criticise the holy grail of medical journals, the very journal that all researchers hope to get into, if only once in a lifetime?