Deadly Medicines and Organised Crime

by Peter Gotzsche

  Of all general medical journals, this journal has the highest impact factor, which is the average number of citations in a year to papers published in the two previous years. Many doctors regard it as the most prestigious one, but I am not among the admirers. Here are a couple of examples why (more will follow later; see also the previous chapter). We did a Cochrane review of Pfizer’s antifungal drug, voriconazole (Vfend),16 and found two relevant studies, both from the New England Journal of Medicine and both with misleading abstracts.

  In one of the trials, voriconazole was significantly inferior to the comparator drug, liposomal amphotericin B, according to the prespecified analysis plan, which staff at the FDA pointed out in a subsequent letter, but the paper concluded that voriconazole was a suitable alternative.17 More patients died in the voriconazole group and a claimed significant reduction in ‘breakthrough’ fungal infections in favour of voriconazole disappeared when we included infections that had arbitrarily been excluded from analysis. The abstract described manipulated results that misleadingly claimed not only a significant benefit for voriconazole in terms of fungal infections but also in terms of less nephrotoxicity. The latter result was obtained by reporting the number of patients that experienced a 1.5-fold increase in serum creatinine. The convention is to report those with a 2-fold increase, which didn’t show any difference (29 versus 32 patients).

  The other trial used amphotericin B deoxycholate as comparator, but handicapped the drug by not requiring pre-medication to reduce infusion-related toxicity or substitution with electrolytes and fluid to reduce nephrotoxicity, although the planned duration of treatment was 84 days.18 Voriconazole was given for 77 days on average, but the comparator for only 10 days, which precludes a meaningful comparison. The last sentence in the abstract was: ‘In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B.’ A trial that is seriously flawed by design doesn’t allow any such a conclusion.

  By publishing such terribly flawed trial reports, the New England Journal of Medicine not only earns a lot of money from selling reprints, the editors also boost the journal’s impact factor, especially because companies usually orchestrate a large number of ghostwritten, secondary publications that cite the trial reports.

  Indeed, in the first 3 years after publication, Pfizer’s voriconazole trials were cited an astounding 192 and 344 times, respectively, much more than expected given the journal’s impact factor of around 50. We selected a random sample of 25 references to each of these trials and found that the unwarranted conclusions were mostly uncritically propagated.19 It was particularly disappointing – but not unexpected as most papers were likely ghostwritten by Pfizer – that the FDA’s relevant criticism of the analysis of the first trial was only quoted once, and that none of the 25 articles mentioned the obvious flaws in the design of the second trial.

  We have previously described how a series of trials sponsored by Pfizer of another antifungal drug, fluconazole, in cancer patients with neutropenia, handicapped the control drug, amphotericin B, by flaws in design and analysis.20 The standard antifungal agent, intravenous amphotericin B, is highly effective, but most of the patients in Pfizer’s trials were randomised to oral amphotericin B, which is poorly absorbed and not an established treatment. Three of these trials were large, and they all had a third arm where the patients received nystatin, but the results for amphotericin B were combined with those for nystatin. This doesn’t make any sense because nystatin was recognised as ineffective in these circumstances, which we confirmed in a separate meta-analysis of nystatin trials.20 Despite repeated requests, neither the trial authors nor Pfizer provided us with separate data for each of the three arms in these studies. Further, Pfizer didn’t respond to our questions why they had used the two comparators the way they had, even though one of the Pfizer scientists we asked was an author of one of the trials.

  Another example of a highly misleading abstract in the New England Journal of Medicine came from a trial aiming at finding out whether it could be beneficial to give corticosteroids to patients with smoker’s lungs.21,22 The market is huge and so was the trial. GlaxoSmithKline randomised 6184 patients to its steroid (fluticasone), or placebo, and randomised all patients again to its asthma drug, salmeterol, or placebo. This created four groups: placebo, salmeterol, fluticasone, and both drugs together. The design is factorial and the correct analysis showed that fluticasone had no effect, rate ratio 1.00 (95% CI 0.89 to 1.13; P = 0.99). However, the abstract said: ‘The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P = 0.052, adjusted for the interim analyses).’

  The editors allowed Glaxo to present a totally inappropriate analysis in the abstract that only included half of the patients, thereby spoiling the advantage of the factorial design. The misleading result in the abstract gives the clinicians the impression that both of Glaxo’s drugs should be used, although one of them didn’t work. I believe this is scientific misconduct.

  Cool cash may be more important than scientific integrity for medical journals. Such problems are worst in specialty journals. Their editors often have financial conflicts of interest in relation to the companies that submit papers to them, including owning shares and being paid consultants, and some of the journals are financially supported by drug companies via the specialist societies that publish the journals.

  Many specialist journals publish industry-sponsored symposia. These are the worst type of papers. The industry usually pays for getting them published, they are rarely peer reviewed, have misleading titles, use brand names instead of generic names for the drugs and praise them more highly than other types of articles.23,24

  Despite three good peer reviews, the editor of a leading nephrology journal, Transplantation and Dialysis, rejected an editorial questioning the value of epoetin in end stage renal disease. The editor admitted to the author that he had been overruled by his marketing department: ‘The publication of your editorial would, in fact, not be accepted in some quarters … and apparently went beyond what our marketing department was willing to accommodate.’8

  A US Congressional investigation of spinal device products revealed in 2009 that Thomas Zdeblick, an orthopaedic surgeon, had received more than $20 million in patent royalties and more than $2 million in consulting fees from Medtronic during his tenure as editor of the Journal of Spinal Disorders & Techniques.25 Medtronic sells spinal implants, and Zdeblick’s journal published in every issue, on average, papers about Medtronic’s spinal products, which were usually favourable and failed to disclose the financial ties between the authors and Medtronic.

  An incestuous relationship, particularly considering that papers about Medtronic’s spinal fusion device had rather consistently left out all the serious harms that the surgeons had observed. Not a single device-associated adverse event was reported in 13 industry-sponsored publications regarding safety and efficacy in 780 patients treated with the device.25 FDA documents revealed internal inconsistencies in Medtronic’s reports and suggested an occurrence of adverse events in 10%–50% of the patients, including some life-threatening ones.26

  We have analysed by how much the impact factor depends on publication of trials with industry funding.9 As expected, it had very little effect on the BMJ, whereas the impact factor dropped by 24% for the New England Journal of Medicine when we only included original research and reviews as citable papers. We also asked by how much (in relative terms, we carefully avoided asking for absolute amounts) the sales of advertisements and reprints contributed to the journal’s economy. None of the four top US journals we included in our study (Annals of Internal Medicine, Archives of Internal Medicine, JAMA and New England Journal of Medicine) gave us any data, as it was their policy not to disclose financial information (which we didn’t ask for, only relative am
ounts!). We got the data from the two top European journals, the BMJ and the Lancet; only 3% of the BMJ’s income was from reprints whereas it was 41% for the Lancet.

  In agreement with these data, a drug industry insider told the BMJ in 2005 that it was a tough nut to crack; publishing a ‘favourable’ research paper was far trickier in the BMJ than in other journals.27 However, if successful, the paper might be worth £200 million to the company, some of which would find its way into the ‘swimming pool’ funds of highly paid doctors who trotted the globe’s conference venues putting a positive spin on the company’s products.

  What these examples, and numerous others, demonstrate is that, by buying doctors and editors, the industry has transformed medical science from a public good whose purpose is to improve health into a commodity whose primary function is to maximise financial returns.28 Sadly, and although there are notable exceptions, our medical journals contribute substantially to the corruption of medical science.

  References

  1 Smith R. A ripping yarn of editorial misconduct. BMJ. Group blogs. 2008 Oct 21.

  2 Smith R. The Trouble with Medical Journals. London: Royal Society of Medicine; 2006.

  3 Schafer A. Biomedical conflicts of interest: a defence of the sequestration thesis – learning from the cases of Nancy Olivieri and David Healy. J Med Ethics. 2004; 30: 8–24.

  4 Uniform Requirements for Manuscripts Submitted to Biomedical Journals: writing and editing for biomedical publication. February 2006. International Committee of Medical Journal Editors website. Available online at: www.icmje.org (accessed 23 January 2006).

  5 Smith R. Medical journals are an extension of the marketing arm of pharmaceutical companies. PLoS Med. 2005; 2: e138.

  6 Smith R, Roberts I. Patient safety requires a new way to publish clinical trials. PLoS Clin Trials. 2006; 1(1): e6.

  7 Wilkes MS, Doblin BH, Shapiro MF. Pharmaceutical advertisements in leading medical journals: experts’ assessments. Ann Intern Med. 1992; 116: 912–19.

  8 Lexchin J, Light DW. Commercial influence and the content of medical journals. BMJ. 2006; 332: 1444–7.

  9 Lundh A, Barbateskovic M, Hróbjartsson A, et al. Conflicts of interest at medical journals: the influence of industry-supported randomised trials on journal impact factors and revenue – cohort study. PLoS Med. 2010; 7: e1000354.

  10 Drazen JM, Curfman GD. Financial associations of authors. N Engl J Med. 2002; 346: 1901–2.

  11 Kassirer J. What the New England Journal of Medicine did. BMJ. 2011; 343: d5665.

  12 Horton R. The dawn of McScience. New York Rev Books. 2004; 51: 7–9.

  13 Eaton L. Editor claims drug companies have a ‘parasitic’ relationship with journals. BMJ. 2005; 330: 9.

  14 Handel AE, Patel SV, Pakpoor J, et al. High reprint orders in medical journals and pharmaceutical industry funding: case-control study. BMJ. 2012; 344: e4212.

  15 Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001; 344: 1594–602.

  16 Jørgensen KJ, Johansen HK, Gøtzsche PC. Voriconazole versus amphotericin B in cancer patients with neutropenia. Cochrane Database Syst Rev. 2006; 1: CD004707.

  17 Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002; 346: 225–34.

  18 Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002; 347: 408–15.

  19 Jørgensen KJ, Johansen HK, Gøtzsche PC. Flaws in design, analysis and interpretation of Pfizer’s antifungal trials of voriconazole and uncritical subsequent quotations. Trials. 2006, 7: 3.

  20 Johansen HK, Gøtzsche PC. Problems in the design and reporting of trials of antifungal agents encountered during meta-analysis. JAMA. 1999; 282: 1752–9.

  21 Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007; 356: 775–89.

  22 Suissa S, Ernst P, Vandemheen KL, et al. Methodological issues in therapeutic trials of COPD. Eur Respir J. 2008; 31: 927–33.

  23 Bero LA, Galbraith A, Rennie D. The publication of sponsored symposiums in medical journals. N Engl J Med. 1992; 327: 1135–40.

  24 Cho MK, Bero LA. The quality of drug studies published in symposium proceedings. Ann Intern Med. 1996; 124: 485–9.

  25 Lenzer J. Editor earned over $20m in royalties and $2m in fees from device manufacturer. BMJ. 2010; 340: c495.

  26 Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011; 11: 471–91.

  27 Abbasi K. Editor’s choice: a tough nut to crack. BMJ. 2005; 330: Jan 29.

  28 Abramson J. Overdo$ed America: the broken promise of American medicine. New York: HarperCollins; 2004.

  7

  The corruptive influence of easy money

  About 20 years ago, an incident alerted me to the way the industry buys friends. Clinical investigators from several countries had attended a planning meeting where we discussed various trials that both the company and we might be interested in. When we were on our way to a lavish dinner paid by the company, the person in charge of clinical trials in the company handed me an envelope, which I didn’t open till later.

  The envelope contained a letter thanking me for my contribution to the one-day meeting and a $1000 bill. I had never seen such a large bill before and realised that this is how corruption starts. Little by little. You don’t get more in the beginning than you are able to justify to yourself: ‘Isn’t it reasonable that I get a handsome honorarium for ripping a day off my busy schedule to provide expert advice to a drug company?’ Back then, $1000 was a good deal of money.

  If you don’t send the money back, you have signalled that you might be willing to think you are even more valuable for the company next time. Helped by flattering company people who tell you how important and indispensible you are, you go on telling yourself that the increasing payments are fully reasonable, until you no longer notice that the amounts have become obscene.

  To pay cash leaves no trails. In December 2000, I lectured at a course in Bern, Switzerland, and during a lunch in town I talked with a woman who once worked for a Swiss drug company. She was asked by her boss to go to the Nordic countries with a stack of brown envelopes to be delivered to doctors who participated in trials in hypertension. She felt it was a weird assignment and asked what was in the envelopes. Dollar bills. She then asked why the company didn’t simply transfer the money electronically and was told she could leave the company if she continued asking questions. She refused to deliver the envelopes and left the company. Twelve years later, we moved offices, and when cleaning up, I found a hand-written note where I had asked her to write her name. I Googled it, found her current phone number and called her, and she confirmed the story. She no longer works in the drug industry but with public health.

  Other insiders have told similar stories and have described the practice as routine.1 One of my friends in industry has confirmed that it’s common to pay doctors in cash. A well-known male oncologist was nicknamed wall-to-wall H…… [first name left out by me] because he preferred to get paid in Persian rugs. By using far-fetched arguments that didn’t hold water, this doctor had prevented the introduction of a far cheaper generic drug into the hospital containing the same active substance as the original cancer drug.

  You may wonder what his interest could be in this, but it’s simple. By being ‘loyal’ to the company that introduced the drug on the market in the first place, and which still charged far too much for it considering it ran out of patent years ago and much cheaper generics are available, the benefits he receives from the company will continue. It’s like Pavlov’s dogs. You’ll be rewarded as long as you do what’s e
xpected of you.

  There is a culture among doctors that allows acceptance of easy money,2,3,4,5,6,7,8,9,10,11,12,13,14 and companies may offer to transfer the money in ways that cannot be traced.15 In 2006, Transparency International focused on the healthcare sector in its Global Corruption Report, which left no doubt that there is widespread corruption in healthcare. It is usually the drug industry that takes the initiative, but doctors, ministers and other government officials have sometimes extorted the firms.7

  UK researchers found that the Polish government’s system for deciding which drugs will be paid for by the state is deeply flawed.16 One heart drug was accepted for reimbursement even though the scientific evidence supporting it was doubtful. Later, the press discovered that the decision had been taken after the relative of a high-ranking ministerial official had a new flat ‘arranged’ by the drug company.

  The pharmaceutical giants have many friends in high places. When a person from the Pennsylvania Office of the Inspector General had uncovered payments into an off-the-books account from Pfizer and Janssen, he was appointed lead investigator.17 After his findings had revealed that these payments went to state employees who developed guidelines recommending expensive new drugs over older, cheaper drugs, he was escorted out of his workplace and told not to come back after being told by a manager that ‘drug companies write cheques to politicians on both sides of the aisle’.

  The approach from the drug industry is subtle in the beginning, but the size of the favours quickly escalates if a doctor proves useful for the company. A common method of getting friends is to pay them excessively for services, or even for services not rendered.6

  A pizza and a penlight are like early inoculations, tiny injections of self-confidence that make a doctor think he will never be corrupted by money.18 But let’s see how obscene payments from the industry to doctors can be and how deep the corruption.