Deadly Medicines and Organised Crime

by Peter Gotzsche

  The lies continued. A vice president for clinical research at Pharmacia in the United States claimed in 2002 that the analyses and outcomes were prespecified and that CLASS was a single study.11 The lies were forcefully rejected by independent researchers, who noted that also in Pharmacia’s successor study to CLASS, the SUCCESS-1 study, the company had pooled results from different protocols with different comparator drugs.12 Pharmacia’s statements were also rejected by the FDA’s statistical reviewer, who remarked that the company had conducted at least 34 subgroup analyses that were not prespecified in violation of the trial protocol that stated that the primary outcome should show a statistically significant difference before any subgroup analyses would be undertaken.7,13 As with Vioxx, trials purporting not to have found a risk of thromboses found their way to cardiology journals, e.g. American Journal of Cardiology.14

  Even as late as in 2009, Pfizer played games denying the problems with its drug. It funded a trial in general practice, comparing celecoxib with other NSAIDs, but the funding was concealed in the invitation for an investigators’ meeting, which said the University of Dundee sponsored the trial.15 There was a 2-week run-in phase before the randomisation where all patients would receive celecoxib, which invalidates the trial because those who cannot tolerate the drug don’t get randomised. The information to the patients stated that the evidence wasn’t conclusive as to whether celecoxib increased heart disease and strokes. This lie should have caused the research ethics committee to reject the trial. I have a product summary from February 2005 that mentions the cardiovascular problems and a letter from Pfizer to doctors that acknowledges that the drug causes them and says that celecoxib should not be used in patients with ischaemic heart disease or with cerebrovascular disease.

  Furthermore, in 2005, the US National Cancer Institute published a trial of celecoxib for prevention of colorectal adenoma in the New England Journal of Medicine, which was terminated prematurely for safety reasons, as celecoxib increased significantly cardiovascular events.16 And a meta-analysis conducted by independent researchers using FDA data showed in 2006 that celecoxib doubles the number of heart attacks compared with placebo.17 The authors contacted Pfizer for details about its trials, but Pfizer didn’t provide any.

  This illustrates that the responsibility of doing trials should be taken away from the drug companies. We let them get away with their frauds and lies far too easily. When Merck withdrew Vioxx from the market in 2004, Pfizer grabbed the opportunity immediately. The next day, the company wrote to Danish doctors that celecoxib had been used in more than 50 million people worldwide and that the company had reviewed clinical trials in more than 400 000 patients (that’s what they wrote; I suppose they meant 40 000), and that this had not yielded any signs that celecoxib increased the risk of cardiovascular side effects. The fine for this ruthless misinformation was $2000.18

  Fifty million people. How many deaths because of thrombosis is this? Using the same calculation as for rofecoxib (see here), we get 75 000 deaths. In addition, celecoxib has killed many thousands of patients because of ulcer complications. And that’s only up till 2004; the drug is still on the market.

  This is similar to the estimated number of deaths caused by Vioxx. I wonder why our drug agencies haven’t withdrawn celecoxib and similarly dangerous NSAIDs? The Danish drug agency did react, however. It withdrew the reimbursement of celecoxib and similar drugs 1 month after Vioxx was withdrawn, which saved many lives. Compared to 2003, the use of celecoxib in 2005 was only 10% and in 2007 it was 4%.

  Pfizer continued to protect its drug rather than the patients’ lives. Four days before the reimbursement disappeared, the company wrote to all Danish doctors complaining it created a dilemma for the doctors and was a step backwards for the patients who were denied access to new medicines. Pfizer’s letter contained a form the doctors could use to apply for reimbursement for individual patients, and the company established a separate phone line where doctors could be advised what they should do. The company also put ads in the Journal of the Danish Medical Association showing an elderly lady dancing on the table with the text: ‘Life is too long to have pain.’ I reproduced the ad in a paper I published in the same journal and added: ‘and too short to die of myocardial infarction.’19

  Apart from withdrawing a drug from the market, withdrawal of reimbursement is the most powerful tool the authorities have. The committee that deals with these decisions has received remarkably similar letters of complaint from doctors in the whole country, orchestrated by the company. Another example of drug whores.

  Pfizer was very worried that its fraud could lead to many legal proceedings and its lawyers harassed not only JAMA but several other prominent journals.20,21 More than 3000 lawsuits had been raised against Pfizer alleging the company marketed celecoxib and valdecoxib as being without the adverse effects of the old NSAIDs.20 Pfizer issued subpoenas to get access to all peer reviews, rejected manuscripts and editorial decisions about papers submitted to JAMA on the two drugs. Obviously, these unpublished materials couldn’t have played any role in Pfizer’s appalling marketing conduct, and the judge appropriately quashed Pfizer’s subpoenas. Although peer reviewers are guaranteed anonymity, Pfizer asked for their identity. I wonder what the idea was. To sue the peer reviewers, or harass them in other ways, e.g. via their superiors (see Chapter 19)?

  The habitual lying took a new turn in 2012 when investors’ lawyers accused Pfizer of having destroyed documents about the development of celecoxib and valdecoxib in bad faith and compounded their initial misconduct by making false statements about the existence of centralised databases.22 Pfizer denied the existence of electronic databases containing millions of files about the drugs and argued that the existence of the ‘e-Rooms were a figment of plaintiffs’ imagination’. However, Pfizer officials later acknowledged the rooms existed and turned over documents stored electronically. The lawyers also complained that Pfizer’s technical staff undertook ‘two dismantling projects while this case was pending’. In response, Pfizer’s lawyer filed a new lie saying, ‘At no time did Pfizer ever mislead plaintiffs concerning the existence of databases.’

  Marketing is harmful

  A Canadian study showed that the bombardment of doctors with sales pitches about COX-2 inhibitors claiming that the drugs have fewer gastrointestinal adverse effects than the old NSAIDs aggravated the problem. The total sales of NSAIDs (including celecoxib and rofecoxib) increased, and as more patients were now treated, a declining trend in hospital admissions for gastrointestinal haemorrhage changed to an increase.23

  The COX-2 inhibitors are a prime example that fraudulent research and fraudulent marketing are very harmful for patients and very lucrative for the companies and that our most prestigious journals lend their pages to the deceptions. A 2001 review article in the New England Journal of Medicine about the coxibs was utterly flawed.24 The two authors had financial ties to the makers of Vioxx and Celebrex and their paper was a shameful advertisement for the drugs to the point of even mentioning the non-existing advantage of Celebrex that the FDA had forbidden the company to make.25 The serious harms of the two drugs were dismissed in a most unacademic fashion. I wonder how many millions of dollars the journal made on selling reprints of this totally misleading review. The same year, both drugs were among the top 10 selling drugs in the United States.25

  Were it not for the power of marketing, the popularity of new drugs would be difficult to understand. The risk of taking a new drug is greater than the risk of using an old one, as it takes time before the harms of new drugs become known. As an example, the COX-2 inhibitor lumiracoxib (Prexige from Novartis) was approved by the EMA in 2006 and withdrawn a year later because of serious liver problems, including deaths. It was never approved by the FDA.

  NSAIDs are very dangerous. Even before the COX-2 inhibitors, we caused deaths on a terrible scale with NSAIDs. It has been estimated that 3700 deaths occur each year in the United Kingdom due to peptic ulcer complications in NSAID users,2
6 corresponding to about 20 000 deaths each year in the United States. In agreement with this, it was estimated in 1999 that more than 16 000 Americans died from stomach ulcers caused by NSAIDs, roughly the same number as those who died from AIDS.27 This makes NSAIDs one of the most deadly drug groups (see Chapter 21 about drug deaths). The tragedy is that many of these people could have had a good life without NSAIDs, but marketing has lured doctors into using NSAIDs for virtually every kind of pain, assisted by prostituted rheumatologists. A journalist writing about Vioxx and Celebrex called a national society of US rheumatologists in 2000 to speak to an expert who wasn’t being paid by either company. She was told there was none.27

  People who tell the truth get punished (see also Chapters 13 and 19). In 2002, an independent Spanish drug bulletin wrote that the so-called advantages of celecoxib and rofecoxib were scientific fraud.28 Merck sued while Pfizer did not, perhaps because taking action would lead to a worse outcome for the company. Merck misrepresented the court’s verdict, which was that the Spanish article was accurate, that it reflected the debate on the ethics of publications in medical research and echoed the FDA’s warnings to Merck regarding misleading information on the cardiovascular adverse effects of rofecoxib in promotional materials.29

  Merck stated only 6 months before it withdrew Vioxx that ‘MSD is fully committed to the highest standards of scientific integrity, ethics, and protection of patient’s wellbeing in our research. We have a tradition of partnership with leaders in the academic research community.’30 Great. Let’s have some more of such ethical partnerships. They often kill our patients while everyone else prospers.

  Perhaps Hells Angels should consider something similar in their PR: We are fully committed to the highest standards of integrity, ethics and protection of citizens’ well-being when we push narcotic drugs. We have a tradition of partnership with leaders in the police force.

  References

  1 Celecoxib and the CLASS trial: data massaging by industry. Prescrire International. 2002; 11: 190–1.

  2 Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000; 284: 1247–55.

  3 Okie S. Missing data on Celebrex. Washington Post. 2001 Aug 5.

  4 Lichtenstein DR, Wolfe MM. COX-2-Selective NSAIDs: new and improved? JAMA. 2000; 284: 1297–9.

  5 Jüni P, Rutjes AW, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ. 2002; 324: 1287–8.

  6 Thomas K. In documents on pain drug Celebrex, signs of doubt and deception. New York Times. 2012 June 24.

  7 Lu HL. Statistical Reviewer Briefing Document for the Advisory Committee. FDA. 2000; NDA20-998.

  8 FDA. Summary minutes, AAC & DSaRM. 2005 Feb 16–18. Available online at: www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4090M1: Final.htm (accessed February 2005).

  9 Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ. 2002; 325: 619.

  10 Deeks JJ, Smith LA, Bradley MD. Systematic review of celecoxib for osteoarthritis and rheumatoid arthritis. BMJ. 2003; 326: 335–6.

  11 Geis GS. Pharmacia’s response to editorial. BMJ. 2002; 325: 161–2.

  12 Jüni P, Rutjes AWS, Dieppe P. Authors’ reply. BMJ. 2002; 325: 163–4.

  13 Hrachovec JB, Mora M. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA. 2001; 286: 2398.

  14 White WB, Faich G, Whelton A, et al. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol. 2002; 89: 425–30.

  15 Andrade M. In clear sight. BMJ. 2009; 339: 538–40.

  16 Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005; 352: 1071–80.

  17 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.

  18 Crone M. [Pfizer gets additional fine for illegal marketing]. Berlingske. 2004 Nov 16.

  19 Gøtzsche PC. [COX-2 inhibitors and other nonsteroidal, anti-inflammatory drugs – what future?] Ugeskr Læger. 2006; 168: 1972–3.

  20 DeAngelis CD, Thornton JP. Preserving confidentiality in the peer review process. JAMA. 2008; 299: 1956.

  21 Dyer C. Pfizer asks journal for comments made by peer reviewers. BMJ. 2008; 336: 575.

  22 Feeley J, Van Voris B. Pfizer destroyed arthritis drugs’ files, investors claim. Bloomberg. 2012 Nov 21. Available online at: www.bloomberg.com/news/2012-11-21/pfizer-destroyed-arthritis-drugs-files-investors-claim.html (accessed 10 July 2013).

  23 Mamdani M, Juurlink DN, Kopp A, et al. Gastrointestinal bleeding after the introduction of COX 2 inhibitors: ecological study. BMJ. 2004; 328: 1415–6.

  24 FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001; 345: 433–42.

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

  26 Blower AL, Brooks A, Fenn GC, et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther. 1997; 11: 283–91.

  27 Petersen M. Our Daily Meds. New York: Sarah Crichton Books; 2008.

  28 Gibson L. Drug company sues Spanish bulletin over fraud claim. BMJ. 2004; 328: 188.

  29 Laporte J-R. Merck Sharpe and Dohme versus Laporte. Lancet. 2004; 364: 416.

  30 Honig P. Merck Sharp and Dohme versus Laporte. Lancet. 2004; 363: 1079–80.

  15

  Switching cheap drugs to expensive ones in the same patients

  Seeding trials lure doctors into prescribing new expensive drugs instead of old cheap ones that are equally good or better (see Chapters 8 and 9). The worst of them are designed to persuade prescribers to switch patients who are already well treated with the old drug. As doctors are paid for each patient they switch, this kickback clouds clinical judgement.

  Novo Nordisk switches patients to expensive insulin

  Switch campaigns are sometimes carried out without the faintest guise of research. Insulin was obtained from animal pancreas until the 1980s when biosynthetic human insulin began to replace animal insulins, with important supply implications but no clinical advantage.1 To overcome this marketing problem, the first worldwide insulin switch campaigns were launched. In 2006, Novo Nordisk paid doctor’s assistants and a pharmacy chain to switch diabetic patients to the company’s high-priced new insulin products. Novo’s district manager wrote to the salespeople:2

  ‘Our goal is 50 or more scripts per week for each territory … If you are not achieving this goal, ask yourself if those doctors that you have such great relationships with are being fair to you. Hold them accountable for all of the time, samples, lunches, dinners, programs and past preceptorships that you have provided or paid for and get the business!! You can do it!!’

  Such actions are unlawful, as federal anti-kickback statutes prohibit drug companies from offering financial incentives to doctors or pharmacists to encourage or reward the prescribing of particular drugs, but the crimes are highly successful. While Novo’s insulin sales rose 364%, Eli Lilly’s sales rose only 13%. Health professionals warned that switches to newer, more rapidly acting insulin types could be dangerous and even lethal if the patients have not been thoroughly informed. This wasn’t always the case. Some patients first became aware of the switches when they picked up the new medicines at a pharmacy.2

  Another switch campaign began when human insulin was replaced by genetically engineered insulin analogues at several times the cost.1> Company reports for 2010 show that insulin glargine, the most successful analogue, help
ed to give Sanofi-Aventis insulin sales of around $5.1 billion, compared with $4.7 billion for Novo and $3.1 billion for Eli Lilly. However, the insulin analogues offer little benefit to most people with type 2 diabetes, except those who experience troublesome hypoglycaemia.1

  In 2012, a paper in the BMJ described that Novo had recruited nearly 360 000 patients for questionable ‘studies’.3 Most studies were performed in middle or low income countries, even though the patients may have difficulty affording the more expensive insulin. In India, the new insulin was nine times more expensive than the cheapest human insulin. One of the studies lacked a control arm and a well-defined question, and its results were highly implausible, as almost no one reported hypoglycaemia. Clearly, if one wants to know something about the new insulin, hundreds of thousands of patients aren’t needed, but we would need a comparator group that received the old insulin. Some of Novo’s ‘results’ were published, but with selected subanalyses with positive outcomes, and with co-authors or writing support from the company.1 The doctors were paid, which might constitute kickbacks. Everyone prospers while the poorest patients pay the bill, hardly an example of the ‘ethical partnerships’ between industry and doctors we hear so much about.