Some doctors are so influential that drug companies may tacitly accept when they pocket money given for another purpose. Finnish neurologists cashed money intended to cover research costs, e.g. laboratory examinations and assistants’ salaries, which they let patients, communities and the university pay for.19 In one case, the fraud amounted to millions of Euros, which involved 180 bank accounts, many in Switzerland. Ironically, two professors involved in the crimes were responsible for supervising the ethical status of scientific projects nationwide, but one of them and his son, who was found guilty of 23 crimes, ended up in prison, and the other professor was also likely to get a prison sentence.
Sometimes the industry’s initial approach to doctors is blunt and leaves no doubt about the corruption. Sandoz offered a $30 000-a-year consulting position to a primary investigator to convince him to accept a favourable conclusion of a trial, although the company’s drug, isradipine, a calcium channel blocker for hypertension, had a higher rate of complications than the comparator.3,20 An unsolicited check of $10 000 arriving in the mail from Schering-Plough with a ‘consulting’ agreement requiring only the doctor’s commitment to prescribe the company’s drugs leaves no doubt either.21 Schering-Plough’s tactics included paying doctors large sums to prescribe its drug for hepatitis C and to take part in company-sponsored clinical trials that were little more than thinly disguised marketing efforts that required little effort on the doctors’ part. The company ‘flooded the market with pseudo-trials’ and paid physicians $1000–$1500 per patient for prescribing interferon, which the patients or insurers paid for.10
One thing is the copious amount of money doctors may receive when they are entangled in the medico-industrial complex. An equally interesting issue is how widespread the corruption of academic integrity is.
Before I reveal these data, try to think for yourself. What proportion of all doctors do you think receive money from the drug industry? Including those who are retired, work in general practice, work with public health, don’t prescribe drugs, or don’t make important decisions on their own, e.g. the thousands of junior doctors who are required to follow guidelines written by their seniors.
In Denmark, it is required by law to get permission from the drug agency if a doctor wants to work for a drug company unless the assignment is trivial, such as giving a single lecture at an industry-sponsored meeting. These permissions are published on a public website, but until recently the compliance was poor. In June 2010, the drug agency sent a warning to 650 doctors on industry payroll without permission.22 At that time, 1694 doctors were listed, but including the 650 who weren’t approved, 12% of all Danish doctors worked for the drug industry. Some doctors had several roles in the same company and some worked for several companies, the maximum being 13.22
When we looked at the registry in November 2010, 4036 roles were listed, which is one for every five doctors in Denmark. This number is shocking, as Denmark is regarded as one of the least corrupt countries in the world, and a leading politician remarked that is must be difficult for the doctors to attend to their usual work when working for so many masters.22
Table 7.1 shows the 10 companies that collaborated with most doctors. It is hardly a coincidence that seven of them are also in the top 10 as concerns sales (see Chapter 3).
Table 7.1 The 10 companies that collaborated with most doctors
1 Pfizer 586
2 AstraZeneca 334
3 Merck 245
4 Novo Nordisk 204
5 GlaxoSmithKline 197
6 Novartis 190
7 Sanofi-Aventis 177
8 Bristol-Myers Squibb 166
9 Boehringer Ingelheim 157
10 Roche 118
The Danish Medical Association denied there were any problems, and it met requests for more transparency, including the nature of the hired work and the size of the honoraria, with arrogant remarks that this didn’t concern others, including the patients.23 We shall see in the next chapter whether this is a tenable position.
References
1 Virapen J. Side Effects: death. College Station: Virtualbookworm.com Publishing; 2010.
2 Angell M. The Truth about the Drug Companies: how they deceive us and what to do about it. New York: Random House; 2004.
3 Abramson J. Overdo$ed America: the broken promise of American medicine. New York: HarperCollins; 2004.
4 Wilmshurst P. Academia and industry. Lancet. 2000; 356: 338–44.
5 Steinman MA, Bero LA, Chren MM, et al. Narrative review: the promotion of gabapentin: an analysis of internal industry documents. Ann Intern Med. 2006; 145: 284–93.
6 Braithwaite J. Corporate Crime in the Pharmaceutical Industry. London: Routledge & Kegan Paul; 1984.
7 Transparency International. Global Corruption Report 2006. Available online at: www.transparency.org/publications/gcr (accessed 8 February 2008).
8 House of Commons Health Committee. The Influence of the Pharmaceutical Industry. Fourth Report of Session 2004–05. 2005. Available online at: www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/42.pdf (accessed 26 April 2005).
9 Chren MM, Landefeld CS. Physicians’ behavior and their interactions with drug companies. A controlled study of physicians who requested additions to a hospital drug formulary. JAMA. 1994; 271: 684–9.
10 Wazana A. Physicians and the pharmaceutical industry: is a gift ever just a gift? JAMA. 2000; 283: 373–80.
11 Grill M. Kranke Geschäfte: wie die Pharmaindustrie uns manipuliert. Hamburg: Rowohlt Verlag; 2007.
12 Mundy A. Dispensing with the Truth. New York: St. Martin’s Press; 2001.
13 Avorn J. Powerful Medicines: the benefits, risks, and costs of prescription drugs. New York: Vintage Books; 2005.
14 Kassirer JP. On the Take: how medicine’s complicity with big business can endanger your health. Oxford: Oxford University Press; 2005.
15 Gale EA. Conflicts of interest in guideline panel members. BMJ. 2011; 343: d5728.
16 Boseley S. Drug firms using backdoor tactics to boost sales, report reveals. The Guardian. 2011 Sept 23.
17 Lenzer J. Whistleblower removed from job for talking to the press. BMJ. 2004; 328: 1153.
18 Elliott C. The drug pushers. The Atlantic Monthly. 2006 April.
19 Palo J. Why did my colleagues turn to crime? BMJ. 2004; 328: 1083.
20 Applegate WB, Furberg CD, Byington RP, et al. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). JAMA. 1997; 277: 297.
21 Harris G. As doctors write prescriptions, drug company writes a check. New York Times. 2004 June 27.
22 Elkjær B, Rebouh D, Jensen J, et al. [See if your doctor is in industry’s pocket]. Ekstra Bladet. 2010 June 24.
23 Editorial. [The greedy doctors]. Ekstra Bladet. 2010 June 24.
8
What do thousands of doctors on industry payroll do?
We become doctors to help our patients, and some doctors do valuable work for the companies that might potentially benefit patients too, e.g. as investigators in relevant trials. But most doctors on industry payroll don’t. It’s simply not possible for so many doctors to do meaningful work for the companies of potential value for patients.
The truth is that by far most doctors assist the companies in marketing their products. This becomes clear if we look at the 4036 roles Danish doctors had in 2010 (see Table 8.1).1 There were 1626 investigators, which was the most common role. However, true progress in drug treatment is very rare. In 2009, Prescrire analysed 109 new drugs or indications: 3 were considered a minor therapeutic breakthrough, 76 added nothing new, while 19 were deemed to represent a possible public health risk.2 Others have estimated that 11%–16% of new drugs represent a therapeutic gain,3 but that was with very generous definitions of what a gain is; if the gains and the trials behind them were scrutinised more closely, there wouldn’t be much left.
Table 8.1 Roles of Danish doctors with permission to work for the drug industry. Data from 2010
Investigator 1626
Advisory Board member or consultant 1160
Lecturer 950
Stock ownership 175
Author 36
Other 89
Total 4036
If a company has developed a truly superior drug, it doesn’t require many doctors to assist it in proving this in one or two multinational trials. Since Denmark is so small, not more than five Danish doctors would need to participate to such an extent that they needed permission from the drug agency to collaborate with the company. But as there are additional relevant projects for a superior drug, let’s be generous and say that 50 doctors are needed and compare this with the 1626 doctors with permission to be clinical investigators, which is 30 times as many. What are all these other doctors doing?
We actually know a good deal about this. Because of our foolish patent system and the unlimited powers of marketing, it is highly profitable to develop so-called me-too drugs, which have a molecular structure similar to drugs already on the market. For common diseases, with a large market potential, more than 100 different drugs may have been developed within the same therapeutic class, e.g. antihistamines. As these drugs are variations of known substances, one could argue that they aren’t really new discoveries, in the same way as the development of a new set of bumpers for a Volvo doesn’t make it a different car.
It is very rare for me-too drugs to represent any therapeutic advance, but very common that it looks as if they do. The industry uses two main tricks. One is to perform a lot of entirely superfluous – and therefore by definition unethical – placebo-controlled trials long after the effect of the new drug has been proven. This may seem a foolish thing to do, but it isn’t, as exemplified by the highly expensive triptans for treatment of migraine. The first such drug was sumatriptan from GlaxoSmithKline. There are at least 24 published trials with oral sumatriptan where the only comparator is placebo.4 The large effect compared with placebo was used to convince doctors to prescribe these ‘modern’ drugs rather than the old ones. It is strange that this can work but it does; anything can be sold to a doctor it seems.
This ploy went on for many years after sumatriptan came on the market in 1991. In 2009, a researcher reported that Glaxo had omitted to publish several of its negative trials on sumatriptan,5 and finally, in 2011, after our societies had wasted loads of money on these drugs for 20 years, the Danish National Board of Health tried to roll the clock back, announcing that aspirin was equally effective as the triptans and should be preferred because of its much lower price.6 I’m sure this won’t work. Nothing beats industry marketing, particularly not when it comes 20 years too late.
As already explained, the other way the industry fools us into believing new drugs are better than old ones is to manipulate the design, analysis and reporting of head-to-head trials that compare two active drugs.
Whether they have placebo or an active drug as comparator, few industry trials provide anything of value for patients. In fact, they generally impact negatively on patients, as their purpose is to provide support for the marketing of expensive drugs that have nothing to offer and sometimes turn out later to have caused serious harms.
Internal company documents obtained through litigation demonstrate why the drug industry performs clinical trials. Forget all the bullshit about helping patients. Pfizer has made it very clear and even speak of off-label marketing, which they call off-label data dissemination:7
Pfizer-sponsored studies belong to Pfizer, not to any individual
Purpose of data is to support, directly or indirectly, marketing of our product
Through use in label enhancements, & NDA [New Drug Application] filings
Through publications for field force use
Through publications that can be utilized to support off-label data dissemination
Therefore commercial marketing/medical need to be involved in all data dissemination efforts.
It seems that at least 97% of the 1626 Danish doctors who help the companies as ‘investigators’ don’t do valuable research but help the companies with marketing. The worst of these studies are seeding trials, one of the darkest sides of doctors’ collaboration with the drug industry.
Seeding trials
Seeding trials usually have no scientific value and usually don’t even have a control group. The doctors are given a portion of the company’s new drug and are asked to try it out on their patients and note how it goes. The assembled data are pretty useless and are rarely published. The real aim of seeding trials is to lure as many doctors as possible into using the new drug. The doctors get a fee for each patient, and although the companies call it research, it has the character of bribery.
A German survey found that two-thirds of such ‘studies’ didn’t even have a study plan or an aim for the study, and only 19% mentioned anything about publication.8 The drugs being promoted in the seeding trials were 10 times as expensive, on average, than the drugs generally being used. When a German journalist exposed the corruption, the CEO of Novartis wrote to his employees that his company in all respects strictly lived up to the codes of honour Novartis had bound itself to follow. Bullshit on paper has the advantage that it doesn’t stink, at least only indirectly.
Few physicians would knowingly enrol their patients in a study that placed them at risk in order to provide a company with a marketing advantage, and few patients would agree to participate.9 Seeding trials can therefore occur only because the company doesn’t disclose their true purpose to anyone. We need a societal consensus that it is immoral to deceive ethics committees and participants in this way about the true purpose of a trial.
A hallmark of seeding trials is that they involve huge numbers of doctors who treat few patients each. The law varies in different countries, but seeding trials rarely require approval by a research ethics committee or a drug regulatory agency because they are not regarded as research, but ordinary use of an approved drug. The irony is total because at the same time many doctors think they contribute to research. In contrast to ordinary clinical trials, seeding trials are usually run by marketing people and salespeople try to influence the prescribing practices while they collect the data in the doctors’ offices.
In 2006, Danish researchers documented that their participation in a seeding trial led to a significant increase in the use of the company’s drugs in their practices even though the effect was much diluted, as only 11 of the 26 general practitioners recruited patients for the study.11,12 The rationale for the study was very thin, to compare an asthma drug with itself given in two different ways, in a nonblinded trial. AstraZeneca paid the doctors $800 for each patient. We have no idea how many doctors or patients were enrolled, as the study has never been published, although it appeared to have ended in 2002. I found an undated internal company report that mentioned 796 patients and that the data were on file.
A PhD thesis revealed AstraZeneca’s purpose with the study: ‘[AstraZeneca] is very concerned with the production of clinical evidence both as a means of making doctors aware of upcoming products and as a prerequisite for further commercial marketing,’ and ‘in my view it was a much easier way to get a number of GPs aboard, instead of having to go out and convince them.’13
An accompanying editorial noted that when a gift or gesture of any size is bestowed, it imposes on the recipient a sense of indebtedness. The obligation to directly reciprocate, whether or not the recipient is conscious of it, tends to influence behaviour. Food, flattery and friendship are powerful tools of persuasion, particularly when combined.12
A final point about research is worth noting. Even when academic investigators perform so-called independent clinical research on drugs, the drug industry tries to meddle with it. Internal documents that were never meant to become publicly known, but which were released through US court proceedings, are revealing.7 An internal AstraZeneca email says that:
Lilly run a large and highly effective IIT [Investigator-initiated trials] program … They offer significant financial support but want co
ntrol of the data in return. They are able to spin the same data in many different ways through an effective publications team. Negative data usually remains well hidden.
BMS [Bristol-Myers Squibb] IIT program is growing very fast in launched markets … most proposals are modified by BMS. Strategic focus is unlicensed indications.
Janssen have a well organized IIT plan … no IIT data is allowed to be published without going through Janssen for approval, and communication is controlled by Janssen. High expectations are set on investigators who publish favourable results but they are well rewarded for their involvement. They seem less concerned than Lilly about negative data reaching the public domain.
It seems rather strange to me that companies can run investigator-initiated trials and even have programmes for this. And if it’s correct that Janssen rewards investigators who publish favourable results, it looks like corruption.
Rent a key opinion leader to ‘give advice’
No less than 1160 Danish doctors were hired by the drug industry to give advice to one or more companies, in a role described either as Advisory Board member or consultant (see Table 8.1). This huge number suggests that people working in the drug industry are either exceptionally dumb, as they seem to need advice every hour around the clock, or they are smart, as they buy doctors. Pharmaceutical Marketing has provided the answer:14
The advisory process is one of the most powerful means of getting close to people and of influencing them. Not only does it help shape medical education overall, it can help in the process of evaluating how individuals can best be used, motivate them to want to work with you – and with subliminal selling of key messages ongoing all the while.
The guide for marketers was even bold enough to call opinion leaders for trainees, though many of them are professors.
Most of these consultancies can best be described as bribery, and the consultants as pseudo-consultants. In a criminal fraud case that was settled with TAP Pharmaceuticals, the report described that the ‘consultants’ never prepared reports or billed TAP for their time; further, the sales employees who nominated the doctors to attend the ‘consulting’ programmes typically had no discussions with the doctors regarding the consulting services to be provided.15
Deadly Medicines and Organised Crime Page 14
