For richer,for poorer,in sickness and in health: The entanglement of science and marketing

‘Psychiatrist claims campaign to discredit him’ (Griffiths, 2012). This claim was made by Professor Ian Hickie, Director of the Brain and Mind Institute and high-profile Australian psychiatrist, in response to letters to the Lancet criticising the alleged bias of the review article he wrote with Associate Professor Naomi Rogers on the pharmacology and clinical profile of novel melatonin-based antidepressants (Hickie and Rogers, 2011). While there may be people who take exception to his role in the national reform agenda, only one of the letters was from an Australian source (Jureidini and Raven, 2012). An international conspiracy perhaps, or simply a diversion from a serious issue confronting contemporary medical practice: the relationship that exists at multiple levels between the pharmaceutical industry and the medical profession?

The controversy surrounded claims that the authors show bias in the interpretation of the data relating to the efficacy and safety of agomelatine, one of a number of melatonin analogues being developed for the treatment of depression. Questions were raised about the transparency of the financial and other arrangements between the authors and Servier, the manufacturer of agomelatine. As Hickie and Rogers replied, ‘our other academic, educational, public research, and financial relationship with Servier Laboratories (and other government and industry-related entities) were disclosed exhaustively at the time of publication’ (Hickie and Rogers, 2012).

And herein lies a major problem with contemporary practice in the reporting of conflicts of interest: the relationship between the author(s) and the relevant pharmaceutical company is frequently buried in a plethora of other interests not relevant to the current research. In this case, the critical issue is the details of the arrangements between the researchers and Servier, particularly relevant given that Professor Hickie appeared at a company media briefing to promote agomelatine (Rose, 2011).

Almost a third of the 105 cited references relate to agomelatine (Hickie and Rogers, 2011). Of the 16 I have been able to access online to date, all have reported some form of financial arrangement between the author(s) and Servier, including funding for the current research, honoraria, membership of speaker or advisory boards, donations of drugs, collection and analysis of data and data checking of manuscripts, funding for development and review of manuscripts, and inclusion of Servier employees in the research team.

The Australian media’s interest in this particular case was clearly aroused by the high profile of the principal author. But, to put it in context, most clinical trials are now funded by the pharmaceutical industry and, as Angell (2008), a former Editor-in-Chief of the New England Journal of Medicine stated: ‘It would be naïve to conclude that the bias is only a matter of a few isolated instances. It permeates the entire system.’

Documents relating to the promotion of gabapentin, describing the strategies developed in the mid- to late 1990s by Parke-Davis to market the drug, revealed that the company had used a comprehensive and multifaceted approach making use of advisory boards, consultant meetings, and accredited continuing medical education events organised through third parties, funding of research with key customers, and payment of communication companies to develop and publish articles. These strategies were augmented by ‘the engagement of thought leaders, who could be used to communicate favourable messages about the drug’ (Steinman et al., 2006).

The NHMRC recently advised that it would not endorse its draft guidelines on the management of ADHD following findings of violation of Harvard Medical School’s conflict of interest policy against Professor Biederman, a leading ADHD researcher whose work was heavily referenced in the draft. He and two of his colleagues had failed to report all their income from the pharmaceutical industry (NHMRC, 2009). But much more significant was the disclosure of documents showing that Biederman: ‘pushed the company [Johnson & Johnson, manufacturers of risperidone (Risperdal)] to finance a research centre … with a goal to “move forward the commercial goals of J. & J”.’ (Harris, 2008). This is particularly pertinent given his strong advocacy for the diagnosis of bipolar disorder in children and the role his research has had in promoting the use of antipsychotic medication in children (Parry and Allison, 2008).

Over the last two and a half decades the pharmaceutical industry has ‘gained unprecedented control over the evaluation of its own products’ (Angell, 2008) and ‘this threatens the independence and impartiality essential to medical research’ (Angell, 2010). There is now irrefutable evidence from both primary studies and systematic reviews that show a clear association between the pharmaceutical funding of clinical trials and pro-industry results (Bakelman et al., 2003; Doucet and Sismondo, 2008; Lexchin et al., 2003; Sismondo, 2007). Essentially, ‘industry sponsorship biases published scientific research in favour of the sponsors’ (Doucet and Sismondo, 2008).

There are many studies that have observed that ‘specialists participating in industry-sponsored research express confidence in their capacity to remain impervious to industry influence’. This is at odds with the considerable research on gift-giving and the ‘unconscious and unintentional processes through which obligation may be established’ (Doucet and Sismondo, 2008). Furthermore, the pharmaceutical industry has learned to influence physician prescribing behaviour indirectly through its control of research and the use of ‘opinion leaders’ from within the profession to promote its products.

Financial interests are ‘not the only, nor necessarily the most powerful, secondary interests that determine physicians’ attitudes and behaviour’ (Henry et al., 2005). Factors such as professional standing and desire for academic advancement may be just as powerful as gifts and payments.

It is argued that ‘Big Pharma’ is not ‘Big Tobacco’ and that many people experiencing mental illness benefit from medication. However, they have one overriding interest in common and that is accountability to shareholders. In 2011, the top 10 pharmaceutical companies in the US Fortune 500 made a combined profit of US$46 billion. As Angell (2005) asserts: ‘Drug companies don’t have educational budgets; they have marketing budgets from which their ostensibly educational activities are funded.’

In 2011, payments to pharmaceutical companies by the Australian Government through the Pharmaceutical Benefits Scheme (PBS) amounted to AUD$7.3 billion (Pharmaceutical Policy and Analysis Branch, 2008, p.2, Table 2). Between 1992/93 and 2007/08, the PBS payments for psychiatric medications increased from AUD$94 million to AUD$702 million; or from 14% to 37% of Commonwealth Government expenditure on mental health. By comparison, total payments under MBS for psychiatrists, general practitioners and allied health went from AUD$437 million to AUD$550 million in that period (Department of Health and Ageing, 2010, p.26, Table 3). In 2011, four of the top 20 PBS drugs in terms of cost were olanzapine (8th), quetiapine (12th), venlafaxine (13th) and risperidone (17th), with a combined total cost of AUD$436 million (Pharmaceutical Policy and Analysis Branch, 2011, p.11, Table 9(a)).

There have been a variety of proposals about how medicine should redefine its relationship with the pharmaceutical industry. These have essentially fallen into two broad categories, ‘management’ and ‘divestment’ strategies (Brody, 2010): the former aimed at enhancing disclosure rules to limit ill effects and the latter designed to ‘wean ourselves off a dependency that is generally inappropriate’ (Moynihan, 2003).

The Hickie case highlights the complexity of the medical–pharmaceutical entanglement. The ‘foundation’ of an evidence-based health system is medical research on which stands evidence-based practice, training, continuing medical education and professional development. It involves multiple ‘players’ including the pharmaceutical companies, the individual researchers, academic medical centres, clinical opinion leaders, departments of health, medical journals and medical colleges. This is essentially the system that the community relies upon and trusts for its health care.

Many of these players are currently looking at a combination of management and divestment strategies aimed at better defining the boundaries between medicine and industry. The Royal Australian and New Zealand College of Psychiatrists (RANZCP), which has major responsibility in training, continuing medical education, standard setting and professional development in psychiatry, must show leadership in moving to progressively divest itself of financial ties with the pharmaceutical industry. This will enhance its credibility with a community that is ‘no longer … confident that the testing of new drugs is unbiased’ (Relman and Angell, 2002).

As long as the pharmaceutical industry controls the foundation of medical research, we will not be able to eliminate sponsorship bias from the system. Because sponsorship bias results from the entanglement of science and marketing, strategies that do not address this relationship will at best be only partially effective. The only way of effectively eliminating the problem is by separating or putting at arm’s length clinical research from pharmaceutical industry funding (DeAngelis and Fontanarosa, 2008; Doucet and Sismondo, 2008).

Moynihan (2003) asks, ‘Who pays for the pizza?’ In the Australian context it is the Australian community, mainly through PBS. Is it not time for the Australian Government to take a critical look at the quality and escalating cost of the pizza that is being delivered to the medical profession through the pharmaceutical industry and to give consideration to direct delivery – through increased funding for research, training and professional development?

‘Is academic medicine for sale?’ was a question posed by Angell (2000) in an editorial in the New England Journal of Medicine. Among the many letters she received, one commented: ‘No. The current owner is very happy with it.’ Let’s make sure we know who that owner is!