A brief history of pharmacogenetics

The aim of this chapter is to briefly set out the debates about personalised medicine in the professional literature, outline theoretical ideas that might help us get to grips with these arguments, and introduce the two case studies used in this book. As a sociologist of science, one of the interesting things about coming to personalised medicine is the sheer range of people who are willing to write about it and tell you how they think it will develop. The profusion of reviews, editorials and opinion pieces in scientific and medical journals (what we might collectively call ‘commentaries’) that speculate about how medical practice and drug development might look in a few years' time provides a wonderful resource for sociological analysis. What follows is an attempt to unpack some of the claims being made about pharmacogenetics by academic scientists, company representatives and other commentators. Although it is not a comprehensive, quantitative review such as those found in the scientific literature, it does provide a detailed outline of the kinds of concerns that form the context within which pharmacogenetics will move into clinical practice.

It was a most peculiar newspaper headline. On 8 December 2003 the British broadsheet newspaper the Independent announced: ‘Glaxo chief: Our drugs do not work on most patients’ (Connor 2003a). The subsequent report covered a conference at which Allen Roses, vice-president of genetics at the pharmaceutical giant GlaxoSmithKline, admitted the ‘open secret within the drugs industry that most of its products are ineffective in most patients’ (Connor 2003a). Yet rather than this being a cause of outrage and falling share prices, for Roses and others like him in the industry such an admission is the first step on the road to a revolution in the way drugs are developed and, in the long run, how healthcare is provided. For Allen Roses ‘is a pioneer of a new culture within the drugs business based on using genes to test for who can benefit from a drug’ (Connor 2003a). And it is this use of genetic testing to develop and prescribe drugs, pharmacogenetics, that will drive the coming revolution. As Roses states, ‘Pharmacogenetics has the promise of removing much of the uncertainty’ that surrounds current drug use (Connor 2003a).

Industry's intense interest in pharmacogenetics and genomic technologies as a whole is relatively recent, dating from around 1997, but it has stimulated considerable investment on the part of pharmaceutical companies.

Discussing the clinical application of pharmacogenetics in Alzheimer's disease is complicated, because as things currently stand there is considerable professional debate over whether Alzheimer's disease exists as a separate clinical entity at all. Since at least the mid-1990s the relationship between Alzheimer's disease and other forms of dementia, such as Lewy body dementia or vascular dementia, has been in a state of flux: ‘Different forms of dementia are now known to have common underlying neuropathologies and histopathological studies have shown that mixed states (people presenting with features of more than one type of dementia) are probably more usual than pure dementia syndromes’ (Ritchie & Lovestone 2002: 1759). For many of my interviewees, ‘the dichotomy between vascular dementia and Alzheimer's Disease is probably artificial’ (CR 10). Yet in the clinic Alzheimer's disease is still treated as a separate condition. In the NHS, for example, while clinicians can prescribe drugs such as Aricept or Rivastigmine for patients suffering from Alzheimer's disease, they are discouraged from doing so for Lewy body and other kinds of dementia.

For clinicians, Alzheimer's is a progressive neurological disease leading to the permanent loss of cells in parts of the brain associated with higher functions.

Pharmacogenetics in the clinic

The past two chapters have shown how Roche mobilised support behind Herceptin and moved it into clinical practice in the UK. This chapter is about what happened when it got there. Thus we have moved from broad issues about how you get a pharmacogenetic drug into clinical practice, to the small-scale, ‘micropolitics’ of the clinical encounter (Waitzkin 1991). Within this context the ‘shape’ the technology takes is influenced by the institutional and cultural setting within which it comes to be used. We have seen how Herceptin is seen by many in the media and outside oncology as a clear example of pharmacogenetics, the first drug of its kind to make it into clinical practice, and how Roche managed to get Herceptin into the clinic by enrolling a variety of actors in a network of support behind the new drug. This chapter starts by looking at how clinicians see Herceptin in terms of its value as a treatment. It then moves on to discuss the way in which HER2 testing and Herceptin are presented to patients: what women are told about HER2 testing and their eligibility for Herceptin.

Herceptin, breast cancer and drugs

If the story so far has been about resistance to personalised medicine, how not to get pharmacogenetics into the clinic, then the next three chapters are an example of pharmacogenetics that did successfully make that move. In 1998 the US Food and Drug Administration (FDA) licensed a new drug called Herceptin. Aimed specifically at women with metastatic (i.e. severe) breast cancer, the drug was rushed through the FDA's licensing procedures using a special mechanism. With little or no effective treatment for this kind of cancer, Herceptin, like so many other drugs, was heralded by the popular press as a breakthrough. Beyond the headlines, it is an extremely interesting drug if you happen to be interested in the way in which pharmacogenetics moves into the clinic, because, depending on who you talk to, Herceptin may just be the first example of a pharmacogenetic drug in regular clinical use.

The story of the development of Herceptin, its shepherding through clinical trials and the internal company politics that almost killed the drug off make a fantastic narrative about the role of the contingent and the social in technoscience. But this is not the story I am going to tell, for two reasons.

At the same time as Allen Roses and his colleagues were trying to convince the research community that APOE4 was implicated in increased risk of Alzheimer's disease, the pharmaceutical company Warner-Lambert was preparing to launch the first Alzheimer's drug treatment. Tacrine, as the product was called, is one of a family of compounds called acetyl cholinesterase (AChE) inhibitors, which delay the breakdown of the neurotransmitter acetylcholine, thought to have a central role in thought processes and memory function. The loss of the forebrain cholinergic system is characteristic of AD sufferers' brains; therefore it was supposed that AChE inhibitors would slow the development of symptoms of dementia.

These drugs have been around since the mid-nineteenth century, as variously: glaucoma treatment, insecticides, nerve gas and finally cognition enhancers (Taylor 1996). But, in a pattern which will be echoed later in this chapter, Tacrine's development was far from smooth. Initial claims about the drug's success in reducing the symptoms of AD were met with enthusiasm by other professionals, patients and family members (Summers et al. 1986; Herrman, Sadavoy & Steingart 1987). Over time however, questions were raised about the study's validity, with the US Food and Drug Administration (FDA) taking the unusual step in 1991 of publishing a report in the New England Journal of Medicine which was highly critical of the methods, assumptions and conclusions of the original study (FDA 1991).

Ordinary coalface knowledge

This book has followed two high-profile examples of pharmacogenetics, unpacking assumptions, beliefs and contexts along the way. I have shown both how to, and how not to, get an example of personalised medicine into clinical practice, and have explored the messy intersection between industry, health service funders and clinicians. This chapter draws together ideas around pharmacogenetics by returning to the three dichotomies introduced in chapter 1: coalface–expectations, knowledge–resistance and ordinary–revolutionary technology.

Having just explored the ordinariness of Herceptin, it is to this dichotomy that I first turn. In both case studies, I have shown how pharmacogenetic tests do not arise out of nowhere, but rather, how they are enmeshed in their technical, social and ethical context and can only be understood in those terms. Whatever the claims of commentators, APOE testing for Alzheimer's pharmacogenetics does raise some of the same ethical issues as ‘ordinary’ susceptibility gene testing. And however revolutionary Herceptin seems when it is discussed on the financial pages, once it enters the clinic it becomes an ordinary cancer treatment, subject to the same institutional stresses and strains, with clinicians' attitudes towards and understating of it shaped by their experience of other, older treatments, for example Tamoxifen. If, when they arrive, pharmacogenetic tests are better thought of as ordinary, as opposed to revolutionary, then this should alert us to the importance of the context within which such tests are used.

While Roche set out to overcome the informal resistance presented to Herceptin and HER2 testing by clinicians, a separate struggle was taking place on a more formal footing. Herceptin was being considered by the National Institute for Clinical Excellence (NICE), to see whether it was suitable for funding by the NHS. While acceptance (or not) by clinicians matters, whether a new treatment gets funding or not is, in a system like the NHS, obviously the most important factor in determining whether it gets taken up in the clinic. Many clinicians felt that the only way they would get to prescribe Herceptin on a regular basis was if NICE decided that it was both clinically and cost effective. This situation is not unique to the UK of course, even private insurance schemes have their limits and a list of techniques and treatment that they do not cover. But more specifically, it is also important to note that NICE's influence spreads beyond just the UK's National Health Service. In the past few years a number of different countries have put in place organisations to carry out the same sort of assessments, and even a number of US-managed care organisations are introducing health technology assessment (Paul & Trueman 2001: 433).

The previous two chapters have shown how the current consensus view of clinical APOE4 testing for both differential diagnosis of Alzheimer's and the prescription of Tacrine and other acetyl cholinesterase inhibitors has come about. In general, there is significant reluctance to introduce APOE testing into the clinic, a reluctance based on a complex mesh of technical, social and ethical factors. At the same time, there is widespread APOE genotyping in the research setting, both academic and commercial, and increasing interest in bringing APOE into the clinic. This final chapter on Alzheimer's disease explores the role of APOE genotyping in current pharmacogenetic research and how this relates to industry concerns. It also uses theoretical ideas from the sociology of science to explain the differences between expectations and the coalface in Alzheimer's pharmacogenetics, and to get to grips with the source and solutions to clinical resistance.

APOE testing in research and the clinic

Although resistance to clinical APOE4 testing is strong, there is a great deal of genotyping going on in specialist Alzheimer and memory clinics throughout the US and the UK. While the location for such testing may be the same as for clinical treatment, the motivation of this work is ostensibly quite different.