Pharmacogenetics

To realise the potential of genetics research concerted activity by both academic and industry researchers is needed. Currently the research conducted by the pharmaceutical industry centres on two main strands: new drug development and pharmacogenetics.¹

Pharmacogenetics aims at understanding how genetic variation contributes to variations in response to medicines. The variation that exists in all genes causes different members of a population to express different forms of proteins, including those that metabolise drugs or are the sites of drug action. This can lead to different responses to these drugs. Measuring the DNA differences can thus predict the variation in response to the medicine.¹ In the past, systematic research into the basis of adverse drug reactions has been hampered by the fact that these events are rare and individuals are difficult to trace and study while suffering a reaction. The ability to conduct genetic research retrospectively, at the end of a clinical trial or after a medicine has been launched, using stored samples of DNA, gives researchers a powerful new tool to explore how medicines work.

Such research will result in tests for responses to drugs that clinicians can use to identify patients with a greater chance of effective response and reduced risk of adverse reactions. Genetic markers to select appropriate treatment have, of course, been used for decades. Whenever a patient needs a blood transfusion, the ABO blood types—classic genetic markers—are used to identify the best match of blood. Tissue typing before transplantation and Rhesus factor testing are other examples. Trastuzumab (Herceptin; Genentech) has recently been licensed for treating some types of breast cancer. It is a humanised monoclonal antibody against the HER2 receptor and has been licensed together with a specific test (Herceptest) to identify the appropriate subgroup of patients who overexpress the HER2 receptor in the tumour tissue.² This is the direction that pharmacogenetics is likely to take drug treatment.

Most observers agree that this technology will affect medical practice—in some diseases—within five years (see p 1031)³ Moreover, pharmacogenetics is associated with fewer ethical problems than other medical applications of genetics, such as presymptomatic diagnosis of highly penetrant single gene diseases with no treatment currently available—the scenario that dominates ethical issues in genetics.

What is the role of industry in this area? Companies are responsible for developing most new medicines or devices, so it is important to consider how they can collaborate with academics to expedite new therapies. Pharmacogenetics is increasingly driven by industrial researchers, partly because of their ready access to clinical trial data on which pharmacogenetic research can be carried out. The rigours of drug registration require a high level of data quality (and hence high cost) that few academic groups can afford.

Counterintuitively, industry can also provide leadership in procedures such as consent for such studies. For example, the need to establish clear procedures for generating and handling genetic information in the context of pharmacogenetic research has led to a cross industry group proposing standard definitions under which such research can be carried out (see www3.diahome.org/committees/pharmacogenetics/mission.asp). This has been welcomed by ethics committees and regulatory authorities, who find the current diversity of terminologies and approaches confusing (see, for example, www.emea.eu.int/pdfs/human/regaffair148300en.pdf). The usefulness of such an approach can be seen from the recent agreement of the Pharmacogenetics Research Network, funded by the US National Institute of General Medicine, to adopt these definitions as their standards (www.pharmgkb.org/pdfs/model.pdf).

In addition, industry is at the forefront of initiatives to use modern communication tools, such as the internet, to allow patients to provide samples for future research yet retain control of them in the light of future developments. When technology is evolving rapidly the research outlined in an original consent form can easily become superseded. If a valuable research resource is not to be lost, efficient methods of maintaining contact with patients to ask for further consent need to be developed. Possible approaches under consideration include having DNA samples and patient contact details held by an independent third party, who can release DNA for research after contacting patients using email or the internet.

Increasingly, the common needs for research tools of both industry and academic researchers are leading to joint activities. A successful recent example is the SNP Consortium, a grouping of 13 companies, five leading academic centres, and a charity (the Wellcome Trust) established to identify 300 000 single nucleotide polymorphisms in the human genome and make the information public as a research tool for all. This map, now available on the web (http://snp.cshl.org/index.html), will be a central tool, allowing genetic markers that affect disease susceptibility or drug response to be identified more rapidly. This should help to speed up the implementation of pharmacogenetic tests. There may be other lessons to be learnt from this initiative as it was managed to industrial timelines, identified five times more single nucleotide polymorphisms than originally conceived, and still finished ahead of schedule and under budget.

Both industry and academic researchers want to bring innovative solutions into clinical practice to improve health care. It is important that the skills of both are used to ensure the benefits from genetic research are delivered sooner rather than later.