Karen Smith

Ethics and Pharmacogenomics, does one size fit all ?

In the second half of the 20th century, enormous strides were made in the development of effective drugs for a wide range of conditions. These drugs have undoubtedly made major contributions to saving lives and reducing the burden of disease. On the whole, however, this progress has been achieved by focusing on large groups of patients with precisely defined disease entities. The strategy ensured that drugs were safe relative to the expected benefits for the group, even if they were not always effective in every patient. The public policy implications of this were relatively clear: identical products were to be delivered to large sections of the population following a long period of testing. This required large-scale trials providing information to large sections of the population where the emphasis was on a safe regime rather than an individualised regime. This strategy of 'one size fits all' in drug development was challenged, however, almost from the beginning, by accumulating evidence of individual differences in response to drugs. In several cases such differences were traced to individual differences in enzyme structure and function, which had dramatic effects on the safety and effectiveness of specific compounds in certain individuals (Motulsky, 1957). Public policy had to be adapted incrementally to manage these exceptions. Many of these differences were soon recognised to be genetically driven.

In the last decade, new techniques in genetics have provided powerful and potentially inexpensive tools for studying the genetic basis of such differences in drug response on a large scale. The mapping of the human genome and the technology that made it possible opened up a new vision, in which individual patients could be tested for a host of relevant genetic differences, and the results could be used to choose the safest and most effective compound for each patient - finding each person's 'very own medicine'. This poses new challenges for public policy makers.

Uses of genetic testing for drug choice

Genetic testing of individual patients to guide drug treatment choices in clinical settings is referred to as pharmacogenetics. There are three main potential uses of genetic tests in guiding individualised drug treatment: -To adjust doses -To choose the most effective drug for a particular individual -To avoid serious adverse events due to individual metabolic idiosyncrasies" (See Quotation source*) However, such testing has major ethical, legal and social implications.

The Cambridge Genetics Knowledge Park (CGKP)

The Cambridge Genetics Knowledge Park (CGKP) is one of six in England and Wales, funded by the Genetics Knowledge Challenge Fund established by the Department of Health and the Department of Trade and Industry and focuses on these ethical, legal and social implications. The Five sectors of genetics knowledge: Clinical; Commercial; Ethical, Legal and Social; Scientific; and Public Health are brought together within the Cambridge Genetics Knowledge Park for the benefit of society (right).

Ethical issues in patients' consent to pharmacogenomic trials

Blood samples are currently being collected from patients participating in clinical drug trials, to be used for pharmacogenomics research. While there has been a great deal of attention given to the collection of blood samples for use in public genetic databases, there has been virtually no discussion of the formation of such databases by or on behalf of the pharmaceutical industry. In pharmacogenomics studies, patients are asked to consent to three separate aspects of research: the main clinical drug trial, research involving a specific genetic test related to a drug effect, and unspecified genetic tests to be used in future pharmacogenetics research. They give the sponsoring pharmaceutical company permission to link genetic research on their blood sample to personal medical information, such as details of their medical condition and family history. It may be suggested that the limits of consent for pharmacogenomics studies are being overreached.

Given evidence of the inability of patients who have decided to take part in clinical trials to comprehend information about trial procedures or to recall information about potential risks, it is possible that patients entering into pharmacogenomics related trials may not have given careful consideration to all potential risks and benefits of this additional research. Patients who already feel overburdened with information and anxiety, and in a weakened position to make independent decisions, may be exploited in this situation. Although in conventional clinical drug trials patients are subjected to additional risks over and above conventional therapy, patients have at least the possibility of benefiting either from the comparative drug being tested or from the trial drug. By contrast, there is no direct benefit to the patient in the pharmacogenomics study and thus compromises in the consent process cannot be offset against potential therapeutic benefit. As against this, it could be argued that the risks are much smaller than those accepted in conventional therapeutic trials. Following the US case of John Moore, a patient whose cell-line was patented and sold to the drug company Sandoz for $15 million, issues of property rights are increasingly being raised in relation to tissue samples. Blood samples that are donated for genetic testing during the pharmacogenomics part of a clinical trial may potentially be extremely valuable commodities for genetic-based drug development. In addition to their consent to take part in the research, patients are required to agree in writing that they have no property rights over the sample or any data generated from it. These considerations all raise profound questions about the meaning of consent for pharmacogenomics trials. Should patients be financially rewarded for their involvement, as is the case for healthy subjects in Phase I trials and for the physicians who recruit, conduct and oversee clinical trials? Or should the fact that patients in the main trial are likely to receive benefit in the form of therapy be sufficient reward for taking part in additional pharmacogenetics research? Is it right that participants be excluded from taking a financial interest in products that have been developed using their blood or tissue? And to what extent should altruistic reasons on the part of patients be taken into consideration? While pharmaceutical companies are foremost profit-making organisations and economic generators, they are also the vehicle by which successive governments have chosen to develop and test new drugs. We are thus left with the challenge of determining how to regulate clinical drug trials and pharmacogenomics research in a way that better protects patients and research subjects, but does not overly restrict potential medical breakthroughs.

About the authors:

• Dr. Oonagh Corrigan, is a social scientist and Cambridge Genetics Knowledge Park Lecturer.
• Dr. Karen Smith is a neuroanatomist and the Business Development Manager for Life Sciences at the University of Cambridge Corporate Liaison Office (CLO).

Acknowledgements: The Wellcome Trust's Biomedical Ethics Programme sponsored Oonagh's research.

- May 2004

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