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INTERNATIONAL JOURNAL OF PHARMACEUTICAL MEDICINE 2001, 15:54–56

COMMENTARY ......................................................................................................................................................................

Pharmacogenetics: pharmacogenie or pharmacogenerality in future drug discovery and development? Anthony D. Dayan London

For those not kept up-to-date by children or grandchildren a genie is a magic spirit able to do whatever you wish, and all of us should accept a ‘Generality’ usually as a boring truism more than an invigorating synthesis. What is your view of ‘Pharmacogenetics’ now and what might it become after reading a new report about it? For about the past year we have been so bombarded professionally and in the lay media with news and tales about the genome and genetics, and how they will swiftly lead to new diagnoses and powerful cures, that one might almost wonder whether there is anything left to discuss in their application to the health and disease of man and animals. In fact, the experienced professional, who is only a hardened cynic or a withdrawn Diogenes when he has to be, will have discounted much of the propaganda and will still be wondering what does it really mean for medical practice in general and, in the context of pharmaceutical medicine, for the development and use of new medicines? Building on past successes, the Society of Pharmaceutical Medicine has brought together a fruitful Working Party, which has critically analysed the nature of ‘Pharmacogenetics’ and its likely role in the discovery and proper use of pharmaceuticals. Their work has culminated in a lengthy report and an open meeting to discuss it. My purpose is to give the reader some flavour of the document, to encourage everyone to read and discuss it with colleagues and lay people and so to contribute to the debate that we must have about a major influence on the future nature of much medical practice and especially of our beloved medicines. Any report dealing with a broad subject can properly be evaluated for the skill and clarity with which it answers four or perhaps six questions: What is discussed? Why should we do anything about it? What should we do about it? Who should do it? And these days – what are the benefits and the costs and savings, and who will take responsibility for whatever has to be done? Have we an invaluable genie here or yet another set of pharmacogeneralizations with which to pass the committee time between lunch and tea?

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What? A clear distinction is drawn between the study of ‘Pharmacogenetics’ as the differences between individuals in their response to a drug and ‘Pharmacogenomics’ as the differences between compounds in the responses they evoke at the level of gene expression within a single genome. Both are fundamentally dependent upon nucleic acid technology, predominantly concerned with DNA but with important contributions from RNAbased techniques, and, although a separate discipline, increasingly too from ‘Proteomics’, the analogous study of changes in protein expression. The growing ability to dissect individual differences in the response to a drug given to treat a disease has shown, in addition to the well-recognized variation in pharmacokinetics (and in compliance with treatment), that the single phenotypic expression of many diseases conceals considerable genetic heterogeneity in their underlying causes; for example, single nucleotide polymorphism analysis (SNP) has demonstrated many genotypic variants in pharmacological receptors and other processes associated with the control of blood pressure. The end result in the patient is still hypertension. This is termed Type I Pharmacogenetics. The corresponding Type II pharmacogenetics represents genotypic variation that influences the response to a drug, which is not related to the pathogenesis of the disease. There are corresponding links to major types of adverse reactions. Recognizing and distinguishing Type I and II processes will enormously increase our understanding of the causes of disease, especially of the complex disorders and degenerative conditions that are increasingly important in the aging population. Pharmacogenomics will be of more direct interest to drug developers because it will display the intimate details of how drugs can influence basic cell mechanisms and so how therapeutically valuable substances can be sought for development.

2001

Vol 15, No 2

COMMENTARY

Why bother? Two main movements are driving activities in this area. Inevitably one is the availability of techniques for dissecting genetic mechanisms and structures and the increasing facility for their application in the clinical setting. The other is the rising popular expectation of perfect therapeutic results balanced against the harsh reality of limited therapeutic benefits and high costs of adverse events. At a different level the realization that there is an exploding number of potential therapeutic targets and their counterparts of potentially harmful responses is stimulating and directing research funding into genetics and genomics and away from more conventional areas. A revolution of this depth generates much excitement and catches wide attention in a way that will be self-accelerating for some while yet. There is clear promise of new diagnostic methods, new treatments and better and more rational application of existing therapies. Can one ask for more – provided all is feasible?

What should we do? This is where it becomes more difficult because understanding of the techniques and their implications is still patchy within the health care professions and the social and financial costs are only just being recognized. It may be unfortunate that the invigorating scientific possibilities are emerging at a time of burgeoning socio-legal excitement about individual freedom and privacy versus one’s responsibilities to the community, which are leading to legalistic uncertainties and political cloudiness about what information can be collected about individuals, how to hold it and who can use it. Much work on pharmacogenetics is based initially on the collection of simple samples, e.g. blood or a cheek scraping. However, the same samples can permit a great deal of individually identifiable information to be obtained, and as family investigations may be important, questions of parentage may also become apparent. The value of looking at whole communities has been recognized and there is already much controversy, for example about Iceland and certain ethnic groups in South America, as to the ownership of genetic information, the right to buy and sell it, and appropriate compensation for the individuals and communities who supply it. A corollary of the increasing value of information about families and lines is growing pressure to record identifiable information about individuals within their family groups. What price privacy and what value to place on an individual’s responsibility to the community? Professionals involved in health care and scientists need great sensitivity about the status of the individual in such circumstances, whilst being careful not to lose any opportunity to evaluate and benefit from differences – but always without suggesting that the possessor of one variant is somehow ‘ better’ or ‘inferior’ to another. The coming ability to select treatment that should work according to the genotype, and to avoid treatments that will be less effective or harmful on the same grounds, will put the same responsibility on the prescriber to be frank about the choices and risks of treatment with patients as the government and insurance industry are now having to face in dealing with genetic identification in the young of delayed serious conditions, such

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as Huntington’s chorea. Do prescribers, physicians or others, know enough to understand the choices and are they able to explain them clearly to patients? And, are developers, manufacturers and regulators ready to take on those responsibilities, often including making decisions as surrogates for the community as a whole? At the least we must ensure our that professionals and patients have sufficient education to understand the problems and to appreciate the difficulties and often partial nature of the solutions. Who will undertake those tasks? In a closely regulated licensing system for medicines what judgements will be required, by whom and on what grounds? All that was easy to write but it will require a huge and sustained effort at many levels and a great deal of expensive continuing education to turn knowledge that has to be gained into the understanding that is needed. Over the years reasonably good mechanisms have developed for evaluating the ethics of clinical trials, which have fed back in various ways into earlier stages of drug development. We may claim to have ethical mechanisms to control the availability of medicines and the appropriateness of their use in the community but I wonder how many of you would feel that these processes are financial and political in nature and have only a partial basis in ethics in the true sense of that term? The new possibilities will sharpen and expand the problems, so we need equal effort to enhance solutions.

Who should do it? This is less directly considered in the report by the SPM but there are responsibilities on physicians, other health care professionals, scientists involved in genetic studies and equally on those who influence and control political, social and legal standards in the community. The concepts both of the genetic ‘Superman’ and the ‘Pariah’ must be avoided if there is not to be damaging political restriction on medically-related research and even on processes leading to drug development. I believe we have yet to evolve mechanisms to cope with the problems of the feasibility of selecting therapies on an individual basis other than the conventional patient-doctor model. But where does the GP and other health care professionals fit in the system, what will be the role of the public health provider, how will formulary controls work and how will HMOs respond? How do we cope with pharmacoeconomics when accounting for pharmacogenetic variation may risk shrinking many pharmacotherapies into near-orphan products?

Whose benefit and whose cost and how much? No one can answer these questions at the moment because the problems have yet to be fully defined and there is not sufficient understanding to reach agreement on how to solve them. The intellectual and financial costs of the research will be enormous and will have to be recouped from citizens everywhere, who should benefit in terms of better therapies and improved health. However, we are all well aware that the distribution of health care benefits is uneven and on top of that problem will be the opportunity costs of exploiting pharmacogenetics whilst not doing work in other areas of science. Is there a need for a mechanism for a more equitable distribution of costs and benefits and is one feasible? As briefly noted the ethical cost of possible intrusion on individual privacy must not

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be forgotten nor the altruistic and other benefits of developments in the community.

The SPM’s report The Working Party has done an excellent job of identification and explanation and has attempted resolution of the scientific and medical issues raised by pharmacogenetics in relation to the development and use of medicines. They have not shirked moral and ethical problems whilst placing them in the context of existing structures.

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They have certainly avoided the generalizations and platitudes common to many such groups, they have not spared us deep science and they have brought out many philosophical and social questions. Above all, they have produced a readable and stimulating report which sets out a basis for the arguments that we all need to be involved in over the next few years. I at least am happy to regard them as having done the job of the pharmacogenie in relation to pharmacogenetics. The rest of us now have to live with and control what that spirit has brought, but at least we shall be better informed because of their work.

2001

Vol 15, No 2