Pharmacogenomics: Personalized Drugs And Personalized Medicine
Introduction:
Modern drug development is a complex process. The first step is the identification of a promising molecular target for drug action. This requires screening of the innumerable possibilities suggested by gene sequencing efforts, for example by the Human Genome Project. Validation aims to test the link between a target sequence and specific diseases. Then there is the need to clarify how the activity of the target sequence is regulated, its physiological relevance and the interaction of the products for which it codes. Advances in genomics (the systematic analysis of an entire genome) will eventually enable the identification of the genetic principles of most pathological and non-pathological phenotypes. It will also redefine the understanding and traditional definitions of diseases.
As the tools for identifying and understanding diseases become more sophisticated and precise, more specific treatments will clearly also have to be offered. Drugs that are precise enough to address a single gene within a gene-family need to be developed, otherwise ‘sledgehammers are created instead of the lasers that are needed’ (Cooke, 1998).
Pharmacogenomics aims to explore whether patients will respond to new drugs, and how. It aims to bridge the gap between gene discovery and drug development, and it is immediately applicable to clinical studies of existing drugs. The rapid growth in information and technology are stimulating enormous progress in this field (Lin, 1996). One important outcome of research in this area is the development of diagnostic tests that help identify the appropriate drug for a given individual.
The benefits of such tests are obvious: Patients avoid risky, painful and often extended investigative procedures to find the optimal treatment methods. A rapid test helps avoid harmful side effects. The systematic discovery and analysis of genetic variety in drug response should also lead to more cost effective drug development. Given that 80% of the compounds fail in clinical trials and industry spends $500-700 million for each new drug approval, considerable benefits may be reaped (Housman, 1998). Prescription based on a precise and rapid instrument for disease identification could also reduce treatment costs. "With this advancement in molecular technology and the financial implications of the results obtained, genotyping of patients before prescribing certain drug therapies is likely to become routine" (Prows, 1998).
The American National Institute for Health has already launched a $36-million programme to detect single nucleotide polymorphisms, so-called SNPs², which can be used in characterizing drug responses, disease susceptibilities, and to study population genetics (Stix, 1998).
New Therapeutic Approaches
Most therapeutic drugs undergo a biotransformation process that takes place, for example, in the liver. Typically, in a one or two-phase process, enzymes transform the lipophilic drug molecules to a more water-soluble metabolite which usually represents the active form of the drug. These metabolites are then further metabolized and eliminated from the body.
This idealized pathway, as it depends on the activity of biocatalysts, is determined by genetic parameters. Small differences or mutations in the genetic make-up, so-called polymorphisms, can cause modifications in the enzymes they encode. These modifications can subsequently be responsible for altered enzyme activity, the genotype determines the phenotype.
Three different drug-response phenotypes have been described (Johnsson, 1993).
Extensive metabolators, which represent the ‘normal’ population,
Slow metabolators, which show little or no ability to metabolize a drug, and
Ultra-extensive metabolators, which metabolize a drug far quicker than the ‘normal’ population.
Both slow metabolators and ultra-extensive metabolators show abnormal concentrations of drugs and their metabolites in their blood plasma. Those who are not able to metabolize these can accumulate high, possibly toxic doses. The ultra-extensive metabolators usually show no clinical response at all because of their tendency to eliminate drugs from body before they can take effect.
Biochemical tests can examine the patient’s phenotype. But these tests, which determine the metabolization ratio of a test drug, are complicated and often they do not exclude the risk of an adverse drug reaction (Prows, 1998). External conditions, such as interacting drugs or the overall disease process, can influence and distort the test.
Genetic tests can circumvent these problems. They do not try to detect the symptoms that are caused by a genetic alteration, they aim to detect the genetic alteration itself. In a subsequent process, this information can be used to draw conclusions about the phenotype.
A New Way For A Personalized Medicine
For the time being genotyping is only used in research. However, many companies are developing genetic tests for pharmacological purposes. In his review of the clinical implications of drugs based on genetic differences David Prows from the University of Cincinnati estimates that genotyping will become an accepted tool within the next five years (Prows, 1998).
The possibility of genotyping patients in order to estimate the risk of adverse drug reactions could pave the way for a more patient-centred health care model. Methods and tests developed by pharmaceogenomics will make it possible to identify groups of patients that will react positively to drugs prescribed to them. Disease-relevant drug-targets will be identified and used "to develop extremely efficacious, broadly tolerated drugs that can be prescribed to the largest possible population. New pharmaceutical products could be marketed alongside a corresponding diagnostic test kit, so as to permit the selective prescription of the drug" (Housman, 1998).
Together with new developments in protein analysis, where simultaneous assays of thousands of analytes will be possible, new integrated approaches in diagnostics can be foreseen. New fabrication technologies and progress in automation will support developments in diagnostics. Miniaturization and micro-fabrication technologies will make this new type of biosensor suitable for automation or even for implantation into the human body. The latter will enable on-line monitoring of high-risk patients. In order to detect the tiny differences in the human genome, which are responsible for diseases or variability in drug response, micro-chips, so-called SNP-chips will soon be on the market. They will definitely "mark the beginning of a personalized medicine" (Schmidt, 1998).
It is estimated that between 1.6 and 4.2 billion dollars are spent each year in the United States for additional treatments to deal with adverse reaction (Classen, 1997), and that they may have caused over 100,000 deaths during 1994 (Lazarou, 1998). Genetic tests would enable the physician to avoid some of these risks and so treat patients more effectively. Tests of this kind can also ensure patients have more information available to help them to make decision affecting their health. Such technologies and procedures will circumvent long-term trial-and-error measures and may reduce costs and risks tremendously. Patients could be checked before or even while a new drug is being administered. It may therefore strengthen the role of primary care, as more accurate diagnosis may reduce the need to consult experts.
In the US such targeted healthcare models have been predicted for 2008, (Poste, 1998), these include:
Genetic and pharmacogenomic profiling, to identify people at risk of developing serious illnesses because of their genetic predisposition
Diagnostics, to complement and support genetic tests
Smart cards for storage of patient information
Database applications for research, development and clinical care,
Counselling in clinical genetics
Pro-active disease management protocols for prophylactic therapy, lifestyle modification, and monitoring.
Although this model seems to be closely tailored to the US health market, some parts may also apply to some European health-care systems. Biotechnology, micro-and nano-technology, and information technology will drive new developments in diagnosis and treatment of disease.
However, despite the promising beneficial trends forecasted for the area of pharmacogenomics and the ability to personalize treatments and drugs, some concerns have been raised. Too sharply focused drugs and therapies may detract from the goal of medicine and pharmacy to find treatments for as many people as possible: pharmacogenomics should not be used to pinpoint the people who are ‘genetically right’ for the drugs pharmaceutical companies want to sell (Schmidt, 1998).
Such a trend would be worrying. It could be a source of new "rare" diseases, and possibly lead to "therapeutic discrimination" against patients with diseases and genotypes that are expensive to treat.
Other experts, however, argue that these fears are unfounded. They reply that both human genomes and diseases are polymorphic enough to make such a development unlikely to happen. The development of niche products for these markets could be an interesting and challenging market for SMEs given an appropriate intellectual property rights framework
In the USA, patient pressure resulted in the Orphan Drug Act in 1983, to stimulate the development of orphan drugs, which cannot be developed economically by industry without incentives. In 1999, the European Parliament approved, at the first reading, the proposed European Regulation on Orphan Medicinal Products, which might be implemented by mid 2000 in the EU Member States. Because of the emphasis on rare diseases, larger number of orphan drugs will result, but in addition the genetic origin of a number of more common diseases will be better understood.
Ethical, Legal And Social Implications
The information produced by pharmacogenomic tests, while potentially valuable for medical treatment, may also be used out of context in ways that are contrary to the interests of the patient. The interests of health-care providers, which-with best intentions – want to produce personalized and evidence based medicine, may be counter to those of the insurance companies, which want to reduce their risks. The risk is a genetic discrimination against people who, while currently healthy, may be genetically predisposed to various diseases. For example, Paul Seymur, of the Faculty and Institute of Actuaries in Great Britain, is concerned that a successful test for Alzheimer’s disease could create an "uninsurable underclass" (Financial Time 1997).
The ability to screen the genetic profile and the predisposition of humans to certain diseases caused by environmental or work related pollutants, for instance, raises the question of the confidentiality of these data and of the possible duty to life insurance. Examples given below show that the communication even of initially harmless information may ultimately have far-reaching consequences:
Some people are known to be "slow acetylators". Slow acetylators show an adverse drug reaction towards certain anaesthetics used in surgery. The adverse reactions can be severe or even fatal. For patients and physicians a genetic test determining the risk of an adverse reaction therefore is a very helpful and potentially life-saving tool. But at the same time insurance companies may be interested in the test result. "Slow acetylator"-women are known to have – under certain conditions – an increased risk of developing breast cancer (Schmidt, 1998).
Genotyping for the "apoE-gene" gives another example of this kind of cross-implication. The "apoE-gene" encodes a protein that is involved in the metabolism of cholesterol. The uptake and the adequate metabolism of cholesterol is directly related to risks of cardiovascular diseases. Testing for apoE genotypes therefore has diagnostic significance for their detection, particularly in the risk assessment of coronary artery disease. However, there is also some evidence that carriers of a certain apoE allele have a higher risk of developing Alzheimer’s Disease.
To Know or Not To Know
The two examples show the kinds of conflicts that may emerge in the near future. Pharmacognomics will definitely help us to sharpen our medical and pharmaceutical tools. Drugs will become more precise and efficient, the risk of toxic side effects will be reduced. But at the same time increasing amounts of information will be collected which may be put to a variety of uses. As shown above some ‘disorders’ which seem to have nothing common on the phenotype level are strongly interwoven on the genetic level. It is therefore possible for patients to become aware inadvertently that they harbour a gene which may have future consequences for their health. This is compounded by the fact that the information will not only affect patients’ own lives, but also those of their relatives. Thus the person affected may be forced to decide whether they should be told. Patients may wish to keep the test information secret, even if it is important information for relatives. Some people may find it hard to cope with this situation and may need properly-trained professional help.
Education And Training
The rapid pace of developments in this area is making it hard for education and training of health-care professionals, in genomics to keep pace. Lack of experience and competence in understanding the clinical implications of genomics may pose serious threats to the successful introduction of these new technologies (Post, 1998).
Educating health-care professionals about the implications and the potential impact of (pharmaco)genetic testing is of tremendous importance in order to ensure the proper evaluation of the data retrieved and to avoid malpractice and misuse. Taking for granted that genetic testing for diseases and physiological characteristics will increase, the need for more specialized doctors and genetic counsellors, is obvious. But, the role of genetic counsellors needs to be defined. Their task could be to examine the value of a test in a particular case and advice whether it makes sense and what information it may provide. They could then further analyse and evaluate the test results together with the experts from the testing laboratory or company (Euroscreen, 1998). The genetic counsellor could give advice and support to both physicians and patients. It could also be their function to prevent malpractice in both the application of tests and the handling of data.
The latter is of tremendous importance for the acceptance of genetically based therapy. Trust and confidence in the new technology is crucial, as the emotionally-charged debates surrounding genetically modified organisms in agriculture and food production have shown. The subjective perception of risks and threats associated with a certain technology can be decisive.
In order to avoid a backlash, protective measures and standards will be required to control the misuse of personal data and malpractice in testing procedures. Also, it will probably be prudent if patient profiling tools are not commercialized prematurely and without rigorous validation (Poste, 1998).
Conclusion
Progress in genomics will lead to the development of various genetic tests applicable in medical practice. They will expand the range of tools available to physicians and complement diagnostic methods. Pharmacogenomics will help to avoid the prescription of potentially toxic drugs, lead to more rapid diagnoses and enable the identification of more effective therapies.
For policy makers, though, there are a number of crucial issues at stake in these developments:
Genetic privacy and confidentiality.
To safeguard the potential benefits of new genetic testing and to enable its optimal use by society, more education and information is not just helpful but essential. A broad social dialogue will be needed on how to implement these new developments acceptably, covering discussions about privacy and confidentiality issues. Clear policies and guidelines are needed to avoid the enormous potential of human genetics being squandered.
Education and training
In contrast to most laboratory tests performed in clinical laboratories on blood or other body fluids or tissues, genetic tests may require extensive counselling before and/or after the test. With the growing availability of tests, the need for well-trained genetic counsellors will increase.
Insurance and the disclosure of information
The disclosure of genetic information needs to be regulated. A further major concern is the problem that in the future more, as yet unknown, conclusions, may be drawn from today’s test results.
Equal access to genetic testing
The availability of genetic tests for a variety of purposes will affect health-care costs. The new methods clearly imply additional costs for the funding system. The question whether the clinical utility of the information retrieved will be sufficient to justify additional payment needs to be addressed. Policy measurers should ensure that the positive trend towards a perosnalized medicine for many does not lead to the social exclusion of others.
For further details please contact: Thomas Munker, IPTS, Tel: +34 95 448 83 19 Fax: +34 95 448 83 26. E-mail: tomas.munker@jrc.es
Thomas Munker
