The study of pharmacogenetics holds out the promise of personalised medicine in which the drug and its dose will be selected on the basis of the genetic make-up of the patient.Â Summarise the potential advantages that this would, have and the obstacles that will need to be overcome in order to achieve this aim.Â Where possible, include specific examples in your answer.
This essay discusses both the potential advantages and obstacles that occur in the development of "personalised medicine" where the dose and drug are tailored to the patients needs. Many obstacles occur in the development of drugs through pharmacogenetics leading to a complex debate about whether pharmacogenetics will provide the promised advancements to medicine, such as reduced side effects and more targeted drug treatments. Development of this particular part of the drug industry leads to issues surrounding ethics, increased costs, legal and social issues.
Pharmacogenetics is taken from the words "pharmacology" and "genetics" and is associated with the science of how variability in reaction to drugs is genetically determined. A main focus of pharmacogenetics is determining how genetic makeup affects the way drugs metabolise. This is a huge problem clinically, as individual responses to drugs vary significantly. Through the use of pharmacogenetics, the responses of an individual to a particular drug may be able to be predicted. Although very few drugs use the developments in pharmacogenetics to treat individuals, there has been an enormous gain in the momentum in the research of pharmacogenetics. The technologies that allow for screening of variations in genes and polymorphisms have enabled this.
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Pharmacogenetics offers personalised medicine which improves safety, efficacy and minimises side effect risk by allowing optimisation of dosage.
Genetically determined adverse reactions to drugs are known to have damaging side effects, occasionally resulting in death. Many UK hospital admissions are due to adverse drug reactions resulting in a huge burden on the NHS. It is suggested that about 1 in 15 hospital admissions are due to these reactions.
Pharmacogenetics is particularly important in research into how variations in genes can affect the way we respond to medicines to potentially eliminate the risk of adverse drug reactions.
The experience in the US with Warfarin's response in variation caused by the genes CYP2C9Â andÂ VKORC1 illustrates:
"Warfarin therapy-associated haemorrhage is one of the leading causes of drug-related adverse events, including death, and is the second most common drug after insulin implicated in emergency room visits in the U.S. according to FDA data. The risk of severe bleeding is the highest when the drug introduced to a patient for the first time. American Enterprise Institute Brookings Report states that incorporating routine genetic testing into warfarin dosing will result in an estimated 85,000 fewer serious bleeds and 17,700 fewer strokes, resulting in savings of $1.1 billion (November 2006)"
The advantages of being able to determine a genetic variant associated with the reaction to a drug are clear with this example.
As well as determining the reaction of conventional drugs, pharmacogenetics also offers the possibility of developing drugs to target specific genes. Whilst this offers great potential, the risks associated with these types of drugs are also greatly elevated.
Because of the specificity of the drugs to individual genes, animal testing becomes even more unreliable. With conventional drugs animal tests are only able to predict the side effects between 5-25 per cent of the time. This is particularly serious because if a drug is going to target a specific gene then the drug is likely to be highly effective but its side effects have the potential to be very serious. The failed drug trial of 13th of March 2006 was a sobering example when six healthy men were injected with TGN1412. Within minutes the men presented extreme reactions to the drug, including multiple organ failure, fever, writhing in their beds, vomiting and "screaming that their heads were going to explode". Although this drug was said to be tested on monkeys and rabbits there were no deaths of the animals associated with the drugs.
The ability to produce the desired effects from drugs varies from person to person; some medicines are much more effective for some people than they are for others. For example drugs such as SSRI antidepressants are more effective in some individuals than others. A widely used genetic test is the test for CYP2D6 enzymes; the CYP2D6 gene is inactive in around six per cent of Caucasians. The level of expression of these genes is genetically determined, and enzymes can be poor metabolizers due to "genes encoding specific cytochrome P450s often contain inactivating mutations" the metabolism of drug in the body is therefore compromised. Drugs used to treat psychiatric, neurological and cardiovascular diseases are metabolised by this enzyme.
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The use of pharmacogenetic test could be used to allow doctors to prescribe drugs that would be expected to work on the patient. Another way in which prescription of medicines could be improved is creating new medicines based on genetic information about the disease.
Patients with acute forms of cancer have an extremely short intervention times which precludes the use of conventional trial-and-error drug therapy treatments. Pharmocogenetics offers the prospect of much high survival rates by reducing the time period to identify optimum treatment. In recent years thirty eight different forms of leukaemia have been identified, some with genetic markers, using genetic analysis allows improved diagnostic techniques for the improved treatment and increased survival rates. For example in the treatment of chronic myeloid leukaemia a genetic test can determine if a patient has the abnormal BCR-ABL gene, a Novartis drug Gleevec may then be prescribed to deactivate the abnormal gene. More than ninety-five per cent of patients with this time of treatment respond positively to this genetic specific treatment. This led to a measurable reduction in cancer death rates between 2003 and 2004.
Genes also influence the response to breast cancer treatment, some individuals with a variation in the enzyme CYP2D6 do not respond well to treatment with tamoxifen. The inability to respond well to this drug is shown to reduce life expectancy of the cancer victim. Therefore genetic testing would also advance the treatment for breast cancer by showing which patients would respond well to treatment of the disease with tamoxifen and increase life expectancy.
Although the use of pharmacogenetic information has the potential to improve efficacy and safety of the drug it has ethical, legal, social and regulatory issues which give rise to the complex debate of whether pharmacogenetics will provide the advancements that its proponents suggest.
If a personalised medicine scheme was introduced prescription drugs and dosing would not fit a "one-size-fits-all" mindset. This would lead to extremely high costs in the development of the drug. In order to prescribe such medicines based of the practice of pharmacogenetics you would need to screen for gene mutations, many of the genetic modifiers of drug response arise from mutations in single genes, in which case it may not be cost effective or even possible to screen for them. However in the long run it could be cheaper for individuals as they may not have to purchase drugs that are no use to them or produce adverse side effects. It would reduce the cost of treating patients with adverse drug reactions; it would also lead to doctors prescribing drugs that are better suited to the patient therefore reducing the expenditure associated with drugs.
For example there are reports of drug companies that are deliberately hiding pharmacogenetic reaction results and suppressing research papers. Drug companies may not want to push the use of personalised medicine as it narrows down their market, leading to reduced sales. As there will be fewer people being prescribed the drug the cost of the drug will therefore increase. The main factor blocking the development of pharmacogenetics is not the researcher and development departments but the marketing department. One of the big risks about pharmacogenetics is it is opening up a whole new industry of lies where by the drug companies exploit loopholes in regulations to maximise their profits at the expense of other peoples health and financial well being. There is currently no regulatory framework in place that prevents drugs companies determining an outcome to maximise their profits. For example the use of genetic testing for CYP450 enzymes is discouraged in the prescription of SSRIs as "no evidence is available showing that the results of CYP450 testing influenced SSRI choice or dose and improved the patient's outcome". For example some websites and drugs companies advertise the use of genetic testing for CYP450 in order to offer pharmacogenetic testing saying this is "alternative to the one size fits all" in prescribing of drugs, it lists drugs including SSRI and TCA antidepressants as well as other medications including warfarin. Some tests seem to be more applicable in the role of prescribing medication, for example warfarin. It is less likely that pharmacogenetic tests will give reliable results for antidepressant type drugs as the brain is so incredibly complicated that many genes are going to influence the outcome of the symptoms.
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In order to reduce cost of drug trials, drug companies have opted to use people in third world countries, people experiencing unemployment, students, poor people, giving rise to serve ethical issues.
Access to drugs may become more difficult if pharmacogenetics was to be implemented widely. Its correct administration relies on the skills of the doctors and this varies from country to county. If you are a minority race it may be difficult to get access to appropriate medication as medicines are more likely to be targeted to the majority. If life saving medication is required and there is no access to it then it is likely to have life threatening implications.
Other problems surrounding pharmacogenetic testing is ethnicity, there may be a possibility that drugs will be prescribed to different ethnic groups rather that prescribed based on the genetics of an individual. For example a drug treating heart failure (BiDil) was only available to African-Americans. This emphasises the difference between pharmacogenetic based medicine and race based medicine. The initial trials of BiDil were not going very well, and when they re-looked at the data they found that there was a slight variation between racial groups. The whole issue about BiDil is about exploiting the drug, not actually about designing a drug that was specific to African-Americans; they exploited weaknesses in the food and drug agency regulatory process in America.
Many diseases are caused from multiple genes; this makes the pharmacogenetic tests hard. It would be more cost effective to treat diseases using pharmacogenetics if the disease is caused by a single gene mutation. Disease like arthritis, high blood pressure and heart disease are disease caused by variations in many different genes. Other diseases such as schizophrenia are not as well understood and multifactorial making pharmacogenetic tests inherently impossible.
There are many other factors that have an influence on the response to drugs other than genetics. Many diseases are a complex interaction between the environment, lifestyle and the genetic makeup of a patient. For example diet, smoking, alcohol consumption, disease (particularly liver disease), and interactions with other drugs all have effects on the response to the drugs. Factors such as these affect how the drug is metabolised, how they are excreted through the system and absorbed and what effects it may have on the body. For example in the use of the SSRI drug fluoxetine, side effects of the drugs are increased when alcohol is consumed.
Another problem with drugs based around pharmacogenetics is the inability to find a sample which would be statistically significant because the test subjects have to have the exact genetic makeup. Therefore smaller groups of participants in the trials would be selected jeopardising the safety of the drug. This would also increase the cost of the production of the drug as more testing would be required.
If pharmacogenetics is successful then large databases containing personal genetic information will be created. This leads to a major question as to who should have access to this personal information. There will be technical challenges, although these can be relatively easily overcome. The worries regarding this information are the privacy and security of the data. For example in 1992 studies carried out under the proposed federal violence initiative they sought to search for a violence gene and find biochemical imbalances and intervening by medicating children with this gene with a psychiatric drug. The danger is that if everyone is subjected to genetic testing, then the government at some stage in the future could demand the genetic information and start identifying people for pre-emptive intervention for example the violence initiative carried out in America.
Another danger is if your genetic information is crossed with someone else and you are likely to receive highly specialised drug or dose of drug that specific for your genetic makeup. For example if you are given a warfarin dose based on your genetic makeup then if the genetic information is not yours then this can result in serious side effects or even death.
If you have a pre-disposition to some illness or a defective gene that is revealed during the genetic testing then it potentially places the doctor with conflicts of interest, for example the patient may not want to be advised about their condition however the doctor would be subject to the general medical council booklet which states "You should not withhold information necessary for decision-making unless you judge that disclosure of some relevant information would cause the patient serious harm. In this context, serious harm does not mean that the patient would become upset, or decide to refuse treatment". An even bigger conflict for the doctor to reconcile is that other family members may need to be advised about the condition against the wishes of the patient. Therefore a key role for regulatory bodies would be to classify tests and to provide guidance on which tests should only be provided with appropriate genetic counselling.
A further issue for doctors is in the scenario that a patient may refuse a pharmacogenetic test because of concerns about security and privacy which then may force the doctor to withhold drug treatment. At the same time the doctor has a legal and professional duty to provide the best possible treatment based on their clinical judgment.
To conclude pharmacogenetics has potentially very large benefits in the transition to personalised medicine, as the example with warfarin shows. It could help reduce hospital admissions and therefore the costs associated with adverse side effects to drugs. Evidence is showing that there is promise for cancer treatments by using genetic markers to identify drug that inactivate the genes. However it is a process that can be abused by the drug companies or politicians especially in treatment of psychiatric conditions such as schizophrenia and depression. There are insufficient regulations, and as yet there is no robust regulatory framework.
This all shows that the development of pharmacogenetic based techniques is uncertain; there are many different components that offer both potential advantages and obstacles. The expectation of drugs based pharmacogenetics is high but to make pharmacogenetics a reality there are many obstacles to overcome.
"Personalised medicine is a paradigm that exists more in conceptual terms than in reality". The success associated with genetic testing for warfarin by no mean guarantees success with other treatments.