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Clinical Pharmacogenetics Implementation. Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin. Pharmacol. Ther.
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Implementation of pharmacogenetics in clinical practice is challenging “The success of implementing a pharmacogenetic interaction in clinical practice depends on the many parties involved…” KEYWORDS: clinical practice n implementation n pharmacogenetics

Pharmacogenetic information is already used in clinical practice for some therapies, such as abacavir [1,2] and azathioprine [3] . For several other therapies, there are studies that imply that pharmacogenetic testing could improve the safety or efficacy of the treatment. However, this knowledge is not yet used in daily practice. Some of these findings are currently being tested in clinical trials [4,5] . If these trials confirm that safety or efficacy are increased by genotyping of patients and when it appears to be cost-effective, the next step would be to implement the use of pharmacogenetic information into clinical practice. However, the implementation process is challenging since many different parties are involved and adequate facilities are required. This article elaborates on the implementation of pharmacogenetic testing and which hurdles to overcome.

Evidence for implementation At this point in time, it is difficult to get a pharmacogenetic interaction implemented into clinical practice. Most physicians are reluctant to implement genetic testing, and require clinical trial evidence to be convinced. However, in the future it does not seem feasible to perform a clinical trial for each newly found pharmacogenetic interaction because that would simply cost too much time and money. On the other hand, it is not clear how much observational evidence is sufficient, especially in the field of pharmacogenetics where nonreplication of results is a major issue. Therefore, it is important to define a balance between clinical evidence on the one hand, and available resources on the other. At this time, we are at the early stage of implementing pharmacogenetic interactions and clinical trials are desired. In the future, observational evidence should be suitable to implement a pharmacogenetic interaction into clinical practice. This is not different from other 10.2217/PGS.11.81 © 2011 Future Medicine Ltd

biomarkers, such as for liver or kidney function. These markers are used to adjust pharmacotherapy and no randomized controlled trial (RCT) data is available as evidence for their clinical implementation. It is obvious that it is important that pharmacogenetic interactions are replicated in various independent patient cohorts, most preferably in different countries as well. In our opinion, RCTs that require large investment are needed in the near future to demonstrate that pharmacogenetic testing improves the safety or efficacy of the therapy. In a few years, when RCTs have provided evidence for the advantage of genotyping the patients for certain therapies, the need for the use of RCTs to reach clinical acceptation for the implementation of new pharmacogenetic interactions will be less. Therefore, well-powered and well-designed observational studies and results that are replicated will then be sufficient for clinical implementation. If pharmacogenetic interactions are implemented without evidence of a RCT, it remains important to carefully observe whether the safety and efficacy of the therapy is indeed improved by this implementation.

Parties involved The success of implementing a pharmacogenetic interaction in clinical practice depends on the many parties involved, that is, patients, healthcare professionals, authorities, health insurance companies and scientists. First, there is a patient who needs the therapy. It could be questioned whether patients would mind the use of genetic information to choose the right medication or dose. In a study performed by Van Wieren et al., where nonresponders were asked for their reason not to participate in an observational study on the pharmacogenetics of cardiovascular drugs, only a small percentage of the patients (1.1%) did not Pharmacogenomics (2011) 12(9), 1231–1233

Rianne MF van Schie Department of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80 082, 3508 TB, Utrecht, The Netherlands

Anthonius de Boer Department of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80 082, 3508 TB, Utrecht, The Netherlands

Anke Hilse Maitland-van der Zee Author for correspondence: Department of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80 082, 3508 TB, Utrecht, The Netherlands Tel.: +31 622 736 715 Fax: +31 302 539 166 [email protected]

ISSN 1462-2416

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van Schie, de Boer & Maitland-van der Zee

want to participate in the study because of DNA sampling [6] . Therefore, patients seem to be positive about determining their genotype if it means that their therapy becomes more effective or safe. Second, healthcare professionals are of major importance for implementing pharmacogenetics into clinical practice. The physician is one of the healthcare professionals who plays a large role, since (s)he makes a decision about the therapy. Currently, liver- and kidney-function tests are taken into account when prescribing certain therapies. Although the US FDA updated the warfarin label in 2008 so that genotyping is advised before prescribing the drug, genotyping is not commonly performed before starting coumarin therapy. Physicians need to get familiarized with the idea to perform a pharmacogenetic test, like they are with liver- and kidney-function tests. In our opinion, recommendation of pharmacogenetic testing to improve pharmacotherapy in treatment guidelines, more education and favorable experiences with pharmacogenetic tests that are already implemented might help to convince the physician about the value of pharmacogenetic tests. Pharmacists should also be involved in this process. The Royal Dutch Association for the Advancement of Pharmacy developed pharmacogenetics-based therapeutic (dose) recommendations [7,8] to enhance the implementation of pharmacogenetic testing. In addition, pharmacists could genotype the patient (easy to use point-of-care tests will be available soon) and in some cases, for example with polymorphisms in genes encoding for the CYP enzymes, also use the patient’s genetic information for other therapies. It could also be reasoned that not only the pharmacist should genotype the patient, but possibly the nurse in the hospital or the GP. Whoever genotypes the patients, this person’s attitude towards genotyping is of importance for the success of the implementation. In addition, the dissemination of the genetic results is very important. If the patient is genotyped by the physician, the information should also be available to the pharmacist so that the information can be availabe to use if other drugs are prescribed to the patient. Third, the authorities can enhance the implementation of pharmacogenetics in clinical practice by adjusting label information of drugs or making rules that healthcare providers are obliged to follow. This will benefit the implementation of pharmacogenetics enormously. Fourth, the health insurance companies will play a role in the implementation too. If genotyping kits will be paid for by the health insurance 1232

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companies, it is more likely that pharmacogenetics will be part of every day clinical practice, rather than when patients need to pay for the test kits themselves. Therefore, it is of major importance that research in this field also includes pharmacoeconomic evaluations, since health insurance companies will only provide the money for genotyping when the use of these pharmacogenetic tests are shown to be cost effective [9] .

“…if all parties are willing to take the challenge, better applied therapies with increased safety and efficacy will be the result.” Finally, the scientists also play a role in the process. Sound scientific research is required for the implementation of pharmacogenetic testing. Well-designed observational studies and RCTs are required to show importance for the implementation of pharmacogenomics into clinical practice.

Availability of adequate facilities An important example of a strong pharmacogenetic interaction is the interaction between the VKORC1 and CYP2C9 genotypes and the dose requirements of coumarins. In 2008 the FDA updated the label of warfarin, which advises genotyping. However, physicians were not able to apply this information in clinical practice, since there were no guidelines on how to adjust the dose for a specific genotype. With the availability of dose algorithms, implementation of this pharmacogenetic information can now become a reality [10,11] . On most occasions, it is desirable that genetic information of the patient is available before the start of the therapy. However, in the current clinical situation, healthcare professionals need to collect blood samples of a number of patients to be able to genotype a batch of samples. Therefore, it can sometimes take a few weeks before the genotype is known. Especially for therapies that need to start as soon as possible, this could be problematic. A point-of-care-test has been developed and is currently being tested in a clinical situation. This instrument is able to genotype the sample within 2 h, which makes pharmacogenetics more attractive to implement in daily practice since it allows the treatment to start on the same day [12] . As stated in this article, there are many hurdles to overcome to implement pharmacogenetics in clinical practice. However, if all parties are willing to take the challenge, better applied therapies with increased safety and efficacy will be the result. future science group

Implementation of pharmacogenetics in clinical practice is challenging

Financial & competing interests disclosure The EU-PACT trial is supported by the European Union Seventh Framework Programme (223062). The Division of Pharmacoepidemiology and Clinical Pharmacology employing all authors, has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private–public funded Top Institute Pharma, which includes cofunding from universities,

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government and industry), the Dutch Medicines Evaluation Board and the Dutch Ministry of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was ­u tilized in the ­production of this manuscript.

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