Unraveling heterogeneity of the clinical pharmacogenomic guidelines in oncology practice among major regulatory bodies.

Pharmacogenomics (PGx) implementation in clinical practice is steadily increasing. PGx uses genetic information to personalize medication use, which increases medication efficacy and decreases side effects. The availability of clinical PGx guidelines is essential for its implementation in clinical settings. Currently, there are few organizations/associations responsible for releasing those guidelines, including the Clinical Pharmacogenetics Implementation Consortium, Dutch Pharmacogenetics Working Group, the Canadian Pharmacogenomics Network for Drug Safety and the French National Network of Pharmacogenetics. According to the US FDA, oncology medications are highly correlated to PGx biomarkers. Therefore, summarizing the PGx guidelines for oncology drugs will positively impact the clinical decisions for cancer patients. This review aims to scrutinize side-by-side available clinical PGx guidelines in oncology.

Evaluation of Current Regulation and Guidelines of Pharmacogenomic Drug Labels: Opportunities for Improvements.

Pharmacogenomic drug labels in the Summary of Product Characteristics (SmPC) provide an instrument for clinical implementation of pharmacogenomics. We compared pharmacogenomic guidance by Clinical Pharmacogenetics Implementation Consortium (CPIC), Dutch Pharmacogenetics Working Group (DPWG), the US Food and Drug Administration (FDA), and by the European agencies the European Medicines Agency (EMA), College ter Beoordeling van Geneesmiddelen Medicines Evaluation Board (CBG-MEB), and Federal Institute for Drugs and Medical Devices (FIDMD), collectively assigned as EMA/FIDMD+MEB shortened as EMA/FM. Of 54 drugs with an actionable gene-drug interaction in the CPIC and DPWG guidelines, only 50% had actionable pharmacogenomic information in the SmPCs and the agencies were in agreement in only 18% of the cases. We further compared 450 additional drugs, lacking CPIC or DPWG guidance, and found 126 actionable gene-drug labels by the FDA and/or the EMA/FM. Based on these 126 drugs in addition to the 54 above, the consensus of actionable pharmacogenomic labeling between the FDA and the EMA/FM was only 54%. In conclusion, guidelines provided by CPIC/DPWG are only partly implemented into the SmPCs and the implementation of pharmacogenomic drug labels into the clinics would strongly gain from a higher extent of consensus between agencies.

Unveiling the guidance heterogeneity for genome-informed drug treatment interventions among regulatory bodies and research consortia.

Pharmacogenomics and personalized medicine interventions hold promise to optimize drug treatment modalities and hence, improve the quality of life of the patients by minimizing the occurrence of adverse drug reactions and/or maximizing drug treatment efficacy. To this end, proper guidance for accurately prescribing the correct drug at the right dose is empowered by major regulatory bodies, namely the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and well-recognized research consortia, like the Clinical Pharmacogenetics Implementation Consortium (CPIC), that propose therapeutic recommendations after the thorough evaluation of the existing scientific evidence base. In this context, the consistency of these recommendations is crucial for smoothly integrating pharmacogenomics into the clinic. Here, we collected all of the important and clinically actionable pharmacogenomics information provided by the aforementioned renowned sources and documented it in order to assess potential similarities and, most importantly, differences. Our data show that the level of concordance regarding the guidance provided for the same drug-gene association pairs varies significantly, despite the fact that it all derives from a single evidence base. In particular, apart from the expected similarities in a number of association pairs, especially the ones related to cancer genomics, there are still major discrepancies that create confusion as to which guidance should be followed in order to properly inform drug prescribing. This regulatory deficiency calls for the fruitful engagement of the regulatory agencies involved with the contribution of other experts engaged in the field of pharmacogenomics in an effort to harmonize the existing arsenal of guidance for genome-informed drug prescription. The achievement of harmonization would in turn expedite bringing personalized medicine closer to clinical fruition.

The Ethical, Legal and Regulatory Issues Associated with Pharmacogenomics: Systematically Quantifying the Literature.

Since the human genome was successfully mapped much academic attention has been given to ethical, legal and regulatory issues associated with the integration and application of genomics in health care. In line with the recent political commitment to promoting precision medicine that relies heavily on omic knowledge, it is timely to review the issues that this body of literature has addressed. Focusing on pharmacogenomics, this review quantifies the issues identified in this body of academic work. It reveals that, after nearly two decades, interest in the regulatory and legal issues associated with pharmacogenomics continues to generate significant attention. The ethical issues, while not as predominant, also persist. The analyses highlights that there is a dearth of empirical research exploring the impact that these issues have had.

Pharmacogenetics in Pain Treatment.

Pain is an unpleasant feeling usually resulting from tissue damage that can persist along weeks, months, or even years after the injury, turning into pathological chronic pain, the leading cause of disability. Currently, pharmacology interventions are usually the first-line therapy but there is a highly variable analgesic drug response. Pharmacogenetics (PGx) offers a means to identify genetic biomarkers that can predict individual analgesic response opening doors to precision medicine. PGx analyze the way in which the presence of variations in the DNA sequence (single-nucleotide polymorphisms, SNPs) could be responsible for portions of the population reaching different levels of pain relief (phenotype) due to gene interference in the drug mechanism of action (pharmacodynamics) and/or its concentration at the place of action (pharmacokinetics). SNPs in the cytochrome P450 enzymes genes (CYP2D6) influence metabolism of codeine, tramadol, hydrocodone, oxycodone, and tricyclic antidepressants. Blood concentrations of some NSAIDs depend on CYP2C9 and/or CYP2C8 activity. Additional candidate genes encode for opioid receptors, transporters, and other molecules important for pharmacotherapy in pain management. However, PGx studies are often contradictory, slowing the uptake of this information. This is likely due, in large part, to a lack of robust evidence demonstrating clinical utility and to its polygenic response modulated by other exogenous or epigenetics factors. Novel therapies, including targeting of epigenetic changes and gene therapy-based approaches, broaden future options to improve understanding of pain and the treatment of people who suffer it.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy.

Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N-desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.

Pharmacogenetic Information in Clinical Guidelines: The European Perspective.

Surveys among pharmacists and physicians show that these healthcare professionals have successfully adopted the concept of pharmacogenomics (PGx).1-3 In addition, patients are willing to consent to participate in PGx implementation studies.4 However, the surveys also show that healthcare professionals do not frequently order or recommend a PGx test.1,2 Among others, a frequently perceived hurdle for clinical uptake of PGx is the availability of guidelines translating PGx test results into clinical actions for individual patients.5,6.

Clinical Implementation of Pharmacogenomics for Personalized Precision Medicine: Barriers and Solutions.

Clinical implementation of pharmacogenomics (PGx) leads to personalized medicine, which improves the efficacy, safety, and cost-effectiveness of treatments. Although PGx-based research has been conducted for more than a decade, several barriers have slowed down its widespread implementation in clinical practice. Globally, there is an imbalance in programs and solutions required to empower the clinical implementation of PGx between countries. Therefore, we aimed to review these issues comprehensively, determine the major barriers, and find the best solutions. Through an extensive review of ongoing clinical implementation programs, scientific, educational, ethical, legal, and social issues, information technology, and reimbursement were identified as the key barriers. The pace of global implementation of genomic medicine coincided with the resource limitations of each country. The key solutions identified for the earlier mentioned barriers are as follows: building of secure and suitable information technology infrastructure with integrated clinical decision support systems along with increasing PGx evidence, more regulations, reimbursement strategies for stakeholder's acceptance, incorporation of PGx education in all institutions and clinics, and PGx promotion to all health care professionals and patients. In conclusion, this review will be helpful for the better understanding of common barriers and solutions pertaining to the clinical application of PGx.

Health regulatory communications of well-established safety-related pharmacogenomics associations in six developed countries: an evaluation of alignment.

Recommendations on genetic testing are typically conveyed by drug regulatory authorities through drug labels, which are legal requirements for market authorization of drugs. We conducted a cross-sectional study of drug labels focusing on three crucial aspects of regulatory pharmacogenomics communications: (i) intent; (ii) interpretation in the local context; and (iii) implications of the genetic information. Labels of drugs associated with well-established safety-related genetic markers for adverse drug reactions across six developed countries of United States, Canada, United Kingdom, Australia, New Zealand and Singapore were reviewed. We found differing medical advice for genotype-positive HLA-B*15:02, HLA-A*31:01, UGT1A1*28 and CYP2D6 ultra-rapid metabolisers in breastfeeding women. This raises questions on implications to clinical practice between these countries. Varying ways of presenting at-risk population and allele frequencies also raises question in incorporating such information in drug labels. An international guidance addressing these crucial aspects of regulatory pharmacogenomic communications in drug labels is long overdue.

Clinical and regulatory considerations in pharmacogenetic testing.

PURPOSE: Both regulatory science and clinical practice rely on best available scientific data to guide decision-making. However, changes in clinical practice may be driven by numerous other factors such as cost. In this review, we reexamine noteworthy examples where pharmacogenetic testing information was added to drug labeling to explore how the available evidence, potential public health impact, and predictive utility of each pharmacogenetic biomarker impacts clinical uptake. SUMMARY: Advances in the field of pharmacogenetics have led to new discoveries about the genetic basis for variability in drug response. The Food and Drug Administration recognizes the value of pharmacogenetic testing strategies and has been proactive about incorporating pharmacogenetic information into the labeling of both new drugs and drugs already on the market. Although some examples have readily translated to routine clinical practice, clinical uptake of genetic testing for many drugs has been limited. CONCLUSION: Both regulatory science and clinical practice rely on data-driven approaches to guide decision making; however, additional factors are also important in clinical practice that do not impact regulatory decision making, and these considerations may result in heterogeneity in clinical uptake of pharmacogenetic testing.

The integration and interpretation of pharmacogenomics - a comparative study between the United States of America and Europe: towards better health care.

The study of pharmacogenomics has, by harnessing sequence information from human genomes, the potential to lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. For this potential to be realized results need to be interpreted to the prescriber into a format which dictates an action. This mini review briefly describes the history, the regulatory environment, opinions towards, and implementation, integration and interpretation of pharmacogenomics in the United States of America and Europe. The article discusses also how interpretation of pharmacogenomics could move forward to better implementation in health care.

[Pharmacogenetics in anesthesia and intensive care medicine : Clinical and legal challenges exemplified by malignant hyperthermia]. / Pharmakogenetik in Anästhesie und Intensivmedizin : Klinische und juristische Herausforderung am Beispiel der Malignen Hyperthermie.

Pharmacotherapy is a key component of anesthesiology and intensive care medicine. The individual genetic profile influences not only the effect of pharmaceuticals but can also completely alter the mode of action. New technologies for genetic screening (e.g. next generation sequencing) and increasing knowledge of molecular pathways foster the disclosure of pharmacogenetic syndromes, which are classified as rare diseases. Taking into account the high genetic variability in humans and over 8000 known rare diseases, up to 20 % of the population may be affected. In summary, rare diseases are not rare. Most pharmacogenetic syndromes lead to a weakening or loss of pharmacological action. In contrast, malignant hyperthermia (MH), which is the most relevant pharmacogenetic syndrome for anesthesia, is characterized by a pharmacologically induced overactivation of calcium metabolism in skeletal muscle. Volatile anesthetic agents and succinylcholine trigger life-threatening hypermetabolic crises. Emergency treatment is based on inhibition of the calcium release channel of the sarcoplasmic reticulum by dantrolene. After an adverse pharmacological event patients must be informed and a clarification consultation must be carried out during which the hereditory character of MH is explained. The patient should be referred to a specialist MH center where a predisposition can be diagnosed by the functional in vitro contracture test from a muscle biopsy. Additional molecular genetic investigations can yield mutations in the genes for calcium-regulating proteins in skeletal muscle, e.g. ryanodine receptor 1 (RyR1) and calcium voltage-gated channel subunit alpha 1S (CACNA1S). Currently, an association to MH has only been shown for 35 mutations out of more than 400 known and probably hundreds of unknown genetic variations. Furthermore, MH predisposition is not excluded by negative mutation screening. For anesthesiological patient safety it is crucial to identify individuals at risk and warn genetic relatives; however, the legal requirements of the Patients Rights Act and the Human Genetic Examination Act must be strictly adhered to. Specific features of insurance and employment law must be respected under consideration of the Human Genetic Examination Act.

Precision medicine in the age of big data: The present and future role of large-scale unbiased sequencing in drug discovery and development.

High throughput molecular and functional profiling of patients is a key driver of precision medicine. DNA and RNA characterization has been enabled at unprecedented cost and scale through rapid, disruptive progress in sequencing technology, but challenges persist in data management and interpretation. We analyze the state-of-the-art of large-scale unbiased sequencing in drug discovery and development, including technology, application, ethical, regulatory, policy and commercial considerations, and discuss issues of LUS implementation in clinical and regulatory practice.

The 3-I framework: a framework for developing public policies regarding pharmacogenomics (PGx) testing in Canada.

The 3-I framework of analyzing the ideas, interests, and institutions around a topic has been used by political scientists to guide public policy development. In Canada, there is a lack of policy governing pharmacogenomics (PGx) testing compared to other developed nations. The goal of this study was to use the 3-I framework, a policy development tool, and apply it to PGx testing to identify and analyze areas where current policy is limited and challenges exist in bringing PGx testing into wide-spread clinical practice in Canada. A scoping review of the literature was conducted to determine the extent and challenges of PGx policy implementation at federal and provincial levels. Based on the 3-I analysis, contentious ideas related to PGx are (i) genetic discrimination, (ii) informed consent, (iii) the lack of knowledge about PGx in health care, (iv) the value of PGx testing, (v) the roles of health care workers in the coordination of PGx services, and (vi) confidentiality and privacy. The 3-I framework is a useful tool for policy makers, and applying it to PGx policy development is a new approach in Canadian genomics. Policy makers at every organizational level can use this analysis to help develop targeted PGx policies.

The role of ADME pharmacogenomics in early clinical trials: perspective of the Industry Pharmacogenomics Working Group (I-PWG).

Genetic polymorphisms in metabolizing enzymes and drug transporters have been shown to significantly impact the exposure of drugs having a high dependence on a single mechanism for their absorption, distribution or clearance, such that genotyping can lead to actionable steps in disease treatment. Recently, global regulatory agencies have provided guidance for assessment of pharmacogenomics during early stages of drug development, both in the form of formal guidance and perspectives published in scientific journals. The Industry Pharmacogenomics Working Group (I-PWG), conducted a survey among member companies to assess the practices relating to absorption, distribution, metabolism, excretion pharmacogenomics) during early stages of clinical development, to assess the impact of the recent Regulatory Guidance issued by the US FDA and EMA on Industry practices.

Stakeholder analysis in pharmacogenomics and genomic medicine in Greece.

BACKGROUND: The pace of discoveries and advances in genomic research is not reflected in the pace of their translation and incorporation into day-to-day clinical medicine to individualize healthcare decision-making processes. One of the main obstacles is the poor understanding of the policies and the key stakeholders involved in these translation processes. METHODS: We used the computerized version of the PolicyMaker political mapping tool to collect and organize important information about the pharmacogenomics and genomic medicine policy environment, serving as a database for assessments of the policy's content, the major players, their power and policy positions, their interests, and networks and coalitions that interconnect them. RESULTS AND CONCLUSIONS: Our findings indicate that the genomic medicine policy environment in Greece seems to be rather positive, as the vast majority of the stakeholders express their medium to high support in the initially set goals of genomic medicine policy environment. The Ministry of Health and public healthcare insurance funds seem to oppose it, most likely due to financial constrains. These findings would contribute in selecting and implementing policy measures that will expedite the adoption of genomics into conventional medical interventions.

Pharmacogenomics: history, barriers, and regulatory solutions.

Pharmacogenomics is the branch of pharmacology which looks at the influence of genetic variation on drug response, connecting particular genetic markers with the effectiveness or safety of a drug. Pharmacogenomic products promise to improve medical treatment, lower health care costs, and make the new drug pipeline for FDA approval more efficient. In the last fifteen years, the FDA has approved pharmacogenomic drugs to treat a variety of cancers, HIV-AIDS, and coronary artery disease. Yet, progress in the field of pharmacogenomics has lagged behind the optimistic predictions of many researchers and policymakers. A lack of clear regulatory guidance dealing with pharmacogenomic products has been a major barrier to progress in the field. The FDA has, however, made some headway. In a series of guidance documents released between 2005 and 2011, the FDA has clarified much of its policy with respect to the development, approval, and labeling of pharmacogenomic products. Despite these efforts, many regulatory questions remain unanswered. This paper highlights a number of these regulatory gaps and provides recommendations to address them in a way which encourages increased development and clinical uptake of pharmacogenomic products.