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"Today, data from real-world health care databases are not as broadly employed among regulators and payers as data from randomized controlled trials, leaving a vast opportunity to use this real-world evidence to inform decisions that impact patients," said Jeremy Rassen, ScD, co-founder, president, and chief science officer at Aetion. "The REPEAT program is aimed at progressing standards for the use of real-world evidence, employing the Aetion Evidence Platform to conduct meta-research, or 'research about how to do research,' in order to evaluate what information could increase the use of real-world data for decision-making."
As part of its work to develop standards for real-world evidence that result in more effective treatments and faster implementation, REPEAT is guided by a scientific advisory board with representatives from regulatory agencies including the FDA, European Medicines Agency, and the Pharmaceuticals & Medical Devices Agency of Japan, as well as participants from academia, medical journals, public and commercial health plans, and the biopharma industry.
Dr. Wang presented interim results from REPEAT at the 34th International Conference on Pharmacoepidemiology & Therapeutic Risk Management. There, she discussed the state of current health care database studies and progress to date on using the Aetion Evidence Platform to replicate the first 56 of the targeted 150 studies.
ISPE 34ICPE 2018: Session Info
Wednesday, August 22, 2018
8:30am – 12:30pm
Precision Medicine with a Skills-based Focus for the Pharmacoepidemiologist
South Hall 1
Ticket required.
Brief overview of course:
This course, sponsored by the Molecular Epidemiology, Biomarkers, and Pharmacogenomics (MEBP) SIG will focus on the essentials every pharmacoepidemiologist should know about real world applications of pharmacogenomics epidemiology including (1) the role of epidemiology in pharmacogenomics (pre-course video); (2) definitions of genetic terms and basic genetic concepts (pre-course video); (3) quality control and analytical procedures required in a pharmacogenetic analysis; (4) step-by-step planning guide to designing a pharmacogenomic analysis; (5) phenotyping considerations and breaking down examples of pharmacogenomic successes; (6) databases available to study pharmacogenomics; (7) designing a companion pharmacogenomic diagnostic in drug development; (8) designing a prospective observational cohort or case-control study of pharmacogenomics; (9) designing a clinical utility trial: a guide with examples; (10) clinical utility and policy issues: a debate.
Educational Objectives:
• To understand basic genetic and pharmacogenomic terminology.
• To understand how pharmacogenomics research relates to the current focus on Precision Medicine (aka Personalized Medicine), using real world examples.
• To better understand the study design and methodologic approaches, their strengths and weakness used in pharmacogenomic epidemiology, specifically in relation to clinical applications.
• To understand the role that pharmacogenomics can play in pharmacovigilance and comparative effectiveness research
• To gain knowledge about some available databases with linkage with genomic information
• To understand the benefits and challenges of pharmacogenomics in pharmacoepidemiology in both research and clinical practice applications.
Target Audience:
Entry level.
Attendees should have basic knowledge of pharmacogenomics, or have watched the pre-Course Videos (Available Online only)
• The convergence of Pharmacoepidemiology and Precision Medicine [Gillian Bartlett]
• A Primer on Genetic Terms and Basic Concepts [Geoffrey Liu]
Course Faculty/Presentations:
8:00 am-8:10am: Welcome and Introduction [Amalia Issa]
• Quick introduction of the topics and course logistics and faculty members.
8:15am-8:55am: Precision Medicine in the Real World Needs Pharmacogenomic Epidemiology [Amalia Issa]
• Will provide an overview of pharmacogenomics and how pharmacoepidemiologists can contribute meaningfully to precision medicine, including the methodologies, current status, and future direction.s Will discuss real-world examples, and share the experience of working as a pharmacoepidemiologist in industry, government, and academia.
8:55am-9:35am: What You Need to Consider When Applying Pharmacogenomic Research into Clinical Practice [Bruce Carleton]
• Will present up-to-date state of the science and describe real-world clinical applications.
9:35am-9:50pm: Bio Break
9:50am-10:30am: Pharmacoepidemiologic Methods in Genomics Research: It’s all about the application [Anke-Hilse Maitland van der Zee]
• Will discuss robust pharmacoepidemiologic methods for use in pharmacogenomics research.
• Will introduce different databases with both rich clinical, treatment, outcomes information and genomic information Will compare the pros and cons of different databases to guide future database selection and research.
10:30am-11:00am: Clinical Utility Research and Pharmacogenomics: Trials and Tribulations [Stephen Kimmel]
• Will share the roles, responsibilities and contributions of a pharmacoepidemiologist in pharmacogenomic clinical trials and provide up-to-date examples of recent and ongoing trials.
•
11:00am-11:10am: Bio Break
11:10am-11:55am: DEBATE: Clinical Utility and Policy Issues: The Many Meanings of “Utility” [Amalia Issa vs. Bruce Carleton]
• This popular feature of the course will focus on the latest hot topic related to clinical utility and will evolve as we get closer to the date of the course to reflect the latest findings. As always, it will be a highly engaging and interactive debate and discussion with ample active audience participation.
11:55am-12:10pm: Closing Remarks [Gillian Bartlett]
• Final summary of what are covered in the afternoon course, and collect ideas for future courses
Presenters:
Bartlett-Esquilant, Gillian
Carleton, Bruce
Issa, Amalia
Maitland-van der Zee, Anke-Hilse
Meet Dr. Gillian Bartlett-Esquilant, Family Medicine Research and ...
https://www.mcgill.ca/familymed/meet-dr-gillian-bartlett
Jan 25, 2017 - When Research and Graduate Program Director Dr. Gillian Bartlett-Esquilant, joined McGill’s Department of Family Medicine in 2005, primary care research in Canada was still in its infancy. Dr. Bartlett-Esquilant — who completed her PhD in Epidemiology and Biostatistics at ...
Bruce Carleton - International Congress on Personalized Health Care
www.icphc.org/Carleton-Bruce.html
Bruce C. Carleton, PhD. Professor of Paediatrics and Co-Chair, Division of Translational Therapeutics, Faculty of Medicine, University of British Columbia.
Amalia M. Issa, PhD, MPH, FCPP
Amalia M. Issa PhD, MPH, FCPP
Founding Director, Personalized Medicine & Targeted Therapeutics
Professor of Health Policy and Public Health
Professor of Pharmaceutical Sciences
Education
BS (Concordia)
MS (McGill)
PhD (McGill)
MPH (UCLA)
Post-doctoral Fellowship (Harvard Medical School)
Research Interests
Personalized medicine; pharmacogenomics; pharmaceutical outcomes research and policy; pharmacoepidemiology
Synopsis
Amalia M. Issa, PhD, MPH, FCPP is a pharmacologist and internationally renowned scientist in the field of personalized genomic medicine (precision medicine). Dr. Issa was one of the first scientists to develop a new and unique area of health outcomes and translational research focused on pharmacogenomics and personalized genomic medicine applications, and how they will be translated and integrated into health care delivery and health systems. She founded one of the first centers on Personalized Medicine and Targeted Therapeutics focused on the translation of personalized medicine into clinical practice and health policy in 2001. She joined the University of the Sciences in 2011, and brought this center with her. This Center accomplishes its mission through state-of-the-art research, training programs, consultation to government agencies on public policy initiatives, and national and international collaborations. Dr. Issa leads and collaborates with an interdisciplinary team of scientists nationally and internationally who are actively engaged in research aimed at translating personalized genomic medicine research from the laboratory bench to the bedside and to the clinic, community, and policy. Dr. Issa has numerous publications in the peer-reviewed scientific literature on pharmacogenomics and personalized medicine as well as in pharmacoepidemiology, neuropharmacology and drug safety. She has served or is serving as the principal investigator on a number of funded projects and is a reviewer for several scientific journals and national and international granting agencies. Dr. Issa serves on editorial boards and in leadership positions in several national and international professional associations and has received many awards and honors for her work, including the 2013 University of the Sciences’ Founder’s Day Faculty Award of Merit given to the faculty member who “represents the innovative and entrepreneurial spirit of the University Founders, and who has engaged in research that results in new developments or innovations” and is a Fellow of the College of Physicians of Philadelphia, the oldest national medical society.
Anke-Hilse Maitland-van der Zee, PharmD, PhD
Professor Precision Medicine in Respiratory Disease, Academic Medical Center, Amsterdam, Netherlands
President of the Federation of Innovative Drug Research in the Netherlands, Coordinator of the ERANET SysPharmPediA project
PHARMACOGENOMICSVOL. 19, NO. 7 EDITORIALFree Access
What do we need to transfer pharmacogenetics findings into the clinic?
Elise MA Slob, Susanne JH Vijverberg, Mariëlle W Pijnenburg, Gerard H Koppelman & Anke-Hilse Maitland-van der Zee
Published Online:27 Apr 2018https://doi.org/10.2217/pgs-2018-0026
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Keywords:
infrastructureimplementationpharmacogeneticsprecision medicine
Recently, a portable USB compatible handheld DNA sequencer became commercially available to genotype individuals without need of a laboratory [1]. However, does the rise of point-of-care testing imply that we are ready to implement pharmacogenetics into daily practice? Pharmacogenetics can help in defining optimal drug dosage, identifying patients at risk of drug-induced toxicity or adverse drug effects and predicting whether a prescribed drug will be effective [2]. In an ideal world, individual genetic information should be integrated in computer provider order entry (CPOE) systems and/or clinical decision support tools to calculate precise dosing regimens or to establish effectivity or risks of treatment before physicians generate electronic prescriptions. But what do we need to reach this stage?
First, evidence is key in implementation of pharmacogenetics testing in clinical practice, yet one can argue how much evidence is ‘enough’ to convince stakeholders. According to the clinical evidence pyramid, most weight is given to randomized controlled trials (RCTs) that compare pharmacogenetic-guided treatment strategy to usual care. However, these trials are often expensive and not always feasible to perform due to small patient populations in certain diseases. Furthermore, an RCT can even be considered unethical. For example, in case of strong observational evidence of genetic variants associated with life-threatening drug-induced toxicities [3], such as CYP2D6 genotype of breastfeeding mothers and codeine-induced neonate mortality [4]. Thus, it is important to reach consensus what level of evidence is needed to change clinical practice when precision medicine RCTs are not feasible or ethical. In our opinion strong observational evidence should be sufficient in some cases, when further randomized studies are deemed not feasible and/or ethical.
The request for precision medicine trials to gather clinical evidence is nicely illustrated by long-acting ß-agonists (LABA) pharmacogenomics. These drugs are used in asthma treatment to relieve bronchoconstriction. An SNP in the ADRB2 gene – encoding the beta2-adrenergic receptor – has been associated with poor response to LABA in children. The variant (rs1042713) leads to a change in amino acids of the receptor at position 16 (glycine into arginine), and is also known as Arg16. A large meta-analysis of observational studies [5] as well as a genotype-stratified trial [6] showed that children carrying the variant have poor response to LABA and would benefit from alternative treatment. Despite this evidence, there is no movement toward genotyping before treatment with LABA yet. A precision medicine RCT is currently ongoing to compare ADRB2-guided treatment to usual care [7] in order to change clinical practice in case of positive results.
In addition to gathering ‘enough’ evidence and reporting effect measures, it is important that measures of clinical validity are reported in pharmacogenetic studies. Clinical validity and utility outcome measures as population impact measures (number needed to treat, number needed to genotype) and predictive values of utility (positive predictive value, negative predictive value) need to be evaluated [8]. This is important to interpret pharmacogenetics results for use in clinical practice. However, often pharmacogenetic studies only report measures of association.
Another important outcome measure is cost–effectiveness. Before society is willing to pay for pharmacogenetic tests, it should be assessed whether implementation of such tests are worth the money. Do they lead to an important difference in the patient's health, quality of life and healthcare resource utilization? What is the price of the test, and what are the costs per quality adjusted life year? Only if these costs are under a certain threshold, genetic testing will be implemented in standard clinical care [9].
Furthermore, a proper infrastructure is one of the other key conditions that is required to implement pharmacogenetics into clinical practice. A good infrastructure relies on sufficient facilities for genotyping, involvement of all stakeholders and education for healthcare providers. One of the current ongoing studies to optimize infrastructure is the PREPARE trial [10]. This is a prospective, European RCT across multiple genes, multiple drugs, multiple ethnicities and multiple healthcare systems conducted by the Ubiquitous Pharmacogenomics (U-PGx) consortium. In the PREPARE trial, a panel of 50 variants will be tested covering 13 ‘pharmacogenes’. These variants have clinical consequence regarding drug and dose selection of the 41 drugs for which genotyping guidelines already exist [11]. These drugs will be started in patients randomized to a pharmacogenetics and a usual care arm. Adverse events will be documented as a primary end point for at least 12 weeks up to a maximum of 18 months. A decrease of the adverse events and increase in effectiveness is expected in the pharmacogenetics arm compared with the usual care arm [10]. It is expected that this project will facilitate pharmacogenomics testing in clinical practice in Europe.
To transfer pharmacogenetic findings to the clinic, it is important that the healthcare framework contains facilities to have the patient's genotype information available in electronic healthcare records at the time of prescribing or dispensing a drug [12]. Currently, this is often missing. Pharmacogenetic testing is still reactive (testing specific pharmacogenetic variants to explain adverse effects or poor response) instead of preemptive (screening panel of pharmacogenetic variants in an early stage) [13]. This preemptive approach is also used in the PREPARE trial. But at which moment in time should such a screening be offered and be cost effective: in elderly, polypharmacy patients with high risk of using drugs of interest? Or should it be offered in early adulthood before prescription of any drugs of interest? We can save pharmacogenetic information for the rest of a patients’ life, but we need to take care of protection of these genetic data to prevent it from unethical or commercial usage and also consider storage requirements [2].
A remaining question is: where in the healthcare system should genotyping be placed? This depends on the infrastructure and the velocity that is required to obtain a genotyping result. We should consider using rapid point-of-care tests for genotyping variants that are going to be commonly requested and where rapid outcomes are required. For example, coumarin genotyping outcomes should ideally be available within 1 day. In the EU-PACT trial, rapid point-of-care coumarin testing was used successfully [14]. The earlier mentioned DNA sequencer might fulfill this demand [1].
To make implementation of pharmacogenetics into the clinic a success, many stakeholders need to be involved: patients and their families, healthcare professionals, authorities, academic institutions, disease-centric organizations, healthcare insurance companies, developers of genome analyzers and scientists. All parties should be accurately informed about possibilities and limitations of genotyping for drug response [15,16]. As shared decision making is considered to become the standard, we must provide the patient insight in their treatment plan. The benefit–harm charts, for example, show different combinations of outcome risks in low-dose aspirin treatment for primary prevention of cardiovascular disease to the patients. They can help to make individual treatment decisions [17]. These charts are a good example of involving the patient and should inspire future precision medicine guideline developers.
If we want to actively involve healthcare professionals and patients in pharmacogenetics, we should invest in education on genotype–drug relations and the interpretation of genotyping outcomes. Studies show that the majority of physicians and other healthcare providers currently do not feel confident using pharmacogenetic knowledge in daily practice [12]. Pharmacogenetic courses are increasingly included in curricula of medical and pharmaceutical education programs at universities. However, understandable information for practicing health care providers and patients on how to interpret pharmacogenetic test results is important. In order to stimulate education, the U-PGx consortium provides e-learning modules on their website and education days to increase knowledge of healthcare professionals and patients [10].
Furthermore, to facilitate healthcare providers to use pharmacogenetics in daily practice, we need to integrate pharmacogenetic-prescribing tools in the prescribing system and pharmacogenetic guidelines need to be widely available [16]. In The Netherlands, The Royal Dutch Society for Pharmacy (KNMP) defined in guidelines how to bring pharmacogenetics results into dosing advices and updates these advices at least every 4 years. Computer provider order entry systems and clinical decision support tools in Dutch hospitals and pharmacies are able to integrate these advices to help pharmacists and doctors in precision dosing [18]. This should be further developed for worldwide use. The U-PGx consortium is taking another step forward by translating these advices into Greek, Slovenian, English, German, Spanish and Italian [10]. This hopefully leads to rapid implementation in these countries.
To conclude, we are moving onward towards implementation of pharmacogenetics into clinical practice. Corner stones in future steps should be evidence and infrastructure. New evidence must include sufficient outcome measures focusing on clinical validity, utility and cost–effectiveness. The infrastructure should contain sufficient facilities for genotyping, involvement of all stakeholders and education for healthcare providers. With new rapid point-of-care tests coming to the clinics, the way is paved to further implement pharmacogenetics into usual care.
