ClinGen Pharmacogenomics Working Group (PGxWG) Survey To Close Soon

 

The ClinGen Pharmacogenomics Working Group (PGxWG)'s anonymous survey will close soon after this Friday, June 30, 2023. Our goal is to gather opinions and feedback regarding the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. If you have not yet had the chance to fill it out or pass it along, please do so soon! 

Pharmacogenomics expertise is not required - we are also looking for responses across the broader global genetics and medical communities as well (clinicians, pharmacists, labs, genetic counselors, etc.) All responses are appreciated, no matter who you are or where you are in the world. If you’ve previously completed the survey, we appreciate your contribution and there's no need to submit a second response. 

The survey can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4.  We sincerely appreciate your time and participation, and your willingness to help.

ClinPGx Sessions at PGRN 2023 Conference and ClinGen Summer Workshops

At the upcoming PGRN 2023 annual conference in Memphis, Dr. Teri E. Klein, the principle investigator for PharmGKB, ClinGen, CPIC and PharmCAT,  will hold a town hall discussion on ClinPGx: a single integrated resource for Pharmacogenomics (PGx). Dr. Klein will discuss the challenge of the separation of pharmacogenomic resources from clinical genomic resources, and present a long-term, conceptual framework for broadly integrating the available PGx resources into a single resource, ClinPGx. 

Dr. Klein will also present at the upcoming ClinGen 2023 Summer Workshop Series on June 16 11am PT. Please come join us. We are actively seeking feedback from the PGx and genomics community on the interest and development of ClinPGx to facilitate the incorporation of PGx into standard of care. Zoom link below: 

June 16th, 2023, 11am PT/ 2pm ET 

Join Zoom Meeting : 

https://acmg.zoom.us/j/87027015818?pwd=S2U2OTFhQ1oranFZZjNlTEhHN0FlUT09 

Meeting ID: 870 2701 5818 

Passcode: 83854960 

One tap mobile 

+16699006833,,87027015818# US (San Jose) 

+17193594580,,87027015818# US 

ClinGen Pharmacogenomics Working Group (PGxWG) Follow-Up Survey

The ClinGen Pharmacogenomics Working Group (PGxWG) has just launched a second survey to solicit feedback about the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants from both the PGx community and the wider genetics and medical communities. Please note that this second survey is not independent of the first, and if you’ve taken the previous survey and have significant PGx familiarity or expertise, there is no need to take this iteration, as it would be redundant due to the overlap in questions.

The ClinGen PGxWG is a multi-disciplinary team of researchers and professionals with expertise in pharmacogenomics (PGx), clinical pharmacology, medical genetics, regulatory affairs, and molecular diagnostics. It was launched in February 2022 with the goal of developing a framework of tiered standard terminology and definitions that reflect clinical significance for genes and genomic variants implicated in drug response, in order to facilitate the incorporation of PGx knowledge into ClinGen and more consistent interpretation of PGx variants identified by panel testing and/or sequencing.

The survey is open now and can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4. All responses are greatly appreciated, no matter who you are or where you are in the world. Unlike the previous survey, this survey does not assume PGx familiarity, though if you have not taken the previous survey and have PGx familiarity, your feedback is still greatly appreciated. The survey takes approximately 15 minutes to complete. We sincerely appreciate your time and attention, and your willingness to help.

ClinGen Pharmacogenomics Working Group (PGxWG) Survey

The ClinGen Pharmacogenomics Working Group (PGxWG) has launched a survey to solicit feedback about the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. 

The ClinGen PGxWG is a multi-disciplinary team of researchers and professionals with expertise in pharmacogenomics (PGx), clinical pharmacology, medical genetics, regulatory affairs, and molecular diagnostics. It was launched in February 2022 with the goal of developing a framework of tiered standard terminology and definitions that reflect clinical significance for genes and genomic variants implicated in drug response, in order to facilitate the incorporation of PGx knowledge into ClinGen and more consistent interpretation of PGx variants identified by panel testing and/or sequencing.

The survey is open now and can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_bKqeKf2YmCVS1LM.  All responses are greatly appreciated, no matter who you are or where you are in the world. This survey does assume some PGx familiarity, though we plan to launch another survey targeting those with less PGx experience in the near future. The survey takes approximately 10 minutes to complete. We sincerely appreciate your time and attention, and your willingness to help.

PharmGKB selected in the first list of Global Core Biodata Resources

We are pleased to announce that PharmGKB is included in the first list of Global Core Biodata Resources (GCBRs), a collection of resources whose long term funding and sustainability is critical to life science and biomedical research worldwide.

The Global Biodata Coalition (GBC) brings together major public and charitable funders, with the aim to “stabilize sustainable financial support for the global biodata infrastructure and in particular to identify for prioritized long-term support a set of Global Core Biodata Resources that are crucial for sustaining the broader biodata infrastructure.” After a rigorous two-stage process evaluating scientific quality and impact, 37 resources were selected in the first list of GCBRs. One key feature of the GCBRs is that the data from these resources are available openly and can be accessed and used without restriction by researchers worldwide. PharmGKB is honored to be recognized as a Global Core Biodata Resource and we fully support GBC's mission to stabilize support for the global biodata infrastructure.

We would like to take this opportunity to thank all the present and past members of PharmGKB, our funding agencies, scientific advisors and collaborators, and especially our users, for their continued support and contribution to build this vital resource. PharmGKB serves both basic science investigators as well as clinicians and laboratories. Sustainable long-term support is critically important for us to provide stable, comprehensive, and dependable pharmacogenomic information to our users across the globe.

Expansion of pharmacogenetics education agreed as part of lawsuit settlement

Oregon Health & Science University (OHSU) will introduce new educational initiatives on the risks of prescribing the chemotherapy drug capecitabine to patients with DPD deficiency as part of a lawsuit settlement.

The settlement was reached with Joanne McIntyre, whose husband David died as a result of severe capecitabine toxicity. David carried variations in the gene DPYD, which encodes the DPD enzyme. DPD is involved in metabolism of fluoropyrimidine drugs, including capecitabine. Variants in DPYD, such as those that David carried, can inactivate the DPD enzyme, leading to DPD deficiency. Patients with DPD deficiency are unable to properly metabolize capecitabine and other fluoropyrimidines, and are at risk of experiencing severe drug toxicity. In David's case, this toxicity was fatal.

PharmGKB has annotations of several clinical guidelines for capecitabine and DPYD, including those from CPIC and the DPWG. These guidelines uniformly recommend either a dose reduction or selection of an alternative drug in patients with DPD deficiency.

OHSU will hold seminars to educate clinicians on the risks associated with DPD deficiency, how to identify severe capecitabine toxicity in patients and how to administer the antidote. They will also include a module on the topic in their fellowship program and provide a written resource guide to staff in their oncology department. Going forward, patients identified as candidates for capecitabine chemotherapy will be informed of the risks associated with DPD deficiency and, where appropriate, will be offered testing.

We at PharmGKB applaud Joanne's singular dedication to saving patients' lives and OHSU's commitment to implement these changes. Resources on capecitabine pharmacogenomics, including annotations on clinical guidelines for the use of DPYD genotypes in capecitabine prescribing, can be found at the PharmGKB capecitabine drug page.

Plavix manufacturers to pay $834 million to state of Hawaii

Bristol-Myers Squibb Co and Sanofi, the manufacturers of Plavix (clopidogrel) have been ordered to pay over $834 million to the state of Hawaii after failing to warn about the drug’s potential health risks to patients with combinations of CYP2C19 variants which result in a CYP2C19 poor metabolizer status.

Clopidogrel is metabolized to its active metabolite by CYP2C19, as shown in the PharmGKB clopidogrel pathway. Patients carrying CYP2C19 no function alleles (e.g. CYP2C19*2) have reduced or no conversion of clopidogrel to the active metabolite, which puts them at an increased risk of cardiovascular events. The CPIC guideline for clopidogrel recommends that CYP2C19 intermediate and poor metabolizers receive alternative antiplatelet therapy.

The companies were found to have violated Hawaii’s consumer protection laws by not disclosing that Plavix would be ineffective for as many as 30% of patients in Hawaii, many of whom are of Asian and Pacific Islander descent. Some CYP2C19 no function variants, such as CYP2C19*2, are found at higher frequencies in Asian and Pacific Islander populations compared to their frequency in European populations (see the CYP2C19 allele frequency table).

Judge Dean Ochiai ruled that Bristol-Myers Squibb Co and Sanofi “knowingly placed Plavix patients at grave risk of serious injury or death in order to substantially increase their profits” over a 12-year period from 1998 to 2010. Information about the effect of CYP2C19 no function alleles on the efficacy of Plavix was added to the drug label in 2009, and a Black Box warning to consider alternate therapy for CYP2C19 poor metabolizers was added in 2010. PharmGKB has annotated the Plavix label and highlights pharmacogenomic information found within the label.

Hawaii Attorney General Clare Connors emphasized the growing impact of pharmacogenomics on the pharmaceutical industry: “The order entered by the court today puts the pharmaceutical industry on notice that it will be held accountable for conduct that deceives the public and places profit above safety”.

In a joint statement, the companies said that “the overwhelming body of scientific evidence demonstrates that Plavix is a safe and effective therapy, including for people of Asian descent.” and that they plan to appeal.

LCD announces coverage for PGx testing under Medicare

The Centers for Medicare and Medicaid Services (CMS) have posted a FUTURE Local Coverage Determination (LCD) for MolDX: Pharmacogenomics Testing (L38294). This includes broad coverage for pharmacogenomic testing to go in effect this summer.

CPIC provided presentations to Palmetto prior to their draft LCD, and provided written comments on LCD ID L38294 back in November of 2019. CPIC members were instrumental in the feedback provided, and many of CPIC’s suggestions have been incorporated, and CPIC guidelines are cited throughout their document. For example, their post states:  “PGx tests are indicated when medications are being considered for use (or already being administered) that are medically necessary, appropriate, and approved for use in the patient’s condition and are known to have a gene(s)-drug interaction that has been demonstrated to be clinically actionable as defined by the FDA (PGx information required for safe drug administration) or Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines (category A and B).”

The LCD defines ‘actionable use’ of PGx as “when the genotype information may lead to selection of or avoidance of a specific therapy or modification of dosage of a therapy. The selection, avoidance, or dose change must be based on the FDA-label for the drug, an FDA warning or safety concern, or a CPIC level A or B gene-drug interaction”. PharmGKB uses the ‘Alternate Drug’ and ‘Dosing Info’ tags to highlight drug label annotations where the label contains information about contraindications or dosing changes based on genotype information. These tags can be used to filter our table of drug label annotations.

PGRN Transition

After 20 years of NIH funding, the Pharmacogenomics Research Network (PGRN) is becoming an independent scientific society on July 1, 2020. The deadline for becoming a founding member has been extended. If you are interested in joining, please visit www.pgrn.org.

On behalf of all of the NIH PGRN funded investigators, we thank NIH for their past support, particularly our original program officer, Dr. Rochelle Long (NIGMS Director, Division of Pharmacology, Physiology and Biological Chemistry).

Update 6/29/2020 The inaugural Research In Progress (RIPS) webinar from the PGRN society will be given by Alan Shuldiner, MD, on Friday July 17 at 11am Eastern time. Dr. Shuldiner will speak on "Building bridges between industry, academia, health care systems and communities to advance Precision Medicine".

From Friday August 14, RIPS webinars will be held on the second Friday of every month at 11am Eastern time for all PGRN members. A schedule of upcoming RIPS webinars can be found here. If you are interested in joining the PGRN, you can become a member at www.pgrn.org.

DPYD goes live on PharmVar

PharmVar has announced the introduction of DPYD to its database. DYPD is the rate limiting enzyme involved in the catabolism of fluoropyrimidines (5-fluorouracil and capecitabine) which are used in several cancer treatment regimens. Clinical laboratories provide preemptive DPYD genotyping to avoid potentially life-threatening toxicity in patients carrying DPYD risk alleles. Annotations of clinical guidelines for DPYD are available on PharmGKB here.

Prior to its introduction to PharmVar, there was no centralized resource for DPYD nomenclature. Some of the allelic variants were assigned star allele numbers when first published (DPYD*1-*13) or were referred to by a trivial name.

Although star nomenclature based on haplotypes was initially used to name DPYD variants, this system was deemed impractical for DPYD due to the size of the gene and recombination between exons. To accommodate DPYD (and other genes with similar challenges in the future), PharmVar has developed a gene page format using rsIDs as PharmVar names instead of star allele designations.

Check out the new DPYD page at https://www.pharmvar.org/gene/DPYD. PharmVar welcomes any feedback and encourages DPYD submissions to grow its inventory.

Announcing Dr. Kelly Caudle as co-PI of CPIC

CPIC is pleased to announce that Dr. Kelly Caudle (St. Jude Children’s Research Hospital) joins Dr. Teri Klein (Stanford University) as the co-Principal Investigator of the NHGRI U24 grant (HG 010135) that provides funds for CPIC.

Dr. Caudle has been the CPIC Coordinator/Director for CPIC for 8 years. During this time she has overseen the CPIC guideline development for 22 CPIC guidelines and 13 guideline updates and has led several CPIC projects. We thank Dr. Mary Relling for her outstanding leadership and we are thrilled that she continue her involvement in CPIC as a co-Investigator at SJRCH.

Congratulations, Dr. Caudle!

Join the new PGRN society!

After 20 years of NIH funding, the Pharmacogenomics Research Network (PGRN) is transitioning to an independent, nonprofit scientific society, and all interested individuals are invited to sign up to become a member of the new PGRN!  The independent scientific society will continue many of the functions of the current PGRN, and we encourage you to join today to stay involved.  Benefits of joining the new PGRN include:

•         Reduced registration fees for PGRN meetings and workshops, including member receptions and poster sessions at annual meetings with large scientific societies such as ASHG and ASCPT

•         Participation in member calls/webinars and Research in Progress Seminars

•         Membership on PGRN program committees for meetings and workshops

•         Network with colleagues and establish collaborations

•         Leadership opportunities for members (e.g., serve on PGRN committees, board, and as leaders)

•         Awards for trainees and mentorship opportunities

•         Access to PGRN web pages highlighting pharmacogenomics tools and resources, events and other useful information for PGx research, education and clinical practice

Special membership rates are available for trainees, multi-year memberships, early sign ups and those from developing countries. In addition, take advantage of the opportunity to be listed on the PGRN website as a founding member if you choose that option during signup. Sign up today at https://pgrn.regfox.com/pgrn-membership-dues.

Therapeutic Resource for COVID-19

PharmGKB has assembled a COVID-19 webpage containing therapeutic drugs from clinical trials and adjuvant therapies linking to PharmGKB annotations of gene and variant associations with these drugs.  While no trials currently discuss pharmacogenomics directly, some drugs have known associated genes and pathways.  Due to the potential QT-prolonging action of some of the drugs on this list, such as hydroxychloroquine, and the risk of concomitant treatment with other QT-prolonging agents, we have included a list of drugs associated with QT prolongation.  Additionally, we provide a list of antidepressants with Clinical Pharmacogenetic Implementation Consortium (CPIC) prescribing guidelines in light of the likelihood of depression and/or anxiety associated with the impact of COVID-19.

Following a drug link on the PharmGKB COVID-19 webpage takes the user to PharmGKB annotations about that drug, including FDA-approved drug labels, variant and clinical annotations based on peer-reviewed literature and pharmacokinetic and/or pharmacodynamic pathways.  This resource is under development.  The COVID-19 space is changing rapidly and new clinical trials continue to be added for investigational drugs, some of which are being repurposed and some of which are experimental with very limited information.  We will update the PharmGKB webpage as we get new information. 

CPIC launches second Term Standardization project – seeking PGx experts

CPIC leadership has put out a call for gene experts to participate in the second CPIC Term Standardization project, which will begin in early 2020.

This project continues the work of the first term standardization effort in 2016, where standardized terms for pharmacogenetic (PGx) allele function and associated phenotypes were developed and agreed upon by a Delphi process (see Caudle et al. 2017 for further details). The work of the previous project was adopted by many external groups and has helped build consensus between different PGx testing platforms, PGx implementation processes and scientific publications.

The second Term Standardization project will use the same Delphi process to find drug-agnostic allele function and phenotype terms that can be used by pharmacogenes not included in the 2016 work, including VKORC1, RYR1, mt-RNR1 and others. As with the first term standardization project, iterative surveys will be used to find consensus among the group. It is expected that 2-4 rounds of surveys will be needed to achieve consensus. As with the 2016 project, the resulting standardized terms will be published in a peer-reviewed journal and used in future CPIC guidelines.

If you meet the criteria below and would like to join this expert panel, please take this survey (5-10 minutes) to be included in the project. Further information can also be found at the CPIC website.

• Clinician with a working knowledge of pharmacogenetics (pharmacists, physicians, nurses, genetic counselors, etc).

• Researcher with at least 2 years of PGx research experience

• Clinical laboratory scientist or staff with at least 2 years of PGx experience

• EHR standards expert/medical informatic (PGx experience not required but involvement in HL7 or similar experience preferred)

• Gene specific experts and/or CPIC or DPWG guideline author for the following genes to be included in this project: RYR1, CACNA1S, CFTR, G6PD, IFNL3, mt-RNR1, GBA, NAGS, HPRT1, POLG, COMT, OPRM1, SCN1A, SLC6A4, F5, ABL2, ASL, ASS1, CPS1, and OTC

Pharmacogenomics in the clinic

In 2018, Stanford Medicine launched a pilot project, Humanwide, using precision health approaches to predict, prevent and treat disease based on the individual patient in primary care. Over the past year, the Humanwide project provided care to a diverse group of 50 patients based on their individual factors, from lifestyle to DNA data. In addition to disease screening, the patients also underwent pharmacogenomic screening and patients with unusual drug responses received consultation from the Stanford Pharmacogenomics Clinic, led by Dr. Russ Altman.

In this video, Dr. Altman gives an introduction to pharmacogenomics and explains to the patients how their genetic information can be used to guide prescribing decisions to lower the side effects and improve the efficacy of the drugs they are using now and in the future.

“If we can bring pharmacogenomics to the frontlines of medicine, I think we have a better chance of managing health instead of disease," said Dr. Altman. "This is where Precision Health is a powerful idea, where we’re trying to keep people out of the system by giving them the minimum medication at the right time and not having their disease progress, get worse and become chronic diseases”.

To learn more about Stanford Pharmacogenomics Clinic:

https://stanfordhealthcare.org/medical-clinics/center-personalized-wellness/pharmacogenomics/how-it-works.html

To learn more about Stanford Precision Health Initiative:

http://med.stanford.edu/precisionhealth.html