Introduction
The Clinical Pharmacogenetics Implementation Consortium has been communicating with the FDA (Food and Drug Administration) about ways to advance pharmacogenetic (PGx) testing, and Dr. Kelly Caudle is a big part of this movement. During a workshop at the 2022 AMP (Association for Molecular Pathology) conference, Dr. Caudle presented on The Advancement of Pharmacogenetic PGx Testing: Development of Evidence-based Guidelines and the Ongoing Effort to Drive Alignment with Regulatory Bodies. She opened with a patient case study to show how with prior guidelines and few PGx resources a physician or a pharmacist might translate any pharmacogenomic knowledge into a prescribing recommendation.
The Need for PGx: A Case Study
AG is a nine-year-old male with Acute Lymphocytic Leukemia and is immunocompromised. He presents with a fever; the medical team suspects a fungal infection and wants to start voriconazole. The patient has a CYP2C19 genotype in the chart, and it is CYP2C19 *17/*17.
As the pharmacist on the team, what would you recommend to the patient regarding the use of voriconazole? The group’s pharmacist searched the FDA label on voriconazole and CYP2C19.
The pharmacist noticed that in the metabolism section, it does say some in-vitro studies showed CYP2C19, CYP2C9 and 3A4 metabolize voriconazole, and there are also in vivo studies that indicated that CYP2C19 is significantly involved in the metabolism of voriconazole, and this enzyme exhibits genetic polymorphisms. There is also a section that talks a little bit about populations and says that studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, fourfold higher concentrations of exposure than homozygous extensive metabolizers, and subjects who are heterozygous have twofold.
The pharmacist did not know what that meant. Her patient is CYP2C19 *17/*17, and there is no mention of it on the label. She continues researching to see what else she can find and discovers a list of the FDA-approved labeling of 120 drugs with pharmacogenomic information. Voriconazole is not on the list.
In Feb. 2020, The FDA put out three lists:
- Support therapeutic management recommendations list that recommends one should use this information.
- Indicate the potential impact of safety or response.
- Pharmacogenetic associations for which the data demonstrate a potential impact on pharmacokinetic properties only, which translates to “we don’t really know if you should use this information,” said Dr. Caudle, and intermediate or poor metabolizers of voriconazole with CYP2C19 variants are on this list at the bottom.
Not knowing what this meant, the pharmacist advised the team to go ahead and start voriconazole at standard doses. It takes five days to see if it is working if you have in-house testing. If you have outside testing, it could take more than five days. This patient has an invasive fungal infection and is now on a drug that may not be appropriate, but this pharmacist and the team did not know how to use the genetic test result.
Five days later, the voriconazole labs were undetectable, and the dose increased by 20%. The team waits another five days, and the drug is still undetectable. This patient is now getting a hefty dose ten days into therapy and still not getting the therapeutic ranges of that drug. Now it is time to switch medicines since the patient has been on inappropriate therapy for an invasive fungal infection for ten days.
What went wrong here? Why was this information not already on the label? When voriconazole came on the market, PGx labeling was not mandatory, and these companies did not even have to study pharmacogenetics to put it on the label. Post-market relabeling has an exceedingly high threshold for revisions, which is why FDA labels are not necessarily up to date with new literature. Some of these labels were created 40-plus years ago and have not had updated information since, whereas Clinical Pharmacogenetics Implementation Consortium guidelines are up to date.
Many factors influence variability in drug effects, and as a clinician, you must think of these things. Take lactation, for example; you do not have to worry about lactation in a four-year-old, but you do have to consider this factor in an adult woman who is pregnant or just had an infant. Clinicians must individualize whatever they are prescribing to their patients.
Dr. Caudle reiterated that a clinician should never pull an FDA label, instead recommends the use of PharmGKB as an excellent website and resource where you can put in any gene or drug to find information, annotations of the label, and compare the FDA label to the European label to the Japanese label. She also suggested Lexicomp or Micromedex as a resource for more updated drug information.
How The Clinical Pharmacogenetics Implementation Consortium Was Established
Mary Relling and Terry Klein started the Clinical Pharmacogenetics Implementation Consortium in 2009. When Dr. Caudle began with the consortium in 2012, there were 60 members, and it has since grown to over 550 members, with over 260 institutions and members in 36 different countries. There are now 26 guidelines, not including all the updates with 45 written guidelines, 25 genes, and with the recent G6PD guideline, there are over 100 drugs, many of which are in the top 200 most used medications.
When thinking about pharmacogenomic testing, the Clinical Pharmacogenetics Implementation Consortium answers two questions: 1) should I order the PGx test? and 2) how should I use this PGx test result?
The Clinical Pharmacogenetics Implementation Consortium uses standardized formats to ensure each guideline looks the same. The recommendations have the same sections with one system for grading the evidence and another for grading the peer-reviewed recommendations. All consortium members can review the guidelines before submission for publication. The Clinical Pharmacogenetics Implementation Consortium is NIH (National Institute of Health) funded. Publications are available for free at cpicpgx.org, pharmgkb.org, and also through PUBMed Central. Guidelines are also cited in the genetic testing registry. These are filtered as practice guidelines in PubMed. The Clinical Pharmacogenetics Implementation Consortium follows IOM conflict of interest policy for writing trustworthy clinical guidelines.
Besides the Clinical Pharmacogenetics Implementation Consortium, there are other pharmacogenomic resources like PharmGKB, which does not write guidelines, but it is a great place to see whether guidelines exist. There are also the Dutch Pharmacogenetic Working Group and the Canadian Pharmacogenomics Network for Drug Safety groups. The Clinical Pharmacogenetics Implementation Consortium is a shared project between PharmGKB and the Pharmacogenomic Research Network.
The consortium has 26 guidelines covering 25 genes and over 100 drugs to date. Recently, G6PD was added, the RESPIRA case guideline was updated, and there are many more drugs. Several of the drugs they recommend are low-risk drugs for G6PD deficiency as a caution or a contraindication in the FDA label. The guidelines are all available at cpicpgx.org. Had the pharmacist in the case study known about the website, she would have seen the guideline for voriconazole and CYP2C19, the supplement table, and implementation resources, including frequency tables and diplotype to phenotype tables.
The Process for Creating a Guideline
The process of nominating a guideline to the Clinical Pharmacogenetics Implementation Consortium can take anywhere from a year to a year and a half. Coming to a consensus with the authors can take some time. Dr. Caudle stated that limited resources could hinder the process of moving quickly on creating new guidelines and relying on surveys from members to decide which ones should be moved forward. Once agreed upon, there is a selection process for authors, who go through a strict conflict of interest policy. Then the steering committee makes the final call on the authors, and finally, drafting of the guideline is started. The evidence review takes 3-4 months sometimes, depending on the amount of evidence they are reviewing. Several conference calls are made to discuss the recommendation table, and the guideline is written around those recommendations. The draft is then sent out to consortium members and submitted for publication. The final guideline is posted to the Clinical Pharmacogenetics Implementation Consortium website. Revisions are made if needed.
Clinical Pharmacogenetics Implementation Consortium guidelines and content are subject to updates and modifications, and users should refer to cpicpgx.org to confirm they are accessing the most current content.
The Clinical Pharmacogenetics Implementation Consortium guidelines help clinicians translate genotype to phenotype to a clinical recommendation. This part of the guideline is essential because recommendations are based on the phenotype. If the genotype to phenotype translation is wrong, the recommendation will also be wrong. Referencing the opening case study where the patient has the gene CYP2C19 *17/*17, the guideline shows this individual would have been an ultra-rapid metabolizer and the Clinical Pharmacogenetics Implementation Consortium recommends avoiding voriconazole. This patient should never have received this drug. There are alternatives to voriconazole that should have been used in that patient.
Genotype to Phenotype to Clinical Recommendation
To translate genotype to phenotype, the Clinical Pharmacogenetics Implementation Consortium uses the allele definition tables translated and maintained by PharmVar that lays out the haplotypes for each gene. Next, a function is assigned to those alleles, defining the phenotype and its written recommendation. The interpretation consult notes can be used for lab results or in the patient’s electronic health record (EHR) system so that the results remain in their medical records throughout their lifetime.
In the future, the Clinical Pharmacogenetics Implementation Consortium will add strength of evidence and a summary of findings based on FDA feedback after submitting the allele functionality tables for FDA recognition.
The Clinical Pharmacogenetics Implementation Consortium uses diplotype to phenotype tables to translate diplotypes into phenotypes. They also perform gene-drug associations by searching PubMed for papers such as observational type studies and preclinical and clinical studies that show a drug phenotype based on that variant. They also consider the drug’s therapeutic index, the disease’s severity, the availability of genetic tests, and the availability of alternative therapy before making a recommendation. The Clinical Pharmacogenetics Implementation Consortium only uses case reports to analyze data and will only move forward with a guideline or recommendation if it has been clinically tested or if there is evidence for alternative therapy.
How The Clinical Pharmacogenetics Implementation Consortium Reviews Evidence for Guidelines
An example of how the consortium would think through a guideline using the opening case study: Voriconazole is extensively metabolized with less than 2% of the original dose excreted in an unchanged form and the main circulating metabolite, the voriconazole N-oxide, has zero antifungal therapy in a patient who is an ultra-rapid metabolizer. There is a very defined therapeutic index for voriconazole, which helps with that recommendation. Some patients have toxicity if they do step out of this one area of concentration, and on the other hand, if they metabolize too quickly, it will fail to work. Then there is the severity of the underlying disease to consider, like in the case of the 9-year-old patient with an invasive fungal infection, and the consequences of suboptimal prescribing, which in the case of an invasive fungal infection can result in death. Another consideration is the availability of genetic tests like CYP2C19, which are widely tested. A doctor may have ordered CYP2C19 testing for clopidogrel but may find genetic variants in the patients on voriconazole, which is something else to think about. The last consideration is the availability of evidence for alternative therapy. In this case, there are many antifungal alternatives that have been shown to be just as effective.
The Clinical Pharmacogenetics Implementation Consortium uses an evidence review table with evidence from two to three authors, which is independently reviewed, then have several discussions to reach a consensus rating of high, moderate, and weak. A high consensus means the evidence includes consistent results from well-designed, well-conducted studies. A moderate consensus means that the evidence is sufficient to determine the effects, but the number, quality, or consistency of the individual study generally limits the strength of the evidence. And a weak consensus means that the evidence is insufficient to assess the effects on health outcomes because of a limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information.
Conclusion
The current aim of the Clinical Pharmacogenetics Implementation Consortium is to improve standardization in the processes required to implement PGx, including the standardization of the clinical laboratory, results reporting, test ordering, and reimbursement. The ultimate goal is to have a standard that will simplify information for physicians and pharmacists where they won’t have to translate genotype to phenotypes, they will only need to know that if the patient is an ultra-rapid metabolizer this is the course of action needed, but this can only happen once standardization is uniform.
All the slides presented above are from Dr. Caudle’s workshop, The Advancement of Pharmacogenetic PGx Testing: Development of Evidence-based Guidelines and the Ongoing Effort to Drive Alignment with Regulatory Bodies.