The latest CPIC 2019 conference drew a diverse community of more than 200 attendees. The participants were mostly pharmacists (89) and laboratory professionals (102), confirming that successful implementations of pharmacogenetics (PGx) programs depend upon close collaboration between these two specialists. Limited physician attendance (19) indicates that efforts are still needed to encourage the use of PGx amongst this group.
Since its inception ten years ago the consortium, and the PGx community at large have matured. The topics covered by the presenters showed that the several PGx implementers have moved from the pilot phase to a stabilization phase. To proceed further, they are focusing on overcoming logistical challenges, expanding their activities, and above all, improving quality.
Challenges and opportunities that were debated on three main domains: improving quality of testing, disseminating clinical recommendations responsibly and building technologies to support and maintain programs.
Improving the quality of testing: standards
Dr. Victoria Pratt of the Association for Molecular Pathology (AMP) highlighted the efforts of their PGx standardization group to harmonize the variants that pharmacogenetic testing panels should include. Dr. Pratt presented the rationale for the tiered-classification system that the AMP group used in their CYP2C9 and CYP2C19 standards and invited implementers to provide feedback on their utility and possible improvements. Dr. Gwendolyn McMillin’s presentation focused on the pitfalls of PGx testing, highlighting the need for documenting the limitations of a PGx test as well as properly selecting the targets for every gene that is tested.
Interestingly, Dr. McMillin pointed out that when it comes to pharmacogenes, laboratorians have minimal or no exposure to pharmacology principals and therefore are not very good at assigning phenotypes. To help improve phenotype assignment, CPIC is working to harmonize the definition complex genotype to phenotype relationships (e.g CYP2D6) by convening an expert community to arrive at a consensus. Clear and standardized assignments will help to guide laboratorians to assign phenotypes accurately and consistently.
In summary, both presentations were calls to action for clinical laboratories to use evolving standards and to be transparent about what is tested by their laboratories and how it is analyzed. A reliance on freely available resources such as the PharmVar database and CPIC databases were highlighted.
Responsible dissemination of clinical PGx recommendations
A key point made by many implementers was the importance of selecting the right type of PGx information to present to physicians or patients. While presenting his experience implementing PGx in behavioral health setting, Dr. Jeffrey Bishop underscored the importance of engaging subject matter experts when it comes to selecting the drug-gene pairs that are “ready for prime time.” He pointed out that there are often assays that are widely available from commercial testing panels for which the evidence of clinical utility is limited or emerging and therefore debatable. Having resources such as CPIC drug-gene pairs with assigned levels of evidence can help to avoid overloading reports with information that can confuse clinicians. Dr. Bishop called for more transparency when a “combinatorial” approach is undertaken to interpret the impact of multiple gene signatures on a single drug, particularly when the level of evidence is different for different signatures. He commented that “the reader of a PGx report needs to understand how the interpreter arrived at the recommendations.” A presentation by Dr. Philip Empey focused on the PGx community’s responsibility to inform patients. Dr. Empey underscored the need to balance “the duty to prevent harm” and “patient autonomy” when establishing pathways for returning PGx test results to patients and their families. He also stressed the essential role that pharmacists play in educating patients and healthcare providers as well as tracking the effectiveness of educational efforts.
Dr. Larisa Cavallari presented an example of efforts by the Center for Pharmacogenomics and Precision Medicine at the University of Florida Health to improve clinical recommendations by accounting for potential phenoconversion that occurs when the genotype-predicted metabolizer status for CYP2D6 is insufficient to infer the patient’s likely phenotype. The program’s ability to rely on clinical pharmacists’ expertise to address genetic and non-genetic factors to inform opioid dosing is an example during which 21% of a cohort of 200 patients were identified as having drug-interaction liabilities that had to be taken in account along with CYP2D6 genotypes to guide proper opioid prescription.
Technical implementers discussed tools aimed at facilitating proper analysis of raw test genotyping results, as well as tools aimed at facilitating the uptake of PGx recommendations by prescribers and pharmacists. The first group of analytical tools leverages the combined PharmGKB and CPIC teams’ expertise. It includes PharmCAT a research tool that automatically translates variants calls into diplotypes for of the most important pharmacogenes and a CPIC database with an accompanying Application Program Interface (API). Both tools will reduce manual processes and automate quality controls of results and associated clinical annotations. The second group of technical tools focuses on IT efforts to integrate PGx content into EMR systems. In their implementation of PGx testing for patients, both Dr. Cyrine Haidar and Dr. Sara Van Driest nicely reminded the audience of the multidisciplinary efforts required by an organization to maintain their clinical decision support systems (CDSS) for PGx. When faced with the need to either update clinicians or patients when key clinical knowledge emerges (e.g. updated to CPIC recommendations) or to update the supportive IT infrastructure both presenters underlined that changes and maintenance tend to occur at a slow pace and a high cost that small clinical organizations might not be able to bear. Unless an organization properly allocates resources and addresses its dependence on complex Electronic Health Records systems, its ambition to scale its existing pilot PGx programs will remain unachievable.
CPIC’s 2019 meeting highlighted both the progress and challenges that active PGx programs face. In complex areas such as conveying the limitations of tests or informing patients, implementors demonstrated that the answers to problems are not always obvious or easy to agree upon. Above all, the meeting as Dr Relling pointed out, reminded us that active involvement in implementation, as well as open sharing of our successes and challenges, is an indispensable factor in moving pharmacogenetics into the mainstream.