CPIC Informatics Working Group publishes article in JAMIA

An article from the Clinical Pharmacogenetics Implementation Consortium (CPIC) Informatics Working Group has now been published ahead-of-print on the Journal of the American Medical Informatics Association (JAMIA) website. Within the paper, the authors discuss principles that will support the implementation of precision medicine, particularly pharmacogenomics, into routine clinical care.                                                                                

Hoffman et al. write that successful adoption of pharmacogenomics in the clinic requires a database of knowledge that can be used in an electronic health record (EHR) with Clinical Decision Support (CDS). To this end, the CPIC Informatics Working group has been developing and incorporating EHR vendor-agnostic resources into CPIC guidelines. Based on this experience, the working group outlines five principles that can apply to future knowledge resources that implement precision medicine. Though the principles are mainly in reference to pharmacogenomics, they are applicable any type of precision medicine initiative. The five principles cover the limitations of current genetic testing methods, the importance of levels of evidence, integration of different types of medical knowledge and handling of new knowledge, and the use of standardized terminology. By laying out these principles, the CPIC Informatics Working Group provides a reference for the design and implementation of future, national-level precision medicine resources.

CPIC is a shared project between PharmGKB and the Pharmacogenomics Research Network. Read more about CPIC and the Informatics Working Group at cpicpgx.org.

Read the paper on JAMIA:

Developing knowledge resources to support precision medicine: principles from the Clinical Pharmacogenetics Implementation Consortium (CPIC). James M. Hoffman; Henry M Dunnenberger; J Kevin Hicks; Kelly E Caudle; Michelle Whirl Carrillo; Robert R Freimuth; Marc S Williams; Teri E Klein; Josh F Peterson. Journal of the American Medical Informatics Association 2016; doi: 10.1093/jamia/ocw027.

DPYD testing saves money as well as prevents fluoropyrimidine toxicity

A recent article [PMID: 26573078] and editorial [PMID: 26644533] in The Journal of Clinical Oncology looked at prospective testing for DPYD *2A and prevention of grade 3 or higher toxicity. The study examined a large number of patients (n=2,038) and identified 22 carriers of DPYD *2A who then received a reduced dose of fluoropyrimidines or alternative drug regimen, as per CPIC and DPWG guidelines. The FDA and EMA drug labels for fluorouricil and capecitabine do not currently recommend DPYD testing prior to fluoropyrimidine therapy.

Deenen et al stated that “the risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P <0.001); drug-induced death was reduced from 10% to 0%.”

The authors found when average total treatment costs were examined, “the cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs. “

Although several DPYD variants have been reported to decrease DPD activity the frequency of each are very low, (in the range of 1%, see supplementary table 3 from the CPIC guideline) which has been considered a barrier to testing.  As the editorial states “The per-genotype cost of genotypic tests is continually decreasing, and studies of pre-emptive genotyping have suggested that large-scale, multitarget tests could further drive down that cost in the future”

A follow up study from the same authors is already underway and will look at DPYD*2A, rs67376798, rs56038477/HapB3 and DPYD*13. 

The full dosing guidelines, including details for all functional variants of DPYD, and drug labels regarding DPYD and fluoropyrimidines can be found on PharmGKB.

The Wall Street Journal Discusses PGx

An article in the Wall Street Journal this week by Health Editor Melinda Beck called “Is Your Medicine Right for Your Metabolism?” discusses the current state of pharmacogenetics and obstacles to implementation of pharmacogenetics (PGx) in routine clinical care. The article and an accompanying video explain that variations in enzymes can drastically alter the metabolism of many commonly prescribed medications and may affect drug response, efficacy, and safety. The article goes on to discuss how some professional medical groups have hesitated to implement PGx testing because of insufficient evidence from large randomized controlled trials, but it also highlights medical research centers such as Vanderbilt University, the University of Pittsburgh, the Mayo Clinic, and St. Jude’s Children’s Research Hospital that are currently implementing PGx testing into care. Information about FDA approved drug labels mentioned in the article as well as detailed information about all of the genes and drugs discussed in the article can be found by searching PharmGKB. In addition, some of the cited gene-drug pair interactions such as CYP2D6 and codeine, clopidogrel and CYP2C19, warfarin and CYP2C9, and statins and SLCO1B1, are also the subjects of Clinical Pharmacogenetic Implementation Consortium (CPIC) dosing guidelines, which are available on the CPIC and PharmGKB websites.  For more information about research institutions currently implementing pharmacogenomics, see the lists on the PharmGKB and CPIC websites.

Integrating PGx throughout the Drug Development Process

Nelson, et al. argue for integrating more pharmacogenomic research into drug screening and the pre-approval process, with benefits for patient outcomes and drug development. Their article  “The genetics of drug efficacy: opportunities and challenges,” published this week in Nature Reviews Genetics reviews currently known associations of genetic variants with drug efficacy. In addition to using other sources, they selected genes from the list of CPIC guidelines. Clinical annotations describing the relationships and evidence for the variants that appear on their list of robust associations (Table 1 of the review), such as for the association of CYP2D6 and codeine efficacy, can be found on the PharmGKB website.

With nearly all pharmacogenetic relationships discovered post-approval, dozens of drugs currently on the market and in development are likely to benefit from clinical application of pharmacogenetics. Many relevant studies simply haven’t been done. Additionally, with genetic testing platforms becoming progressively cheaper, now at $1K for whole genome sequencing, it is possible to interrogate rare variation in addition to common variation, which until now has limited the discoveries of pharmacogenetic relationships to common variants with large effect sizes. 

Even while the majority of drugs may not have clinically useful genetic predictors of efficacy, Nelson, et al. have calculated that somewhere between 2 and 20% of drugs likely do, with important implications for clinical outcomes. We would like to add that beyond their statistic for drug efficacy, genetic variation can have important implications for drug safety, including risk of toxicity and hypersensitivity reactions. By integrating pharmacogenetic research earlier and more comprehensively into the drug development process, the benefit of personalized medicine related to efficacy AND safety can achieved more quickly and more completely, with additional benefits for understanding the biological mechanism of drug activity and targeted development of future drugs.

DTC genetic testing and the role of primary care providers

An original research manuscript and a corresponding editorial published recently in Annals of Internal Medicine analyze interactions of patients with their primary care providers (PCP) regarding their direct to consumer (DTC) genetic testing results. Van der Wouden et al. found that out of 1026 respondents, 277 discussed their results with their PCP.  Of those, 35% were very satisfied while 18% were not at all satisfied with the interaction (the remainder were “somewhat” satisfied). Those who were very satisfied were more likely to report that their provider was willing to discuss their test results (83.7% compared to 7.8% of not satisfied) and use the results in medical care (67.4% vs. 1%).   The study, however, does not report any health care provider perspective on these interactions. 

The editorial piece by Burke and Trinidad focuses on problems with DTC testing, comparing them with tests such as whole body scans, stating “They are tests that deliver uncertain information and create patient expectations that may align poorly with evidence; clinical priorities; or, in some cases, the patient's best interests.”  While they cite the numbers for the customers who were not at all satisfied with their PCP interaction in the van der Wouden study, there is no mention of those who were satisfied.  They conclude the lack of satisfaction suggests that the DTC companies create unrealistic expectations of the health care system. They even go so far as to say that DTC companies have been able to “[externalize] the dissatisfaction consumers feel when their experience falls short of marketing promises”, presumably deflecting customer dissatisfaction onto health care providers.  This statement is surprising given the van der Wouden study showed that the customers who discussed their results with their PCP expressed the most satisfaction with the test overall (as compared to those who consulted with another health care provider other than the PCP, or did not consult with a health care provider at all).  Not a single customer in this group reported being completely dissatisfied with their decision to obtain the DTC test.

Both the original article and the editorial raise questions around the customer expectations of DTC testing, and around the responsibilities and capabilities of healthcare providers in understanding and interpreting genetic test results. The conclusions differ markedly.  Regardless, there is a need to address the disconnect in patient/customer expectations and the responses of healthcare providers as genetic testing becomes more prevalent in precision medicine.

FDA-approved drug label for abacavir updated

In an update to the FDA-approved drug label for abacavir (ZIAGEN), the wording within the Boxed Warning section has changed. It now uses stronger language to support screening for HLA-B*57:01 prior to treatment with abacavir. The following is an excerpt from the boxed warning:

"All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment"

The previous label used the following wording:

"Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction".

The new stronger wording on the drug label has changed its PGx level ranking on PharmGKB from "Genetic testing recommended" to "Genetic testing required". The label now has the same PGx level ranking as the European Medicines Agency (EMA) label. PharmGKB blogged in 2013 about the vague language used within FDA-approved labels that often stops short of requiring action. With this recent change, the wording on this label now has firm and direct guidance regarding testing.

Patients who carry the HLA-B*57:01 allele are at a significantly increased risk of developing a hypersensitivity reaction to abacavir as compared to those without the allele, with odds ratios well into the quadruple digits in some studies. Symptoms include fever, rash, cough, gastrointestinal symptoms, dyspnea and fatigue. A 2008 study (PREDICT-1) found that screening for this allele eliminated immunologically-confirmed hypersensitivity reactions.

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See the new drug label annotation on PharmGKB

Read more about drug labels on PharmGKB

Read the PREDICT-1 study:
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jagel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008 Feb 7;358(6):568-79. PMID 18256392.