PharmGKB opinion piece on pharmacogenomic RCTs published in Clinical Pharmacology and Therapeutics

Is supporting evidence from a randomized controlled trial (RCT) always necessary when implementing pharmacogenomics in the clinic? In an opinion piece authored by members of the PharmGKB team and published in Clinical Pharmacology and Therapeutics, we argue that an overreliance on evidence from RCTs is not beneficial to pharmacogenomic implementation.

An insistence that RCT evidence is made available prior to implementation assumes that RCTs will eventually be carried out for every actionable gene-drug pair. This is an unrealistic assumption, especially in the case of generic drugs. We also question why other factors which can influence drug clearance in a patient, such as hepatic or renal impairment, are easily incorporated into clinical care without RCT evidence while pharmacogenomics is held, seemingly arbitrarily, to a different standard.

There are also significant issues with pharmacogenomic RCTs, in terms of cohort diversity, adequate allele representation and statistical power; all of which can have serious, even fatal, consequences for patients. Furthermore, a reliance on evidence from RCTs overlooks the substantial evidence base from other studies, much of which is curated in PharmGKB. Evidence from non-RCT studies already informs clinical guidelines from international consortia, including CPIC and the DPWG.

The paper is available online and will be included in an upcoming special issue of Clinical Pharmacology and Therapeutics. Dr. Andrea Gaedigk of Children’s Mercy Kansas City, and leader of the PharmVar consortium, will be the guest editor of this issue.

CYP2C19 testing may assist with prescribing sertraline and escitalopram

Mary Relling (St. Jude Children's Research Hospital) and I (Teri Klein) as Co-Principal Investigators of the Clinical Pharmacogenetics Implementation Consortium (CPIC) have been discussing the letter that the FDA recently sent to a genomics laboratory expressing concern that “providers may make inappropriate treatment decisions based” on pharmacogenetic testing offered by that lab. The FDA specifically highlighted that “the relationship between CYP2C19 genotype and drug response to escitalopram and sertraline is not established.”

While it is true that some pharmacogenomic testing laboratories may be including genetic variants in their tests, along with prescribing advice, that do not have adequate evidence for clinical utility, testing for variants in this particular gene does have utility for prescribing decisions for escitalopram and sertraline. In fact, CYP2C19 phenotypes are specifically included as actionable for these 2 drugs in CPIC’s Guideline for SSRIs.

Many CPIC guidelines encompass gene/drug pairs for which the mechanism of gene/drug association is pharmacokinetic in nature; therefore, gene-based dosing in these cases is analogous to medication dose adjustments that are routinely made on the basis of renal or hepatic function or due to drug-drug interactions, most of which are supported by mechanistic evidence rather than clinical trial data. The drug labels for both sertraline and escitalopram include recommendations for reduced dosages in hepatic impairment, based on similar mechanistic pharmacokinetic considerations as apply to CYP2C19 status, and presumably without randomized clinical trial-level “evidence.” Using genotype to evaluate CYP2C19 metabolism is certainly more relevant to hepatic metabolism of these agents than is using nonspecific clinical markers of “hepatic impairment.”

CPIC assigns an evidence level of A, B, C, or D to gene/drug pairs, with CPIC levels A and B deemed to have actionable prescribing based on genetics; importantly, gene/drug pairs with a CPIC level of C or D are not considered to have adequate evidence to support using a genetic test for prescribing, and this can serve as a useful starting point in deciding whether clinical genetic testing of that gene for that drug is likely to be justified.

In FDA’s warning letter, it is stated that “providers may make inappropriate treatment decisions based on these test results, including inappropriate dosing adjustments, prescribing an ineffective therapy, and not prescribing a therapy that could benefit the patient.” The same criticism could apply to any test result, even for the liver function tests that are already included in the FDA approved labels for these drugs. We agree that prescribers should be warned about the impact of hepatic function on drug effects; we advocate that pharmacokinetically based genetic tests may also be worthy of consideration by prescribers. Such a useful pharmacokinetically based genetic test includes use of CYP2C19 testing to assist with prescribing sertraline and escitalopram.