There are 5 likely culprits:
- A lack of clinically useful pharmacogenetic tests.
- A lack of test standardization and availability.
- A lack of coverage by third-party payers.
- A low level of physician knowledge about genetic testing.
- A lack of evidence of improved outcomes.
How useful are pharmacogenetic tests?
For a laboratory test to be clinically useful, it should provide information that will influence a therapeutic decision. Decisions that could be influenced by this information include the dose of a particular drug and the potential use of an alternative because of a contraindication or likelihood of a poor outcome based on a particular genetic polymorphism.
The use of pharmacogenetic laboratory information can place a patient into one of several groups:
- ultra-rapid metabolizers, who need a larger dose of medication
- normal metabolizers, often called extensive metabolizers, who do not need dose modifications
- poor metabolizers, who need lower doses.9
Most medications have a wide therapeutic margin of effectiveness and safety. This means that the medication works within a wide range of serum drug levels and is safe at these different levels, making refinement in dosing based on genetic information unnecessary. In medications with narrower therapeutic windows for effectiveness or adverse reactions, there are frequently alternative means of drug level monitoring.
In many instances, the genetic test predictability of a patient’s actual metabolic responses—and resulting drug levels—is poor, leading to the need to monitor drug levels anyway.14-16 This occurs because there is often a great deal of overlap in the response to a medication dose among the different metabolism classifications.9,14,16-18 All of these realities have limited the clinical usefulness of pharmacogenetics up to this point.
Test standardization: Poised to improve?
Genotyping, the determination of the actual genetic makeup of the patient is not always predictive of an individual patient’s metabolic response. In other words, genotype does not always equate to a phenotype. Further complicating matters is the fact that many of the pharmacogenetic studies have been performed at research laboratories and have used tests that are not standardized, or widely available.19-21
The recent commercial availability of pharmacogenetic tests by well-established and reputable laboratories will probably improve both standardization and availability.
An example is the AmpliChip CYP450 test by Roche Diagnostics.22 This microassay-based test identifies 29 CYP-2D6 polymorphisms and 2 CYP-2C19 polymorphisms. These genes affect the metabolism of 25% of currently prescribed drugs. Using this test, patients can be classified as poor, intermediate, extensive, or ultra rapid metabolizers of CYP-2D6 affected drugs, including antidepressants, antiarrhythmics, and antipsychotics. They can also be classified as poor or extensive metabolizers of CYP-2C19 affected drugs, including phenytoin and proton pump inhibitors.
How costly?
The cost of genetic testing will also affect availability. Tests will be widely available only if covered by third-party payers. The AmpliChip test costs between $300 and $500. Clearly, then, both cost and insurance coverage are issues that impede the adoption of pharmacogenetic testing, though there is little written about this in the medical literature.19,23
AAFP explores ways to teach genomics
Physicians who are currently in practice received little or no training in the clinical use of pharmacogenetics or other genetic tests, such as genetic testing for the prediction of cancer risk.24,25 The main resources of pharmacological information for practicing physicians do not contain much, if any, useful genomic information. A recent continuing education monograph for family physicians on clinical genetics mentioned pharmacogenetics only as a promising future technology.26
For its part, the American Academy of Family Physicians has formed a genomics work group and is exploring how to educate family physicians on clinically useful genomic topics.
Evidence-based outcomes are needed
To date there has not been a head-to-head comparison of the outcomes of using clinical pharmacogenetics with those obtained from standard drug level monitoring practices. The CDC has formed a committee modeled after the USPSTF, the Evaluations of Genomics Applications in Practice and Prevention (EGAPP), which will evaluate the effectiveness of genomic clinical tests and make recommendations to physicians on their use.27 The group’s first report, on the use of CYP450 testing in depression, concluded that there is a paucity of good quality data that addresses whether testing for CYP450 polymorphisms in adults entering SSRI treatment leads to improved outcomes.28
In addition, SACGHS, the Department of Health and Human Services’ Committee, recommends in its draft report that HHS “provide resources to identify and address evidentiary gaps in the analytic validity, clinical validity, clinical utility, and cost effectiveness of pharmacogenomics.”3