What do ‘clinical validity’ and ‘clinical utility’ mean?
These are higher evidence thresholds than is needed for analytic validity, although the latter is a necessary first step on the path to achieving these higher thresholds.
Clinical validity is the ability of a test to detect:
- a clinically meaningful measure, such as clinical response
- an adverse effect
- a biologically meaningful measure (eg, a drug level or a change in the electrocardiographic pattern).
Above the threshold of clinical validity is clinical utility, which is proof that the test can reliably be used to guide clinical management and thus meaningfully improve outcomes, such as guiding drug or dosage selection.
Is the use of PG testing recommended? If so, in what instances?
Specific types of PG testing is recommended by the FDA recommended. The FDA has been incorporating PG information into the labels of specific medications for several years; the agency has a Web site (www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm) that continuously updates this information. The involved drugs are in all therapeutic classes—from oncology to psychiatry.
More than 30 psychotropic drugs have PG information in their label; some of those drugs’ labels contain specific recommendations, such as obtaining PG information before selecting or starting a drug in a specific patient. An example is carbamazepine, for which the recommendation is to obtain HLA testing before starting the drug in patients of Han Chinese ancestry, because members of this large ethnic group are at greater risk of serious dermatologic adverse effects, including Stevens-Johnson syndrome.
In other instances, the recommendation is to do the testing before increasing beyond a specific dose. Examples of psychiatric drugs whose labels contain such PG information include pimozide and iloperidone as well as citalopram. In the FDA-approved label, guidance is provided that these drugs can be started without testing if prescribed at a reduced recommended starting dosage range, rather than the full starting dosage range. The guidance on these drugs further recommends testing for genetic CYP2D6 poor metabolizer (PM) status before dosing above that initial recommended, limited, starting dosage range.
The rationale for this guidance is to reduce the risk that (1) patients in question will achieve an excessively high plasma drug level that can cause significant prolongation of intracardiac conduction (eg, QTc prolongation) and thus (2) develop the potentially fatal arrhythmia torsades de pointes. Guidance is based on thorough QTc studies that were performed on each drug,7,8 which makes them examples of instances in which the test has clinical validity and utility as well as analytical validity.
To find PG labeling in the package insert for these drugs, visit: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
What about data for other tests that are marketed and promoted by developers?
Sometimes, there are—literally—no data on available tests beyond the analytical validity of the test; other times, the amount and quality of clinical data are quite variable, ranging from results of ≥1 small retrospective studies without controls to results of prospective, randomized, controlled studies. Even among the latter, the developer may conduct and analyze their studies without oversight by an independent agency, such as the FDA.
This situation (1) raises concern that study results are not independent of the developer’s business interests and, as one might expect, (2) leads to controversy about whether the data are compelling—or not.9-12
What is a critical difference between PG test results and results of most laboratory tests?
PG tests are, as noted, trait rather than state characteristics. That means that the results do not change except for a phenomenon known as phenocoversion, discussed below. (Of course, advances in gene therapy might make it possible someday to change a person’s genetic makeup and for mitochondrial genes that is already possible.)
For this reason, PG test results should not get buried in the medical record, as might happen with, say, a patient’s serum potassium level at a given point in time. Instead, PG test results need to be carried forward continuously. Results also should be given to the patient as part of his (her) personal health record and to all other health care providers that the patient is seeing or will see in the future. Each health care provider who obtains PG test results should consider sending them to all current clinicians providing care for the patient at the same time as they are.
Is your functional status at a given moment the same as your genetic status?
No. There is a phenomenon known as phenoconversion in which a person’s current functional status may be different from what would be expected based on their genetic status.
CYP2D6 functional status is susceptible to phenoconversion as follows: Administering fluoxetine and paroxetine, for example, at 20 or 40 mg/d converts 66% and 95%, respectively, of patients who are CYP2D6 extensive (ie, normal) metabolizers into phenocopies of people who, genetically, lack the ability to metabolize drugs via CYP2D6 (ie, genotypic CYP2D6 PM). Based on a recent study of 900 participants in routine clinical care who were taking an antidepressant, 4% of the general U.S. population are genetically CYP2D6 PM; an additional 24% are phenotypically CYP2D6 PM because of concomitant administration of a CYP2D6 substantial inhibitor, such as bupropion, fluoxetine, paroxetine, or terbenafine.13