Exploring psychotherapeutic issues and agents in clinical practice
Detection of genetic polymorphisms (i.e., DNA sequence variants) associated with cytochrome P-450 (CYP) drug metabolizing enzyme (DME) genes and pharmacodynamic drug target genes is possible using different technical methods. To the extent that genetic factors play a significant role in the efficacy, tolerability, and safety of different drugs, pharmacogenetic tests may be used to personalize a medication treatment for an individual (Drozda, Müller, & Bishop, 2014). Major DMEs of interest in clinical psychopharmacology are 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. Examples of pharmacodynamic genes relevant to psychiatric drugs are the serotonin reuptake transporter (SERT), serotonin receptor subtypes (e.g., 5HT2A), dopamine receptor subtypes (e.g., DRD2), a gated calcium channel protein (i.e., CACNA1C), the ankyrin-G protein (i.e., ANK3), the catechol-O-methyl transferase enzyme (i.e., COMT), and the methylenetet-rahydrofolate reductase enzyme (i.e., MTHFR). Many pharmacogenetic tests for these genes and others are now available for research and/or clinical use (Rubinstein et al., 2013).
The widely publicized order issued by the U.S. Food and Drug Administration (FDA) in 2013 to the company 23andMe directing them to discontinue marketing its personal genome service (PGS) brought much needed attention to the issue of the validity of genetic testing and how genetic tests should be regulated (Annas & Elias, 2014). In its letter to 23andMe, the FDA indicated that the company had not analytically or clinically validated the PGS for its intended use despite discussions about this issue between the company and the FDA going back to 2009 (FDA, 2014b). The regulation of genetic testing is complicated, but useful information is available from the National Human Genome Research Institute (2014). Physician and nurse prescribers interested in using pharmacogenetic tests should understand how they are currently regulated, as well as the concepts of analytical validity, clinical validity, and clinical utility.
Analytical validity refers to a test’s accuracy and reliability in measuring a parameter of interest. For a pharmacogenetic test, this would be a genotype and its variants (e.g., 2D6 or SERT polymorphisms). The FDA considers nucleic acid–based tests (i.e., genetic tests) to be medical devices and uses certain criteria for evaluating their analytical validity. Medical devices are classified by the FDA into Class I, II, and III, and regulatory control increases from Class I to Class III. Most Class III devices require premarket approval because they are considered high-risk devices that pose a significant risk of illness or injury. The premarket approval process is more involved and includes the submission of analytical and clinical data to support claims made for the device.
The degree of FDA regulation of a genetic test as a medical device is based on its intended use, the risks posed by an inaccurate test result, and how a test is to be marketed. In its discussions with 23andMe, the FDA indicated that their PGS was considered a Class III device that required premarket approval “because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body” (FDA, 2014b).
The FDA mainly regulates tests that are marketed as commercial test kits for processing genetic samples that are packaged together and sold to multiple laboratories. Only 51 genetic tests are actually FDA-approved, and 12 of these tests are for DMEs (FDA, 2014d). The AmpliChip CYP450 Test (Roche Molecular Diagnostics, 2014) was the first commercially available product (approved by the FDA in 2004) that could analyze genetic polymorphisms. The AmpliChip detects polymorphisms associated with the activity of the DMEs 2D6 and 2C19.
Most marketed tests, including genetic tests, are laboratory-developed tests (LDTs), which are tests developed and performed by a single laboratory. Specimen samples are sent only to that laboratory to be tested. Despite considering genetic tests as medical devices, the FDA exercises little direct oversight over LDTs and does not necessarily approve them prior to marketing. Clinical tests in the United States, including LDTs, can only be provided by laboratories that are certified by the Centers for Medicare & Medicaid Services, according to the Clinical Laboratory Improvement Amendments of 1988 (CLIA; FDA, 2014a). CLIA-certified laboratories are required to demonstrate the analytical validity of tests they offer. Unlike drugs, whose safety and effectiveness must be reviewed by the FDA before approval, no requirement exists to systematically evaluate the analytical validity of an LDT before it is offered by a laboratory. The laboratory needs to only demonstrate analytical validity if they are audited, according to CLIA regulations. The concept of analytical validity (i.e., the “accuracy” of a test) is seemingly simple, but genetic testing is complex and can involve different technical methods that are not generally standardized across laboratories. Because CLIA was enacted in 1988 before the age of genomics, no special requirements exist for laboratories performing genetic tests. Although 23andMe did not introduce its PGS product after premarket approval from the FDA, it is assumed that their testing was conducted in a CLIA-certified laboratory.
Clinical Validity and Utility
Clinical validity is the answer to the following question: Is the test result medically meaningful? For a pharmacogenetic test, clinical validity would be a measure of how consistently and accurately the test detects an outcome of interest (e.g., a drug level), clinical response, or adverse effect rather than just how accurately the test measures a DME or pharmacodynamic genotype. Clinical validity of a test is highly dependent on the patient population in which testing is performed. Clinical utility of a test is the likelihood that using the test to guide drug choices or doses will significantly improve patient outcomes. Analytical and clinical validity do not guarantee that a test has clinical utility (Rubinstein et al., 2013). No specific requirement exists for laboratories to establish or verify the clinical validity of genetic tests they offer, and laboratories do not generally have the capability to develop evidence of clinical utility.
Little or no information exists about the clinical validity of many LDTs, especially genetic tests, and even less evidence exists to support their clinical utility. Partly because of this problem, the FDA has developed draft guidelines on the regulation of LDTs, which would include pharmacogenetic test products (FDA, 2014c). Final guidelines will not be issued until after the public comment period on the draft guidelines ends on February 2, 2015.
Where Can Genetic Test Information Be Found?
The National Institutes of Health (NIH) Genetic Testing Registry (GTR) is available online (access http://www.ncbi.nlm.nih.gov/gtr); it maintains a comprehensive database of information about genetic testing offered for drug responses and disorders with a genetic basis (Rubinstein et al., 2013). The database provides details of each test (i.e., purpose, target populations, methods, what it measures, analytical validity, clinical validity, clinical utility, and ordering information) and information on laboratories (i.e., location, contact information, certifications, and licenses) that provide testing. Information in the GTR database is voluntarily submitted by test providers, and the NIH does not independently verify the information.
The product labels for some drugs contain pharmacogenetic information that may be useful for identifying medication responders and nonresponders, thus helping avoid adverse events and optimizing drug dose (Drozda et al., 2014). The labels sometimes describe specific actions to be taken based on this information. The FDA maintains a list of drugs, including more than 25 medications used in psychiatry, whose labels contain pharmacogenetic information (FDA, 2014e).
Do Pharmacogenetic Tests Improve Patient Outcomes?
The Federal Agency for Healthcare Research and Quality reviewed existing studies (i.e., 37 studies as of May 2006) to determine if testing for CYP450 polymorphisms in patients taking anti-depressant drugs leads to improvement in outcomes (Thakur et al., 2007). No prospective studies of CYP450 genotyping and its relationship to clinical outcomes exist; and no correlation between CYP450 polymorphisms and drug levels, efficacy, or tolerability was found. In addition, no data exist regarding whether testing leads to improved depression outcomes; whether testing influences medical, personal, or public health decision making; or whether any harms are associated with testing itself or subsequent management decisions.
Since this review, a new pharmacogenetic test product (i.e., GeneSight Psychotropic) has been marketed. This test, which is registered on the NIH GTR Web site, is based on technology developed at the Mayo Clinic, but it has been commercialized by Assurex Health. It is considered an LDT and has not been approved by the FDA. Blood samples or mouth swabs are sent to a central laboratory for analysis. The test currently detects polymorphisms associated with six DMEs (i.e., 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4) and two pharmacodynamic genes (i.e., 5HT2A and SERT), which are potentially relevant to the use of 22 antidepressant drugs and 16 antipsychotic drugs.
The test results for a particular patient categorize each of these 38 drugs into one of three groups: (a) little or no gene–drug interaction, (b) moderate gene–drug interaction, and (c) severe gene–drug interaction. The use of drugs within each group is characterized as use as directed (group 1; referred to as green bin drugs), use with caution (group 2; referred to as yellow bin drugs), and use with caution and with more frequent monitoring (group 3; referred to as red bin drugs). The green bin drugs require no special dosing considerations for the patient. For yellow and red bin drugs, additional comments about their potential use are provided in the laboratory report. These comments may explain expected changes in drug blood levels (i.e., too high or too low) or expected clinical effects (i.e., reduced efficacy or increased side effects).
An important issue is whether this information leads to better clinical outcomes (i.e., having clinical utility). Two open-label, non-randomized, parallel-group cohort studies have reported that GeneSight Psychotropic was effective for managing patients with depression (Hall-Flavin et al., 2012, 2013). In each study, a pharmacogenetic test report was used to guide the selection and dosing of medication for one patient cohort but not for the other cohort. The guided group in each study had greater depression symptom improvements. However, assignment to each cohort in both studies was not done randomly, and the use of pharmacogenetic testing was not conducted in a double-blind fashion in either study.
A subsequent prospective, double-blind randomized trial comparing the use of GeneSight Psychotropic (26 participants) to unguided treatment as usual (25 participants) found a slightly greater improvement in depression scores with guided treatment, but the difference between groups was not statistically significant (Winner, Carhart, Altar, Allen, & Dechairo, 2013). The overall likelihood of medication switches, augmentations, or dose-adjustments did not differ between groups. However, GeneSight participants taking a red bin medication at baseline were significantly more likely to have this medication changed and had a significantly greater depression improvement than unguided participants taking a red bin medication.
A retrospective health care utilization study of 96 depressed patients who had GeneSight Psychotropic testing found that patients taking a red bin medication had higher rates of health care visits, work absences, and disability claims than patients taking yellow or green bin medications (Winner, Allen, Altar, & Spahic-Mihajlovic, 2013). Whether prospective use of this product (compared to treatment as usual) would demonstrate clinical utility by reducing health care utilization is unknown.
Pharmacogenetic tests are being marketed directly to patients and prescribers, despite a lack of evidence to support their clinical validity or utility. Assurex Health has commercialized two other pharmacogenetic LDTs: GeneSight ADHD (released in May 2012) and GeneSight Analgesic (released in April 2014). Using the three-bin categorization scheme described previously, GeneSight ADHD classifies eight stimulant and nonstimulant drugs used for treating attention-deficit/hyperactivity disorder and GeneSight Analgesic classifies 22 opioid and non-opioid drugs. The current author is unaware of any published literature on the clinical validity or utility associated with the use of these two tests. Neither test is registered on the NIH GTR Web site.
The Genecept Assay (i.e., Genomind) is another pharmcogenetic LDT, marketed since 2011. The test uses a mouth swab sample and detects genetic polymorphisms associated with three DMEs (i.e., 2C19, 2D6, and 3A4) and seven pharmacodynamic genes (i.e., SERT, 5HT2A, DRD2, CACNA1C, ANK3, COMT, and MTHFR). The test results are provided in a clinical interpretations report sent directly to a prescriber, but a psychopharmacologist is available if requested to provide a consult on the test results. This LDT product is not registered on the NIH GTR web-site. The only published study the current author could find is a retrospective study of health claims data suggesting that assay-guided treatment was associated with better medication adherence and a small savings in outpatient costs (Fagerness et al., 2014). Several authors of the study have financial relationships with Genomind. No other published studies exist on the clinical validity or utility of the Genecept Assay, although two open-label (i.e., NCT01507155 and NCT01438242) and two single-blind, randomized trials (i.e., NCT01426516 and NCT01555021) are listed on the ClinicalTrials.gov Web site.
Pharmacogenetic testing is potentially useful in certain clinical situations, but its usefulness will depend on the knowledge base of the physician or nurse prescriber to be able to interpret the findings for a particular patient (Drozda et al., 2014; Salm et al., 2014). The cost of testing varies (e.g., GeneSight Psychotropic is approximately $3,800 [J. Ruffing, personal communication, August 2014]) and is sometimes covered by insurance. However, more work is needed before pharmacogenetic testing becomes a standard-of-care practice. The findings from the GeneSight Psychotropic studies should be considered not only in the context of study design limitations but also in the context of conflicts of interest bias. Several authors of the four Gen-eSight publications have financial relationships with Assurex Health. Independent assessment of the clinical validity and utility of any genetic test would be ideal. Assurex Health is funding a multicenter, randomized, double-blind trial that is currently underway (i.e., NCT02109939 on the ClinicalTrials.gov Web site). A single-site trial funded by the Mayo Clinic is also listed on the ClinicalTrials.gov Web site (i.e., NCT02189057). The forthcoming FDA guidelines on LDTs will likely encourage, if not require, evidence of clinical validity and/or utility of pharmacogenetic tests before they are approved for marketing.
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