 |
 |
|
Rapid Responses to:
|
|
Electronic letters published:
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif){kind=icon}
Clinical laboratory needs for pharmacogenomic testing
|
|
|||
|
Alan H.B. Wu, Ph.D. University of California, San Francisco, Joseph Guglielmo, Tim Hamill, and Christine Haller
Send rapid response to journal:
wualan{at}labmed2.ucsf.edu Alan H.B. Wu, et al.
|
In their review, Roden et al. present an excellent clinical “primer” for defining pharmacogenomics, including current research challenges and those drugs that might benefit from clinical pharmacogenomic testing. While the review clarifies many of these issues, we note relatively little discussion regarding the real world application of pharmacogenomics in the clinical setting. The ordering of any clinical laboratory test should be accompanied by the question, “How will this test impact upon my decision, including that associated with selection of drug and dose?” While of academic interest to know whether a patient is a slow, intermediate, or rapid drug metabolizer, this information may not be relevant in the clinic setting. As an example, a colon cancer patient with a UGT1A1 *7/*7 genotype may be at risk for irinotecan-induced neutropenia (see Table 2 of review). What should be the oncologist’s response to this data? Should the dose be decreased in response to this information? If a decreased dose is recommended, how much lower? Should this genotype result in a selection of different chemotherapeutic regimen? Outcome studies are critically needed to validate the utility of these genomic tests. The finding of an association between drug response and genetic variants represents the first step toward offering a clinical laboratory genomic testing service. One potential use of pharmacogenomic data is toward the establishment of algorithms which might guide decisions regarding drug and/or dose. Development of algorithms requires integration of genotypic variables and other important patient demographics. As an example, algorithms have been developed based on age, gender, ethnicity, body size, and CPY 2C9 and VKORC1 genotype to predict the optimal initial warfarin dose to achieve optimum anticoagulation as measured by the prothrombin time and calculation of the International Normalized Ratio (2). These algorithms have not yet been approved by the Food and Drug Administration (FDA), and must be validated in the clinical setting. Draft, non-binding guidance documents issued by the FDA regarding multi-marker analysis have been released and may ultimately assist manufacturers toward the creation of interpretative algorithms (3). Discovery of novel pharmacogenomic markers and targets involves the use of gene sequencing and large SNP (single nucleotide polymorphism) arrays. These are expensive, require specialized research equipment and operator training, and are therefore difficult to implement in routine clinical laboratory practice. Fortunately, commercialization of equipment designed for clinical laboratory practice may result in lower-cost reagents dedicated to specific pharmacogenomic applications. When these platforms and tests are approved by the FDA, practical implementation of pharmacogenomics in the clinical setting can commence. Roden et al. (1) question how can pharmacogenetic information be incorporated into product labels that inform clinicians and patients. While such information does not currently exist in product labels for approved drugs today, the FDA Center for Drug Evaluation and Research and the Clinical Pharmacology Subcommittee of the Advisory Committee on Pharmaceutical Science has taken a different approach. The FDA will require the relabeling of irinotecan, warfarin, and tamoxifen, stating that genotyping is recommended prior to initial dosing. Unfortunately, guidance from the FDA regarding the interpretation and use in clinical practice is not yet available. Nevertheless, these mandates have become a major impetus for personalized medicine for manufacturers of pharmacogenomic tests and clinical laboratories. We anticipate that these mandates will also motivate physicians to order these tests avoid adverse medication events and/or for medical legal reasons. Practical regulatory issues remain for those clinical laboratories considering such services. These include validation studies (e.g., versus bidirectional sequencing), establishment of a quality control program, proficiency testing, etc., all elements required by CLIA. The College of American Pathologists has instituted a proficiency testing program to begin in 2007 which will be very helpful in assisting laboratories wishing to conduct pharmacogenomic testing. While the cost for performing the test likely will decline due to increased competition among vendors, perhaps a more important issue is reimbursement. At the present, there are payment codes for individual steps involved with pharmacogenomic testing, DNA extraction, amplification, and individual SNP detection; however, these reimbursements costs are relatively modest. Importantly, no CPT codes currently exist that are specific to pharmacogenomic testing. Unless the cost of the testing decreases or the reimbursement for testing increases, widespread implementation of laboratory-based personalized medicine will be limited. Increased research efforts linking pharmacogenomic testing with patient outcomes, as well as changes in regulatory agencies and reimbursement policy are urgently needed to allow for increased utilization of pharmacogenomic testing in the clinical setting. 1. Roden DM, Altman RB, Benowitz NL, et al. For the Pharmacogenetics Research Network. Pharmacogenomics: challenges and opportunities. Ann Intern Med 2006;145:749-757. 2. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 gnetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329-22. 3. U.S. Food and Drug Administration. In vitro diagnostic multivariate index assays. http://www.fda.gov/cdrh/oivd/guidance/1610.pdf Conflict of Interest:None declared |
|||
