The National Association for Clinical Biochemistry — the academy of the American Association for Clinical Chemistry — in two weeks will present a set of draft guidelines that will likely impact how reference labs perform pharmacogenetic tests, and thus influence the performance characteristics and types of tests that laboratories require from molecular diagnostics companies.
The NACB's Guidelines and Recommendations for Laboratory Analysis and Application of Pharmacogenetics to Clinical Practice, also known as laboratory medicine practice guidelines for pharmacogenetics — or LMPGs for pharmacogenetics — have no regulatory power. However, they can become incorporated into laboratory accreditation requirements and have the potential to affect how laboratory technicians at reference labs and academic centers use molecular diagnostics. They may also affect demand for specific tests by favoring different approaches.
When they are posted by the NACB, LMPGs can also become a part of checklists used by the College of American Pathologists for inspection and accreditation of laboratories. In general, an LMPG "sets the standard that labs should strive for," according to Deborah Payne, vice chair of the NACB guidelines committee, and an associate professor in the University of Texas Southwestern Medical Center department of pathology.
The new document is a result of recent moves by the FDA to accelerate the adoption of pharmacogenomics, and the agency provides the NACB ideas about how to proceed, Payne said. "We're trying to embrace the regulatory component early on, rather than spend a tremendous amount of effort generating a guideline that the FDA just says, 'No, that won't do.'"
Broadly, the guidelines are intended to: define appropriate clinical pharmacogenomic testing methods; standardize and assure the quality of pharmacogenomic testing; guide lab technicians' selection of appropriate pharmacogenomic testing profiles; recommend how lab technicians might best report results for clear interpretation by clinicians; recommend standards by which to judge the clinical utility and efficacy of tests; and inform lab technicians and clinicians about regulatory and other factors impacting effective clinical use.
Previous LMPGs include guidelines for such procedures as therapeutic drug monitoring, thyroid testing, and diabetes testing.
In general, the guidelines should serve to clarify how pharmacogenomic testing should be conducted, making it easier for labs, pharmacists, and clinicians to follow the approach, Payne told Pharmacogenomics Reporter this week.
The guidelines were spearheaded by Roland Valdes, a professor of pathology and laboratory medicine, biochemistry, and molecular biology at the University of Louisville, Ky.
All of LMPG's pharmacogenomic goals — listed in the draft document's opening section — appear relevant to molecular diagnostics firms, but two seem particularly important. First, the authors define specific requirements for acceptable and ideal pharmacogenomic testing, including "turn-around time requirements for [pharmacogenomic] test results, number of alleles needed on test reports, and advisability or need for interpretative reporting."
"We're trying to embrace the regulatory component early on, rather than spend a tremendous amount of effort generating a guideline that the FDA just says, 'No, that won't do.'"
Second, the document aims to provide "in vitro diagnostic companies guidance on clinical assays and their performance characteristics in pharmacogenetics-testing," including "Which tests are needed, with what analysis times, etc.?"
Regarding the use of pharmacogenomic testing in the clinic, the LMPG draft contains "whatever information we have available, and all of the recommendations are basically ranked depending on whether there have been any studies in the literature based on which these guidelines are presented," said Jortani.
But the NACB is hoping to improve the guidelines at the upcoming AACC meeting. There, members of the NACB guidelines committee and other LMPG authors will present the document, and some specific recommendations will be presented by speakers. Industry will be able to comment on the guidelines until Sept. 1. The LMPG will then be amended with the aid of those suggestions, and the final guidelines will be published on the NACB, probably by early 2007, according to Payne.
"The FDA will probably also provide some feedback and some comments on these documents," Payne said.
Felix Frueh, associate director of the FDA Center for Drug Evaluation and Research and head of the agency's Interdisciplinary Pharmacogenomics Research Group, is a member of the NACB guidelines committee, and will serve as a liaison with the agency.
Some LMPG Elements for Molecular Diagnostics
Among the LMPG's recommendations and information for laboratory technicians, pharmacists, and clinicians are several elements that could be used by players in the molecular diagnostics industry developing tests used by these healthcare workers.
For example, the LMPG suggests that diagnostic methods should be developed to analyze genomic DNA from blood or buccal swabs "whenever possible." However, due to service requirements, technical capabilities, and healthcare provider safety issues, the demand for non-blood based diagnostics is growing, according to the LMPG.
The draft also recommends that a pharmacogenomic test result should include a description of "all physical characteristics of the genetic locus that is being determined by the assay." Not all assays can test for the same factors at a given genetic locus, and information about each type of result is constantly being updated, so reporting should be as specific as possible, according to the LMPG draft. Information, such as the identity of a particular genetic polymorphism, should not be abbreviated. So, a polymorphism such as CYP2C9*1 should be explained in its entirety — for example, as CYP2C9 430C/T.
The LMPG also said that turn-around times should be short enough to avoid risk to the patient. However, there are no studies available to provide an idea of how long that might take for each relevant drug. The authors recommend that pharmacogenomic testing used for screening patients who might suffer adverse drug reactions should generally be available before or at the same time that therapy begins.
Alternatively, results should be available before enough time passes for drug concentrations in any patient can surpass the minimal concentration found in a typical extensive metabolizer. In patients prescribed warfarin, for example, the LMPG recommends that results should be available before the fourth dose to avoid overdosing patients with slow-metabolizing variants of CYP2C9.
The Response So Far
So far, the NACB has received comments from pharmacists and laboratory technicians, but not from clinicians, said Payne. No comments have been critical of the guidelines, she said. Due to concerns about commenter privacy, Payne offered only one specific example of the feedback received so far: the Centers for Disease Control and Prevention told the NACB committee that it had developed "control [experiment] material" for pharmacogenomic testing.
Adding information to the guidelines concerning such resources is "very useful for people to know where they can go to get cell lines for controls and sample exchanges and proficiency," she said.
Currently, most of the laboratory technicians to whom the guidelines apply will likely hail from reference laboratories and academic centers, at least for the next five years, said Payne. Community hospital labs and other small testing facilities probably will not adopt molecular diagnostics and pharmacogenomics in that time, she said.
The lack of standard approaches to molecular testing has led to incomparable methods in the past. "One example would be … years ago, when we had introduced hepatitis C viral load [testing] and every different instrument platform gave a different value on copies per [milliliter], because the different methodology would generate a different kind of result. So a patient getting a [test] in one lab may have one result, and then if they moved cross country and a different lab [measured the same sample], it would generate a different result," said Payne. That situation did not necessarily result from the lack of practice guidelines, she added.