Implementation Of Laboratory Developed Tests

3.1. TEST SELECTION Similar to any other clinical test, the primary goal of molecular tests should be to provide reliable and timely results necessary for patient care. The introduction of new molecular tests has the primary goal of improving patient care. Clinical needs, as well as advances in basic and translational research, often prompt the development of new molecular tests. Several key elements are highly important during test selection. It is necessary to realize that any new test should aid in cost-effective patient care and provide a less expensive or more effective diagnosis and/or patient management. It is also important not only to make test selection based solely in the cost of tests performance but also to determine how the new test would impact the overall care and management of the patient. There are several circumstances in which molecular tests seem to increase the cost of managing patients; however, the introduction of a new test can make this management more effective. One example of this situation was the introduction of HIV-1 viral load to clinical practice for monitoring disease progression and effectiveness of drug therapy in individuals infected with HIV-1. Current standard of practice for patients infected with HIV-1 is to treat these patients with a combination or cocktail of different drugs, including protease inhibitors, nucleoside inhibitors, and non-nucleoside reverse transcriptase inhibitors, all of which are very effective in reducing morbidity and mortality in a large number of HIV-1-infected patients. Even though a new test was added to the battery of tests used for these patients increasing the cost of their management, it has provided a tool that rapidly and accurately determines the effectiveness of an expensive drug treatment. Furthermore, mutations in the HIV-1 genome associated with resistance to antiretroviral therapy have been shown to be a major cause of treatment failure in patients infected with HIV-1. Despite the increased number of antiretroviral agents currently available, virologic failure remains a significant problem. Drug-resistance testing is designed to identify gene mutations that suggest reduced drug susceptibility. These resistance mutations can be assessed by a genotyping test that probes for specific mutations within the HIV-1 genome. The widespread use of these drugs and virologic benefits of resistance testing have prompted the development of formal guidelines by expert panels for clinical use of this test. HIV-1-resistance testing has resulted in better clinical outcomes and lower incidence of virologic failures, which are associated with lower cost of treatment. These examples show the impact of the introduction of new tests on patient's management; however, there are many examples of the cost-effectiveness of replacing existing laboratory tests. In addition, it is important to realize that for a molecular test to be effective, it should provide increased sensitivity, increased specificity, or reduced turnaround time that directly impacts on the patient's management.

The identification of tests that would be useful at each medical center is primarily the responsibility of the director of the molecular diagnostic laboratory. Sometimes, this could be aided by the performance of a review of the send-out list of tests for the medical center. Sometimes, key players, clinicians and pathologists, could be a valuable source for identifying the needs for each specific medical center. It is important for the laboratory directors to clearly identify an area where there is a perceived need for improving the tools available for patient diagnosis and management. It is important that during the process of test selection, realistic matching of the technical capabilities within the laboratory with the real-world clinical needs in terms of test volume, required turnaround time, and associated costs of performing the assay are matched. It is also important to estimate the cost of development and test volume, this last parameter is critical to be considered, not only to assure recovery of test development but also to maintain proficiency by the testing personnel, avoiding excessive reagent outdates. The establishment of a period of clinical trial for evaluation of the clinical utility of a particular test for a particular clinical condition is an important market approach. If carefully designed, this approach allows the laboratory to directly work with the end user of the test and provide an avenue for these individuals to understand the clinical utility and its limitations and eventually more effective utilization of the particular test. Laboratory developed assays are costly to develop and validate, and for that reason, it is recommended to be sure that FDA review for a similar assay is not pending from a commercial manufacturer for the same analyte.

Once a particular analyte and clinical condition have been identified, it is important to give some consideration to the different methodologies that might be available for evaluating the particular analyte or disorder. Furthermore, careful consideration of the advantages and disadvantages of the different methodologies and the particular condition that is under evaluation should be performed. As an example, we can mention the detection of t(9;22) in patients with chronic myelogenous leukemia (CML). Conventional cytogenetic analysis is the recommended test for detecting t(9;22) in newly diagnosed patients; however, these tests require viable cells or at least 10% of blasts in peripheral blood to obtain reliable results. Cytogenetic analysis carries a sensitivity of 5%. Fluorescent in situ hybridization (FISH) allows the detection of the translocation in metaphase or interphase cells and can be applied directly to blood leukocytes or other non-dividing cells with a

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