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This article was originally published in The Gray Sheet

Executive Summary

TB AMPLIFICATION IVD STUDIES SHOULD INCLUDE AT LEAST 150 POSITIVE PATIENTS and at least 300 total positive specimens, FDA says in a July 6 guidance document. Studies should be conducted "at a minimum of three" sites, and each site should obtain a minimum of 20 patients who test positive for the mycobacterium, the guidance adds. FDA says the guidance "represents the current major concerns and suggestions regarding in vitro diagnostic devices employing nucleic acid amplification and hybridization, or other methodologies, for direct detection of Mycobacterium tuberculosis and/or other Mycobacterium spp. in clinical specimens." FDA points out that the nucleic acid amplification/hybridization procedures under development "are specific and potentially more sensitive for direct detection in clinical specimens" than other currently marketed methods. Amplification techniques include polymerase chain reaction (PCR), ligase chain reaction (LCR) and cycling probe reaction. Other methods of identification of Mycobacterium spp. include nucleic acid hybridization without amplification, microscopic screening, conventional culture, and the Tuberculin skin test. The "reemergence of tuberculosis as a major health problem in the United States," FDA notes, has increased the need for "rapid, safe and effective diagnostic implement necessary infection control procedures and provide appropriate patient care." In outlining clinical study design for the IVDs, FDA says that "if more than one specimen type (i.e. sources other than digested/decontaminated and concentrated respiratory specimens) is indicated for testing with the new device," additional data should be provided that includes at least 20 total positive patients from each additional source. The guidance also suggests that manufacturers include results of testing at least 100 sputum specimens obtained from patients with other pulmonary diseases. Manufacturers should provide final clinical diagnosis for this group of patients and include results of skin and lab tests "as a data subset." Manufacturers should also demonstrate that the "performance of the device is substantially equivalent to culture and/or fluorochrome stained comparison to a well-controlled culture method." These comparison studies should be conducted at sites representing "diverse geographic regions and diverse patient populations" including "HIV-positive, IV drug users, and low socioeconomic status groups." The agency says that manufacturers should discuss the "merits and limitations" of test methodologies used in their premarket applications. Among FDA's concerns with the limitations of nucleic acid amplification techniques are "adequate sample preparation, presence of sample-related or other inhibitors, risks of sample contamination, adequate quality control, relationship of a positive/negative result to a disease presence/absence," and the lab's ability to "reproducibly detect a consistent level of organism load." In addition to the IVD guidance specific to Mycobacterium spp., the device center recently issued a more general guidance on nucleic acid amplification-based IVDs. The agency notes that nucleic acid amplification methods "offer the potential for timely identification of many causative agents of infectious disease" which otherwise would require "lengthy and/or difficult isolation and identification procedures." However, the guidance cautions that as amplification is a "new and evolving technology," manufacturers must address issues specific to molecular diagnostic methods. The guidance does not make specific recommendations regarding the size of clinical studies for the IVDs using amplification/hybridization techniques. It does state, however, that studies may be necessary to show the relationship of the results obtained to a patient's "clinical condition." These conditions may include the patient's "pre- disease state, disease presence, carrier state, asymptomatic or symptomatic infection." In addition, clinical studies should compare the amplification/hybridization procedure with the "gold standard" of nucleic acid detection, the culture test method. FDA notes, however, that "when the gold standard [culture technique] is flawed, or there is none, clinical data from well-controlled trials will be required to support performance characteristics." The guidance also says that manufacturers should "indicate the steps taken to assure that the labs performing tests for the studies use optimal procedures" for the gold standard. The guidance further instructs manufacturers to include in their submissions the specific intended use of the device, detailed substantiation for the device methodology, and "specific performance characteristics," which should include the parameters of the firm's Phase I and II analytical laboratory studies. The guidance also outlines labeling considerations such as the warning statements and quality control instructions.

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