January 2009
As the diagnostic and clinical laboratory industries await the United States Food and Drug Administration (FDA)’s final guidance on the regulation of in vitro diagnostic multivariate index assays (IVDMIAs), Genentech (South San Francisco, Calif.) has filed a citizen petition urging the government regulatory agency to hold in vitro diagnostic tests developed by clinical laboratories for in-house testing to the same standards as those tests developed and sold as test kits. FDA currently regulates tests sold in kit form but not laboratory-developed tests (LDTs).
In a copy of the 32-page document obtained by DTTR shortly after its December 5 filing date, Genentech requests that FDA "initiate rulemaking to exercise regulatory jurisdiction over all LDTs and use its current risk-based classification system to determine the level of regulatory oversight and review that is necessary and appropriate for these tests."
The biopharmaceutical company also calls for FDA to simultaneously begin enforcement action against "any clinical laboratory or any other company that is selling an LDT or making claims about its potential indication for use, effectiveness, or value, or that otherwise impacts patient safety without having sufficient analytical and clinical evidence to support such claims."
Genentech’s petition is particularly concerned with LDTs that are used to guide clinical treatment decisions. The company is the maker of Herceptin, the breast cancer therapy that targets tumors that express the HER2 protein and therefore requires that patients be tested for this genetic characteristic before receiving the drug. FDA-approved LDTs for determining HER2 status include the HercepTest (Dako), PathVysion (Abbott Molecular), and HER2 FISH pharmDx kit (Dako).
The petition points out that while the Herceptin label does not provide information on HER2 LDTs that have not been approved by FDA, some clinical laboratories market and perform nonapproved tests for the purpose of selecting patients for Herceptin therapy. The petition points to HER2 tests developed and marketed by CombiMatrix Molecular Diagnostics (HerScan) and Monogram Biosciences (HERmark). Other nonapproved companion diagnostics (for use with drugs other than Herceptin) mentioned in the petition include those offered by Rosetta Genomics, Clinical Data, and Genzyme.
In cases such as these, Genentech urges FDA to "take immediate enforcement action to remove the test from the market until the clinical laboratory conducts the necessary studies to demonstrate, to FDA’s satisfaction, the analytical and clinical validity of the test’s intended use."
With regard to the frequently cited lack of resources that would hamper FDA’s ability to exercise full-scale regulatory control over LDTs, Genentech’s petition points out the staff increases at the FDA Center for Devices and Radiological Health that were made possible by the passage of the Medical Device Amendments of 2002. "Additional 510(k) or PMA submissions would be accompanied by user fees, helping to offset the additional resources FDA would need to devote to this effort," notes Genentech.
The FDA Office of In Vitro Diagnostic Devices (OIVD)’s recent efforts to step up its oversight have focused on IVDMIAs, a subset of LDTs or manufactured test kits that a) combine the values of multiple variables using an interpretation function to yield a single, patient-specific result that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, and b) provide a result whose derivation is nontransparent and cannot be independently derived or verified by the end-user.
In revised draft guidance issued in July 2007, the FDA clarified that LDTs or test kits that meet the definition of an IVDMIA will soon require OIVD premarket submissions. "FDA intends to enforce regulatory requirements for all currently marketed laboratory-developed IVDMIAs that do not receive marketing clearance or approval within 18 months of publication of the final guidance document," noted the draft guidance document.
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