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by: Pharmacogenetic diagnostic tests that are laboratory-developed tests (LDTs) are currently regulated by the Center for Medicare and Medicaid Services by authority of the Clinical Laboratory Improvement Amendments of 1988. LDTs are not marketed outside the single laboratory that developed the test service and are not required to submit data for FDA review. The FDA has generally exercised enforcement discretion over standard LDTs that use primarily analyte specific reagents, general purpose reagents, laboratory equipment, instrumentation and controls and fall under the regulation of CMS CLIA requirements. However, when laboratory developed test systems are sold by a manufacturer or developed by a laboratory for interstate commerce as in vitro diagnostic devices (IVDs), the tests are regulated by the Office of in Vitro Diagnostic Device Evaluation and Safety (OIVD) of the Center for Devices and Radiological Health. The FDA classifies IVDs on the basis of risk, and clears them through a premarket notification (510(k)) for certain tests classified as low or moderate risk for medical-decision making (Class I or II) or approves them through a premarket approval (PMA) process for tests classified as high risk (Class III) before marketing. A more detailed review on the FDA classification, regulation and processes for clearance or approval of IVDs is found in special article published by Mansfield, O'Leary and Gutman in the Journal of Molecular Diagnostics, vol. 7, No. 1, 2005. The FDA has issued three key guidances for pharmacogenetic IVDs submissions that require FDA clearance or approval. A brief description of the FDA recommendations and requirements for Pharmacogenetic IVDs follows. At the time of the issuance of this guidance, the FDA announced the classification of a DME genotyping system as a Class II device that requires submission of a 510(k) premarket notification that addresses the issues covered in this special control guidance. The FDA defines a drug metabolizing enzyme (DME) genotyping system as "a device intended for use in testing DNA extracted from clinical samples to identify the presence or absence of human genotypic markers encoding a drug metabolizing enzyme. This device is used as an aid in determining treatment choice and individualizing treatment dose for therapeutics that are metabolized primarily by the specific enzyme about which the system provides genotypic information" (21 CFR 862.3360 (a)). The
FDA has identified the two major risks to health associated with
the use of DME genotyping assays: 1) failure to correctly identify
genotype encoding a DME and 2) failure to properly interpret genotyping
results. In both situations, a patient might be prescribed an incorrect
drug or drug dose with concomitant increased risk of adverse reactions
due to increased or decreased drug metabolism and incorrect patient
management decisions. The FDA recommends that physicians use professional
judgment when interpreting results from this type of test. The guidance
further recommends measures to mitigate these identified risks. This Class II Special Controls document is limited to the drug metabolizing enzyme genotyping system as described in 21 CFR 862.3360. DME genotyping systems that are multiplex tests may be run on instrumentation for clinical multiplex test systems. Such systems are regulated under 21 CFR862.2570 and guidance for "Instrumentation for Clinical Multiplex Test Systems". If a device includes a DME genotyping assay with instrumentation for clinical multiplex test systems for that assay, both devices may be submitted under one 510k. The
FDA recommends that a manufacturer of the device obtain a substantial
equivalence determination from the FDA prior to marketing the device
(interstate commerce). An Abbreviated 510k submission follows the
guidance recommendations and includes the required elements in 21
CFR 807.87 of proposed labeling, intended use and directions for
use and a summary report including descriptions of the device, risk
analysis and performance methods. A copy of this guidance is available HERE. This FDA guidance for Industry and Staff is intended to facilitate the development and review of pharmacogenomics and genetic diagnostic devices. It provides recommendations for the preparation and review of premarket notification (510(k)) submissions and premarket approval (PMA) applications whether testing for single markers or for multiple markers simultaneously (multiplex tests). The recommendations apply to pharmacogenetic (e.g. drug-metabolizing enzyme allele tests, single nucleotide polymorphism (SNP) analysis and other types of genetic tests. Most pharmacogenetic and genetic device submissions will be traditional 510 (k) s or de novo classifications; however some will require a PMA. FDA recommends consultation with the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) to determine the appropriate type of submission. While the FDA views pharmacogenetic polymorphisms and genetic mutations testing to be the same type of results, they consider pharmacogenetic tests for clinical use to be intended to provide information that may aid in selection of certain therapeutics, and possibly dosage selection for patients needing therapy. On the other hand, genetic tests are used for patients suspected of having or at risk for developing a particular disease or condition. The guidance discusses the appropriate information to be addressed in preparation of a submission. The areas include: intended use, device design, analytical studies, software and instrumentation, comparison studies using clinical specimens, clinical evaluation studies comparing device performance to accepted diagnostic procedures, effectiveness of the device. For each of these areas, the FDA gives detailed advice in the level of information expected. The guidance further emphasizes that for 510(k)s as well as PMAs, the submission must include labeling in sufficient detail to satisfy the requirements of 21 CFR 807.87 (e). FDA recommendations are specific to address the requirements for: directions for use, quality control, interpretations and precautions, stability, performance. As an appendix, there are general considerations for planning and evaluating clinical studies. A copy of this guidance is available HERE. This draft guidance identifies IVDMIAs as a discrete category of device, and clarifies that as a laboratory-developed test (LDT), IVDMIAs must meet pre- and post market device requirements under the Food, Drug, and Cosmetic Act and FDA regulations, including premarket review requirements in the case of most class II and class III devices. General information on device regulation is provided in an appendix to this guidance. The FDA defines an IVDMIA as a device that 1) combines the values of multiple variables using an interpretation function to yield a single, patient-specific result (e.g. a "classification," "score," "index,") that is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease; and 2) provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user. This guidance describes an IVDMIA as a subset of LDTs which are tests that are developed by a single clinical laboratory for use only in that laboratory. The FDA have acknowledged that clinical laboratories that develop in-house tests are acting as manufacturers of medical devices and therefore subject to FDA jurisdiction under the Act (62FR 62249); however, the FDA has generally exercised enforcement discretion over standard LDTs that use primarily analyte specific reagents, general purpose reagents, laboratory equipment, instrumentation and controls (21 CFR 862 and 864). The FDA does not consider IVDMIAs as falling under this scope of LDTs because of the test complexity and unique interpretation functions. The FDA believes it must ensure the IVDMIA is clinically validated to be safe and effective. Their reasoning is italicized in the document and reads: "While
the input variables, alone or in combination, might have meaning
to the clinician, the clinician could not verify the clinical significance
of the IVDMIA result on his or her own. In addition, the ordering
physician cannot reach the IVDMIA result on his or her own, nor
could he or she independently interpret that result. The ordering
clinician requires information from the test developer, rather than
generally accepted information from the clinical community, in order
to interpret the IVDMIA result for use in the management of the
patient. For an IVDMIA, it is the single patient-specific result
that is associated with the intended use of the device. The IVDIA
device includes all elements necessary for obtaining the result." On the other hand, genotype determination is an example of the devices that simply facilitate the interpretation of multiple variables that health care practitioners could otherwise interpret since genotype identification has an established association with the phenotype of interest. A single genotype or predicted phenotype is generated and the device provides standard interpretation of the individual variables that clinicians could do themselves. The document also provides general information on the pre and post marketing requirements for FDA regulated devices that would apply to laboratory-developed IVDMIAs. The FDA intends to exercise enforcement discretion for 12 months following the publication of the final guidance. An additional 6 months of discretion will be allowed if a 510(k) or PMA submission is made within the 12 months of the final guidance document. FDA will enforce regulatory requirements for all marketed LDT- IVDMIAs within 18 months of the final guidance. As
of this writing, no estimate of the date for final guidance is available.
A copy of this draft guidance is available HERE. For further information, Contact Dr. Ron Salerno... Page Updated: 21 August, 2008 |
