The FDA's Center for Biologics Evaluation and Research (CBER) is responsible for reviewing applications to market resistance assays that are produced and sold as kits. Assays that are developed and run within individual labs, known as "home brews," are not regulated by the FDA, however (see related article, "Clinical Availability and Reimbursement Status of Antiretroviral Drug Resistance Assays"). The FDA regulates tests (considered "devices") according to three categories (class I, II and III). Each category requires progressively more detailed information to be submitted to the agency in order for the FDA to determine that the device is safe and effective prior to marketing. If a device was not on the market prior to 1976 (when these regulations came into effect), and there is no similar or "predicate" device on the market, it is automatically classified in the most demanding category, class III, unless it is specifically down-classified by the agency.
On September 17, 1999, CBER convened a Medical Device Panel to consider a proposal that HIV genotypic resistance assays be reclassified from class III to class II devices. The Blood Products Advisory Committee (BPAC) was asked to act as this panel.
The FDA asked the committee to consider the following questions:
- Would the committee support the reclassification of HIV genotypic drug resistance assays from class III medical devices to class II medical devices?
- If the answer to number 1 is yes, what additional special controls or requirements, if any, would the committee recommend?
The FDA requires, for all three test classifications, that the manufacturer comply with "general controls." These include registration and listing of the product so the FDA has a record of what laboratories and manufacturing plants to inspect, labeling instructions, record keeping, and pre-market notification via the submission of an application to FDA. Class I and II device applications are known as 510(K)s. When a 510(K) has been reviewed and accepted by the FDA, the device is cleared for marketing. Class III devices require the submission of a Pre-Market Approval (PMA) application which includes data from prospective clinical trials, while a 510(K) may or may not require such clinical trial-derived data. Class II and III devices are also subject to specified "special controls," that must be submitted and approved prior to clearance (in the case of a class II device) or approval (in the case of a class III device).
When special controls are required (class II and III devices), the FDA publishes, in the Federal Register, a Guidance Document that outlines the specific special controls and attendant requirements. These special controls can include (1) design controls to ensure the integrity of the manufacturing, (2) stipulations of adherence to international performance standards (when these exist), (3) a requirement for clinical trial data, (4) specific labeling instructions, and (5) requirements for post-market surveillance.
The review time allowed to the FDA differs across classes. Class II device 510(K) applications are reviewed within 90 days; class III PMAs have a 180 day review cycle. After initial review, the manufacturer must respond to a letter outlining deficiencies in the application, and the FDA again has a 90 or 180 day review period for the re-submission. Multiple reviews may be required.
The BPAC considered presentations on the currently available data correlating specific genotypic mutations with phenotypic resistance along with retrospective and prospective clinical trial data (from the GART and VIRADAPT studies) correlating genotypic assay availability with clinical outcome. A representative of the FDA Center for Drug Evaluations and Research (CDER) described CDER's interest in requiring drug manufacturers to submit genotypic and phenotypic resistance data with their New Drug Applications (NDAs). A meeting about this issue will be held in November. Finally, representatives of several manufacturers of genotypic resistance tests, including three companies developing kit-based assays (Visible Genetics, Innogenetics and Applied Biosystems) and one that is currently marketing home-brew genotypic and phenotypic assays (Virco), presented their perspectives.
The FDA presentations to the committee suggested that reclassification could facilitate post-marketing clinical trials and that special controls regarding labeling would restrict the reporting of mutations to those for which there is a consensus vis-à-vis their correlation with phenotypic resistance. Significant discussion regarding what specific data would be required to validate specific resistance mutations is anticipated by the FDA and will be incorporated into the forthcoming Guidance Document. Additional data would also need to be submitted before new resistance mutations, that had not previously been cleared by CBER, could be reported. Documentation regarding assay sensitivity, precision and reproducibility could be provided by the use of "spiked panels," where all single and multiple mutations of interest could be described along with data on the minimum viral load needed to reliably detect them and the mutant proportions reliable detected. Validation of the phenotypes predicted by the genotypes could be supported by the use of unspiked patient panels representing all genotypes for which a claim is sought, as well as by retrospective and/or prospective clinical trial data. Post-marketing surveillance requirements would be claim-specific, pertaining to the specific product and manufacturer. All of these issues are examples of where special controls could be incorporated in to the Guidance Document.
The panel did recommend the reclassification of genotypic drug resistance assays from class III to class II devices. There was a suggestion that the FDA could define, via a consensus process, those mutations that currently have adequate clinical data available to be considered prognostically important. Then each manufacturer would need to address the specific performance characteristics of their assay with respect to those mutations. There was also significant discussion about the limitations of currently available prospective clinical trial data and the possibility of the FDA requiring some additional prospective trial data in a 510(K) application.
The FDA will now draft a Guidance Document that will be published for comment in the Federal Register. HIVresistanceWeb will post a notice when this publication is available for public comment. The final revised version will also be published in the Federal Register for use by manufacturers in preparing their 510(K) submissions. The FDA also plans to have a similar advisory panel meeting regarding phenotypic assay classification and regulation in the future.
Related HIVresistanceWeb articles:
FDA Considers the Uses of Resistance Evaluation in New Drug Development and Product Labeling
California State Office of AIDS ad hoc Advisory Committee Considers State Reimbursement Policy for Drug Resistance Assays
Clinical Availability and Reimbursement Status of Antiretroviral Drug Resistance Assays
