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Clinical Chemistry Forum |
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Abstract |
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 Top Abstract The Food and Drug...The Analyte-specific Reagent...Applications of FDA Regulation...References |
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The Food and Drug Administration Program for Premarket Review of In Vitro Diagnostic Devices |
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TopAbstractThe Food and Drug...The Analyte-specific Reagent...Applications of FDA Regulation...References |
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). The agency approves fundamentally new devices or devices
considered high risk under the premarket application approval portion
of the law. These premarket approval applications (PMAs) also have
well-established administrative procedures (Table 1
).
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In FDA terminology, "in vitro diagnostic device" is the term used for materials (for example, reagents, instruments, and software) used to perform laboratory tests. The FDA term for an old or established marketed device is "predicate device"; this term applies to a wide variety of devices traceable to devices in medical use before passage of the Law in 1976, which were grandfathered (exempted from premarket review). In the late 1970s and early 1980s, the agency undertook a comprehensive review of all existing medical devices, including IVDs, classifying these according to risk and appropriate required controls into three categories: class I (low-risk), class II (moderate-risk), and class III (high-risk) products. Today, class I products are largely exempt or occasionally reviewed as 510(k)s, class II products are subject to 510(k) review, and class III products are subject to PMA review.
For IVDs, the vast majority of review work occurs in the area of 510(k)s. The division currently processes ~1000 510(k) submissions in the course of a year. The operative term in dealing with these is "substantial equivalence". Before clearing a device for marketing, the FDA assures that the new product is substantially equivalent to an identified predicate. Review is focused on an evaluation of data sets designed to establish the essential features of device performance. Depending on the claims being made for a product and the laboratory methods or clinical information used to support these claims, performance may be defined in terms of a variety of parameters including accuracy, bias, precision, repeatability, linearity, limits of detection, and analytical and/or clinical sensitivity and analytical and/or clinical specificity, as appropriate. Limitations of the premarket review of 510(k) submissions include the fact that our reviews are entirely paper-based. DCLD has no wet laboratories to allow direct device testing and instead reviews data sets submitted by manufacturers based on testing by them or their clinical investigators. In addition, the division is constantly challenged by the difficult task of trying to establish appropriate standards to apply to making equivalence determinations.
DCLD handles a much smaller number of fundamentally new or high-risk PMA devices—usually 12 to 24 in the course of 1 year. PMA review of an IVD is based, not on a comparison with a predicate device, but on a de novo determination that the new device is "safe and effective". Because the safety of an IVD is based not on its contact with the patient, but on the impact that information generated by the device has on patient management (harm from false-positive or -negative results), the terms safety and effectiveness are linked. The standard for effectiveness is specifically defined in section 806(3) of the Code of Federal Regulations (21 CFR), which indicates: "There is reasonable assurance that a device is effective when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate direction for use and warnings against unsafe use, will provide clinically significant results". In 1990, Congress amended the device law, expanding FDA regulatory purview to include interest in safety and effectiveness for all medical devices. As a result, for PMAs and for a growing number of 510(k)s, the analytical base for FDA review of IVDs has been expanded, and the agency looks for information on clinical or diagnostic sensitivity and specificity as well as for information on analytical performance. Review limitations for PMAs are similar to those experienced for 510(k)s, but are complicated by the fact that for fundamentally new devices or new uses of old devices, establishing yardsticks for safety and effectiveness can be quite challenging.
Over the past 7 years, the FDA review process for IVDs has moved from a descriptive to a more data-driven model. It is our view that there is no excuse for poor characterization of performance of new IVDs because there is such a rich variety of sources to draw from in method evaluation, including a growing body of scientific literature, voluntary standards, and FDA guidance. In the last several years, major advances have been made in our understanding of the study design models available to elucidate IVD performance and of the statistical techniques to be applied to these studies. DCLD is actively involved in working with both industry and professional groups in an attempt to better incorporate these advances into our review work.
FDA review is predicated on three basic tenets: (a) identification of an up-front study design with a clear study hypothesis; (b) careful collection of data; and (c) use of appropriate statistical models for data interpretation. For quantitative tests, at a minimum we evaluate information on accuracy or bias compared with reference or predicate methods, an analysis of precision preferably using analysis of variation methodologies, and experiments to define analytical specificity and sensitivity. For qualitative tests, we evaluate similar information, but in addition attempt to ensure that cutoff points have been appropriately identified and defined at clinically and analytically relevant values. Clinical data when provided are frequently evaluated using receiver-operator characteristic curves.
FDA review of IVDs generally does not require outcome studies (unless outcome claims are made as part of the intended use of the device), but instead are based on concurrent analysis of the data generated by a new test in comparison with one or more predicate and/or reference methodologies and/or appropriate clinical or diagnostic information. The agency works hard to interact with sponsors of new devices to help select appropriate endpoints or surrogate endpoints to properly define performance for a wide range of complex tests with both old and new intended uses. A very important final issue is the concept of "truth in labeling" and the proper application of the labeling requirements outlined in the Code of Federal Regulations, section 809.10(b). Scientific reviewers carefully evaluate product labeling to ensure that this labeling properly reflects the studies performed to establish performance and clearly identifies both the strengths and weaknesses of a new test.
Although FDA review of medical devices is most commonly performed by FDA scientists, medical officers, and statisticians, the expertise of agency personnel is sometimes supplemented by outside scientists who serve as special government employees on FDA advisory panels. Currently, DCLD has >100 such individuals serving on four separate panels: chemistry/toxicology, hematology/pathology, immunology, and microbiology. These individuals lend their expertise to the agency either by participating in formal panel meetings to allow for public discussion of new products or by providing supplementary review of products through so-called homework assignments in which submissions are provided to one or more panel members for external review. Through this mechanism, FDA acquires valuable input from practitioners and academics who help maintain grounding to our regulatory process.
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The Analyte-specific Reagent Rule and the Role of the FDA in the Development of Home-Brew Tests |
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TopAbstractThe Food and Drug...The Analyte-specific Reagent...Applications of FDA Regulation...References |
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FDA has always considered tests developed in house to be medical devices subject to regulatory oversight. However, with very few exceptions, the agency has chosen on a discretionary basis not to apply its authority in this area. This policy decision has been based on the limited review resources available to FDA and on the understanding that laboratories developing in-house tests for clinical use are regulated by the Health Care Financing Administration under the provisions of CLIA 1988.
In 1996, the FDA proposed modifications to its regulatory oversight of
this area by introducing a new IVD classification category called
"analyte-specific reagents" (ASRs; Table 1
) (4). This
new rule was based on the agency's appreciation that in-house tests
were a well-recognized and standard laboratory practice of public
health benefit. The agency sought a mechanism for clarifying its
role in the oversight of these devices and the use of its regulatory
authority to provide some incremental improvement in the general
controls and labeling applied to these devices without imposing a new
burden for premarket review.
In this new rule, the FDA defined ASRs as "antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reaction with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens". In essence, the FDA recognized ASRs as the active ingredients of in-house tests, which when used in combination with general purpose reagents (such as buffers or reactive materials without specific intended uses) and general purpose laboratory instruments could be the basis for a home-brew assay.
In addition to defining ASRs, the FDA proposed a set of controls and restrictions to be applied to their use to ensure their quality and consistency and to clarify the fact that laboratories setting up in-house tests using these were responsible for test performance. These new controls apply to both the manufacturers of the ASRs and the laboratories developing in-house tests.
Manufacturers are required to register and list their ASR products, to make them following good manufacturing practices, and to report adverse patient events resulting from product failures. For all except a very small list of high-risk products related to blood banking or to diagnostics with particularly high public risk profiles (tests for human immunodeficiency virus or tuberculosis), ASRs are exempt from premarket review. These devices are subject to both restricted labeling and use; the sale of ASRs is restricted to laboratories certified under CLIA as high complexity. The products must be labeled to indicate they are the active ingredients or building blocks for in-house test development.
Laboratories are required to meet CLIA high-complexity certification requirements, to establish the performance of the in-house test following CLIA regulations, and to label in-house tests developed using ASRs with the statement, "This test was developed and its performance characteristics determined by (Laboratory Name). It has not been cleared or approved by the U.S. Food and Drug Administration". FDA has indicated that additional explanatory language or communication to clarify the meaning and importance of this disclaimer is permissible and appropriate.
The ASR rule became effective on November 23, 1998. The FDA continues to work with the industry and professional groups to educate the IVD community on proper interpretation of this new regulation and to ensure implementation is as smooth and trouble-free as possible.
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Applications of FDA Regulation to Genetic Testing |
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TopAbstractThe Food and Drug...The Analyte-specific Reagent...Applications of FDA Regulation...References |
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The Office of Device Evaluation currently is in the process of chartering a new genetics advisory panel to provide DCLD with outside expertise to deal with genetic testing issues. Candidates for this new panel have been identified, and an inaugural meeting is expected to take in place in 1999. Our center also is continuing to work with other agencies within the Department of Health and Human Services to help address the issues raised by the Task Force on Genetics Testing and to determine how we can cooperatively help foster this important new technology.
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Footnotes |
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1 Nonstandard abbreviations: DCLD, Division of Clinical Laboratory Devices; FDA, Food and Drug Administration; IVD, in vitro diagnostic device; PMA, premarket approval application; and ASR, analyte-specific reagent. 
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References |
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TopAbstractThe Food and Drug...The Analyte-specific Reagent...Applications of FDA Regulation...References |
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The following articles in journals at HighWire Press have cited this article:
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  K. A. Phillips and S. L. Van Bebber Regulatory Perspectives on Pharmacogenomics: A Review of the Literature on Key Issues Faced by the United States Food and Drug Administration Med Care Res Rev, June 1, 2006; 63(3): 301 - 326. [Abstract] [PDF]
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 D. S. Young and D. G.B. Leonard Issues in Genetic Testing Clin. Chem., June 1, 1999; 45(6): 915 - 926. [Full Text] [PDF]
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D. S. Young Issues in Genetic Testing Clin. Chem., May 1, 1999; 45(5): 725 - 725. [Full Text] [PDF]
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