Medical Device Link.

Originally Published IVD Technology May 2004

Commentary

Steven Gutman, MD, is director of the Office of In Vitro Diagnostic Device Evaluation and Safety, and David W. Feigal Jr., MD, is the former director  of the Center for Devices and Radiological Health. The authors can be reached at sig@cdrh.fda.gov and feigal_david@msn.com,  respectively.

In-house tests, so-called “home brews” or laboratory testing services, have long been a staple in laboratory medicine. In-house testing refers to the practice in which a laboratory develops a test for use at a single site. This test may be produced using reagents also generated in-house. Alternatively, this test may be produced using reagents obtained commercially from IVD manufacturers. Recently, these in-house tests have been subjected to regulation by the Centers for Medicare and Medicaid Services (CMS; Baltimore) under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). CLIA oversight involves a systematic approach that emphasizes analytical test performance and quality control.

The ASR Rule 

In 1995, FDA began to consider its regulatory role in the oversight of in-house tests. The agency eventually focused on the controls applicable to the active ingredients provided to laboratories, better known as analyte specific reagents (ASRs). In November 1997, FDA published in the Federal Register the ASR rule that identified a new class of reagents. According to this rule, these reagents were defined 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.¹ 

Under the ASR rule, ASRs are restricted devices with sales generally limited to CLIA high-complexity laboratories (i.e., scientific entities most likely to be capable of developing and establishing performance standards CQ for this type of testing). ASR manufacturers must follow a variety of general controls, including registration and listing, compliance with quality system regulations, and postmarket reporting of serious device failures. Labeling requirements were also established.²

With these controls in place, most ASRs were considered Class I exempt with no requirements for premarket notification. A few notable exceptions were made for a subset of higher-risk products considered Class II or III. These included analytes used for blood banking tests and for diagnosing “a contagious condition that is highly likely to result in a fatal outcome and prompt, accurate diagnosis offers the opportunity to mitigate the public health impact of the condition.”¹

In addition, high-complexity CLIA labs using ASRs are required to include language in test reports explaining that the labs themselves determined the test’s performance characteristics. FDA has indicated that test reports or promotional materials could include such information to clarify the legitimacy of this alternative marketing pathway. Consequently, many laboratories chose to take advantage of this option. 

ASRs and Total Product Life Cycle

The ASR rule preceded by several years the Center for Devices and Radiological Health’s strategic initiative that emphasizes ensuring consumer protection throughout a product’s total life cycle. However, the ASR rule clearly presaged this initiative. The rule was heavily vested in a paradigm that focused not on traditional tools of premarket review, but rather on new and refined tools that emphasized postmarket regulation under the quality system regulation and the use of postmarket surveillance. The ASR rule leveraged FDA regulation off the existing oversight provided by CMS through CLIA and the professionalism and expertise offered by laboratorians. This provided a unique triad of responsible parties that all had vested interests in ensuring the quality of in-house laboratory tests.

Challenges in Applying the ASR Rule

FDA has encountered several challenges in implementing the ASR rule. While manufacturers are required to register and list their ASRs with FDA, the existing databases are not user- friendly and do not lend themselves to easy identification of ASRs. FDA is currently working on mechanisms to make this menu of devices more accessible. 

The ASR rule also failed to predict the complex variety of marketing options being used for ASRs, and application of the rule to certain product lines is not always intuitive. To clarify its position on these issues, FDA released a guidance document titled Analyte Specific Reagents; Small Entity Compliance Guidance; Guidance for Industry.³ However, the agency may consider developing additional guidance documents to clarify further marketing options.

In addition, some outside groups, most notably the Secretary’s Advisory Committee on Genetic Testing, have recommended that FDA exert increased oversight of in-house tests. Along with other government units, FDA is working to address these recommendations.

New Review Models

As FDA considers ways to improve or clarify its approach to ASR regulation, a number of alternative review models have been suggested. One such alternative is a formal proposal to review IVDs based on analytical performance only by using a model referred to as the in vitro analytical test (IVAT). The idea of using analytical performance for premarket review is actually not completely new. For some common analytes (e.g., hemoglobin, sodium, amylase), premarket clearance is based on using analytical data alone. This is because the association between analytical and clinical results in these analytes is well established. However, in the absence of such well-established links, FDA generally considers devices to be investigational and requires both analytical and clinical data to assess a device’s safety and effectiveness. Nonetheless, FDA will continue to consider the IVAT proposal.

FDA has also been considering new ways of reviewing IVDs based on a total product life cycle approach. This approach could incorporate elements of the quality system regulation and postmarket surveillance into the review process, thereby allowing for decreased scrutiny of the usual premarket review threshold. While this approach parallels the concept of total product life cycle, implementing such a model within the framework of the statute presents challenges. In addition, the trade-off for both FDA and firms between reduced premarket activities and increased pan-regulatory responsibilities remains uncertain.

Finally, FDA is working on an electronic format for 510(k) submissions that would allow standardized and simplified work processes for both IVD companies and FDA. Referred to as the turbo 510(k), this initiative builds off FDA’s past review and regulatory experiences that were highly successful in using checklists, templates, and, most recently, electronic formats. 

Future Directions

FDA continues to consider the ASR rule to determine how it can be better applied to new technologies and new uses of technologies in the area of IVDs. The agency has recently noted that like all other devices, device exemptions for ASRs are not without limitations and should be based on concerns about safety and effectiveness. Sections of both the law and the regulations limit the premarket exemptions for ASRs. 

At the same time, FDA recognizes that IVD manufacturers and laboratories would benefit from a clarification of the definition of an ASR. The factors that may result in a product being considered a Class II or Class III device, whether it’s an ASR or not, also could be better explained. FDA is working on accomplishing this and on determining how existing or revised regulations might better be applied to the oversight of high-risk devices.

FDA’s new initiatives in the area of regulation of ASRs are likely to be a collaborative effort with other parts of the Department of Health and Human Services, professional groups, and the IVD industry. These initiatives will also be in concert with the FDA commissioner’s goals of having risk-based and cost-effective regulations. These changes will inevitably take time, and FDA will work hard to ensure adequate public comment and input from interested stakeholders. 

References

1. Code of Federal Regulations, 21 CFR 864.4020.

2. Code of Federal Regulations, 21 CFR 809.10(e)(1)

3. Analyte Specific Reagents; Small Entity Compliance Guidance; Guidance for Industry (Rockville, MD: Office of In Vitro Diagnostic Device Evaluation and Safety, 2003 [cited 22 April 2004]) ; available from Internet: www.fda.gov/cdrh/oivd/guidance/1205.html.  

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