IVD Technology Magazine
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Originally published January, 1998

Regulations and Standards

ASRs: FDA issues final rule

Jeffrey N. Gibbs

Two years ago, FDA identified analyte specific reagents (ASRs) as its highest regulatory priority in the field of IVDs. Now the agency has issued its final rule on the subject. Published in the Federal Register on November 21, 1997, the rule will become effective on November 23, 1998.¹

It has been several years since FDA first asserted its authority to regulate so-called "home-brew" assays directly through the premarket approval (510(k)) process. While the agency has not disavowed its jurisdiction over laboratories that produce ASRs, the final rule takes a different direction. At least for now, the agency has abandoned the notion of regulating home-brew assays directly. Instead, under the ASR regulation, it has shifted the regulatory focus away from the assays developed in laboratories in favor of regulating the reagents purchased by laboratories to develop those assays.

In its final version, then, the stated goal of the ASR regulation is to ensure the quality of the reagents used by IVD manufacturers and laboratories that make their own home-brew assays. This approach largely mirrors that of FDA's first proposed rule for ASRs, which was published on March 14, 1996, shortly after an advisory panel endorsed the ASR concept. The final rule amends two FDA regulations, 21 CFR 809.10 and 864.4010, and adds two new sections, 21 CFR 809.30 and 864.4020.

ASRs Defined. One of the most important parts of the rule is its definition of ASRs. The language of the final rule defines 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.²

This definition differs from the 1996 proposal by adding the term ligand, because ligands bind the reagents to the analytes. The final rule also clarifies the fact that binding between ASRs and their analytes may take place through either physical or chemical means. And FDA agreed with industry comments supporting the inclusion of nucleic acids in the ASR definition. But the most important change is the addition of the term diagnostic, making it clear that a substance can be an ASR only if it is intended for diagnostic use.

Application to Manufacturers. Not everything that falls within this definition will be regulated under the rule. ASRs are excluded from the provisions of the rule when they are sold to IVD manufacturers or organizations that use the reagents to make tests for purposes other than providing diagnostic information to patients and practitioners (e.g., forensic, academic, research, and other nonclinical laboratories).

The final rule classifies or reclassifies the majority of ASRs as Class I medical devices exempt from 510(k)s. (The FDA Modernization Act of 1997 independently exempts Class I devices from 510(k) notices.) However, ASRs will be subject to general controls. Accordingly, suppliers of ASRs must satisfy the following requirements:

• Register with FDA and provide it with a list of the ASRs they supply to laboratories for use in developing in-house tests.

• Comply with the requirements of FDA's quality system regulation (21 CFR 820), including good manufacturing practices (GMPs), as applicable.

• Comply with the requirements of the medical device reporting (MDR) regulation (21 CFR 803).

The ASR industry includes many small device manufacturers, some of which have not previously been subject to GMPs. Some companies commented that the proposed rule, by requiring GMP compliance, would harm these companies. FDA has not been sympathetic to this view. In its preface to the regulation, the agency declares that "the size of a company that commercially markets ASRs will not exempt that manufacturer from compliance with appropriate CGMPs."³

Regulatory Requirements

The final rule also imposes restrictions on the distribution, use, and labeling of ASRs. ASRs are restricted devices under section 520(e) of the Federal Food, Drug, and Cosmetic Act and are subject to the restrictions set forth in the new regulation. ASRs may be sold only to IVD manufacturers, clinical laboratories regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and qualified to perform high-complexity testing, and organizations that use the reagents to make tests for purposes other than providing diagnostic information to patients and practitioners.⁴

The regulation differs from the 1996 proposal by referring to laboratories regulated rather than certified under CLIA. This clarification allows ASRs to be sold to state and Department of Veterans Affairs laboratories, which are not covered by CLIA.

Labeling. The final regulation also imposes new requirements for the labeling of ASRs.⁵ For example, the labeling, advertising, and promotional materials for Class I 510(k)-exempt ASRs must include the statement: "Analyte Specific Reagent. Analytical and performance characteristics are not established." Similarly, the labeling, advertising, and promotional materials for Class II and Class III ASRs must include the statement: "Analyte Specific Reagent. Except as a component of the approved/cleared test (name of approved/cleared test), analytical and performance characteristics of this ASR are not established."

In addition, advertising and promotional materials for ASRs must include the identity and purity of the ASR, including its source and method of acquisition, and the identity of the analyte. These materials may not include any statement regarding analytical or clinical performance. These restrictions may make it more difficult to promote ASRs.

FDA believes that "except for those ASRs sold to in vitro diagnostic manufacturers, almost all ASRs will require relabeling."⁶ For this reason, the final regulation allows manufacturers and suppliers up to one year to deplete their current labeling stock before they must comply with the new labeling requirements. FDA states that all ASR manufacturers or suppliers must review their labeling, including promotional materials, to determine compliance with the new labeling requirements.⁶

In its economic analysis, FDA estimates that redesigning and reviewing the new labeling will take only four hours, and cost just $89.50 per product.⁶ This estimate is far too low. Given the number of steps necessary to draft, revise, and review labeling in accordance with the agency's quality system regulation, four hours significantly understates the work load for most companies.

In-House Use. The restrictions on ASRs are not intended to apply to products developed by laboratories for their own in-house use. FDA's preface notes that "the focus of this rule is the classification and regulation of ASRs that move in commerce, not tests developed in-house by clinical laboratories or ASRs created in-house and used exclusively by that laboratory for testing services."⁷

However, results generated by such tests will need to be accompanied by a disclaimer regarding the lack of FDA approval. The new rule requires laboratories that develop in-house tests to provide a disclaimer stating: "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."⁸ The legal basis for imposing this requirement is unclear. Laboratories will need to assess the impact of this statement on reimbursement coverage.

Another restriction relates to ordering tests. In-house tests that are developed using ASRs can be ordered only by practitioners licensed by the relevant state. FDA specifically rejected direct consumer access to test results generated with ASRs.⁹

ASR Classification. Although most ASRs will fall into Class I, some will not. ASRs used in blood-banking tests classified as Class II devices, where the underlying tests have already been cleared for marketing pursuant to a 510(k), will themselves fall into Class II. These Class II blood-banking tests fall into two categories: FDA-required screens for diseases with a low potential for transmission (e.g., treponema pallidum nontreponemal test reagents, which are used in tests that aid in the diagnosis of syphilis); and tests used electively by blood banks to screen for diseases that are likely to be transmitted to subsets of blood-unit recipients known to be at greater risk of infection (e.g., certain cytomegalovirus serological reagents).

In addition, the rule identifies another subset of ASRs as Class III, and therefore subject to premarket approval (PMA) requirements. This subset consists of ASRs incorporated in tests intended to diagnose contagious diseases that are highly likely to be fatal and where accurate diagnosis offers an opportunity to mitigate the risk to the public health. Examples include ASRs used in tests to diagnose human immunodeficiency virus/acquired immune deficiency syndrome or tuberculosis. Class III ASRs also include those incorporated in Class III tests intended to establish the safety of blood and blood products, such as hepatitis assays, including genetic tests intended to ensure the safety of the blood supply.

In order to determine the substantial equivalence of Class II ASRs, or the safety and effectiveness of Class III ASRs, FDA intends to review the performance of both the ASRs and the tests of which they are components. Thus, FDA expects that most Class II and Class III ASRs will not be marketed as independent components. Under the ASR rule, there will be little incentive for companies to commercialize most Class II or Class III ASRs.

Genetic ASRs. One of the most controversial topics covered in the rule is the regulation of genetic tests. Agreeing that ASRs used in such tests should be regulated as Class I 510(k)-exempt devices, FDA states that it "does not believe there is a scientific basis to distinguish between tests based on the use of DNA and tests based on the use of other proteins or substances, or between tests based on the use of DNA and tests based on the use of other molecular diagnostic technologies."¹⁰ Accordingly, "FDA does not intend, at this time, to regulate ASRs used in genetic testing differently from other restricted Class I medical devices that are exempt from premarket notification requirements."¹¹

However, FDA adds that the issuance of these regulations does not preclude it from someday reevaluating whether additional controls may be needed for genetic testing or for the ASRs used in such tests. If further developments in the field result in significant uses of ASRs in genetic assays, the agency may reevaluate the need for additional controls.

Relation to Other Regulations. In the preamble to the final rule, FDA discusses how this regulation relates to the definition and proposed regulation for immunohistochemistry reagents and kits (IHCs) and to the compliance policy guide (CPG) on the distribution of research- and investigational-use products. FDA explains that IHCs can be marketed in a variety of ways, depending on their labeling and intended use. When an IHC is developed as a kit or system for IVD use (with a proposed intended use, indications for use, instructions for use, and performance characteristics), it would be subject to review as a Class I, II, or III device according to its intended use, as outlined in the IHC regulation proposed in June 1996.¹² When an IHC is developed and marketed as an ASR (intended for ASR use only, with no instructions for use, and no defined performance characteristics), it would be exempt from premarket notification and review, but would be subject to general controls and ASR restrictions.¹³

FDA also mentions that, in August 1992, it invited comment on a draft CPG relating to research-use only (RUO) and investigational-use only (IUO) devices. (Curiously, FDA does not mention the 1996 "final" version of the CPG.) In that 1992 draft, FDA described its enforcement policy concerning RUO and IUO IVDs that are commercialized for diagnostic or prognostic purposes. Without providing any indication of when a final CPG might be issued, FDA states that any such guide will be consistent with the ASR final rule.¹⁴

Conclusion

The ASR rule affects many companies in the diagnostic arena: suppliers of ASRs, IVD manufacturers and laboratories that purchase ASRs, and laboratories that develop their own home-brew assays. The rule also affects companies selling kits that compete with ASRs. And it offers IVD companies a new strategic option: the chance to weigh whether speedier access to market via the ASR route offers better potential for success than selling a complete diagnostic kit.

In 1996, describing their agency's proposal to regulate ASRs, FDA officials commented that it would have far-reaching impact. Looking over the final version, IVD manufacturers will have to agree they were right.

References

1. Federal Register, FR 62(225):62243—62260, November 21, 1997.

2. Code of Federal Regulations, 21 CFR 864.4020.

3. FR 62(225):62252, November 21, 1997.

4. 21 CFR 809.30(b).

5. 21 CFR 809.10(e) and 809.30(c)—(e).

6. FR 62(225):62257, November 21, 1997.

7. FR 62(225):62249, November 21, 1997.

8. 21 CFR 809.30(e).

9. 21 CFR 809.30(f).

10. FR 62(225):62247, November 21, 1997.

11. FR 62(225):62245, November 21, 1997.

12. FR 61(116):30197—30200, June 14, 1996.

13. FR 62(225):62250, November 21, 1997.

14. FR 62(225):62250—62251, November 21, 1997.

Jeffrey N. Gibbs is a partner in the law firm of Hyman, Phelps & McNamara (Washington, DC).