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Originally published September, 1998

REGULATIONS AND STANDARDS

FDA makes a better rule for IHCs

In June, FDA issued its final regulation classifying immunohistochemicals (IHCs). The final rule includes some significant—and beneficial—changes from FDA's proposed rule.¹

Some IHCs were introduced into the market before May 28, 1976, and are therefore preamendment devices. Many other IHCs were introduced after 1976. Thus, the final rule both reclassifies IHCs (the ones sold before 1976) and classifies the remaining IHCs (postamendment IHCs).

Some IHCs have received premarket notification (510(k)) clearance. The vast majority of IHCs, though, have been sold without 510(k) clearance. The lack of 510(k) clearance was due to a variety of factors, including the sheer number of products and the difficulties experienced by companies that did submit 510(k)s in successfully navigating the 510(k) process.

The Proposed Rule

FDA's proposed rule threatened to exacerbate the problem by requiring companies to submit many more 510(k)s and concurrently increase FDA's workload. Published in June 1996, the proposed rule would have required 510(k) clearance for virtually all IHCs.²

The proposal attracted 26 comments.³ Many industry comments reflected objections to the need to submit 510(k) notices for a low-risk, adjunctive diagnostic tool used by trained professionals. Industry was also concerned by FDA's apparent intention to actively regulate IHC kits sold for research purposes. Concerns about FDA's efforts to increase IHC regulation had already spurred the formation of a new trade association, the Joint Council of Immunohistochemical Manufacturers (JCIM). Comments by industry and pathologists pointed out that because of the role IHCs play in medicine and their well-established history of safe use, (510(k)s) were not needed to ensure the safety and effectiveness of IHCs.

One of the more unusual comments came from the Small Business Administration (SBA). FDA, like other federal agencies, is required to consider the costs to small businesses of proposed regulations. SBA accused FDA of imposing excessive costs on small businesses.

The proposed rule was also challenged for relying on a recommendation by the Hematology and Pathology Device Panel. In its meeting on the subject, the panel had recommended that most IHCs be placed in Class II. A letter sent to FDA shortly after that meeting criticized the panel meeting for a variety of serious procedural flaws.

The Final Rule

To FDA's credit, the final rule is quite different from the proposal. Most significantly, the great majority of IHCs are placed into Class I and exempted from the need for 510(k) clearance. Citing "ongoing initiatives" to ensure "that pre- and post-analytic, as well as analytic procedures are properly performed," FDA decided that general controls, excluding 510(k) clearance, would suffice. The final rule defines IHCs as follows:

Immunohistochemistry test systems (IHCs) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHCs.⁴

The 510(k) exemption does not apply to all IHCs. Rather, the exemption covers IHCs "that provide the pathologist with adjunctive diagnostic information that may be incorporated into the pathologist's report, but that is not ordinarily reported to the clinician as an independent finding."

Conversely, IHCs will fall into Class II and be subject to 510(k) clearance if they "are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or prediction data that are not directly confirmed by routine histopathologic internal and external control specimens." In addition, to be in Class II the "claims associated with these data are widely accepted and supported by valid scientific evidence." An example of a Class II IHC is a hormone receptor for breast cancer. This represents a shift in FDA's position; under the draft rule, hormone receptors were in Class III. Companies submitting 510(k) notices for Class II IHCs will need to include the elements set out in a guidance document entitled Guidance for Submission of Immunohistochemistry Applications to the FDA.⁵ This guidance document has been designated as a special control.

All remaining IHCs are placed in Class III. The rule does not give any examples of Class III IHCs.

Research-Use IHCs

One of the most significant aspects of the rule is what products are not included in the new classification. The proposal appeared to cover all IHCs, including those used for research. As JCIM, SBA, and others emphasized in their comments, many IHCs are sold only to researchers. The fear that 510(k)s would be required for these research-use products prompted an outcry. However, the preamble to the final rule makes it clear that marketing applications are not needed for IHCs intended and labeled for research use.

The IHC definition is unusual in that a product's regulatory status hinges, at least in part, on how the laboratories use the product rather than what the manufacturer claims. For example, Class I status rests on the test result not generally being reported "to the clinician as an independent finding." A manufacturer cannot directly control how a laboratorian writes a report. However, the preamble clarifies that the primary determinant of an IHC's regulatory status is the manufacturer's intent, as embodied in labeling, rather than an individual laboratory's practice. A manufacturer should not be held responsible if a laboratory elects to report the results in a manner inconsistent with the labeling.

Unfortunately, an example used by FDA in the preamble to the final rule tends to confuse this point rather than clarify it. FDA says that a Ki-67 monoclonal antibody clone will be Class I if it satisfies four requirements, one of which is that "the result will not be reported as independent information to the clinician." Conversely, Class II status—and the need for a 510(k)—would result if "the analytic result will be reported as independent information to the clinician." The manufacturer cannot dictate how a particular laboratorian will describe the results of Ki-67—or other IHC—testing. The best advice would seem to be to include labeling that explicitly notes the adjunctive nature of the IHC. Promotional material should not encourage the independent reporting of Class I IHCs.

Conclusion

The final IHC rule is better than the proposal. It aids researchers and laboratories by ensuring an adequate supply of IHCs. And FDA benefits by not having to review hundreds of 510(k) notices for low-risk products. These advantages in the final rule can be attributed to the diligence of industry and laboratories in submitting information to FDA, and the agency's willingness to change its position in response to this information.

References

1. "Medical Devices; Classification/Reclassification of Immunohistochemistry Reagents and Kits," final rule, Federal Register, 63(105):30132–30142, June 3, 1998.

2. "Medical Devices; Classification/Reclassification of Immunohistochemistry Reagents and Kits," proposed rule, FR 61(116):30197–30200, June 14, 1996.

3. Preamble to final rule, FR 63(105):30133–30140, June 3, 1998.

4. 21 Code of Federal Regulations 864.1860(a).

5. Guidance for Submission of Immunohistochemistry Applications to the FDA, Rockville, MD, Immunology Branch, Division of Clinical Laboratory Devices, Office of Device Evaluation, Center for Devices and Radiological Health, FDA, 1998.

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