[Federal Register Volume 61, Number 116 (Friday, June 14, 1996)]
[Proposed Rules]
[Pages 30197-30200]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-15140]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. 94P-0341]


Medical Devices; Classification/Reclassification of 
Immunohistochemistry Reagents and Kits

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
classify/reclassify immunohistochemistry reagents and kits (IHC's) (in-
vitro diagnostic devices) into three classes depending on intended use. 
These actions are being taken under the Federal Food, Drug, and 
Cosmetic Act (the act), as amended by the Medical Device Amendments of 
1976 (the 1976 amendments) and the Safe Medical Devices Act of 1990 
(the SMDA). The intention of this proposal is to regulate these pre- 
and post-1976 devices in a consistent fashion. Therefore, FDA is 
proposing classification or reclassification of these products as 
applicable.

DATES: Submit written comments by August 30, 1996.

ADDRESSES: Submit written comments on the proposed rule to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Max Robinowitz, Center for Devices and 
Radiological Health (HFZ-440), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD, 20850-4011, 301-594-1293, ext. 136, or FAX 
301-594-5941.

SUPPLEMENTARY INFORMATION:

I. Background

    The act (21 U.S.C. 201 et seq.), as amended by the 1976 amendments 
(Pub. L. 94-295) and the SMDA (Pub. L. 101-629), established a 
comprehensive system for the regulation of medical devices intended for 
human use. Section 513 of the act (21 U.S.C. 360c) established three 
categories (classes) of devices, depending on the regulatory controls 
needed to provide reasonable assurance of their safety and 
effectiveness. The three categories of devices are: Class I (general 
controls), class II (special controls), and class III (premarket 
approval).
    Under section 513 of the act (21 U.S.C. 360c), devices that were in 
commercial distribution before May 28, 1976, the enactment date of the 
1976 amendments, are classified after FDA has: (1) Received a 
recommendation from a device classification panel (an FDA advisory 
committee); (2) published the panel's recommendations for comment, 
along with a proposed regulation classifying the device; and (3) 
published a final regulation classifying the device. A device that is 
first offered in commercial distribution after May 28, 1976, and which 
FDA determines to be substantially equivalent to a device classified 
under this scheme, is classified into the same class as the device to 
which it is substantially equivalent. The agency determines whether new 
devices are substantially equivalent to previously offered devices by 
means of premarket notification procedures in section 510(k) of the act 
(21 U.S.C. 360 (k)) and part 807 of the regulations (21 CFR 807). A 
device that was not in commercial distribution prior to May 28, 1976, 
and that has not been found by FDA to be substantially equivalent to a 
legally marketed device, is classified automatically by statute 
(section 513(f) of the act) into class III, without any FDA rulemaking 
proceeding.
    The scope of products covered by this proposal includes both pre-
1976 devices which have not been previously classified as well as post-
1976 devices which are statutorily classified into class III. The 
intention of this proposal is to regulate these pre- and post-1976 
devices in a consistent fashion. Therefore, FDA is proposing 
classification or reclassification of these products, as applicable.
    Fluorescent-labeled immunohistochemistry in vitro diagnostic 
devices (IHC's) have been used for patient diagnosis since the early 
1940's and enzyme-linked IHC's have been used since the early 1970's. 
IHC's, however, were not classified as a part of the 1979 FDA 
classification activities. In addition, new IHC's have been marketed 
for the first time since the passage of the 1976 amendments. When used 
in a standardized controlled manner, IHC's enhance the accuracy and 
scope of surgical pathology, provide objective data to 
histopathological examination, and contribute to improved patient care. 
IHC's can specifically and objectively demonstrate the presence and 
distribution of antigens that may be of use in narrowing differential 
diagnoses. IHC results are integrated by the user pathologist and 
interpreted together with other types of data used in pathological 
diagnostic decisionmaking (Refs. 1 through 4). Because pathologists, 
the principal users of IHC's, were concerned about the regulation of 
IHC's, the College of American Pathologists, the American Society of 
Clinical Pathologists, the Association of Pathology Chairs, the 
Biological Stain Commission, and the Association of Directors of 
Anatomic and Surgical Pathology requested a review of the 
classification of IHC reagents and submitted a Petition for 
Classification of IHC's as class II (special controls) medical devices 
during the summer of 1994. In response to this petition, FDA convened 
the Panel to consider classification/reclassification of these devices.

II. Panel Recommendation

    The Hematology and Pathology Devices Panel (the Panel) met on 
October 21, 1994, and made the following recommendation regarding the 
classification of five Immunohistochemistry devices.

A. Identification

    Immunohistochemistry test systems (IHC's) are in-vitro diagnostic 
devices that consist of polyclonal or monoclonal antibodies and 
ancillary reagents that are used to identify, by immunological 
techniques, antigens in specimens of tissues or intact cells in 
cytologic specimens. IHC's are primary antibody reagents that are 
labeled with instructions for use and performance

[[Page 30198]]

claims and packaged either prediluted or concentrated (neat), or as 
kits consisting of optimally-diluted primary antibody combined with 
detector systems. IHC's identify antigens in tissue or cell 
preparations using ligand-specific antibodies whose reactivity is 
detected and marked by secondary reagents that are recognized by 
pathologists using light or electron microscopes. Most IHC's are 
adjunctive to conventional histopathology and aid in the qualitative 
identification of antigens, thereby supplementing the conventional 
hematoxylin and eosin stains used in the diagnostic classification of 
normal and abnormal cells and tissues. Some IHC's may provide semi-
quantitative or quantitative information about the antigen they 
identify in normal and abnormal cells and tissues.

B. Recommended Classification of the Hematology and Pathology Devices 
Panel

    Class II (special controls). The Panel recommended that 
establishing special controls for IHC devices should be a high 
priority.

C. Summary of Reasons for Recommendation

    The Panel recommended that IHC devices be classified into class II 
(special controls) because they perceived the need for special controls 
for IHC's that prescribe acceptable sensitivity, specificity, 
stability, accuracy and precision for these devices, and thereby 
minimize the possibility that these devices may generate inaccurate 
diagnostic information. Patients may be placed at unnecessary risk when 
reliance upon inaccurate diagnostic information results in initiating 
inappropriate therapies or withholding appropriate therapies.
    The Panel stated that general controls for IHC's would not provide 
sufficient control over sensitivity, specificity, stability, accuracy 
and precision of IHC devices. The Panel stated that special controls 
are needed to provide reasonable assurance of the safety and 
effectiveness of IHC devices and that sufficient information is 
available to establish these special controls. The Panel recommended 
that manufacturers of IHC devices should follow the FDA's Guidance for 
Submission of Immunohistochemistry Applications and that this guidance 
should serve as a special control.
    A major concern of the Panel was that manufacturers of IHC devices 
should be subject to current good manufacturing practice (CGMP) 
inspections in a timely manner to ensure safe, reliable, stable, and 
consistent IHC products.

D. Summary of Data Upon Which the Recommendation is Based

    The Panel based its recommendation on the Panel members' personal 
knowledge of, and clinical experience with IHC devices, and 
presentations by Panel members, manufacturers, other interested 
parties, and FDA (Ref. 5).

E. Risks to Health

    IHC in vitro diagnostic devices are intended for use as diagnostic 
tools. Risk to the patient may result from misdiagnosis and initiation 
of inappropriate therapies or withholding of appropriate therapies 
based on the results obtained with the IHC diagnostic device. The 
degree of risk depends on whether the product is used as an adjunct to 
conventional histopathological diagnostic techniques or provides 
information that is used independently of the usual diagnostic process. 
The highest risk products are those used as independent, stand-alone 
diagnostic tests that are the sole or major determinant for a medical 
decision and cannot be confirmed by conventional histopathologic 
techniques or other diagnostic tests or clinical procedures.

III. Proposed Classification/Reclassification

    Following the Hematology and Pathology Devices Panel meeting, the 
agency considered the Panel's recommendation. The agency agrees in part 
and disagrees in part with the Panel's recommendation. FDA believes 
that general class I controls are sufficient to ensure safety and 
effectiveness for those adjunctive IHC's that furnish information that 
may be incorporated into the pathologist's histopathology or 
cytopathology report but that is not reported directly to clinicians. 
These general controls include: (1) Existing labeling requirements (21 
CFR 809.10) for in vitro devices, (2) compliance with good 
manufacturing practices, (3) registration, listing, and premarket 
notification (510(k)), (4) recordkeeping and medical device reporting 
(MDR), (5) restriction to prescription use (21 CFR 801.109.) Those 
IHC's that provide pathologists 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, are 
therefore proposed to be categorized as class I. These IHC's are used 
in adjunctive tests to subclassify malignant tumors, but the primary 
diagnosis of tumor (neoplasm) and malignancy is made by conventional 
histopathology using nonimmunological histochemical stains such as 
hematoxylin and eosin. Examples of these IHC's proposed for class I are 
differentiation markers, such as antikeratin antibodies.
    The manufacturer (sponsor) of a class I IHC would be required to 
provide a premarket notification submission to FDA, including data 
documenting compliance with the labeling requirements in Sec. 809.10 
(21 CFR 809.10). Such manufacturers or sponsors may wish to follow the 
``FDA Guidance for Submissions of Immunochemistry Applications to FDA'' 
(Guidance), for the purpose of documenting manufacturing. The FDA 
Guidance provides details about data that may be submitted to comply 
with Sec. 809.10.
    In considering whether to place any adjunctive IHC's into class I, 
FDA focused on whether this level of regulation is adequate for the 
protection of public health. FDA considers the total test performance 
for any in vitro diagnostic device to be dependent on the net results 
of preanalytic, analytic, and postanalytic factors. For example, 
variability in IHC results may be introduced at every step including 
collection and fixation of the specimen, automated processing, 
embedding, sectioning, staining of the final slide preparation, and the 
microscopic interpretation by the pathologist. FDA regulation and 
review are directed at ensuring that the manufacturer characterizes, 
manufacturers, and labels the IHC appropriately before it is marketed 
for professional use. Ongoing initiatives by professional 
organizations, manufacturers, and FDA are directed at ensuring that 
pre- and postanalytic, as well as analytic procedures, are properly 
performed. In the context of these initiatives, FDA believes that class 
I regulation will assure that these adjunctive IHC's are used safely 
and effectively.
    IHC's that provide the pathologist with adjunctive diagnostic 
information that is ordinarily reported as independent diagnostic 
information to the ordering clinician are proposed to be classified in 
class II. Examples are IHC's for immunologic detection and semi-
quantitative measurement of specific ligand markers of proliferation, 
such as Ki-67, or semi-quantitative determination of other analytes, 
such as hormone receptors, if they are reported for their prognostic 
implications. However, this classification does not apply to estrogen 
and progesterone receptors, which are in class III by previous 
regulation, and which provide

[[Page 30199]]

information that is the basis for significant medical decisions 
substantially independent of other pathological tests. FDA is proposing 
that class II IHC's be subject to general controls and to a special 
control: The FDA Guidance for submissions of Immunohistochemistry 
Applications to FDA (the guidance) (Ref. 6). The agency believes that 
the manufacturer/sponsor can establish reasonable assurance of the 
safety and effectiveness of a class II IHC by providing valid 
scientific evidence from sponsor-supported studies, as described in the 
guidance, or from the scientific literature. The guidance was drafted 
with input from the Biological Stain commission, the Joint Council of 
Immunohistochemistry Manufacturers, the College of American 
Pathologists, the American Society of Clinical Pathology, FDA, and 
comments from the public. The guidance also will provide information to 
aid the end-users of IHC's (pathologists and other laboratorians) with 
recommendations about appropriate positive and negative control tissue 
sections (or cytologic preparations) for each intended use of the IHC. 
The guidance will also describe the form and content for the package 
insert of IHC's and provide the sponsor with detailed recommendations 
about how to comply with Sec. 809.10 (Ref. 6).
    IHC's that generate information that is reported directly to the 
clinician to be used as the basis for significant medical decisions, 
and that either provide information substantially independent of other 
pathological (or cytopathological) aspects of the specimen or that have 
novel claims not supported by current widely accepted scientific 
pathophysiologic principles, would be categorized as class III. 
Examples of IHC's FDA proposes to put in class III are markers of 
clinically significant genetic mutations in tissues that are normal by 
conventional histopathology.

IV. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Taylor, C. R., and Cote, R. C., ``Immunomicroscopy: A 
Diagnostic Tool for the Surgical Pathologist,'' 2d ed., 
Philadelphia, W. B. Saunders, 1994.
    2. True, L. D. (ed)., Atlas of Diagnostic Immunohistopathology, 
Philadelphia, Lippincott, 1990.
    3. Nadji, M., and Morales, A. R., ``Immunoperoxidase Techniques: 
A Practical Approach to Tumor Diagnosis'' Chicago, American Society 
of Clinical Pathologists Press, 1986.
    4. Taylor, C. R., ``Quality Assurance and Standardization in 
Immunohistochemistry,'' A Proposal for the Annual Meeting of the 
Biological Stain Commission, June 1991, Biotechnic & Histochemistry, 
67:110-117, 1992.
    5. Transcripts of the Hematology and Pathology Devices Panel 
meeting, October 21, 1994.
    6. FDA Guidance for Submission of Immunohistochemistry 
Applications to the FDA, FDA Center for Devices and Radiologic 
Health, 1995, available through the Division of Small Manufacturers' 
Assistance (DSMA), 1-800-638-2041.
    7. Taylor, C. R., et al., Report of the Immunohistochemistry 
Steering Committee of the Biological Stain Commission, ``Proposed 
Format: Package Insert for Immunohisto Chemistry Products,'' 
Biotechnic & Histochemistry, 67:328-338, 1992.

V. Environmental Impact

    The agency has determined under 21 CFR 25.24(e)(2) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VI. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the agency believes only a small number of 
firms will be affected by this rule when finalized, the agency 
certifies that the proposed rule will not have a significant economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required.

VII. Request for Comment

    Interested persons may, on August 30, 1996 submit to the Dockets 
Management Branch (address above) written comments regarding this 
proposal. Two copies of any comments are to be submitted except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. 
Received comments may be seen in the office above between 9 a.m and 4 
p.m., Monday through Friday.

List of Subjects in 21 CFR Part 864

    Blood, Medical devices, Packaging and containers.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 864 be amended as follows:

PART 864--HEMATOLOGY AND PATHOLOGY DEVICES

    1. The authority citation for 21 CFR part 864 continues to read as 
follows:

    Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c, 360e, 360j, 
371).

    2. Section 864.1860 is added to subpart B to read as follows:

Sec. 864.1860  Immunohistochemistry reagents and kits.

    (a) Identification. Immunohistochemistry test systems (IHC's) 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 IHC's.
    (b) Classification of immunohistochemistry devices. (1) Class I for 
IHC's 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. These IHC's are used after the primary diagnosis of tumor 
(neoplasm) and malignancy is made by conventional histopathology using 
nonimmunologic histochemical stains such as hematoxylin and eosin. 
Examples of class I IHC are differentiation markers, such as keratin, 
which are used in adjunctive tests to subclassify malignant tumors.
    (2) Class II for IHC's that provide the pathologist with adjunctive 
diagnostic information that is ordinarily reported

[[Page 30200]]

as independent diagnostic information to the ordering clinician. 
Examples are IHC's for immunologic detection and semi-quantitative 
measurement of specific ligand markers of proliferation, such as Ki-67, 
or semi-quantitative determination of other analytes, such as hormone 
receptors, if they are reported for their prognostic implications. 
However, this classification does not apply to estrogen and 
progesterone receptors that are classified as class III devices.
    (3) Class III for IHC's that generate information that is reported 
directly to the clinician to be used as the basis for significant 
medical decisions, and that either provide information substantially 
independent of other pathological (or cytopathological) aspects of the 
specimen or that have novel claims not supported by current widely 
accepted scientific pathophysiologic principles. Examples are markers 
used to identify clinically significant genetic mutations in tissues 
that are normal by conventional histopathologic examination.
    (c) Date PMA or notice of completion of a PDP is required. No 
effective date has been established for the requirement for premarket 
approval for the devices described in paragraph(b)(3) of this section. 
See Sec. 864.3 for effective dates of requirement for premarket 
approval.

    Dated: May 31, 1996.
D.B. Burlington,
Director, Center for Devices and Radiological Health.
[FR Doc. 96-15140 Filed 6-13-96; 8:45 am]
BILLING CODE 4160-01-F