[Federal Register Volume 63, Number 106 (Wednesday, June 3, 1998)]
[Rules and Regulations]
[Pages 30132-30142]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-14605]



[[Page 30132]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. 94P-0341]
RIN 0910-ZA10


Medical Devices; Classification/Reclassification of 
Immunohistochemistry Reagents and Kits

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
to classify/reclassify immunohistochemistry reagents and kits (IHC's) 
into three classes depending on intended use. FDA is classifying/
reclassifying into class I (general controls) and exempt from premarket 
notification requirements IHC's used as adjunctive tests and presenting 
a low risk to public health. FDA is classifying/reclassifying into 
class II (special control) IHC's that detect or measure certain target 
analytes and that provide prognostic or predictive data that is not 
confirmed by routine histopathologic control specimens. The results of 
the class II IHC's are reported independently to the clinician, and the 
performance claims are widely accepted and supported by valid 
scientific evidence. FDA is classifying/reclassifying into class III 
(premarket approval) IHC's intended for any other use. The scope of 
products covered by this final rule includes both pre-1976 devices that 
have not been previously classified, as well as post-1976 devices that 
are statutorily classified into class III. The intent of this final 
rule is to regulate pre-1976 devices and post-1976 devices in a 
consistent fashion. Therefore, FDA is classifying or reclassifying 
these products as applicable.
EFFECTIVE DATE:  This rule is effective August 17, 1998.

FOR FURTHER INFORMATION CONTACT: Max Robinowitz, Center for Devices and 
Radiological Health (HFZ-440), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD 20850, 301-594-1293, ext. 136, or FAX 301-
594-5941.

SUPPLEMENTARY INFORMATION:

I. Background

    Immunohistochemistry (IHC) is the diagnostic laboratory practice 
that combines immunologic techniques, using specially prepared antibody 
reagents, with the examination of intact cells and tissues under the 
microscope by a pathologist or other trained laboratory scientist. An 
IHC device is an in vitro diagnostic reagent or test kit that uses 
immunological methods to identify antigens in tissues or intact cells. 
An IHC reagent is the primary antibody of an IHC assay that is 
developed to specifically target, react to, or combine with, a 
particular cellular or tissue constituent, or antigen, using specific 
immunological characteristics of the antibody. IHC's may be used 
together with a secondary or reporter antibody, buffers, washing 
solutions, and controls. If an IHC primary antibody reagent is sold 
separately, there should be recommendations for what ancillary reagents 
and equipment should be used with the IHC reagent to achieve the 
performance characteristics claimed for the primary IHC reagent. If the 
IHC is marketed as a test kit, there should be performance data with 
the finished test kit.

II. Highlights of the Final Rule

    In response to public comments, FDA has revised and clarified 
certain provisions of the final regulation. The revisions maintain the 
protection of the public health while reducing the regulatory burden on 
manufacturers by lowering the classification of a number of IHC's. The 
most significant changes from the proposed rule are as follows:
    1. Under the final rule, most IHC's are being classified as class I 
devices, exempt from premarket notification. Class I includes all IHC's 
being used as adjuncts to conventional histopathologic diagnostic 
examination.
    2. The definition of class II IHC's has been changed to include 
IHC's that are not directly confirmed by routine histopathologic 
control specimens and with claims that are widely accepted and 
supported by valid scientific evidence. Class II IHC's now include such 
products as estrogen and progesterone receptors (ER/PR's).
    3. The definition of class III IHC's has been narrowed to include 
only those IHC's that do not meet the criteria for class I or II.
    4. Accordingly, the rule lessens the regulatory burden for bringing 
IHC's to market because most IHC's are now classified/reclassified as 
class I or II. As post-1976 devices, most IHC's previously were class 
III devices under section 513(f)(1) of the Federal Food, Drug, and 
Cosmetic Act) (the act) (21 U.S.C. 360c(f)(1)).
    In addition, the agency clarifies and reinforces the following 
points:
    1. This final rule regulates only IHC's being used for diagnostic 
purposes. Neither the proposed rule nor the final rule would require 
submissions for reagents or test kits used for research purposes only. 
Nor does FDA require manufacturers of such research use only reagents 
or test kits to comply with general controls; and
    2. IHC's used for diagnostic purposes have been and will continue 
to be subject to the current good manufacturing practices (CGMP's) 
under the act. The requirement to comply with CGMP's is a general 
control that all devices must meet (unless expressly exempt under 
section 513(d)(2)(A)) of the act without regard to their level of 
classification or whether they have been previously classified. (See H. 
Rept. 94-853 at 17 (1976).)

III. The Final Rule

A. General Approach

    FDA believes that the final rule establishes reasonable 
requirements that can be implemented by the regulated industry without 
unnecessary burden. To ensure safety and effectiveness, all classes of 
IHC's will be subject to the following general controls: (1) Labeling 
requirements for in vitro devices (Sec. 809.10 (21 CFR 809.10)), (2) 
compliance with CGMP's, (3) registration and listing, (4) recordkeeping 
and medical device reporting (MDR), and (5) labeling for prescription 
use (Sec. 801.109 (21 CFR 801.109)). FDA has determined that these 
controls are necessary for a reasonable assurance of safety and 
effectiveness.

B. Class I Exempt From Premarket Notification

    In the final rule, FDA has broadened the class I identification to 
include all adjunctive IHC's. This change places the majority of IHC's 
into class I. The final rule also modifies the language in the 
regulation to clarify that class I IHC's are used to classify tumors.
    In response to comments submitted on the proposed rule, FDA 
reconsidered the regulation of class I IHC's and decided to exempt them 
from premarket notification (510(k)) requirements. In considering 
whether to exempt class I devices from premarket notification, FDA 
focuses on whether notification for the type of device is necessary for 
the protection of the public health. For the devices exempted from 
premarket notification by this rule, FDA has concluded that 
notification is unnecessary primarily for the following reasons:
    1. The devices do not have a significant history of false or 
misleading performance claims or of risks

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associated with inherent characteristics of the device, such as device 
design or materials. When making such determinations, FDA generally has 
considered the frequency, persistence, cause, or seriousness of such 
performance claims or risks, as well as other relevant factors.
    FDA is unaware of IHC failure being reported in the MDR data base. 
IHC failures have been reported in the medical literature; the risks of 
such failure, however, are mitigated by widely accepted practices that 
are based on valid scientific evidence.
    2. In general, FDA will exempt a device from premarket notification 
when the following factors apply: (a) Characteristics of the device 
necessary for its safe and effective performance are well established; 
(b) anticipated changes in the device that could affect safety and 
effectiveness will either be readily detectable by users by visual 
examination or other means, such as routine testing, before causing 
harm (e.g. testing of a clinical laboratory reagent with positive and 
negative controls), or not materially increase the risk of injury, 
incorrect diagnosis, or ineffective treatment; and (c) any changes in 
the device would not be likely to result in a change in the device's 
classification. FDA makes these determinations based on its knowledge 
of the device, including past experience and relevant reports or 
studies on device performance.
    The characteristics of IHC's are well established. Although the 
method is not generally quantitative, the results generated using this 
technology are sufficiently accurate and precise to support 
subclassification of tumors (neoplasms), and detection and measurement 
of the presence or absence of clinically significant target analytes. 
There are sufficient quality assurance techniques in the use of IHC's 
to enhance the precision of the methodology and minimize the risks of 
misdiagnosis.
    Because class I IHC's are identified as those that are used 
adjunctively to support conventional histopathological diagnosis and 
are controlled by readily available internal and external control 
materials, minor changes to the IHC would not materially increase the 
risk of injury, incorrect diagnosis, or ineffective treatment. 
Adjunctive test results are evaluated and incorporated into the 
diagnostic interpretation by the pathologist and are not usually 
reported directly to the clinician. Because laboratories certified 
under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) are 
required to run positive and negative quality control samples with all 
special stains, reagent failures are likely to be easily identified by 
pathologists. In addition, most slides will have normal along with 
abnormal tissue included as part of the tissue sample on the slide and 
this juxtaposition affords an additional opportunity to identify 
inappropriate or uncommon staining patterns.
    Manufacturers are reminded that exemption from the requirement of 
premarket notification is not an exemption from CGMP's and the other 
applicable general controls.
    Because IHC's have been classified in accordance with the risk 
associated with their intended use, a change in intended use or 
indications for use of an IHC would likely result in a 
reclassification. Such a change would not be considered minor and would 
probably require a submission to the agency. For a discussion of 
whether a change to a device would require a manufacturer to submit a 
510(k), see the FDA's guidance entitled ``Deciding when to Submit a 
510(k) for a Change to an Existing Device.''

C. Class II

    In contrast to all adjunctive IHC's being placed into class I, the 
final rule clarifies that class II IHC's are IHC's that generate 
results that are not directly confirmed by routine histopathologic 
internal and external control specimens. Class II IHC's are intended to 
provide information that is ordinarily reported as independent 
diagnostic information to the clinician. For an IHC to be classified 
into class II, the claims associated with this information must be 
widely accepted and supported by valid scientific evidence. FDA 
believes that the manufacturer/sponsor can establish the acceptance of 
the intended use of the IHC and valid scientific evidence through 
sponsor-supported studies or scientific literature references, 
materials from professional educational seminars, and/or the citation 
of practice standards or guidelines, as described in the special 
control noted in the paragraph below. These IHC's must be developed and 
established by validation and correlation testing with well 
characterized clinical specimens that support the intended use of the 
IHC test system as an independent prognostic or predictive marker. FDA 
believes that providing valid scientific evidence of performance claims 
that are widely accepted and complying with the general controls should 
be sufficient to ensure the safe and effective use of these IHC's.
    Class II IHC's are subject to a special control entitled ``FDA 
Guidance for Submission of Immunohistochemistry Applications to the 
FDA,'' FDA, Center for Devices and Radiologic Health, 1998. The updated 
guidance will assist sponsors in collecting and presenting data to FDA 
to establish that the claims associated with use of the device are 
widely accepted and that there is valid scientific evidence to support 
performance claims with clinical specimens. The special control is also 
intended to provide guidance to manufacturers about labeling for use of 
the device. This guidance has been issued as a Level 2 guidance 
consistent with the ``Good Guidance Practices'' (GGP's) FDA adopted for 
the development, issuance, and use of guidance documents (62 FR 8961, 
February 27, 1997). Persons interested in obtaining this document 
should refer to section VI of this document entitled ``Access to the 
Special Control.''
    Several comments urged that IHC's for ER/PR's be classified as 
class II devices rather than as class III, as proposed. FDA concurs 
with this suggestion. By using well characterized clinical specimens 
and validating their IHC's against appropriate FDA approved chemical 
receptor assays, manufacturers can reliably characterize these products 
and support their clearance as class II devices. FDA believes that 
class II classification can now safely apply to IHC's for ER/PR's, 
including hormone receptors in breast cancer, because clinical reliance 
on such testing has been established in the medical literature and the 
information derived from such test results are well understood.

D. Class III

    In response to comments on the proposed rule and changes to the 
class II classification, FDA has narrowed the scope of the class III 
identification. Under the final rule, IHC's that do not meet the 
criteria for class I or II will be classified into class III. 
Manufacturers of these IHC's must submit valid scientific evidence to 
support the new intended uses. An example of a class III IHC would be 
markers used to identify new, clinically significant target analytes in 
tissue specimens that cannot be confirmed by conventional 
histopathologic examination.
    FDA has amended proposed Sec. 864.1860(c) to indicate that 
postamendment class III IHC's cannot be commercially distributed unless 
the manufacturer has an approval under section 515 of the act (21 
U.S.C. 360e).

IV. The Proposed Rule

    In the Federal Register of June 14, 1996 (61 FR 30197), FDA 
published a

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proposed rule to classify/reclassify IHC's. The proposed rule contained 
the reasons for the proposed classification/reclassification, 
summarized the Hematology and Pathology Device Panel's recommendation 
regarding the classification of IHC devices, identified the risks to 
health presented by the devices, included a summary of the data upon 
which the proposed classification/reclassification was based, and 
delineated the statutory authority under which FDA issues this rule. 
Written comments were due August 30, 1996.
    The agency received 26 comments from individuals, manufacturers, 
professional societies, and the U.S. Small Business Administration. A 
summary of the written comments and FDA's response to them is provided 
in section V of this document.

V. Response to Comments

A. Classification

    1. Two comments supported the classification of IHC reagents and 
test kits into classes based on intended use as a balanced and 
responsible level of regulation that would: (1) Not impinge on the 
continued availability of these materials; (2) not negatively impact 
the advance of new technology due to application of inappropriately 
stringent regulatory controls; (3) not be overly burdensome to FDA or 
industry; or (4) not be inconsistent with the needs and interests of 
the medical professions, clinical laboratories, FDA, and industry.
    A third comment agreed with most of the proposed classification 
designations. A fourth comment stated that IHC's intended for 
adjunctive use were appropriately classified into class I. A fifth 
comment stated that most immunohistochemical antibody reagents should 
be regulated as class I because if they were ``over-regulated'' it 
would be difficult to bring the antibodies to market and the reagents 
were needed daily in the practice of surgical pathology.
    A sixth comment suggested that the proper classification for many 
IHC reagents and test kits would be class I 510(k) exempt in vitro 
diagnostic (IVD) devices. The comment argued that premarket 
notification (510(k)) should not be necessary because: (1) 510(k) 
clearance will not impact significantly on the expertise of the 
pathologist nor on the quality or reproducibility of 
immunocytochemistry/immunohistochemistry, which was the central factor 
in the safe and effective use of immunocytochemistry/
immunohistochemistry; (2) 510(k) clearance provided false reassurance 
to the inexperienced end user in making diagnoses based on possibly 
erroneous interpretations of data; and (3) of the negative implications 
of the cost of 510(k) clearance.
    A seventh comment argued that the benefits do not outweigh the 
costs for class I devices to be required to submit a 510(k). The 
comment argued that manufacturers have no control over how accurately a 
pathologist interprets results and that the correct focus should be on 
CGMP standards and other key determinants of manufacturing consistency 
and compliance.
    An eighth comment believed the majority of IHC's should be class I 
and exempt from premarket notification requirements. The comment argued 
that production of the antibody product was not the most critical and 
subjective step in this diagnostic technique and that FDA's resources 
were better spent in the area of ensuring reliable and consistent 
production through the controls of CGMP's, medical device reporting, 
registration, etc., to assure manufacturing consistency and compliance.
    FDA has considered these comments and has concluded that premarket 
notification is unnecessary for the protection of the public health for 
class I IHC's, which are those used to produce diagnostic information 
that is confirmed readily by other tests or procedures. Section 
513(d)(2)(A) of the act authorizes FDA to exempt class I IHC's from the 
requirement of premarket notification in section 510(k) of the act (21 
U.S.C. 360(k)). This exemption permits manufacturers to introduce into 
commercial distribution those IHC's that fall within the class I 
classification without obtaining premarket clearance from FDA. 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 classifying these devices as class I and 
applying general controls will ensure that the majority of adjunctive 
IHC's are used safely and effectively without the need to require 
premarket notification. The Food and Drug Administration Modernization 
Act of 1997, which became effective on February 19, 1998, does not 
eliminate the need for this rule or require changes with respect to 
FDA's determinations about classification of these products. The rule 
establishes a classification scheme for all IHC's including many that 
were not previously classified as well as class III IHC's. The class I 
IHC's that are exempt from premarket notification under this rule do 
not fall into the category of those class I devices that continue to 
require premarket notification under the new legislation (section 
510(l) of the act). Nor does the agency believe that the IHC's being 
classified into class II by this rule are appropriate for exemption 
from 510(k) submissions under new section 510(m) of the act.
    2. One comment requested clarification concerning the scope of the 
proposed regulation as it pertains to ``ancillary reagents'' (including 
detection systems). The comment recommended that ancillary reagents, 
including secondary antibodies, buffers, and chromogens, should most 
appropriately be regulated as general purpose reagents under 
Sec. 864.4010 (21 CFR 864.4010), and subject to Sec. 864.1860 (21 CFR 
864.1860) only when packaged with one or more primary antibodies as 
components of a complete test system.
    FDA agrees in part with the comment. ``Ancillary reagents'' are 
subject to Sec. 864.1860 when they are packaged with one or more 
primary antibodies as a complete test system. In addition, ancillary 
reagents are also subject to this regulation when they are sold with 
performance claims for their use as a general detection system in 
conjunction with primary antibodies that are sold separately. FDA 
agrees that secondary antibodies, buffers, and chromogens may be 
regulated as general purpose reagents under Sec. 864.4010 when these 
reagents are sold without performance claims.
    3. Two comments requested clarification concerning whether devices 
in commercial distribution prior to May 28, 1976, must comply with the 
classification and requirements in the proposed rule, particularly the 
proposed labeling recommended in the March 28, 1995, guidance listed as 
Ref. 6 in the proposal (61 FR 30197 at 30199). The comment argued that 
the regulation of ``pre 1976 devices which have not been previously 
classified'' contradicts Sec. 807.85(b)(1) (21 CFR 807.85(b)(1)), which 
exempts ``grandfathered'' products from 510(k) review.
    These comments misunderstand the meaning of Sec. 807.85(b)(1). 
Section 807.85(b)(1) establishes exemptions from premarket notification 
for private label distributors and repackagers who distribute devices 
that already are being legally marketed without making any changes to 
the device or its labeling beyond the addition of the private label 
name. The exemptions in Sec. 807.85(b)(1) do not apply to device 
manufacturers and distributors generally.
    It is true that the requirement to submit a premarket notification 
before introducing a device into the market

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after May 28, 1976, does not apply to devices that were legally 
marketed prior to that date. However, as explained in 21 CFR 
807.81(a)(3), a manufacturer of a device that was marketed prior to the 
1976 amendments is required to file a 510(k) if the devices was 
significantly changed or modified in design, components, methods of 
manufacture, or intended use. A first time manufacturer of a device 
that the manufacturer believes to be the same or substantially 
equivalent to a device that is already marketed also must submit a 
510(k) to establish that substantial equivalence, unless the product 
has been exempted from notification under 513(d)(2)(A).
    As discussed previously, preamendment devices have been and will 
continue to be subject to general controls, such as CGMP's and the 
existing labeling requirements (Sec. 809.10) for in vitro devices. 
Although manufacturers of preamendment class II IHC's that are not 
required to submit 510(k)'s will have no need to utilize FDA's guidance 
being established as a special control, manufacturers of preamendment 
devices that are modified in a way that will require submission of a 
new 510(k) should consult the special control: ``FDA Guidance for 
Submission of Immunohistochemical Applications to the FDA'' when 
submitting premarket notifications for class II devices. Because this 
special control is a guidance, no manufacturer is bound to follow the 
details of the document (see response to comment 13 in section V of 
this document).
    4. Three comments argued that additional regulation will do nothing 
to lower the risk of misinterpretation of results. The comment stated 
that IHC's have almost always been used as an adjunct to other 
diagnostic techniques and that the proposed regulations would not 
necessarily accomplish FDA's stated objectives of reducing risks to 
patients.
    FDA's regulation of IHC assays is limited to oversight of the 
manufacturers of IHC reagents or test kits; the rule does not regulate 
the end users or their laboratories. FDA recognizes that safe and 
effective IHC's do not by themselves guarantee that an IHC in the end 
user's laboratory will be used accurately and reliably. FDA agrees that 
IHC assays are multistep IVD test systems that require the expert 
supervision of a qualified pathologist or laboratory scientist to 
ensure that all the preanalytic, analytic, and postanalytic steps are 
performed accurately and reliably.
    FDA believes, however, that the building blocks of those assays 
should be safe, effective, and properly labeled for their intended use. 
The risks associated with use of an IHC include the likelihood of 
obtaining a false result, while the effectiveness of an IHC is 
dependent upon the likelihood of the IHC performing as claimed by the 
manufacturer. In accordance with Sec. 809.10, the label must include, 
among other things, the intended use, indications for use, the 
instructions for use, and limitations. The manufacturer is required to 
support any performance claims for accuracy, precision, sensitivity, 
and specificity included on the label of the IHC device with valid 
scientific evidence. The labeling also should include statements that 
remind the end user of the variable nature of the specimens to be 
examined by the IHC, i.e., biologic variability of the tissues and 
patients, the need for procedures relating to preanalytic fixation, 
handling, processing, storage, and the variability and subjectivity in 
the interpretation of the IHC slides.
    Contrary to the assertion of some comments, FDA believes that such 
regulation does reduce risks associated with use of IHC's. The 
requirements that labeled performance claims be supported by valid 
scientific evidence and that labeling include instructions for use, 
limitations, and information about variability significantly increases 
the likelihood that the end user will have a product that will be used 
safely and effectively in the laboratory.
    In response to comments that implied that industry experts did not 
believe regulation of IHC's was necessary to reduce risks associated 
with their use, FDA notes that its classification/reclassification 
initiatives with respect to IHC's are based on input from public 
workshops, advisory panels to the FDA, and industry petitions for 
reclassification, as well as FDA experience with assessment of the 
safety and effectiveness of IHC devices.
    FDA is aware that its regulation of IHC's is supported by other 
assurances of safe and effective performance of the assays. For 
example, there is widespread participation by end users in voluntary 
and mandatory training in IHC assays and proficiency testing in IHC 
assays by other government and professional organizations. End users 
may also use voluntary guidelines to ensure reliable and accurate 
performance of IHC assays within their laboratories, e.g., ``The 
National Committee for Clinical Laboratory Standards (NCCLS) Quality 
Assurance for Immunocytochemistry; Proposed Guideline, MM4-P,'' 
February, 1997. (The approved NCCLS guideline is expected within 2 
years.) However, FDA believes such voluntary standards and practices 
cannot serve as a complete substitute for government regulation of 
these devices. The existence of such guidelines and widespread 
compliance with their recommendations has contributed to FDA's 
determination that most of these devices can be regulated at the least 
stringent level of control and be exempt from premarket notification.
    5. One comment did not support placing IHC's in which test results 
were ``ordinarily reported as independent diagnostic information'' into 
class II because the manner in which IHC test results were reported was 
determined independent of the IHC supplier or FDA. The comment stated 
that because there may be significant laboratory-to-laboratory and 
within-laboratory variation in how results were reported, it would be 
difficult to consistently determine device classification on the basis 
of how results were reported.
    FDA agrees that the IHC manufacturer is not responsible for how 
each end user laboratory scientist will report the results of an IHC 
assay. However, the manufacturer is responsible for recommendations and 
performance claims on the product's label (see Sec. 809.10). Such 
indications and directions for use are important for the proper 
performance of the assay and as a reference for compliance with the 
CLIA requirements for the end user laboratory (42 CFR 493.1211). An 
individual laboratory that chooses to use the device differently or 
report results in a manner contrary to labeled recommendations is 
responsible for that decision and validation of that use.
    FDA defines independent diagnostic information as information that: 
(1) Is the sole or a major determinant of a diagnosis; (2) is used by 
itself as the basis for a significant medical decision; or (3) may not 
be readily confirmed by other diagnostic tests or clinical procedures. 
FDA believes it is possible to identify IHC's for which test results 
ordinarily are reported as independent diagnostic information to the 
ordering clinician, and for which the claims associated with these data 
are widely accepted and supported by valid scientific evidence. Those 
IHC's that generate independent diagnostic information and where the 
claims are not widely accepted will be reviewed as class III devices 
and approved for marketing if there is valid scientific evidence to 
support those claims.
    6. One comment stated that it was unclear why Ki-67 was class II, 
while hematoxylin and eosin (H & E) staining, which was the more 
critical assay, was class I. The comment added that class II reagents 
had no characteristics clearly

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distinguishable from those proposed to be in class I.
    The agency believes there are differences between H & E stains and 
IHC's. Despite the critical nature of the assay, biologic stains such 
as H & E have been placed in class I and exempted from 510(k) review 
because FDA determined that the stains were well understood, with 
commonly used controls that permit the user to readily detect 
deviations in staining properties. For these reasons, FDA concluded 
that general controls were sufficient and 510(k) submissions were not 
necessary to establish reasonable assurance of safe and effective use 
of H & E stains. IHC's, on the other hand, use monoclonal or polyclonal 
antibodies that may require specific testing or reagents to verify that 
the assay meets the manufacturer's specification for performance (see 
also comment 14 of section V of this document). Under the final rule, 
however, most IHC's will also be regulated as class I devices exempt 
from premarket notification.
    FDA has made changes to the final rule that further distinguish 
class I from class II IHC's. Class I IHC's are adjunctive IHC's. Class 
II IHC's generate results that ordinarily are independently reported to 
the clinician. However, the primary difference between a class I or II 
IHC depends on the manufacturer's claims in the proposed product 
labeling for an IHC reagent or test kit because it is these claims that 
establish the intended use of the IHC. An identical device can be 
subject to a range of regulatory controls--from the lowest to the 
highest levels of regulation--depending on the claims being made and on 
the issues of safety and effectiveness associated with those claims.
    Ki-67, the example referenced in the comment, is the name of a 
monoclonal antibody clone that recognizes a nuclear antigen that is 
expressed only in proliferating cells. A Ki-67 IHC will yield a 
positive qualitative result in normal and abnormal proliferating cells. 
This result correlates with the presence of mitotic activity. A Ki-67 
IHC would be classified into class I, exempt from premarket 
notification if: (a) The intended use of the assay result is to provide 
adjunctive information that indicates the presence or absence of cell 
proliferation in all or some of the cells within a tissue sample; (b) 
the IHC can be controlled by the user with readily available positive 
and negative tissues controls; (c) the result will be incorporated into 
the pathologist's differential diagnosis; and (d) the result will not 
be reported as independent information to the clinician.
    A Ki-67 IHC would be classified into class II if: (a) The sponsor 
claims that the IHC results could be used as a stand-alone test to 
determine prognosis independent of other findings; (b) the user must 
use clinically well-characterized tissues to serve as positive and 
negative controls; or (c) the analytic result will be reported as 
independent information to the clinician. A Ki-67 IHC would be 
classified into class III if the sponsor claims that the IHC will be 
used in combination with a novel amplification method that would allow 
this IHC to be used as a stand-alone detection system for 
micrometastases in tissue, or some other new intended use.
    The previous comment was in response to the proposed rule. As 
discussed previously, the final rule establishes that the majority of 
IHC's are adjunctive and will fall within class I, exempt from 
premarket notification. For those IHC's that are not adjunctive, the 
majority will be class II because they have claims that are widely 
accepted and supported by valid scientific evidence.
    7. FDA received conflicting comments about the necessity of 
classifying certain types of IHC's in class III. Two comments stated 
that IHC's intended for stand-alone use in making clinically 
significant determinations, such as markers used for the detection of 
medically important genetic mutations in tissues that were normal by 
conventional histopathology, should be regulated as class III devices 
until more information regarding the safety and effectiveness of these 
tests became available. A third comment stated that, with the exception 
of a limited number of class III devices that define a site-specific 
therapeutic intervention and were used to provide circumstantial 
information in support of H & E based histopathological diagnosis, 
markers should be classified as class I exempt from premarket 
notification. A fourth comment added that the higher classifications 
were not relevant because currently there was no IHC for a prognostic/
proliferation marker that was a reliable ``stand-alone'' indicator and 
whose use was generally accepted.
    FDA agrees that the IHC's described in the first two comments 
should be regulated as class III devices and not be commercially 
marketed until a premarket approval application (PMA) establishes that 
there is valid scientific evidence to support safe and effective use of 
such products. The agency also agrees with the general point being made 
by the third comment and has classified the majority of IHC's into 
class I and exempted them from premarket notification requirements. 
With respect to the fourth comment, the agency does not agree that the 
identification of class III IHC's is not relevant. The fact that the 
comment is unaware of products currently on the market that fit the 
identification does not obviate the need for FDA to have regulations in 
place for review of such products when they become available.

B. Costs

    8. One comment stated the FDA may also have underestimated the cost 
associated with the submission of 510(k) and PMA's and compliance 
inspections for many firms engaged in manufacturing IHC's for research 
purposes that will be required to register under the new rule.
    This comment was made under the mistaken assumption that this rule 
applied to manufacturers of research products as well as to 
manufacturers of IHC's marketed for diagnostic use. As noted 
previously, this rule does not apply to manufacturers of research 
products and, therefore, imposes no new burden on them. FDA also 
believes that this comment was made under the mistaken assumption that 
this rule would create a new requirement for firms to comply with 
CGMP's. As discussed previously, the requirement to meet CGMP's is not 
the result of this rulemaking; manufacturers of IHC devices marketed 
for diagnostic use have always been required to comply with CGMP's 
under section 520(f) of the act (21 U.S.C. 360j(f). Finally, FDA 
reiterates that it has reconsidered its position since the proposed 
rule and has established a classification scheme that does not require 
510(k)'s for the majority of these IHC devices, and that places most 
remaining IHC's in class II. Therefore, existing firms that are 
currently in compliance with CGMP's should not experience any increased 
costs because of this rule.

C. Definition of IHC

    9. One comment supported the proposed definition for IHC reagents 
and test kits because the definition distinguished between IHC reagents 
and analyte specific reagents (ASR's) or flow cytometry reagents. The 
comment also supported the use of performance claims and directions for 
use with IHC's.
    FDA agrees with this comment. The definition of IHC's and labeling 
requirements have been retained in the final rule.
    10. One comment was concerned that the IHC definition was 
``technology-specific'' and limited to only those devices that employ 
monoclonal or polyclonal antibodies. The comment

[[Page 30137]]

argued that the operating technology used by the device should be of 
secondary consideration, provided that the test was intended for 
adjunctive use along with other conventional histopathology techniques.
    FDA disagrees with this comment. Although the operating technology 
of the device is of primary importance in identifying an IHC, the 
intended use of the device will establish its regulatory class. The 
final rule provides a broad and inclusive regulatory path for 
commercialization of new versions of currently available IHC devices or 
IHC devices that are intended to detect a new analyte in tissues or 
cells. This classification/reclassification is intended to decrease the 
burden on FDA and industry by obviating the need to individually 
classify IHC devices that detect previously identified or newly 
identified analytes.

D. Estrogen and Progesterone Receptors

    11. Three comments recommended that ER/PR's be placed in class II 
instead of class III, as had been proposed. One comment argued that 
regulating hormone receptors as class III medical devices may limit the 
availability of an important testing modality, forcing patients to rely 
upon less accurate methodology for testing results. Two comments 
maintained that ER/PR's should not be class III because they were not 
used as stand-alone tests; the information they provided was 
substantially dependent on other pathological or cytopathological 
aspects of the specimen, and these tests did not have novel claims not 
supported by current widely accepted scientific pathophysiologic 
principles. A third comment recommended reclassifying ER/PR assays into 
class II because it was likely that there was a sufficient accumulated 
history of safe and effective use of the tests to support the 
reclassification and because FDA had published a guideline for 
premarket submissions of ER/PR assays that could be used as a special 
control.
    FDA agrees with these comments and has modified the regulation 
accordingly. The first IHC tests for ER/PR's were in vitro steroid-
binding chemical assays that used dextran-coated charcoal to separate 
bound from free fractions. These IHC tests were subject to class III 
premarket approval because there was no substantially equivalent 
legally marketed predicate device, a necessary requirement to qualify 
for premarket notification (510(k)). There were additional safety and 
effectiveness considerations raised by these devices, including the 
likelihood that ER/PR results would be used as stand-alone test results 
that would serve as the basis for choice of therapy and the inability 
to confirm these results by other IVD tests or clinical procedures. 
However, after evaluating the comments and reviewing the peer-reviewed 
literature regarding use of these IHC's, FDA believes that IHC's for 
estrogen, progesterone, or other hormone receptors now can be 
classified/reclassified into class II under the final regulation when 
their claims are widely accepted and there is valid scientific evidence 
to support those claims.
    12. Two comments stated that there was confusion about which 
products were covered under the proposed rule and used estrogen 
receptor (ER) as an example. The comment suggested it was not 
appropriate to place all ER's in a single class because that class 
could not take into account differences between broad antigen 
recognition and clones reacting with certain epitopes or populations of 
ER, even though there was no clinical utility for some clones.
    FDA disagrees with these comments and believes they are based on a 
misunderstanding of the proposed rule. FDA does not intend to require 
premarket submissions for reagents or tests kits that are for 
``research use only.'' The regulation requires premarket submissions 
only for ER/PR reagents or test kits that are intended to be marketed 
``for in vitro diagnostic use'' to obtain clinical information. If an 
IHC reagent or test kit marketed for clinical use includes antibodies, 
FDA requires the IHC manufacturer to identify the clones of those 
monoclonal antibodies used in the IHC reagent or test kit that support 
that intended use.

E. Guidance Document

    13. One comment argued that a guidance document cannot be a special 
control because using a draft guidance document as a special control is 
an inappropriate use of guidance documents, and that it seemed to 
contradict the interim policy announced by FDA concerning guidances to 
use a guidance as if it were a rule.
    FDA disagrees that a guidance document cannot be a special control. 
``Guidelines (including guidelines for the submission of clinical data 
in premarket notification submission * * *)'' are expressly listed in 
section 513(a)(1)(B) of the act as an example of special controls. In 
addition, FDA guidance documents are specifically listed as potential 
special controls in the legislative history of the Safe Medical Devices 
Act of 1990 (H. Committee Rept. 101-808, October 5, 1990, p. 28).
    Moreover, consistent with FDA's policy on GGP's, the agency 
published for public comment a ``draft'' of this FDA guidance document 
in advance of it being used as a special control (62 FR 8961, February 
27, 1997). The guidance entitled ``FDA Guidance for Submission of 
Immunohistochemical Applications to the FDA'' was developed by FDA in 
conjunction with professional organizations, manufacturers of 
immunohistochemical products, and the advisory committees of FDA. The 
draft has been revised in response to public comments, and the guidance 
is available to the public as delineated in section VI of this 
document.
    FDA is using this guidance in conformance with its policy 
concerning guidances. The guidance is intended to provide information 
about acceptable ways to facilitate the gathering of data to ensure 
reasonable safety and effectiveness of those IHC devices whose safety 
and effectiveness cannot be ensured by general controls alone. Although 
the guidance represents FDA's best thinking about ways to efficiently 
and effectively gather and submit data to support the marketing of 
these devices, neither the manufacturer nor the agency is bound by the 
details of that guidance. As stated in the guidance document, 
manufacturers are free to use alternative methods that achieve the same 
underlying standard of safety and effectiveness.

F. Impact of Proposed Rule

    14. One comment stated the author's belief that IHC's were utilized 
under the guidance of board certified pathologists a significant 
percentage of the time and had a performance record equal to or greater 
than stains used since the turn of the century. This comment maintained 
that undue restrictions on the use of the reagents would impact on the 
availability of existing and future antibodies to the detriment of 
patient care.
    FDA agrees in part with this comment. FDA is treating IHC's used to 
provide adjunctive information the same as H & E stains by classifying 
these products into class I and exempting them from the requirement to 
submit 510(k)'s. Histopathologic and cytologic diagnostic tests that 
use either conventional stains such as hematoxylin and eosin or IHC 
methodologies are part of a multistep process that requires the direct 
supervision of a qualified pathologist or other laboratory scientist to 
ensure safe and effective results. However, FDA does not consider IHC's 
to be equivalent to conventional biologic stains and has not exempted 
IHC's from CGMP requirements although it did exempt the stains from 
CGMP's. FDA considers IHC's to be

[[Page 30138]]

more complex to develop, manufacture, and standardize. FDA exempted 
conventional biologic stains from premarket notification and compliance 
with CGMP's because these stains have well-established chemical and 
physical specifications and quality assurance. In addition, there are 
voluntary organizations such as the Biologic Stain Commission that test 
and certify the specifications of biologic stains. The final rule 
ensures that all commercialized IHC reagents and test kits for in vitro 
diagnosis are manufactured under general controls including CGMP, 
thereby enhancing reliability and consistency for end users of these 
products.

G. Panel Meeting

    15. One comment stated that the October 21, 1994, meeting of the 
Hematology and Pathology Devices Panel (the Panel) was procedurally 
flawed. The comment referenced a complaint filed by a Washington, DC, 
law firm that FDA inaccurately described the regulations to the Panel 
members, and that this alleged misinformation was the basis for their 
recommendations. The comment recommended that it be stated in the 
administrative record that the advisory Panel meeting was procedurally 
flawed, that the Panel recommendations should not be used to support 
the decisions made by FDA about the classification of these products, 
or that the Panel meeting should be invalidated and reconvened for 
further consideration of the issue.
    This comment refers to a complaint about a FDA employee's public 
comment that CGMP inspections for class I IVD device manufacturers are 
so relatively low on the priority list for the agency actions that 
there is a strong likelihood that these manufacturers will not get 
timely CGMP inspections. The comment argues that this statement exerted 
undue influence on the Panel. Because requiring compliance with CGMP's 
was a high priority for pathologists and other laboratory scientists, 
the comment asserts that the Panel recommended that IHC's should be 
class II medical devices in large part to ensure timely CGMP 
inspections.
    FDA does not agree with this comments' characterization of the 
Panel meeting. While FDA agrees the Panel was concerned that IHC's be 
subject to CGMP's, FDA believes the availability and need for a special 
control is the basis for the Panel's recommendation that most IHC's be 
classified as class II. However, as discussed previously, FDA has 
reconsidered this recommendation of the Panel and amended the proposed 
rule to place most IHC's in class I and exempt from premarket 
notification. FDA does not believe that class II regulation is required 
for all IHC reagents and test kits for the reasons discussed in section 
III.B of this document. Unless specifically exempted, all manufacturers 
of FDA regulated medical devices must comply with general controls, 
which include CGMP's, regardless of whether or not the device is in 
class I, II, or III, or exempt from premarket notification. While FDA 
acknowledges that its limited resources do not allow inspections to be 
as frequent as it might wish, the agency's experience shows that 
competitors and dissatisfied customers will provide the agency with 
information about circumstances that require more immediate followup.

H. Practice of Medicine

    16. One comment argued that whether a reagent was used to make 
``significant medical decisions'' was an inappropriate criterion for 
classification. The comment argued that classifications did not rely on 
the intent of the manufacturer, but on the physician's usage, which the 
comment argued was the practice of medicine and beyond the 
responsibility of a manufacturer. The comment stated that the basis for 
device classification in this rule was medical practice (e.g. 
``significant medical decisions,'' ``markers of clinically significant 
genetic mutations,'' and ``adjunctive diagnostic information that was 
ordinarily reported as independent diagnostic information to the 
ordering clinician'') that was inconsistent with the current 
requirements of law for determining classification and an attempt to 
regulate the practice of medicine.
    FDA does not regulate medical practice. FDA regulates the 
manufacturers of IVD tests to ensure reasonable safety and 
effectiveness of these products for the claimed intended use and 
indications for use. The rule focuses on the use to which the 
information being generated by the IHC will be put because it is the 
IHC's intended use that determines the level of safety and 
effectiveness that must be assured. An IHC manufacturer must document 
the safety and effectiveness of these intended uses and indications for 
use with valid scientific evidence. If a laboratorian or clinician uses 
an IHC test for purposes not recommended by the IHC manufacturer, these 
would be off-label uses that become the responsibility of the 
laboratory scientist or clinician to establish and validate.
    The level of risk to a patient associated with use of an IVD must 
account for the consequences of inaccurate results. The level of risk 
rises with the seriousness of consequences from a false result, the 
likelihood of the false result occurring, and the number of persons 
likely to be exposed to the risk of a false result. All of these risks 
are weighed against the benefit of the assay if it is performed 
accurately for its intended use and the risk from not having the 
results from the IHC assay. When evaluation of risks and benefits 
requires FDA to seek information about the use to which test results 
are to be put, such data collection is not an intrusion into the 
practice of medicine but the necessary review of information that is 
essential to establish whether the product can be marketed as labeled 
by the manufacturer with reasonable assurance of safety and 
effectiveness.

I. Prescription

    17. One comment stated that it was inappropriate to include 
Sec. 801.109, which provides that antibodies be provided only upon 
authorization by a physician, as a general control applying to IHC's. 
The comment argued that it would put severe restrictions on a 
researcher wishing to purchase the reagents and was a complete change 
from the way IHC's were currently ordered. The comment maintained that 
many of the requirements of Sec. 801.109 were inappropriate for IHC's, 
such as frequency or duration of administration and side effects, and 
that generating and tracking this information would be burdensome to 
the manufacturers and result in added cost to the customer. The comment 
added that this requirement appeared to impose a ``drug model'' on 
device manufacturers. The comment recommended that the proper general 
control was 21 CFR 801.119. A related comment questioned whether a 
physician prescription was necessary for the research use of FDA-
approved and marketed IHC reagents and stated that such a requirement 
had a high potential to hinder legitimate biomedical research efforts. 
Five other comments stated that a key concern was that IHC reagents be 
purchased only on the order of a physician, even if the reagents were 
being used for research use.
    FDA disagrees with these comments. As stated previously, the rule 
does not apply to IHC's used for research and FDA does not require any 
premarket submissions from manufacturers of products labeled and 
intended ``for research use only.'' FDA does not restrict the purchase 
of reagents or test kits used for research, and FDA does not require a 
physician's prescription if

[[Page 30139]]

these products are not to be used for diagnosis or management of 
patients.
    Section 801.109 applies only to IVD devices intended for clinical 
use in the diagnosis and management of patients. These devices are 
required to be in the possession of practitioners licensed by law to 
use or order such devices. Physicians are not the only practitioners 
allowed to use or order IVD tests. Other practitioners include 
dentists, veterinarians, nurses, or others licensed by applicable State 
law to use or order the use of the device.

J. Research Use

    18. Several comments were concerned that the proposed rule would 
limit basic research by requiring IHC's used only in research to be 
subject to the requirements of this regulation. Another comment 
requested clarification about FDA's position with respect to antibodies 
intended for use as immunohistochemical research reagents and whether 
such antibodies could be marketed as ASR's. The comment also questioned 
whether low or moderate complexity clinical laboratories would be able 
to use these products if the products were marketed as ASR's.
    As discussed previously, FDA does not require premarket submissions 
from manufacturers or users of in vitro reagents or test kits that are 
labeled ``for research use only.'' FDA introduced the ASR regulations 
to allow manufacturers to simplify the commercialization of new ASR's 
for diagnostic use before these reagents have established performance 
characteristics. IHC reagents may be marketed as ASR's as long as they 
comply with the ASR regulations(Sec. 809.10, 21 CFR 809.30, and 
864.4020). The product must be manufactured under general controls, 
which include CGMP's. The product cannot be sold with any performance 
claims, intended use, indications for use or instructions for use. It 
is the responsibility of the end user to validate the intended use, 
indications for use, and performance characteristics of the ASR. It is 
because of the high level of proficiency required of the end user that 
the ASR regulations restrict the use of ASR's to high complexity 
laboratories.

K. Reimbursement Status

    19. One comment asked FDA to discuss with the Health Care Financing 
Administration (HCFA) and announce the Medicare reimbursement status 
of: (1) IHC reagents in the interim period while manufacturers prepared 
and FDA cleared 510(k) submissions, and (2) IHC reagents that have been 
designated as ASR's.
    Manufacturers who have questions about HCFA reimbursement should 
address their questions directly to HCFA. FDA's regulatory decisions 
are based on providing assurance of safety and effectiveness of these 
devices and are made independent of HCFA's reimbursement decisions. 
HCFA does consider FDA's clearance and approval of IVD devices as part 
of HCFA's decision to approve reimbursement. HCFA's decision to 
reimburse for IVD devices is a cost-benefit decision about whether the 
device is reasonable and necessary to establish a diagnosis or for 
patient management.

L. Small Entities

    20. One comment from a trade association requested that FDA re-
examine its assertion that ``the proposed rule will not have 
significant impact on a large number of small entities.'' The comment 
stated it was aware that FDA made no formal study in arriving at its 
conclusion and has not placed any data in the docket to support the 
decision. The comment stated that most of the suppliers of antibodies 
to the research community are small businesses that would be severely 
affected by a requirement to manufacture small quantities of a large 
number of products under CGMP regulations. The comment argued that its 
membership estimates the cost of an antibody submission at between 
$10,000 and $40,000 per antibody when the manufacturer follows the 
draft guidance document and that the sales volume of most of these 
products could not justify this expense.
    Another comment stated that FDA had offered no analysis or study to 
support its conclusion that there would be no significant economic 
impact on a substantial number of small entities. The comment stated 
that, in order for an agency to certify that a rule would not have a 
significant economic impact on a substantial number of small entities, 
an agency must first demonstrate that it had made a reasonable 
preliminary assessment of what constituted a small entity in the 
affected industry, the number of small entities likely to be affected, 
and the impact of the regulation on those businesses. The comment 
argued that FDA had an affirmative obligation to explain why reasonable 
alternatives were rejected and to demonstrate that there had been 
outreach to the affected industry.
    These comments were made under the mistaken assumption that this 
rule applied to manufacturers of research IHC products. Manufacturers 
of preamendment IHC medical devices for diagnostic use already are 
required to comply with general controls applicable to all 
manufacturers of devices, and this rule does not add any new obligation 
with respect to that requirement. All postamendment IHC devices require 
premarket approval or an order finding substantial equivalence unless 
exempted by statute or regulation. The effect of this rule is to 
establish that the majority of these postamendment devices will now be 
in class I and exempt from any premarket submissions. Although these 
devices will continue to be subject to general controls, the rule will 
impose no new burdens for most of these devices. In fact, the rule will 
reduce the economic burden for many of these manufacturers because they 
will no longer be required to submit PMA or 510(k) applications for 
most of their products.
    FDA has prepared an analysis of impact for this rule in section VII 
of this document and alternatives to the final rule are discussed 
there. In response to the comment on agency outreach to the affected 
industry, FDA notes that it convened a public meeting of the Hematology 
and Pathology Devices Panel in October 1994 and received written 
comments from interested parties before, during, and after the meeting.
    FDA believes this final regulation will not have a significant 
adverse impact on small businesses that currently are in the business 
of manufacturing IHC's. FDA believes the regulation ensures the public 
that IHC reagents and test kits are reasonably safe and effective for 
their intended use. At the same time, FDA does not intend or expect the 
regulation to impede the timely development of safe and effective 
medical devices. The level of regulation is designed to be in 
proportion to the need for regulatory oversight based on claims and 
promotion that a manufacturer makes for its products and the risks the 
products pose. A product that is to be sold and used as a ``for 
research use only'' reagent or test kit does not fall within the scope 
of the rule and the manufacturer of these devices currently does not 
have to comply with CGMP's. However, an IHC manufacturer that wants to 
promote reagents for diagnosis or management of patients is required to 
comply with the final rule and provide valid scientific evidence to 
support its claims for the intended use of the device, indications for 
use, and performance characteristics, unless exempted by the rule.
    The agency notes that the final rule exempts most IHC's from 
premarket submission requirements because the majority of IHC's are 
adjunctive and will be classified as class I, exempt from

[[Page 30140]]

premarket notification. Even when premarket submissions are required, 
for the most part premarket notification (510(k)) is required, rather 
than premarket approval. Most of the remaining IHC's will be classified 
as class II devices because they provide independent information and 
have claims that are widely accepted and supported by valid scientific 
evidence. Moreover, FDA is providing guidance for those IHC's requiring 
510(k)'s. The guidance entitled ``FDA Guidance for Submission of 
Immunohistochemical Applications to the FDA'' serves as a special 
control to assist sponsors in collecting and presenting these data to 
FDA for clearance of their class II devices. The guidance may also 
serve as a resource for manufacturers of class I IHC's who do not have 
to submit 510(k)'s but will nevertheless want to properly develop and 
validate their products prior to marketing. PMA's are only needed for 
those IHC's that do not meet the class I and II criteria.
    The regulation does require manufacturers of class II and class III 
IHC's to submit valid scientific evidence to support the intended use 
of these products. In many cases, much of the necessary data may be 
available in the peer reviewed/refereed scientific literature. In those 
cases where published data are available, the burden on the 
manufacturer is minimal, and the guidance being established as a 
special control can provide small and large firms with information to 
help identify and submit such data. However, published data may not be 
available for other IHC reagents or test kits that the manufacturer 
wishes to modify or for new intended uses or indications for use of 
these IHC devices. In those cases, manufacturers will have to gather 
new testing data to support the claims.
    There also may be IHC reagents or test kits that do not have the 
potential volume of sales to justify any manufacturer's business 
decision to comply with FDA's requirements for data to support the 
reasonable assurance of safety and effectiveness for particular labeled 
claims and uses. In those cases, the manufacturer may commercialize the 
IHC products with lesser performance claims or as an ASR and transfer 
the responsibility for validation of the finished assay to the user. In 
addition, manufacturers of low use/low revenue products may choose to 
commercialize the IHC under the humanitarian device exemption 
procedures (21 CFR part 800, subpart H). Each IHC manufacturer, whether 
a large or small firm, will be able to control the impact of the final 
rule on its business by carefully evaluating the claims and uses it 
intends to promote for particular products.
    The minimal level of IHC IVD device regulation will be the ASR 
regulation. Class I ASR's are exempt from premarket notification, but 
must be manufactured in compliance with general controls to be legally 
marketed as IVD reagents for diagnosis and management of patients. 
Because ASR's do not require data to support an intended use, 
indications for use, or performance characteristics; ASR product 
labeling cannot include any claims for intended use, indications for 
use, or performance characteristics. The sale of ASR's is restricted to 
high complexity laboratories that are able to take the responsibility 
for establishing and validating the reagent for an intended use, 
indications for use, and performance characteristics of the finished 
assay (62 FR 62243, November 21, 1997).
    21. One comment requested that new hearings be held and that 
representatives of all small companies who will be affected by the 
regulation be given an opportunity to speak and be heard not only by 
FDA but also by congressional representatives.
    The Administrative Procedures Act gives agencies discretion over 
whether to hold oral hearings in connection with informal rulemakings 
(5 U.S.C. 553(c)). FDA believes that providing an opportunity for 
written comment on the proposed rule has provided sufficient 
opportunity for small entities to comment on this rulemaking. Moreover, 
FDA has already held a public hearing soliciting comment on the 
classification of immunohistochemical devices. That hearing, which was 
convened on October 21, 1994, was open to all interested parties, 
including small business entities and their representatives. Input from 
regulated industry played an important part in shaping FDA's proposal 
for regulating IHC's. Moreover, FDA has made extensive changes to the 
final rule based on the agency's evaluation of the written comments. 
FDA believes that it would be an unnecessary use of scarce agency 
resources to hold a hearing for this rulemaking. Furthermore, FDA has 
no authority to require congressional attendance or participation at 
the agency's hearings.

VI. Access to the Special Control

    To receive the special control entitled ``FDA Guidance for 
Submission of Immunohistochemistry Applications to the FDA,'' FDA, 
Center for Devices and Radiologic Health, 1998, via fax machine, call 
the CDRH Facts-On-Demand system at 800-399-0381 or 301-827-0111 from a 
touch-tone telephone. At the first voice prompt, press 1 to access the 
Division of Small Manufacturers Assistance (DSMA) Facts. At the second 
voice prompt, press 2, and then enter the document No. 364 followed by 
the pound sign (#). Then follow the remaining voice prompts to complete 
your request.
    CDRH maintains an entry on the World Wide Web (www) for easy access 
to information, including text, graphics, and files that may be 
downloaded to a PC with access to the www. The CDRH home page is 
updated on a regular basis and includes the guidance cited previously, 
as well as other guidance documents; device safety alerts; Federal 
Register reprints; information on premarket submissions (including 
lists of approved applications and manufacturers' addresses); small 
manufacturers' assistance; and information on video conferencing and 
electronic submissions, mammography matters, and other device-oriented 
information. The CDRH home page may be accessed at http://www.fda.gov/
cdrh.
    A text-only version of the CDRH Web site is also available from a 
computer or VT-100 compatible terminal by dialing 800-222-0185 
(terminal settings are 8/1/N). Once the modem answers, press ENTER 
several times and then select menu choice 1: FDA BULLETIN BOARD 
SERVICE. From there follow instructions for logging in, and at the BBS 
TOPICS PAGE, arrow down to the FDA home page (do not select the first 
CDRH entry). Then select MEDICAL DEVICES AND RADIOLOGICAL HEALTH. From 
there select CENTER FOR DEVICES AND RADIOLOGICAL HEALTH for general 
information, or arrow down for specific topics.

VII. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Enforcement 
Fairness Act of 1966 (Pub. L. 104-121), and the Unfunded Mandates 
Reform Act of 1995 (Pub. L. 104-4)). 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 final 
rule is consistent with the regulatory philosophy and principles 
identified in the Executive Order. In addition, the final rule has been 
determined to be a

[[Page 30141]]

significant regulatory action as defined by the Executive Order and so 
is subject to review under the Executive Order.

A. Description of Impact

    The intended purpose of this final rule is to regulate pre- and 
postamendment IHC devices in a consistent manner. Presently, 
preamendment IHC's are unclassified, while most postamendment IHC's are 
statutorily classified into class III. Both pre- and postamendment 
devices are currently subject to general controls, and postamendment 
devices require FDA approval before marketing. This rule will 
categorize IHC devices based on their potential risk to public health 
into one of the three device classes. The great majority of IHC's will 
be categorized as class I devices and will be exempt from premarket 
notification. The IHC's that fall into class II will require premarket 
clearance and be subject to a special control, in addition to general 
controls. Currently, there are no IHC devices on the market that will 
fall into class III.
    The economic impact of this rule on manufacturers of IHC's will be 
negligible. Currently, manufacturers of all IHC devices are required to 
follow general controls. Under this rule, most preamendment IHC devices 
marketed with their original (pre-1976) claims will be categorized as 
class I devices and consequently exempt from premarket notification 
requirements. Therefore, there will be no change in the regulatory 
requirements that manufacturers of these devices must follow. The 
manufacturers of postamendment devices may realize an economic savings 
as a result of this rule. Manufacturers of the postamendment devices, 
which are currently statutorily classified into class III, would have 
been required to submit 510(k)'s or PMA's to be legally marketed. The 
final rule classifies most IHC's in class I and exempts them from 
premarket notification, eliminating the requirement for manufacturers 
to make premarket submissions for these devices. Most postamendment 
devices that will require submissions have been classified into class 
II and will not require a PMA approval. One comment suggested that the 
cost to submit a 510(k) ranged from $10,000 to $40,000 per antibody 
(see comment 21 of this document). The cost of preparing a PMA would be 
much higher. In addition, the special control established by this rule 
for class II IHC's is a guidance document intended to help 
manufacturers prepare 510(k)'s efficiently and effectively.
    FDA can not reliably estimate the total number of manufacturers of 
IHC's affected by this rule. Currently, there are fewer than 25 firms 
listed with the agency as manufacturers of 510(k) or PMA IHC devices. 
Most, if not all, of these firms are small, based on the Small Business 
Administration's definition of a small medical device entity (fewer 
than 500 employees).

B. Response to Comments by Small Business

    Some small businesses and the Small Business Administration 
commented that the proposed rule would impose a severe economic burden 
on IHC manufacturers, driving some companies out of business. These 
comments misunderstood the scope of the proposed rule by assuming that 
it would apply to IHC's used for research. In fact, there will be no 
new regulatory costs for research firms. As discussed previously, FDA 
has classified the majority of IHC devices as class I, exempt from 
premarket notification. The final rule also narrowed the identification 
of class III devices so that many devices that would have been class 
III under the proposal will be class II under the final rule and not 
require a PMA.
    There were also comments from small businesses that stated the 
rule, as proposed, would have a negative effect on new product 
introduction. With the changes made to the proposal, the agency 
believes that the final rule will have no negative effect on new 
product introduction and will introduce consistency in the regulation 
of IHC's. Currently, postamendment IHC's require PMA's or 510(k)'s. 
With this rule, most new products will be classified as class I exempt 
from premarket notification.

C. Summary

    In the proposed rule, FDA considered requiring 510(k)'s or PMA's 
for all IHC's. In response to comments, the agency reconsidered its 
position and determined that the necessary safeguards to public health 
could be achieved with general controls alone for the majority of 
currently marketed IHC's. Because this rule classifies these 
postamendment devices into class I, exempt from premarket notification, 
or into class II, the cost of the rule will be far below the $100 
million threshold that determines an economically significant 
regulation under Executive Order 12866 and the Unfunded Mandates Reform 
Act. Because the rule will safeguard the public health and impose 
almost no new burden on industry, the agency certifies that the rule 
will not have a significant impact on a substantial number of small 
entities.

VIII. 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. Baddoura, F. K. , C. Cohen, E. R. Unger, P. B. DeRose, and M. 
Chenggis, ``Image Analysis for Quantitation of Estrogen Receptor in 
Formalin-fixed Paraffin-embedded Sections of Breast Carcinoma,'' 
Modern Pathology, January 1991, 4(1):91-95.
    2. Esteban, J. M., P. L. Kandalaft, P. Mehta, T. L. Odom-Maryon, 
S. Bacus, and H. Battifora, ``Improvement of the Quantification of 
Estrogen and Progesterone Receptors in Paraffin-embedded Tumors by 
Image Analysis,'' American Journal of Clinical Pathology, January 
1993, 99(1):32-38.
    3. Esteban, J. M., C. Ahn, P. Mehta, and H. Battifora, 
``Biologic Significance of Quantitative Estrogen Receptor 
Immunohistochemical Assay by Image Analysis in Breast Cancer,'' 
American Journal of Clinical Pathology, August 1994, 102(2):158-162.
    4. Esteban, J. M., C. Ahn, H. Battifora, and B. Felder, 
``Predictive Value of Estrogen Receptors Evaluated by Quantitative 
Immunohistochemical Analysis in Breast Cancer,'' American Journal of 
Clinical Pathology, October 1994, 102 (4 Supplement 1), S9-S12.
    5. Molino, A., R. Micciolo, M. Turazza, F. Bonetti, Q. Piubello, 
A. Corgnati, L. Sperotto, G. Martignoni, A. Bonetti, R. Nortilli, et 
al., ``Estrogen Receptors in 699 Primary Breast Cancers: A 
Compatison of Immunohistochemical and Biochemical Methods,'' Breast 
Cancer Research Treatment, June 1995, 34(3):221-228.

IX. 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.

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, 21 CFR part 
864 is amended as follows:

PART 864--HEMATOLOGY AND PATHOLOGY DEVICES

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

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.

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

[[Page 30142]]

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 considered IHC's.
    (b) Classification of immunohistochemistry devices--(1) Class I 
(general controls). Except as described in paragraphs (b)(2) and (b)(3) 
of this section, these devices are exempt from the premarket 
notification requirements in part 807, subpart E of this chapter. This 
exemption applies to 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) has been made by conventional histopathology using 
nonimmunologic histochemical stains, such as hematoxylin and eosin. 
Examples of class I IHC's are differentiation markers that are used as 
adjunctive tests to subclassify tumors, such as keratin.
    (2) Class II (special control, guidance document: ``FDA Guidance 
for Submission of Immunohistochemistry Applications to the FDA,'' 
Center for Devices and Radiologic Health, 1998). These IHC's are 
intended for the detection and/or measurement of certain target 
analytes in order to provide prognostic or predictive data that are not 
directly confirmed by routine histopathologic internal and external 
control specimens. These IHC's provide the pathologist with information 
that is ordinarily reported as independent diagnostic information to 
the ordering clinician, and the claims associated with these data are 
widely accepted and supported by valid scientific evidence. Examples of 
class II IHC's are those intended for semiquantitative measurement of 
an analyte, such as hormone receptors in breast cancer.
    (3) Class III (premarket approval). IHC's intended for any use not 
described in paragraphs (b)(1) or (b)(2) of this section.
    (c) Date of PMA or notice of completion of a PDP is required. As of 
May 28, 1976, an approval under section 515 of the Federal Food, Drug, 
and Cosmetic Act is required for any device described in paragraph 
(b)(3) of this section before this device may be commercially 
distributed. See Sec. 864.3.

    Dated: February 6, 1998.
D.B. Burlington,
Director, Center for Devices and Radiological Health.
[FR Doc. 98-14605 Filed 6-2-98; 8:45 am]
BILLING CODE 4160-01-F