[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
[[Page 30133]]
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
[[Page 30136]]
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
