[Federal Register Volume 61, Number 116 (Friday, June 14, 1996)]
[Proposed Rules]
[Pages 30197-30200]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-15140]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 864
[Docket No. 94P-0341]
Medical Devices; Classification/Reclassification of
Immunohistochemistry Reagents and Kits
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is proposing to
classify/reclassify immunohistochemistry reagents and kits (IHC's) (in-
vitro diagnostic devices) into three classes depending on intended use.
These actions are being taken under the Federal Food, Drug, and
Cosmetic Act (the act), as amended by the Medical Device Amendments of
1976 (the 1976 amendments) and the Safe Medical Devices Act of 1990
(the SMDA). The intention of this proposal is to regulate these pre-
and post-1976 devices in a consistent fashion. Therefore, FDA is
proposing classification or reclassification of these products as
applicable.
DATES: Submit written comments by August 30, 1996.
ADDRESSES: Submit written comments on the proposed rule to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Max Robinowitz, Center for Devices and
Radiological Health (HFZ-440), Food and Drug Administration, 2098
Gaither Rd., Rockville, MD, 20850-4011, 301-594-1293, ext. 136, or FAX
301-594-5941.
SUPPLEMENTARY INFORMATION:
I. Background
The act (21 U.S.C. 201 et seq.), as amended by the 1976 amendments
(Pub. L. 94-295) and the SMDA (Pub. L. 101-629), established a
comprehensive system for the regulation of medical devices intended for
human use. Section 513 of the act (21 U.S.C. 360c) established three
categories (classes) of devices, depending on the regulatory controls
needed to provide reasonable assurance of their safety and
effectiveness. The three categories of devices are: Class I (general
controls), class II (special controls), and class III (premarket
approval).
Under section 513 of the act (21 U.S.C. 360c), devices that were in
commercial distribution before May 28, 1976, the enactment date of the
1976 amendments, are classified after FDA has: (1) Received a
recommendation from a device classification panel (an FDA advisory
committee); (2) published the panel's recommendations for comment,
along with a proposed regulation classifying the device; and (3)
published a final regulation classifying the device. A device that is
first offered in commercial distribution after May 28, 1976, and which
FDA determines to be substantially equivalent to a device classified
under this scheme, is classified into the same class as the device to
which it is substantially equivalent. The agency determines whether new
devices are substantially equivalent to previously offered devices by
means of premarket notification procedures in section 510(k) of the act
(21 U.S.C. 360 (k)) and part 807 of the regulations (21 CFR 807). A
device that was not in commercial distribution prior to May 28, 1976,
and that has not been found by FDA to be substantially equivalent to a
legally marketed device, is classified automatically by statute
(section 513(f) of the act) into class III, without any FDA rulemaking
proceeding.
The scope of products covered by this proposal includes both pre-
1976 devices which have not been previously classified as well as post-
1976 devices which are statutorily classified into class III. The
intention of this proposal is to regulate these pre- and post-1976
devices in a consistent fashion. Therefore, FDA is proposing
classification or reclassification of these products, as applicable.
Fluorescent-labeled immunohistochemistry in vitro diagnostic
devices (IHC's) have been used for patient diagnosis since the early
1940's and enzyme-linked IHC's have been used since the early 1970's.
IHC's, however, were not classified as a part of the 1979 FDA
classification activities. In addition, new IHC's have been marketed
for the first time since the passage of the 1976 amendments. When used
in a standardized controlled manner, IHC's enhance the accuracy and
scope of surgical pathology, provide objective data to
histopathological examination, and contribute to improved patient care.
IHC's can specifically and objectively demonstrate the presence and
distribution of antigens that may be of use in narrowing differential
diagnoses. IHC results are integrated by the user pathologist and
interpreted together with other types of data used in pathological
diagnostic decisionmaking (Refs. 1 through 4). Because pathologists,
the principal users of IHC's, were concerned about the regulation of
IHC's, the College of American Pathologists, the American Society of
Clinical Pathologists, the Association of Pathology Chairs, the
Biological Stain Commission, and the Association of Directors of
Anatomic and Surgical Pathology requested a review of the
classification of IHC reagents and submitted a Petition for
Classification of IHC's as class II (special controls) medical devices
during the summer of 1994. In response to this petition, FDA convened
the Panel to consider classification/reclassification of these devices.
II. Panel Recommendation
The Hematology and Pathology Devices Panel (the Panel) met on
October 21, 1994, and made the following recommendation regarding the
classification of five Immunohistochemistry devices.
A. Identification
Immunohistochemistry test systems (IHC's) are in-vitro diagnostic
devices that consist of polyclonal or monoclonal antibodies and
ancillary reagents that are used to identify, by immunological
techniques, antigens in specimens of tissues or intact cells in
cytologic specimens. IHC's are primary antibody reagents that are
labeled with instructions for use and performance
[[Page 30198]]
claims and packaged either prediluted or concentrated (neat), or as
kits consisting of optimally-diluted primary antibody combined with
detector systems. IHC's identify antigens in tissue or cell
preparations using ligand-specific antibodies whose reactivity is
detected and marked by secondary reagents that are recognized by
pathologists using light or electron microscopes. Most IHC's are
adjunctive to conventional histopathology and aid in the qualitative
identification of antigens, thereby supplementing the conventional
hematoxylin and eosin stains used in the diagnostic classification of
normal and abnormal cells and tissues. Some IHC's may provide semi-
quantitative or quantitative information about the antigen they
identify in normal and abnormal cells and tissues.
B. Recommended Classification of the Hematology and Pathology Devices
Panel
Class II (special controls). The Panel recommended that
establishing special controls for IHC devices should be a high
priority.
C. Summary of Reasons for Recommendation
The Panel recommended that IHC devices be classified into class II
(special controls) because they perceived the need for special controls
for IHC's that prescribe acceptable sensitivity, specificity,
stability, accuracy and precision for these devices, and thereby
minimize the possibility that these devices may generate inaccurate
diagnostic information. Patients may be placed at unnecessary risk when
reliance upon inaccurate diagnostic information results in initiating
inappropriate therapies or withholding appropriate therapies.
The Panel stated that general controls for IHC's would not provide
sufficient control over sensitivity, specificity, stability, accuracy
and precision of IHC devices. The Panel stated that special controls
are needed to provide reasonable assurance of the safety and
effectiveness of IHC devices and that sufficient information is
available to establish these special controls. The Panel recommended
that manufacturers of IHC devices should follow the FDA's Guidance for
Submission of Immunohistochemistry Applications and that this guidance
should serve as a special control.
A major concern of the Panel was that manufacturers of IHC devices
should be subject to current good manufacturing practice (CGMP)
inspections in a timely manner to ensure safe, reliable, stable, and
consistent IHC products.
D. Summary of Data Upon Which the Recommendation is Based
The Panel based its recommendation on the Panel members' personal
knowledge of, and clinical experience with IHC devices, and
presentations by Panel members, manufacturers, other interested
parties, and FDA (Ref. 5).
E. Risks to Health
IHC in vitro diagnostic devices are intended for use as diagnostic
tools. Risk to the patient may result from misdiagnosis and initiation
of inappropriate therapies or withholding of appropriate therapies
based on the results obtained with the IHC diagnostic device. The
degree of risk depends on whether the product is used as an adjunct to
conventional histopathological diagnostic techniques or provides
information that is used independently of the usual diagnostic process.
The highest risk products are those used as independent, stand-alone
diagnostic tests that are the sole or major determinant for a medical
decision and cannot be confirmed by conventional histopathologic
techniques or other diagnostic tests or clinical procedures.
III. Proposed Classification/Reclassification
Following the Hematology and Pathology Devices Panel meeting, the
agency considered the Panel's recommendation. The agency agrees in part
and disagrees in part with the Panel's recommendation. FDA believes
that general class I controls are sufficient to ensure safety and
effectiveness for those adjunctive IHC's that furnish information that
may be incorporated into the pathologist's histopathology or
cytopathology report but that is not reported directly to clinicians.
These general controls include: (1) Existing labeling requirements (21
CFR 809.10) for in vitro devices, (2) compliance with good
manufacturing practices, (3) registration, listing, and premarket
notification (510(k)), (4) recordkeeping and medical device reporting
(MDR), (5) restriction to prescription use (21 CFR 801.109.) Those
IHC's that provide pathologists with adjunctive diagnostic information
that may be incorporated into the pathologist's report, but that is not
ordinarily reported to the clinician as an independent finding, are
therefore proposed to be categorized as class I. These IHC's are used
in adjunctive tests to subclassify malignant tumors, but the primary
diagnosis of tumor (neoplasm) and malignancy is made by conventional
histopathology using nonimmunological histochemical stains such as
hematoxylin and eosin. Examples of these IHC's proposed for class I are
differentiation markers, such as antikeratin antibodies.
The manufacturer (sponsor) of a class I IHC would be required to
provide a premarket notification submission to FDA, including data
documenting compliance with the labeling requirements in Sec. 809.10
(21 CFR 809.10). Such manufacturers or sponsors may wish to follow the
``FDA Guidance for Submissions of Immunochemistry Applications to FDA''
(Guidance), for the purpose of documenting manufacturing. The FDA
Guidance provides details about data that may be submitted to comply
with Sec. 809.10.
In considering whether to place any adjunctive IHC's into class I,
FDA focused on whether this level of regulation is adequate for the
protection of public health. FDA considers the total test performance
for any in vitro diagnostic device to be dependent on the net results
of preanalytic, analytic, and postanalytic factors. For example,
variability in IHC results may be introduced at every step including
collection and fixation of the specimen, automated processing,
embedding, sectioning, staining of the final slide preparation, and the
microscopic interpretation by the pathologist. FDA regulation and
review are directed at ensuring that the manufacturer characterizes,
manufacturers, and labels the IHC appropriately before it is marketed
for professional use. Ongoing initiatives by professional
organizations, manufacturers, and FDA are directed at ensuring that
pre- and postanalytic, as well as analytic procedures, are properly
performed. In the context of these initiatives, FDA believes that class
I regulation will assure that these adjunctive IHC's are used safely
and effectively.
IHC's that provide the pathologist with adjunctive diagnostic
information that is ordinarily reported as independent diagnostic
information to the ordering clinician are proposed to be classified in
class II. Examples are IHC's for immunologic detection and semi-
quantitative measurement of specific ligand markers of proliferation,
such as Ki-67, or semi-quantitative determination of other analytes,
such as hormone receptors, if they are reported for their prognostic
implications. However, this classification does not apply to estrogen
and progesterone receptors, which are in class III by previous
regulation, and which provide
[[Page 30199]]
information that is the basis for significant medical decisions
substantially independent of other pathological tests. FDA is proposing
that class II IHC's be subject to general controls and to a special
control: The FDA Guidance for submissions of Immunohistochemistry
Applications to FDA (the guidance) (Ref. 6). The agency believes that
the manufacturer/sponsor can establish reasonable assurance of the
safety and effectiveness of a class II IHC by providing valid
scientific evidence from sponsor-supported studies, as described in the
guidance, or from the scientific literature. The guidance was drafted
with input from the Biological Stain commission, the Joint Council of
Immunohistochemistry Manufacturers, the College of American
Pathologists, the American Society of Clinical Pathology, FDA, and
comments from the public. The guidance also will provide information to
aid the end-users of IHC's (pathologists and other laboratorians) with
recommendations about appropriate positive and negative control tissue
sections (or cytologic preparations) for each intended use of the IHC.
The guidance will also describe the form and content for the package
insert of IHC's and provide the sponsor with detailed recommendations
about how to comply with Sec. 809.10 (Ref. 6).
IHC's that generate information that is reported directly to the
clinician to be used as the basis for significant medical decisions,
and that either provide information substantially independent of other
pathological (or cytopathological) aspects of the specimen or that have
novel claims not supported by current widely accepted scientific
pathophysiologic principles, would be categorized as class III.
Examples of IHC's FDA proposes to put in class III are markers of
clinically significant genetic mutations in tissues that are normal by
conventional histopathology.
IV. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Taylor, C. R., and Cote, R. C., ``Immunomicroscopy: A
Diagnostic Tool for the Surgical Pathologist,'' 2d ed.,
Philadelphia, W. B. Saunders, 1994.
2. True, L. D. (ed)., Atlas of Diagnostic Immunohistopathology,
Philadelphia, Lippincott, 1990.
3. Nadji, M., and Morales, A. R., ``Immunoperoxidase Techniques:
A Practical Approach to Tumor Diagnosis'' Chicago, American Society
of Clinical Pathologists Press, 1986.
4. Taylor, C. R., ``Quality Assurance and Standardization in
Immunohistochemistry,'' A Proposal for the Annual Meeting of the
Biological Stain Commission, June 1991, Biotechnic & Histochemistry,
67:110-117, 1992.
5. Transcripts of the Hematology and Pathology Devices Panel
meeting, October 21, 1994.
6. FDA Guidance for Submission of Immunohistochemistry
Applications to the FDA, FDA Center for Devices and Radiologic
Health, 1995, available through the Division of Small Manufacturers'
Assistance (DSMA), 1-800-638-2041.
7. Taylor, C. R., et al., Report of the Immunohistochemistry
Steering Committee of the Biological Stain Commission, ``Proposed
Format: Package Insert for Immunohisto Chemistry Products,''
Biotechnic & Histochemistry, 67:328-338, 1992.
V. Environmental Impact
The agency has determined under 21 CFR 25.24(e)(2) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
VI. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the agency believes only a small number of
firms will be affected by this rule when finalized, the agency
certifies that the proposed rule will not have a significant economic
impact on a substantial number of small entities. Therefore, under the
Regulatory Flexibility Act, no further analysis is required.
VII. Request for Comment
Interested persons may, on August 30, 1996 submit to the Dockets
Management Branch (address above) written comments regarding this
proposal. Two copies of any comments are to be submitted except that
individuals may submit one copy. Comments are to be identified with the
docket number found in brackets in the heading of this document.
Received comments may be seen in the office above between 9 a.m and 4
p.m., Monday through Friday.
List of Subjects in 21 CFR Part 864
Blood, Medical devices, Packaging and containers.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 864 be amended as follows:
PART 864--HEMATOLOGY AND PATHOLOGY DEVICES
1. The authority citation for 21 CFR part 864 continues to read as
follows:
Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c, 360e, 360j,
371).
2. Section 864.1860 is added to subpart B to read as follows:
Sec. 864.1860 Immunohistochemistry reagents and kits.
(a) Identification. Immunohistochemistry test systems (IHC's) are
in-vitro diagnostic devices consisting of polyclonal or monoclonal
antibodies labeled with directions for use and performance claims,
which may be packaged with ancillary reagents in kits. Their intended
use is to identify, by immunological techniques, antigens in tissues or
cytologic specimens. Similar devices intended for use with flow
cytometry devices are not IHC's.
(b) Classification of immunohistochemistry devices. (1) Class I for
IHC's that provide the pathologist with adjunctive diagnostic
information that may be incorporated into the pathologist's report, but
that is not ordinarily reported to the clinician as an independent
finding. These IHC's are used after the primary diagnosis of tumor
(neoplasm) and malignancy is made by conventional histopathology using
nonimmunologic histochemical stains such as hematoxylin and eosin.
Examples of class I IHC are differentiation markers, such as keratin,
which are used in adjunctive tests to subclassify malignant tumors.
(2) Class II for IHC's that provide the pathologist with adjunctive
diagnostic information that is ordinarily reported
[[Page 30200]]
as independent diagnostic information to the ordering clinician.
Examples are IHC's for immunologic detection and semi-quantitative
measurement of specific ligand markers of proliferation, such as Ki-67,
or semi-quantitative determination of other analytes, such as hormone
receptors, if they are reported for their prognostic implications.
However, this classification does not apply to estrogen and
progesterone receptors that are classified as class III devices.
(3) Class III for IHC's that generate information that is reported
directly to the clinician to be used as the basis for significant
medical decisions, and that either provide information substantially
independent of other pathological (or cytopathological) aspects of the
specimen or that have novel claims not supported by current widely
accepted scientific pathophysiologic principles. Examples are markers
used to identify clinically significant genetic mutations in tissues
that are normal by conventional histopathologic examination.
(c) Date PMA or notice of completion of a PDP is required. No
effective date has been established for the requirement for premarket
approval for the devices described in paragraph(b)(3) of this section.
See Sec. 864.3 for effective dates of requirement for premarket
approval.
Dated: May 31, 1996.
D.B. Burlington,
Director, Center for Devices and Radiological Health.
[FR Doc. 96-15140 Filed 6-13-96; 8:45 am]
BILLING CODE 4160-01-F